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Browse Health
Obstetrician & Gynecologist (OB/GYN)
35 years of experience
Accepting new patients

Credentials

Education ?

Medical School
Government Medical College, Patiala (1977)
Foreign school

Awards & Distinctions ?

Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Aggarwal is affiliated with 9 hospitals.

Hospital Affiliations

Score

Rankings

  • Trumbull Memorial Hospital
    1350 E Market St, Warren, OH 44483
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    Top 50%
  • HMHP St Elizabeth Health Center
    1044 Belmont Ave, Youngstown, OH 44504
    •  
    Top 50%
  • Hillside Rehabilitation Hospital
    8747 Squires Ln NE, Warren, OH 44484
    •  
  • St Joseph Health Center
    667 Eastland Ave SE, Warren, OH 44484
    •  
  • St Elizabeth Health Center
    8401 Market St, Youngstown, OH 44512
  • St Joseph Health Ctreastland
  • Trumbull
  • Northside
  • Northside Medical Center
    500 Gypsy Ln, Youngstown, OH 44504
  • Publications & Research

    Dr. Aggarwal has contributed to 156 publications.
    Title Acrodermatitis Continua of Hallopeau: Evolution of Treatment Options.
    Date January 2012
    Journal International Journal of Dermatology
    Excerpt

    Ever since its inception, acrodermatitis continua of Hallopeau, has been recognized as an uncommon clinical entity which has been sparingly reported from across the globe. The attempt to have cumulative information on prevalent nomenclature, definition, reminiscences, and clinical overtures has brought differential diagnosis and diagnosis in sharp focus, the highlights of which are outlined. Hence, it was considered important to review the evolution of treatment options available thus far including use of biologics.

    Title Role of Human Dna Polymerase κ in Extension Opposite from a Cis-syn Thymine Dimer.
    Date June 2011
    Journal Journal of Molecular Biology
    Excerpt

    Exposure of DNA to UV radiation causes covalent linkages between adjacent pyrimidines. The most common lesion found in DNA from these UV-induced linkages is the cis-syn cyclobutane pyrimidine dimer. Human DNA polymerase κ (Polκ), a member of the Y-family of DNA polymerases, is unable to insert nucleotides opposite the 3'T of a cis-syn T-T dimer, but it can efficiently extend from a nucleotide inserted opposite the 3'T of the dimer by another DNA polymerase. We present here the structure of human Polκ in the act of inserting a nucleotide opposite the 5'T of the cis-syn T-T dimer. The structure reveals a constrained active-site cleft that is unable to accommodate the 3'T of a cis-syn T-T dimer but is remarkably well adapted to accommodate the 5'T via Watson-Crick base pairing, in accord with a proposed role for Polκ in the extension reaction opposite from cyclobutane pyrimidine dimers in vivo.

    Title Anatomical Variation in Formation of Brachial Plexus and Its Branching.
    Date February 2011
    Journal Surgical and Radiologic Anatomy : Sra
    Excerpt

    Variant brachial plexus formation with two trunks and two cords is uncommon and has clinical implications as it may result in failure of regional brachial or axillary block. During routine anatomical dissection, unilateral variation in the formation of brachial plexus accompanied by unusual positional relationship with axillary artery was discovered in the left upper extremity of a 52-year-old Indian male cadaver. Brachial plexus showed two trunks formed by ventral rami of C5, C6 and C7, C8, T1 spinal nerves, respectively, which first split and then reunited in an unusual manner to form two cords: posterior and lateral instead of three. Medial cord was absent. The branching pattern of the brachial plexus also showed important variations. Second part of axillary artery was found lying inferomedial to brachial plexus instead of passing between medial and lateral cords. Transverse cervical artery was found to be coursing between two trunks instead of passing superficial to brachial plexus. Median nerve was observed to be formed from a single root, instead of usual two roots. Embryologically, this rare variation may be due to the development of axillary artery from ninth segmental artery instead of usual seventh cervical intersegmental artery. Such rare variation is clinically important as this knowledge may help the anesthesiologists and the surgeons to avoid any inadvertent damage to nerves and axillary artery during blocks and surgical interventions.

    Title Structural Basis for Error-free Replication of Oxidatively Damaged Dna by Yeast Dna Polymerase η.
    Date February 2011
    Journal Structure (london, England : 1993)
    Excerpt

    7,8-dihydro-8-oxoguanine (8-oxoG) adducts are formed frequently by the attack of oxygen-free radicals on DNA. They are among the most mutagenic lesions in cells because of their dual coding potential, where, in addition to normal base-pairing of 8-oxoG(anti) with dCTP, 8-oxoG in the syn conformation can base pair with dATP, causing G to T transversions. We provide here for the first time a structural basis for the error-free replication of 8-oxoG lesions by yeast DNA polymerase η (Polη). We show that the open active site cleft of Polη can accommodate an 8-oxoG lesion in the anti conformation with only minimal changes to the polymerase and the bound DNA: at both the insertion and post-insertion steps of lesion bypass. Importantly, the active site geometry remains the same as in the undamaged complex and provides a basis for the ability of Polη to prevent the mutagenic replication of 8-oxoG lesions in cells.

    Title Structural Basis for the Suppression of Skin Cancers by Dna Polymerase Eta.
    Date July 2010
    Journal Nature
    Excerpt

    DNA polymerase eta (Poleta) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Poleta (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Poleta (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Poleta to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Poleta's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.

    Title Replication Across Template T/u by Human Dna Polymerase-iota.
    Date December 2009
    Journal Structure (london, England : 1993)
    Excerpt

    Human DNA polymerase-iota (Poliota) incorporates correct nucleotides opposite template purines with a much higher efficiency and fidelity than opposite template pyrimidines. In fact, the fidelity opposite template T is so poor that Poliota inserts an incorrect dGTP approximately 10 times better than it inserts the correct dATP. We determine here how a template T/U is accommodated in the Poliota active site and why a G is incorporated more efficiently than an A. We show that in the absence of incoming dATP or dGTP (binary complex), template T/U exists in both syn and anti conformations, but in the presence of dATP or dGTP (ternary complexes), template T/U is predominantly in the anti conformation. We also show that dATP and dGTP insert differently opposite template T/U, and that the basis of selection of dGTP over dATP is a hydrogen bond between the N2 amino group of dGTP and Gln59 of Poliota.

    Title Structural Insights into Yeast Dna Polymerase Delta by Small Angle X-ray Scattering.
    Date December 2009
    Journal Journal of Molecular Biology
    Excerpt

    DNA polymerase delta (Poldelta) is a multisubunit polymerase that plays an indispensable role in replication from yeast to humans. Poldelta from Saccharomyces cerevisiae is composed of three subunits: Pol3, Pol31, and Pol32. Despite the elucidation of the structures and models of the individual subunits (or portions, thereof), the nature of their assembly remains unclear. We present here a small-angle X-ray scattering analysis of a yeast Poldelta complex (Poldelta(T)) composed of Pol3, Pol31, and Pol32N (amino acids 1-103 of Pol32). From the small angle X-ray scattering global parameters and reconstructed envelopes, we show that Poldelta(T) adopts an elongated conformation with a radius of gyration (R(g)) of approximately 52 A and a maximal dimension of approximately 190 A. We also propose an orientation for the accessory Pol31-Pol32N subunits relative to the Pol3 catalytic core that best agrees with the experimental scattering profile. The analysis also points to significant conformational variability that may allow Poldelta to better coordinate its action with other proteins at the replication fork.

    Title Structure of Human Dna Polymerase Kappa Inserting Datp Opposite an 8-oxog Dna Lesion.
    Date November 2009
    Journal Plos One
    Excerpt

    Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA and 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the major lesions formed. It is amongst the most mutagenic lesions in cells because of its dual coding potential, wherein 8-oxoG(syn) can pair with an A in addition to normal base pairing of 8-oxoG(anti) with a C. Human DNA polymerase kappa (Polkappa) is a member of the newly discovered Y-family of DNA polymerases that possess the ability to replicate through DNA lesions. To understand the basis of Polkappa's preference for insertion of an A opposite 8-oxoG lesion, we have solved the structure of Polkappa in ternary complex with a template-primer presenting 8-oxoG in the active site and with dATP as the incoming nucleotide.

    Title Anatomic Consideration of Caudal Epidural Space: a Cadaver Study.
    Date October 2009
    Journal Clinical Anatomy (new York, N.y.)
    Excerpt

    The knowledge of sacral hiatus anatomy is imperative in clinical situations requiring caudal epidural block for various diagnostic and therapeutic procedures of the lumbosacral spine to avoid failure and dural injury. In this study, a detailed anatomic study of the sacral region was carried out on 49 male adult Indian cadavers. Dorsal surface of sacral region was dissected to study sacral cornua, sacral hiatus, and the dimensions of triangle formed by the right and left posterosuperior iliac spines with apex of the hiatus. Midsagittal sections were subjected for various anatomical measurements. The angle of needle insertion and the depth of caudal space were noted. Cornu was not palpable bilaterally in 7 (14.3%) and palpable unilaterally in 12 (24.5%) specimens. Mean (standard deviation) distance between apex of hiatus and coccyx tip was 57.5 (8.7) mm and length of sacrococcygeal ligament was 34.2 (7.4) mm. The dimensions of the triangle were found to be interchangeable in 25 cadavers. Once the needle is introduced into the canal after penetrating the sacrococcygeal ligament, it should not be advanced >5 mm to prevent dural puncture. The level of maximum curvature of sacrum was S3 in 34 (69.4%) of cases. The dural sac was found to terminate at S2 in 41 (83.6%). The mean (SD) angle of depression of the needle was 65.7 (5.5) (range 58-78). The measurements described for the identification of the sacral hiatus, optimal angle of depression, and depth of the needle may improve the safety and reliability of a caudal epidural block.

    Title Structural Basis of High-fidelity Dna Synthesis by Yeast Dna Polymerase Delta.
    Date September 2009
    Journal Nature Structural & Molecular Biology
    Excerpt

    DNA polymerase delta (Pol delta) is a high-fidelity polymerase that has a central role in replication from yeast to humans. We present the crystal structure of the catalytic subunit of yeast Pol delta in ternary complex with a template primer and an incoming nucleotide. The structure, determined at 2.0-A resolution, catches the enzyme in the act of replication, revealing how the polymerase and exonuclease domains are juxtaposed relative to each other and how a correct nucleotide is selected and incorporated. The structure also reveals the 'sensing' interactions near the primer terminus, which signal a switch from the polymerizing to the editing mode. Taken together, the structure provides a chemical basis for the bulk of DNA synthesis in eukaryotic cells and a framework for understanding the effects of cancer-causing mutations in Pol delta.

    Title Structure of the Human Rev1-dna-dntp Ternary Complex.
    Date September 2009
    Journal Journal of Molecular Biology
    Excerpt

    Y-family DNA polymerases have proven to be remarkably diverse in their functions and in strategies for replicating through DNA lesions. The structure of yeast Rev1 ternary complex has revealed the most radical replication strategy, where the polymerase itself dictates the identity of the incoming nucleotide, as well as the identity of the templating base. We show here that many of the key elements of this highly unusual strategy are conserved between yeast and human Rev1, including the eviction of template G from the DNA helix and the pairing of incoming deoxycytidine 5'-triphosphate with a surrogate arginine residue. We also show that the catalytic core of human Rev1 is uniquely augmented by two large inserts, I1 and I2, wherein I1 extends >20 A away from the active site and may serve as a platform for protein-protein interactions specific for Rev1's role in translesion DNA synthesis in human cells, and I2 acts as a "flap" on the hydrophobic pocket accommodating template G. We suggest that these novel structural features are important for providing human Rev1 greater latitude in promoting efficient and error-free translesion DNA synthesis through the diverse array of bulky and potentially carcinogenic N(2)-deoxyguanosine DNA adducts in human cells.

    Title Co-occupancy of Two Pumilio Molecules on a Single Hunchback Nre.
    Date July 2009
    Journal Rna (new York, N.y.)
    Excerpt

    Pumilio controls a number of processes in eukaryotes, including the translational repression of hunchback (hb) mRNA in early Drosophila embryos. The Pumilio Puf domain binds to a pair of 32 nucleotide (nt) Nanos response elements (NRE1 and NRE2) within the 3' untranslated region of hb mRNA. Despite the elucidation of structures of human Pumilio Puf domain in complex with hb RNA elements, the nature of hb mRNA recognition remains unclear. In particular, the site that mediates regulation in vivo is significantly larger than the 8-10-nt RNA elements bound to single Puf molecules in crystal structures. Here we present biophysical and biochemical data that partially resolve the paradox. We show that each NRE is composed of two binding sites (Box A and Box B) and that two Puf domains can co-occupy a single NRE. The Puf domains have a higher affinity for the 3' Box B site than the 5' Box A site; binding to the intact NRE appears to be cooperative (at least in some experiments). We suggest that the 2 Pumilio:1 NRE complex is the functional regulatory unit in vivo.

    Title Dna Synthesis Across an Abasic Lesion by Human Dna Polymerase Iota.
    Date June 2009
    Journal Structure (london, England : 1993)
    Excerpt

    Abasic sites are among the most abundant DNA lesions formed in human cells, and they present a strong block to replication. DNA polymerase iota (Poliota) is one of the few DNA Pols that does not follow the A-rule opposite an abasic site. We present here three structures of human Poliota in complex with DNAs containing an abasic lesion and dGTP, dTTP, or dATP as the incoming nucleotide. The structures reveal a mechanism of translesion synthesis across an abasic lesion that differs from that in other Pols. Both the abasic lesion and the incoming dNTPs are intrahelical and are closely apposed across a constricted active site cleft. The dNTPs partake in distinct networks of hydrogen bonds in the "void" opposite the lesion. These different patterns of hydrogen bonds, as well as stacking interactions, may underlie Poliota's small preference for insertion of dGTP over other nucleotides opposite this common lesion.

    Title Psoriasiform Dermatoses.
    Date July 2008
    Journal Indian Journal of Dermatology, Venereology and Leprology
    Excerpt

    Psoriasiform reaction pattern is a commonly encountered denominator in a wide variety of unrelated disorders. It may be a reaction to either the internal or the external environmental, allergic, infective, parasitic, bacterial, fungal, viral and/or malignant stimuli. The degree of evolution of such a pattern and its significance vary according to the dermatosis. The age of the skin lesions may also influence the histopathological presentation and its clinico-histopathological disparity can often bewilder an expert. However, such a situation warrants more astute and sustained observations to unveil the exact underlying condition(s). Thus, psoriasiform dermatoses should only be an initial caption until an exact dermatological disorder is defined. There has been greater number of instances of psoriasiform drug eruptions where a confirmation of the diagnosis can be achieved after their remission by doing a provocation test. Similarly, such instances have also been on the rise in HIV/AIDS-affected individuals all over the world. Besides mycosis fungoides and Hodgkin's disease, several unrelated malignancies have been preceded or accompanied by psoriasiform skin eruptions.

    Title Alopecia Areata Progressing to Totalis/universalis in Non-insulin Dependent Diabetes Mellitus (type Ii): Failure of Dexamethasone-cyclophosphamide Pulse Therapy.
    Date July 2008
    Journal Indian Journal of Dermatology, Venereology and Leprology
    Title Structures of Human Pumilio with Noncognate Rnas Reveal Molecular Mechanisms for Binding Promiscuity.
    Date June 2008
    Journal Structure (london, England : 1993)
    Excerpt

    Pumilio is a founder member of the evolutionarily conserved Puf family of RNA-binding proteins that control a number of physiological processes in eukaryotes. A structure of human Pumilio (hPum) Puf domain bound to a Drosophila regulatory sequence showed that each Puf repeat recognizes a single nucleotide. Puf domains in general bind promiscuously to a large set of degenerate sequences, but the structural basis for this promiscuity has been unclear. Here, we describe the structures of hPum Puf domain complexed to two noncognate RNAs, CycB(reverse) and Puf5. In each complex, one of the nucleotides is ejected from the binding surface, in effect, acting as a "spacer." The complexes also reveal the plasticity of several Puf repeats, which recognize noncanonical nucleotides. Together, these complexes provide a molecular basis for recognition of degenerate binding sites, which significantly increases the number of mRNAs targeted for regulation by Puf proteins in vivo.

    Title Protein-template-directed Synthesis Across an Acrolein-derived Dna Adduct by Yeast Rev1 Dna Polymerase.
    Date April 2008
    Journal Structure (london, England : 1993)
    Excerpt

    Acrolein is generated as the end product of lipid peroxidation and is also a ubiquitous environmental pollutant. Its reaction with the N2 of guanine leads to a cyclic gamma-HOPdG adduct that presents a block to normal replication. We show here that yeast Rev1 incorporates the correct nucleotide C opposite a permanently ring-closed form of gamma-HOPdG (PdG) with nearly the same efficiency as opposite an undamaged G. The structural basis of this action lies in the eviction of the PdG adduct from the Rev1 active site, and the pairing of incoming dCTP with a "surrogate" arginine residue. We also show that yeast Polzeta can carry out the subsequent extension reaction. Together, our studies reveal how the exocyclic PdG adduct is accommodated in a DNA polymerase active site, and they show that the combined action of Rev1 and Polzeta provides for accurate and efficient synthesis through this potentially carcinogenic DNA lesion.

