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Natural Withanolides in the Treatment of Chronic Diseases. - Advances in experimental medicine and biology
Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000Â years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-ÎºB, JAK/STAT, AP-1, PPARÎ³, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.
Development and Evaluation of the American College of Surgeons NSQIP Pediatric Surgical Risk Calculator. - Journal of the American College of Surgeons
There is an increased desire of patients and families to be involved in the surgical decision making process. A surgeon's ability to provide patients and families with patient-specific estimates of postoperative complications is critical for shared decision making and informed consent. Surgeons can also use patient-specific risk estimates to decide whether or not to operate and what options to give to patients. Our objective was to develop and evaluate a publicly available risk estimation tool that would cover many common pediatric surgical procedures across all specialties.ACS NSQIP Pediatric standardized data from 67 hospitals were used to develop a risk estimation tool. Surgeons enter 18 preoperative variables (demographics, comorbidities, procedure) that are used in a logistic regression model to predict nine postoperative outcomes. A surgeon adjustment score is also incorporated to adjust for any additional risk not accounted for in the 18 risk factors.A pediatric surgical risk calculator was developed based on 181,353 cases covering 382 CPT codes across all specialties. It had excellent discrimination for mortality (c-statistic=0.98), morbidity (c-statistic=0.81), and 7 additional complications (c-statistics>0.77). The HL statistic and graphical representations also showed excellent calibration.The ACS NSQIP Pediatric Surgical Risk Calculator was developed using standardized and audited, multi-institutional data from the ACS NSQIP Pediatric and provides empirically derived, patient-specific postoperative risks. It can be used as a tool in the shared decision making process by providing clinicians, families, and patients with useful information for many of the most common operations performed on pediatric patients in the U.S.Copyright Â© 2016. Published by Elsevier Inc.
Frozen section analysis in the post-Bethesda era. - The Journal of surgical research
The utility of frozen section (FS) for indeterminate thyroid nodules is controversial. In 2009, the Bethesda System for Reporting Thyroid Cytopathology was established to further subcategorize indeterminate fine-needle aspiration results (follicular lesions, FL) into Bethesda category 3 (BC3) and Bethesda category 4 (BC4). We hypothesize that FS will have less utility in the evaluation of BC3 lesions when compared to BC4.A total of 479 patients who underwent thyroid lobectomy from January 2008 to July 2014 were retrospectively reviewed. Patients without appropriate Bethesda categorization were excluded. A total of 135 patients (65 FL, 45 BC3, 25 BC4) comprised the study groups. The sensitivity and specificity of FS within these three categories were determined.In the FL group, 6 of 65 patients were found to have thyroid cancer. Three were identified on frozen section (FS) resulting in a sensitivity and specificity of 50% and 100%, respectively. Thus, FS changed the operation in 3 of 65 cases (4.6%). In the BC3 group, 5 of 45 patients were found to have cancer. One was identified on FS resulting in a sensitivity and specificity of 20% and 100%, respectively. Thus, FS changed the operation in 1 of 45 patients (2.2%). In the BC4 group, 4 of 25 patients were found to have cancer. Two were identified on FS resulting in a sensitivity and specificity of 50% and 100% respectively. Thus, FS changed the operation in 2 of 25 patients (8%).There is improved utility of FS in BC 4 patients as 8% avoided reoperation. However, this benefit hinges on surgeon practice regarding the management of differentiated thyroid cancer >1Â cm and <4Â cm.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Increased Population Risk of AIP-related Acromegaly and Gigantism in Ireland. - Human mutation
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1000 Greater Belfast (both in NI) and 2094 Republic of Ireland (ROI) volunteers and in 116 acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) vs. non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1275-5000) years. tMRCA-based simulations predicted 432 (90-5175) current carriers, including 86 affected (18-1035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically-targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
