Pathologic manifestations of levamisole-adulterated cocaine exposure.

UnlabelledRheumatic manifestations of cocaine have been well described, but more recently, a dramatic increase in the levamisole-adulterated cocaine supply in the United States has disclosed unique pathologic consequences that are distinct from pure cocaine use. Most notably, patients show skin lesions and renal dysfunction in the setting of extremely high perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). Unexpectedly, antibodies to myeloperoxidase, the typical target of p-ANCA, are relatively low if at all present. This discrepancy is due to the fact that p-ANCA seen in association with levamisole-adulterated cocaine exposure is often directed against atypical p-ANCA-associated antigens within the neutrophil granules such as human neutrophil elastase, lactoferrin, and cathepsin G. Biopsies of the skin lesions reveal leukocytoclastic vasculitis often involving both superficial and deep dermal vessels. Renal injury most typically manifests as crescentic and necrotizing pauci-immune glomerulonephritis. In this review, the manifestations of levamisole-adulterated cocaine-induced vasculitis are discussed with an emphasis on the typical histomorphologic findings seen on biopsy.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1764738711370019

Pauci-immune glomerulonephritis in individuals with disease associated with levamisole-adulterated cocaine: a series of 4 cases.

Exposure to levamisole-adulterated cocaine can induce a distinct clinical syndrome characterized by retiform purpura and/or agranulocytosis accompanied by an unusual constellation of serologic abnormalities including antiphospholipid antibodies, lupus anticoagulants, and very high titers of antineutrophil cytoplasmic antibodies. Two recent case reports suggest that levamisole-adulterated cocaine may also lead to renal disease in the form of pauci-immune glomerulonephritis. To explore this possibility, we reviewed cases of pauci-immune glomerulonephritis between 2010 and 2012 at an inner city safety net hospital where the prevalence of levamisole in the cocaine supply is known to be high. We identified 3 female patients and 1 male patient who had biopsy-proven pauci-immune glomerulonephritis, used cocaine, and had serologic abnormalities characteristic of levamisole-induced autoimmunity. Each also had some other form of clinical disease known to be associated with levamisole, either neutropenia or cutaneous manifestations. One patient had diffuse alveolar hemorrhage. Three of the 4 patients were treated with short courses of prednisone and cyclophosphamide, 2 of whom experienced stable long-term improvement in their renal function despite ongoing cocaine use. The remaining 2 patients developed end-stage renal disease and became dialysis-dependent. This report supports emerging concern of more wide spread organ toxicity associated with the use of levamisole-adulterated cocaine

Iterative annotation to ease neural network training: Specialized machine learning in medical image analysis

Neural networks promise to bring robust, quantitative analysis to medical fields, but adoption is limited by the technicalities of training these networks. To address this translation gap between medical researchers and neural networks in the field of pathology, we have created an intuitive interface which utilizes the commonly used whole slide image (WSI) viewer, Aperio ImageScope (Leica Biosystems Imaging, Inc.), for the annotation and display of neural network predictions on WSIs. Leveraging this, we propose the use of a human-in-the-loop strategy to reduce the burden of WSI annotation. We track network performance improvements as a function of iteration and quantify the use of this pipeline for the segmentation of renal histologic findings on WSIs. More specifically, we present network performance when applied to segmentation of renal micro compartments, and demonstrate multi-class segmentation in human and mouse renal tissue slides. Finally, to show the adaptability of this technique to other medical imaging fields, we demonstrate its ability to iteratively segment human prostate glands from radiology imaging data.Comment: 15 pages, 7 figures, 2 supplemental figures (on the last page

Noninvasive in vivo imaging of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance.

