Sterile Corneal Infiltrate Management After Corneal Crosslinking in Pediatric Keratoconus.
A 6-year-old female was admitted to the ophthalmology department with a preliminary diagnosis of keratoconus. An accelerated cross-linking (CXL) protocol (9 mW/cm2 in 10 minutes) was performed on the right eye. On postoperative day 2, a slit-lamp examination revealed 2 corneal infiltrates with grade 3 haze. Since there was no growth in the cultivated cultures and no response to topical antibiotic treatment, the infiltrates were considered to be sterile, and topical 1% prednisolone drops were applied hourly. Despite topical steroid treatment of 1% prednisolone on postoperative day 5, no significant improvement was observed in the patient's symptoms and slit-lamp findings. Therefore, systemic 1 mg/kg prednisolone (total dose, 15 mg) was added to the treatment on postoperative day 5. One day after initiating the systemic steroid treatment, the infiltrates had shrunk, and the patient's complaints decreased. In patients with keratoconus who are under 10 years of age, the addition of a potent steroid regimen to the treatment may be essential in cases with suspected infiltrates after CXL treatment.


Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
Steroid hormone production within the gonads and adrenals requires a continuous supply of cholesterol derived from de novo synthesis within the gland and from uptake of circulating plasma lipoproteins. Steroid hormone secretion was prospectively studied over 24 months in 64 hypercholesterolemic subjects (group I, aged 52 +/- 1 years [mean +/- SEM], 61% male) participating in a randomized double-blind clinical trial of pravastatin (20 to 80 mg daily), a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, compared with patients taking cholestyramine or other lipid-lowering drugs (group II). Attempts were made in both groups to maintain serum low-density lipoprotein cholesterol (LDL-C) levels between the 25th and 50th percentile for age and gender. At 24 months, serum LDL-C level decreased by 42% +/- 3% in group I and 44% +/- 1% in group II (P < .001 v baseline, NS between groups). Basal secretion of cortisol, aldosterone, and dehydroepiandrostenedione sulfate (DHEA-S) was maintained throughout the study. However, the serum DHEA-S secretory response to Cortrosyn (Organon, West Orange, NJ) diminished in both treatment groups at 6 and 12 months (P < .05). In men, basal serum testosterone levels and the testosterone response to human chorionic gonadotropin (HCG) did not change. There was some diminution of sperm motility noted in both treatment groups at 6 and 12 months in the subset of men undergoing semen analysis (n = 14, P < .05). In conclusion, pravastatin had no significant effect on steroid metabolism. Changes noted in DHEA-S were not specific for pravastatin, suggesting that this impairment is related to lipid-lowering effects.


Relative importance of Ixodes ricinus and Ixodes trianguliceps as vectors for Anaplasma phagocytophilum and Babesia microti in field vole (Microtus agrestis) populations.
The importance of Ixodes ricinus in the transmission of tick-borne pathogens is well recognized in the United Kingdom and across Europe. However, the role of coexisting Ixodes species, such as the widely distributed species Ixodes trianguliceps, as alternative vectors for these pathogens has received little attention. This study aimed to assess the relative importance of I. ricinus and I. trianguliceps in the transmission of Anaplasma phagocytophilum and Babesia microti among United Kingdom field voles (Microtus agrestis), which serve as reservoir hosts for both pathogens. While all instars of I. trianguliceps feed exclusively on small mammals, I. ricinus adults feed primarily on larger hosts such as deer. The abundance of both tick species and pathogen infection prevalence in field voles were monitored at sites surrounded with fencing that excluded deer and at sites where deer were free to roam. As expected, fencing significantly reduced the larval burden of I. ricinus on field voles and the abundance of questing nymphs, but the larval burden of I. trianguliceps was not significantly affected. The prevalence of A. phagocytophilum and B. microti infections was not significantly affected by the presence of fencing, suggesting that I. trianguliceps is their principal vector. The prevalence of nymphal and adult ticks on field voles was also unaffected, indicating that relatively few non-larval I. ricinus ticks feed upon field voles. This study provides compelling evidence for the importance of I. trianguliceps in maintaining these enzootic tick-borne infections, while highlighting the potential for such infections to escape into alternative hosts via I. ricinus.


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.


