Effects of Bacillus subtilis PB6 supplementation on production, metabolism, inflammatory biomarkers, and gastrointestinal tract permeability in transition dairy cows.

Objectives were to evaluate the effects of Bacillus subtilis PB6 (BSP) on gastrointestinal tract permeability, metabolism, inflammation, and production parameters in periparturient Holstein cows. Multiparous cows (n = 48) were stratified by previous 305-d mature equivalent milk yield and parity and assigned to 1 of 2 top-dressed dietary treatments 21 d before expected calving through 63 DIM: (1) control (CON; 13 g/d calcium carbonate; n = 24) or (2) BSP (13 g/d BSP; CLOSTAT, Kemin Industries, Des Moines, IA; n = 24). Gastrointestinal tract permeability was evaluated in vivo using the oral paracellular marker chromium (Cr)-EDTA. Effects of treatment, time, and treatment × time were assessed using PROC MIXED of SAS version 9.4 (SAS Institute Inc.). Prepartum dry matter intake (DMI) was unaffected by treatment; however, BSP supplementation decreased postpartum DMI relative to CON (0.7 kg). Milk yield, energy-corrected milk (ECM), fat-corrected milk (FCM), and solids-corrected milk (SCM) increased in BSP cows compared with CON (1.6, 1.8, 1.6, and 1.5 kg, respectively). Decreased DMI and increased production collectively improved feed efficiency of milk yield, ECM, FCM, and SCM for BSP cows (6, 5, 5, and 5%, respectively). No treatment differences were observed for concentrations of milk fat, protein, total solids, somatic cell count, somatic cell score, body weight, or body condition score. Milk urea nitrogen concentrations decreased (5%), whereas milk protein and lactose yield increased (5 and 2%, respectively) with BSP supplementation. Prepartum fecal pH did not differ among treatments; conversely, postpartum fecal pH was increased with BSP supplementation (0.09 pH units). Prepartum fecal dry matter percentage, starch, acetic acid, propionic acid, butyric acid, and ethanol did not differ among treatments. Postpartum concentrations of the aforementioned fecal parameters were also unaffected by treatment, but fecal propionic acid concentration was decreased (24%) in BSP cows relative to CON. Circulating glucose, nonesterified fatty acids, l-lactate, and insulin were similar between treatments both pre- and postpartum. Prepartum ß-hydroxybutyrate (BHB) did not differ between treatments, but postpartum BSP supplementation decreased (21%) circulating BHB relative to CON. Regardless of treatment, inflammatory markers (serum amyloid A and haptoglobin) peaked immediately following parturition and progressively decreased with time, but this pattern was not influenced by treatment. Postpartum lipopolysaccharide binding protein tended to be decreased on d 3 in BSP relative to CON cows (19%). Neither treatment nor time affected Cr-EDTA area under the curve. In summary, supplementing BSP had no detectable effects prepartum, but increased key postpartum production parameters. Bacillus subtilis PB6 consistently increased postpartum fecal pH and decreased fecal propionate concentrations but did not appear to have an effect on gastrointestinal tract permeability.

Effects of dietary microbial feed supplement on production efficacy in lactating dairy cows.

