Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study.

Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred

Risk Factors, Molecular Epidemiology and Outcomes of Ertapenem-Resistant, Carbapenem-Susceptible Enterobacteriaceae: A Case-Case-Control Study

Background: Increasing prevalence of ertapenem-resistant, carbapenem-susceptible Enterobacteriaceae (ERE) in Singapore presents a major therapeutic problem. Our objective was to determine risk factors associated with the acquisition of ERE in hospitalized patients; to assess associated patient outcomes; and to describe the molecular characteristics of ERE. Methods: A retrospective case-case-control study was conducted in 2009 at a tertiary care hospital. Hospitalized patients with ERE and those with ertapenem-sensitive Enterobacteriaceae (ESE) were compared with a common control group consisting of patients with no prior gram-negative infections. Risk factors analyzed included demographics; co-morbidities; instrumentation and antibiotic exposures. Two parallel multivariate logistic regression models were performed to identify independent variables associated with ERE and ESE acquisition respectively. Clinical outcomes were compared between ERE and ESE patients. Results: Twenty-nine ERE cases, 29 ESE cases and 87 controls were analyzed. Multivariate logistic regression showed that previous hospitalization (Odds ratio [OR], 10.40; 95 % confidence interval [CI], 2.19–49.20) and duration of fluoroquinolones exposure (OR, 1.18 per day increase; 95 % CI, 1.05–1.34) were unique independent predictors for acquiring ERE. Duration of 4 th-generation cephalosporin exposure was found to predict for ESE acquisition (OR, 1.63 per day increase; 95 % CI, 1.05– 2.54). In-hospital mortality rates and clinical response rates were significantly different between ERE and ESE groups

Nodular Worm Infection in Wild Chimpanzees in Western Uganda: A Risk for Human Health?

This study focused on Oeosophagostomum sp., and more especially on O. bifurcum, as a parasite that can be lethal to humans and is widespread among humans and monkeys in endemic regions, but has not yet been documented in apes. Its epidemiology and the role played by non-human primates in its transmission are still poorly understood. O. stephanostomum was the only species diagnosed so far in chimpanzees. Until recently, O. bifurcum was assumed to have a high zoonotic potential, but recent findings tend to demonstrate that O. bifurcum of non-human primates and humans might be genetically distinct. As the closest relative to human beings, and a species living in spatial proximity to humans in the field site studied, Pan troglodytes is thus an interesting host to investigate. Recently, a role for chimpanzees in the emergence of HIV and malaria in humans has been documented. In the framework of our long-term health monitoring of wild chimpanzees from Kibale National Park in Western Uganda, we analysed 311 samples of faeces. Coproscopy revealed that high-ranking males are more infected than other individuals. These chimpanzees are also the more frequent crop-raiders. Results from PCR assays conducted on larvae and dried faeces also revealed that O. stephanostomum as well as O. bifurcum are infecting chimpanzees, both species co-existing in the same individuals. Because contacts between humans and great apes are increasing with ecotourism and forest fragmentation in areas of high population density, this paper emphasizes that the presence of potential zoonotic parasites should be viewed as a major concern for public health. Investigations of the parasite status of people living around the park or working inside as well as sympatric non-human primates should be planned, and further research might reveal this as a promising aspect of efforts to reinforce measures against crop-raiding

The "Persuadable Middle" on Same-Sex Marriage: Formative Research to Build Support among Heterosexual College Students

Same-sex marriage is a controversial policy issue that affects the welfare of gay and lesbian couples throughout the USA. Considerable research examines opinions about same-sex marriage; however, studies have not investigated the covariates of the “persuadable middle”— those individuals who are neutral or unsure about their views. This group of people is often the target of same-sex marriage campaigns, yet they have received no empirical attention.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89607/1/Woodford et al 2011 Persuadable Middle.pd

Two cases of monomicrobial intraabdominal abscesses due to KPC - 3 Klebsiella pneumoniae ST258 clone

<p>Abstract</p> <p>Background</p> <p>Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of <it>Klebsiella pneumoniae </it>carbapenemase-producing bacteria is an emerging cause of abdominal infections.</p> <p>Case presentation</p> <p>We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by <it>Klebsiella pneumoniae </it>Sequence Type 258 producing <it>K. pneumoniae </it>carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV- negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen.</p> <p>Conclusions</p> <p>Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.</p

Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals

Renal epithelial cells release ATP constitutively under basal conditions and release higher quantities of purine nucleotide in response to stimuli. ATP filtered at the glomerulus, secreted by epithelial cells along the nephron, and released serosally by macula densa cells for feedback signaling to afferent arterioles within the glomerulus has important physiological signaling roles within kidneys. In autosomal recessive polycystic kidney disease (ARPKD) mice and humans, collecting duct epithelial cells lack an apical central cilium or express dysfunctional proteins within that monocilium. Collecting duct principal cells derived from an Oak Ridge polycystic kidney (orpkTg737) mouse model of ARPKD lack a well-formed apical central cilium, thought to be a sensory organelle. We compared these cells grown as polarized cell monolayers on permeable supports to the same cells where the apical monocilium was genetically rescued with the wild-type Tg737 gene that encodes Polaris, a protein essential to cilia formation. Constitutive ATP release under basal conditions was low and not different in mutant versus rescued monolayers. However, genetically rescued principal cell monolayers released ATP three- to fivefold more robustly in response to ionomycin. Principal cell monolayers with fully formed apical monocilia responded three- to fivefold greater to hypotonicity than mutant monolayers lacking monocilia. In support of the idea that monocilia are sensory organelles, intentionally harsh pipetting of medium directly onto the center of the monolayer induced ATP release in genetically rescued monolayers that possessed apical monocilia. Mechanical stimulation was much less effective, however, on mutant orpk collecting duct principal cell monolayers that lacked apical central monocilia. Our data also show that an increase in cytosolic free Ca2+ primes the ATP pool that is released in response to mechanical stimuli. It also appears that hypotonic cell swelling and mechanical pipetting stimuli trigger release of a common ATP pool. Cilium-competent monolayers responded to flow with an increase in cell Ca2+ derived from both extracellular and intracellular stores. This flow-induced Ca2+ signal was less robust in cilium-deficient monolayers. Flow-induced Ca2+ signals in both preparations were attenuated by extracellular gadolinium and by extracellular apyrase, an ATPase/ADPase. Taken together, these data suggest that apical monocilia are sensory organelles and that their presence in the apical membrane facilitates the formation of a mature ATP secretion apparatus responsive to chemical, osmotic, and mechanical stimuli. The cilium and autocrine ATP signaling appear to work in concert to control cell Ca2+. Loss of a cilium-dedicated autocrine purinergic signaling system may be a critical underlying etiology for ARPKD and may lead to disinhibition and/or upregulation of multiple sodium (Na+) absorptive mechanisms and a resultant severe hypertensive phenotype in ARPKD and, possibly, other diseases

Heterogeneously catalyzed lignin depolymerization

Biomass offers a unique resource for the sustainable production of bio-derived chemical and fuels as drop-in replacements for the current fossil fuel products. Lignin represents a major component of lignocellulosic biomass, but is particularly recalcitrant for valorization by existing chemical technologies due to its complex cross-linking polymeric network. Here, we highlight a range of catalytic approaches to lignin depolymerisation for the production of aromatic bio-oil and monomeric oxygenates

Topoisomerase IIα Binding Domains of Adenomatous Polyposis Coli Influence Cell Cycle Progression and Aneuploidy

Truncating mutations in the tumor suppressor gene APC (Adenomatous Polyposis Coli) are thought to initiate the majority of colorectal cancers. The 15- and 20-amino acid repeat regions of APC bind beta-catenin and have been widely studied for their role in the negative regulation of canonical Wnt signaling. However, functions of APC in other important cellular processes, such as cell cycle control or aneuploidy, are only beginning to be studied. Our previous investigation implicated the 15-amino acid repeat region of APC (M2-APC) in the regulation of the G2/M cell cycle transition through interaction with topoisomerase IIalpha (topo IIalpha).We now demonstrate that the 20-amino acid repeat region of APC (M3-APC) also interacts with topo IIalpha in colonic epithelial cells. Expression of M3-APC in cells with full-length endogenous APC causes cell accumulation in G2. However, cells with a mutated topo IIalpha isoform and lacking topo IIbeta did not arrest, suggesting that the cellular consequence of M2- or M3-APC expression depends on functional topoisomerase II. Both purified recombinant M2- and M3-APC significantly enhanced the activity of topo IIalpha. Of note, although M3-APC can bind beta-catenin, the G2 arrest did not correlate with beta-catenin expression or activity, similar to what was seen with M2-APC. More importantly, expression of either M2- or M3-APC also led to increased aneuploidy in cells with full-length endogenous APC but not in cells with truncated endogenous APC that includes the M2-APC region.Together, our data establish that the 20-amino acid repeat region of APC interacts with topo IIalpha to enhance its activity in vitro, and leads to G2 cell cycle accumulation and aneuploidy when expressed in cells containing full-length APC. These findings provide an additional explanation for the aneuploidy associated with many colon cancers that possess truncated APC

Pyrosequencing of Antibiotic-Contaminated River Sediments Reveals High Levels of Resistance and Gene Transfer Elements

The high and sometimes inappropriate use of antibiotics has accelerated the development of antibiotic resistance, creating a major challenge for the sustainable treatment of infections world-wide. Bacterial communities often respond to antibiotic selection pressure by acquiring resistance genes, i.e. mobile genetic elements that can be shared horizontally between species. Environmental microbial communities maintain diverse collections of resistance genes, which can be mobilized into pathogenic bacteria. Recently, exceptional environmental releases of antibiotics have been documented, but the effects on the promotion of resistance genes and the potential for horizontal gene transfer have yet received limited attention. In this study, we have used culture-independent shotgun metagenomics to investigate microbial communities in river sediments exposed to waste water from the production of antibiotics in India. Our analysis identified very high levels of several classes of resistance genes as well as elements for horizontal gene transfer, including integrons, transposons and plasmids. In addition, two abundant previously uncharacterized resistance plasmids were identified. The results suggest that antibiotic contamination plays a role in the promotion of resistance genes and their mobilization from environmental microbes to other species and eventually to human pathogens. The entire life-cycle of antibiotic substances, both before, under and after usage, should therefore be considered to fully evaluate their role in the promotion of resistance