    Title Parapsoriasis: a Complex Issue.
    Date January 2008
    Journal Skinmed
    Excerpt

    Parapsoriasis is a peculiar reaction pattern of the skin that appears to have a spectrum with small plaque parapsoriasis at one end and large plaque at the other. The spectrum between is bridged by pityriasis lichenoides, pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, and lymphomatoid papulosis. The highlights of the clinical pattern of these diseases has been succinctly elucidated here to facilitate their recognition in day-to-day dermatologic practice. Their possible etiopathogenesis has been brought to focus in the light of changing concepts reported in the literature. Further, possible future implications demand a meticulous follow-up because, in a few cases, true neoplasms may ultimately develop. Treatment modalities are briefly discussed.

    Title Functional Specificity of a Hox Protein Mediated by the Recognition of Minor Groove Structure.
    Date December 2007
    Journal Cell
    Excerpt

    The recognition of specific DNA-binding sites by transcription factors is a critical yet poorly understood step in the control of gene expression. Members of the Hox family of transcription factors bind DNA by making nearly identical major groove contacts via the recognition helices of their homeodomains. In vivo specificity, however, often depends on extended and unstructured regions that link Hox homeodomains to a DNA-bound cofactor, Extradenticle (Exd). Using a combination of structure determination, computational analysis, and in vitro and in vivo assays, we show that Hox proteins recognize specific Hox-Exd binding sites via residues located in these extended regions that insert into the minor groove but only when presented with the correct DNA sequence. Our results suggest that these residues, which are conserved in a paralog-specific manner, confer specificity by recognizing a sequence-dependent DNA structure instead of directly reading a specific DNA sequence.

    Title Bstyi Bound to Noncognate Dna Reveals a "hemispecific" Complex: Implications for Dna Scanning.
    Date October 2007
    Journal Structure (london, England : 1993)
    Excerpt

    DNA recognition by proteins is essential for specific expression of genes in a living organism. En route to a target DNA site, a protein will often sample noncognate DNA sites through nonspecific protein-DNA interactions, resulting in a variety of conformationally different binding states. We present here the crystal structure of endonuclease BstYI bound to a noncognate DNA. Surprisingly, the structure reveals the enzyme in a "hemispecific" binding state on the pathway between nonspecific and specific recognition. A single base pair change in the DNA abolishes binding of only one monomer, with the second monomer bound specifically. We show that the enzyme binds essentially as a rigid body, and that one end of the DNA is accommodated loosely in the binding cleft while the other end is held tightly. Another intriguing feature of the structure is Ser172, which has a dual role in establishing nonspecific and specific contacts. Taken together, the structure provides a snapshot of an enzyme in a "paused" intermediate state that may be part of a more general mechanism of scanning DNA.

    Title An Em View of the Foki Synaptic Complex by Single Particle Analysis.
    Date July 2007
    Journal Journal of Molecular Biology
    Excerpt

    FokI is a type IIS restriction endonuclease that recognizes the 5'-GGATG-3' sequence and cleaves non-specifically at 9 and 13 base-pairs away on the top and bottom strands, respectively, to produce a 5' overhang. FokI is a bipartite endonuclease with separate recognition and cleavage domains. Because of its bipartite nature, FokI has received considerable interest in generating chimeric nucleases for use in biotechnology, and recently as possible therapeutic agents in gene therapy by initiating homologous gene recombination and repair. Here we show, using single-particle electron microscopic studies, that the FokI active complex prefers a single conformation in which the subunits are arranged in a doughnut shape complex with protein-protein and possibly protein-DNA interactions stabilizing the cleavage complex. Our electron microscopy (EM) model provides new insights into the activation mechanism of FokI and how non-specific cleavage is avoided.

    Title Structure of Irf-3 Bound to the Prdiii-i Regulatory Element of the Human Interferon-beta Enhancer.
    Date July 2007
    Journal Molecular Cell
    Excerpt

    Interferon regulatory factor 3 (IRF-3) is a key transcription factor in the assembly of the mammalian interferon-beta (IFN-beta) enhanceosome. We present here the structure of IRF-3 DNA binding domain in complex with the complete PRDIII-I regulatory element of the human IFN-beta enhancer. We show that four IRF-3 molecules bind in tandem to, variably spaced, consensus and nonconsensus IRF sites on the composite element. The ability of IRF-3 to bind these variable sites derives in part from two nonconserved arginines (Arg78 and Arg86) that partake in alternate protein-DNA contacts. We also show that the protein-DNA contacts are highly overlapped and that all four IRF sites are required for gene activation in vivo. In addition, we show that changing the nonconsensus IRF sites to consensus sites creates a more efficient enhancer in vivo. Together, the structure and accompanying biological data provide insights into the assembly of the IFN-beta enhanceosome in mammals.

    Title Topology of Type Ii Reases Revisited; Structural Classes and the Common Conserved Core.
    Date June 2007
    Journal Nucleic Acids Research
    Excerpt

    Type II restriction endonucleases (REases) are deoxyribonucleases that cleave DNA sequences with remarkable specificity. Type II REases are highly divergent in sequence as well as in topology, i.e. the connectivity of secondary structure elements. A widely held assumption is that a structural core of five beta-strands flanked by two alpha-helices is common to these enzymes. We introduce a systematic procedure to enumerate secondary structure elements in an unambiguous and reproducible way, and use it to analyze the currently available X-ray structures of Type II REases. Based on this analysis, we propose an alternative definition of the core, which we term the alphabetaalpha-core. The alphabetaalpha-core includes the most frequently observed secondary structure elements and is not a sandwich, as it consists of a five-strand beta-sheet and two alpha-helices on the same face of the beta-sheet. We use the alphabetaalpha-core connectivity as a basis for grouping the Type II REases into distinct structural classes. In these new structural classes, the connectivity correlates with the angles between the secondary structure elements and with the cleavage patterns of the REases. We show that there exists a substructure of the alphabetaalpha-core, namely a common conserved core, ccc, defined here as one alpha-helix and four beta-strands common to all Type II REase of known structure.

    Title Onychomycosis: a 3-year Clinicomycologic Hospital-based Study.
    Date May 2007
    Journal Skinmed
    Excerpt

    BACKGROUND: Despite onychomycosis being an established entity, only a few studies are available from the Indian subcontinent. The authors investigated the comprehensive pattern of the condition. AIM: To investigate the epidemiologic, clinical, and mycologic factors associated with onychomycosis in 50 patients using a prospective study design. METHODS: Fifty patients with potassium hydroxide-positive tests were evaluated according to a predetermined protocal recording details of epidemiologic, clinical, and mycologic characteristics. The collected data were analyzed to determine the correlation of various parameters. RESULTS: Distal and lateral subungual onychomycosis, total dystrophic onychomycosis, and superficial white onychomycosis variants of onychomycosis were identified, mostly in men 21-30 years of age (mean age, 34.5 years). Epidemiologic characteristics were instrumental to either initiate, perpetuate, or disseminate the disease process. Trichophyton rubrum and Trichophyton mentagrophytes were the main causative dermatophytes; yeasts and molds were less common. CONCLUSIONS: Recognition of onychomycosis is less difficult providing the clinician is aware of the entity. Should the etiologic diagnosis be made, its eradication is desirable to surmount its implication in the society at large.

    Title Mrna Regulation by Puf Domain Proteins.
    Date May 2007
    Journal Science's Stke : Signal Transduction Knowledge Environment
    Excerpt

    Puf domain proteins bind specific sequences in mRNAs to regulate their translation or stability, or both. Neither the mechanism of their action nor the identities of targeted mRNAs have been well defined. Recent work suggests that Puf proteins generally act by recruiting Pop2, a deadenylation enzyme that is part of a large complex. Recent work from a separate group defines a subset of the Drosophila transcriptome that is bound by the fly Puf protein, Pumilio. Together, these papers substantially increase our understanding of the biology of the Puf family of mRNA regulators.

    Title Solitary Plexiform Neurofibroma(s): Role of Magnetic Resonance Imaging.
    Date May 2007
    Journal Skinmed
    Excerpt

    A 10-year-old boy presented with a painless progressive swelling on the nape of the neck of 8 years' duration. When the child was 1 year old, the swelling appeared as a minute raised skin eruption the size of a pearl at the back of the neck. It was painless and progressive, continuing to increase in size until it reached the size of a walnut. At age 2 years, a minor surgical intervention was undertaken to remove the swelling, but a year later, it recurred at the same site. The size continued to increase until it reached the present size. Examination of the afflicted skin surface showed the presence of a globular, nonreducible swelling measuring 7.5 cm x 5 cm located on the upper posterior portion of the neck. Both the swelling and the skin over it were mobile and nontender. Otherwise, the boy's skin surface was without blemishes. On palpation, the swelling was plexiform, resembling a bag of worms. Magnetic resonance imaging (MRI) was performed on 1.5T MR (Signa, GE Healthcare, Chalfont St Giles, England) using T1 and T2 weighted fast spin echo and short tau inversion recovery sequences in the axial and sagittal planes. The images were marked by a well-defined, homogeneous signal intensity lesion in the subcutaneous plane of the nape of the neck. The lesion appeared isointense in T1W images and hyperintense in T2W images with few flow voids within the lesion. Based on the MRI findings, a diagnosis of superficial plexiform neurofibroma was considered. Results of routine liver and kidney function blood examination tests were within normal limits. Surgical resection was done under general anesthesia. As soon as the skin was excised, the swelling started bleeding profusely, but bleeding stopped almost immediately on the complete excision of the swelling. No cavities were present in the mass, and the underlying structures were normal. The wound was closed with nonabsorbable monofilament nylon suture. The postoperative period was uneventful. In addition to initial excision biopsy, all of the resected tissue material was subjected to serial sectioning for microscopic pathologic examination. Hematoxylin- and eosin-stained sections showed unremarkable epidermis with slight hyperkeratosis. Upper dermis showed circumscribed, lobular proliferation of spindle cells in a loose fibular background distorting much of the dermis and subcutaneous fat. Subcutis showed numerous thin-walled, ectatic blood vessels lined with prominent endothelium. Intervening tissue consisted of wavy bundles of collagen lined with elongated thin cells with tapering and wavy nuclei. The nuclear chromatin was bland without significant polymorphism or raised mitotic activity. A few nerve twigs were also seen within the tumor, which was infiltrating the surrounding fat.

    Title Efficacy of Isotretinoin in Pityriasis Rubra Pilaris: Unapproved Use.
    Date April 2007
    Journal International Journal of Dermatology
    Title Human Dna Polymerase Kappa Encircles Dna: Implications for Mismatch Extension and Lesion Bypass.
    Date March 2007
    Journal Molecular Cell
    Excerpt

    Human DNA polymerase kappa (Pol kappa) is a proficient extender of mispaired primer termini on undamaged DNAs and is implicated in the extension step of lesion bypass. We present here the structure of Pol kappa catalytic core in ternary complex with DNA and an incoming nucleotide. The structure reveals encirclement of the DNA by a unique "N-clasp" at the N terminus of Pol kappa, which augments the conventional right-handed grip on the DNA by the palm, fingers, and thumb domains and the PAD and provides additional thermodynamic stability. The structure also reveals an active-site cleft that is constrained by the close apposition of the N-clasp and the fingers domain, and therefore can accommodate only a single Watson-Crick base pair. Together, DNA encirclement and other structural features help explain Pol kappa's ability to extend mismatches and to promote replication through various minor groove DNA lesions, by extending from the nucleotide incorporated opposite the lesion by another polymerase.

    Title Male Pattern Androgenetic Alopecia.
    Date November 2006
    Journal Skinmed
    Excerpt

    Androgenic alopecia is a common physiologic disorder that is induced by androgens in genetically predisposed persons. It is described by dermatologists as a disorder of perception. Its original classification in men was made by Hamilton in 1951 and modified by Norwood in 1975. Ludwig's classification of androgenic alopecia in women was made in 1977. More study on this subject is needed with respect to searching for a medication to promote hair growth.

    Title Folding Mirror Schlieren Diffraction Interferometer.
    Date October 2006
    Journal Applied Optics
    Excerpt

    We demonstrate the use of a mirror as a viewing diaphragm to generate a built-in diffracted reference beam in schlieren diffraction interferometry (SDI). The use of a mirror edge as a diffracting element instead of a conventional knife edge considerably enhances the contrast of the schlieren pattern, and it is shown to be equal to that of a phase knife edge. This increase in contrast is due to the fact that the otherwise unutilized diffracted beam in SDI is recombined in the described folding mirror geometry.

    Title Contribution of Germline Brca1 and Brca2 Sequence Alterations to Breast Cancer in Northern India.
    Date October 2006
    Journal Bmc Medical Genetics
    Excerpt

    BACKGROUND: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls. METHOD: Cases were selected with regard to early onset disease (< or =40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants. RESULTS: In total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation. CONCLUSION: BRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients.

    Title Hybrid External Fixation in Periarticular Tibial Fractures. Good Final Outcome in 56 Patients.
    Date October 2006
    Journal Acta Orthopaedica Belgica
    Excerpt

    Out of 65 patients with periarticular fractures of the tibia treated by use of hybrid external fixation (a combination of indigenously manufactured version of ring and AO tubular fixator) from February 1997 to October 2003, 56 cases were taken up for this study with a minimum follow-up of 12 months. The injury was due to a high-velocity motor vehicle accident in 49 and a fall in 7 patients. Thirty five were tibial plateau fractures and 21 were distal tibial plafond fractures. Forty eight were compound fractures and eight were closed. They were treated by debridement (48 compound) and hybrid external fixator (n = 56). All the patients were assessed clinically and radiographically for an average follow-up of 42.5 months (range: 12 to 67). In tibial plateau fractures (n = 35), the final outcome was good to excellent in 30, fair in 2 and poor in 3. In tibial plafond fractures (n = 21), results were good to excellent in 16, fair in 3 and poor in 2. We recommend the use of hybrid external fixator for periarticular tibial fractures occurring due to high-energy trauma. In addition, rates of complications as seen with other modalities of fixation are greatly reduced. It facilitates adequate care of associated soft tissue injuries.

    Title Hoogsteen Base Pair Formation Promotes Synthesis Opposite the 1,n6-ethenodeoxyadenosine Lesion by Human Dna Polymerase Iota.
    Date September 2006
    Journal Nature Structural & Molecular Biology
    Excerpt

    The 1,N6-ethenodeoxyadenosine (epsilon dA) lesion is promutagenic and has been implicated in carcinogenesis. We show here that human Pol iota, a Y-family DNA polymerase, can promote replication through this lesion by proficiently incorporating a nucleotide opposite it. The structural basis of this action is rotation of the epsilon dA adduct to the syn conformation in the Pol iota active site and presentation of its 'Hoogsteen edge' for hydrogen-bonding with incoming dTTP or dCTP. We also show that Pol zeta carries out the subsequent extension reaction and that efficiency of extension from epsilon dA x T is notably higher than from epsilon dA x C. Together, our studies reveal for the first time how the exocyclic epsilon dA adduct is accommodated in a DNA polymerase active site, and they show that the combined action of Pol iota and Pol zeta provides for efficient and error-free synthesis through this potentially carcinogenic DNA lesion.

    Title An Incoming Nucleotide Imposes an Anti to Syn Conformational Change on the Templating Purine in the Human Dna Polymerase-iota Active Site.
    Date July 2006
    Journal Structure (london, England : 1993)
    Excerpt

    Substrate-induced conformational change of the protein is the linchpin of enzymatic reactions. Replicative DNA polymerases, for example, convert from an open to a closed conformation in response to dNTP binding. Human DNA polymerase-iota (hPoliota), a member of the Y family of DNA polymerases, differs strikingly from other polymerases in its much higher proficiency and fidelity for nucleotide incorporation opposite template purines than opposite template pyrimidines. We present here a crystallographic analysis of hPoliota binary complexes, which together with the ternary complexes show that, contrary to replicative DNA polymerases, the DNA, and not the polymerase, undergoes the primary substrate-induced conformational change. The incoming dNTP "pushes" templates A and G from the anti to the syn conformation dictated by a rigid hPoliota active site. Together, the structures posit a mechanism for template selection wherein dNTP binding induces a conformational switch in template purines for productive Hoogsteen base pairing.

    Title Management of Odontoid Fractures with Anterior Screw Fixation.
    Date June 2006
    Journal Journal of Surgical Orthopaedic Advances
    Excerpt

    Type II odontoid fractures are prone to undergo nonunion. Stabilization of such fractures with anterior screw fixation provides rigid internal fixation and preserves C1-C2 motion. During a 5-year period, 17 patients with displaced type II fractures of the odontoid were treated Thirteen were male and four were female with a mean age of 38.2 years. All patients were operated on for anterior screw fixation within a mean of 10.1 days from injury. Postoperatively, the patients were evaluated clinically and radiologically at regular intervals. With a mean follow-up of 3.2 years, union was observed in 16 of 17 patients (94%). One patient developed nonunion for which he required C1-C2 fusion subsequently. Screw back-out by a few millimeters was seen in another patient resulting in mild restriction of neck movements. No approach-related complications were noted. Anterior odontoid screw fixation has relatively low complication and high fusion rates. It not only restores normal anatomy but also gives better functional results by preserving intrinsic C1-C2 motion. Thus it should be considered the treatment of choice in acute displaced type II odontoid fractures.