This study evaluated the effects of a microbial feed supplement (MFS; Galaxis, Ascus Biosciences Inc.) comprising 2 native rumen microbes on performance parameters in mid-lactation dairy cows. Forty-six lactating primiparous and multiparous Holstein cows [629 ± 62 kg of body weight, mean ± standard deviation (SD); parity 1.64 ± 0.49; 119 ± 38 days in milk; 45.11 ± 3.81 and 52.73 ± 4.77 kg/d of milk yield for primiparous and multiparous, respectively] were enrolled in a study containing 3 experimental periods (P). During all periods, enrolled cows were fed the same base total mixed ration (TMR) ad libitum once daily. During P1 (7 d), baseline data were obtained for covariate analysis. At the beginning of P2 (60 d), cows were assigned to 1 of 2 dietary treatment groups in a randomized complete block design to balance for milk yield (MY), parity, and days in milk: (1) a control diet (CON; base TMR; n = 23), or (2) a control diet supplemented with 5 g/d of MFS (MFS; n = 23). Sample size was determined based on previous, unpublished results involving this MFS; a 3-kg difference between groups with a SD of 3.5 kg could be detected with sufficient power (0.81) using a total sample size of 46 cows. Treatment was top-dressed and hand-mixed into the top one-third of the TMR. During P3 (7 d), no treatment was administered, and all cows were fed the base TMR. When analyzing all cows in the data set, MFS had little to no effect on performance. However, modeling revealed that the fixed effect of covariate milk production level had a significant effect on the response of MY and ECM, and further investigation of the data revealed that treatment effectiveness in P2 correlated with milk production during P1. Cows were retrospectively categorized into 2 milk production groups (MPG) balanced for parity: MPG1 (i.e., <53 kg/d of ECM during P1; n = 34) or MPG2 (i.e., ≥53 kg/d of ECM during P1; n = 12). Energy-corrected milk was increased by 4.4% in MFS-administered MPG1 cows compared with CON cows during P2. Although there were no significant effects of MFS on production variables for MPG2 cows, MY tended to be decreased by 3.9% in MFS-administered cows compared with CON cows. Further investigation is needed to understand production level response differences and the effect of supplemented native rumen microbes on animal health and productivity.

Epidemiology of paediatric gastrointestinal colonisation by extended spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates in north-west Cambodia.

BACKGROUND: Extended-spectrum cephalosporin resistance (ESC-R) in Escherichia coli and Klebsiella pneumoniae is a healthcare threat; high gastrointestinal carriage rates are reported from South-east Asia. Colonisation prevalence data in Cambodia are lacking. The aim of this study was to determine gastrointestinal colonisation prevalence of ESC-resistant E. coli (ESC-R-EC) and K. pneumoniae (ESC-R-KP) in Cambodian children/adolescents and associated socio-demographic risk factors; and to characterise relevant resistance genes, their genetic contexts, and the genetic relatedness of ESC-R strains using whole genome sequencing (WGS). RESULTS: Faeces and questionnaire data were obtained from individuals < 16 years in north-western Cambodia, 2012. WGS of cultured ESC-R-EC/KP was performed (Illumina). Maximum likelihood phylogenies were used to characterise relatedness of isolates; ESC-R-associated resistance genes and their genetic contexts were identified from de novo assemblies using BLASTn and automated/manual annotation. 82/148 (55%) of children/adolescents were ESC-R-EC/KP colonised; 12/148 (8%) were co-colonised with both species. Independent risk factors for colonisation were hospitalisation (OR: 3.12, 95% CI [1.52-6.38]) and intestinal parasites (OR: 3.11 [1.29-7.51]); school attendance conferred decreased risk (OR: 0.44 [0.21-0.92]. ESC-R strains were diverse; the commonest ESC-R mechanisms were blaCTX-M 1 and 9 sub-family variants. Structures flanking these genes were highly variable, and for blaCTX-M-15, - 55 and - 27 frequently involved IS26. Chromosomal blaCTX-M integration was common in E. coli. CONCLUSIONS: Gastrointestinal ESC-R-EC/KP colonisation is widespread in Cambodian children/adolescents; hospital admission and intestinal parasites are independent risk factors. The genetic contexts of blaCTX-M are highly mosaic, consistent with rapid horizontal exchange. Chromosomal integration of blaCTX-M may result in stable propagation in these community-associated pathogens.

Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of a liposomal formulation to horses.

