Comparing novel antibiotics and carbapenems for complicated intra-abdominal infections: a systematic review and meta-analysis of randomized controlled trials.

Background: Carbapenem-sparing antibiotics are needed urgently for patients with complicated intra-abdominal infections (cIAIs). Although several novel antibiotics - novel β-lactam/β-lactamase inhibitor combinations (e.g.

Unintentional drug-related deaths in people with mental illness in NSW Australia, 2012-2016: a retrospective cohort study.

Purpose: People with mental illness are a vulnerable and stigmatised group with poor health outcomes including greater premature mortality. This study aimed to investigate trends and rates of change in unintentional drug-related deaths for people with mental illness, describe types of medicines involved, and identify populations at risk in a cohort from New South Wales, Australia.

Methods: Features of unintentional drug-related deaths for people with mental illness between 2012 and 2016 were identified in a retrospective review of data from the National Coronial Information System.

High levels of engagement with testing for HIV and sexually transmissible infection among gay Asian men in Sydney and Melbourne: an observational study.

Unlabelled: Background Gay and other men who have sex with men of Asian background (GAM) have been identified as a key population in efforts to eradicate HIV in New South Wales. The aims of the present study were to evaluate current levels of engagement with HIV and sexually transmissible infection (STI) testing services, assess knowledge of pre- and post-exposure prophylaxis and to identify factors associated with service engagement in this group.

Methods: A survey of 604 GAM residing in Sydney and Melbourne was undertaken.

Inflammatory Responses Reprogram T Through Impairment of Neuropilin-1.

Chronic inflammatory insults compromise immune cell responses and ultimately contribute to pathologic outcomes. Clinically, it has been suggested that bone debris and implant particles, such as polymethylmethacrylate (PMMA), which are persistently released following implant surgery evoke heightened immune, inflammatory, and osteolytic responses that contribute to implant failure. However, the precise mechanism underlying this pathologic response remains vague.

Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis.

Skeletal abnormalities are common comorbidities of inflammatory bowel disease (IBD). Patients suffering from IBD, including ulcerative colitis and Crohn's disease, present with skeletal complications. However, the mechanism underpinning IBD-associated bone loss remains vague.

NUMBL Interacts with TAK1, TRAF6 and NEMO to Negatively Regulate NF-κB Signaling During Osteoclastogenesis.

NF-κB signaling is essential for osteoclast differentiation and skeletal homeostasis. We have reported recently that NUMB-like (NUMBL) protein modulates osteoclastogenesis by down regulating NF-κB activation. Herein, we decipher the mechanism underlying this phenomenon.

Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing.

Unlabelled: A specialized axonal ending, the basket cell "pinceau," encapsulates the Purkinje cell axon initial segment (AIS), exerting final inhibitory control over the integrated outflow of the cerebellar cortex. This nonconventional axo-axonic contact extends beyond the perisomatic chemical GABAergic synaptic boutons to the distal AIS, lacks both sodium channels and local exocytotic machinery, and yet contains a dense cluster of voltage-gated potassium channels whose functional contribution is unknown. Here, we show that ADAM11, a transmembrane noncatalytic disintegrin, is the first reported Kv1-interacting protein essential for localizing Kv1.

Osteopetrosis in TAK1-deficient mice owing to defective NF-κB and NOTCH signaling.

The MAP kinase TGFβ-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis.

Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy.

Objective: To explore the potential contribution of genetic variation in voltage-gated chloride channels to epilepsy, we analyzed CLCN family (CLCN1-7) gene variant profiles in individuals with complex idiopathic epilepsy syndromes and determined the expression of these channels in human and murine brain.

Methods: We used parallel exomic sequencing of 237 ion channel subunit genes to screen individuals with a clinical diagnosis of idiopathic epilepsy and evaluate the distribution of missense variants in CLCN genes in cases and controls. We examined regional expression of CLCN1 in human and mouse brain using reverse transcriptase PCR, in situ hybridization, and Western immunoblotting.

Constitutively active canonical NF-κB pathway induces severe bone loss in mice.

Physiologic osteoclastogenesis entails activation of multiple signal transduction pathways distal to the cell membrane receptor RANK. However, atypical osteoclastogenesis driven by pro-inflammatory stimuli has been described. We have reported recently a novel mechanism whereby endogenous mutational activation of the classical NF-κB pathway is sufficient to induce RANKL/RANK-independent osteoclastogenesis.

Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined.

IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development.

Secreted factors from the epicardium are believed to be important in directing heart ventricular cardiomyocyte proliferation and morphogenesis, although the specific factors involved have not been identified or characterized adequately. We found that IGF2 is the most prominent mitogen made by primary mouse embryonic epicardial cells and by a newly derived immortalized mouse embryonic epicardial cell line called MEC1. In vivo, Igf2 is expressed in the embryonic mouse epicardium during midgestation heart development.

Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced CA1 neurodegeneration.