    Title Reproductive Health Education Intervention Trial.
    Date April 2006
    Journal Indian Journal of Pediatrics
    Excerpt

    OBJECTIVE: To measure the effectiveness of a reproductive health education package in improving the knowledge of adolescent girls aged 15-19 years in Chandigarh (India). METHODS: A reproductive health education package, developed in consultation with parents, teachers and adolescents, was delivered to randomly sampled classes of two senior secondary schools and one school was selected as control. In one school, a nurse conducted 15 sessions for 94 students in three batches using conventional education approach. In another school she conducted sessions for a selected group of 20 adolescents who later disseminated the messages informally to their 84 classmates (peer education). Using a 70-item structured questionnaire the knowledge of 95 adolescents from conventional, 84 from peer, and 94 from control school were assessed before and one month after the last session. Change in the score in intervention and control groups was tested by ANOVA taking age and socio-economic status as covariates. RESULTS: Teachers, parents and students overwhelmingly (88%, 95.5% and 93% respectively) favoured reproductive health education program. Five percent of the respondents reported that someone in their class is having sexual relations, and 13% of the girls approved of pre-marital sexual relations. Reproductive health knowledge scores improved significantly after intervention in conventional education (27.28) and peer education group (20.77) in comparison to the controls (3.64). Post-test scores were not significantly different between peer education group and conventional education group (43.65 and 40.52 respectively) though the time consumed in delivering the peer education intervention was almost one third of the time taken to implement conventional education. CONCLUSION: Peer education and conventional education strategies were effective in improving the reproductive health knowledge of adolescent girls but peer strategy was less time consuming.

    Title Solution Structure of the Vts1 Sam Domain in the Presence of Rna.
    Date March 2006
    Journal Journal of Molecular Biology
    Excerpt

    The yeast Vts1 SAM (sterile alpha motif) domain is a member of a new class of SAM domains that specifically bind RNA. To elucidate the structural basis for RNA binding, the solution structure of the Vts1 SAM domain, in the presence of a specific target RNA, has been solved by multidimensional heteronuclear NMR spectroscopy. The Vts1 SAM domain retains the "core" five-helix-bundle architecture of traditional SAM domains, but has additional short helices at N and C termini, comprising a small substructure that caps the core helices. The RNA-binding surface of Vts1, determined by chemical shift perturbation, maps near the ends of three of the core helices, in agreement with mutational data and the electrostatic properties of the molecule. These results provide a structural basis for the versatility of the SAM domain in protein and RNA-recognition.

    Title Insular Carcinoma of Thyroid--a Case Report.
    Date January 2006
    Journal Indian Journal of Pathology & Microbiology
    Excerpt

    Insular carcinoma of thyroid (ICT) is a rare tumor, which accounts for 4-6% of thyroid malignancies. ICT arising from follicular cells of thyroid shows a characteristic insular growth pattern characterized by solid nests of tumor cells separated by vessels. A 52-year-old female presented with a huge swelling in midline of the neck with retrosternal extension. The patient was euthyroid. Near total thyroidectomy was done. Grossly, the tumour was involving both the lobes and isthmus of thyroid. Microscopic examination revealed features of insular carcinoma. On immunohistochemistry, tumour cells were positive for thyroglobulin and negative for calcitonin.

    Title Human Dna Polymerase Iota Incorporates Dctp Opposite Template G Via a G.c + Hoogsteen Base Pair.
    Date January 2006
    Journal Structure (london, England : 1993)
    Excerpt

    Human DNA polymerase iota (hPoliota), a member of the Y family of DNA polymerases, differs in remarkable ways from other DNA polymerases, incorporating correct nucleotides opposite template purines with a much higher efficiency and fidelity than opposite template pyrimidines. We present here the crystal structure of hPoliota bound to template G and incoming dCTP, which reveals a G.C + Hoogsteen base pair in a DNA polymerase active site. We show that the hPoliota active site has evolved to favor Hoogsteen base pairing, wherein the template sugar is fixed in a cavity that reduces the C1'-C1' distance across the nascent base pair from approximately 10.5 A in other DNA polymerases to 8.6 A in hPoliota. The rotation of G from anti to syn is then largely in response to this curtailed C1'-C1' distance. A G.C+ Hoogsteen base pair suggests a specific mechanism for hPoliota's ability to bypass N(2)-adducted guanines that obstruct replication.

    Title A View of Consecutive Binding Events from Structures of Tetrameric Endonuclease Sfii Bound to Dna.
    Date January 2006
    Journal The Embo Journal
    Excerpt

    Many reactions in cells proceed via the sequestration of two DNA molecules in a synaptic complex. SfiI is a member of a growing family of restriction enzymes that can bind and cleave two DNA sites simultaneously. We present here the structures of tetrameric SfiI in complex with cognate DNA. The structures reveal two different binding states of SfiI: one with both DNA-binding sites fully occupied and the other with fully and partially occupied sites. These two states provide details on how SfiI recognizes and cleaves its target DNA sites, and gives insight into sequential binding events. The SfiI recognition sequence (GGCCNNNN[downward arrow]NGGCC) is a subset of the recognition sequence of BglI (GCCNNNN[downward arrow]NGGC), and both enzymes cleave their target DNAs to leave 3-base 3' overhangs. We show that even though SfiI is a tetramer and BglI is a dimer, and there is little sequence similarity between the two enzymes, their modes of DNA recognition are unusually similar.

    Title Proximity-induced Activation of Human Cdc34 Through Heterologous Dimerization.
    Date December 2005
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Cdc34 is an E2-conjugating enzyme required for catalyzing the polyubiquitination reaction mediated by the Skp1.CUL1.F-box (SCF) protein E3 ubiquitin (Ub) ligase. Here, we show that the activity of human Cdc34 in the Ub-Ub ligation reaction was enhanced dramatically by SCF's core Ub ligase module, composed of a heterodimeric complex formed by the ROC1 RING finger protein and the CUL1 C terminus that contains a Nedd8 moiety covalently conjugated at K720. Unexpectedly, we found that N-terminal fusion of a GST moiety to human Cdc34 generated dimeric GST-Cdc34 that was constitutively active in supporting the assembly of K48-linked polyUb chains independently of SCF. Furthermore, fusion of a FK506-binding protein (FKBP) to the N terminus of human Cdc34 yielded FKBP-Cdc34 that was induced to form a dimer upon treatment with the chemical inducer AP20187. The AP20187-induced dimeric form of FKBP-Cdc34 was substantially more active than the monomer in catalyzing Ub-Ub ligation. Thus, juxtaposition of human Cdc34 activates its catalytic capability, suggesting that the SCF-mediated polyubiquitination reaction may require the conversion of Cdc34 from an inactive monomer to a highly active dimeric form.

    Title Syndromic Management of Vaginal Discharge and Pelvic Inflammatory Disease Among Women in a Rural Community of Haryana, India: Agreement of Symptoms Enquiry with Clinical Diagnosis.
    Date December 2005
    Journal The Journal of Communicable Diseases
    Excerpt

    World Health Organisation (1984) advocated syndromic approach for management of reproductive tract infections/sexually transmitted diseases. Some investigators have cautioned against using this approach to diagnose and treat vaginal discharge and pelvic inflammatory disease. The prevalence of RTIs in rural areas of Haryana is high and availability of per-speculum examination facility is scarce. The scope for laboratory diagnosis of RTI in rural areas is remote in near future. A community-based study was conducted to assess the agreement of symptoms enquiry with the syndromic diagnosis of RTIs/STDs (based upon per speculum examination). A total of 812 women were interviewed by ANMs and were examined by a lady doctor. History based ANM's diagnosis was found to be having high sensitivity (80.5%) and high positive predictive value (81.3%). However it had low specificity (48.6%) and low negative predictive value (47.5%) compared to clinical diagnosis. Level of agreement was found to be fair (Kappa = 0.28, 95% CI = 0.20-0.36). The chances of over treatment for vaginal discharge and pelvic inflammatory disease were only 16% and 15% respectively. However, history based syndromic protocols need revision. Proposed protocol is discussed in this paper.

    Title Brown-vialetto-van Laere Syndrome; Variability in Age at Onset and Disease Progression Highlighting the Phenotypic Overlap with Fazio-londe Disease.
    Date November 2005
    Journal Brain & Development
    Excerpt

    We report four siblings showing features of a pontobulbar palsy, a mixed spinal and upper motor neuropathy and variable deafness. The observation of affected males and females born to consanguineous first cousin parents suggests autosomal recessive inheritance. Two children presented in the first 16 months of life with stridor and died of respiratory failure by the age of 2 years. Hearing loss was not apparent in these infants. In contrast, 2 further siblings developed a bulbar palsy in their sixth year followed by the onset of deafness and features of an anterior horn neuropathy with corticospinal tract involvement. They exhibited a relatively slow but relentless decline over a period of several years. These cases highlight the phenotypic overlap of Brown-Vialetto-Van Laere syndrome with Fazio-Londe disease. Rather than representing two separate disorders, our findings suggest the possibility of a single disease entity which may usefully be considered a form of juvenile amyotrophic lateral sclerosis.

    Title Rev1 Employs a Novel Mechanism of Dna Synthesis Using a Protein Template.
    Date October 2005
    Journal Science (new York, N.y.)
    Excerpt

    The Rev1 DNA polymerase is highly specialized for the incorporation of C opposite template G. We present here the crystal structure of yeast Rev1 bound to template G and incoming 2'-deoxycytidine 5'-triphosphate (dCTP), which reveals that the polymerase itself dictates the identity of the incoming nucleotide, as well as the identity of the templating base. Template G and incoming dCTP do not pair with each other. Instead, the template G is evicted from the DNA helix, and it makes optimal hydrogen bonds with a segment of Rev1. Also, unlike other DNA polymerases, incoming dCTP pairs with an arginine rather than the templating base, which ensures the incorporation of dCTP over other incoming nucleotides. This mechanism provides an elegant means for promoting proficient and error-free synthesis through N2-adducted guanines that obstruct replication.

    Title Lupus Miliaris Disseminatus Faciei Part Ii: an Overview.
    Date September 2005
    Journal Skinmed
    Excerpt

    Lupus miliaris disseminatus faciei, a chronic inflammatory disorder, is a controversial and enigmatic diagnostic/therapeutic entity. Multiple, discrete, smooth 1-3 mm brown/red or brown-to-yellowish dome-shaped papules (sometimes with mild scaling) are its clinical characteristics. The lesions are usually located on the central and lateral side of the face. The condition is most often seen in young adults of both sexes, and diascopy may reveal apple-jelly nodules. Lupus miliaris disseminatus faciei has clearly been defined into four histopathologic groups: epithelioid cell granuloma with central necrosis; epithelioid cell granuloma without central necrosis (sarcoid/foreign body reaction); epithelioid cell granuloma with abscesses; and nongranulomatous, nonspecific inflammatory infiltrate. While in early lesions granuloma is absent and lymphocytes and a few neutrophils surround the follicles, fully developed lesions show well formed granuloma surrounding ruptured hair follicles, often with large numbers of neutrophils. Lupus miliaris disseminatus faciei must be differentiated from other conditions; to facilitate this, in Part I of this paper the histopathologic undertones were delineated into early, intermediate (first stage, second stage, and third stage), and late stages. This part of the article presents an overview of lupus miliaris disseminatus faciei.

    Title Implications for Switching Restriction Enzyme Specificities from the Structure of Bstyi Bound to a Bglii Dna Sequence.
    Date September 2005
    Journal Structure (london, England : 1993)
    Excerpt

    The type II restriction endonuclease BstYI recognizes the degenerate sequence 5'-RGATCY-3' (where R = A/G and Y = C/T), which overlaps with both BamHI (GGATCC) and BglII (AGATCT), and thus raises the question of whether BstYI DNA recognition will be more BamHI-like or BglII-like. We present here the structure of BstYI bound to a cognate DNA sequence (AGATCT). We find the complex to be more BglII-like with similarities mapping to DNA conformation, domain organization, and residues involved in catalysis. However, BstYI is unique in containing an extended arm subdomain, and the mechanism of DNA capture has both BglII-like and BamHI-like elements. Further, DNA recognition is more minimal than BglII and BamHI, where only two residues mediate recognition of the entire core sequence. Taken together, the structure reveals a mechanism of degenerate DNA recognition and offers insights into the possibilities and limitations in altering specificities of closely related restriction enzymes.

    Title Lupus Miliaris Disseminatus Faciei. Part I: Significance of Histopathologic Undertones in Diagnosis.
    Date August 2005
    Journal Skinmed
    Excerpt

    BACKGROUND: Since its clinical discovery, lupus miliaris disseminatus faciei has sporadically been reported to have different modes of clinicopathologic expression. OBJECTIVE: The purpose of this study was to work up a list of histopathologic undertones and to project and propagate lupus miliaris disseminatus faciei as an exclusive entity. An upcoming Part II of this study will present an overview of the disease. METHODS: All patients visiting the outpatient clinic conforming to hitherto accepted clinical features were included to study patients' age and sex, duration of the disease, and above all, conduct a detailed histopathology review. Using the detailed information obtained, an endeavor was made to organize the disease into early, fully developed, and late lesions. RESULTS: The details of the various parameters were of great help in evolving this modus operandi. The clinical as well as histopathologic features of lupus miliaris disseminatus faciei are fairly distinct and facilitate visualizing the entity as a spectrum comprising early, fully developed, and late lesions. Further studies are called for.

    Title Open Reduction and Internal Fixation of Volar Barton's Fractures: a Prospective Study.
    Date June 2005
    Journal Journal of Orthopaedic Surgery (hong Kong)
    Excerpt

    PURPOSE: To assess the functional and clinical outcomes of open reduction with internal fixation in the treatment of Barton's fracture of the wrist. METHODS: From January 1997 to July 2003, a total of 19 cases of volar Barton's fracture were operated on by open reduction and internal fixation at the Nehru Hospital, Chandigarh, India. Records of 16 cases were available for study. Special care was taken during surgery to achieve articular congruity. The injury was caused by motor vehicle accidents in 13 cases and by a fall in 3. All cases were type-B3 fractures: 10 were of the B3.3 subtype, 4 of the B3.2 subtype, and 2 of the B3.1 subtype. Most (12) cases were operated on within one week of injury, 3 in one to 2 weeks, and one in 2 to 3 weeks. RESULTS: All patients were assessed clinically and radiographically after a mean follow-up duration of 32.4 months (range, 12.0-65.0 months). Fractures healed after 7.0 to 10.0 weeks (mean, 8.8 weeks). Results of evaluations according to functional criteria were excellent in 9 cases, good in 5, and fair in 2. Radiocarpal osteoarthrosis developed secondary to trauma in 2 cases. There was no involvement of the median nerve in any of the 16 cases. CONCLUSION: Open reduction and internal fixation of volar Barton's fracture can restore articular congruity and result in good to excellent function.

    Title Knowledge of Men and Women About Reproductive Tract Infections and Aids in a Rural Area of North India: Impact of a Community-based Intervention.
    Date May 2005
    Journal Journal of Health, Population, and Nutrition
    Excerpt

    This study of a community-level health-education intervention on reproductive tract infections/sexually transmitted diseases (RTIs/STDs) was conducted in three villages of Haryana in north India. The study was aimed at increasing awareness among men and women of reproductive age about the prevention and treatment of RTIs, modes of HIV/AIDS transmission, and methods of prevention. Health education was imparted through one-to-one interactions with men and women during home visits, at village-based clinics and health camps, and through health-education talks with men and women. Cumulative effects of the intervention were examined at the end of the survey by comparing the change in knowledge from the baseline. Records of clinic attendance were examined to assess the probable impact of the intervention on clinic attendance. Baseline and follow-up evaluations revealed that there was an improvement in the median total knowledge score of women from 0 to 6, whereas it remained at 5 for men both at baseline and follow-up. Knowledge about RTI/STIs increased among both men and women from the median score of 0 to 2 and from 0 to 3 respectively. The median knowledge score on HIV/AIDS declined among men from 4 to 2 but increased from 0 to 3 among women. Clinic attendance for RTI/STI cases, referred to the Naraingarh hospital, showed an eight-fold rise from an average of four cases per month in 1998-1999 to an average of 35 cases per month in 1999-2000. The findings of the study suggest that health-education strategy through home visits, RTI case management and counselling, and organizing a weekly clinic and occasional camps and health-education talks can increase the level of awareness about RTIs/STIs among both men and women and improve clinic attendance.