Ten questions about systems biology.
In this paper we raise 'ten questions' broadly related to 'omics', the term systems biology, and why the new biology has failed to deliver major therapeutic advances for many common diseases, especially diabetes and cardiovascular disease. We argue that a fundamentally narrow and reductionist perspective about the contribution of genes and genetic variants to disease is a key reason 'omics' has failed to deliver the anticipated breakthroughs. We then point out the critical utility of key concepts from physiology like homeostasis, regulated systems and redundancy as major intellectual tools to understand how whole animals adapt to the real world. We argue that a lack of fluency in these concepts is a major stumbling block for what has been narrowly defined as 'systems biology' by some of its leading advocates. We also point out that it is a failure of regulation at multiple levels that causes many common diseases. Finally, we attempt to integrate our critique of reductionism into a broader social framework about so-called translational research in specific and the root causes of common diseases in general. Throughout we offer ideas and suggestions that might be incorporated into the current biomedical environment to advance the understanding of disease through the perspective of physiology in conjunction with epidemiology as opposed to bottom-up reductionism alone.


Trans-Right-Ventricle and Transpulmonary MicroRNA Gradients in Human Pulmonary Arterial Hypertension.
We investigated whether concentrations of circulating microRNAs differ across the hypertensive right ventricle and pulmonary circulation, and correlate with hemodynamic/echocardiographic variables in patients with pulmonary arterial hypertension versus nonpulmonary arterial hypertension controls. Prospective blood collection during cardiac catheterization from the superior vena cava, pulmonary artery, and ascending aorta in 12 children with pulmonary arterial hypertension and nine matched nonpulmonary arterial hypertension controls, followed by an unbiased quantitative polymerase chain reaction array screen for 754 microRNAs in plasma. Children's hospital at a medical school. Twelve pulmonary arterial hypertension patients included as follows: idiopathic pulmonary arterial hypertension (5), pulmonary arterial hypertension (2), pulmonary arterial hypertension-repaired congenital heart disease (4), portopulmonary pulmonary hypertension (1). Nine nonpulmonary arterial hypertension controls included as follows: mild/moderate left ventricular outflow tract obstruction (7), mediastinal teratoma (1), portal vein stenosis (1). Standard pulmonary arterial hypertension treatment. Analysis of differential concentrations (false discovery rate < 0.05) revealed two trans-right-ventricle microRNA gradients (pulmonary artery vs superior vena cava): miR-193a-5p (step-up in pulmonary arterial hypertension and step-down in control) and miR-423-5p (step-down in pulmonary arterial hypertension and step-up in control) and two transpulmonary microRNA gradients (ascending aorta vs pulmonary artery): miR-26b-5p (step-down only in control) and miR-331-3p (step-up only in pulmonary arterial hypertension). Between-group comparison revealed miR-29a-3p, miR-26a-5p, miR-590-5p, and miR-200c-3p as upregulated in pulmonary arterial hypertension-superior vena cava and miR-99a-5p as downregulated in pulmonary arterial hypertension-pulmonary artery. The differential microRNA-concentrations correlated with prognostic hemodynamic variables (pulmonary vascular resistance, tricuspid annular plane systolic excursion, etc.). We identified for the first time in human disease (pulmonary arterial hypertension) trans-right-ventricle and transpulmonary microRNA gradients in blood plasma. Several of these microRNAs regulate transcripts that drive cardiac remodeling and pulmonary arterial hypertension and are now emerging as epigenetic pulmonary arterial hypertension biomarkers and targets for therapy.


Social insects dominate eastern US temperate hardwood forest macroinvertebrate communities in warmer regions.
Earthworms, termites, and ants are common macroinvertebrates in terrestrial environments, although for most ecosystems data on their abundance and biomass is sparse. Quantifying their areal abundance is a critical first step in understanding their functional importance. We intensively sampled dead wood, litter, and soil in eastern US temperate hardwood forests at four sites, which span much of the latitudinal range of this ecosystem, to estimate the abundance and biomass m(-2) of individuals in macroinvertebrate communities. Macroinvertebrates, other than ants and termites, differed only slightly among sites in total abundance and biomass and they were similar in ordinal composition. Termites and ants were the most abundant macroinvertebrates in dead wood, and ants were the most abundant in litter and soil. Ant abundance and biomass m(-2) in the southernmost site (Florida) were among the highest values recorded for ants in any ecosystem. Ant and termite biomass and abundance varied greatly across the range, from <1% of the total macroinvertebrate abundance (in the northern sites) to >95% in the southern sites. Our data reveal a pronounced shift to eusocial insect dominance with decreasing latitude in a temperate ecosystem. The extraordinarily high social insect relative abundance outside of the tropics lends support to existing data suggesting that ants, along with termites, are globally the most abundant soil macroinvertebrates, and surpass the majority of other terrestrial animal (vertebrate and invertebrate) groups in biomass m(-2). Our results provide a foundation for improving our understanding of the functional role of social insects in regulating ecosystem processes in temperate forest.


