Defining the rate of nutritional and metabolic derangements after pancreatic resection.

BACKGROUND AND AIMS: Pancreatic resection is associated with pancreatic exocrine insufficiency (PEI) leading to nutritional consequences. The Pancreatic Nutrition Clinic was established to diagnose and manage PEI through standardised nutritional assessment. In this prospective observational study, we aimed to define the rate of PEI, diabetes mellitus and nutritional abnormalities in patients who underwent pancreatic resection. METHODS: All Pancreatic Nutrition Clinic patients were included for analysis. Clinical data were prospectively obtained at initial assessment. Biochemical data included micronutrient levels, faecal elastase-1 and haemoglobin A1c. Bone mineral density and nutritional assessment were undertaken. RESULTS: Ninety-eight patients were included. Fifty-nine per cent (58/98) had undergone a pancreatoduodenectomy. Ninety-three patients had a faecal elastase-1 result, 65% (60/93) of which had a faecal elastase-1 less than 200 µg/g of faeces. Seventy-five patients (76%) of the total population required PERT, and thirty-nine (40%) were classified as malnourished using the patient-generated subjective global assessment tool. Seventy-two per cent (70/97) had a biochemical deficiency of one or more micronutrients. Thirty-eight people (39%) had diabetes mellitus. Of the seventy-eight patients with a bone mineral density scan available for analysis, 29% (23/78) had osteoporosis and 49% (38/78) osteopenia. CONCLUSIONS: Pancreatic exocrine insufficiency, micronutrient deficiency, bone disease, diabetes mellitus and malnutrition are highly prevalent in patients who have undergone pancreatic resection.

Transcriptomic analysis of the mouse retina after acute and chronic normobaric and hypobaric hypoxia.

Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors. Chronically reduced oxygen supply leads to retinal pathologies in patients and causes age-dependent retinal degeneration in mice. Hypoxia can result from decreased levels of inspired oxygen (normobaric hypoxia) or reduced barometric pressure (hypobaric hypoxia). Since the response of retinal cells to chronic normobaric or hypobaric hypoxia is mostly unknown, we examined the effect of six hypoxic conditions on the retinal transcriptome and photoreceptor morphology. Mice were exposed to short- and long-term normobaric hypoxia at 400 m or hypobaric hypoxia at 3450 m above sea level. Longitudinal studies over 11 weeks in normobaric hypoxia revealed four classes of genes that adapted differentially to the hypoxic condition. Seventeen genes were specifically regulated in hypobaric hypoxia and may affect the structural integrity of the retina, resulting in the shortening of photoreceptor segment length detected in various hypoxic groups. This study shows that retinal cells have the capacity to adapt to long-term hypoxia and that consequences of hypobaric hypoxia differ from those of normobaric hypoxia. Our datasets can be used as references to validate and compare retinal disease models associated with hypoxia.

Creating and sustaining effective pipeline initiatives to increase diversity in biostatistics: the ENAR Fostering Diversity in Biostatistics Workshop.

Biostatisticians with advanced degrees are highly sought after. Employment opportunities in the fields of mathematics and statistics are expected to increase dramatically by 2028. Underrepresentation of minorities in biostatistics has been a persistent problem, yielding a demographic landscape that differs substantially from the general US population. In some instances, students may have the appropriate quantitative skills, but are unaware of biostatistics and in other instances, students may not yet have the appropriate quantitative background, but are intellectually capable and willing to shore up those skills once they learn about biostatistics as a viable, exciting career option. Therefore, in order to ensure robust scientific advancement, there must be a concerted effort to increase the pipeline of intellectually talented persons available with exposure to the appropriate quantitative skills who are interested in careers in biostatistics. The overarching goal of this paper is to discuss the development, implementation, and impact of a federally funded pipeline initiative aimed at increasing the number of underrepresented minorities successful in graduate training and professional careers in biostatistics as well as establishing effective mentoring and networking relationships. Our findings provide a roadmap for the development of sustainable initiatives to promote diversity in biostatistics and STEM fields more broadly.

The future of lasers in onychomycosis.

