Changes in renal enzyme activities following the administration of gentamicin to unilateral nephrectomized rats

The effects of unilateral nephrectomy and the impact of gentamicin administration on renal tissue enzyme activities in adult Wistar rats were investigated. Gentamicin 200 mg/kg body wt. or an equivalent volume of saline to control rats was administered subcutaneously on three consecutive days, followed by unilateral nephrectomy. Rats were killed on day 3, 7 or 14 following nephrectomy. Alkaline phosphatase, predominantly a proximal tubular brush border enzyme, rose in both the experimental and control groups, however, significantly less in the gentamicin treated rats. Aspartate aminotransferase activity, an enzyme participating in renal glucogenesis, increased transiently in the control but remained unchanged in the experimental group. No difference in glucose-6-phosphate dehydrogenase activity between the two groups was observed, probably reflecting the localization of this enzyme to distal tubular segments, a site unaffected by gentamicin. Significant and similar increases in Mg2+ and Na+ K+ ATPase were observed on day 14 in both groups. The administration of the drug resulted in a marked reduction in oxygen consumption, with a higher oxidation to phosphorylation ratio (P/O). Serum creatinine concentration was significantly higher on days 3 and 7 in the experimental group reverting to control values on the 14th day. Urea concentration increased significantly on days 3 and 7, decreasing on the 14th day to values slightly, but significantly, higher than those of the controls.     

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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Grandparental genotyping enhances exome variant interpretation

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband‐only sequencing, mainly due to the rapid identification of de novo disease‐causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X‐inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X‐inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.     

Cyclic nucleotide levels in human breast cancer and in rat mammary tissues during tumor development

The levels of cyclic adenosine 3:5-monophosphate (cAMP) and cyclic guanosine 3:5-monophosphate (cGMP) were studied in dimethylbenz(a)anthracene (DMBA)-induced mammary tumors of Sprague-Dawley rats and in human breast cancer. In the rat carcinomas, these levels were significantly lower than in non-malignant tissues when calculated on the basis of DNA content, but higher (cAMP) or equal (cGMP) when calculated on the basis of weight. In human breast cancer the cyclic nucleotide levels were higher than in non-malignant tissues according to both methods of calculation. No correlation was found in human carcinomas between the cyclic nucleotide levels and mitotic index, nuclear grade, tumor size, or lymph node involvement. The rat tumors were subclassified according to state of differentiation, mitotic index, and state of development. Not all the sub-groups had cAMP levels different from normal values. Differences in cAMP levels between the sub-groups could not be correlated with tumor growth rates and/or mitotic index. Thus, cyclic nucleotides may not be useful in prognosis of breast cancer.     

Spinal cord injury in the setting of traumatic thoracolumbar fracture is not reliably associated with increased risk of associated intra-abdominal injury following blunt trauma: An analysis of a National Trauma Registry database

Purpose: There is a common opinion that spinal fractures usually reflect the substantial impact of injuries and therefore may be used as a marker of significant associated injuries, specifically for intraabdominal injury (IAI). The impact of concomitant spinal cord injury (SCI) with the risk of associated IAI has not been well clarified. The aim of this study was to evaluate the incidence and severity of IAIs in patients suffering from spinal fractures with or without SCI. Methods: A retrospective cohort study using the Israeli National Trauma Registry was conducted. Patients with thoracic, lumbar and thoracolumbar fractures resulting from blunt mechanisms of injury from January 1, 1997 to December 31, 2018 were examined, comparing the incidence, severity and mortality of IAIs in patients with or without SCI. The collected variables included age, gender, mechanism of injury, incidence and severity of the concomitant IAIs and pelvic fractures, abbreviated injury scale, injury severity score, and mortality. Statistical analysis was performed using GraphPad InStat ® Version 3.10, with Chi-square test for independence and two sided Fisher’s exact probability test. Results: Review of the Israeli National Trauma Database revealed a total of 16,878 patients with spinal fractures. Combined thoracic and lumbar fractures were observed in 1272 patients (7.5%), isolated thoracic fractures in 4967 patients (29.4%) and isolated lumbar fractures in 10,639 patients (63.0%). The incidence of concomitant SCI was found in 4.95% (63/1272), 7.65% (380/4967) and 2.50% (266/10639) of these patients, respectively. The overall mortality was 2.5%, proving higher among isolated thoracic fracture patient than among isolated lumbar fracture counterparts (11.3% vs. 4.6%, p < 0.001). Isolated thoracic fractures with SCI were significantly more likely to die than non-SCI counterparts (8.2% vs. 3.1%, p < 0.001). There were no differences in the incidence of IAIs between patients with or without SCI following thoracolumbar fractures overall or in isolated thoracic fractures; although isolated lumbar fractures patients with SCI were more likely to have renal (3.4% vs. 1.6%, p = 0.02) or bowel injuries (2.3% vs. 1.0%, p = 0.04) than the non-SCI counterparts. Conclusion: SCI in the setting of thoracolumbar fracture does not appear to be a marker for associated IAI. However, in a subset of isolated lumbar fractures, SCI patient is associated with increased risks for renal and bowel injury.     