Total hip resurfacing in patients who are sixty years of age or older.
Metal-on-metal total hip resurfacing arthroplasty has been associated with excellent early results in patients who are younger than sixty years of age, but it remains controversial whether this procedure is appropriate in older patients. The purpose of the present study was to compare the clinical and radiographic outcomes after hip resurfacing in two cohorts of patients: those who were sixty years of age or older, and those who were younger than sixty years of age. Between November 2002 and August 2005, thirty-five patients (forty hips) who were sixty years of age or older were managed with metal-on-metal total hip resurfacing arthroplasty. The outcomes of these patients were compared with those of 130 patients (153 hips) who were younger than sixty years of age but otherwise had similar preoperative parameters and who had resurfacing arthroplasty performed during the same time interval and by the same surgeon. We evaluated Harris hip scores, Short Form-12 scores, and complications as well as radiographic alignment and radiolucencies. At a mean follow-up time of thirty-six months, the mean Harris hip scores improved from 52 points to 94 points in the older patient cohort and from 53 points to 92 points in the younger patient cohort. The final Short Form-12 scores of the two groups were also similar. Two patients who were sixty years or older and five of the younger patients required conversion to a conventional total hip arthroplasty. Femoral neck fracture was the reason for one conversion in each group. There were no impending radiographic failures in either cohort. Although national registries indicate that the risk of femoral neck fracture is higher in older patients, the present study found that these patients had excellent clinical outcomes that were similar to those of patients who were younger. We await longer follow-up results to determine further outcomes in these patients.


Current management of aortic arch lesions with hybrid procedures: a tailored approach to a progressive disease.
In the current era of cardiac and aortic surgery lines between open and endovascular approaches are becoming blurred. Hybrid techniques emerged with the availability of endovascular devices and the idea that combining open operations with a stent graft might provide a treatment option to those patients deemed too high-risk for conventional surgery. As these procedures evolved, it became clear that they still carried significant risk especially for the "inoperable" or "high-risk" patients, but they also offered new options for treating complex pathologies involving multiple segments of the aorta. Hybrid techniques not only provide the potential for less invasive aortic repair, but must be considered as an important complementary treatment option for patients with aortic disease, allowing for a potentially more effective and complete repair. The objective of this article is to review the current options for hybrid arch repair and the indications for choosing the various techniques based on pathologic presentation.


Identification of three novel mutations in fourteen patients with citrullinemia type 1.
Citrullinemia type 1 (CTLN1) is an autosomal recessive genetic disorder caused by mutations in the argininosuccinate synthetase 1 (ASS1) gene, which encodes for the argininosuccinate synthetase enzyme. Here, we report genetic and clinical characterizations of 14 patients with citrullinemia type 1. The study group consisted of 14 patients (4 females, 10 males) diagnosed with citrullinemia type 1 from three centers in Turkey. Age of onset, clinical presentation, initial citrulline and ammonia levels, family history and molecular genetic analysis were retrospectively evaluated. The mean age of the cohort and the mean age at the time of diagnosis were 48.3±36.5months (min: 12days, max: 10years) and 11.6±26.2months (min: 3days, max: 8years), respectively. In four patients, a homozygous p.Gly390Arg pathogenic variant was detected. All patients homozygous for p.Gly390Arg were diagnosed during the newborn period with the clinical presentation of classical citrullinemia. In each two patients, homozygous p.Arg86His, c.773+49C>T and p.Gly362Val pathogenic variants were detected. Clinical presentation was compatible with the mild form of the disease in patients homozygous for c.773+49C>T and for Gly362Val. Novel compound heterozygous genotypes (p.Ala164Pro/p.Gly390Arg; p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in five patients. Of these, three siblings with CTLN1 were diagnosed with the compound heterozygous genotype p.Ala164Pro/p.Gly390Arg at the age of 4days, 5days and 2years, respectively. The other two patients with novel compound heterozygous genotypes (p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in the first month of life as neonatal onset form and were born to non-consanguineous parents. In our study, consistent with the literature, a correlation was found between homozygous p.Gly390Arg mutation and the classic neonatal onset form. Mild citrullinemia was detected in patients with c.773+49C>T or p.Gly362Val pathogenic variants. This study adds to our understanding of the molecular genetic background of patients with CTLN1, and allows to infer on the correlation between the genotype and phenotype of the disease.


