Urologist


Upper East Side
Ny Memorial Sloan Kettering
1275 York Ave
New York, NY 10065
646-422-4359
Locations and availability (1)

Publications & Research

Dr. Tal has contributed to 77 publications.
Title Persistent Erectile Dysfunction Following Radical Prostatectomy: the Association Between Nerve-sparing Status and the Prevalence and Chronology of Venous Leak.
Date November 2010
Journal The Journal of Sexual Medicine
Excerpt

. Failure to recover erectile function after radical prostatectomy (RP) may result from venous leak as a sequela of neuropraxia-induced erectile tissue damage. Venous leak portends a poor prognosis for erections recovery as well as phosphodiesterase type 5 inhibitor (PDE5i) response.

Title The Correlation Between Intracavernosal Pressure and Cavernosal Blood Oxygenation.
Date November 2010
Journal The Journal of Sexual Medicine
Excerpt

Given that regular nocturnal erections are physiological, it has been suggested that erections are pivotal to the maintenance of erectile tissue health. It has been postulated that a critical element to erectile tissue protection is cavernosal oxygenation. It is accepted that the corpora cavernosa are oxygenated fully during a rigid erection. However, it remains unknown what degree of penile rigidity is required to achieve cavernosal oxygenation at the arterial level.

Title Erectile Function Recovery Rate After Radical Prostatectomy: a Meta-analysis.
Date September 2010
Journal The Journal of Sexual Medicine
Excerpt

Erectile function recovery (EFR) rates after radical prostatectomy (RP) vary greatly based on a number of factors, such as erectile dysfunction (ED) definition, data acquisition means, time-point postsurgery, and population studied.

Title Peyronie's Disease Following Radical Prostatectomy: Incidence and Predictors.
Date September 2010
Journal The Journal of Sexual Medicine
Excerpt

Both prostate cancer and Peyronie's disease (PD) are prevalent in men after their fifth decade of life. The evidence to support or refute a link between radical prostatectomy (RP) and PD is limited.

Title Expression, Glycosylation, and Secretion of an Aspergillus Glucoamylase by Saccharomyces Cerevisiae.
Date July 2010
Journal Science (new York, N.y.)
Excerpt

A strain of Saccharomyces cerevisiae capable of simultaneous hydrolysis and fermentation of highly polymerized starch oligosaccharides was constructed. The Aspergillus awamori glucoamylase enzyme, form GAI, was expressed in Saccharomyces cerevisiae by means of the promoter and termination regions from a yeast enolase gene. Yeast transformed with plasmids containing an intron-free recombinant glucoamylase gene efficiently secreted glucoamylase into the medium, permitting growth of the transformants on starch as the sole carbon source. The natural leader sequence of the precursor of glucoamylase (preglucoamylase) was processed correctly by yeast, and the secreted enzyme was glycosylated through both N- and O-linkages at levels comparable to the native Aspergillus enzyme. The data provide evidence for the utility of yeast as an organism for the production, glycosylation, and secretion of heterologous proteins.

Title Preferential Use of Basilic Vein for Surgical Repair of Popliteal Aneurysms Via the Posterior Approach.
Date April 2010
Journal Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
Excerpt

The facedown position used for the posterior surgical approach to repair popliteal aneurysms limits access to the great saphenous vein. Using the basilic vein as the conduit of choice in five patients, we were able to harvest the vein conveniently and simultaneously with aneurysm exposure. On follow-up of 4 to 36 months, all grafts were functioning well.

Title The Psychosocial Impact of Penile Reconstructive Surgery for Congenital Penile Deviation.
Date April 2010
Journal The Journal of Sexual Medicine
Excerpt

A variety of surgical techniques to correct congenital penile deviation (CPD) have been described. Although surgical outcomes have been reported, the impact of this treatment on sexual relationship, confidence, self-esteem, and sexual function has never been established.

Title B-type Natriuretic Peptide Enhances Vasculogenesis by Promoting Number and Functional Properties of Early Endothelial Progenitor Cells.
Date October 2009
Journal Tissue Engineering. Part A
Excerpt

To test the hypothesis that B-type natriuretic peptide (BNP) acts as a potent vasculogenic agent by enhancing the number, proliferation, adhesion, and migration of endothelial progenitor cells (EPCs).

Title Systemic Administration of Radiation-potentiated Anti-angiogenic Gene Therapy Against Primary and Metastatic Cancer Based on Transcriptionally Controlled Hsv-tk.
Date October 2009
Journal Cancer Biology & Therapy
Excerpt

Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer. Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic antiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer. Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease.

Title Impact of Prostate Weight on Radical Prostatectomy Outcomes.
Date September 2009
Journal The Israel Medical Association Journal : Imaj
Excerpt

The management of localized prostate cancer in patients with large prostates is controversial.

Title Systemic Administration of a Conditionally Replicating Adenovirus, Targeted to Angiogenesis, Reduced Lung Metastases Burden in Cotton Rats.
Date April 2009
Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Excerpt

Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells.

Title Vasculogenic Erectile Dysfunction in Teenagers: a 5-year Multi-institutional Experience.
Date March 2009
Journal Bju International
Excerpt

To report the experience of three highly specialized centres in the vascular evaluation of erectile dysfunction (ED) in teenagers, as there is little information on this topic, and although clinical guidelines support the use of vascular studies in selected cases, our experience is that vascular evaluation aimed at diagnosing organic ED is uncommon in teenagers, and most are designated as having psychogenic ED.

Title Specific Induction of Tumor Neovasculature Death by Modified Murine Ppe-1 Promoter Armed with Hsv-tk.
Date February 2009
Journal Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology
Excerpt

One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers.

Title Endothelial-targeted Gene Transfer of Hypoxia-inducible Factor-1alpha Augments Ischemic Neovascularization Following Systemic Administration.
Date January 2009
Journal Molecular Therapy : the Journal of the American Society of Gene Therapy
Excerpt

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key regulator of the response to low oxygen levels and has been used for therapeutic angiogenesis. Various routes of administration have been used for delivering genes to the ischemic region including the intramuscular (IM) and intraarterial routes. When compared with these delivery methods, the intravenous (IV) route confers many advantages, including less invasiveness and lower cost. However, its use is hampered by the fact that it does not result in specific and robust tissue expression of the genes. Our aim was to determine the feasibility, safety, and therapeutic efficacy of systemic administration of adenoviral-mediated HIF-1alpha targeted to the endothelium. Using confocal microscopy and biodistribution studies we demonstrated that a modified murine preproendothelin-1 promoter (PPE1-3x) can target gene expression specifically to endothelial cells within ischemic muscle following systemic IV administration in C57BL/6 mice. Accordingly, an adenovirus expressing a PPE1-3x-regulated stabilized HIF-1alpha molecule, further activated by constitutive activation of its C-transactivation domain (C-TAD), was created. Systemic tail-vein administration of this adenovirus in a mouse hindlimb ischemia model resulted in enhanced blood perfusion, improved clinical outcome, and increased capillary density without systemic toxicity, in contrast to the profound systemic side effects and lack of therapeutic efficacy following cytomegalovirus (CMV)-regulated HIF-1alpha administration. Collectively, these data suggest that transcriptionally controlled systemic proangiogenic gene therapy is feasible, safe, and efficacious.

Title Activation of C-transactivation Domain is Essential for Optimal Hif-1 Alpha-mediated Transcriptional and Angiogenic Effects.
Date November 2008
Journal Microvascular Research
Excerpt

HIF-1 is a transcription factor that regulates genes involved in oxygen homeostasis. In normoxia, degradation of the HIF-1 alpha subunit is enabled by two prolyl hydroxylations at residues P402 and P564, while inactivation occurs through asparaginyl hydroxylation at residue N803 within its C-transactivation domain (C-TAD). For therapeutic angiogenesis purposes, HIF-1 alpha stabilization was previously achieved by either deleting its oxygen-dependent degradation domains, or introducing two proline point mutations at residues P402 and P564. We assessed the hypothesis that constitutive activation of HIF-1 alpha in addition to its stabilization would result in greater HIF-1 alpha transcriptional activity and angiogenic effects than mere stabilization of the molecule. For this, we constructed a Triple mutant HIF-1 alpha (TM), bearing mutations P402A and P564G N803A. Transient co-transfections with hypoxia-responsive element-luciferase construct revealed 2 to 2.5-fold increase in transcriptional activity of TM compared with P402A P564G double mutant and wild-type HIF-1 alpha. In-vitro angiogenesis assay using transfected human umbilical vein endothelial cells (HUVEC) showed that TM stimulated tube formation to a greater extent than both P402A P564G mutant and wild-type HIF-1 alpha. Accordingly, ELISA revealed that VEGF levels within the transfected HUVEC were about 10-fold greater with the TM. CONCLUSIONS: Constitutive activation of the HIF-1 alpha C-TAD, and not merely stabilization of the HIF-1 alpha molecule, is essential for optimal HIF-mediated transcriptional and angiogenic effects. This finding could have important implications for therapeutic angiogenesis using HIF-1 alpha.