Childhood Cancer and the Risk of ESKD

BackgroundIncreasing cancer incidence among children alongside improved treatments has resulted in a growing number of pediatric cancer survivors. Despite childhood cancer survivors’ exposure to various factors that compromise kidney function, few studies have investigated the association between childhood cancer and future kidney disease.MethodsTo assess the risk of ESKD among childhood cancer survivors, we conducted a nationwide, population-based, retrospective cohort study that encompassed all Israeli adolescents evaluated for mandatory military service from 1967 to 1997. After obtaining detailed histories, we divided the cohort into three groups: participants without a history of tumors, those with a history of a benign tumor (nonmalignant tumor with functional impairment), and those with a history of malignancy (excluding kidney cancer). This database was linked to the Israeli ESKD registry to identify incident ESKD cases. We used Cox proportional hazards models to estimate the hazard ratio (HR) of ESKD.ResultsOf the 1,468,600 participants in the cohort, 1,444,345 had no history of tumors, 23,282 had a history of a benign tumor, and 973 had a history of malignancy. During a mean follow-up of 30.3 years, 2416 (0.2%) participants without a history of tumors developed ESKD. Although a history of benign tumors was not associated with an increased ESKD risk, participants with a history of malignancy exhibited a substantially elevated risk for ESKD compared with participants lacking a history of tumors, after controlling for age, sex, enrollment period, and paternal origin (adjusted HR, 3.2; 95% confidence interval, 1.3 to 7.7).ConclusionsChildhood cancer is associated with an increased risk for ESKD, suggesting the need for tighter and longer nephrological follow-up.     

Semantic memory recognition is supported by intrinsic recollection-like processes: “The butcher on the bus” revisited

Dual-process models suggest that recognition memory is independently supported by recollection and familiarity. Current theories attribute recollection solely to hippocampally mediated episodic memory (EM), and familiarity to both episodic and semantic memory (SM) supported by medial temporal lobe cortex (MTLC) and prefrontal cortex. We tested whether, contrary to this view, recollection-like processes also intrinsically support SM recognition and whether MTL structures are involved in their execution. A semantic Process Dissociation Procedure (PDP) with famous and non-famous names was used in three experiments. Experiment 1 revealed that recollection-like processes in semantic memory were not associated with episodic memory for the public events, were predicted by performance on standard SM tasks and were independent of EM tasks, suggesting they are intrinsic to SM. Experiment 2 demonstrated the independence of the two process estimates by showing only familiarity was affected by shifting response criterion while only recollection estimates were significantly altered under divided-attention. Finally experiment 3 tested amnesic patients with varying degrees of hippocampal and MTLC damage. Despite normal overall fame recognition performance, recollection estimates were specifically affected by MTL damage. When damage was primarily hippocampal, only retrograde recollection estimates were reduced, while more extensive MTLC damage led to both retrograde and anterograde recollection deficits. We conclude that recognition of semantic information is supported by at least two independent processes akin to the ones that support EM recognition. Recollection-like processes are intrinsic to SM and likely do not reflect EM contribution to SM performance. Together with previous studies of recollection in remote memory, these data suggest that recollection is not a unitary phenomenon. In EM it involves autonoetic re-experiencing, and is supported by interaction of fronto-temporal networks; in EM and SM it supports retrieval of contextual/associative information regardless of consciousness type, and is dependent on intact MTL function. Familiarity processes and neural substrates may also differ between lifetime familiarity and within-session familiarity.