INTRODUCTION: Laser therapy is one of the most promising device-based therapies for onychomycosis. To date, reported clinical efficacies, as well as anecdotal clinical results, have varied greatly, and the specific mechanism of action has not been well-elucidated. METHODS: Here, we provide an overview of the mechanisms of action and detailed analysis of the technical parameters involved in creating a laser that will be successfully fungicidal in onychomycosis. RESULTS: This review provides important insight into why the efficacies of laser studies reported to date vary so greatly and what is critical in order to obtain high efficacy in the clinical treatment of onychomycosis. CONCLUSIONS: There is substantial opportunity to improve the targeting and anti-targeting properties of lasers to address the specific considerations required to treat onychomycosis and, more generally, other dermal pathogens.

Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma.

BACKGROUND: Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common, there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single-agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. PATIENTS AND METHODS: Sixteen patients received single-agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose-limiting toxicity. The primary end point was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary end points included evaluation of safety, toxicity and progression-free survival (PFS). RESULTS: Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 receiving previous cytotoxic chemotherapy. The best ORR [partial (PR) or complete response (CR)] was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and overall survival were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. CONCLUSIONS: Single-agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.

Terbinafine in the treatment of dermatophyte toenail onychomycosis: a meta-analysis of efficacy for continuous and intermittent regimens.

OBJECTIVE: To compare mycological and complete cures of terbinafine continuous and intermittent regimens in the treatment of toenail onychomycosis. METHODS: The PubMed database was searched using the terms "terbinafine", "onychomycosis", "continuous" and "pulse(d)" or "intermittent". The inclusion criteria were head-to-head comparison of terbinafine pulse and continuous regimens for dermatophyte toenail infections. Risk ratios were calculated for intention-to-treat and evaluable patient analyses, when possible. Pooled estimates for total and subgroup analyses were calculated using a random effect model, Mantel-Haenszel method and their probabilities were calculated with z-statistics. RESULTS: Nine studies from eight publications were included. Two continuous regimens and four intermittent regimens were investigated. A pooled risk ratio of 0.87 was obtained for intention-to-treat (95% CI: 0.79-0.96, P = 0.004, n = 6) and evaluable patient (95% CI: 0.80-0.96, P = 0.003, n = 8) analyses of mycological cure, favouring continuous terbinafine. For complete cure, pooled risk ratios of 0.97 (95% CI: 0.77-1.23, P = 0.82, n = 7) for intention-to-treat and 0.93 (95% CI: 0.76-1.13, P = 0.44, n = 9) for evaluable patient analyses showed equality of the two regimens. The pulse regimen that demonstrated consistently comparable results to the continuous terbinafine regimen was two pulses of terbinafine 250 mg/day for 4 weeks on/4 weeks off. CONCLUSIONS: Meta-analysis of published studies of toenail onychomycosis showed that a continuous terbinafine regimen is generally significantly superior to a pulsed terbinafine regimen for mycological cure. In contrast, some pulse terbinafine regimens were as effective as continuous terbinafine regimens for complete cure.

Device-based therapies for onychomycosis treatment.

Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals, reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies.

Model selection for modified gravity.

In this article, we review model selection predictions for modified gravity scenarios as an explanation for the observed acceleration of the expansion history of the Universe. We present analytical procedures for calculating expected Bayesian evidence values in two cases: (i) that modified gravity is a simple parametrized extension of general relativity (GR; two nested models), such that a Bayes' factor can be calculated, and (ii) that we have a class of non-nested models where a rank-ordering of evidence values is required. We show that, in the case of a minimal modified gravity parametrization, we can expect large area photometric and spectroscopic surveys, using three-dimensional cosmic shear and baryonic acoustic oscillations, to 'decisively' distinguish modified gravity models over GR (or vice versa), with odds of ≫1:100. It is apparent that the potential discovery space for modified gravity models is large, even in a simple extension to gravity models, where Newton's constant G is allowed to vary as a function of time and length scale. On the time and length scales where dark energy dominates, it is only through large-scale cosmological experiments that we can hope to understand the nature of gravity.

An overview of evidence from systematic reviews evaluating early enteral nutrition in critically ill patients: more convincing evidence is needed.