IgG4-related disease causing facial nerve and optic nerve palsies: Case report and literature review. - American journal of otolaryngology
IgG4-related disease (IgG4-RD) is increasingly being recognized as an entity effecting the head and neck region. Although most commonly seen with salivary gland or paranasal sinus involvement, IgG4-RD may also involve the temporal bone and skull base. We report a rare care of a 61-year-old female with IgG4-RD presenting as synchronous lesions of the middle ear and middle cranial fossa with polyneuropathy of cranial nerves II, VI, and VII. Initial histopathological evaluation of her resected ear mass suggested a benign inflammatory process but no specific diagnosis. Her symptoms progressed over 10months prompting re-evaluation of the specimen and consideration of the IgG4-RD diagnosis. Key pathologic features included prominent lymphoplasmacytic population, storiform fibrosis, obliterative phlebitis, and IgG4 specific staining. The patient was treated with high-dose intravenous and oral steroids but was transitioned to azathioprine secondary to steroid-induced myopathy. Radiographic studies before and after treatment reveal marked improvement of the intracranial and extracranial disease. Correspondingly, her cranial neuropathies resolved. A high degree of clinical suspicion is necessary to diagnosis IgG4-RD. The diagnosis can be supported by elevated serum IgG, elevated IgG index, and pathognomonic histopathological findings. Primary treatment is with corticosteroids. However, immunotherapy using azathioprine or rituximab can be utilized in recurrent disease or patients with steroid intolerance.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Controversies in Surgical Management of Recalcitrant Enthesopathy of the Extensor Carpi Radialis Brevis. - The Journal of hand surgery
Enthesopathy of the extensor carpi radialis brevis, often referred to as "tennis elbow," is common and responds to nonsurgical treatment in 80% to 90% of patients within 1 year. For those who proceed with surgery, much remains unclear regarding the ideal treatment. This paper discusses controversies in surgical management of extensor carpi radialis brevis enthesopathy including clinical outcomes of open versus arthroscopic techniques, the relevance of concomitant pathology addressed arthroscopically, and avenues for assessing comparative cost data.Copyright Â© 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.
Is All Inflammation within Temporal Artery Biopsies Temporal Arteritis? - Human pathology
Temporal arteritis peaks during the 8th decade, affecting patients with frequent comorbidities who are especially prone to adverse effects of corticosteroid therapy. Perivascular inflammation involving small periadventitial vessels is not uncommon in otherwise normal temporal artery biopsies (TAB). As ischemic events occur in patients with non-temporal artery based inflammation, it has been recommended any vascular inflammation within temporal artery biopsies be treated with corticosteroids. We sought to determine whether such patients are at increased risk for temporal arteritis-like adverse events compared with age-matched controls devoid of inflammatory infiltrates. TABs without transmural temporal arteritic damage accessioned between 2002 and 2012 were reviewed for inflammation (>15 perivascular lymphocytes) involving small blood vessels and/or temporal artery adventitia. 278/343 (81%) of TABs were negative for transmural arteritis. Inflammation involving small vessels and/or temporal artery adventitia was present in 56 cases (20%). Age-matched controls were available for 39 cases. With a mean follow up of 5 years (range 1-11 years), 6/39 (15%) of patients developed stroke, cardiovascular events or died, compared with 7/39 (18%) of age matched controls. None of the patients with study-positive TAB had documented steroid therapy prior to, or after, temporal artery biopsy. Our results demonstrate that patients with inflammation involving only small vessels or temporal artery adventitia are not at increased risk for temporal arteritis- like adverse events, and suggest that the risks of protracted corticosteroid therapy in this elderly population likely exceed any potential benefits. We advise against diagnosing vasculitis in the absence of temporal arteritic damage.Copyright Â© 2016. Published by Elsevier Inc.