CA1 pyramidal neurons are the final integrators of information flow leaving the hippocampus, yet are singularly vulnerable to activity-dependent cell death. Zinc (Zn) entry into cells may add to this vulnerability. Here, we find that Slc39a1 and Slc39a3, members of the Zip (Zrt/Irt-like protein) plasmalemmal Zn transporter family, are predominantly expressed in the hippocampus.

Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.

Heterozygous deletions spanning chromosome 5q31.2 occur frequently in the myelodysplastic syndromes (MDS) and are highly associated with progression to acute myeloid leukemia (AML) when p53 is mutated. Mutagenesis screens in zebrafish and mice identified Hspa9 as a del(5q31.

Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.

Mice lacking Kv1.1 Shaker-like potassium channels encoded by the Kcna1 gene exhibit severe seizures and die prematurely. The channel is widely expressed in brain but only minimally, if at all, in mouse myocardium.

A novel technique combining platelet gel, skin graft, and fibrin glue for healing recalcitrant lower extremity ulcers.

Background: There is no ideal procedure for the treatment of chronic skin ulcers. The use of platelet gel (PG) in this indication is raising interest.

Objective: To evaluate the safety and efficacy of a new procedure combining allogeneic single-donor PG and fibrin glue (FG) to enhance skin graft take for treating recalcitrant ulcers.

Cranioplasty using osteoconductive scaffold and platelet glue.

Background: An alternative to autogenous bone grafts or to methyl methacrylate in the reconstruction of full-thickness calvarial bone defect is needed.

Methods: The safety and efficacy of biphasic calcium phosphate osteoconductive scaffold (Triosite) combined with platelet glue for the reconstruction of posttraumatic calvarial bone defect was evaluated in six consecutive patients. Follow-up averaged 30 months.

The use of UCOE vectors in combination with a preadapted serum free, suspension cell line allows for rapid production of large quantities of protein.

UCOE vectors contain non-tissue specific chromatin-opening-elements that permit rapid expression of a protein in anintegration independent manner. Efficient expression can bederived from a single copy of an integrated gene site resulting ina higher percentage of cells expressing the marker gene in theselected pool in comparison to standard non-UCOE containingvectors. This, in combination with the utilization of a serum-free, suspension adapted parent cell line allows for rapidproduction of large quantities of protein in a short period oftime.

Pigment pattern in jaguar/obelix zebrafish is caused by a Kir7.1 mutation: implications for the regulation of melanosome movement.

Many animals have a variety of pigment patterns, even within a species, and these patterns may be one of the driving forces of speciation. Recent molecular genetic studies on zebrafish have revealed that interaction among pigment cells plays a key role in pattern formation, but the mechanism of pattern formation is unclear. The zebrafish jaguar/obelix mutant has broader stripes than wild-type fish.

Key role of Kv1 channels in vasoregulation.

Small arteries play an essential role in the regulation of blood pressure and organ-specific blood flow by contracting in response to increased intraluminal pressure, ie, the myogenic response. The molecular basis of the myogenic response remains to be defined. To achieve incremental changes in arterial diameter, as well as blood pressure or organ-specific blood flow, the depolarizing influence of intravascular pressure on vascular smooth muscle membrane potential that elicits myogenic contraction must be precisely controlled by an opposing hyperpolarizing influence.

Phylogenetic analysis of three complete gap junction gene families reveals lineage-specific duplications and highly supported gene classes.

Gap junctions, composed of connexin proteins in chordates, are the most ubiquitous form of intercellular communication. Complete connexin gene families have been identified from human (20) and mouse (19), revealing significant diversity in gap junction channels. We searched current databases and identified 37 putative zebrafish connexin genes, almost twice the number found in mammals.

Myogenic regulation of arterial diameter: role of potassium channels with a focus on delayed rectifier potassium current.

The phenomenon of myogenic constriction of arterial resistance vessels in response to increased intraluminal pressure has been known for over 100 years, yet our understanding of the molecular mechanisms involved remains incomplete. The focus of this paper concerns the potassium (K+) channels that provide a negative feedback control of the myogenic depolarization of vascular smooth muscle cells that is provoked by elevations in intraluminal pressure, and specifically, the contribution of delayed rectifier (KDR) channels. Our knowledge of the important role played by KDR channels, as well as their molecular identity and acute modulation via changes in gating, has increased dramatically in recent years.

Heteromultimeric Kv1 channels contribute to myogenic control of arterial diameter.

Inhibition of vascular smooth muscle (VSM) delayed rectifier K+ channels (K(DR)) by 4-aminopyridine (4-AP; 200 micromol/L) or correolide (1 micromol/L), a selective inhibitor of Kv1 channels, enhanced myogenic contraction of rat mesenteric arteries (RMAs) in response to increases in intraluminal pressure. The molecular identity of K(DR) of RMA myocytes was characterized using RT-PCR, real-time PCR, and immunocytochemistry. Transcripts encoding the pore-forming Kvalpha subunits, Kv1.