    Title Residues Within the B' Motif Are Critical for Dna Binding by the Superfamily 3 Helicase Rep40 of Adeno-associated Virus Type 2.
    Date February 2005
    Journal The Journal of Biological Chemistry
    Excerpt

    We have recently published the crystal structure of the adeno-associated virus type 2 superfamily 3 (SF3) helicase Rep40. Although based on its biochemical properties it is unlikely that Rep40 plays a central role as a replicative helicase the involvement of this motor protein in DNA packaging has recently been demonstrated. Here we focused our attention on residues that fall within and adjacent to the B' motif of SF3 helicases that directly interact with single-stranded DNA during translocation of the motor protein. In vitro, alanine substitution at positions Lys-404 or Lys-406 abrogated the ability of the protein to interact with single-stranded DNA as demonstrated by electrophoretic mobility shift assay and fluorescence anisotropy, and accordingly these mutants could not unwind a partially duplex DNA substrate. Despite this loss of helicase activity, basal ATPase activity in these mutants remained intact. However, unlike the wild-type protein, K404A and K406A ATPase activity was not stimulated by DNA. As predicted, disruption of motor activity through interference with DNA binding resulted in an inability of Rep40 to package adeno-associated virus DNA in a tissue culture-based assay. Taken together, we characterized, for the first time in an SF3 helicase family member, residues that are directly involved in single-stranded DNA binding and that are critical for the Rep motor activity. Based on our findings we propose B' as the signature motif of SF3 helicases that is responsible for the complex interactions required for the coupling of DNA binding and ATP hydrolysis.

    Title Crystal Structure of the Catalytic Core of Human Dna Polymerase Kappa.
    Date January 2005
    Journal Structure (london, England : 1993)
    Excerpt

    We present the crystal structure of the catalytic core of human DNA polymerase kappa (hPolkappa), the first structure of a human Y-family polymerase. hPolkappa is implicated in the proficient extension of mispaired primer termini on undamaged DNAs, and in the extension step of lesion bypass. The structure reveals a stubby "fingers" subdomain, which despite its small size appears to be tightly restrained with respect to a putative templating base. The structure also reveals a novel "thumb" subdomain that provides a basis for the importance of the N-terminal extension unique to hPolkappa. And, most surprisingly, the structure reveals the polymerase-associated domain (PAD) juxtaposed on the dorsal side of the "palm" subdomain, as opposed to the fingers subdomain. Together, these properties suggest that the hPolkappa active site is constrained at the site of the templating base and incoming nucleotide, but the polymerase is less constrained following translocation of the lesion.

    Title Structure of Adeno-associated Virus Type 2 Rep40-adp Complex: Insight into Nucleotide Recognition and Catalysis by Superfamily 3 Helicases.
    Date October 2004
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    We have determined the structure of adeno-associated virus type 2 (AAV2) Rep40 to 2.1-A resolution with ADP bound at the active site. The complex crystallizes as a monomer with one ADP molecule positioned in an unexpectedly open binding site. The nucleotide-binding pocket consists of the P-loop residues interacting with the phosphates and a loop (nucleoside-binding loop) that emanates from the last strand of the central beta-sheet and interacts with the sugar and base. As a result of the open nature of the binding site, one face of the adenine ring is completely exposed to the solvent, and consequently the number of protein-nucleotide contacts is scarce as compared with other P-loop nucleotide phosphohydrolases. The conformation of the ADP molecule in its binding site bears a resemblance to those found in only three other families of P-loop ATPases: the ATP-binding cassette transporter family, the bacterial RecA proteins, and the type II topoisomerase family. In all these cases, oligomerization is required to attain a competent nucleotide-binding pocket. We propose that this characteristic is native to superfamily 3 helicases and allows for an additional mechanism of regulation by these multifunctional proteins. Furthermore, it explains the strong tendency by members of this family such as simian virus 40 TAg to oligomerize after binding ATP.

    Title Shape, Measurements and Weight of the Thyroid Gland in Northwest Indians.
    Date October 2004
    Journal Surgical and Radiologic Anatomy : Sra
    Excerpt

    The shape of the thyroid gland, its extension as the pyramidal lobe (PL) and attachments of the levator glandulae thyroideae (LGT) were studied in 410 male and 160 female adults from the Chandigarh zone in northwest India during medicolegal autopsies performed in the department. Whereas the measurements of the gland were recorded in 210 subjects, the weights were taken only in 160 instances. The shapes of the glands were: lateral lobes (LL) with isthmus (50.2%), horseshoe-shaped gland (36.8%), gland with separate lobes (7.9%) and irregularly shaped gland (5.1%). No sexual dimorphism was seen in the incidence of various shapes of the gland. The incidence of the PL and LGT was 28.9% and 19.5%, respectively. Neither a PL nor LGT was present in irregularly shaped glands. The mean weight of the gland was 15.01+/-7.69 g in males and 13.16+/-5.64 g in females. Sexual and age-wise differences in weights were found to be statistically insignificant. A survey involving 152 subjects in 2 villages in Chandigarh showed that it is an iodine sufficient zone. The size and weight of thyroid glands in adults of the two genders were found to be smaller than in western Caucasian and Japanese subjects.

    Title Nursing Management of Anaemia Among Young Women.
    Date September 2004
    Journal The Nursing Journal of India
    Title Relation Between Birthweight and Blood Pressure Among 7-8 Year Old Rural Children in India.
    Date August 2004
    Journal International Journal of Epidemiology
    Excerpt

    BACKGROUND: Fetal malnutrition has been proposed as a cause of higher blood pressure. However, some studies have shown no or little effect of birthweight on blood pressure. Confounding and selection bias have been a problem in some of the studies. The ideal approach for avoiding selection bias is to conduct a prospective cohort study with minimal loss during follow-up. Therefore, the relationship of birthweight with blood pressure was examined in a cohort born during 1992-1993. METHODS: A cohort of 214 babies, born to usual residents in 10 villages of Haryana state in India on weekdays from September 1992 to November 1993 whose birthweight had been recorded by a trained field worker within 24 hours of delivery, were followed up during 2000-2001. During the 7-8 year period, 17 children had died and 12 had migrated. A trained public health nurse examined the remaining 185 children and measured their weight, height, and blood pressure. RESULTS: Mean birthweight was 2.7 kg and 21.1% had low birthweight (<2500 g). Current weight, height, and body mass index (BMI) were associated with birthweight (P < 0.05). Systolic blood pressure (SBP) increased significantly with rise in current weight and height. Relationship of SBP with birthweight seems to be a U-shaped distribution. Compared with the middle birthweight tertile group, in the lowest and highest birthweight groups boys have higher SBP in the higher BMI category (>or=13.5 kg/m(2)) and girls have higher SBP in both lower and higher BMI categories. ANOVA analysis showed that SBP and diastolic blood pressure (DBP) were not significantly different in birthweight tertile groups among boys, but for SBP the difference was statistically significant among girls (P = 0.03). However, multivariate linear regression analysis that included socioeconomic status and current anthropometeric measures (weight, height, BMI) revealed that birthweight is not associated with SBP or DBP, and the interaction between birthweight and gender was also not significant for SBP and DBP (P = 0.09). CONCLUSION: The findings of this population-representative cohort from rural India with 94% follow-up suggest that birthweight is not associated with blood pressure among 7-8 year old children.

    Title Replication by Human Dna Polymerase-iota Occurs by Hoogsteen Base-pairing.
    Date August 2004
    Journal Nature
    Excerpt

    Almost all DNA polymerases show a strong preference for incorporating the nucleotide that forms the correct Watson-Crick base pair with the template base. In addition, the catalytic efficiencies with which any given polymerase forms the four possible correct base pairs are roughly the same. Human DNA polymerase-iota (hPoliota), a member of the Y family of DNA polymerases, is an exception to these rules. hPoliota incorporates the correct nucleotide opposite a template adenine with a several hundred to several thousand fold greater efficiency than it incorporates the correct nucleotide opposite a template thymine, whereas its efficiency for correct nucleotide incorporation opposite a template guanine or cytosine is intermediate between these two extremes. Here we present the crystal structure of hPoliota bound to a template primer and an incoming nucleotide. The structure reveals a polymerase that is 'specialized' for Hoogsteen base-pairing, whereby the templating base is driven to the syn conformation. Hoogsteen base-pairing offers a basis for the varied efficiencies and fidelities of hPoliota opposite different template bases, and it provides an elegant mechanism for promoting replication through minor-groove purine adducts that interfere with replication.

    Title Giant Combined Dermatofibroma with Satellitosis.
    Date June 2004
    Journal Clinical and Experimental Dermatology
    Excerpt

    An unusual giant combined dermatofibroma is reported in a 34-year-old man who presented with skin-coloured swellings on the medial aspect of the left scapula. The plaque was well defined, reddish-brown and 25-30 cm in diameter. It was also tender and indurated. Several similar smaller lesions (satellites) were present around the plaque. Light microscopy of an incisional biopsy from the main lesion showed architectural features of a deep penetrating type of dermatofibroma, with xanthomatous aggregates, myxoid changes and probable myofibroblastic differentiation. Our case represents an extraordinary example of giant combined dermatofibroma with satellitosis. Despite its benign nature, a wide excision is contemplated because of its unsightly appearance and physical discomfort.

    Title Dpo4 is Hindered in Extending a G.t Mismatch by a Reverse Wobble.
    Date June 2004
    Journal Nature Structural & Molecular Biology
    Excerpt

    The ability or inability of a DNA polymerase to extend a mispair directly affects the establishment of genomic mutations. We report here kinetic analyses of the ability of Dpo4, a Y-family polymerase from Sulfolobus solfataricus, to extend from all mispairs opposite a template G or T. Dpo4 is equally inefficient at extending these mispairs, which include, surprisingly, a G.T mispair expected to conform closely to Watson-Crick geometry. To elucidate the basis of this, we solved the structure of Dpo4 bound to G.T-mispaired primer template in the presence of an incoming nucleotide. As a control, we also determined the structure of Dpo4 bound to a matched A-T base pair at the primer terminus. The structures offer a basis for the low efficiency of Dpo4 in extending a G.T mispair: a reverse wobble that deflects the primer 3'-OH away from the incoming nucleotide.

    Title Crystal Structure of Bstyi at 1.85a Resolution: a Thermophilic Restriction Endonuclease with Overlapping Specificities to Bamhi and Bglii.
    Date May 2004
    Journal Journal of Molecular Biology
    Excerpt

    We report here the structure of BstYI, an "intermediate" type II restriction endonuclease with overlapping sequence specificities to BamHI and BglII. BstYI, a thermophilic endonuclease, recognizes and cleaves the degenerate hexanucleotide sequence 5'-RGATCY-3' (where R=A or G and Y=C or T), cleaving DNA after the 5'-R on each strand to produce four-base (5') staggered ends. The crystal structure of free BstYI was solved at 1.85A resolution by multi-wavelength anomalous dispersion (MAD) phasing. Comparison with BamHI and BglII reveals a strong structural consensus between all three enzymes mapping to the alpha/beta core domain and residues involved in catalysis. Unexpectedly, BstYI also contains an additional "arm" substructure outside of the core protein, which enables the enzyme to adopt a more compact, intertwined dimer structure compared with BamHI and BglII. This arm substructure may underlie the thermostability of BstYI. We identify putative DNA recognition residues and speculate as to how this enzyme achieves a "relaxed" DNA specificity.

    Title Crystallization of Restriction Endonuclease Sfii in Complex with Dna.
    Date April 2004
    Journal Acta Crystallographica. Section D, Biological Crystallography
    Excerpt

    The SfiI endonuclease from Streptomyces fimbriatus (EC 3.1.21.4) is a tetrameric enzyme that binds simultaneously to two recognition sites and cleaves both sites concertedly. It serves as a good model system for studying both specificity and cooperative DNA binding. Crystals of the enzyme were obtained by the hanging-drop vapor-diffusion method in complex with a 21-mer oligonucleotide. The crystals are trigonal, with unit-cell parameters a = b = 85.7, c = 202.6 A, and diffract to 2.6 A resolution on a rotating-anode X-ray generator. Preliminary X-ray analysis reveals the space group to be either P3(1)21 or P3(2)21. Interestingly, the crystals change to space group P6(1)22, with unit-cell parameters a = b = 85.5, c = 419.6 A, when the selenomethionyl (SeMet) derivative of the enzyme is co-crystallized with the same DNA. Phase information is currently being derived from this SeMet SfiI-DNA complex.

    Title Crystal Structure of the Sf3 Helicase from Adeno-associated Virus Type 2.
    Date April 2004
    Journal Structure (london, England : 1993)
    Excerpt

    We report here the crystal structure of an SF3 DNA helicase, Rep40, from adeno-associated virus 2 (AAV2). We show that AAV2 Rep40 is structurally more similar to the AAA(+) class of cellular proteins than to DNA helicases from other superfamilies. The structure delineates the expected Walker A and B motifs, but also reveals an unexpected "arginine finger" that directly implies the requirement of Rep40 oligomerization for ATP hydrolysis and helicase activity. Further, the Rep40 AAA(+) domain is novel in that it is unimodular as opposed to bimodular. Altogether, the structural connection to AAA(+) proteins defines the general architecture of SF3 DNA helicases, a family that includes simian virus 40 (SV40) T antigen, as well as provides a conceptual framework for understanding the role of Rep proteins during AAV DNA replication, packaging, and site-specific integration.

    Title Insular Carcinoma of the Thyroid with a Predominant Microfollicular Pattern: a Diagnostic Pitfall on Cytology.
    Date April 2004
    Journal Acta Cytologica
    Title Evaluation of Graded Strength Glycolic Acid (ga) Facial Peel: an Indian Experience.
    Date January 2004
    Journal The Journal of Dermatology
    Title Energetic and Structural Considerations for the Mechanism of Protein Sliding Along Dna in the Nonspecific Bamhi-dna Complex.
    Date January 2004
    Journal Biophysical Journal
    Excerpt

    The molecular mechanism by which DNA-binding proteins find their specific binding sites is still unclear. To gain insights into structural and energetic elements of this mechanism, we used the crystal structure of the nonspecific BamHI-DNA complex as a template to study the dominant electrostatic interaction in the nonspecific association of protein with DNA, and the possible sliding pathways that could be sustained by such an interaction. Based on calculations using the nonlinear Poisson-Boltzmann method and Brownian dynamics, a model is proposed for the initial nonspecific binding of BamHI to B-form DNA that differs from that seen in the crystal structure of the nonspecific complex. The model is electrostatically favorable, and the salt dependence as well as other thermodynamic parameters calculated for this model are in good agreement with experimental results. Several residues in BamHI are identified for their important contribution to the energy in the nonspecific binding model, and specific mutagenesis experiments are proposed to test the model on this basis. We show that a favorable sliding pathway of the protein along DNA is helical.

    Title Glucocorticoid Receptor-like Zn(cys)4 Motifs in Bsli Restriction Endonuclease.
    Date December 2003
    Journal Journal of Molecular Biology
    Excerpt

    BslI restriction endonuclease cleaves the symmetric sequence CCN(7)GG (where N=A, C, G or T). The enzyme is composed of two subunits, alpha and beta, that form a heterotetramer (alpha(2)beta(2)) in solution. The alpha subunit is believed to be responsible for DNA recognition, while the beta subunit is thought to mediate cleavage. Here, for the first time, we provide experimental evidence that BslI binds Zn(II). Specifically, using X-ray absorption spectroscopic analysis we show that the alpha subunit of BslI contains two Zn(Cys)(4)-type zinc motifs similar to those in the DNA-binding domain of the glucocorticoid receptor. This conclusion is supported by genetic analysis of the zinc-binding motifs, whereby amino acid substitutions in the zinc finger motifs are demonstrated to abolish or impair cleavage activity. An additional putative zinc-binding motif was identified in the beta subunit, consistent with the X-ray absorption data. These data were corroborated by proton induced X-ray emission measurements showing that full BslI contains at least three fully occupied Zn sites per alpha/beta heterodimer. On the basis of these data, we propose a role for the BslI Zn motifs in protein-DNA as well as protein-protein interactions.

    Title Eya Protein Phosphatase Activity Regulates Six1-dach-eya Transcriptional Effects in Mammalian Organogenesis.
    Date December 2003
    Journal Nature
    Excerpt

    The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis (Six), eyes absent (Eya) and dachshund (Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis.

    Title Model of the Brain Tumor-pumilio Translation Repressor Complex.
    Date November 2003
    Journal Genes & Development
    Excerpt

    The Brain Tumor (Brat) protein is recruited to the 3' untranslated region (UTR) of hunchback mRNA to regulate its translation. Recruitment is mediated by interactions between the Pumilio RNA-binding Puf repeats and the NHL domain of Brat, a conserved structural motif present in a large family of growth regulators. In this report, we describe the crystal structure of the Brat NHL domain and present a model of the Pumilio-Brat complex derived from in silico docking experiments and supported by mutational analysis of the protein-protein interface. A key feature of the model is recognition of the outer, convex surface of the Pumilio Puf domain by the top, electropositive face of the six-bladed Brat beta-propeller. In particular, an extended loop in Puf repeat 8 fits in the entrance to the central channel of the Brat beta-propeller. Together, these interactions are likely to be prototypic of the recruitment strategies of other NHL-containing proteins in development.