International quality improvement initiatives such as Fast-Hug bring a focus on improving the delivery of early enteral nutrition to critically ill patients, however surveys demonstrate current practice remains variable. One way to reduce variability in practice is to provide strong evidence to convince clinicians to change. The purpose of this overview was to identify current best evidence supporting the delivery of early enteral nutrition in critical illness. We sought high-quality evidence in the form of systematic reviews containing meta-analyses of randomised controlled trials. Two authors independently identified studies and assessed methodological quality. Data sources included Medline, EMBASE and hand-searching of guideline reference lists. The literature search identified five systematic reviews that summarised 30 clinical trials. These systematic reviews focused on acutely hospitalised patients, critical illness, burns, elective intestinal surgery and pancreatitis. Early enteral nutrition significantly reduced mortality in elective intestinal surgery patients (relative risk 0.41, 95% confidence interval 0.18 to 0.93, P = 0.03, I2 = 0.0%) and significantly reduced infectious complications in acutely ill hospitalised patients (relative risk 0.45, 95% confidence interval 0.3 to 0.66, P = 0.00006, heterogeneity P = 0.049). Four of five identified systematic reviews had key methodological quality deficiencies. The results of this overview highlight the variability in the evidence regarding the benefits of early enteral nutrition in critically ill patient populations. The inconsistent delivery to critically ill patients may be explained by the lack of convincing evidence. Better evidence may be needed to reduce the irregularity in the provision of early enteral nutrition to critically ill patients.

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress.

After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15(PAF). We further show that the expressions of ATF3 and p15(PAF) is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15(PAF) compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15(PAF) expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15(PAF) expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15(PAF) as novel gatekeepers of genomic integrity after UV exposure.

Catalytic relationships between type I and type II iterative polyketide synthases: The Aspergillus parasiticus norsolorinic acid synthase.

Norsolorinic acid synthase (NSAS) is a type I iterative polyketide synthase that occurs in the filamentous fungus Aspergillus parasiticus. PCR was used to clone fragments of NSAS corresponding to the acyl carrier protein (ACP), acyl transferase (AT) and beta-ketoacyl-ACP synthase (KS) catalytic domains. Expression of these gene fragments in Escherichia coli led to the production of soluble ACP and AT proteins. Coexpression of ACP with E. coli holo-ACP synthase (ACPS) let to production of NSAS holo-ACP, which could also be formed in vitro by using Streptomyces coelicolor ACPS. Analysis by mass spectrometry showed that, as with other type I carrier proteins, self-malonylation is not observed in the presence of malonyl CoA alone. However, the NSAS holo-ACP serves as substrate for S. coelicolor MCAT, S. coelicolor actinorhodin holo-ACP and NSAS AT domain-catalysed malonate transfer from malonyl CoA. The AT domain could transfer malonate from malonyl CoA to NSAS holo-ACP, but not hexanoate or acetate from either the cognate CoA or FAS ACP species to NSAS holo-ACP. The NSAS holo-ACP was also active in actinorhodin minimal PKS assays, but only in the presence of exogenous malonyl transferases.

Host choice promotes reproductive isolation between host races of the larch budmoth Zeiraphera diniana.

The chances for sympatric speciation are improved if ecological divergence leads to assortative mating as a by-product. This effect is known in parasites that find mates using host cues, but studies of larch- and pine-feeding races of the larch budmoth (Zeiraphera diniana, Lepidoptera: Tortricidae) suggest it may also occur when mate attraction is via sex pheromones that are independent of habitat. We have previously shown that females releasing pheromones on or near their own host attract more males of their own race than if placed on the alternative host. This host effect would enhance assortative mating provided adults preferentially alight on their native hosts. Here we investigate alighting preferences in natural mixed forest using a novel likelihood analysis of genotypic clusters based on three semidiagnostic allozyme loci. Both larch and pine females show a realized alighting preference for their own host of 86%. The equivalent preferences of males were 79% for the larch race and 85% for the pine race. These preferences are also detectable in small-scale laboratory experiments, where alighting preferences of larch and pine races towards their own hosts were, respectively, 67 and 66% in females and 69 and 63% in males. Pure larch race moths reared in the laboratory had alighting choice similar to moths from natural populations, while hybrids were intermediate, showing that alighting preferences were heritable and approximately additive. The field estimates of alighting preference, coupled with earlier work on mate choice, yield an estimated rate of natural hybridization between sympatric host races of 2.2-3.8% per generation. Divergent alighting choice enhances pheromone-mediated assortative mating today, and is likely to have been an important cause of assortative mating during initial divergence in host use. Because resources are normally 'coarse-grained' in space and time, assortative mating due to ecological divergence may be a more important catalyst of sympatric speciation than generally realized.