Title Fk506 and Erectile Function Preservation in the Cavernous Nerve Injury Model: Optimal Dosing and Timing.
Date September 2008
Journal The Journal of Sexual Medicine
Excerpt

INTRODUCTION: The immunophilin-ligand FK506 has been shown to ameliorate erectile function and preserve cavernous nerve (CN) architecture in short-term-studies using rat models of CN injury. AIM: The aim of this series was to ascertain the optimal dose and timing of FK506 administration in this animal model. METHODS: Rats underwent bilateral CN crush and were treated with FK506 at different time points. There were control (C) and sham groups for each time point. Based on preliminary experiments, the CN-crush rats had no treatment (C) or either FK506 1 mg/kg (BL) or 3.2 mg/kg (BH) for 3 days prior to and the day of CN crush (PRE), on the day of and for 3 days following CN crush (POST) and for 3 days pre-, on the day of, and 3 days post-CN crush (PP). MAIN OUTCOME MEASUREMENTS: All animals had measurement of intracavernosal pressure/mean arterial blood pressure (ICP/MAP) ratios at 28 days post-CN crush. Structural analysis was conducted in the POST groups. Penile tissue was assessed for apoptosis with terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay and immunohistochemically for neural factors (growth associated protein 43 [GAP43], nerve growth factor [NGF], and neural nitric oxide synthase [nNOS]). The CN architecture was examined by transmission electron microscopy (TEM). RESULTS: Sham animals had an ICP/MAP ratio of 70%. Only the BH-POST group revealed an improved ICP/MAP ratio compared with C (50 +/- 9% vs. 32 +/- 8%, P < 0.01). nNOS staining was significantly restored reaching sham levels in BL-POST and BH-POST groups vs. C (P < 0.05). NGF and GAP43 staining displayed no significant differences between C and treatment groups (P < 0.05). Apoptosis was significantly reduced in BL-POST and BH-POST groups compared with C (16 +/- 4%, 21 +/- 9%, and 63 +/- 7%, P < 0.001). TEM exhibited preservation of CN architecture for BH-POST compared with C. CONCLUSION: These results suggest that short-term treatment with doses of FK506 higher than previously utilized preserves erectile function in the rat CN-injury model. Pretreatment appears to offer no advantage. However, FK506 administration just prior to CN injury and for a short-time post-injury achieves the best functional and structural preservation outcomes.

Title Antiangiogenic Systemic Gene Therapy Combined with Doxorubicin Administration Induced Caspase 8 and 9-mediated Apoptosis in Endothelial Cells and an Anti-metastasis Effect.
Date September 2008
Journal Cancer Gene Therapy
Excerpt

Ad-PPE-Fas-c is an adenovector that expresses Fas-c under the control of the modified pre-proendothelin-1 (PPE-1) promoter. Fas-c is a chimeric death receptor containing the extracellular portion of tumour necrosis factor 1 receptor (TNFR1) and the transmembrane and intracellular portion of Fas. We recently demonstrated that Ad-PPE-Fas-c induced Fas-receptor-mediated endothelial cell apoptosis. Previously, doxorubicin was shown to enhance Fas-receptor clustering and the induction of its cascade. Therefore, the goal of this work was to test whether doxorubicin augments the capacity of Ad-PPE-Fas-c to induce endothelial cell apoptosis and to elucidate whether either the death-receptor-mediated apoptotic cascade or the mitochondria-associated apoptotic cascade is involved in the combined treatment effect. We found that a combined treatment of Ad-PPE-Fas-c and doxorubicin synergistically induced a reduction in endothelial cell viability and apoptosis. z-IETD-FMK, a caspase-8 inhibitor, and z-LEHD-FMK, a caspase-9 inhibitor, significantly decreased apoptosis induced by the combined treatment. Systemically administered combined therapy significantly reduced the lung metastases burden (70%) in mice as compared to each treatment alone. Thus, a combined treatment of Ad-PPE-Fas-c gene therapy and chemotherapy may be effective in the treatment of metastatic diseases and both the Fas cascade and the mitochondria-associated cascade are essential for this effect.

Title Intracavernosal Injections and Fibrosis: Myth or Reality?
Date September 2008
Journal Bju International
Title The Effects of External Counter Pulsation Therapy on Circulating Endothelial Progenitor Cells in Patients with Angina Pectoris.
Date August 2008
Journal Cardiology
Excerpt

External counter pulsation therapy (ECPT) offers symptomatic relief and improves ischemia in patients with refractory angina pectoris. We aimed to determine the effects of ECPT on circulating endothelial progenitor cells (EPCs).

Title The Functional and Structural Consequences of Cavernous Nerve Injury Are Ameliorated by Sildenafil Citrate.
Date June 2008
Journal The Journal of Sexual Medicine
Excerpt

INTRODUCTION: Radical prostatectomy (RP) is associated with erectile dysfunction (ED). A single, placebo-controlled, human study has assessed the effects of regular sildenafil use after RP and demonstrated an increased chance of preservation of preoperative erectile function. Aim. This study was undertaken to define the effects of such a regimen in an animal model. METHODS: Using the cavernous nerve (CN) crush injury model, animals were divided into a number of groups: no CN injury (sham), bilateral CN injury exposed to either no sildenafil (control) or sildenafil at two doses (10 and 20 mg/kg) subcutaneously daily for three different durations (3, 10, 28 days). MAIN OUTCOME MEASURES: At these time points, CN electrical stimulation was used to assess erectile function by mean intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio. For the structural analyses, whole rat penes were harvested. Staining for Masson's trichrome was utilized to calculate the smooth muscle-collagen ratio. Immunohistochemical antibody staining was performed for endothelial (CD31 and eNOS) and neural (GAP43, NGF, and nNOS) factors and immunoblotting was performed to analyze the AKT/eNOS pathway. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay was used for the assessment of apoptotic indices and the CN architecture was evaluated by transmission electron microscopy (TEM). RESULTS: Erectile function was improved with sildenafil in a time- and dose-dependent fashion with maximization of erectile function recovery occurring with daily 20 mg/kg at the 28-day time point. Sildenafil use resulted in smooth muscle-collagen ratio protection and CD31 and eNOS expression preservation. Sildenafil reduced apoptotic indices significantly compared with control. Animals exposed to sildenafil had increased phosphorylation of akt and eNOS. Tem demonstrated distinct differences in architecture between control and sildenafil groups toward an increased amount of myelinized nerve fibers. CONCLUSIONS: Sildenafil use in the CN crush injury model preserves erectile function that appears to be mediated predominantly through preservation of smooth muscle content and endothelial function as well as through reduction in apoptosis.

Title The Impact of Shock Wave Therapy at Varied Energy and Dose Levels on Functional and Structural Changes in Erectile Tissue.
Date May 2008
Journal European Urology
Excerpt

OBJECTIVES: Only minimal literature exists on consequences of shock wave therapy (SWT) on erectile function in treatment of Peyronie's disease (PD). This study was undertaken to define SWT impact at varied energy/dose levels at different time points on functional and structural changes in erectile tissue. METHODS: In 45 rats 2000 shock waves (sw) at 2 BAR were applied to the penis weekly sorted by one, two, and three sessions (high-dose/energy level, HD-1, HD-2, HD-3). Each group was followed for 1, 7, or 28 d before measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Fifteen control animals (C1, C7, C28) underwent anesthesia alone. Another 15 animals were exposed to three SWT sessions applying 1000 sw at 1 BAR and analyzed identically (low-dose/energy level, LD-3-1, -7, -28). Terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling assay was used to define the apoptotic index (AI) and Masson's trichrome (MT) staining was prepared to evaluate smooth muscle-to-collagen ratios. RESULTS: ICP/MAP ratios for all C groups displayed a mean of 64%. All SWT groups demonstrated significantly reduced ICP/MAP ratios compared to their corresponding C groups (p<0.05). The LD-3 groups showed a trend toward improved ICP/MAP ratios. LD-3-28 demonstrated significant recovery compared to HD-3-28 (55+/-8% vs. 41+/-10%, p=0.004), but remained reduced compared to C28 (63+/-5%, p=0.03). No statistical differences were seen for MT staining in SWT groups compared to C (p>0.05). AIs for the LD-3 groups were significantly lower compared to the HD-3 groups (p<0.001), but all AIs were significantly increased compared to C groups (p<0.01). CONCLUSIONS: Overall, at both energy/dose levels, SWT resulted in a time- and treatment-dependent reduction of ICP/MAP ratios, which might be mediated partly through apoptosis and collagenization of corporal smooth muscle.