    Title Are Primary Health Workers Skilled Enough to Assess the Severity of Illness Among Young Infants?
    Date October 2003
    Journal Indian Pediatrics
    Excerpt

    OBJECTIVE: To evaluate the skills of health workers in assessing the severity of illness among young infants. DESIGN: Cross sectional. SETTING: Five different health institutions viz, subcenter, primary health center, community health center, sub-divisional hospital, district hospital. METHODS: 110 young infants aged <2 months who attended the selected health institutions on specific week days were assessed by a physician. Subsequently 10 female health workers assessed these babies. Physician and health workers used same symptom and sign based guidelines for classification of the illness. Level of agreement between the physician and the health workers were assessed using kappa statistics. RESULTS: Physician classified 37.3% infants as not sick or mildly sick, 42.7% as moderately sick and 20% as severely sick. In comparison to the physician, the sensitivity and specificity of the health workers' assessment of severe illness was 77% and 76% respectively. Of 22 babies classified as severely sick by the physician, female health workers classified 5 as not sick or mildly sick, 8 as moderately sick and 9 as severely sick. On the other hand health workers classified one not sick or mildly sick and 9 moderately sick infants as severely sick. Level of agreement between the physician and health workers was poor (Kappa value = 0.39, 95% CI = 0.26, 0.52). Health workers misclassified illness mainly due to 'not counting the respiratory rate and 'not looking for chest retractions, purulent discharge and jaundice'. CONCLUSION: Trained health workers' skills were not satisfactory for assessment of illness severity among young infants. During training, importance of these signs needs to be emphasized.

    Title Rna Recognition Via the Sam Domain of Smaug.
    Date July 2003
    Journal Molecular Cell
    Excerpt

    The Nanos protein gradient in Drosophila, required for proper abdominal segmentation, is generated in part via translational repression of its mRNA by Smaug. We report here the crystal structure of the Smaug RNA binding domain, which shows no sequence homology to any previously characterized RNA binding motif. The structure reveals an unusual makeup in which a SAM domain, a common protein-protein interaction module, is affixed to a pseudo-HEAT repeat analogous topology (PHAT) domain. Unexpectedly, we find through a combination of structural and genetic analysis that it is primarily the SAM domain that interacts specifically with the appropriate nanos mRNA regulatory sequence. Therefore, in addition to their previously characterized roles in protein-protein interactions, some SAM domains play crucial roles in RNA binding.

    Title Deoxynucleotide Triphosphate Binding Mode Conserved in Y Family Dna Polymerases.
    Date May 2003
    Journal Molecular and Cellular Biology
    Excerpt

    Although DNA polymerase eta (Pol eta) and other Y family polymerases differ in sequence and function from classical DNA polymerases, they all share a similar right-handed architecture with the palm, fingers, and thumb domains. Here, we examine the role in Saccharomyces cerevisiae Pol eta of three conserved residues, tyrosine 64, arginine 67, and lysine 279, which come into close contact with the triphosphate moiety of the incoming nucleotide, in nucleotide incorporation. We find that mutational alteration of these residues reduces the efficiency of correct nucleotide incorporation very considerably. The high degree of conservation of these residues among the various Y family DNA polymerases suggests that these residues are also crucial for nucleotide incorporation in the other members of the family. Furthermore, we note that tyrosine 64 and arginine 67 are functionally equivalent to the deoxynucleotide triphosphate binding residues arginine 518 and histidine 506 in T7 DNA polymerase, respectively.

    Title Crystallization and Characterization of Pu.1/irf-4/dna Ternary Complex.
    Date March 2003
    Journal Journal of Structural Biology
    Excerpt

    PU.1 and IRF-4, members of the Ets and interferon regulatory families of transcription factors, respectively, form a cooperative ternary complex that is implicated in the regulation of B-cell-specific gene expression. A portion of the cooperativity involves interaction between the PU.1 and IRF-4 DNA-binding domains. We report here the crystallization and preliminary characterization of PU.1 and IRF-4 DNA-binding domains bound to a 21-mer DNA site from the lambdaB element of immunoglobulin light chain lambda(2-4) enhancer. The crystals belong to space group P2(1) with unit cell dimensions of a=40.7A, b=62.3A, c=67.9A, beta=95.6 degrees with one complex molecule per asymmetric unit. Crystals diffract to a resolution of 3A using X-rays from a rotating anode generator but improve to 2.3A with synchrotron radiation. The crystals are highly mosaic, but the mosaicity can be improved following a series of steps involving the addition of additives, use of peritone oil as a cryoprotectant, slow flash-cooling in the cryostream, and several cycles of crystal annealing.

    Title Animal Bite Management Practices: a Survey of Health Care Providers in a Community Development Block of Haryana.
    Date March 2003
    Journal The Journal of Communicable Diseases
    Excerpt

    It is seen that outcome of animal bites is influenced by various factors including the treatment procedures practiced by health care providers (HCPs). A cross sectional study of health care providers was conducted during May 2000 in PHC Kurali and Naraingarh town of community development block Naraingarh in district Ambala, Haryana. A total of forty-four HCPs were interviewed at their health facility. They were asked about the qualification and number of years in practice. Health care providers were assessed for their knowledge regarding history taking, immediate management of animal bite, post bite anti-rabies treatment, follow up advice and availability of vaccines. Pre-exposure prophylaxis was known to 18.8% of HCPs. Fifty-nine per cent of HCPs were confident in managing dog bites and 93.1% knew about tissue culture vaccine. Vaccine cost was the commonest barrier (38.8%) in the management of animal bites. This study shows a gross difference between awareness and actual practice of management of animal bites.

    Title Crystal Structure of Pu.1/irf-4/dna Ternary Complex.
    Date January 2003
    Journal Molecular Cell
    Excerpt

    The Ets and IRF transcription factor families contain structurally divergent members, PU.1, Spi-B and IRF-4 (Pip), IRF-8 (ICSBP), respectively, which have evolved to cooperatively assemble on composite DNA elements and regulate gene expression in the immune system. Whereas PU.1 recruits IRF-4 or IRF-8 to DNA, it exhibits an anticooperative interaction with IRF-1 and IRF-2. We report here the structure of the ternary complex formed with the DNA binding domains of PU.1 and IRF-4 on a composite DNA element. The DNA in the complex contorts into an unusual S shape that juxtaposes PU.1 and IRF-4 for selective electrostatic and hydrophobic interactions across the central minor groove. Together, the protein-protein and protein-DNA interactions provide insights into the stereochemical basis of cooperativity and anti-cooperativity between Ets and IRF factors.

    Title Structure of Nf-kappab P50/p65 Heterodimer Bound to the Prdii Dna Element from the Interferon-beta Promoter.
    Date December 2002
    Journal Structure (london, England : 1993)
    Excerpt

    Upon viral infection, NF-kappaB translocates to the nucleus and activates the IFN-beta gene by binding to the PRDII element. Strikingly, NF-kappaB loses its ability to activate the IFN-beta gene when the PRDII element is substituted by closely related sites. We report here the crystal structure of NF-kappaB p50/p65 heterodimer bound to the PRDII element from the IFN-beta promoter. The structure reveals an unexpected alteration in configuration, in which the p50 specificity domain moves by as much as approximately 9 A when compared to NF-kappaB heterodimer bound to the immunoglobulin kappaB site (Ig-kappaB) while maintaining the same base-specific contacts with the DNA. Taken together, the structure offers new insights into the allosteric effects of closely related DNA sites on the configuration of NF-kappaB and its transcriptional selectivity.

    Title Crystallization and Characterization of Smaug: a Novel Rna-binding Motif.
    Date December 2002
    Journal Biochemical and Biophysical Research Communications
    Excerpt

    During Drosophila embryogenesis, Smaug protein represses translation of Nanos through an interaction with a specific element in its 3(')UTR. The repression occurs in the bulk cytoplasm of the embryo; Nanos is, however, successfully translated in the specialized cytoplasm of the posterior pole. This generates a gradient of Nanos emanating from the posterior pole that is essential for organizing proper abdominal segmentation. To understand the structural basis of RNA binding and translational control, we have crystallized a domain of Drosophila Smaug that binds RNA. The crystals belong to the space group R3 with unit cell dimensions of a=b=129.3A, c=33.1A, alpha=beta=90 degrees, gamma=120 degrees and diffract to 1.80A with synchrotron radiation. Initial characterization of this domain suggests that it encodes a novel RNA-binding motif.

    Title Translational Repressors in Drosophila.
    Date December 2002
    Journal Trends in Genetics : Tig
    Excerpt

    Translational regulation is an important aspect of gene regulation, particularly during early development of the fruit fly embryo when transcriptional mechanisms are untenable. Study of pattern formation and dosage compensation has identified several repressors that bind discrete sites in the untranslated portions of target mRNAs. These repressors do not work in isolation - each binds multiple sites in the appropriate mRNA, and the resulting RNA-protein complexes appear to recruit co-repressors by a variety of mechanisms.

    Title Transcription Corepressor Ctbp is an Nad(+)-regulated Dehydrogenase.
    Date November 2002
    Journal Molecular Cell
    Excerpt

    Transcriptional repression is based on the selective actions of recruited corepressor complexes, including those with enzymatic activities. One well-characterized developmentally important corepressor is the C-terminal binding protein (CtBP). Although intriguingly related in sequence to D2 hydroxyacid dehydrogenases, the mechanism by which CtBP functions remains unclear. We report here biochemical and crystallographic studies which reveal that CtBP is a functional dehydrogenase. In addition, both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked to the binding of the PXDLS consensus recognition motif on repressors, such as E1A and RIP140. Together, our data suggest that CtBP is an NAD(+)-regulated component of critical complexes for specific repression events in cells.

    Title Localized Scleroderma/morphea.
    Date October 2002
    Journal International Journal of Dermatology
    Title A Serological Study of Human Toxocariasis in North India.
    Date September 2002
    Journal The National Medical Journal of India
    Excerpt

    BACKGROUND: Human toxocariasis owing to lodgement of the larvae of Toxocara canis in different organs can result in serious clinical syndromes such as visceral larva migrans or ocular larva migrans. Detection of an antibody response to Toxocara canis excretory-secretory (TES) antigen in serum samples is sensitive and specific for diagnosis and epidemiological surveys. To assess the extent of this problem in northern India, we tested the antibody response to the TES antigen by ELISA technique in subjects residing in a rural area near Chandigarh and in patients attending Nehru hospital, Chandigarh and clinically suspected to have toxocariasis. METHODS: Serum samples were collected from 94 randomly selected subjects, residents of Kheri village, Ambala district, Haryana; 30 patients clinically suspected to have toxocariasis attending Nehru hospital, Chandigarh; 25 control patients and 15 normal healthy individuals. These were subjected to ELISA technique for detection of an antibody response to TES antigen usinga commercial kit (LMD Laboratories Inc. Ca. USA). All the samples were tested in duplicate and positive samples were tested by a different kit (Melotec Biotechnology, Spain). RESULTS: Of the 94 subjects residing in Kheri village and 30 clinically suspected toxocariasis patients, 6 (6.4%) and 7 (23.3%), respectively, were seropositive for anti-Toxocara antibody response. A history of pica and/or contact with puppies could not be obtained from all the subjects/patients, hence the exact mode of transmission could not be ascertained. However, 3 (3.2%), 2 (2.13%) and 1 (1.06%) seropositive subjects in Kheri village were in the age groups of 1-10, 11-20 and 21-30 years, respectively, while 4 (13.33%) and 3 (10%) seropositive patients who attended Nehru hospital, Chandigarh were in the age groups of 1-10 and 21-30 years, respectively. None of the control patients/healthy individuals were seropositive. CONCLUSION: A positive antibody response to TES antigen in 6.4% subjects residing in a rural area near Chandigarh and in 23.3% of patients clinically suspected to have toxocariasis indicates that human toxocariasis may be endemic in certain regions of northern India. A detailed epidemiological study is needed to determine the extent of this problem.

    Title A Community-based Rheumatic Fever/rheumatic Heart Disease Cohort: Twelve-year Experience.
    Date June 2002
    Journal Indian Heart Journal
    Excerpt

    BACKGROUND: A pilot rheumatic fever and rheumatic heart disease control porject was started in 1988 in blocks of district Ambala (Haryana) to test the feasibility of early detection, treatment and secondary prophylaxis for rheumatic fever/rheumatic heart disease cases. School teachers, students and health workers were trained to identify and refer suspected cases of rheumatic fever/rheumatic heart disease to the community health center where physicians examined the suspected cases and monthly secondary prophylaxis was provided to the confirmed cases. METHODS AND RESULTS: A survey of registered cases was done in 1999 to determine the compliance rate of secondary prophylaxis and to describe clinical and epidemiologic features of the registered cohort of rheumatic fever/rheumatic heart disease patients. A total of 257 patients had been registered till the end of 1999 with 1263 person-years of follow-up. Out of these registered patients, 132 were receiving secondary prophylaxis, 52 had died, 17 had migrated, 8 were lost to follow-up, 18 had stopped prophylaxis and 30 completed the prophylaxis course. The mean age at registration was 18 years. Half of the cases were in the 6-15 years age group at registration. Over half of the patients were registered with a history of rheumatic fever. Fever was the most common symptom (75.9%). Carditis was more common among cases with recurrent attacks of rheumatic fever than after a first attack. The mortality in rheumatic fever/rheumatic heart cases was 32.5/1000 person-years. The mean age at death was 24.4 years. Compliance with secondary prophylaxis was 92% during the past 12 years. CONCLUSIONS: A rheumatic fever/rheumatic heart disease control program can be sustained within the primary health care system and the case registry can be utilized not only for monitoring the program but also to gain insight into the epidemiology of the disease.

    Title Structure of the Catalytic Core of S. Cerevisiae Dna Polymerase Eta: Implications for Translesion Dna Synthesis.
    Date October 2001
    Journal Molecular Cell
    Excerpt

    DNA polymerase eta is unique among eukaryotic polymerases in its proficient ability to replicate through a variety of distorting DNA lesions. We report here the crystal structure of the catalytic core of S. cerevisiae DNA polymerase eta, determined at 2.25A resolution. The structure reveals a novel polydactyl right hand-shaped molecule with a unique polymerase-associated domain. We identify the catalytic residues and show that the fingers and thumb domains are unusually small and stubby. In particular, the unexpected absence of helices "O" and "O1" in the fingers domain suggests that openness of the active site is the critical feature which enables DNA polymerase eta to replicate through DNA lesions such as a UV-induced cis-syn thymine-thymine dimer.

    Title Foki Requires Two Specific Dna Sites for Cleavage.
    Date August 2001
    Journal Journal of Molecular Biology
    Excerpt

    FokI is a bipartite restriction endonuclease that recognizes a non-palindromic DNA sequence, and then makes double-stranded cuts outside of that sequence to leave a 5' overhang. Earlier kinetic and crystallographic studies suggested that FokI might function as a dimer. Here, we show, using dynamic light-scattering, gel-filtration and analytical ultracentrifugation, that FokI dimerizes only in the presence of divalent metal ions. Furthermore, analysis of the DNA-bound complex reveals that two copies of the recognition sequence are incorporated into the dimeric complex and that formation of this complex is essential for full activation of cleavage. These results have broad implications for the mechanism by which monomeric type II endonucleases achieve high fidelity.

    Title Effect of Continuing Training on Knowledge and Practices of Traditional Birth Attendants About Maternal and Newborn Care.
    Date July 2001
    Journal Indian Journal of Public Health
    Excerpt

    Seventy nine traditional birth attendants (TBAs) of Raipur Rani community development block, Haryana were interviewed to assess the effectiveness of continuing training in changing their knowledge and practices regarding maternal and newborn care. Seventy three percent of them reported participation in continuing training sessions. However, analysis of attendance register showed that only 35.4% had attended more than 50% sessions in year 1993. Most (83.5%) of the TBAs gave advice to pregnant women for increased food intake, 47% advised tetanus toxoid, 16.5% for more rest, and 31.6% for iron tablets. Many of them were aware of maternal complications i.e. anaemia (64.6%), oedema (26.6%), bleeding per veginum (39.2%), abnormal presentation (77.2%) and high fever (48.1%). Risks to newborn like low birth weight, fever, cough/rapid breathing and hypothermia were known to 20.2%, 31.6%, 17.7% and 1.3% of the TBAs respectively. Knowledge regarding causes of low birth weight baby like 'weak' mother, less diet in pregnancy, short birth interval and preterm delivery were reported by 69.6%, 63.3%, 12.6% and 3.8% respectively. About two fifth of TBAs advised referral to hospital in case of prolonged labour and 88.6% for very low birth weight babies. Disposable Dai Kit and weighing machine were available with 32% and 73% TBAs. Significantly higher proportion of TBAs participating in continuing training advised tetanus toxoid vaccination, appropriate feeding practices of the newborn, hospital referral in case of prolonged labour and were less inclined to advise injection to speed up labour. Therefore, efforts should be made to increase the attendance of TBAs in continuing training sessions so as to sustain modern maternal and newborn care practices acquired after initial training.

    Title Crystallization and Characterization of Pumilo: a Novel Rna Binding Protein.
    Date June 2001
    Journal Journal of Structural Biology
    Excerpt

    Axis determination in early Drosophila embryos is controlled, in part, by regulation of translation of mRNAs transcribed in maternal cells during oogenesis. The Pumilio protein is essential in posterior determination, binding to hunchback mRNA in complex with Nanos to suppress hunchback translation. In order to understand the structural basis of RNA binding, Nanos recruitment, and translational control, we have crystallized a domain of the Drosophila Pumilio protein that binds RNA. The crystals belong to the space group P6(3) with unit cell dimensions of a = b = 94.5 A, c = 228.9 A, alpha = beta = 90 degrees, gamma = 120 degrees and diffract to 2.6 A with synchrotron radiation. We show that the purified protein actively binds RNA and is likely to have a novel RNA binding fold due to a very high content of alpha-helical secondary structure.

    Title Structure of Pumilio Reveals Similarity Between Rna and Peptide Binding Motifs.
    Date May 2001
    Journal Cell
    Excerpt

    Translation regulation plays an essential role in the differentiation and development of animal cells. One well-studied case is the control of hunchback mRNA during early Drosophila embryogenesis by the trans-acting factors Pumilio, Nanos, and Brain Tumor. We report here a crystal structure of the critical region of Pumilio, the Puf domain, that organizes a multivalent repression complex on the 3' untranslated region of hunchback mRNA. The structure reveals an extended, rainbow shaped molecule, with tandem helical repeats that bear unexpected resemblance to the armadillo repeats in beta-catenin and the HEAT repeats in protein phosphatase 2A. Based on the structure and genetic experiments, we identify putative interaction surfaces for hunchback mRNA and the cofactors Nanos and Brain Tumor. This analysis suggests that similar features in helical repeat proteins are used to bind extended peptides and RNA.

    Title E-commerce in Healthcare: Changing the Traditional Landscape.
    Date May 2001
    Journal Journal of Healthcare Information Management : Jhim
    Excerpt

    The healthcare industry, with more than one trillion dollars in revenue, accounts for about one-seventh of the U.S. economy. A significant portion of this revenue is lost to escalating healthcare system costs. This article examines the shortcomings of the traditional healthcare delivery system in terms of information flow, communication standards, case collections, and IT spending. It makes the case that e-commerce has the ability to transact some healthcare business more efficiently and cost-effectively. With the Internet as a delivery platform, several models offer improvement over the status quo.

    Title Bglii and Muni: What a Difference a Base Makes.
    Date May 2001
    Journal Current Opinion in Structural Biology
    Excerpt

    Restriction endonucleases are resilient to alterations in their DNA-binding specificities. Structures of the BglII and MunI endonucleases bound to their palindromic DNA sites, which differ by only their outer base pairs from the recognition sequences of BamHI and EcoRI, respectively, have recently been determined. A comparison of these complexes reveals surprising differences and similarities in structure, and provides a basis for understanding the immutability of restriction endonucleases.

    Title Intensive Pulse Polio Immunization Workers and Vaccine Vial Monitors.
    Date April 2001
    Journal The National Medical Journal of India
    Title Adolescent Behaviour Regarding Reproductive Health.
    Date April 2001
    Journal Indian Journal of Pediatrics
    Excerpt

    A cross-sectional household survey was undertaken in rural areas of district Sirmaur, Himachal Pradesh, to assess the knowledge, beliefs and practices of adolescents about reproductive health. Six hundred and forty three unmarried adolescents aged 15-19 years were selected by 30-cluster sampling method from 2400 households. They were interviewed using a semi-structured schedule. Fifty-six per cent were girls. More girls (14%) were illiterate than boys (6%). Most of the boys (88%) and 58% girls knew that a female conceives through sexual intercourse. Seventy seven per cent girls and eighty seven per cent boys were aware of at least one contraceptive method. Majority of the girls (71%) and boys (82.5%) favoured termination of an unwanted pregnancy. About one-fourth respondents considered husband responsible for infertility and for sex of the baby. Boys considered night emission, poor body built and less growth of hair as reproductive health problems, whereas, girls were worried about menstruation and inadequate breast development. Almost 6% boys reported use of a contraceptive method indicating existence of pre-marital sexual activity. Knowledge on reproductive health is low and there is a big gap between actual and desired practices.

    Title Amino-terminal Domain Exchange Redirects Origin-specific Interactions of Adeno-associated Virus Rep78 in Vitro.
    Date April 2001
    Journal Journal of Virology
    Excerpt

    The unique ability of adeno-associated virus type 2 (AAV) to site-specifically integrate its genome into a defined sequence on human chromosome 19 (AAVS1) makes it of particular interest for use in targeted gene delivery. The objective underlying this study is to provide evidence for the feasibility of retargeting site-specific integration into selected loci within the human genome. Current models postulate that AAV DNA integration is initiated through the interactions of the products of a single viral open reading frame, REP, with sequences present in AAVS1 that resemble the minimal origin for AAV DNA replication. Here, we present a cell-free system designed to dissect the Rep functions required to target site-specific integration using functional chimeric Rep proteins derived from AAV Rep78 and Rep1 of the closely related goose parvovirus. We show that amino-terminal domain exchange efficiently redirects the specificity of Rep to the minimal origin of DNA replication. Furthermore, we establish that the amino-terminal 208 amino acids of Rep78/68 constitute a catalytic domain of Rep sufficient to mediate site-specific endonuclease activity.

    Title Structure of Free Bglii Reveals an Unprecedented Scissor-like Motion for Opening an Endonuclease.
    Date March 2001
    Journal Nature Structural Biology
    Excerpt

    Restriction endonuclease BglII completely encircles its target DNA, making contacts to both the major and minor grooves. To allow the DNA to enter and leave the binding cleft, the enzyme dimer has to rearrange. To understand how this occurs, we have solved the structure of the free enzyme at 2.3 A resolution, as a complement to our earlier work on the BglII-DNA complex. Unexpectedly, the enzyme opens by a dramatic 'scissor-like' motion, accompanied by a complete rearrangement of the alpha-helices at the dimer interface. Moreover, within each monomer, a set of residues--a 'lever'--lowers or raises to alternately sequester or expose the active site residues. Such an extreme difference in free versus complexed structures has not been reported for other restriction endonucleases. This elegant mechanism for capturing DNA may extend to other enzymes that encircle DNA.

    Title Allosteric Effects of Pit-1 Dna Sites on Long-term Repression in Cell Type Specification.
    Date December 2000
    Journal Science (new York, N.y.)
    Excerpt

    Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question, then, is whether a critical transcriptional activator of cell type-specific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitary-specific POU domain factor Pit-1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lactotrope. This distinction depends on a two-base pair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on Pit-1, in combination with other DNA binding factors, results in the recruitment of a corepressor complex, including nuclear receptor corepressor N-CoR, which, unexpectedly, is required for active long-term repression of the growth hormone gene in lactotropes.

    Title Gene Repression by Coactivator Repulsion.
    Date December 2000
    Journal Molecular Cell
    Excerpt

    We show that the IRF-2 oncoprotein represses virus-induced IFN-beta gene transcription via a novel mechanism. Virus infection induces recruitment of IRF-2 to some of the endogenous IFN-beta enhancers as part of the enhanceosome. Enhanceosomes bearing IRF-2 cannot activate transcription, due to the presence of a domain in IRF-2 that prevents enhanceosome-dependent recruitment of the CBP-Pol II holoenzyme complex. As a consequence, IRF-2 incorporation into enhanceosomes restricts the number of IFN-beta promoters directing transcription. Remarkably, deletion of the IRF-2 gene increases IFN-beta expression by expanding the number of cells capable of inducing IFN-beta gene transcription in response to virus infection.

    Title Otomycosis: a Clinicomycologic Study.
    Date September 2000
    Journal Ear, Nose, & Throat Journal
    Excerpt

    Otomycosis is a common fungal infection of the ear that is seen in the tropical and subtropical regions of the world. We performed mycologic analyses on debris and scraping samples from the external ear canals of 95 patients who had been clinically diagnosed with otomycosis. Seventy-one samples (74.7%) were positive for fungal growth; two of these samples contained two fungi, bringing the total number of isolates to 73. The most common pathogens were Aspergillus fumigatus (41.1% of all isolates), A niger (36.9%), and Candida albicans (8.2%).

    Title Community Based Study of Reproductive Tract Infections Among Ever Married Women of Reproductive Age in a Rural Area of Haryana, India.
    Date August 2000
    Journal The Journal of Communicable Diseases
    Excerpt

    A community based study was carried out to estimate the load of reproductive tract infections (RTIs) among ever married rural women aged 15-44 years and utilisation of a mobile village based treatment facility by them, during 1997. Complete household survey was done in 10 randomly selected villages of Mahindergarh district in Haryana, India. A total of 2325 women were interviewed by auxiliary nurse midwives and were invited for medical examination in a health camp set-up in their village. Sixty-one percent (1415/2325) women reported symptoms of RTIs. Only 35% (812/2325) had their per-speculum examination done. Out of those examined, 32% (263/812) had vaginitis, 21% (175/812) had cervicits, and 19% (156/812) had pelvic inflammatory disease. Vaginal smear of those having discharge revealed that 48% (231/476) had bacterial vaginosis, 0.8% (4/476) had fungal infection 9% (44/496) had trichomonal infection and none was found to be having gonococcal infection. Tests for chlamydial infection could not be performed as the cost was not affordable. Eighty-nine percent of women who reported symptoms of RTIs had not consulted anyone for their problem prior to our village based camp. Only 42% symptomatic and 24% asymptomatics availed the services even in the village based camps. Study revealed high load of reproductive tract infections and low utilisation of treatment facility. In-depth studies are required to understand for high RTI morbidity load and low treatment seeking rate so as to design an appropriate RTI control programme.

    Title Crystallization of Restriction Endonuclease Bamhi with Nonspecific Dna.
    Date July 2000
    Journal Journal of Structural Biology
    Excerpt

    Restriction endonucleases show extraordinary specificity in distinguishing specific from nonspecific DNA sequences. A single basepair change within the recognition sequence results in over a million-fold loss in activity. To understand the basis of this sequence discrimination, it is just as important to study the nonspecific complex as the specific complex. We describe here the crystallization of restriction endonuclease BamHI with several nonspecific oligonucleotides. The 11-mer, 5'-ATGAATCCATA-3', yielded cocrystals with BamHI, in the presence of low salt, that diffracted to 1.9 A with synchrotron radiation. The cocrystals belong to the space group P2(1)2(1)2(1) with unit cell dimensions of a = 114.8 A, b = 91.1 A, c = 66.4 A, alpha = 90 degrees, beta = 90 degrees, gamma = 90 degrees. This success in the cocrystallization of BamHI with a nonspecific DNA provides insights for future attempts at crystallization of other nonspecific DNA-protein complexes.

    Title Structure of Bamhi Bound to Nonspecific Dna: a Model for Dna Sliding.
    Date July 2000
    Journal Molecular Cell
    Excerpt

    The central problem faced by DNA binding proteins is how to select the correct DNA sequence from the sea of nonspecific sequences in a cell. The problem is particularly acute for bacterial restriction enzymes because cleavage at an incorrect DNA site could be lethal. To understand the basis of this selectivity, we report here the crystal structure of endonuclease BamHI bound to noncognate DNA. We show that, despite only a single base pair change in the recognition sequence, the enzyme adopts an open configuration that is on the pathway between free and specifically bound forms of the enzyme. Surprisingly, the DNA drops out of the binding cleft with a total loss of base-specific and backbone contacts. Taken together, the structure provides a remarkable snapshot of an enzyme poised for linear diffusion (rather than cleavage) along the DNA.

    Title Monomeric Midkine Induces Tumor Cell Proliferation in the Absence of Cell-surface Proteoglycan Binding.
    Date June 2000
    Journal Biochemistry
    Excerpt

    Midkine (MK), a retinoic acid-inducible heparin-binding protein, is a mitogen which initiates a cascade of intracellular protein tyrosine phosphorylation mediated by the JAK/STAT pathway after binding to its high affinity p200(+)/MKR cell surface receptor in the G401 cell line [Ratovitski, E. A. (1998) J. Biol. Chem. 273, 3654-3660]. In this study, we determined the biophysical characteristics of purified recombinant murine MK and analyzed the requirements for ligand multimerization and cell surface proteoglycan binding for the G401 cell mitogenic activity of MK. Our studies indicate that the secreted form of MK (M = 13 kDa) exists in solution as an asymmetric monomer with a frictional coefficient of 1. 48 and a Stokes radius of 23.7 A. By constructing bead models of MK using the program AtoB and the program HYDRO to predict the hydrodynamic properties of each model, our data suggest that MK has a dumb-bell shape in solution composed of independent N- and C-terminal domains separated by an extended linker. This asymmetric MK monomer is a biologically active ligand with mitogenic activity on G401 cells in vitro. Neither heparin-induced formation of noncovalent MK multimers nor tissue transglutaminase II covalent multimerization of MK enhanced MK mitogenic activity in this system. Since neither heparin competition nor cell treatment with chondroitinase ABC or heparinase III abolished the mitogenic effects of MK on G401 cells, cell-surface proteoglycan binding by MK does not appear to be a requirement for its observed mitogenic effects. These results provide strong evidence that the MK-specific p200(+)/MKR has distinctive biochemical properties which distinguish it from the receptor tyrosine phosphatase cell-surface proteoglycan PTPzeta/RPTPbeta and support the hypothesis that the diverse biological effects of MK are mediated by multiple cell-specific signal transduction receptors.

    Title Understanding the Immutability of Restriction Enzymes: Crystal Structure of Bglii and Its Dna Substrate at 1.5 A Resolution.
    Date March 2000
    Journal Nature Structural Biology
    Excerpt

    Restriction endonucleases are remarkably resilient to alterations in their DNA binding specificity. To understand the basis of this immutability, we have determined the crystal structure of endonuclease BglII bound to its recognition sequence (AGATCT), at 1. 5 A resolution. We compare the structure of BglII to endonuclease BamHI, which recognizes a closely related DNA site (GGATCC). We show that both enzymes share a similar alpha/beta core, but in BglII, the core is augmented by a beta-sandwich domain that encircles the DNA to provide extra specificity. Remarkably, the DNA is contorted differently in the two structures, leading to different protein-DNA contacts for even the common base pairs. Furthermore, the BglII active site contains a glutamine in place of the glutamate at the general base position in BamHI, and only a single metal is found coordinated to the putative nucleophilic water and the phosphate oxygens. This surprising diversity in structures shows that different strategies can be successful in achieving site-specific recognition and catalysis in restriction endonucleases.

    Title 1h, 15n and 13c Resonance Assignments for the Bromodomain of the Histone Acetyltransferase P/caf.
    Date November 1999
    Journal Journal of Biomolecular Nmr
    Title Low Birth Weight Prevalence and Antenatal Care Practices in a Rural Area of Haryana.
    Date August 1999
    Journal Indian Pediatrics
    Title Reciprocal Interactions of Pit1 and Gata2 Mediate Signaling Gradient-induced Determination of Pituitary Cell Types.
    Date June 1999
    Journal Cell
    Excerpt

    The mechanisms by which transient gradients of signaling molecules lead to emergence of specific cell types remain a central question in mammalian organogenesis. Here, we demonstrate that the appearance of four ventral pituitary cell types is mediated via the reciprocal interactions of two transcription factors, Pit1 and GATA2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA binding-independent function of Pit1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to generate distinct cell phenotypes.

    Title Structure and Ligand of a Histone Acetyltransferase Bromodomain.
    Date June 1999
    Journal Nature
    Excerpt

    Histone acetylation is important in chromatin remodelling and gene activation. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are approximately 110-amino-acid modules found in many chromatin-associated proteins. Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

    Title Structure of a Dna-bound Ultrabithorax-extradenticle Homeodomain Complex.
    Date March 1999
    Journal Nature
    Excerpt

    During the development of multicellular organisms, gene expression must be tightly regulated, both spatially and temporally. One set of transcription factors that are important in animal development is encoded by the homeotic (Hox) genes, which govern the choice between alternative developmental pathways along the anterior-posterior axis. Hox proteins, such as Drosophila Ultrabithorax, have low DNA-binding specificity by themselves but gain affinity and specificity when they bind together with the homeoprotein Extradenticle (or Pbxl in mammals). To understand the structural basis of Hox-Extradenticle pairing, we determine here the crystal structure of an Ultrabithorax-Extradenticle-DNA complex at 2.4 A resolution, using the minimal polypeptides that form a cooperative heterodimer. The Ultrabithorax and Extradenticle homeodomains bind opposite faces of the DNA, with their DNA-recognition helices almost touching each other. However, most of the cooperative interactions arise from the YPWM amino-acid motif of Ultrabithorax-located amino-terminally to its homeodomain-which forms a reverse turn and inserts into a hydrophobic pocket on the Extradenticle homeodomain surface. Together, these protein-DNA and protein-protein interactions define the general principles by which homeotic proteins interact with Extradenticle (or Pbx1) to affect development along the anterior-posterior axis of animals.

    Title The Role of Metals in Catalysis by the Restriction Endonuclease Bamhi.
    Date November 1998
    Journal Nature Structural Biology
    Excerpt

    Type II restriction enzymes are characterized by their remarkable specificity and simplicity. They require only divalent metals (such as Mg2+ or Mn2+) as cofactors to catalyze the hydrolysis of DNA. However, most of the structural work on endonucleases has been performed in the absence of metals, leaving unanswered questions about their mechanisms of DNA cleavage. Here we report structures of the endonuclease BamHI-DNA complex, determined in the presence of Mn2+ and Ca2+, that describe the enzyme at different stages of catalysis. Overall, the results support a two-metal mechanism of DNA cleavage for BamHI which is distinct from that of EcoRV.