BACKGROUND: The use of intra-articular (IA) local anaesthetics has proven to be an effective means to treat post-operative pain. The effects of local anaesthetics on equine chondrocytes are mixed with some studies reporting chondrodestruction and others no adverse effects. A liposomal formulation of bupivacaine is used in people and dogs by intra- and peri-articular administration to provide up to 72 h of analgesia. The potential uses, side effects including chondrotoxicity, and likelihood of abuse (long-term analgesic effects) has not been evaluated in horses. OBJECTIVES: Describe bupivacaine concentrations following IA administration and assess biomarkers as indicators of the effects of liposomal bupivacaine on chondrocytes in vivo. STUDY DESIGN: Parallel design. METHODS: Sixteen exercised horses received a single IA administration of 0.12 mg/kg liposomal bupivacaine or 0.9% saline. Blood and urine samples were collected for 96 h post-drug administration. Six horses treated with bupivacaine and those receiving saline, underwent daily arthrocentesis. Six additional bupivacaine treated horses underwent arthrocentesis at 96 h. Drug concentrations were measured using LC-MS/MS and pharmacokinetic analyses performed. Immunoassays were used to measure markers of collagen degradation (C2C, C12C) and cartilage matrix synthesis (CPII, CS846) in synovial fluid. RESULTS: The bupivacaine plasma elimination half-life was 17.8 ± 5.42 and 11.9 ± 5.17 h for horses from which synovial fluid was collected daily and at 96 h respectively. Bupivacaine concentrations in the joint were still detectable at 96 h. Significant increases in C12C and C2C were noted at 96 h in horses undergoing arthrocentesis at 96 h only. CPII was increased at 48 h and CS846 at 24 and 48 h in horses sampled daily. MAIN LIMITATIONS: Limited number of animals and absence of liposome control group. CONCLUSIONS: Sustained concentrations of IA bupivacaine suggest viability of this medication as an intra-articular analgesic. Effects on equine chondrocytes need further study.

MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways.

The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

Electronic effects on the catalytic disproportionation of formic acid to methanol by [Cp*Ir(III)(R-bpy)Cl]Cl complexes.

A series of [Cp*Ir(III)(R-bpy)Cl]Cl (R-bpy = 4,4'-di-R-2,2'-bipyridine; R = CF3, H, Me, tBu, OMe) complexes was prepared and studied for catalytic formic acid disproportionation. The relationship between the electron donating strength of the bipyridine substituents and methanol production of the corresponding complexes was analyzed; the unsubstituted (R = H) complex was the most selective for methanol formation.

Serum, milk, and tissue monensin concentrations in cattle with adequate and potentially toxic dietary levels of monensin: pharmacokinetics and diagnostic interpretation.

Used in both beef cattle and dairy cows, monensin can provide many health benefits but can, when unintended overexposures occur, result in adverse effects. Information on serum and tissue concentrations following overexposure and/or overt toxicosis which may aid in diagnostics and clinical outcome is lacking. The aim of this study was to determine concentrations of monensin in biological specimens following oral exposure for 10 days to an approved dose (1 mg/kg) and a higher dose (5 mg/kg) of monensin given daily on a body weight basis to 10 dairy cows. No deaths were reported; cows receiving 5 mg/kg showed early signs of toxicosis including depression, decreased feed intake, and diarrhea after 4 days of exposure. Histopathological findings were minimal in most cows. Pharmacokinetic modeling of the detected serum concentrations for the 1 and 5 mg/kg dose groups determined the Cmax , Tmax, and t1/2λ to be 0.87 and 1.68 ng/mL, 2.0 and 1.0 h, and 1.76 and 2.32 days, respectively. Mixed regression models showed that the dose level and days since last dose were significantly associated with monensin concentrations in all four tissues, and with cardiac troponin levels. The high dose resulted in a significant elevation of monensin in tissues at approximately 4.7 times compared to the monensin concentrations in the tissues of animals from the low-dose group. The cTnI concentrations in the high-dose group were 2.1 times that of cTnI in the low-dose group. Thus, the ability to diagnose monensin overexposure and/or toxicosis will improve from knowledge of biological monensin concentrations from this study.

Extensive Within-Host Diversity in Fecally Carried Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli Isolates: Implications for Transmission Analyses.