Title The Effect of Hyperbaric Oxygen Therapy on Erectile Function Recovery in a Rat Cavernous Nerve Injury Model.
Date April 2008
Journal The Journal of Sexual Medicine
Excerpt

INTRODUCTION: Cavernosal oxygenation appears to be important for preservation of erectile tissue health. Hyperbaric oxygen therapy (HBOT) has been shown to improve tissue oxygenation and has neuromodulatory effects. AIM: This study was designed to define the effects of HBOT on erectile function (EF) and cavernosal tissue in the rat cavernous nerve (CN) injury model. METHODS: Four groups of Sprague-Dawley rats were studied: rats with bilateral CN crush, HBOT treated (Crush+/HBOT+); bilateral CN-crush/no HBOT (C+/H-); no crush/no HBOT (C-/H-); and no crush/HBOT (C-/H+). HBOT was delivered daily for 90 minutes at three atmospheres for 10 days commencing the day of CN crush. MAIN OUTCOME MEASURES: Ten days after CN injury, the animals underwent CN stimulation measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios. Corporal tissue was harvested pre-sacrifice, and immunohistochemically stained for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), and cluster of differentiation molecule (CD31). Histologic analysis was performed for Masson's trichrome to assess the smooth muscle-collagen ratio. Terminal deoxynucleotidyl transferase Biotin-dUTP Nick End Labeling assay was used to define apoptotic indices (AIs). RESULTS: The C+/H- group had significantly lower ICP/MAP ratios compared with C-/H- rats, (31% vs. 70%, P < 0.001). C+/H+ rats had significantly higher ICP/MAP ratio recovery compared with the C+/H- group (55% vs. 31%, P = 0.005). NGF and eNOS staining densities were higher in C+/H+ rats compared with C+/H- rats (P < 0.05 and P < 0.001, respectively). No difference was seen in CD31 expression. Staining density for MT displayed a trend toward higher smooth muscle preservation after HBOT. AIs were significantly increased by HBOT (P < 0.05). CONCLUSION: HBOT following a CN injury improved EF preservation in this model, supporting the cavernosal oxygenation concept as protective mechanism for EF. The effects appear to be mediated via preservation of neurotrophic and endothelial factor expression.

Title Serum Tumor Markers May Predict Overall and Disease Specific Survival in Patients with Clinically Organ Confined Invasive Bladder Cancer.
Date January 2008
Journal The Journal of Urology
Excerpt

We assessed the value of increased levels of carcinoembryonic antigen, CA (cancer antigen) 125 and CA (carbohydrate antigen) 19-9 in predicting the survival of patients with clinically organ confined bladder cancer.

Title Predictors of Nocturia Quality of Life Before and Shortly After Prostatectomy.
Date October 2007
Journal Urology
Excerpt

To evaluate the predictors of nocturia-related quality of life and to assess the early effect of prostatectomy on these parameters in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

Title Management of Benign Ureteral Strictures Following Radical Cystectomy and Urinary Diversion for Bladder Cancer.
Date August 2007
Journal The Journal of Urology
Excerpt

Ureteral obstruction due to benign strictures is a significant complication of radical cystectomy and urinary diversion for bladder cancer that can lead to renal function loss and infection related morbidity. Treatment may be performed surgically or with minimally invasive techniques. We describe the 10-year experience at our department with various treatment modalities for post-cystectomy benign strictures.

Title Aup1p, a Yeast Mitochondrial Protein Phosphatase Homolog, is Required for Efficient Stationary Phase Mitophagy and Cell Survival.
Date April 2007
Journal The Journal of Biological Chemistry
Excerpt

Autophagy is a catabolic membrane-trafficking process that occurs in all eukaryotic cells and leads to the hydrolytic degradation of cytosolic material in the vacuolar or lysosomal lumen. Mitophagy, a selective form of autophagy targeting mitochondria, is poorly understood at present. Several recent reports suggest that mitophagy is a selective process that targets damaged mitochondria, whereas other studies imply a role for mitophagy in cell death processes. In a screen for protein phosphatase homologs that functionally interact with the autophagy-dedicated protein kinase Atg1p in yeast, we have identified Aup1p, encoded by Saccharomyces cerevisiae reading frame YCR079w. Aup1p is highly similar to a family of protein phosphatase homologs in animal cells that are predicted to localize to mitochondria based on sequence analysis. Interestingly, we found that Aup1p localizes to the mitochondrial intermembrane space and is required for efficient mitophagy in stationary phase cells. Viability studies demonstrate that Aup1p is required for efficient survival of cells in prolonged stationary phase cultures, implying a pro-survival role for mitophagy under our working conditions. Our data suggest that Aup1p may be part of a signal transduction mechanism that marks mitochondria for sequestration into autophagosomes.

Title Bilateral Cavernous Nerve Interposition Grafting During Radical Retropubic Prostatectomy: Memorial Sloan-kettering Cancer Center Experience.
Date February 2007
Journal The Journal of Urology
Excerpt

PURPOSE: Cavernous nerve graft is an option for men requiring bilateral cavernous nerve resection for cancer control during radical prostatectomy. We determined the success rate and identified determinants of success of bilateral cavernous nerve grafting following resection of the 2 nerves during radical prostatectomy in patients who were potent preoperatively. MATERIALS AND METHODS: We retrospectively reviewed the records of 44 consecutive patients who underwent bilateral nerve grafting from 1999 to 2004. Postoperative erectile function was defined as the achievement of erections satisfactory for intercourse with or without oral medication. We calculated cumulative erectile function recovery rates using Kaplan-Meier curves. The log rank test was used to compare variables affecting erectile function recovery with p <0.0083 considered significant after adjusting for the number of variables evaluated using the Bonferroni correction. RESULTS: The overall 5-year cumulative recovery of erectile function permitting penetration was 34% and the rate of consistent penetration was 11%. None of the analyzed variables were significantly associated with recovery of postoperative erectile function, including patient age (p = 0.3), incomplete bilateral cavernous nerve resection (p = 0.045), sural nerve grafts compared to genitofemoral or ilioinguinal nerves as donor sites (p = 0.067), post-radiation salvage radical prostatectomy (p = 0.15), neoadjuvant hormone therapy (p = 0.7) and comorbidities (p = 0.15) or medications (p = 0.4) affecting EF. CONCLUSIONS: Bilateral cavernous nerve grafts might be beneficial in select patients. A definitive answer awaits the performance of a multi-institutional, randomized, controlled trial.

Title Long-term Follow-up of Patients with Stage T1 High-grade Transitional Cell Carcinoma Managed by Bacille Calmette-guérin Immunotherapy.
Date February 2007
Journal Urology
Excerpt

To report the long-term outcome of patients with Stage T1 high-grade transitional cell carcinoma of the bladder treated initially by transurethral resection and adjuvant intravesical bacille Calmette-Guérin.

Title Adjunctive Nephrectomy at Post-chemotherapy Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer.
Date January 2007
Journal The Journal of Urology
Excerpt

PURPOSE: Patients with metastatic testicular cancer with residual masses encasing the renal hilum or kidney after platin based chemotherapy may require adjunctive nephrectomy to achieve complete resection at post-chemotherapy retroperitoneal lymph node dissection. We reviewed our experience with adjunctive nephrectomy to assess the impact on cancer control and renal function. MATERIALS AND METHODS: Of 647 post-chemotherapy retroperitoneal lymph node dissection procedures performed at our institution since 1989 adjunctive nephrectomy has been performed in 32 patients (5%). Patient information was obtained from a prospective database. Median followup was 31 months. RESULTS: Of the adjunctive nephrectomy procedures 17 (53%) were performed in high risk settings such as post-salvage chemotherapy, desperation retroperitoneal lymph node dissection, late relapse and reoperative retroperitoneal lymph node dissection. Disease was present in the adjunctive nephrectomy specimen in 21 patients (66%). Following post-chemotherapy retroperitoneal lymph node dissection 7 patients had disease relapse and 5-year disease-free survival was 66%. No case of relapse required substitution for cisplatin due to compromised renal function. Progression to chronic renal insufficiency occurred in 3 patients, 1 of whom required hemodialysis. The calculated creatinine clearance after adjunctive nephrectomy was more than 30% below the age specific norm in 14 patients (50%) and median patient age was 40 years. CONCLUSIONS: Adjunctive nephrectomy at post-chemotherapy retroperitoneal lymph node dissection is most frequently performed in patients with high risk features to ensure the completeness of resection. When indicated, adjunctive nephrectomy should be performed because residual cancer is frequently present and long-term cancer control can be achieved in 66% of patients. Although adjunctive nephrectomy did not interfere with subsequent chemotherapy, the renal reserve in these patients was substantially reduced in 50%, emphasizing the importance of preventative measures to preserve long-term renal function.

Title Adult Genitourinary Sarcoma: the 25-year Memorial Sloan-kettering Experience.
Date January 2007
Journal The Journal of Urology
Excerpt

Urological sarcomas are rare. We describe a continued single institutional experience during 25 years.