    Title Signal-specific Co-activator Domain Requirements for Pit-1 Activation.
    Date October 1998
    Journal Nature
    Excerpt

    POU-domain proteins, such as the pituitary-specific factor Pit-1, are members of the homeodomain family of proteins which are important in development and homeostasis, acting constitutively or in response to signal-transduction pathways to either repress or activate the expression of specific genes. Here we show that whereas homeodomain-containing repressors such as Rpx2 seem to recruit only a co-repressor complex, the activity of Pit-1 is determined by a regulated balance between a co-repressor complex that contains N-CoR/SMRT, mSin3A/B and histone deacetylases, and a co-activator complex that includes the CREB-binding protein (CBP) and p/CAF. Activation of Pit-1 by cyclic AMP or growth factors depends on distinct amino- and carboxy-terminal domains of CBP, respectively. Furthermore, the histone acetyltransferase functions of CBP or p/CAF are required for Pit-1 function that is stimulated by cyclic AMP or growth factors, respectively. These data show that there is a switch in specific requirements for histone acetyltransferases and CBP domains in mediating the effects of different signal-transduction pathways on specific DNA-bound transcription factors.

    Title Structure of Foki Has Implications for Dna Cleavage.
    Date September 1998
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    FokI is a member an unusual class of restriction enzymes that recognize a specific DNA sequence and cleave nonspecifically a short distance away from that sequence. FokI consists of an N-terminal DNA recognition domain and a C-terminal cleavage domain. The bipartite nature of FokI has led to the development of artificial enzymes with novel specificities. We have solved the structure of FokI to 2.3 A resolution. The structure reveals a dimer, in which the dimerization interface is mediated by the cleavage domain. Each monomer has an overall conformation similar to that found in the FokI-DNA complex, with the cleavage domain packing alongside the DNA recognition domain. In corroboration with the cleavage data presented in the accompanying paper in this issue of Proceedings, we propose a model for FokI DNA cleavage that requires the dimerization of FokI on DNA to cleave both DNA strands.

    Title Foki Dimerization is Required for Dna Cleavage.
    Date September 1998
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    FokI is a type IIs restriction endonuclease comprised of a DNA recognition domain and a catalytic domain. The structural similarity of the FokI catalytic domain to the type II restriction endonuclease BamHI monomer suggested that the FokI catalytic domains may dimerize. In addition, the FokI structure, presented in an accompanying paper in this issue of Proceedings, reveals a dimerization interface between catalytic domains. We provide evidence here that FokI catalytic domain must dimerize for DNA cleavage to occur. First, we show that the rate of DNA cleavage catalyzed by various concentrations of FokI are not directly proportional to the protein concentration, suggesting a cooperative effect for DNA cleavage. Second, we constructed a FokI variant, FokN13Y, which is unable to bind the FokI recognition sequence but when mixed with wild-type FokI increases the rate of DNA cleavage. Additionally, the FokI catalytic domain that lacks the DNA binding domain was shown to increase the rate of wild-type FokI cleavage of DNA. We also constructed an FokI variant, FokD483A, R487A, which should be defective for dimerization because the altered residues reside at the putative dimerization interface. Consistent with the FokI dimerization model, the variant FokD483A, R487A revealed greatly impaired DNA cleavage. Based on our work and previous reports, we discuss a pathway of DNA binding, dimerization, and cleavage by FokI endonuclease.

    Title Body Temperatures of Home Delivered Newborns in North India.
    Date September 1998
    Journal Tropical Doctor
    Excerpt

    In this prospective study, axillary temperature of newborns delivered at home were recorded by a field worker once within a period of 24 h after the birth in 10 villages of Haryana, India, during 1992-1993. Room air temperature was measured at the same time. Family members were interviewed to record newborn care practices. Of the 189 babies, 11.1% were found to be hypothermic (temperature < 35.6 degrees C) and 22.8% were hyperthermic (temperature > 37.3 degrees C). During winter months 19.1% were hypothermic as compared to only 3.1% in summer whereas 8.5% were hyperthermic in winter compared to 36.8% in summer. Room air temperature of < 24 degrees C was recorded in 41%. A strong correlation was observed between room air temperature and neonatal temperature. At the time of birth, 13.2% of the delivery rooms in summer and 73.6% in winter were reported to have heat source: 58.2% babies were reported to be wiped soon after birth; 97.3% were wrapped in cloth; the head was covered in 59.1% cases in winter and 10.5% in summer; 97.3% babies were kept with mother in same bed but not in skin-to-skin contact; and 65% were bathed within 24 h after delivery. Neonatal hypothermia is a common problem in developing countries. It is important that information, education and communication strategy about appropriate technologies for prevention and management of neonatal hypothermia is provided at domiciliary level. A significant proportion of babies are likely to suffer from hyperthermia in warm countries, specially in summer. Therefore, guidelines for thermal control in home births should be tailored to the specific environmental situation.

    Title Novel Site-specific Dna Endonucleases.
    Date April 1998
    Journal Current Opinion in Structural Biology
    Excerpt

    Site-specific hydrolysis of DNA is common to many biological processes. Three new structures, FokI, I-CreI and PI-SceI, were reported in the past year, providing the first view of type IIs endonucleases and homing endonucleases. Together, they reveal an extraordinary set of new mechanisms by which endonucleases target the hydrolysis of specific DNA sequences.

    Title Total Partnership for Primary Health Care Provision: a Proposed Model--part Ii.
    Date April 1998
    Journal International Journal of Health Care Quality Assurance Incorporating Leadership in Health Services
    Excerpt

    This is the second part in a paper which studied the dynamics of primary health care provision. This paper examines external factors related to the management of General Practices. The study revealed that there are major problems at GP/FHSA interfaces involving poor communications, needs evaluation and understanding, and the lack of teamwork. The paper argues that attempts by FHSAs in terms of initiatives are so far failing and have not effectively been able to build strong partnerships between the parties concerned. The paper concludes by proposing a Model of Total Partnership for effective primary health care provision. The model suggests that structures need to be modified in a horizontal way, focusing on patients and building a collaborative way between FHSAs and GPs in a seamless fashion. The model is based on Total Quality Management (TQM) principles and is represented by the building of a customer-supplier chain, the spirit of continuous improvement and synergy through teamwork with the ultimate goal of Total Patient Satisfaction.

    Title Factors Influencing Psychosocial Development of Preschool Children in a Rural Area of Haryana, India.
    Date March 1998
    Journal Journal of Tropical Pediatrics
    Excerpt

    In a cross-sectional survey, 3746 children aged less than 6 years residing in 47 randomly selected villages of district Ambala (India), were studied to find out the environmental risk factors influencing psychosocial development. A culture appropriate test battery comprising 67 test items was administered, and psychosocial development score of each child was computed by scoring each test item passed as 1 and failed as 0. At each age level children having score in lower quartile were categorised as having slow psychosocial development and those in upper quartile were labelled as having accelerated development. Logistic regression revealed that per capita income, education of mother, nutritional status of the child, number of rooms and environmental hygiene in the house, presence of a high school within easy travel distance, availability of a caretaker when mother is busy, child attending a nursery (anganwadi), households having access to newspaper, child having toys or toy substitutes, TV, books, story telling by the mother were found to have a significant association with psychosocial development of preschool children. The risk factors identified in this survey can be used for screening families at risk in rural communities and for selection of interventions for promotion of psychosocial development of children.

    Title Total Partnership for Primary Health Care Provision: a Proposed Model: Part I.
    Date February 1998
    Journal International Journal of Health Care Quality Assurance Incorporating Leadership in Health Services
    Excerpt

    Presents the first of a two part paper, based on a study which examined the dynamics of primary health care provision. The study examined 49 general practices in the Kirklees area, UK, through a detailed questionnaire mode. The response was 67 per cent covering the views of 106 doctors. To capture further input for the study, an in-depth seminar with nine doctors from a range of practices was conducted. Examines internal factors for managing general practices and the levels of competence in addressing financial, strategic, quality issues and whether general practices get involved in any external activities for new learning and benchmarking. Comprehensively covers common areas of concern and areas where expertise may be inadequate or lacking.

    Title Structure of Irf-1 with Bound Dna Reveals Determinants of Interferon Regulation.
    Date January 1998
    Journal Nature
    Excerpt

    The family of interferon regulatory factor (IRF) transcription factors is important in the regulation of interferons in response to infection by virus and in the regulation of interferon-inducible genes. The IRF family is characterized by a unique 'tryptophan cluster' DNA-binding region. Here we report the crystal structure of the IRF-1 region bound to the natural positive regulatory domain I (PRD I) DNA element from the interferon-beta promoter. The structure provides the first three-dimensional view of a member of the growing IRF family, revealing a new helix-turn-helix motif that latches onto DNA through three of the five conserved tryptophans. The motif selects a short GAAA core sequence through an obliquely angled recognition helix, with an accompanying bending of the DNA axis in the direction of the protein. Together, these features suggest a basis for the occurrence of GAAA repeats within IRF response elements and provide clues to the assembly of the higher-order interferon-beta enhancesome.

    Title Expression, Purification, and Co-crystallization of Irf-i Bound to the Interferon-beta Element Prdi.
    Date October 1997
    Journal Febs Letters
    Excerpt

    Interferon regulatory factor 1 (IRF-1) is an essential factor involved in the regulation of type I interferon (IFN) and IFN-inducible genes. The protein consists of 329 amino acids that are highly conserved from mouse to human. Similar to other transcription factors, the protein is modular in nature with a basic N-terminal region involved in DNA binding and an acidic C-terminal region required for activation. We report here the expression, purification and co-crystallization of the minimal N-terminal region of IRF-1 involved in DNA binding (amino acids 1-113) with a 13 bp DNA fragment from the IFN-beta promoter. The crystals diffract to at least 3.0 A in resolution and belong to space group R3 with unit cell parameters of a = b = 84.8 A, c = 203.7 A.

    Title Reproductive Tract Infections--and Associated Difficulties.
    Date September 1997
    Journal World Health Forum
    Excerpt

    In addition to financial constraints there are significant social, educational, moral and religious barriers to the prevention and treatment of reproductive tract infections in rural India. A pilot project aimed at achieving progress in this field is reported below.

    Title Structure of the Multimodular Endonuclease Foki Bound to Dna.
    Date July 1997
    Journal Nature
    Excerpt

    FokI is a member of an unusual class of bipartite restriction enzymes that recognize a specific DNA sequence and cleave DNA nonspecifically a short distance away from that sequence. Because of its unusual bipartite nature, FokI has been used to create artificial enzymes with new specificities. We have determined the crystal structure at 2.8A resolution of the complete FokI enzyme bound to DNA. As anticipated, the enzyme contains amino- and carboxy-terminal domains corresponding to the DNA-recognition and cleavage functions, respectively. The recognition domain is made of three smaller subdomains (D1, D2 and D3) which are evolutionarily related to the helix-turn-helix-containing DNA-binding domain of the catabolite gene activator protein CAP. The CAP core has been extensively embellished in the first two subdomains, whereas in the third subdomain it has been co-opted for protein-protein interactions. Surprisingly, the cleavage domain contains only a single catalytic centre, raising the question of how monomeric FokI manages to cleave both DNA strands. Unexpectedly, the cleavage domain is sequestered in a 'piggyback' fashion by the recognition domain. The structure suggests a new mechanism for nuclease activation and provides a framework for the design of chimaeric enzymes with altered specificities.

    Title Homing in on Intron-encoded Endonucleases.
    Date July 1997
    Journal Nature Structural Biology
    Title Awareness of Aids Among School Children in Haryana.
    Date May 1997
    Journal Indian Journal of Public Health
    Excerpt

    The study is aimed to assess the existing level of knowledge of school children of 9th and 10th classes about Acquired Immune Deficiency Syndrome (AIDS). Three high schools in an urban area and three in the villages of a district of North India were included in the study. A pretested closed-ended questionnaire was administered to 336 students available. Overall level of knowledge about AIDS was found to be high. However, there were significant differences in knowledge among rural-urban and male-female students. There were some misconceptions in knowledge regarding transmission, prognosis and prevention. Books and media were the most common sources of information. Most of the students wanted to learn more about AIDS. Since overall knowledge levels were high we conclude that AIDS education should concentrate on clarifying areas of misconceptions.

    Title Crystallization and Preliminary X-ray Analysis of Restriction Endonuclease Foki Bound to Dna.
    Date March 1997
    Journal Febs Letters
    Excerpt

    FokI is a type IIs restriction endonuclease which recognizes an asymmetric DNA sequence and cleaves DNA a short distance away from the sequence. The enzyme is bipartite in nature with its DNA recognition and cleavage functions located on distinct domains. We report here cocrystals of the complete FokI enzyme (579 amino acids) bound to a 20-bp DNA fragment containing its recognition sequence. The complex is amongst the largest protein-DNA complexes to be crystallized, and required macroseeding techniques for optimal crystal growth. The cocrystals diffract to at least 2.8 A in resolution and belong to space group P2(1) with unit cell dimensions of a=67.9 A, b=119.8 A, c=69.1 A, beta = 96.6 degrees. Using specific amino acid analysis we show that asymmetric unit contains a single FokI molecule bound to the 20-bp DNA fragment. This paper reports the first cocrystals of a type IIs restriction endonuclease.

    Title Structure of Pit-1 Pou Domain Bound to Dna As a Dimer: Unexpected Arrangement and Flexibility.
    Date February 1997
    Journal Genes & Development
    Excerpt

    Pit-1, a member of the POU domain family of transcription factors, characterized by a bipartite DNA-binding domain, serves critical developmental functions based on binding to diverse DNA elements in its target genes. Here we report a high resolution X-ray analysis of the Pit-1 POU domain bound to a DNA element as a homodimer. This analysis reveals that Pit-1 subdomains bind to perpendicular faces of the DNA, rather than opposite faces of the DNA as in Oct-1. This is accomplished by different spacing and orientation of the POU-specific domain. Contrary to previous predictions, the dimerization interface involves the carboxyl terminus of the DNA recognition helix of the homeodomain, which in an extended conformation interacts with specific residues at the amino terminus of helix alpha1 and in the loop between helices alpha3 and alpha4 of the POU-specific domain of the symmetry related monomer. These features suggest the molecular basis of disease-causing mutations in Pit-1 and provide potential basis for the flexible allostery between protein domains and DNA sites in the activation of target genes.

    Title Accuracy of Maternal Perception of Neonatal Temperature.
    Date February 1997
    Journal Indian Pediatrics
    Title Crystallization and Preliminary X-ray Analysis of Pit-1 Pou Domain Complexed to a 28 Base Pair Dna Element.
    Date January 1997
    Journal Proteins
    Excerpt

    The POU domain, representing an approximately 150 amino acid conserved region, serves as the DNA-recognition domain for a large number of eukaryotic transcription factors. Bipartite in nature, the POU domain is comprised of a N-terminal POU-specific domain connected by a linker of variable length to a C-terminal homeodomain. We report here co-crystals of pituitary-specific factor Pit-1 POU domain bound as a dimer to a 28 bp DNA fragment. The crystals diffract to at least 2.3 angstroms in resolution and belong to space group P1 with unit cell dimensions of a = 42.5 angstroms, b = 50.1 angstroms, c = 55.8 angstroms, alpha = 76.7 degrees, beta = 79.3 degrees, and gamma = 67.2 degrees.

    Title The Relevance of Hearing a Crack in Ankle Injuries.
    Date December 1996
    Journal Journal of Accident & Emergency Medicine
    Excerpt

    OBJECTIVE: To examine the predictive value of a crack noise or sensation in the history of injury in the diagnosis of ankle fracture. METHODS: A short questionnaire was filled in on 464 patients with isolated ankle injuries attending the accident and emergency department in a three month period from July to September. These patients were seen in the usual way in the department and the need for x ray assessed according to clinical judgement and existing departmental guidelines. Cases which subsequently proved to be other than ankle injuries, for example, fractured calcaneus, were excluded from the study. RESULTS: A positive history of hearing or feeling a crack did not indicate the need for an x ray or increase the possibility of a fracture; indeed the history of a crack made the presence of a fracture less likely. The clinical diagnosis of absence of fracture without radiological examination may require careful explanation to the patient. CONCLUSIONS: Hearing a crack in the ankle does not suggest a fracture.