Studies of the transmission epidemiology of antimicrobial-resistant Escherichia coli, such as strains harboring extended-spectrum beta-lactamase (ESBL) genes, frequently use selective culture of rectal surveillance swabs to identify isolates for molecular epidemiological investigation. Typically, only single colonies are evaluated, which risks underestimating species diversity and transmission events. We sequenced the genomes of 16 E. coli colonies from each of eight fecal samples (n = 127 genomes; one failure), taken from different individuals in Cambodia, a region of high ESBL-producing E. coli prevalence. Sequence data were used to characterize both the core chromosomal diversity of E. coli isolates and their resistance/virulence gene content as a proxy measure of accessory genome diversity. The 127 E. coli genomes represented 31 distinct sequence types (STs). Seven (88%) of eight subjects carried ESBL-positive isolates, all containing blaCTX-M variants. Diversity was substantial, with a median of four STs/individual (range, 1 to 10) and wide genetic divergence at the nucleotide level within some STs. In 2/8 (25%) individuals, the same blaCTX-M variant occurred in different clones, and/or different blaCTX-M variants occurred in the same clone. Patterns of other resistance genes and common virulence factors, representing differences in the accessory genome, were also diverse within and between clones. The substantial diversity among intestinally carried ESBL-positive E. coli bacteria suggests that fecal surveillance, particularly if based on single-colony subcultures, will likely underestimate transmission events, especially in high-prevalence settings.

Susceptibility artifacts detected on 3T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study.

OBJECTIVE: To determine the prevalence of intraarticular susceptibility artifacts and to detect longitudinal changes in the artifacts, on 3T magnetic resonance imaging (MRI) of the knee in a cohort of patients with knee pain, and to assess the association of susceptibility artifacts with radiographic intraarticular calcifications. DESIGN: Three hundred and forty-six knees of 177 subjects aged 35-65 were included. 3T MRI was performed at baseline and at 6 months. Baseline radiographs were assessed for presence/absence of linear/punctate calcifications within the tibiofemoral joint (TFJ) space. Corresponding MRIs were assessed for susceptibility artifacts (i.e., linear/punctate hypointensities) in the TFJ space on coronal dual-echo steady-state (DESS) sequences. Kappa statistics were applied to determine agreement between findings on baseline DESS and radiography. Changes in artifacts over time were recorded. RESULTS: In the medial compartment, 13 (4%) of the knees showed susceptibility artifacts at baseline. Six knees had persistent artifacts and six knees had incident artifacts at follow-up. Agreement between DESS and radiography was κ = 0.18 (-0.15, 0.51) in the medial compartment. Frequency of artifacts in the lateral compartment was low (2%). CONCLUSION: Susceptibility artifacts detected on knee MRI are not frequent, and likely correspond to vacuum phenomena as they commonly change over time and are not associated with intraarticular calcifications. Radiologists should be aware of these artifacts as they can interfere with cartilage segmentation.

Septic arthritis of the hip in a Cambodian child caused by multidrug-resistant Salmonella enterica serovar Typhi with intermediate susceptibility to ciprofloxacin treated with ceftriaxone and azithromycin.

Septic arthritis is a rare complication of typhoid fever. A 12-year-old boy without pre-existing disease attended a paediatric hospital in Cambodia with fever and left hip pain. A hip synovial fluid aspirate grew multidrug-resistant Salmonella enterica ser. Typhi with intermediate susceptibility to ciprofloxacin. Arthrotomy, 2 weeks of intravenous ceftriaxone and 4 weeks of oral azithromycin led to resolution of symptoms. The optimum management of septic arthritis in drug-resistant typhoid is undefined.

Healthcare-associated outbreak of meticillin-resistant Staphylococcus aureus bacteraemia: role of a cryptic variant of an epidemic clone.