Title Significance of Intraoperative Ureteral Evaluation at Radical Cystectomy for Urothelial Cancer.
Date December 2006
Journal Cancer
Excerpt

BACKGROUND: Patients undergoing radical cystectomy (RC) for urothelial cancer are at increased risk for upper tract recurrence and anastomotic recurrence. In an attempt to reduce this recurrence risk, urologists employ intraoperative frozen sections to achieve an uninvolved ureteral margin. The utility of this surgical approach was examined. METHODS: A retrospective review identified 1330 bladder cancer patients from 1990 to 2004 with pathologic evaluation of their ureters. Using pathologic findings on permanent section as the reference standard, the accuracy of ureteral frozen sections was examined. Ureteral involvement and margin status were examined as risk factors for upper tract and anastomotic recurrence and overall survival. RESULTS: Of 2579 ureteral margins evaluated in 1330 patients, ureteral involvement was noted in 9% of ureters (13% of patients). The sensitivity and specificity of frozen section analyses were approximately 75% and 99%, respectively. The 5-year probability of anastomotic and upper tract recurrences was low: 2% and 13%, respectively. Evidence of involvement of the ureter or at the ureteral anastomotic margin was associated with higher likelihood of upper tract recurrence but not anastomotic recurrence or overall survival. Furthermore, sequential resection of ureters to reach a negative anastomotic ureteral margin did not eliminate the risk of anastomotic or upper tract recurrence. CONCLUSIONS: Patients with involved ureters and/or ureteral anastomotic margins have a higher risk of upper tract recurrence. However, the overall risk of recurrence is low and is not clearly associated with overall survival. The data do not support routine intraoperative frozen sections to assess ureteral involvement.

Title Endothelin B Receptor Antagonist Increases Preproendothelin-1 Transcription in Bovine Aortic Endothelial Cells and in Vivo.
Date November 2006
Journal Journal of Cardiovascular Pharmacology
Excerpt

Endothelin-1 (ET-1) receptor antagonists increase plasma immunoreactive ET-1 levels. However, their effect on preproendothelin-1 (PPE-1) mRNA levels is still controversial. Few studies have found a decrease in PPE-1 mRNA levels in endothelial cells treated with the nonselective ETA/B receptor antagonist, and others demonstrated that an ETB blockade by the selective antagonist BQ788 increases PPE-1 mRNA levels. We studied the effect of ETA and ETB selective receptor antagonists on PPE-1 transcription, both in vitro and in vivo. Endothelial cells, transiently transfected with PPE-1 luciferase plasmid, were treated with ET-1 receptor antagonists. Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control. In contrast, the ETA receptor antagonist, BQ123, had no effect on luciferase activity. Transgenic mice that express the luciferase gene under the control of PPE-1 promoter were treated with Bosentan. Luciferase activity, PPE-1 mRNA levels, and plasma immunoreactive ET-1 levels were increased by 1.6-fold to 2.0-fold in the Bosentan-treated group compared with the untreated, control group. ET-1 receptor blockade increased PPE-1 transcription both in vitro and in vivo. The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription.

Title Prolonged International Normalized Ratio Correlates with a Large Intravascular Fluid Balance After Major Abdominal Surgery.
Date August 2006
Journal Anesthesia and Analgesia
Excerpt

We performed a prospective randomized study of 32 patients who had undergone pancreaticoduodenectomy and did not receive blood during and after surgery. The patients were prospectively assigned to two groups related to fluid balance in the immediate postoperative period. Group 1 (14 patients) were maintained at a positive intravascular fluid balance of 0-1000 mL; Group 2 (18 patients) were maintained at a positive balance of 1000-2000 mL. Complete blood counts and coagulation tests (International Normalized Ratio) and activated partial thromboplastin time (aPTT) were performed at three time points: the day before surgery, on arrival at the postanesthesia care unit, and on leaving the postanesthesia care unit (16 h later). There were significant differences in International Normalized Ratio values between the groups with deterioration during the time they were in the postanesthesia care unit but not in aPTT values. Positive correlation was found between the amount of positive fluid balance and International Normalized Ratio prolongation, but not with aPTT, suggesting that restricted intravascular fluid balance is beneficial for preservation of coagulation after major abdominal surgery.

Title Sexual Health Issues in Men with Cancer.
Date July 2006
Journal Oncology (williston Park, N.y.)
Excerpt

While the cancer patient may be affected by sexual dysfunction throughout the entire course of the disease, sexual health is largely underevaluated and undertreated. Sexual problems should be anticipated and patients should be actively screened as they are unlikely to initiate discussion on sexual issues. Cancer-related sexual dysfunction may involve several components, and an understanding of the underlying etiologies is essential to tailoring the appropriate treatment to the individual patient. This article reviews the numerous factors potentially involved in male sexual dysfunction associated with a variety of cancers.

Title Dismembered Pyeloplasty in Children: a Review of 5 Years Single Center Experience.
Date June 2006
Journal International Journal of Urology : Official Journal of the Japanese Urological Association
Excerpt

Dismembered pyeloplasty is the treatment of choice for significant ureteropelvic junction obstruction in children. In the present study, we review our experience in 103 pediatric patients and present the clinical characteristics, the surgical treatment and its complications and the long term results.

Title Prediction of Extravesical Disease by Preoperative Serum Markers in Patients with Clinically Organ Confined Invasive Bladder Cancer.
Date May 2006
Journal The Journal of Urology
Excerpt

We assessed the value of preoperative levels of CEA, CA-125 or CA 19-9 in patients with clinically organ confined bladder cancer to predict pathological extravesical and/or node positive disease.

Title Sexual Function-preserving Cystectomy.
Date November 2005
Journal Urology
Title International, Multicenter, Randomized, Controlled Study Comparing Dynamically Individualized Versus Standard Treatment in Patients with Chronic Hepatitis C.
Date November 2005
Journal Journal of Hepatology
Excerpt

The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response.

Title Predictors of Erectile Function Improvement in Obstructive Sleep Apnea Patients with Long-term Cpap Treatment.
Date July 2005
Journal International Journal of Impotence Research
Excerpt

The long-term effect of treatment with continuous positive airway pressure (CPAP) on erectile function was assessed in 60 patients with obstructive sleep apnea syndrome (OSAS). Severity of OSAS was evaluated by respiratory disturbance index (RDI) and minimal oxygen saturation (OxiMin). Severity of erectile dysfunction (ED) was assessed with the five question International Index of Erectile Function (IIEF-5) before and after CPAP treatment. Subjects were categorized into three groups on the basis of the change in IIEF-5 score: Group 1, no change (n=37); Group 2, improvement from 10+/-5.65 to 19.1+/-5.7, P<0.01 (n=12); Group 3, worsening from 19.9+/-4.7 to 9.5+/-7.8, P<0.01 (n=11). Group 2 had significantly higher RDI and lower OxiMin than the other groups, and was also more compliant and satisfied with CPAP. Change in IIEF-5 with CPAP treatment was negatively correlated (Pearson coefficient) with OxiMin (r=-0.374), and positively correlated with adherence to CPAP treatment (r=0.689). In conclusion, in selected patients, CPAP treatment for OSAS may by itself have a positive effect on erectile function by improving respiration during sleep. Predictors of erectile improvement include high RDI, low OxiMin, and CPAP compliance.

Title The "b-bladder"-an Ileocolonic Neobladder with a Chimney: Surgical Technique and Long-term Results.
Date September 2004
Journal European Urology
Excerpt

A modified version of the "Le Bag" ileocolonic neobladder with a "Studer"-like ileal chimney (B-bladder) is presented. The surgical technique, perioperative complications, and long-term results, including cancer control and continence, are described.

Title Incidental Testicular Tumors in Infertile Men.
Date September 2004
Journal Fertility and Sterility
Excerpt

To characterize the population of infertile men with an incidental finding of testicular tumor diagnosed during infertility work-up and to describe their unique presentation and pathological findings.

Title External-internal Nephro-uretero-ileal Stents in Patients with an Ileal Conduit: Long-term Results.
Date June 2004
Journal Urology
Excerpt

To describe an improved technique for upper urinary tract drainage in patients with ureteroileal anastomotic stricture after radical cystectomy and urinary diversion to an ileal conduit, and to review our experience and long-term results.

Title Abdominal Compartment Syndrome: Urological Aspects.
Date May 2004
Journal Bju International
Excerpt

ACS is prevalent in various surgical conditions and in a large percentage of critically ill patients. Measuring the IAP is important in the early diagnosis of ACS and can be easily done by measuring the intravesical pressure. ACS adversely affects many organ systems; the pathogenesis of renal dysfunction is probably multifactorial, from a combination of reduced cardiac output, reduced GFR mediated by secretion of renin and angiotensin, aldosterone-mediated water reabsorption, increased renal parenchymal pressure and direct compression of the renal vein. Successful treatment requires a high index of suspicion, prompt recognition and early surgical abdominal decompression.

Title Metastatic Renal Carcinoid: Case Report and Review of the Literature.
Date August 2003
Journal Urology
Excerpt

Primary renal carcinoid tumor is a rare tumor of the kidney. Metastatic renal carcinoid tumor has not been described in the medical literature. We report a case of renal metastasis of a primary bronchial carcinoid tumor and review the literature about renal carcinoid tumors.

Title Empirical Management of Urinary Tract Infections Complicating Transrectal Ultrasound Guided Prostate Biopsy.
Date June 2003
Journal The Journal of Urology
Excerpt

Although urinary tract infection is a recognized complication of transrectal ultrasound guided prostate biopsy, to our knowledge there are no recommendations in the literature for its management. We studied the unique features of this infection and provide management recommendations.

