129 Route 37 West Suite 3
Toms River NJ 08755
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Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. - Nature communications
It has been hypothesized that G-quadruplexes can sequester the 3' end of the telomere and prevent it from being extended by telomerase. Here we purify and characterize stable, conformationally homogenous human telomeric G-quadruplexes, and demonstrate that human telomerase is able to extend parallel, intermolecular conformations in vitro. These G-quadruplexes align correctly with the RNA template of telomerase, demonstrating that at least partial G-quadruplex resolution is required. A highly purified preparation of human telomerase retains this extension ability, establishing that the core telomerase enzyme complex is sufficient for partial G-quadruplex resolution and extension. The parallel-specific G-quadruplex ligand N-methyl mesoporphyrin IX (NMM) causes an increase in telomeric G-quadruplexes, and we show that telomerase colocalizes with a subset of telomeric G-quadruplexes in vivo. The ability of telomerase to partially unwind, extend and localize to these structures implies that parallel telomeric G-quadruplexes may play an important biological role.
Long-term outcomes after surgical repair of complete atrioventricular septal defect. - The Journal of thoracic and cardiovascular surgery
Survival after surgical repair for complete atrioventricular septal defect (CAVSD) has improved, but patients are at risk for reoperation to address left atrioventricular valve regurgitation and left ventricular outflow tract obstruction. We examined the long-term survival, need for reoperation, and associated risk factors after CAVSD repair at our institution.Between 1974 and 2000, a total of 198 patients underwent surgical repair for CAVSD. Of these, 178 patients survived to hospital discharge, of whom 153 (86%) had available follow-up data at a median postoperative time point of 17.2 years (range: 2 months to 38.1 years).Overall perioperative mortality was 10.1%, with a significant decrease to 2.9% in the late surgical era: 1991 to 2000 (PÂ <Â .001). The overall estimated survival for the entire cohort was 85% at 10 years, 82% at 20 years, and 71% at 30 years after initial CAVSD repair. Requiring a reoperation after initial CAVSD repair was a risk factor for late mortality (PÂ =Â .04). The estimated freedom from reoperation was 88% at 10 years, 83% at 20 years, and 78% at 30 years after initial CAVSD repair. Indications for reoperation included left atrioventricular valve regurgitation in 14 patients (7.1%) and left ventricular outflow obstruction in 7 patients (3.5%).Long-term survival after repair of CAVSD remains good. However, the need for reoperation is common and affects long-term survival after CAVSD repair.Copyright Â© 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
The Impact of Obesity on Postoperative Outcomes in Adults with Congenital Heart Disease Undergoing Pulmonary Valve Replacement. - Congenital heart disease
The impact of obesity on surgical morbidity in adults with congenital heart disease is currently unknown. The aim of our study was to investigate the impact of obesity on postoperative outcomes in adults with congenital heart disease undergoing reoperation for pulmonary valve replacement.A retrospective analysis was performed assessing the influence of obesity on surgical outcomes. Obesity was defined as a body mass index â‰¥30â€‰kg/m(2) .The mean body mass index of the cohort was 25.9 Â± 6.9â€‰kg/m(2) . The cohort included 71 patients with 17 patients (24%) being obese. There was no postoperative mortality. Obese patients had a longer hospital length of stay (6.6 vs. 4.7 days; P < .001) and increased incidence of postoperative arrhythmias (29% vs. 5.6%; P = .003) compared with nonobese patients. Multivariable analysis performed using logistic regression with backwards elimination demonstrated obesity was independently associated with hospital length of stay >5 days (odds ratio [OR] = 5.2; 95% confidence interval [CI]: 1.5-18.2, P = .01) and with increased postoperative arrhythmias (OR = 4.2; 95% CI: 1.7-40, P < .01).Obesity is associated with increased morbidity in adults with congenital heart disease undergoing pulmonary valve replacement, including longer hospitalization and higher risk for postoperative arrhythmias.Â© 2015 Wiley Periodicals, Inc.
Takeuchi repair of anomalous left coronary artery from the pulmonary artery. - Journal of cardiovascular computed tomography
Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare form of congenital heart disease that has been successfully palliated for decades. Prior to coronary reimplantation, the Takeuchi repair was the most common operative palliation. The Takeuchi repair is still seen today at less experienced congenital centers or when reimplantation is not possible. Patients who have had the Takeuchi repair are at risk of having subsequent complications related to this repair. Unfortunately, due to the surgical rarity, the post surgical anatomy is often poorly understood by cardiologists leading to inadequate risk factor assessment and compromised patient care. Coronary computed tomography angiography is a useful imaging modality to follow patients who have had the Takeuchi repair.Copyright Â© 2015 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. - Science (New York, N.Y.)
Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERT messenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and UC patient outcome, we find that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in two independent UC patient cohorts (n = 35; n = 87). These results suggest that high telomerase activity may be a better marker of aggressive UC tumors than TERT promoter mutations alone.Copyright Â© 2015, American Association for the Advancement of Science.
Circulating and urinary microRNA profile in focal segmental glomerulosclerosis: a pilot study. - European journal of clinical investigation
MicroRNAs (miRNAs) are noncoding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease.Exosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n = 16) or MCD (n = 5) and healthy controls (n = 5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT-PCR was used to validate the findings from the array.Comparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were downregulated in both plasma and urine samples of patients with FSGS compared to those with MCD. Plasma levels of miR-30b, miR-30c, miR-34b, miR-34c and miR-342 and urine levels of mir-1225-5p were upregulated in patients with MCD compared to patients with FSGS and controls (P < 0.001). Urinary levels of mir-1915 and miR-663 were downregulated in patients with FSGS compared to MCD and controls (P < 0.001), whereas the urinary levels of miR-155 were upregulated in patients with FSGS when compared to patients with MCD and controls (P < 0.005).Patients with FSGS and MCD have a unique circulating and urinary miRNA profile. The diagnostic and prognostic potential of miRNAs in FSGS and MCD warrants further studies.Â© 2015 Stichting European Society for Clinical Investigation Journal Foundation.