    Title Physical Growth of Rural Pre-school Children in Haryana.
    Date December 1996
    Journal Indian Journal of Maternal and Child Health : Official Publication of Indian Maternal and Child Health Association,
    Title Nutritional Status of Children: Validity of Mid-upper Arm Circumference for Screening Undernutrition.
    Date October 1996
    Journal Indian Pediatrics
    Excerpt

    OBJECTIVES: To determine the nutritional status and validity of mid upper arm circumference (MAC) in diagnosing malnutrition among preschool children. DESIGN: Cross-sectional household survey. SETTING: 47 villages in District Ambala, Haryana. SUBJECTS: 3747 children aged less than six years. METHODOLOGY: Trained field workers recorded age, weight, length/ height and MAC of children. Prevalence of underweight, stunting, and wasting were calculated in reference to National Centre for Health Statistics (NCHS) standards. Sensitivity and specificity of MAC for detecting underweight, wasting and stunting among children aged 1 to 4 years were determined. RESULTS: At the cut-off level of < -2.00 SD of Z-scores, 48.8% children were stunted, 49.6% were underweight and 9.1% were wasted whereas 47.6% children had neither wasting nor stunting. Prevalence of severe stunting, underweight, and wasting (Z-score < -3 SD) was 18.1%, 11.5% and 0.6%, respectively. Undernutrition showed a significant rise after 12 months of age (p < 0.0001). Stunting and underweight were significantly more among girls compared to boys (p < 0.01) but wasting was not significantly different in them. Compared to the conventional MAC cut off levels of < 13.5 cm and < 12.5 cm, sensitivity and specificity in our setting were optimum at < 13.5 cm for detection of wasting and < 14.0 cm for diagnosis of underweight and stunting, and < 13.0 cm for detection of severe wasting and < 13.5 cm for diagnosis of severe underweight and severe stunting. CONCLUSIONS: Almost every second child was undernourished. Optimum cut off level of MAC in our setting were higher than the conventional cut off points for detection of undernutrition among children.

    Title Structure of the Even-skipped Homeodomain Complexed to At-rich Dna: New Perspectives on Homeodomain Specificity.
    Date February 1996
    Journal The Embo Journal
    Excerpt

    even-skipped is a homeobox gene important in controlling segment patterning in the embryonic fruit fly. Its homeobox encodes a DNA binding domain which binds with similar affinities to two DNA consensus sequences, one AT-rich, the other GC-rich. We describe a crystallographic analysis of the Even-skipped homeodomain complexed to an AT-rich oligonucleotide at 2.0 A resolution. The structure reveals a novel arrangement of two homeodomains bound to one 10 bp DNA sequence in a tandem fashion. This arrangement suggests a mechanism for the homeoproteins' regulatory specificity. In addition, the functionally important residue Gln50 is observed in multiple conformations making direct and water-mediated hydrogen bonds with the DNA bases.

    Title Structure of Bam Hi Endonuclease Bound to Dna: Partial Folding and Unfolding on Dna Binding.
    Date August 1995
    Journal Science (new York, N.y.)
    Excerpt

    The crystal structure of restriction endonuclease Bam HI complexed to DNA has been determined at 2.2 angstrom resolution. The DNA binds in the cleft and retains a B-DNA type of conformation. The enzyme, however, undergoes a series of conformational changes, including rotation of subunits and folding of disordered regions. The most striking conformational change is the unraveling of carboxyl-terminal alpha helices to form partially disordered "arms." The arm from one subunit fits into the minor groove while the arm from the symmetry related subunit follows the DNA sugar-phosphate backbone. Recognition of DNA base pairs occurs primarily in the major groove, with a few interactions occurring in the minor groove. Tightly bound water molecules play an equally important role as side chain and main chain atoms in the recognition of base pairs. The complex also provides new insights into the mechanism by which the enzyme catalyzes the hydrolysis of DNA phosphodiester groups.

    Title Glaucoma Screening.
    Date August 1995
    Journal The British Journal of General Practice : the Journal of the Royal College of General Practitioners
    Title Purification, Crystallization, and Preliminary X-ray Diffraction Analysis of Even-skipped Homeodomain Complexed to Dna.
    Date July 1995
    Journal Proteins
    Excerpt

    Embryonic development in metazoa, to a significant extent, is directed by genes which contain a conserved sequence motif named the homeobox. This sequence encodes a polypeptide called the homeodomain which has sequence specific DNA-binding activity. We report the purification, crystallization, and preliminary diffraction analysis of the Drosophila Even-skipped homeodomain (Eve HD) bound to two different oligonucleotides. Crystals of Eve HD complexed with an AT-rich sequence belong to space group P2(1), a = 34.06, b = 61.61, c = 39.99 Angstrom, beta = 90.0 degrees. These crystals diffract to at least 2.0 Angstrom and both native and derivative data sets have been collected. Crystals of Eve HD complexed with a GC-rich sequence belong to space group P6(3), a = b = 124.52, c = 66.78 Angstrom and diffract to 3.5 Angstrom resolution. A native data set has been collected.

    Title Structure and Function of Restriction Endonucleases.
    Date July 1995
    Journal Current Opinion in Structural Biology
    Excerpt

    Structures of two restriction endonucleases, BamHI and PvuII, were reported in the past year. This doubles the number of restriction endonuclease structures now known from two to four, and enables a comparative analysis of their structures and modes of DNA recognition. Despite a lack of sequence homology between the enzymes, BamHI turns out to resemble EcoRI, and PvuII turns out to resemble EcoRV. The active-site regions are structurally similar in all four enzymes, but their mechanisms of cleavage may differ.

    Title A Gripping End to Nf-kappa B.
    Date July 1995
    Journal Nature Structural Biology
    Title An Innovative Method of Tourniquet Application in Proximal Lower Limb Surgery.
    Date April 1995
    Journal Tropical Doctor
    Title Ewing's Sarcoma in a Toddler.
    Date October 1994
    Journal Tropical Doctor
    Title Structure of Restriction Endonuclease Bamhi Phased at 1.95 A Resolution by Mad Analysis.
    Date October 1994
    Journal Structure (london, England : 1993)
    Excerpt

    BACKGROUND: Type II restriction endonucleases recognize DNA sequences that vary between four to eight base pairs, and require only Mg2+ as a cofactor to catalyze the hydrolysis of DNA. Their protein sequences display a surprising lack of similarity, and no recurring structural motif analogous to the helix-turn-helix or the zinc finger of transcription factors, has yet been discovered. RESULTS: We have determined the crystal structure of restriction endonuclease BamHI at 1.95 A resolution. The structure was solved by combining phase information derived from multi-wavelength X-ray data by algebraic and maximum likelihood methods. The BamHI subunit consists of a central beta-sheet with alpha-helices on both sides. The dimer configuration reveals a large cleft which could accommodate B-form DNA. Mutants of the enzyme that are deficient in cleavage are located at or near the putative DNA-binding cleft. BamHI and endonuclease EcoRI share a common core motif (CCM) consisting of five beta-strands and two helices. It remains to be determined if other restriction enzymes also contain the CCM. CONCLUSIONS: The structure of BamHI provides the first clear evidence that there may be substantial structural homology amongst restriction enzymes, even though it is undetectable at the sequence level.

    Title Crystallization and Preliminary X-ray Analysis of Restriction Endonuclease Bamhi-dna Complex.
    Date July 1994
    Journal Journal of Molecular Biology
    Excerpt

    Restriction endonuclease BamHI from Bacillus amyloliquefaciens has been co-crystallized with a 12 bp DNA fragment that encompasses its recognition site. The co-crystals diffract to at least 1.95 A resolution and belong to space group P2(1)2(1)2(1). The unit cell parameters are a = 108.8 A, b = 81.9 A, c = 68.8 A, consistent with one complex in the crystallographic asymmetric unit. The direction of the DNA appears to be along the b axis. In order to achieve end to end stacking of DNA, the complex must lie on the screw axis along b. A self-rotation function has determined the directions of the non-crystallographic 2-fold axes.

    Title Structure of Restriction Endonuclease Bamhi and Its Relationship to Ecori.
    Date May 1994
    Journal Nature
    Excerpt

    Type II restriction endonucleases are characterized by the remarkable specificity with which they cleave specific DNA sequences. Surprisingly, their protein sequences are in most cases unrelated, and no recurring structural motif has yet been identified. We have determined the structure of restriction endonuclease BamHI at 1.95 A resolution. BamHI shows striking resemblance to the structure of endonuclease EcoRI (refs 3, 4), despite the lack of sequence similarity between them. We also observe some curious differences between the two structures, and propose an evolutionary scheme that may explain them. The active site of BamHI is structurally similar to the active sites of EcoRI and EcoRV (ref. 5), but the mechanism by which BamHI activates a water molecule for nucleophilic attack may be different.

    Title Overexpression, Purification and Crystallization of Bamhi Endonuclease.
    Date June 1991
    Journal Nucleic Acids Research
    Excerpt

    The type II restriction endonuclease BamHI has been expressed in E. coli, producing 100-fold more enzyme than the wild type Bacillus amyloliquefaciens H strain. This high yield has facilitated purification to homogeneity of large amounts of the enzyme, along with its crystallization in a form which diffracts to at least 1.9 A in X-ray analysis.

    Title Dna Recognition by Proteins with the Helix-turn-helix Motif.
    Date August 1990
    Journal Annual Review of Biochemistry
    Title Conserved Residues Make Similar Contacts in Two Repressor-operator Complexes.
    Date April 1990
    Journal Science (new York, N.y.)
    Excerpt

    Comparison of a lambda repressor-operator complex and a 434 repressor-operator complex reveals that three conserved residues in the helix-turn-helix (HTH) region make similar contacts in each of the crystallographically determined structures. These conserved residues and their interactions with phosphodiester oxygens help establish a frame of reference within which other HTH residues make contacts that are critical for site-specific recognition. Such "positioning contacts" may be important conserved features within families of HTH proteins. In contrast, the structural comparisons appear to rule out any simple "recognition code" at the level of detailed side chain-base pair interactions.

    Title Computer Modelling Studies of the Covalent Interactions Between Dna and the Enantiomers of Anti-7,8-diol,9,10-epoxy-benzo[a]pyrene.
    Date March 1990
    Journal Journal of Biomolecular Structure & Dynamics
    Excerpt

    The molecular structures of adducts between the + and - enantiomers of 7,8-diol 9,10-epoxy benzo[a]pyrene and a double-stranded model for DNA, have been examined by empirical energy calculations. Low-energy structures were only obtained for A form, and not B form DNA. Both + and - adducts are of approximately equal energy. Some structural differences in the orientation of the BP chromophore in the two adducts were found.

    Title Hydrometrocolpos with Respiratory Distress.
    Date April 1989
    Journal Indian Pediatrics
    Title Recognition of a Dna Operator by the Repressor of Phage 434: a View at High Resolution.
    Date December 1988
    Journal Science (new York, N.y.)
    Excerpt

    The repressors of temperate bacteriophages such as 434 and lambda control transcription by binding to a set of DNA operator sites. The different affinity of repressor for each of these sites ensures efficient regulation. High-resolution x-ray crystallography was used to study the DNA-binding domain of phage 434 repressor in complex with a synthetic DNA operator. The structure shows recognition of the operator by direct interactions with base pairs in the major groove, combined with the sequence-dependent ability of DNA to adopt the required conformation on binding repressor. In particular, a network of three-centered bifurcated hydrogen bonds among base pairs in the operator helps explain why 434 repressor prefers certain sites over others. These bonds, which stabilize the conformation of the bound DNA, can form only with certain sequences.

    Title Nucleic Acid Binding Drugs. Part Xiii. Molecular Motion in a Drug-nucleic Acid Model System: Thermal Motion Analysis of a Proflavine-dinucleoside Crystal Structure.
    Date October 1985
    Journal Nucleic Acids Research
    Excerpt

    The high-resolution crystal structure of the intercalation complex between proflavine and cytidylyl-3',5'-guanosine (CpG) has been studied by thermalmotion analysis. This has provided information on the translational and librational motions of individual groups in the complex. Many of these motions are similar to, though of larger magnitude than in uncomplexed dinucleosides. Pronounced librational effects were observed along the base pairs and in the plane of the drug chromophore.

    Title Serum Ceruloplasmin Levels in Patients of Leukaemias, Hodgkin's and Non-hodgkin's Lymphomas.
    Date July 1985
    Journal Indian Journal of Pathology & Microbiology
    Title Structural Studies on Sequence Selectivity in Drug-nucleic Acid Interactions.
    Date June 1985
    Journal Progress in Clinical and Biological Research
    Title Oral Papillomatosis Treated with Cryotherapy: a Case Report.
    Date November 1984
    Journal Journal of Dentistry
    Title Dissociation of the Locomotor and Hypotensive Effects of Adenosine Analogues in the Rat.
    Date November 1984
    Journal Neuroscience Letters
    Excerpt

    Rats implanted with chronic indwelling cannulae were injected in the lateral cerebral ventricle with two adenosine analogues and the effects on spontaneous locomotor activity and blood pressure recorded. Both analogues produced dose-related decreases in locomotor activity, with 5'-N-ethylcarboxamidoadenosine (NECA) exhibiting slightly more potent depressant activity than (-)-N-(1-methyl-2-phenylethyl)adenosine (L-phenylisopropyladenosine) (L-PIA). NECA and L-PIA also produced dose-related reductions in blood pressure but the threshold dose for hypotensive activity was 10-100-fold higher than the dose required for depression of spontaneous locomotor activity. The depression of locomotor activity and the hypotensive effect of both analogues were antagonized by parenteral injections of caffeine. These results show that the hypoactive and hypotensive effects of adenosine analogues can be dissociated and that methylxanthines probably exert an antagonism of central adenosine receptors in the rat.

    Title Diffuse Toxic Alopecia Due to Thiacetazone.
    Date November 1983
    Journal The Indian Journal of Chest Diseases & Allied Sciences
    Title Cleido Cranial Dysostosis in Five Generations of a Family with Some Atypical Roentgenologic Features.
    Date June 1980
    Journal Indian Pediatrics
    Title Depression Across Cultures.
    Date November 1971
    Journal The British Journal of Psychiatry : the Journal of Mental Science
    Title Remote Surface Contouring Using a Cross-correlation Speckle Technique.
    Date
    Journal Applied Optics
    Title Highly Sensitive Pulsed Digital Holography for Built-in Defect Analysis with a Laser Excitation.
    Date
    Journal Applied Optics
    Excerpt

    A highly sensitive method is presented for noninvasive defect analysis on thin structures with a Q-switched double-pulsed ruby laser with frequency doubling (347 nm). In our research we feature an all-optical arrangement, where a focused laser pulse derived from the same ruby laser (694 nm) acts as a built-in synchronous excitation source for digital holographic interferometry. The recordings are made with a CCD camera for capturing two holograms (two states of the specimen) corresponding to the two UV laser pulses with a short time separation (10-50 mus). Subtraction of the phase distribution in two digital holograms gives a fringe phase map that shows the change in deformation of the specimen between the recordings. The advantage of the proposed method is two fold. First, the use of a shorter wavelength results in a higher sensitivity. Second, owing to the induced synchronous built-in optical excitation, the specimen is not subjected to any external physical excitation devices. Experimental results are presented on identification and evaluation of defects in thin metal sheets.

    Title Comparative Study of Various Endoscopes for Pulsed Digital Holographic Interferometry.
    Date
    Journal Applied Optics
    Excerpt

    A comparison of several endoscopes as object image carriers in pulsed digital holography is presented. Three multicore flexible fiber endoscopes of different spatial resolution and one rigid endoscope are investigated. The four endoscopes are integrated in a setup for the recording of digital holograms on a CCD camera. A double-pulsed ruby laser is used as the light source. A spatial carrier is introduced by an off-axis reference beam, which permits quantitative evaluation of the phase difference between two holograms recorded with a short time separation (5-600 mus). From reported studies it may be inferred that the quality of the phase maps so derived from digital holographic interferometry has a strong correlation to the spatial resolution of the multicore fiber used in these endoscopes. With the endoscopic technique combined with pulsed digital holography a number of useful applications (in areas such as medical endoscopy, micromechanics, and microelectronics) are envisaged for which access to the objects of interest is otherwise difficult.

    Title Variable Osseous Anatomy of Costal Surface of Scapula and Its Implications in Relation to Snapping Scapula Syndrome.
    Date
    Journal Surgical and Radiologic Anatomy : Sra
    Excerpt

    Variation in normal anatomy of costal surface of scapula may disrupt smooth scapulothoracic movements and may cause snapping scapula. The aim of this study was to assess variable anatomy of costal surface of scapula and its role in etiopathogenesis of snapping scapula syndrome.

    Title Dna Synthesis Across an Abasic Lesion by Yeast Rev1 Dna Polymerase.
    Date
    Journal Journal of Molecular Biology
    Excerpt

    Abasic (apurinic/apyrimidinic) sites are among the most abundant DNA lesions in humans, and they present a strong block to replication. They are also highly mutagenic because when replicative DNA polymerases manage to insert a nucleotide opposite the lesion, they prefer to insert an A. Rev1, a member of Y-family DNA polymerases, does not obey the A-rule. This enzyme inserts a C opposite an abasic lesion with much greater catalytic efficiency than an A, G, or T. We present here the structure of yeast Rev1 in ternary complex with DNA containing an abasic lesion and with dCTP as the incoming nucleotide. The structure reveals a mechanism of synthesis across an abasic lesion that differs from that in other polymerases. The lesion is driven to an extrahelical position, and the incorporation of a C is mediated by an arginine (Arg324) that is conserved in all known orthologs of Rev1, including humans. The hydrophobic cavity that normally accommodates the unmodified G is instead filled with water molecules. Since Gs are especially prone to depurination through a spontaneous hydrolysis of the glycosidic bond, the ability of Rev1 to stabilize an abasic lesion in its active site and employ a surrogate arginine to incorporate a C provides a unique means for the "error-free" bypass of this noninstructional lesion.

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