Title Pitfalls and Complications with Laparoscopic Intraperitoneal Expanded Polytetrafluoroethylene Patch Repair of Postoperative Ventral Hernia.
Date May 2002
Journal Surgical Endoscopy
Excerpt

This study reviewed our experience with laparoscopic ventral postoperative (incisional) hernia repair.

Title Lidocaine Inhibits Secretion of Il-8 and Il-1beta and Stimulates Secretion of Il-1 Receptor Antagonist by Epithelial Cells.
Date May 2002
Journal Clinical and Experimental Immunology
Excerpt

Lidocaine and related local anaesthetics have been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms underlying their therapeutic effect are poorly defined. Intestinal epithelial cells play an important role in the mucosal inflammatory response that leads to tissue damage in UC via the secretion of pro-inflammatory cytokines and chemokines. The aim of this study was to evaluate the direct immunoregulatory effect of lidocaine on pro-inflammatory cytokine and chemokine secretion from intestinal epithelial cells. HT-29 and Caco-2 cell lines were used as a model system and treated with lidocaine and related drugs. The expression of IL-8, IL-1beta and the IL-1 receptor antagonist (RA) were assessed by ELISA and quantification of mRNA. In further experiments, the effect of lidocaine on the secretion of IL-8 from freshly isolated epithelial cells stimulated with TNFalpha was tested. Lidocaine, in therapeutic concentrations, inhibited the spontaneous and TNFalpha-stimulated secretion of IL-8 and IL-1beta from HT-29 and Caco-2 cell lines in a dose-dependent manner. Similarly, suppression of IL-8 secretion was noted in the freshly isolated epithelial cells. Other local anaesthetics, bupivacaine and amethocaine, had comparable effects. Lidocaine stimulated the secretion of the anti-inflammatory molecule IL-1 RA. Both the inhibitory and the stimulatory effects of lidocaine involved regulation of transcription. The results imply that the therapeutic effect of lidocaine may be mediated, at least in part, by its direct effects on epithelial cells to inhibit the secretion of proinflammatory molecules on one hand while triggering the secretion of anti-inflammatory mediators on the other.

Title Biochemical and Immunological Properties of Human Cardiac Troponin I Fragments.
Date August 2001
Journal Biotechnology and Applied Biochemistry
Excerpt

Cardiac troponin I (cTnI) is the inhibitory subunit of the troponin complex and is a biochemical marker for myocardial infarction (MI). It is found in human serum within 4-6 h following MI. One of us has shown [Morjana (1998) Biotechnol. Appl. Biochem. 28, 105-111] that MI patient serum TnI is cleaved at the N- and C-terminals and that the TnI fragments exist as a complex with tropinin C (TnC) and troponin T (TnT). In the present study, we have generated C-terminal truncated TnI fragments and studied their immunological and biochemical properties. Human recombinant TnI (rTnI) expressed in Escherichia coli is cleaved into a major fragment with a molecular mass of 17500 Da using CNBr. The major CNBr fragment contains the first 153 amino acids of human cTnI (TnI153). Cleavage of the rTnI with the endoproteinase Asp-N generates a smaller TnI fragment (TnI88, residues 6-96). TnI153 has higher immunological activity than that of rTnI and lower activity than that of TnI88, as judged by the Stratus II TnI Immunoassay. TnI153 exhibits biochemical and immunological properties similar to those of intact TnI. It binds TnC at a molar ratio of 1:1 and forms a ternary complex with TnC and TnT. TnC enhances the immunological activity of TnI153, but has little effect on the activity of TnI88. The TnI153-TnC complex exhibits higher immunological activity than rTnI-TnC and TnI88-TnC, and much higher activity than free rTnI, TnI153 and TnI88. The presence of TnT has no effect on the immunological activity of the TnI153-TnC complex, suggesting that the addition of TnT does not interfere with TnI153 recognition by TnI monoclonal antibodies. Free TnI153 and TnI88 degrade rapidly in human serum. TnC protects TnI153 from proteolytic degradation, but offers less protection for TnI88. The TnI88-TnC complex lost 80% of its immunological activity after incubation for 2 days in human serum at 37 degrees C. However, there was no loss in the immunological activity of the TnI153-TnC complex under the same conditions. A cTnI fragment (TnI80, residues 1-80), expressed in E. coli as a fusion protein, exhibits immunological activity and stability similar to that of TnI88.

Title Disaccharides Derived from Heparin or Heparan Sulfate Regulate Il-8 and Il-1 Beta Secretion by Intestinal Epithelial Cells.
Date March 2001
Journal Gastroenterology
Excerpt

Intestinal epithelial cells can produce cytokines and chemokines that play an important role in the mucosal immune response. Regulation of this secretion is important to prevent inflammatory tissue damage. Disaccharides derived from heparan sulfate and heparin have been shown to down-regulate inflammation in vivo. We tested the effect of such disaccharides on cytokine secretion by intestinal epithelial cells.

Title Follow-up of Sperm Concentration and Motility in Patients with Lymphoma.
Date October 2000
Journal Human Reproduction (oxford, England)
Excerpt

Lymphomas are a group of diseases, prevalent at reproductive age. Fertility is notoriously reduced among lymphoma patients. This study evaluates pre- and post-treatment semen concentration and motility, and factors associated with semen quality deterioration. We followed-up 33 patients with non-Hodgkin's lymphoma or with Hodgkin's disease during the years 1987-1997 who were referred for semen cryopreservation. Pretreatment semen analysis, and hormonal profile were recorded at diagnosis and at least 1 year after completion of the treatment, and compared. Medical records for disease type, disease stage and treatment protocols were related to long-term sperm outcome. Hormonal concentrations were not predictive of post-treatment sperm concentration. In patients with localized disease, initial sperm concentration and motility tended to be preserved, compared with patients with widespread disease (P: = 0. 016). In Hodgkin's disease patients, treatment with the adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) protocol was superior to the mechloretamine, vincristine, procarbazine and prednisone with ABV protocol regarding germinal toxicity (P: = 0.0008). The post-treatment sperm outcome was better in patients treated with local irradiation than in those who did not undergo irradiation (P: = 0.0027). No predictive tools for post-treatment fertility were found and, therefore, every patient with a lymphoma should have his semen cryopreserved at diagnosis.

Title Somatostatin Through Its Specific Receptor Inhibits Spontaneous and Tnf-alpha- and Bacteria-induced Il-8 and Il-1 Beta Secretion from Intestinal Epithelial Cells.
Date October 2000
Journal Journal of Immunology (baltimore, Md. : 1950)
Excerpt

Intestinal epithelial cells secrete proinflammatory cytokines and chemokines that are crucial in mucosal defense. However, this secretion must be tightly regulated, because uncontrolled secretion of proinflammatory mediators may lead to chronic inflammation and mucosal damage. The aim of this study was to determine whether somatostatin, secreted within the intestinal mucosa, regulates secretion of cytokines from intestinal epithelial cells. The spontaneous as well as TNF-alpha- and Salmonella-induced secretion of IL-8 and IL-1beta derived from intestinal cell lines Caco-2 and HT-29 was measured after treatment with somatostatin or its synthetic analogue, octreotide. Somatostatin, at physiological nanomolar concentrations, markedly inhibited the spontaneous and TNF-alpha-induced secretion of IL-8 and IL-1beta. This inhibition was dose dependent, reaching >90% blockage at 3 nM. Furthermore, somatostatin completely abrogated the increased secretion of IL-8 and IL-1beta after invasion by Salmonella. Octreotide, which mainly stimulates somatostatin receptor subtypes 2 and 5, affected the secretion of IL-8 and IL-1beta similarly, and the somatostatin antagonist cyclo-somatostatin completely blocked the somatostatin- and octreotide-induced inhibitory effects. This inhibition was correlated to a reduction of the mRNA concentrations of IL-8 and IL-1beta. No effect was noted regarding cell viability. These results indicate that somatostatin, by directly interacting with its specific receptors that are expressed on intestinal epithelial cells, down-regulates proinflammatory mediator secretion by a mechanism involving the regulation of transcription. These findings suggest that somatostatin plays an active role in regulating the mucosal inflammatory response of intestinal epithelial cells after physiological and pathophysiological stimulations such as bacterial invasion.

Title Human Gastrin: a Helicobacter Pylori--specific Growth Factor.
Date December 1999
Journal Gastroenterology
Excerpt

Helicobacter pylori resides within the gastric mucosa, a niche hostile to other microorganisms. Human gastrin levels are elevated after infection and return to normal after eradication. The aim of this study was to test the direct effect of gastrin on the growth of H. pylori.