BACKGROUND: New strains of meticillin-resistant Staphylococcus aureus (MRSA) may be associated with changes in rates of disease or clinical presentation. Conventional typing techniques may not detect new clonal variants that underlie changes in epidemiology or clinical phenotype. AIM: To investigate the role of clonal variants of MRSA in an outbreak of MRSA bacteraemia at a hospital in England. METHODS: Bacteraemia isolates of the major UK lineages (EMRSA-15 and -16) from before and after the outbreak were analysed by whole-genome sequencing in the context of epidemiological and clinical data. For comparison, EMRSA-15 and -16 isolates from another hospital in England were sequenced. A clonal variant of EMRSA-16 was identified at the outbreak hospital and a molecular signature test designed to distinguish variant isolates among further EMRSA-16 strains. FINDINGS: By whole-genome sequencing, EMRSA-16 isolates during the outbreak showed strikingly low genetic diversity (P < 1 × 10(-6), Monte Carlo test), compared with EMRSA-15 and EMRSA-16 isolates from before the outbreak or the comparator hospital, demonstrating the emergence of a clonal variant. The variant was indistinguishable from the ancestral strain by conventional typing. This clonal variant accounted for 64/72 (89%) of EMRSA-16 bacteraemia isolates at the outbreak hospital from 2006. CONCLUSIONS: Evolutionary changes in epidemic MRSA strains not detected by conventional typing may be associated with changes in disease epidemiology. Rapid and affordable technologies for whole-genome sequencing are becoming available with the potential to identify and track the emergence of variants of highly clonal organisms.

The value of intermittent point-prevalence surveys of healthcare-associated infections for evaluating infection control interventions at Angkor Hospital for Children, Siem Reap, Cambodia.

BACKGROUND: There are limited data on the epidemiology of paediatric healthcare-associated infection (HCAI) and infection control in low-income countries. We describe the value of intermittent point-prevalence surveys for monitoring HCAI and evaluating infection control interventions in a Cambodian paediatric hospital. METHODS: Hospital-wide, point-prevalence surveys were performed monthly in 2011. Infection control interventions introduced during this period included a hand hygiene programme and a ventilator-associated pneumonia (VAP) care bundle. RESULTS: Overall HCAI prevalence was 13.8/100 patients at-risk, with a significant decline over time. The highest HCAI rates (50%) were observed in critical care; the majority of HCAIs were respiratory (61%). Klebsiella pneumoniae was most commonly isolated and antimicrobial resistance was widespread. Hand hygiene compliance doubled to 51.6%, and total VAP cases/1000 patient-ventilator days fell from 30 to 10. CONCLUSION: Rates of HCAI were substantial in our institution, and antimicrobial resistance a major concern. Point-prevalence surveys are effective for HCAI surveillance, and in monitoring trends in response to infection control interventions.

First National Workshop on Antibiotic Resistance in Cambodia: Phnom Penh, Cambodia, 16-18 November 2011.

The First National Workshop on Antibiotic Resistance in Cambodia was organised by the Cambodian Ministry of Health with support from several national and international partner institutions. It brought together policy-makers, clinicians, pharmacists, laboratory technicians and other professionals dealing with the problems of bacterial infection and antibiotic resistance across the country. Antibiotic resistance data from starting up and experienced laboratories were presented, showing high rates of resistance in key pathogens to most antibiotics currently available in Cambodia, e.g. 70-90% multidrug resistance and 70-80% decreased ciprofloxacin susceptibility in Salmonella enterica serovar Typhi, 20-40% meticillin resistance rates in Staphylococcus aureus and 30-50% extended-spectrum ß-lactamase production in Escherichia coli. A five-point plan was discussed, which included initiatives from government and non-governmental partners, focusing on rational prescribing, clinical practice guidelines, improved laboratory services, infection prevention and enhanced education at all levels. Implementation, however challenging, is a priority given the high levels of resistance seen in key pathogens and the overall health needs in the country.

[Orbital invasion of a maxillary ameloblastoma]. / Orbitale Infiltration durch ein Ameloblastom der Maxilla.

A 66-year-old man with a history of repeated surgery, external radiation and brachytherapy for ameloblastoma presented with a recurrence of the tumor with sinus, intraorbital and skull base infiltration. Histopathologic examination of the resected orbital and sinus tissue confirmed the diagnosis of ameloblastoma. Immunohistochemical staining for CD56 was strongly positive in the tumor cells. Although ameloblastoma is usually a low-grade malignant tumor, it can be locally aggressive with invasion of the surrounding tissue. Maxillary ameloblastomas are more likely to infiltrate the orbit.

