Regional doxorubicin delivery reduces testicular toxicity

Many anti-cancer drugs cause infertility. Regional delivery of these agents is a potential method to avoid this problem. We investigated the protective effect of normothermic testicular circulatory arrest on gonadal toxicity during doxorubicin administration in the Sprague-Dawley rat. Four groups of eight rats each were used. Animals in group 1 received no treatment. Rats in group 2 were anesthetized and received a bolus of intravenous doxorubicin (6 mg/kg). In groups 3 and 4, normothermic circulatory isolation of the left testis was induced by cross-clamping of the spermatic cord and gubernaculum immediately before doxorubicin administration. This was maintained for 15 min after doxorubicin administration in group 3 and for 45 min in group 4. Cessation and return of testicular blood flow were confirmed by Doppler. On Day 56, all rats were killed and necropsied. Testicular toxicity was evaluated qualitatively by histology and quantitatively by measurement of testicular weight, sperm count, repopulation index, and epididymal index. The results indicated that 15 min of testicular circulatory isolation mitigated testicular toxicity to a small extent and that 45 min of circulatory isolation provided moderate protection against doxorubicin-induced testicular toxicity.     

Successful treatment of acute inferior vena cava and unilateral renal vein thrombosis by local infusion of recombinant tissue plasminogen activator

Renal vein thrombosis can occur as a complication of nephrotic syndrome. We present the case of a young man with nephrotic syndrome caused by minimal change disease who developed acute inferior vena cava and left renal vein thrombosis. He was treated initially with intravenous heparin. Because of the persistence of severe left flank pain and gross hematuria, local infusion of recombinant tissue plasminogen activator was tried, with resolution of thrombi and subsidence of symptoms. Functional preservation of the involved kidney is good, as indicated by Tc-99m DMSA scan (involved kidney, 47.4%; uninvolved kidney, 52.6%). Anticoagulation is usually recommended as the treatment of choice in renal vein thrombosis. We believe that in cases with critical presentations, such as bilateral involvement, extension into inferior vena cava, acute renal failure, pulmonary embolism or severe flank pain, thrombolytic therapy should be considered as a second-line treatment if good response is not obtained with heparin.     

Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women

Background: Glyphosate is the most commonly used herbicide in the world and is purported to have a variety of health effects, including endocrine disruption and an elevated risk of several types of cancer. Blood DNA methylation has been shown to be associated with many other environmental exposures, but to our knowledge, no studies to date have examined the association between blood DNA methylation and glyphosate exposure.Objective: We conducted an epigenome-wide association study to identify DNA methylation loci associated with urinary glyphosate and its metabolite aminomethylphosphonic acid (AMPA) levels. Secondary goals were to determine the association of epigenetic age acceleration with glyphosate and AMPA and develop blood DNA methylation indices to predict urinary glyphosate and AMPA levels.Methods: For 392 postmenopausal women, white blood cell DNA methylation was measured using the Illumina Infinium MethylationEPIC BeadChip array. Glyphosate and AMPA were measured in two urine samples per participant using liquid chromatography–tandem mass spectrometry. Methylation differences at the probe and regional level associated with glyphosate and AMPA levels were assessed using a resampling-based approach. Probes and regions that had an false discovery rate q<0.1 in ≥90% of 1,000 subsamples of the study population were considered differentially methylated. Differentially methylated sites from the probe-specific analysis were combined into a methylation index. Epigenetic age acceleration from three epigenetic clocks and an epigenetic measure of pace of aging were examined for associations with glyphosate and AMPA.Results: We identified 24 CpG sites whose methylation level was associated with urinary glyphosate concentration and two associated with AMPA. Four regions, within the promoters of the MSH4, KCNA6, ABAT, and NDUFAF2/ERCC8 genes, were associated with glyphosate levels, along with an association between ESR1 promoter hypomethylation and AMPA. The methylation index accurately predicted glyphosate levels in an internal validation cohort. AMPA, but not glyphosate, was associated with greater epigenetic age acceleration.Discussion: Glyphosate and AMPA exposure were associated with DNA methylation differences that could promote the development of cancer and other diseases. Further studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure. https://doi.org/10.1289/EHP10174     

A Computer-Aided Decision Support System for Detection and Localization of Cutaneous Vasculature in Dermoscopy Images Via Deep Feature Learning