Title Wrist and Forearm Postures and Motions During Typing.
Date August 1999
Journal Ergonomics
Excerpt

Awkward upper extremity postures and repetitive wrist motions have been identified by some studies as risk factors for upper extremity musculoskeletal disorders during keyboard work. However, accurate body postures and joint motions of typists typing on standardized workstations are not known. A laboratory study was conducted to continuously measure wrist and forearm postures and motions of 25 subjects while they typed for 10-15 min at a standard computer workstation adjusted to the subjects' anthropometry. Electrogoniometers continuously recorded wrist and forearm angles. Joint angular velocities and accelerations were calculated from the postural data. The results indicate that wrist and forearm postures during typing were sustained at non-neutral angles; mean wrist extension angle was 23.4 +/- 10.9 degrees on the left and 19.9 +/- 8.6 degrees on the right. Mean ulnar deviation was 14.7 +/- 10.1 degrees on the left and 18.6 +/- 5.8 degrees on the right. More than 73% of subjects typed with the left or right wrist in greater than 15 degrees extension and more than 20% typed with the left or right wrist in greater than 20 degrees ulnar deviation. Joint angles and motions while typing on an adjusted computer workstation were not predictable based on anthropometry or typing speed and varied widely between subjects. Wrist motions are rapid and are similar in magnitude to wrist motions of industrial workers performing jobs having a high risk for developing cumulative trauma disorders. The magnitude of the dynamic components suggests that wrist joint motions may need to be evaluated as a risk factor for musculoskeletal disorders during typing.

Title Improving the Binding Affinity of an Antibody Using Molecular Modeling and Site-directed Mutagenesis.
Date May 1999
Journal Protein Science : a Publication of the Protein Society
Excerpt

Activated Factor X releases F1.2, a 271-amino acid peptide, from the amino terminus of prothrombin during blood coagulation. A nine-amino acid peptide, C9 (DSDRAIEGR), corresponding to the carboxyl terminus of F1.2 was synthesized and used to produce a monoclonal antibody, TA1 (K(D)) 1.22 x 10(-6) M). To model the TA1 antibody, we entered the sequence information of the cloned TA1 Fv into the antibody modeling program, ABM, which combines homology methods, conformational search procedures, and energy screening and has proved to be a reliable and reproducible antibody modeling method. Using a novel protein fusion procedure, we expressed the C9 peptide fused to the carboxyl terminus of the PENI repressor protein from Bacillus licheniformis in Escherichia coli. We constructed fusion proteins containing alanine substitutions for each amino acid in the C9 epitope. Binding studies, using the C9 alanine mutants and TA1, and spatial constraints predicted by the modeled TA1 binding cleft enabled us to establish a plausible conformation for C9 complexed with TA1. Furthermore, based on binding results of conservative amino acid substitutions in C9 and mutations in the antibody, we were able to refine the complex model and identify antibody mutations that would improve binding affinity.

Title Three Cdg Operons Control Cellular Turnover of Cyclic Di-gmp in Acetobacter Xylinum: Genetic Organization and Occurrence of Conserved Domains in Isoenzymes.
Date September 1998
Journal Journal of Bacteriology
Excerpt

Cyclic di-GMP (c-di-GMP) is the specific nucleotide regulator of beta-1,4-glucan (cellulose) synthase in Acetobacter xylinum. The enzymes controlling turnover of c-di-GMP are diguanylate cyclase (DGC), which catalyzes its formation, and phosphodiesterase A (PDEA), which catalyzes its degradation. Following biochemical purification of DGC and PDEA, genes encoding isoforms of these enzymes have been isolated and found to be located on three distinct yet highly homologous operons for cyclic diguanylate, cdg1, cdg2, and cdg3. Within each cdg operon, a pdeA gene lies upstream of a dgc gene. cdg1 contains two additional flanking genes, cdg1a and cdg1d. cdg1a encodes a putative transcriptional activator, similar to AadR of Rhodopseudomonas palustris and FixK proteins of rhizobia. The deduced DGC and PDEA proteins have an identical motif structure of two lengthy domains in their C-terminal regions. These domains are also present in numerous bacterial proteins of undefined function. The N termini of the DGC and PDEA deduced proteins contain putative oxygen-sensing domains, based on similarity to domains on bacterial NifL and FixL proteins, respectively. Genetic disruption analyses demonstrated a physiological hierarchy among the cdg operons, such that cdg1 contributes 80% of cellular DGC and PDEA activities and cdg2 and cdg3 contribute 15 and 5%, respectively. Disruption of dgc genes markedly reduced in vivo cellulose production, demonstrating that c-di-GMP controls this process.

Title Expression and Equilibrium Denaturation of Cardiac Troponin I: Stabilization of a Folding Intermediate During Denaturation by Urea.
Date September 1998
Journal Biotechnology and Applied Biochemistry
Excerpt

Human cardiac troponin I has been expressed at high level in Escherichia coli as a fusion protein by using the expression vector Ptac114. The expressed protein forms primarily intracellular inclusion bodies that are solubilized in the presence of 8 M urea. The purified troponin I is recognized by anti-(human cardiac troponin I) monoclonal antibodies. Equilibrium denaturation of recombinant human troponin I and bovine troponin I is compared by monitoring changes in the protein's fluorescence and CD characteristics. At pH 7.5 the equilibrium denaturation of both proteins by urea occurs in two distinct steps involving at least three major conformational states: native, intermediate and fully denatured. The biphasic profile in the presence of urea is observed by both fluorescence and CD spectroscopy. In the intermediate state the native tertiary structure is largely disrupted and 40% of the secondary structure is conserved, as suggested by near-UV and far-UVCD respectively. Thermal denaturation of troponin I, as followed by fluorescence, shows a loss in the signal that is not reversible after heating to 90 degrees C. In the presence of a constant amount of urea (not greater than 0.5 M) the thermal denaturation becomes biphasic, suggesting the accumulation of an intermediate species that is stabilized by urea. The fluorescence of 1-anilino-8-naphthalenesulphonate produced on binding troponin I decreases in the presence of increasing concentrations of urea up to 3 M; at higher urea concentrations no further change in the remaining signal is observed. Kinetic studies show at least two phases of renaturation for troponin I previously denatured with 8 M urea, whereas only a single phase is detected for the renaturation process in the presence of 3 M urea. The results suggest the occurrence of a stable folding intermediate, the formation of which might be related to the two-domain architecture of troponin I.

Title Enzymatic Properties of Two Mutants of Reverse Transcriptase of Human Immunodeficiency Virus Type 1 (tyrosine 181-->isoleucine and Tyrosine 188-->leucine), Resistant to Nonnucleoside Inhibitors.
Date February 1995
Journal Aids Research and Human Retroviruses
Excerpt

A number of structurally diverse compounds have been shown to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus (HIV-1) reverse transcriptase (RT). The compounds can be grouped into two broad classes: nucleoside analogs and nonnucleoside inhibitors. The nonnucleoside inhibitors are quite specific for the polymerase activity of HIV-1 RT; they do not affect the polymerase activity of HIV-2 RT or the ribonuclease H (RNase H) activity of either HIV-1 RT or HIV-2 RT. Structural, biochemical, and genetic analyses showed that this group of inhibitors binds in a hydrophobic pocket near the polymerase active site. Mutations in amino acids that line this hydrophobic pocket, for example at tyrosine 181, tyrosine 188, or lysine 103, lead to enzymes that are resistant to the nonnucleoside inhibitors. We have investigated the enzymatic properties of two mutants of HIV-1 RT in which residues 181 and 188 were replaced by the corresponding amino acids in HIV-2 RT (tyrosine 181-->isoleucine and tyrosine 188-->leucine). The two tyrosine mutants closely resemble the wild-type HIV-1 RT in almost all the catalytic functions tested, including the heat stability, sensitivity of the DNA polymerase activity to inhibition by deoxynucleoside analogs, inhibition by the zinc chelator o-phenanthroline, and the Km values calculated for the DNA polymerase activity. There is, however, a slight difference in the effect of orthophenanthroline on the RNase H activity. In addition, there is a subtle disparity in the fidelity of DNA synthesis (analyzed by a mispair extension assay), thus indicating that these mutant RTs are not likely to confer any selective advantages or disadvantages to the variant virions over wild-type virus.

Title Hexaprenoid Hydroquinones, Novel Inhibitors of the Reverse Transcriptase of Human Immunodeficiency Virus Type 1.
Date April 1994
Journal Journal of Natural Products
Excerpt

Activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in the organic extract of the Red Sea sponge Toxiclona toxius was traced by us to five novel natural compounds, namely toxiusol [1], shaagrockol B [3], shaagrockol C [4], toxicol A [6], all of which are sulfated hexaprenoid hydroquinones, and toxicol B [7], the p-hydroquinone derivative of compound 6. The hydrolysis of the two sulfated compounds 1 and 4 yielded the corresponding hydroquinones designated as compounds 2 and 5, and further oxidation of compound 7 afforded the corresponding p-quinone derivative, compound 8. All compounds exhibited inhibitory activity of both DNA polymerizing functions of HIV-1 RT but failed to inhibit the RT-associated ribonuclease H activity. Toxiusol [1] was found to be the most potent inhibitor of the RNA-dependent DNA polymerase function (with 50% inhibition obtained at 1.5 microM and 95% inhibition at 4.6 microM), whereas the DNA-dependent DNA polymerase was significantly less sensitive to the inhibitor (with 50% inhibition achieved at 6.6 microM and 95% inhibition only at 41.6 microM). The fact that compound 1 discriminates between the two DNA polymerase activities of the RT offers new prospects for developing potent and highly specific anti-RT compounds, since the RNA-dependent DNA polymerase activity of RT is the only unique function that is not expressed at significant levels in uninfected mammalian cells.

