Risk of ESRD in prior living kidney donors

We studied End‐Stage Renal Disease (ESRD) in living kidney donors (LKDs) who donated in the United States between 1994 and 2016 (n = 123 526), using Organ Procurement and Transplantation Network and Centers for Medicare and Medicaid Services data. Two hundred eighteen LKDs developed ESRD, with a median of 11.1 years between donation and ESRD. Absolute 20‐year risk was low but not uniform, with risk associated with race, age, and sex and increasing exponentially over time. LKDs had increased risk of ESRD if they were male (adjusted hazard ratio [aHR]: 1.75, 95% confidence interval [95%CI]: 1.33‐2.31), had higher BMI (aHR: 1.34 per 5 kg/m², 95%CI: 1.10‐1.64) or lower estimated GFR (aHR: 0.89 per 10 mL/min, 95% CI: 0.80‐0.99), were first‐degree relatives of the recipient (parent: [aHR: 2.01, 95% CI: 1.26‐3.21]; full sibling [aHR: 1.87, 95%CI: 1.23‐2.84]; identical twin [aHR: 19.79, 95%CI: 7.65‐51.24]), or lived in lower socioeconomic status neighborhoods at donation (aHR: 0.87 per $10k increase; 95%CI: 0.77‐0.99). We found a significant interaction between donation age and race, with higher risk at older ages for white LKDs (aHR: 1.26 per decade, 95%CI: 1.04‐1.54), but higher risk at younger ages for black LKDs (aHR: 0.75 per decade, 95%CI: 0.57‐0.99). These findings further inform risk assessment of potential LKDs.     

Recurrent invasion and extinction of a selfish gene

Homing endonuclease genes show super-Mendelian inheritance, which allows them to spread in populations even when they are of no benefit to the host organism. To test the idea that regular horizontal transmission is necessary for the long-term persistence of these genes, we surveyed 20 species of yeasts for the omega-homing endonuclease gene and associated group I intron. The status of omega could be categorized into three states (functional, nonfunctional, or absent), and status was not clustered on the host phylogeny. Moreover, the phylogeny of omega differed significantly from that of the host, strong evidence of horizontal transmission. Further analyses indicate that horizontal transmission is more common than transposition, and that it occurs preferentially between closely related species. Parsimony analysis and coalescent theory suggest that there have been 15 horizontal transmission events in the ancestry of our yeast species, through simulations indicate that this value is probably an underestimate. Overall, the data support a cyclical model of invasion, degeneration, and loss, followed by reinvasion, and each of these transitions is estimated to occur about once every 2 million years. The data are thus consistent with the idea that frequent horizontal transmission is necessary for the long-term persistence of homing endonuclease genes, and further, that this requirement limits these genes to organisms with easily accessible germ lines. The data also show that mitochondrial DNA sequences are transferred intact between yeast species; if other genes do not show such high levels of horizontal transmission, it would be due to lack of selection, rather than lack of opportunity.     

Allergic fungal rhinosinusitis

The combination of nasal polyposis, crust formation, and sinus cultures yielding Aspergillus was first noted in 1976 by Safirstein, who observed the clinical similarity that this constellation of findings shared with allergic bronchopulmonary aspergillosis (ABPA). Eventually, this disease came to be known as allergic fungal rhinosinusitis (AFRS). As clinical evidence of AFRS accumulated, controversy regarding its etiology, pathogenesis, natural history, and appropriate treatment naturally emerged. Despite past and current efforts, many of these controversies remain incompletely resolved, but continuing clinical study has illuminated some aspects of the disease and has led to an improved understanding of AFRS and its treatment. In this article, we review current data and theories regarding the pathophysiology and clinical presentation of AFRS, as well as the roles of various surgical and nonsurgical forms of therapy.     

Favorable cardiovascular risk profile in middle age and health-related quality of life in older age

BACKGROUND: Life expectancy is greater for people with favorable midlife cardiovascular risk profiles (ie, low risk). However, some speculate that increased longevity may lead to large numbers of ill, disabled, older persons with lower quality of life. Few data exist on this important issue. This study evaluates the relationship of midlife low-risk status to quality of life and illness in older age. METHODS: Cohort of middle-aged adults from the Chicago Heart Association Detection Project in Industry (2692 women and 3650 men; baseline ages, 36-64 years [average age, 73.2 years in 1996]) without baseline (1967-1973) major electrocardiographic abnormalities or history of diabetes or myocardial infarction. Quality of life (12-item Health Status Questionnaire [HSQ-12] on physical, mental, and social well-being) and self-reported diseases were assessed after 26 years of follow-up. Baseline risk strata included low risk (favorable blood pressure and serum cholesterol levels, no smoking, and no minor electrocardiographic abnormalities); 0 risk factors (ie, no high risk factors but >or=1 risk factors not at favorable levels); or any 1, any 2, or 3 or more of the following 4 risk factors: high blood pressure, high serum cholesterol level, smoking, and minor electrocardiographic abnormalities. The HSQ-12 scores and disease outcomes for low risk were compared with other strata. RESULTS: Adjusted scores for physical, mental, social functioning, and disease-free outcomes were highest for low-risk individuals and decreased significantly with number of risk factors (eg, 58% of low-risk women had excellent/very good health compared with 28% of women with >or=3 risk factors). CONCLUSIONS: Favorable cardiovascular risk profile in middle age is associated with better quality of life and lower risk of diseases in older age. Moreover, the fewer the risk factors, the higher the quality of life.     