Effects of monensin on metabolic parameters, feeding behavior, and productivity of transition dairy cows.

The effects of monensin on transition cow metabolism may be dependent on modulation of feeding behavior, rumen pH, and expression of key metabolic genes. Multiparous Holstein cows were used to determine the effects of monensin (400mg/cow daily) on these variables. Cows were randomly assigned, based on calving date, to control or monensin treatments (n = 16 per treatment) 21 d before their expected calving date, and cows remained on treatments through 21 d postpartum. Feeding behavior and water intake data were collected daily. Liver biopsies were conducted after assessing BCS and BW on d -21, -7, 1, 7, and 21 relative to calving for analysis of triglyceride (TG) content as well as mRNA abundance of cytosolic phosphoenolpyruvate carboxykinase, carnitine palmitoyltransferase 1a, and apolipoprotein B. Blood samples were collected 21, 7, and 4 d before expected calving and 1 (day of calving), 4, 7, 14, and 21 d postpartum for nonesterified fatty acid, ß-hydroxybutyrate, glucose, insulin, and haptoglobin analyses. Ruminal pH was collected every 5 min on d 1 through 6 postpartum via a wireless indwelling probe. On d 7 postpartum, a caffeine clearance test was performed to assess liver function. Data were analyzed using mixed models with repeated measures over time. Monensin decreased mean plasma ß-hydroxybutyrate (734 vs. 616 ± 41 µM) and peak concentrations (1,076 vs. 777 ± 70 µM on d 4 postpartum). Monensin also decreased time between meals prepartum (143 vs. 126 ± 5.0 min) and postpartum (88.8 vs. 81.4 ± 2.9 min), which was likely related to a smaller ruminal pH standard deviation in the first day after cows changed to a lactation ration (0.31 vs. 0.26 ± 0.015). Monensin also increased liver mRNA abundance of carnitine palmitoyltransferase 1a (0.10 vs. 0.15 ± 0.002 arbitrary units), which corresponded to a slower rate of liver TG accumulation from d -7 to +7 (412 vs. 128 ± 83 mg of TG/g of protein over this time period). No significant effects of monensin supplementation were observed on milk production, liver cytosolic phosphoenolpyruvate carboxykinase, apolipoprotein B, plasma nonesterified fatty acid, glucose, insulin, or haptoglobin. No effects on disease incidence were detected, but sample size was small for detecting such effects. Overall, results confirm that the effects of monensin on transition cows extend beyond altered propionate flux.

Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).

AIMS/HYPOTHESIS: Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells. METHODS: Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB. RESULTS: Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. CONCLUSIONS/INTERPRETATION: This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.

Postabsorptive carbohydrate adaptations to heat stress and monensin supplementation in lactating Holstein cows.

Multiparous cows (n=34, 89 d in milk, 537 kg) housed in environmental chambers were fed a control total mixed ration or one containing monensin (450 mg/cow per day) during 2 experimental periods (P): (1) thermal neutral (TN) conditions (constant 20°C) with ad libitum intake for 9 d, and (2) heat stress (HS, n=16) or pair-fed [PF; in TN (PFTN); n=18] for 9 d. Heat-stress was cyclical with temperatures ranging from 29.4 to 38.9°C. Rectal temperatures and respiration rates increased in HS compared with PFTN cows (38.4 to 40.4°C, 40 to 93 breaths/min). Heat stress reduced dry matter intake (DMI, 28%), and by design, PFTN cows had similar intakes. Monensin-fed cows consumed less DMI (1.59 kg/d) independent of environment. Milk yield decreased 29% (9.1 kg) in HS and 15% (4.5 kg) in PFTN cows, indicating that reduced DMI accounted for only 50% of the decreased milk yield during HS. Monensin had no effect on milk yield in either environment. Both HS and PFTN cows entered into calculated negative energy balance (-2.7 Mcal/d), and feeding monensin increased feed efficiency (7%) regardless of environment. The glucose response to an epinephrine (EPI) challenge increased (27%) during P2 for both HS and PFTN cows, whereas the nonesterified fatty acid response to the EPI challenge was larger (56%) during P2 in the PFTN compared with the HS cows. Compared with P1, whole-body glucose rate of appearance (Ra) decreased similarly during P2 in both HS and PFTN cows (646 vs. 514 mmol/h). Although having similar rates of glucose Ra, HS cows synthesized approximately 225 g less milk lactose; therefore, on a milk yield basis, glucose Ra decreased (3.3%) in PFTN but increased (5.6%) in HS cows. Regardless of environment, monensin-fed cows had increased (10%) glucose Ra per unit of DMI. From the results we suggest that the liver remains sensitive but adipose tissue becomes refractory to catabolic signals and that glucose Ra (presumably of hepatic origin) is preferentially utilized for processes other than milk synthesis during HS.