Title 3,5,8-trihydroxy-4-quinolone, a Novel Natural Inhibitor of the Reverse Transcriptases of Human Immunodeficiency Viruses Type 1 and Type 2.
Date April 1994
Journal Archives of Biochemistry and Biophysics
Excerpt

The natural product of the Red Sea sponge Verongia sp., identified as 3,5,8-trihydroxy-4-quinolone, was found to be a potent inhibitor of the RNA-directed DNA synthesis of the reverse transcriptases (RTs) of human immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2, respectively). This inhibition was unaffected by the nature of the primer template used for DNA synthesis. The DNA-dependent DNA polymerase activity was inhibited to a lesser extent, whereas the ribonuclease H (RNase H) function associated with both HIV RTs was only slightly inhibited. The inhibition by the trihydroxyquinolone is reversible and noncompetitive with respect to both substrates--dTTP and the template primer poly(rA)n.oligo(dT)12-18. The inhibitor binds HIV-1 RT with a high affinity (Ki = 0.46 microM). This compound was shown also to inhibit the catalytic activities of the RT of murine leukemia virus, establishing the general inhibitory effect on retroviral RTs. Introductions of acetyl or methoxy moieties at positions with potential activity have generated three synthetic analogs of the natural compound. Only one analog, 5,8-dimethoxy-4-quinolone, exhibited an inhibition potency similar to that of the unmodified compound. Analysis of the three analogs has led us to the conclusion that the hydroxyl group at the ortho position to the carbonyl group in the pyridinone ring is a key structural element for the inhibitory activity. Thus, it could well be that the inhibitor interacts with the enzyme through a hydrogen bond of this hydroxyl group. We hope that the identification of the inhibitory site of the compound might be an important step toward the rational design of new potent anti-HIV RT drugs.

Title Specific Inhibition of the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 and the Chimeric Enzymes of Human Immunodeficiency Virus Type 1 and Type 2 by Nonnucleoside Inhibitors.
Date July 1993
Journal Antimicrobial Agents and Chemotherapy
Excerpt

We have studied the effects of four nonnucleoside inhibitors, including the novel natural product inhibitor calanolide A, on molecular chimeras containing complementary segments of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptases (RTs). All four compounds specifically inhibited the DNA polymerase activity of HIV-1 RT but had no apparent effect on the RNase H activity of this enzyme or on the DNA polymerase or RNase H activity of HIV-2 RT. Three of these compounds showed the generally expected patterns of resistance and susceptibility with the various chimeric RTs. However, the inhibition patterns of the chimeric RTs by calanolide A provided evidence that there is a segment between residues 94 and 157 in HIV-1 RT that is critical for inhibition. However, the data also suggest that there may be a second segment located between amino acids 225 and 427 in HIV-1 RT that is also important for specifying susceptibility to the drug.

Title The Effects of Cysteine Mutations on the Catalytic Activities of the Reverse Transcriptase of Human Immunodeficiency Virus Type-1.
Date August 1992
Journal The Journal of Biological Chemistry
Excerpt

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) has only 2 cysteine residues at positions 38 and 280. In order to investigate the role of these cysteines in the structure and function of the enzyme, we have previously modified each of the cysteines to serines employing site-directed mutagenesis. Two of the mutant forms of HIV-1 RT, the single mutant of cysteine 280 and a double mutant with both cysteines modified, were purified. In the present study we have compared the catalytic properties of the DNA-polymerizing and the ribonuclease H (RNase H) functions of the two mutant RTs to those of the native enzyme. The results indicate that the single mutant RT closely resembles the wild type enzyme in almost all the catalytic functions tested. The double cysteine mutant RT, on the other hand, exhibits several unique features. First, the specific activities of the RNA- and DNA-directed DNA synthesis are significantly lower than the corresponding activities of the other two enzymes. This probably results from the lower Vmax values exhibited by the double mutant RT, since the Km values calculated for all enzymes were similar. Second, the most outstanding differences are associated with the RNase H activity of the double mutant RT. The specific activity of RNase H is about 4-fold higher than the wild type and the single mutant RTs. Furthermore, the heat stability of the RNase H function of the double mutated RT is at least 15-fold higher than that of the other two RTs. The substantial resistance to heat denaturation is apparent only for the RNase H activity, since the DNA polymerizing function of the double mutant RT is as sensitive to heat denaturation as the other two proteins.

Title The Effects of Cysteine Mutations on the Reverse Transcriptases of Human Immunodeficiency Virus Types 1 and 2.
Date February 1992
Journal The Journal of Biological Chemistry
Excerpt

Chemical modification of HIV-1 and HIV-2 (human immunodeficiency virus, types 1 and 2) reverse transcriptases (RT) with three thiol reactive compounds selectively inhibits the RNase H function of the enzyme. HIV-1 RT has 2 cysteines (at positions 38 and 280); HIV-2 RT has 3 (38, 280, 445). Both of the cysteines in HIV-1 RT are in the polymerase domain. To investigate the role of the cysteines in the structure and function of the HIV RTs, we have converted each cysteine to serine and made combinations of the mutations. Since HIV-1 RT has alanine at position 445, we have also substituted alanine for serine at this position in HIV-2 RT. Neither of the single mutations in HIV-1 RT nor the double mutation mimics the effects of the chemical modification. The serine 280 mutation has little effect on either polymerase or RNase H; the serine 38 mutation affects both activities, as does the 38/280 double mutant. The 38 and 280 serine mutations in HIV-2 RT resemble the equivalent mutations in HIV-1 RT. Substitution of serine or alanine at position 445 (which lies in the RNase H domain) diminishes, but does not abolish, the RNase H activity of HIV-2 without affecting polymerase activity. The RNase H activity of a mutant HIV-1 RT with serine at position 280 is completely resistant to inactivation by the three thiol reactive compounds we tested, which demonstrates that cysteine 280 is the critical residue. We suggest that the reason the mutation (cysteine 280 to serine) does not mimic the chemical modification is because the chemical modification produces a greater change in the structure of the protein. We also suggest that position 280 lies at or near the important points of contact between the RNase H and polymerase domains, so that chemical modification of this position, which lies within the polymerase domain, distorts the RNase H domain.

Title Catalytic Properties of the Reverse Transcriptases of Human Immunodeficiency Viruses Type 1 and Type 2.
Date April 1991
Journal The Journal of Biological Chemistry
Excerpt

The enzyme reverse transcriptase (RT) is crucial in the early steps of the life cycle of retroviruses. We have expressed in bacteria the RTs from human immunodeficiency viruses (HIV) types 1 and 2 in order to study the structural-functional relationships of these two multifunctional enzymes that share a relatively high degree of amino acid sequence homology. For comparison purposes, we have analyzed several catalytic functions of both enzymes. The two HIV RTs show a high similarity in many aspects studied but exhibit profound differences in several other properties. For instance, the specific RNase H activity of HIV-2 RT is about 10 times lower than the corresponding activity of HIV-1 RT. There are also significant dissimilarities between some of the apparent Km values calculated for the DNA polymerizing functions of both enzymes. Furthermore, the heat stability of the DNA polymerizing activity of HIV-2 RT is about 15-fold higher than that of HIV-1 RT. On the other hand, the susceptibility of the RNase H activities of the two enzymes to heat inactivation was found to be similar. Other treatments also enable discrimination between the RNase H and DNA polymerizing catalytic properties of the two enzymes (although both reverse transcriptases respond similarily). Thus, the RNase H activity was inactivated by N-ethylmaleimide, suggesting the possible involvement of cysteine residues in performing this activity, whereas the DNA polymerizing functions of the two enzymes were fully resistant to this chemical modification. The zinc chelator 1,10-phenanthroline affected the DNA polymerase activities of both enzymes to a significantly higher extent than the RNase H activity. In all, the two HIV RTs were shown to be substantially different one from the other in several of their properties and also distinct from other RTs thus far studied.

Title Illimaquinone, a Selective Inhibitor of the Rnase H Activity of Human Immunodeficiency Virus Type 1 Reverse Transcriptase.
Date April 1991
Journal Antimicrobial Agents and Chemotherapy
Excerpt

We studied the effect of the natural marine substance illimaquinone on the catalytic activities of reverse transcriptase from human immunodeficiency virus type 1. Illimaquinone inhibited the RNase H activity of the enzyme at concentrations of 5 to 10 microgram/ml, whereas RNA-dependent DNA polymerase and DNA-dependent DNA polymerase activities were considerably less susceptible to this inhibition. Two synthetic derivatives of illimaquinone, in which the 6'-hydroxyl group at the ortho position to one of carbonyl groups of the quinone ring was modified, proved ineffective in inhibiting the human immunodeficiency virus type 1 reverse transcriptase RNase H function, suggesting involvement of the 6'-hydroxyl group in blocking the enzymatic activity.