The Association of Kidney Function and Albuminuria With the Risk and Outcomes of Syncope: A Population-Based Cohort Study

Background

The risks and subsequent outcomes of syncope among seniors with chronic kidney disease (CKD) are unclear.

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment.With improved diagnosis and treatment, cancer survivorship continues to rise but often at the cost of quality of life. The unintended neurocognitive sequelae resulting from cranial irradiation used to treat primary and secondary malignancies of the brain are both progressive and debilitating (1, 2). Despite the recognition and prevalence of these adverse side effects, relatively few, if any, long-term satisfactory solutions exist for this unmet medical need. Past work from our laboratory has optimized transplantation parameters and established many of the long-term benefits of human stem cell-based therapies for the treatment of radiation-induced cognitive dysfunction (3–5). Cranially grafted stem cells have been shown to impart persistent improvements in behavioral performance in irradiated rats over extended postirradiation intervals (1–8 mo) using short- and long-term cognitive testing paradigms (4, 6, 7). These studies have shown that our stem cell-based approaches improve the functional plasticity of the host brain through a variety of mechanisms including (i) the suppression of neuroinflammation (5), (ii) the addition of new cells to active hippocampal circuits (4), and (iii) a long-term trophic support mechanism that facilitates the expression of activity-regulated cytoskeleton-associated protein that functions in multiple ways as a molecular determinant of memory (7). Moreover, using a distinctly different injury paradigm, stem cell grafting preserved host neuronal morphology in rats that otherwise experienced significant disruptions to dendritic complexity following a chronic chemotherapy regimen (8).Although human stem cell therapies have proved promising for a number of clinical scenarios including the treatment of disease or traumatic injury, they are not without risk. Among the concerns regarding stem cell use is the possibility of teratoma formation and immune rejection requiring immunosuppression. One strategy to circumvent the caveats of engrafting stem cells into the irradiated brain is to transplant stem cell-derived microvesicles (MV) instead of the stem cells themselves. These small membrane-bound vesicles are generated by many cell types and contain bioactive cargo such as proteins, lipids, mRNAs, and micro-RNAs (9). MV are now recognized as regulators of biological processes, with specific cargo capable of controlling signaling and function of target cells (10). For this reason, MV represent a unique paracrine signaling mechanism with therapeutic potential. The literature demonstrates that MV are capable of effectively promoting recovery of the CNS after traumatic brain injury or stroke (11, 12). We hypothesize that this same cell-free therapeutic approach will, at least in part, mitigate radiation-induced damage to the brain by delivering beneficial cargo. As proof of principle, in this study we have grafted human neural stem cell (hNSC)-derived MV into the hippocampus of the host brain and assessed their ability to reduce neuroinflammation and protect neuronal structure, ultimately sparing the brain from the cognitive deficits induced by irradiation.     

Causes of Troponin Elevation and Associated Mortality in Young Patients

Background

While increased serum troponin levels are often due to myocardial infarction, increased levels may also be found in a variety of other clinical scenarios. Although these causes of troponin elevation have been characterized in several studies in older adults, they have not been well characterized in younger individuals.

Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction

Hemodynamic abnormalities have been implicated in the pathogenesis of the increased glomerular permeability to protein of diabetic and other glomerulopathies. Vascular permeability factor (VPF) is one of the most powerful promoters of vascular permeability. We studied the effect of stretch on VPF production by human mesangial cells and the intracellular signaling pathways involved. The application of mechanical stretch (elongation 10%) for 6 h induced a 2.4-fold increase over control in the VPF mRNA level (P < 0.05). There was a corresponding 3-fold increase in VPF protein level by 12 h (P < 0.001), returning to the baseline by 24 h. Stretch-induced VPF secretion was partially prevented both by the protein kinase C (PKC) inhibitor H7 (50 μM: 72% inhibition, P < 0.05) and by pretreatment with phorbol ester (phorbol-12-myristate-13 acetate 10⁻⁷ M: 77% inhibition, P < 0.05). A variety of protein tyrosine kinase (PTK) inhibitors, genistein (20 μg/ml), herbimycin A (3.4 μM), and a specific pp60^src peptide inhibitor (21 μM) also significantly reduced, but did not entirely prevent, stretch-induced VPF protein secretion (respectively 63%, 80%, and 75% inhibition; P < 0.05 for all). The combination of both PKC and PTK inhibition completely abolished the VPF response to mechanical stretch (100% inhibition, P < 0.05). Stretch induces VPF gene expression and protein secretion in human mesangial cells via PKC- and PTK-dependent mechanisms.