Evaluation of the ProPublica Surgeon Scorecard "Adjusted Complication Rate" Measure Specifications. - Annals of surgery
The ProPublica Surgeon Scorecard is the first nationwide, multispecialty public reporting of individual surgeon outcomes. However, ProPublica's use of a previously undescribed outcome measure (composite of in-hospital mortality or 30-day related readmission) and inclusion of only inpatients have been questioned. Our objectives were to (1) determine the proportion of cases excluded by ProPublica's specifications, (2) assess the proportion of inpatient complications excluded from ProPublica's measure, and (3) examine the validity of ProPublica's outcome measure by comparing performance on the measure to well-established postoperative outcome measures.Using ACS-NSQIP data (2012-2014) for 8 ProPublica procedures and for All Operations, the proportion of cases meeting all ProPublica inclusion criteria was determined. We assessed the proportion of complications occurring inpatient, and thus not considered by ProPublica's measure. Finally, we compared risk-adjusted performance based on ProPublica's measure specifications to established ACS-NSQIP outcome measure performance (eg, death/serious morbidity, mortality).ProPublica's inclusion criteria resulted in elimination of 82% of all operations from assessment (range: 42% for total knee arthroplasty to 96% for laparoscopic cholecystectomy). For all ProPublica operations combined, 84% of complications occur during inpatient hospitalization (range: 61% for TURP to 88% for total hip arthroplasty), and are thus missed by the ProPublica measure. Hospital-level performance on the ProPublica measure correlated weakly with established complication measures, but correlated strongly with readmission (R = 0.834, P < 0.001).ProPublica's outcome measure specifications exclude 82% of cases, miss 84% of postoperative complications, and correlate poorly with well-established postoperative outcomes. Thus, the validity of the ProPublica Surgeon Scorecard is questionable.
Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults. - Neuro-oncology
Astroblastomas (ABs) are rare glial tumors showing overlapping features with astrocytomas, ependymomas, and sometimes other glial neoplasms, and may be challenging to diagnose.We examined clinical, histopathological, and molecular features in 28 archival formalin-fixed, paraffin-embedded AB cases and performed survival analyses using Cox proportional hazards and Kaplan-Meier methods.Unlike ependymomas and angiocentric gliomas, ABs demonstrate abundant distinctive astroblastic pseudorosettes and are usually Olig2 immunopositive. They also frequently exhibit rhabdoid cells, multinucleated cells, and eosinophilic granular material. They retain immunoreactivity to alpha thalassemia/mental retardation syndrome X-linked, are immunonegative to isocitrate dehydrogenase-1 R132H mutation, and only occasionally show MGMT promoter hypermethylation differentiating them from many diffuse gliomas. Like pleomorphic xanthoastrocytoma, ganglioglioma, supratentorial pilocytic astrocytoma, and other predominantly cortical-based glial tumors, ABs often harbor the BRAF(V600E) mutation, present in 38% of cases tested (n = 21), further distinguishing those tumors from ependymomas and angiocentric gliomas. Factors correlating with longer patient survival included age less than 30 years, female gender, absent BRAF(V600E), and mitotic index less than 5 mitoses/10 high-power fields; however, only the latter was significant by Cox and Kaplan-Meier analyses (n = 24; P = .024 and .012, respectively). This mitotic cutoff is therefore currently the best criterion to stratify tumors into low-grade ABs and higher-grade anaplastic ABs.In addition to their own characteristic histological features, ABs share some molecular and histological findings with other, possibly ontologically related, cortical-based gliomas of mostly children and young adults. Importantly, the presence of BRAF(V600E) mutations in a subset of ABs suggests potential clinical utility of targeted anti-BRAF therapy.Â© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: email@example.com.
Diagnostic delay in psychogenic seizures and the association with anti-seizure medication trials. - Seizure
The average delay from first seizure to diagnosis of psychogenic non-epileptic seizures (PNES) is over 7 years. The reason for this delay is not well understood. We hypothesized that a perceived decrease in seizure frequency after starting an anti-seizure medication (ASM) may contribute to longer delays, but the frequency of such a response has not been well established.Time from onset to diagnosis, medication history and associated seizure frequency was acquired from the medical records of 297 consecutive patients with PNES diagnosed using video-electroencephalographic monitoring. Exponential regression was used to model the effect of medication trials and response on diagnostic delay.Mean diagnostic delay was 8.4 years (min 1 day, max 52 years). The robust average diagnostic delay was 2.8 years (95% CI: 2.2-3.5 years) based on an exponential model as 10 to the mean of log10 delay. Each ASM trial increased the robust average delay exponentially by at least one third of a year (Wald t=3.6, p=0.004). Response to ASM trials did not significantly change diagnostic delay (Wald t=-0.9, p=0.38).Although a response to ASMs was observed commonly in these patients with PNES, the presence of a response was not associated with longer time until definitive diagnosis. Instead, the number of ASMs tried was associated with a longer delay until diagnosis, suggesting that ASM trials were continued despite lack of response. These data support the guideline that patients with seizures should be referred to epilepsy care centers after failure of two medication trials.Copyright Â© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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