Oxidative stress has been proposed to be a unifying cause for diabetic nephropathy and a target for novel therapies. Here we apply a new endogenous reduction-oxidation (redox) sensor, hyperpolarized (HP) (13)C dehydroascorbate (DHA), in conjunction with MRI to noninvasively interrogate the renal redox capacity in a mouse diabetes model. The diabetic mice demonstrate an early decrease in renal redox capacity, as shown by the lower in vivo HP (13)C DHA reduction to the antioxidant vitamin C (VitC), prior to histological evidence of nephropathy. This correlates with lower tissue reduced glutathione (GSH) concentration and higher NADPH oxidase 4 (Nox4) expression, consistent with increased superoxide generation and oxidative stress. ACE inhibition restores the HP (13)C DHA reduction to VitC with concomitant normalization of GSH concentration and Nox4 expression in diabetic mice. HP (13)C DHA enables rapid in vivo assessment of altered redox capacity in diabetic renal injury and after successful treatment

Accumulation of epicardial fat rather than visceral fat is an independent risk factor for left ventricular diastolic dysfunction in patients undergoing peritoneal dialysis

BACKGROUND: Symptoms of heart failure with preserved left ventricular systolic function are common among patients undergoing peritoneal dialysis (PD). Epicardial fat (EpF) is an ectopic fat depot with possible paracrine or mechanical effects on myocardial function. The aim of our current study is to assess the association between EpF and Left ventricular diastolic dysfunction (LVDD) in patients undergoing PD and to clarify the relationships among EpF, inflammation, and LVDD in this population. METHODS: This was a cross-sectional study of 149 patients with preserved left ventricular systolic function who were undergoing PD. LVDD was diagnosed (according to the European Society of Cardiology guidelines) and EpF thickness measured by echocardiography. The patients without LVDD were used as controls. The serum inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) was measured. The location and amount of adipose tissue were assessed by computed tomography (CT) at the level of the fourth lumbar vertebra. RESULTS: Subjects with LVDD had higher levels of hsCRP, more visceral and peritoneal fat, and thicker EpF (all p < 0.001) than controls. Visceral adipose tissue, hsCRP, and EpF all correlated significantly (p < 0.05) with LVDD. Multivariate regression analysis rendered the relationship between visceral adipose tissue and LVDD insignificant, whereas EpF was the most powerful determinant of LVDD (odds ratio = 2.41, 95% confidence interval = 1.43–4.08, p < 0.01). EpF thickness also correlated significantly with the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e’; r = 0.27, p < 0.01). CONCLUSION: EpF thickness is significantly independently associated with LVDD in patients undergoing PD and may be involved in its pathogenesis

Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours

Metabolic syndrome and abdominal fat are associated with inflammation, but not with clinical outcomes, in peritoneal dialysis patients

BACKGROUND: In the general population, metabolic syndrome (MetS) is correlated with visceral fat and a risk factor for cardiovascular disease (CVD); however, little is known about the significance of abdominal fat and its association with inflammation and medication use in peritoneal dialysis (PD) patients. We investigated the relationship of visceral fat area (VFA) with C-reactive protein (CRP) levels and medication use in PD patients and followed their clinical outcomes. METHODS: In a prospective study from February 2009 to February 2012, we assessed diabetes mellitus (DM) status, clinical and PD-associated characteristics, medication use, CRP levels, components of MetS, and VFA in 183 PD patients. These patients were categorized into 3 groups based on MetS and DM status: non-MetS (group 1, n = 73), MetS (group 2, n = 65), and DM (group 3, n = 45). VFA was evaluated by computed tomography (CT) and corrected for body mass index (BMI). RESULTS: Patients in group 1 had smaller VFAs than patients in groups 2 and 3 (3.2 ± 1.8, 4.6 ± 1.9, and 4.9 ± 2.0 cm(2)/[kg/m(2)], respectively, P < 0.05) and lower CRP levels (0.97 ± 2.31, 1.27 ± 2.57, and 1.11 ± 1.35 mg/dL, respectively, P < 0.05). VFA increased with the number of criteria met for MetS. After adjusting for age, body weight, and sex, CRP and albumin levels functioned as independent positive predictors of VFA; on other hand, the use of renin-angiotensin system blockers was inversely correlated with VFA in PD patients without DM. In the survival analysis, DM patients (group 3) had the poorest survival among the 3 groups, but no significant differences were found between groups 1 and 2. CONCLUSION: This study showed that VFA and MetS are associated with CRP levels but cannot predict survival in PD patients without DM. The complex relationship of nutritional parameters to VFA and MetS may explain these results. The type of antihypertensive medication used was also associated with the VFA. The mechanisms behind these findings warrant further investigation