Resistance to mantle flow inferred from the electromagnetic strike of the Australian upper mantle.

Seismic anisotropy is thought to result from the strain-induced lattice-preferred orientation of mantle minerals, especially olivine, owing to shear waves propagating faster along the a-axis of olivine crystals than along the other axes. This anisotropy results in birefringence, or 'shear-wave splitting', which has been investigated in numerous studies. Although olivine is also anisotropic with respect to electrical conductivity (with the a-axis being most conductive), few studies of the electrical anisotropy of the upper mantle have been undertaken, and these have been limited to relatively shallow depths in the lithospheric upper mantle. Theoretical models of mantle flow have been used to infer that, for progressive simple shear imparted by the motion of an overriding tectonic plate, the a-axes of olivine crystals should align themselves parallel to the direction of plate motion. Here, however, we show that a significant discrepancy exists between the electromagnetic strike of the mantle below Australia and the direction of present-day absolute plate motion. We infer from this discrepancy that the a-axes of olivine crystals are not aligned with the direction of the present-day plate motion of Australia, indicating resistance to deformation of the mantle by plate motion.

Different associations of blood pressure with 24-hour urinary sodium excretion among pre- and post-menopausal women. WHO Cardiovascular Diseases and Alimentary Comparison (WHO-CARDIAC) Study.

OBJECTIVE: Having found no definite relationship between blood pressure (BP) and 24h sodium excretion in women aged 48-56 years (in contrast to the results in men of the same age) in the WHO Cardiovascular Diseases and Alimentary Comparison (WHO-CARDIAC) Study, we analyzed the data to investigate whether the sodium-BP association differed between pre- and post-menopausal women. DESIGN AND METHODS: The WHO-CARDIAC is a multicenter cross-sectional study, involving, as of July 2000, 60 collaborating centers in 25 countries. In each center, 100 men and 100 women aged 48-56 years were selected randomly from the general population of the area. In this report, 2,212 women in 21 centers located in 17 countries worldwide, who had data on menopausal status, were studied. RESULTS: After adjustment for age, body mass index (BMI) and 24h urinary potassium excretion, 24h sodium excretion was positively and significantly associated with systolic blood pressure (SBP) [pooled regression coefficient: 0.037 (SE 0.01), P < 0.01] and with diastolic blood pressure (DBP) [0.023 (0.006), P< 0.01] in post-menopausal women. Pooled regression coefficients of sodium-BP association were not significant in pre-menopausal women (P< 0.05). Cross-center correlation analyses of the 21 centers showed that 24h sodium excretion was positively associated with SBP and DBP in both pre- and post-menopausal women, and this positive association between sodium excretion and SBP was significant in post-menopausal women (R2 = 0.23, P = 0.029). CONCLUSION: Different associations between sodium and BP were observed in women with pre- and post-menopausal status. There may be a tendency for salt sensitivity to increase at the menopause.

GLUT4--at the cross roads between membrane trafficking and signal transduction.

GLUT4 is a mammalian facilitative glucose transporter that is highly expressed in adipose tissue and striated muscle. In response to insulin, GLUT4 moves from intracellular storage areas to the plasma membrane, thus increasing cellular glucose uptake. While the verification of this 'translocation hypothesis' (Cushman SW, Wardzala LJ. J Biol Chem 1980;255: 4758-4762 and Suzuki K, Kono T. Proc Natl Acad Sci 1980;77: 2542-2545) has increased our understanding of insulin-regulated glucose transport, a number of fundamental questions remain unanswered. Where is GLUT4 stored within the basal cell? How does GLUT4 move to the cell surface and what mechanism does insulin employ to accelerate this process? Ultimately we require a convergence of trafficking studies with research in signal transduction. However, despite more than 30 years of intensive research we have still not reached this point. The problem is complex, involving at least two separate signal transduction pathways which feed into what appears to be a very dynamic sorting process. Below we discuss some of these complexities and highlight new data that are bringing us closer to the resolution of these questions.

