The progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stromal cell-derived factor-1α (SDF-1)/CXCR4 pathway. Because similar developmental processes may be recapitulated in the disease setting, we hypothesized that the SDF-1/CXCR4 system would regulate microvascular health in CKD. Expression of CXCR4 was observed to be increased in the kidneys of subtotally nephrectomized (SNx) rats and in biopsies from patients with secondary focal segmental glomerulosclerosis (FSGS), a rodent model and human correlate both characterized by aberration of the renal microvessels. A reno-protective role for local SDF-1/CXCR4 signaling was indicated by i) CXCR4-dependent glomerular eNOS activation following acute SDF-1 administration; and ii) acceleration of renal function decline, capillary loss and fibrosis in SNx rats treated with chronic CXCR4 blockade. In contrast to the upregulation of CXCR4, SDF-1 transcript levels were decreased in SNx rat kidneys as well as in renal fibroblasts exposed to the pro-fibrotic cytokine transforming growth factor β (TGF-β), the latter effect being attenuated by histone deacetylase inhibition. Increased renal SDF-1 expression was, however, observed following the treatment of SNx rats with the ACE inhibitor, perindopril. Collectively, these observations indicate that local SDF-1/CXCR4 signaling functions to preserve microvascular integrity and prevent renal fibrosis. Augmentation of this pathway, either purposefully or serendipitously with either novel or existing therapies, may attenuate renal decline in CKD.
An outbreak of infection with Mycobacterium chelonae subsp. abscessus after the injection of penicillin in 86 patients attending a factory hospital is reported. The bacterium was isolated both from lids and from the soil where the drug was stored. Molecular analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of whole-cell proteins and plasmids revealed a pattern identical to that of the strains isolated from the wounds. The source of the infections was soil contamination of the vial lids and was caused by improper use and sterilization of penicillin vials.Mycobacterium chelonae subsp. abscessus, a rapidly growing atypical mycobacterium, is part of the normal flora in the respiratory tract and the digestive tract of healthy human beings and animals and is widely distributed in soil, wastewater, and other materials. As a human pathogen, it seldom infects the lungs, but it often causes infections of skin and soft tissues, especially local infections and abscesses after surgery or intramuscular injection (1-3). Here we describe infection on a large scale caused by M. chelonae subsp. abscessus after the injection of penicillin, the investigation of the reason for the infection, and the development of prevention measures.From January 1997 to July 1998, a factory hospital in Chongqing, China, received 86 patients with local infections at injection sites, on the right or left buttock or both buttocks. Among them, 31 were male and 55 were female, the oldest was 80 years old and the youngest was merely 1 year 1 month old, 55 (64%) were more than 55 years old and 9 (10.5%) were less than 6 years old, and 22 (25.5%) were between 55 and 6 years old. Initially, the skin of the injection sites of the patients became red and swollen, and then scleroma appeared and an abscess formed. The pus was thin and did not give off any extraordinary odor. After the necrotic tissue was resected and the pus was drained, the inflammation still could not be controlled, and the wound would not heal. The infection spread along the interstitial spaces and caused inguinal lymphadenitis through lymphatic vessels. However, general symptoms, such as a sensation of chills or fever, and lung infection did not occur.Samples from the pus, curettage deep in the abscess, and swollen lymph nodes of all patients were examined. The bacteriologic examination was carried out by microscopy of paraffin sections of these materials stained by the Gram stain method. Many gram-positive bacilli were arranged in V or L shapes in the interstitial spaces, with deeply stained granules in the bodies of the bacilli (Fig. 1). After being cultured on blood agar plates for 3 days at 35°C, the organism developed into smooth, mucoid, round, thin, yellow colonies without hemolysis. At that time, according to the shape and staining characteristics, the organism would have been identified as Corynebacterium. Examination with the API Coryne autoanalytical system (Biomerieux, Marcy l'Etoile, France) indicated that the organism was most likely Corynebacterium equi. T...
Binding of the receptor CXCR4 to its ligand stromal cell-derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, up-regulated Bcl-2-associated death promoter, and prevented high glucose/SDF-1-augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy, serine 339 phosphorylation of the receptor, indicative of ligand engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also up-regulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident up-regulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes.
IntroductionThe aim of this meta-analysis was to summarize the evidence on the serum/plasma leptin concentrations in breast cancer (BC) patients, as well as the associations between leptin G-2548A gene polymorphisms and susceptibility to BC.Material and methodsPotentially relevant studies about serum/plasma leptin levels and leptin G-2548A gene polymorphism were selected using the electronic databases PubMed, EMBASE and The Cochrane Library (from January 1 1995 to Jun 30 2017, no language restrictions). The potential sources of heterogeneity were assessed by the Q statistic and quantified using I2; publication bias was qualitatively assessed by funnel plot and quantitatively assessed by Egger’s linear regression test.ResultsA total of 1141 articles were retrieved after database searches, and 27 studies with 9516 subjects (4542 BC patients/4974 controls) were finally included. The results indicated that BC patients had significantly higher leptin levels compared with healthy controls (SMD = 1.65, 95% CI: 1.21–2.09, p < 0.001), but there was no association between leptin G-2548A polymorphism and BC (OR = 1.05, 95% CI: 0.80–1.39, p = 0.722). Subgroup analyses demonstrated increased leptin levels in BC patients of different region, race, body mass index and waist circumference.ConclusionsOur results revealed a significantly higher leptin level in BC patients than in healthy controls, but no association between leptin G-2548A polymorphism and BC susceptibility was found.
Purpose: Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in people with chronic kidney disease (CKD) for which no evidence-based treatment currently exists. Recently, a group of anti-hyperglycemic agents used in the treatment of Type 2 diabetes, termed incretin-based therapies, have come under scrutiny for their putative glucose-independent effects on cardiac function. In the present study, the actions of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of incretin-based therapy in preventing HFpEF induced by chronic renal impairment were investigated. Methods: Sham-operated and subtotally-nephrectomized rats were randomized to receive the DPP-4 inhibitors, linagliptin or sitagliptin for seven weeks before assessment of cardiac and renal structure and function. Results: Analysis of pressure-volume loops revealed that both linagliptin and sitagliptin prevented the development of cardiac diastolic dysfunction, with cardiac collagen I synthesis also being reduced by DPP-4 inhibition. These attenuating cardiac effects occurred without change in renal function or structure where, in the doses administered, neither linagliptin nor sitagliptin affected GFR decline, proteinuria, renal fibrosis or the increased urinary excretion of biomarkers of renal toxicity. Conclusion: The beneficial cardiac effects of DPP-4 inhibition, in the absence of a concurrent improvement in renal dysfunction, raise the possibility that these agents may confer cardiovascular advantages in the CKD population.
This chapter is focused on intuitive interaction with various interfaces for people living with dementia. First, we describe the enhanced intuitive interaction framework, which contains a continuum suggesting various pathways to intuitive use that can be included in the design of interfaces. We discuss how it relates to users, and specifically how it may assist users living with dementia. Then three empirical studies conducted over two continents are discussed. Each involved participants living with dementia using interfaces in a lab. Data were analyzed for task completion, reaction times and completion times (Studies 1 and 2), and presence and effectiveness of physical and perceived affordances (two of the proposed pathways to intuitive use on the EFII continuum). These data were then compared according to the enhanced intuitive interaction framework, and the findings suggested that employing interface features that are more familiar and more ubiquitous for the target population would likely make the interfaces more intuitive for people living with dementia to use. The
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