Vascular structures of skin are important biomarkers in diagnosis and assessment of cutaneous conditions. Presence and distribution of lesional vessels are associated with specific abnormalities. Therefore, detection and localization of cutaneous vessels provide critical information towards diagnosis and stage status of diseases. However, cutaneous vessels are highly variable in shape, size, color and architecture, which complicate the detection task. Considering the large variability of these structures, conventional vessel detection techniques lack the generalizability to detect different vessel types and require separate algorithms to be designed for each type. Furthermore, such techniques are highly dependent on precise hand-crafted features which are time-consuming and computationally inefficient. As a solution, we propose a data-driven feature learning framework based on stacked sparse auto-encoders (SSAE) for comprehensive detection of cutaneous vessels. Each training image is divided into small patches of either containing or non-containing vasculature. A multilayer SSAE is designed to learn hidden features of the data in hierarchical layers in an unsupervised manner. The high-level learned features are subsequently fed into a classifier which categorizes each patch into absence or presence of vasculature and localizes vessels within the lesion. Over a test set of 3095 patches derived from 200 images, the proposed framework demonstrated superior performance of 95.4% detection accuracy over a variety of vessel patterns; outperforming other techniques by achieving the highest positive predictive value of 94.7%. The proposed Computer-Aided Diagnosis (CAD) framework can serve as a decision support system assisting dermatologists for more accurate diagnosis, especially in teledermatology applications in remote areas.     

Tooth-brushing epilepsy with ictal orgasms.

We report a 41-year-old woman with complex reflex epilepsy in which seizures were induced exclusively by the act of tooth brushing. All the attacks occurred with a specific sensation of sexual arousal and orgasm-like euphoria that were followed by a period of impairment of consciousness. Ictal EEG demonstrated two events of epileptic seizure that were provoked after tooth brushing for 38 and 14 seconds, respectively. The interictal EEG showed epileptiform discharges over the right anterior temporal region and interictal single photon emission computed tomography (SPECT) scan showed relative hypoperfusion in the uncus of right temporal lobe. Brain magnetic resonance imaging (MRI) revealed right hippocampal atrophy. We suggest that tooth-brushing epilepsy, especially with sexual ictal manifestations, may provide insight into the cerebral pathophysiology at the right temporolimbic structure.     

Differential interictal activity of the precuneus/posterior cingulate cortex revealed by resting state functional MRI at 3T in generalized vs. partial seizure

PURPOSE: To characterize, using functional MRI (fMRI), the pattern of active brain regions in the resting state in patients with epilepsy. MATERIALS AND METHODS: We studied 28 patients with epilepsy, divided into a partial seizure (PS; N = 9) and a generalized seizure group (GS; N = 19), and 34 control subjects. Resting state fMRI was performed using a GE 3T scanner by collecting 200 volumes of echo-planar imaging (EPI) images with subjects relaxed, eyes closed. Data were processed using a modification of the method of Fransson (Hum Brain Mapp 2005;26:15-29), which reveals information on regional low-frequency Blood Oxygenation Level Dependent (BOLD) signal oscillations in the resting state without any a priori hypothesis. The significant active areas in brain were identified with both individual and group analysis. RESULTS: Controls showed active regions in the precuneus/posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC)/ventral anterior cingulate cortex (vACC), theregions associated with the brain "default mode." Similar active regions were observed in PS, whereas GS showed no significant activation of precuneus/PCC. CONCLUSION: In GS, the lack of activation in precuneus/PCC may partly account for their more severe interictal deficits, compared to PS, in cognitive functions such as concentration and memory.     

Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy

A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese.     

Clinical review: Biomarkers of acute kidney injury: where are we now?

The recognition that acute kidney injury (AKI) is a significant independent risk factor for morbidity and mortality has resulted in a substantial number of publications over the past 5 years or more. In no small part these have, to a degree, highlighted the inadequacy of conventional markers of renal insufficiency in the acute setting. Much effort has been invested in the identification of early, specific AKI markers in order to aid early diagnosis of AKI and hopefully improve outcome. The search for a 'biomarker' of AKI has seen early promise replaced by a degree of pessimism due to the lack of a clear candidate molecule and variability of results. We outline the major studies described to date as well as discuss potential reasons for the discrepancies observed and suggest that evolution of the field may result in success with ultimately an improvement in patient outcomes.