Patient safety incidents associated with obesity: a review of reports to the National Patient Safety Agency and recommendations for hospital practice.

BACKGROUND: The incidence and prevalence of obesity are increasing world wide. In the UK, obesity governmental strategy has primarily focused on prevention measures, with less focus on the demands of treating obese patients in hospital. Increasing service demand by obese patients coupled with a lack of adequate provision for care of these patients may lead to an increase in patient safety incidents. By classifying patient safety incidents associated with obesity reported to the National Patient Safety Agency, this report aims to identify areas for improvement in the quality and safety of care of the obese patient. METHODS: A search of the National Reporting and Learning System database was conducted for all incidents caused by or relating to obesity for the period 1 January 2005 to 31 August 2008. The keywords 'obesity', 'overweight', 'BMI' (body mass index), and 'bariatric' were used. The relevant free text fields of the resulting set of incidents were then searched for the terms designed to isolate incidents occurring in anaesthesia, critical care, and surgery. Reported incidents were analysed and subsequently categorised to identify incident themes. Levels of harm were also established. RESULTS: 555 patient safety incidents were identified; 388 met inclusion criteria for analysis. 148 incidents were related to assessment, diagnosis or treatment, 213 related to infrastructure and 27 related to staffing. The majority of incidents were classified as no or low harm. Three deaths were reported, all within the domain of anaesthesia. CONCLUSIONS: This report identifies that the majority of safety incidents associated with obesity were related to infrastructure, suggesting that there is inadequate provision in place for the care of obese patients. While levels of harm were mostly low, the occurrence of incidents resulting in severe harm or death highlights the specific dangers associated with the care of the obese patient. A global approach to improving the safety of care delivery for obese patients is recommended, including obesity specific training, management structures, care pathways, and equipment provisioning.Further planning and development of operation policies is needed to ensure the safe delivery of healthcare to obese patients in the future.

NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations.

The proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) has a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-kappaB inhibitor, IkappaB-alpha, associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IkappaB-zeta gene NFKBIZ in the development of invasive pneumococcal disease (IPD) has not been reported previously. To investigate this further, we examined the frequencies of 22 single-nucleotide polymorphisms spanning NFKBIZ in two case-control studies, comprising UK Caucasian (n=1008) and Kenyan (n=723) individuals. Nine polymorphisms within a single UK linkage disequilibrium (LD) block and all four polymorphisms within the equivalent, shorter Kenyan LD block displayed either a significant association with IPD or a trend towards association. For each polymorphism, heterozygosity was associated with protection from IPD when compared with the combined homozygous states (for example, for rs600718, Mantel-Haenszel 2 x 2 chi(2)=7.576, P=0.006, odds ratio (OR)=0.67, 95% confidence interval (95% CI) for OR: 0.51-0.88; for rs616597, Mantel-Haenszel 2 x 2 chi(2)=8.715, P=0.003, OR=0.65, 95% CI: 0.49-0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong LD ('transethnic mapping').