Tricuspid repair at pulmonary valve replacement does not alter outcomes in tetralogy of Fallot. - The Annals of thoracic surgery
Chronic pulmonary regurgitation after tetralogy of Fallot repair often leads to progressive right ventricle dilation, dysfunction, and frequently, pulmonary valve replacement. For those with significant tricuspid regurgitation at the time of pulmonary valve replacement, it is unknown whether concomitant tricuspid valve repair improves postoperative outcomes.This is a retrospective review of patients after tetralogy of Fallot repair who underwent pulmonary valve replacement between 1999 and 2012. Preoperative and postoperative echocardiograms were assessed for tricuspid regurgitation (vena contracta) and right ventricular size and function (Tomtec software).Sixty-two patients underwent pulmonary valve replacement. Thirty-six (58%) had greater than or equal to moderate tricuspid regurgitation on preoperative echocardiogram. Significant predictors were not identified. Of the 36, 18 (50%) underwent concomitant tricuspid valve repair at the time of pulmonary valve replacement. After surgery, there was a significant reduction in the degree of tricuspid regurgitation (p < 0.001) and measures of right ventricular size (p < 0.05) in both cohorts. Between surgical groups, there was no statistical difference in the grade of tricuspid regurgitation (pÂ = 0.47) or measures of right ventricular size (p > 0.4) at 6-month follow-up.Tricuspid regurgitation is a common finding in repaired tetralogy of Fallot, although risk factors for its development remain unclear. After pulmonary valve replacement with or without tricuspid valve repair there is significant improvement in the degree of tricuspid regurgitation and right ventricular size. Finally, 6 months after pulmonary valve replacement there were no statistical differences between those patients undergoing concomitant tricuspid valve repair and those undergoing pulmonary valve replacements alone.Copyright Â© 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Two-step mechanism involving active-site conformational changes regulates human telomerase DNA binding. - The Biochemical journal
The ribonucleoprotein enzyme telomerase maintains telomeres and is essential for cellular immortality in most cancers. Insight into the telomerase mechanism can be gained from syndromes such as dyskeratosis congenita, in which mutation of telomerase components manifests in telomere dysfunction. We carried out detailed kinetic and thermodynamic analyses of wild-type telomerase and two disease-associated mutations in the reverse transcriptase domain. Differences in dissociation rates between primers with different 3' ends were independent of DNA affinities, revealing that initial binding of telomerase to telomeric DNA occurs through a previously undescribed two-step mechanism involving enzyme conformational changes. Both mutations affected DNA binding, but through different mechanisms: P704S specifically affected protein conformational changes during DNA binding, whereas R865H showed defects in binding to the 3' region of the DNA. To gain further insight at the structural level, we generated the first homology model of the human telomerase reverse transcriptase domain; the positions of P704S and R865H corroborate their observed mechanistic defects, providing validation for the structural model. Our data reveal the importance of protein interactions with the 3' end of telomeric DNA and the role of protein conformational change in telomerase DNA binding, and highlight naturally occurring disease mutations as a rich source of mechanistic insight.
Quantitative Assessment of Right Ventricular Volumes and Ejection Fraction in Patients with Left Ventricular Systolic Dysfunction by Real Time Three-Dimensional Echocardiography versus Cardiac Magnetic Resonance Imaging. - Echocardiography (Mount Kisco, N.Y.)
The aim of this study was to assess the accuracy and reproducibility of real time three-dimensional echocardiographic (RT3DE) for the determination of right ventricular (RV) volumes and function in patients with left ventricular (LV) systolic dysfunction.Dedicated RT3DE was prospectively performed to assess RV volumes and EF in patients with LV systolic function identified on routine clinical cardiac magnetic resonance (CMR) imaging. RV end-diastolic volume (RV EDV), RV end-systolic volume (RV ESV), and RV EF were obtained using an offline analysis software (TomTec) by two observers blinded to CMR results. In this population of 27 patients with LV systolic dysfunction with a mean LV EF of 36Â Â±Â 12%, RV RT3DE dataset could be assessed in 27 of 30 patients (90%). High correlation was noted between RT3DE and CMR for RV EDV, ESV, and EF (rÂ =Â 0.90, 0.89, and 0.77, respectively). RV EDV was lower by RT3DE as compared to CMR (129Â Â±Â 52 vs. 142Â Â±Â 53Â mL, PÂ =Â 0.005) while there was no significant difference in RV ESV and RV EF (71Â Â±Â 37 vs. 77Â Â±Â 45Â mL, PÂ =Â 0.146; 45Â Â±Â 11 vs. 48Â Â±Â 13%, PÂ =Â 0.134, respectively). The intraclass correlation coefficient ranged from 0.94 to 0.94 between measurements and from 0.84 to 0.96 between observers.Overall, RV volumes and EF assessed by RT3DE correlate well with CMR measurements in patients with LV dysfunction. RT3DE may be used as a more widely available and versatile alternative to CMR for the quantitative assessment of RV size and function in patients with LV dysfunction.Â© 2014, Wiley Periodicals, Inc.
Metabolically Stable tert-Butyl Replacement. - ACS medicinal chemistry letters
Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp(3) C-Hs from a tert-butyl group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-containing analogues had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-containing counterparts.
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129 Route 37 West Suite 3 Toms River, NJ 08755
20 Hospital Dr Suite 17A
1163 Highway 37 Suite B2