The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease.

Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely to be involved in the initiation and progression of DKD. An extensive number of studies have demonstrated the role of microbiota in health and disease. Dysregulation in the microbiota resulting in a deficiency of short chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, by-products of healthy gut microbiota metabolism, have been demonstrated in obesity, type 1 and type 2 diabetes. However, it is not clear to date whether such changes in the microbiota are causative or merely associated with the diseases. It is also not clear which microbiota have protective effects on humans. Few studies have investigated the centrality of reduced SCFA in DKD development and progression or the potential therapeutic effects of supplemental SCFAs on insulin resistance, inflammation, and metabolic changes. SCFA receptors are expressed in the kidneys, and emerging data have demonstrated that intestinal dysbiosis activates the renal renin-angiotensin system, which contributes to the development of DKD. In this review, we will summarize the complex relationship between the gut microbiota and the kidney, examine the evidence for the role of gut dysbiosis in diabetes and obesity-related kidney disease, and explore the mechanisms involved. In addition, we will describe the role of potential therapies that modulate the gut microbiota to prevent or reduce kidney disease progression.

Chronic constipation and abdominal pain: Independent or closely interrelated symptoms?

Constipation is both a symptom and a disorder, seen in both functional constipation and irritable bowel syndrome with constipation predominance (IBS-C). Despite the Rome IV criteria distinguishing between these conditions, they share many therapeutic approaches. This review aims to explore the relationship between constipation and abdominal pain and assess the evidence surrounding whether laxation improves abdominal pain and whether such a response to laxation differs between IBS-C and functional constipation. In patients with functional constipation, increasing frequency of bowel motions by laxatives regardless of mechanism of action is associated with reductions in the severity of abdominal pain, supporting the role of constipation as a contributor to abdominal discomfort. In patients with IBS-C, evidence from systematic reviews indicates that abdominal pain is driven by factors additional to constipation alone and that visceral analgesic modulation is also needed to optimize pain. Changing definitions of IBS-C and heterogeneity in clinical trial design including endpoints have raised uncertainty about the comparative ability of older laxatives without known neuromodulatory effects to improve chronic abdominal pain compared with new secretagogues and prokinetics for the management of IBS-C. While it is known that abdominal pain is associated with constipation and laxation contributes to relief of that pain, it remains unproven whether proposed visceral analgesic properties of new laxatives provide greater pain relief than laxation alone. However, it is likely that the response to laxation in IBS-C is only part of the puzzle.

Rapid identification of group B streptococcus carriage by PCR to assist in the management of women with prelabour rupture of membranes in term pregnancy.

BACKGROUND: Management of prelabour rupture of membranes at term (37 weeks gestation or later) (TPROM) remains complicated in the absence of a rapid assay for group B streptococcus (GBS) colonisation. AIMS: To evaluate the accuracy and clinical utility of a commercial PCR assay, compared with culture, for detection of GBS colonisation in pregnant women presenting with TPROM. METHODS: A prospective study of women presenting with TPROM conducted in a large tertiary hospital (Westmead Hospital, Australia). Five hundred and seventy-four consecutive women with TPROM were enrolled between July 2006 and November 2007. Paired low vaginal and anal swabs were collected from women presenting with TPROM for PCR and culture on GBS selective agar following broth enrichment. Primary outcomes were sensitivity and specificity of PCR compared with GBS selective enrichment culture. Secondary analyses included comparison with a historical but otherwise similar cohort regarding clinical utility, maternal and neonatal outcomes. RESULTS: PCR sensitivity and specificity were 89.0% (95% CI - 82.8-93.6%) and 97.9% (95% CI - 96.0-99.0%), respectively, compared with culture. 72.3% of women were aware of their GBS PCR status within 3 h of presentation. Compared with the historical cohort, PCR reduced the requirement for intrapartum antibiotics by 25.6% (P < 0.001). There were no significant differences in maternal outcomes or combined rates of admissions to neonatal intensive care or special care nursery. CONCLUSIONS: Group B streptococcus PCR is an accurate, rapid, safe and practical alternative to culture for detection of GBS colonisation in pregnant women at the time of TPROM. This method has the potential advantage to reduce costs associated with length of hospital stay.