Immunological and in-vivo neurological studies on a benzoic acid-specific T cell-derived antigen-binding molecule from the serum of a toluene-sensitive patient.

T-cell-derived antigen-binding molecules (TABMs) specific for benzoic acid were isolated from the serum of a toluene-sensitive patient. The resulting purified TABMs (BA-TABMs) did not contain immunoglobulin G and were associated with the cytokine transforming growth factor-beta (TGF-beta). BA-TABMs bound to benzoic acid conjugated to human serum albumin (BA-HSA), as well as to other chemicals conjugated to human serum albumin-including dinitrophenol and oxazolone. The binding of BA-TABMs to the conjugated chemicals increased the level of detectable TGF-beta, and a similar effect was observed with the unconjugated chemicals, benzoic acid and 2,4-dinitrophenol glycine. The increase in TGF-beta was critically dependent on the ratio between BA-TABMs and the conjugated or unconjugated chemicals; the increase was optimum at intermediate concentrations and absent at low and high concentrations. The authors used an established animal model in vivo and demonstrated that TGF-beta enhanced the inflammatory response induced by the release of neuropeptides from sensory nerves; this enhancement occurred in a dose-dependent manner. The BA-TABMs also enhanced this neurogenic inflammatory response in a dose-dependent manner, and this effect was blocked by anti-TGF-beta antibody. When the authors added either BA-HSA or benzoic acid, the effect of BA-TABMs on neurogenic inflammation was further enhanced at intermediate concentrations of antigen and was unaltered or reduced at higher concentrations. TABMs specific to particular chemicals, as a result of their association with cytokines (e.g., TGF-beta), may be implicated in symptom production in chemically sensitive patients.

SH3-domain-containing proteins function at distinct steps in clathrin-coated vesicle formation.

Several SH3-domain-containing proteins have been implicated in endocytosis by virtue of their interactions with dynamin; however, their functions remain undefined. Here we report the efficient reconstitution of ATP-, GTP-, cytosol- and dynamin-dependent formation of clathrin-coated vesicles in permeabilized 3T3-L1 cells. The SH3 domains of intersectin, endophilin I, syndapin I and amphiphysin II inhibit coated-vesicle formation in vitro through interactions with membrane-associated proteins. Most of the SH3 domains tested selectively inhibit late events involving membrane fission, but the SH3A domain of intersectin uniquely inhibits intermediate events leading to the formation of constricted coated pits. These results suggest that interactions between SH3 domains and their partners function sequentially in endocytic coated-vesicle formation.

Casein kinase II activity is required for transferrin receptor endocytosis.

The effect of protein kinase inhibitors on transferrin receptor (TR) internalization was examined in HeLa, A431, 3T3-L1 cells, and primary chicken embryo fibroblasts. We show that TR endocytosis is not affected by tyrosine kinase or protein kinase C inhibitors, but is inhibited by one serine/threonine kinase inhibitor, H-89. Inhibition occurred within 15 min, was completely reversible after H-89 withdrawal, and was specific for endocytosis rather than pinocytosis since a TR mutant lacking an internalization signal was not affected. Interestingly, H-89 also inhibited the internalization of a TR chimera containing the major histocompatibility complex class II invariant chain cytoplasmic tail, indicating that the effect was not specific for the TR. Since H-89 inhibits a number of kinases, we employed a permeabilized cell endocytosis assay to further characterize the kinase. In permeabilized 3T3-L1 cells, addition of pseudosubstrate inhibitor peptides of casein kinase II (CKII) blocked TR internalization by more than 50%, whereas pseudosubstrates of cyclic AMP-dependent kinase A, protein kinase C, and casein kinase I had no effect. Furthermore, addition of purified CKII to the cell-free reactions containing CKII pseudosubstrates reversed the endocytosis block, suggesting that CKII or a CKII-like activity is required for constitutive endocytosis.