Title Mutational Analysis of the Dna Polymerase and Ribonuclease H Activities of Human Immunodeficiency Virus Type 2 Reverse Transcriptase Expressed in Escherichia Coli.
Date January 1991
Journal Virology
Excerpt

We have constructed a plasmid that, when introduced into Escherichia coli, induces the synthesis of large quantities of a polypeptide with an apparent molecular weight of 68 kDa. The HIV-2 reverse transcriptase (RT) made in E. coli is soluble in bacterial extracts and possesses both RNA-dependent DNA polymerase and ribonuclease H (RNase H) activities typical of retroviral RTs. The HIV-2 RT expression clone was used to generate mutations in HIV-2 RT. There is a strong correlation between the effects of individual mutations on the DNA polymerase and RNase H activities. Mutations that profoundly affect the two catalytic functions are not clustered in any particular region of the polypeptide. Those few mutations that selectively affect either the RNase H or the DNA polymerase suggest that, like other retroviral RTs, the DNA polymerase is associated with the amino-terminal portion of HIV-2 RT and the RNase H with the carboxy-terminal portion. Genetically, the HIV-2 RT resembles the HIV-1 RT more closely than it resembles Moloney murine leukemia virus RT. The two catalytic functions of Moloney murine leukemia virus RT can be separately expressed in active form by molecular cloning; those of HIV-1 and HIV-2 RT cannot.

Title Human Csf-1: Gene Structure and Alternative Splicing of Mrna Precursors.
Date January 1988
Journal The Embo Journal
Excerpt

Bone marrow progenitor cells differentiate into mononuclear phagocytes in the presence of colony stimulating factor-1 (CSF-1). Characterization of the human CSF-1 gene shows that it contains 10 exons and 9 introns, which span 20 kb. Analysis of multiple CSF-1 transcripts demonstrates that alternate use of exon 6 splice acceptor sites and 3' noncoding sequence exons occurs. These alternatively spliced transcripts can encode either a 224 or a 522 amino acid CSF-1. Implications of differential splicing for the production and function of CSF-1 are discussed.

Title Human Monoclonal Antibodies Derived from Lymph Nodes of a Patient with Breast Carcinoma React with Mumtv Polypeptides.
Date February 1987
Journal Cancer
Excerpt

Nine human hybridoma cell lines were established from a fusion of axillary lymph node lymphocytes of a patient with breast ductal carcinoma with a human lymphoblastoid cell line. The human hybridoma nature of the fusion products was confirmed by chromosomal analysis and HLA typing. The hybridomas are stable over a year of growth, and can be frozen, thawed and regrown. The carcinoma cells of the patient harbor mouse mammary tumor virus (MuMTV) cross-reacting antigens. The patient's serum and the purified monoclonal antibodies reacted with MuMTV polypeptides. Radioimmunoprecipitation studies using labeled MuMTV confirmed the binding of the patient's serum to the viral proteins. None of the control immunoglobulins reacted with the virus. No binding of the hybridoma immunoglobulins was observed with two other retroviruses (avian myeloblastosis virus and simian sarcoma virus). The ligand binding characteristics of the monoclonal antibodies suggest binding to epitopes on the various structural virus polypeptides. These monoclonal antibodies may serve as a probe to analyze the MuMTV-human breast carcinoma relationship.

Title Isolation and Fractionation of Ferritin from Human Term Placenta--a Source for Human Isoferritins.
Date June 1985
Journal Analytical Biochemistry
Excerpt

A method for isolating ferritin from human term placenta was described. The placenta was homogenized in water containing protease inhibitor and heated at 70 degrees C. The ferritin was precipitated with ammonium sulfate at pH 5.2 and purified by repeated cycles of ultracentrifugation and molecular sieve chromatography through Sepharose 4B columns. Isoelectric focusing revealed a broad spectrum of isoferritins. These isoferritins were separated by ion-exchange chromatography on Sephadex A-25 at pH 7.5 and stepwise elution with increasing concentrations of NaCl. By this method "basic," "intermediate," and "acid" isoferritins were separated. The most basic placental isoferritin was shown to be identical to splenic ferritin by isoelectric focusing, subunit analysis, and fluorescent ELISA. The acid placental isoferritin had similar characteristics to heart-type ferritin. It was suggested that the easily available placental tissue could serve as a source for human isoferritins in research and in clinical assays.

Title Molecular Cloning and Characterization of the Glucoamylase Gene of Aspergillus Awamori.
Date January 1985
Journal Molecular and Cellular Biology
Excerpt

The filamentous ascomycete Aspergillus awamori secretes large amounts of glucoamylase upon growth in medium containing starch, glucose, or a variety of hexose sugars and sugar polymers. We examined the mechanism of this carbon source-dependent regulation of glucoamylase accumulation and found a several hundredfold increase in glucoamylase mRNA in cells grown on an inducing substrate, starch, relative to cells grown on a noninducing substrate, xylose. We postulate that induction of glucoamylase synthesis is regulated transcriptionally. Comparing total mRNA from cells grown on starch and xylose, we were able to identify an inducible 2.3-kilobase mRNA-encoding glucoamylase. The glucoamylase mRNA was purified and used to identify a molecularly cloned 3.4-kilobase EcoRI fragment containing the A. awamori glucoamylase gene. Comparison of the nucleotide sequence of the 3.4-kilobase EcoRI fragment with that of the glucoamylase I mRNA (as determined from molecularly cloned cDNA) revealed the existence of four intervening sequences within the glucoamylase gene. The 5' end of the glucoamylase mRNA was mapped to several locations within a region -52 to -73 nucleotides from the translational start. Sequence and structural features of the glucoamylase gene of the filamentous ascomycete A. awamori were examined and compared with those reported in genes of other eucaryotes.

Title Biochemical Parameters of Vitamin D Nutriture in Old People in Jerusalem.
Date May 1979
Journal Nutrition and Metabolism
Excerpt

Serum 25-hydroxycholecalciferol (25[OH]D3) levels and other parameters of vitamin D nutriture were examined in 58 subjects aged 70 or more, living in Jerusalem. They were compared with those of 54 young adults living in the same neighbourhood. No evidence was obtained of a lower level of vitamin D nutriture in the elderly compared to younger adults. Serum 25 (OH)D3 of the elderly adults was 18.4 (SEM: 1.4) ng/ml and in the younger adults, 17.8 (1.0) ng/ml. There was no seasonal variation in serum 25(OH)D3, nor could a strong association be found between reported vitamin D intake nor with exposure to sunshine. There was a negative correlation between serum alkaline phosphatase and the calcium-phosphorus product in serum. High values of alkaline phosphatase were associated with reported low exposure to sunlight and, in elderly persons, with a reported low consumption of vitamin D.

Title [biochemical Parameters of Vitamin D Nutrition in Institutionalized Old People].
Date May 1979
Journal Harefuah
Title Vitamin A Deficiency Stimulated Phosphatase Activity in Epiphyseal Chick Cartilage.
Date October 1974
Journal Calcified Tissue Research
Title Effect of Vitamin A Deficiency on Several Bone Parameters in Chicks.
Date August 1974
Journal International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Für Vitamin- Und Ernährungsforschung. Journal International De Vitaminologie Et De Nutrition
Title Phosphatase Activity in Epiphyseal Cartilage of the Chicken (gallus Gallus).
Date February 1974
Journal Comparative Biochemistry and Physiology. B, Comparative Biochemistry
Title Lipids in Vitamin A Deficient Chicken Cartilage and New Bone.
Date May 1970
Journal Internationale Zeitschrift Für Vitaminforschung. Internătional Journal of Vitamin Research. Journal International De Vitaminologie
Title Effects of Hypoxia-inducible Factor-1alpha Overexpression in Pregnant Mice: Possible Implications for Preeclampsia and Intrauterine Growth Restriction.
Date
Journal The American Journal of Pathology
Excerpt

Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor-1 (sFLT-1), a central factor in preeclampsia and IUGR pathogenesis. Our objective was to investigate the effects of HIF-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased placental weights, and histopathological placental abnormalities compared with control mice. Glomerular endotheliosis, the hallmark lesion of preeclampsia, was demonstrated in the kidneys of these mice relative to the normal histology in control mice. Moreover, liver enzyme levels were significantly elevated, whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV-HIF mice compared with controls. Blood smears confirmed microangiopathic hemolytic anemia in CMV-HIF mice, consistent with HELLP (hemolysis, elevated liver enzymes, and low platelets)-like syndrome. CMV-HIF mice showed elevation in serum sFLT-1 and soluble endoglin, providing a mechanistic explanation for the observations. Collectively, our results suggest a possible role for HIF-1α in the pathogenesis of both preeclampsia and IUGR.

Title Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia As Distinct Pathologies.
Date
Journal Plos One
Excerpt

The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1α stability is controlled by O(2)-sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L-PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development.

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