11 kGy gamma irradiated demineralized bone matrix enhances osteoclast activity.

BACKGROUND: Demineralized bone matrix (DBM) allografts are widely used in orthopaedic clinics. However, the biological impact on its osteoinductivity after its sterilization process by gamma irradiation is not well studied. Furthermore, little is known about the relationship between residual calcium levels on osteoinductivity. HYPOTHESIS: We hypothesize that low-dose gamma irradiation retains the osteoinducitivity properties of DBM and causes ectopic bone formation. MATERIALS AND METHODS: A randomised animal trial was performed to compare tissue and molecular responses of low-dose (11 kGy) gamma irradiated and non-irradiated human DBM at 6 weeks post-intramuscular implantation using an athymic rat model. In addition, we correlated residual calcium levels and bone formation in gamma irradiated DBM. RESULTS: A modified haematoxylin and eosin stain identified ectopic bony capsules at all implanted sites with no significant difference on the amount of new bone formed between the groups. Statistically significantly lower ratio of alkaline phosphatase expression over tartrate-resistant acid phosphatase and/or cathepsin K expressions was found between the groups. DISCUSSION: This study found that low-dose gamma irradiated DBM, which provides a sterility assurance level of 10(-6) for bone allografts, retained osteoinductivity but exhibited significantly enhanced osteoclastic activity. Furthermore, this is the first study to find a positive correlation between residual calcium levels and bone formation in gamma irradiated DBM.

Semicarbazide-sensitive amine oxidase and kidney disease.

With better understanding of the molecular mechanisms underpinning chronic kidney disease, the roles of inflammation and fibrosis are becoming increasingly inseparable. The progression of renal disease is characterized by pathomorphological changes that consist of early inflammatory responses followed by tubulointerstitial fibrosis, tubular atrophy, and glomerular and vascular sclerosis. Currently available therapies that reduce hypertension, proteinuria, hyperglycemia, and interruption of the renin-angiotensin-aldosterone system are at best only partially effective. Hence, there remains a need to explore agents targeting nonrenin-angiotensin-aldosterone system pathways. In this review, we discuss mechanistic aspects in the physiological and pathological role of semicarbazide-sensitive amine oxidase, a protein enzyme involved in cellular trafficking and inflammation, with respect to the kidney. We explore the evidence for the use of semicarbazide-sensitive amine oxidase inhibitors as potential agents in renal fibrosis to delay the onset and progression of chronic kidney disease.

Is ICSI Risky?

As assisted reproductive technology (ART) methods become the mainstream of infertility treatment, it has become even more critical to reassess its safety. Following the results of a study published by the Robinson Institute in the New England Journal of Medicine, the risk of ART, especially intracytoplasmic sperm injection (ICSI), has never been so closely scrutinized. This paper traces the origins and development of ICSI, assesses the risks documented in the literature, and finally interprets the implications of the study for couples contemplating therapy. We support the need for continued vigilance towards ICSI and the importance in investigating male-factor infertility as a prequel to its use.

microRNA-34 family and treatment of cancers with mutant or wild-type p53 (Review).

In the last decade, microRNAs (miRNAs; small noncoding RNA molecules) as post-transcriptional regulators have been a hotspot in research for their involvement in biological processes and tumour development. However, there have been few reviews focusing on a single miRNA family. The dysregulation of miRNAs appears to play a crucial role in cancer pathogenesis where they exert their effect as oncogenes or as tumour suppressors. This review summarises current studies on the dysregulation of the microRNA-34 (miR-34) family in different types of cancers and its role in the p53 network. The structure of the miR-34 family members includes p53-binding sites reflecting their function as tumour suppressors downstream of the p53 pathway. miR-34 dysregulation occurs in cancers, including several epithelial cancers, melanomas, neuroblastomas, leukemias and sarcomas, in the presence or absence of the p53 mutation. For these cancers, functional restoration of miR-34 is a useful novel therapy. As evidenced from preclinical and clinical studies, the miR-34 family plays an important role in the treatment of miR-34-dysregulated cancers with mutant or wild-type p53. This review will have a potential impact in the clinical treatment of p53-mutant and/or miR-34-dysregulated cancers using a miR-34 restoration approach.