Hypertonic saline reduces metalloproteinase expression in liver during pancreatitis

• 1 We recently demonstrated that hypertonic saline reduces inflammation and mortality in acute pancreatitis. The present study investigated the effects of hypertonic saline in metalloproteinase (MMP) regulation and pancreatitis‐associated hepatic injury.
• 2 Wistar rats were divided into four groups: (i) control, not subjected to insult or treatment; (ii) no treatment (NT), induction of pancreatitis (retrograde infusion of 2.5% sodium taurocholate (1.0 mL/kg)), but no further treatment; (iii) normal saline (NS), induction of pancreatitis and treatment with normal saline (0.9% NaCl, 34 mL/kg, i.v. bolus, 1 h after the induction of pancreatitis); and (iv) hypertonic saline (HS), induction of pancreatitis and treatment with hypertonic saline (7.5% NaCl, 4 mL/kg administered over a period of 5 min, 1 h after the induction of pancreatitis). In all four groups, 4, 12 and 24 h after the induction of pancreatitis, liver tissue samples were assayed to determine levels of MMP‐2, MMP‐9, 47 kDa heat shock protein (HSP47) and collagen (Type I and III).
• 3 Compared with the control group, MMP‐9 expression and activity was increased twofold in the NS and NT groups 4 and 12 h after the induction of pancreatitis, but remained at basal levels in the HS group. In contrast, MMP‐2 expression was increased twofold 12 h after the induction of pancreatitis only in the NS group, whereas the expression of HSP47 was increased 4 h after the induction of pancreatitis in the NS and NT groups. Greater extracellular matrix remodelling occurred in the NS and NT groups compared with the HS group, probably as a result of the hepatic wound‐healing response to repeated injury. However, the collagen content in hepatic tissue remained at basal levels in the HS group.
• 4 In conclusion, the results of the present study indicate that hypertonic saline is hepatoprotective and reduces hepatic remodelling, maintaining the integrity of the hepatic extracellular matrix during pancreatitis. Hypertonic saline‐mediated regulation of MMP expression may have clinical relevance in pancreatitis‐associated liver injury.

     

TRAIL and guardian angel of genome integrity: ATM boards TRAIL blazer

Prostate cancer is a multifaceted progressive multistep disorder that arises because of accumulation of genetic and epigenetic abnormalities, which escort to the transformation of normal cells into malignant derivatives. Despite tremendous strides have been made in the understanding of prostate cancer biology, yet approaches towards cancer-targeted therapy still face confrontations in standardization. This review brings to attention, the regulators in complex genetic backgrounds to enlighten our understanding of transformation and metastasis in human systems. Recent evidence gives a clue that prostate cancer may be linked to deregulated DNA damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints; apoptosis and DNA repair result in prostate cancer progression and aggressiveness. An insight of the orchestration between DNA damage-based molecular responses and TRAIL provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.     

3. FIXED AND MODIFIABLE RISK FACTORS FOR BREAST CANCER

Likely pathogenesis of breast cancer is in two phases, initiation and promotion. Initiating factors include ionising irradiation, dietary factors and possibly alcohol consumption causing DNA mutations uncorrected by repair mechanisms. Subsequent promotional factors include exposure to oestrogens, reduced by late menarche, early pregnancy and lactation and increased by nulliparity, oral contraceptive use and hormone replacement therapy. Only 5% of breast cancers result from inherited genetic mutations of BRCA1 and BRCA2, but individuals with such mutations have a high risk (66–80%) of developing the disease. Most patients with benign breast problems are not at increased risk of breast cancer, but those with atypical epithelial hyperplasia have an increased risk and should be kept under surveillance or asked to participate in trials of prevention.     

Engineering of Phenylboronic Acid Based Glucose‐Sensitive Microgels with 4‐Vinylpyridine for Working at Physiological pH and Temperature

Glucose‐sensitive p(NIPAM‐4‐VP‐PBA) microgels with different 4‐VP content are synthesized by the functionalization of p(NIPAM‐4‐VP‐AA) microgels with 3‐aminophenylboronic acid. The glucose‐, pH‐, and thermosensitive behavior of the microgels are investigated using DLS. The feeding content of the hydrophilic 4‐VP group increases the hydrodynamic radius and volume phase transition temperature of the resultant microgel. The effect of 4‐VP content on hydrodynamic radius and volume phase transition is systematically studied at different pH values. The effect of 4‐VP content on the glucose sensitivity is studied at physiological pH and temperature. The Lewis base moiety 4‐VP adjusts the working pH of the PBA‐based glucose‐responsive microgel to physiological values.

     

Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity

Congenital deficiency of the leptin receptor is a very rare cause of severe early-onset obesity. To date, only 9 families have been reported in the literature to have mutations in the leptin receptor gene. The clinical features include severe early onset obesity, severe hyperphagia, hypogonadotropic hypogonadism, and T cell and neuroendocrine/metabolic dysfunction. Here we report two cousins with severe early onset obesity and recurrent respiratory tract infections. Their serum leptin levels were elevated but they were within the range predicted by the elevated fat mass in both cousins. Direct sequencing of the entire coding sequence of the leptin receptor gene revealed a novel homozygous missense mutation in exon 6, P316T. The mutation was found in the homozygous form in both cousins and in the heterozygote state in their parents. This mutation was not found in 200 chromosomes from 100 unrelated normal weight control subjects of Egyptian origin using PCR-RFLP analysis. In conclusion, finding this new mutation in the LEPR beside our previous mutation in the LEP gene implies that monogenic obesity syndromes may be common in the Egyptian population owing to the high rates of consanguineous marriages. Further screening of more families for mutations in LEP, LEPR, and MC4 might confirm this assumption.     

Screening for the metabolic syndrome using simple anthropometric measurements in south Asian and white Europeans: A population-based screening study. The Leicester Ethnic Atherosclerosis and Diabetes Risk (LEADER) Study

AimsTo estimate the prevalence of metabolic syndrome in a general population sample of south Asians and white Europeans and compare predictors of metabolic syndrome, using ethnic specific definitions of obesity.Methods3099 participants (71.4% white European, 28.6% south Asian) aged 40–75 years were screened using a 75 g oral glucose tolerance test. Metabolic syndrome was defined using National Cholesterol Education Programme and International Diabetes Federation definitions. We compared sensitivity, specificity and area under the curve of waist circumference, body mass index and waist–hip ratio.ResultsThe prevalence of metabolic syndrome using the definitions above was 29.9% (29.2% south Asian, 30.2% white European), and 34.4% (34.2% south Asian, 34.5% white European), respectively. Using the National Cholesterol Education Programme definition, waist circumference was significantly more predictive of metabolic syndrome than body mass index or waist–hip ratio. The area under the curve for waist circumference was 0.75 (95% CI: 0.69–0.80) and 0.76 (0.72–0.81) for south Asian men and women; 0.83 (0.80–0.85) and 0.80 (0.77–0.82) for white European men and women.ConclusionsThe prevalence of metabolic syndrome is high in both south Asian and white European populations. Waist circumference is a simple and effective measure for predicting metabolic syndrome in different populations.     

Major comorbid disease processes associated with increased incidence of acute kidney injury

Acute kidney injury (AKI) is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS). This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including: Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI.