Upregulation of Shiga Toxin Receptor CD77/Gb3 and Interleukin‐1β Expression in the Brain of EHEC Patients with Hemolytic Uremic Syndrome and Neurologic Symptoms

In 2011, a large outbreak of Shiga toxin‐producing enterohemorrhagic Escherichia coli (EHEC) infections occurred in northern Germany, which mainly affected adults. Out of 3842 patients, 104 experienced a complicated course comprising hemolytic uremic syndrome and neurological complications, including cognitive impairment, aphasia, seizures and coma. T2 hyperintensities on magnet resonance imaging (MRI) bilateral in the thalami and in the dorsal pons were found suggestive of a metabolic toxic effect. Five of the 104 patients died because of toxic heart failure. In the present study, the post‐mortem neuropathological findings of the five EHEC patients are described. Histological investigation of 13 brain regions (frontal, temporal, occipital cortex, corpora mammillaria, thalamus, frontal operculum, corona radiata, gyrus angularis, pons, medulla oblongata, cerebellar vermis and cerebellar hemisphere) showed no thrombosis, ischemic changes or fresh infarctions. Further, no changes were found in electron microscopy. In comparison with five age‐matched controls, slightly increased activation of microglia and a higher neuronal expression of interleukin‐1β and of Shiga toxin receptor CD77/globotriaosylceramide 3 was observed. The findings were confirmed by Western blot analyses. It is suggested that CD77/globotriaosylceramide upregulation may be a consequence to Shiga toxin exposure, whereas increased interleukin‐1β expression may point to activation of inflammatory cascades.     

PCB77 Inducing Renal Tubular Cell Apoptosis

PCBs are a family of persistent environmental toxicants with a wide spectrum of toxic features, such as neurotoxic, hepatoxicity, immunotoxicity, endocrine disruption effects, and oncogenic effects. The kidney is the most important organ involved in the elimination of toxins and drugs. To date, little has been done to investigate the potential influence of nephrotoxicity of 3,3’,4,4’- tetrachlorobiphenyl (PCB77). By assessing cell viability and apoptotic cell death in renal tubular epithelial (NRK-52E) cells cultures, we found that PCB77 could decrease cellular viability at least at 30?μM concentration after 3?h exposure. PCB77 was demonstrated to promote DNA breakage resulting in apoptosis. Moreover, apoptotic subcellular morphological changes administration of PCB77 was observed using transmission electron microscopy. Appearance swelling of mitochondria, endoplasmic reticulum dilation and chromatin agglutinate, and other apoptosis cells morphological characteristics could be visible. Due to increased PCB77 concentration, cells viability was decreased. Collectively, our findings identified the morphological mechanism that PCB77-induced nephrotoxicity via promoting renal tubular epithelial cells apoptosis. It is suggested that using and production of PCB77 should be carefully managed to reduce public health risks.     

Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates

In a variety of species, development of attachment to a caregiver is crucial for infant survival and partly mediated by the endogenous opioids. Functional mu-opioid receptor gene polymorphisms are present in humans (OPRM1 A118G) and rhesus macaques (OPRM1 C77G). We hypothesized that rhesus infants carrying a gain-of-function OPRM1 77G allele would experience increased reward during maternal contact and would, therefore, display increased measures of attachment. We collected behavioral data from rhesus macaques (n = 97) during early infancy and at 6 months of age, across four cycles of maternal separation (4 days) and reunion (3 days). Animals were genotyped for the OPRM1 C77G polymorphism, and the effects of this allele on attachment-related behaviors were analyzed. Infants carrying the G allele exhibited higher levels of attachment behavior during early infancy. During prolonged periods of maternal separation, although infant macaques homozygous for the C allele exhibited decreases in their levels of distress vocalization with repeated separation, this response persisted in G allele carriers. The OPRM1 77G allele also affected social preference during reunion. C/G infants spent increasing amounts of time in social contact with their mothers as a function of repeated separation and were less likely to interact with other individuals in the social group, a pattern not observed among infants with the C/C genotype. These findings suggest a role for OPRM1 variation in the expression of attachment behavior in human subjects, especially as a function of separation from the caregiver.     

Spirometric criteria for airway obstruction: Use percentage of FEV1/FVC ratio below the fifth percentile, not < 70%

BACKGROUND: Current authoritative spirometry guidelines use conflicting percentage of FEV1/FVC ratios (FEV1/FVC%) to define airway obstruction. The American Thoracic Society/European Respiratory Society Task Force characterizes obstruction as a FEV1/FVC% below the statistically defined fifth percentile of normal. However, many recent publications continue to use the Global Initiative for Chronic Obstructive Lung Disease (GOLD) primary criterion that defines obstruction as a FEV1/FVC% < 70%. Data from the Third National Health and Nutrition Examination Survey (NHANES-III) should identify and quantify differences, help resolve this conflict, and reduce inappropriate medical and public health decisions resulting from misidentification. METHODS: Using these two guidelines, individual values of FEV1/FVC% were compared by decades in 5,906 healthy never-smoking adults and 3,497 current-smokers of black (African American), Hispanic (Latin), or white ethnicities aged 20.0 to 79.9 years. RESULTS: In the never-smoking population, the lower limits of normal used in other reference equations fit reasonably well the NHANES-III statistically defined fifth percentile guidelines. But nearly one half of young adults with FEV1/FVC% below the NHANES-III fifth percentile of normal were misidentified as normal because their FEV1/FVC% was > 70% (abnormals misidentified as normal). Approximately one fifth of older adults with observed FEV1/FVC% above the NHANES-III fifth percentile had FEV1/FVC% ratios < 70% (normals misidentified as abnormal). CONCLUSIONS: The GOLD guidelines misidentify nearly one half of abnormal younger adults as normal and misidentify approximately one fifth of normal older adults as abnormal.     

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

The pathogenesis and therapy of Shigatoxin 2 (Stx2)‐mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2‐producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2‐receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild‐type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule‐specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2‐associated kidney failure (n = 11, aged 22–44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement‐inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31–17.60) mg/dl, lactate dehydrogenase 1944 (753–2792) U/l, platelets 33 (19–124)/nl and haemoglobin 6.2 (5.2–7.8) g/dl; median (range)], all patients were discharged after 33 (range 19–43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84–2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66–1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2‐mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Mechanical ventilation in ARDS: a state-of-the-art review

Mechanical ventilation is an essential component of the care of patients with ARDS, and a large number of randomized controlled clinical trials have now been conducted evaluating the efficacy and safety of various methods of mechanical ventilation for the treatment of ARDS. Low tidal volume ventilation (相似文献