Stage-specific regulation of caspase activity in drosophila oogenesis.
In Drosophila oogenesis, the programmed cell death of germline cells occurs predominantly at three distinct stages. These cell deaths are subject to distinct regulatory controls, as cell death during early and midoogenesis is stress-induced, whereas the cell death of nurse cells in late oogenesis is developmentally regulated. In this report, we show that the effector caspase Drice is activated during cell death in both mid- and late oogenesis, but that the level and localization of activity differ depending on the stage. Active Drice formed localized aggregates during nurse cell death in late oogenesis; however, active Drice was found more ubiquitously and at a higher level during germline cell death in midoogenesis. Because Drice activity was limited in late oogenesis, we examined whether another effector caspase, Dcp-1, could drive the unique morphological events that occur normally in late oogenesis. We found that premature activation of the effector caspase, Dcp-1, resulted in a disappearance of filamentous actin, rather than the formation of actin bundles, suggesting that Dcp-1 activity must also be restrained in late oogenesis. Overexpression of the caspase inhibitor DIAP1 suppressed cell death induced by Dcp-1 but had no effect on cell death during late oogenesis. This limited caspase activation in dying nurse cells may prevent destruction of the nurse cell cytoskeleton and the connected oocyte.


The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.
Research on suicide prevention and interventions requires a standard method for assessing both suicidal ideation and behavior to identify those at risk and to track treatment response. The Columbia-Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity of suicidal ideation and behavior. The authors examined the psychometric properties of the scale. The C-SSRS's validity relative to other measures of suicidal ideation and behavior and the internal consistency of its intensity of ideation subscale were analyzed in three multisite studies: a treatment study of adolescent suicide attempters (N=124); a medication efficacy trial with depressed adolescents (N=312); and a study of adults presenting to an emergency department for psychiatric reasons (N=237). The C-SSRS demonstrated good convergent and divergent validity with other multi-informant suicidal ideation and behavior scales and had high sensitivity and specificity for suicidal behavior classifications compared with another behavior scale and an independent suicide evaluation board. Both the ideation and behavior subscales were sensitive to change over time. The intensity of ideation subscale demonstrated moderate to strong internal consistency. In the adolescent suicide attempters study, worst-point lifetime suicidal ideation on the C-SSRS predicted suicide attempts during the study, whereas the Scale for Suicide Ideation did not. Participants with the two highest levels of ideation severity (intent or intent with plan) at baseline had higher odds for attempting suicide during the study. These findings suggest that the C-SSRS is suitable for assessment of suicidal ideation and behavior in clinical and research settings.


Eye Gaze Behavior at Turn Transition: How Aphasic Patients Process Speakers' Turns during Video Observation.
The human turn-taking system regulates the smooth and precise exchange of speaking turns during face-to-face interaction. Recent studies investigated the processing of ongoing turns during conversation by measuring the eye movements of noninvolved observers. The findings suggest that humans shift their gaze in anticipation to the next speaker before the start of the next turn. Moreover, there is evidence that the ability to timely detect turn transitions mainly relies on the lexico-syntactic content provided by the conversation. Consequently, patients with aphasia, who often experience deficits in both semantic and syntactic processing, might encounter difficulties to detect and timely shift their gaze at turn transitions. To test this assumption, we presented video vignettes of natural conversations to aphasic patients and healthy controls, while their eye movements were measured. The frequency and latency of event-related gaze shifts, with respect to the end of the current turn in the videos, were compared between the two groups. Our results suggest that, compared with healthy controls, aphasic patients have a reduced probability to shift their gaze at turn transitions but do not show significantly increased gaze shift latencies. In healthy controls, but not in aphasic patients, the probability to shift the gaze at turn transition was increased when the video content of the current turn had a higher lexico-syntactic complexity. Furthermore, the results from voxel-based lesion symptom mapping indicate that the association between lexico-syntactic complexity and gaze shift latency in aphasic patients is predicted by brain lesions located in the posterior branch of the left arcuate fasciculus. Higher lexico-syntactic processing demands seem to lead to a reduced gaze shift probability in aphasic patients. This finding may represent missed opportunities for patients to place their contributions during everyday conversation.


Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thickness.
Pathogenic generation of amyloid β-peptide (Aβ) by sequential cleavage of β-amyloid precursor protein (APP) by β- and γ-secretases is widely believed to causally underlie Alzheimer disease (AD). β-Secretase initially cleaves APP thereby generating a membrane-bound APP C-terminal fragment, from which γ-secretase subsequently liberates 37-43-amino acid long Aβ species. Although the latter cleavages are intramembranous and although lipid alterations have been implicated in AD, little is known of how the γ-secretase-mediated release of the various Aβ species, in particular that of the pathogenic longer variants Aβ(42) and Aβ(43), is affected by the lipid environment. Using a cell-free system, we have directly and systematically investigated the activity of γ-secretase reconstituted in defined model membranes of different thicknesses. We found that bilayer thickness is a critical parameter affecting both total activity as well as cleavage specificity of γ-secretase. Whereas the generation of the pathogenic Aβ(42/43) species was markedly attenuated in thick membranes, that of the major and rather benign Aβ(40) species was enhanced. Moreover, the increased production of Aβ(42/43) by familial AD mutants of presenilin 1, the catalytic subunit of γ-secretase, could be substantially lowered in thick membranes. Our data demonstrate an effective modulation of γ-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic Aβ(42/43) species.


Glucocorticoid therapy-induced memory deficits: acute versus chronic effects.
Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 +/- 1.0 years, mean +/- SE) with low to moderate doses of prednisone (7.5 +/- 0.8 mg, mean +/- SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.


Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas.
Gallbladder carcinoma is the fifth most common malignancy of the gastrointestinal tract. The absolute characteristics of the disease are the high mortality rate due to the late discovery of a tumor and the low therapeutic possibilities except by surgical intervention. In oncology we can predict the outcome of the disease with a combination of classical standard clinico/pathological parameters (stage of the tumors, differentiation) and the intrinsic genetic and biochemical properties of the tumor. Such intrinzic properties of the tumors that are connected with the outcome of the disease are the denominators (markers). The author searched extensively for the expression and influence of 3 markers included in chronic inflammation and early carcinogenesis, cell cycle regulation and tissue hypoxia: cyclooxygenase-2 (COX-2), p53 gene and glucose transporter-1 protein (GLUT-1). The author discusses their possible role in the development as well as fighting this disease, if specific medications targeting them were available.


Proteomics and the search for welfare and stress biomarkers in animal production in the one-health context.
Stress and welfare are important factors in animal production in the context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define the markers of stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of various stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how proteomics and systems biology are key elements to the study of stress and welfare in farm animals and powerful tools for animal welfare, health and productivity.


Human gammadelta T cells from G-CSF-mobilized donors retain strong tumoricidal activity and produce immunomodulatory cytokines after clinical-scale isolation.
Human gammadelta T cells are a small fraction of T cells that have been shown to exert major histocompatibility (MHC)-unrestricted natural cytotoxicity against a variety of solid tumors and some subsets of leukemias and lymphomas. They are also involved in the immune response to certain bacterial, viral, and parasitic infections and expand significantly in CMV- or HSV-infected organ allografts. They are able to mediate antibody-dependent cytotoxicity and are not alloreactive, which makes them attractive candidates for cell-based immunotherapy. However, their frequency in peripheral blood is low and ex vivo expansion of gammadelta T cells is labor-extensive, does not always yield cells with full innate cytotoxic power, and has the potential for microbial contamination. Therefore, the authors developed a clinical-scale, automated cell purification method for the efficient enrichment of gammadelta T cells from leukapheresis products. Six leukapheresis products were purified for gammadelta T cells using a single-step immunomagnetic method. Purity and phenotype were assessed by flow cytometry. A standard Europium release assay was performed to determine the cytotoxic capacity of the cells. Cytokine production was measured using a multiplex sandwich immunoassay. The mean percentage of gammadelta T cells in the final product was 91%, with an average recovery of 63%. The cells showed a high co-expression of CD8, CD56, CD28, and CD11b/CD18. In some products an unusually high proportion of Vgamma9Vdelta1 T cells was found. The isolated cells were cytotoxic against the neuroblastoma cell line NB1691 and the erythroleukemic line K562 in vitro. They were able to produce a variety of immunomodulatory cytokines such as IFNgamma, TNFalpha, and MIP-1beta, but also GM-CSF and G-CSF when co-incubated in culture with and without various stimuli. In summary, the authors describe a rapid, automated, and efficient method for the large-scale enrichment of human gammadelta T cells. The cytotoxic properties of the cells were preserved. This method yields sufficient purified gammadelta T cells for use in adoptive immunotherapy as well as laboratory investigations and animal studies.


Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation.
Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.


The evolutionary roots of human decision making.
Humans exhibit a suite of biases when making economic decisions. We review recent research on the origins of human decision making by examining whether similar choice biases are seen in nonhuman primates, our closest phylogenetic relatives. We propose that comparative studies can provide insight into four major questions about the nature of human choice biases that cannot be addressed by studies of our species alone. First, research with other primates can address the evolution of human choice biases and identify shared versus human-unique tendencies in decision making. Second, primate studies can constrain hypotheses about the psychological mechanisms underlying such biases. Third, comparisons of closely related species can identify when distinct mechanisms underlie related biases by examining evolutionary dissociations in choice strategies. Finally, comparative work can provide insight into the biological rationality of economically irrational preferences.


How frequently do large bowel diverticula perforate? An incidence and cross-sectional study.
The aetiology of perforation of large bowel diverticula is poorly understood and a case-control study is required to identify the causes. Before such a study can be attempted, the incidence must be determined and groups at particular risk identified. Cases of perforated large bowel diverticula living in the Norwich postal code region treated between 1995 and 1997 were identified. Fifty-eight cases presented in a population of 531 241. The incidence was 4.0 cases per 100,000 per year, increased with age and was higher in men than women (5.8 vs 3.1). The most frequently used drugs were non-steroidal anti-inflammatory drugs (NSAIDs) (29%) and opiate analgesics (26% of cases). This is the first report of the incidence of perforated diverticular disease and allows a calculation of the population size needed to recruit sufficient cases for an aetiological investigation. The differences in incidence between genders should prompt a search for factors which differ between the sexes such as diet. NSAIDs are a known risk factor, although the data show that opiate analgesics should be investigated.


Synchrotron x-ray scattering studies of water intercalation in a layered synthetic silicate.
Synchrotron x-ray diffraction studies were performed on a synthetic layered silicate Fluorohectorite clay. Diffraction patterns along the stacking direction were obtained in surface reflection and bulk transmission geometries on bulk pressed samples under controlled temperature and relative humidity. One-dimensional structure factors modeling the positions of the intercalant atoms have been obtained for three stable hydration states. From the narrow (00l) peak widths we conclude that well-crystallized domains consist of stacks of about 100 platelets, forming crystallites of the order of 0.1 microm thick. These crystallites have an orientational angular distribution of about 24 degrees around the stacking direction and represent the solid framework for microporosity in these samples.


Optimization and validation of recombinant serological tests for African Swine Fever diagnosis based on detection of the p30 protein produced in Trichoplusia ni larvae.
We describe the validation of an enzyme-linked immunosorbent assay (ELISA) and confirmatory immunoblotting assays based on a recombinant p30 protein (p30r) produced in insect larvae using a baculovirus vector. Such validation included the following: (i) the scaling up and standardization of p30r production and the associated immunoassays, (ii) a broad immunological analysis using a large number of samples (a total of 672) from Spain and different African locations, and (iii) the detection of the ASF virus (ASFV)-antibody responses at different times after experimental infection. Yields of p30r reached up to 15% of the total protein recovered from the infected larvae at 3 days postinfection. Serological analysis of samples collected in Spain revealed that the p30r-based ELISA presented similar sensitivity to and higher specificity than the conventional Office International des Epizooties-approved ASFV ELISA. Moreover, the p30r ELISA was more sensitive than the conventional ELISA test in detecting ASFV-specific antibodies in experimentally infected animals at early times postinfection. Both the recombinant and conventional ELISAs presented variable rates of sensitivity and specificity with African samples, apparently related to their geographical origin. Comparative analyses performed on the sequences, predicted structures, and antigenicities of p30 proteins from different Spanish and African isolates suggested that variability among isolates might correlate with changes in antigenicity, thus affecting detection by the p30r ELISA. Our estimations indicate that more than 40,000 ELISA determinations and 2,000 confirmatory immunoblotting tests can be performed with the p30r protein obtained from a single infected larva, making this a feasible and inexpensive strategy for production of serological tests with application in developing countries.


A novel family of structurally stable double stranded DNA catenanes.
Here we describe the design, assembly and characterisation of different structurally stable and highly polyvalent DNA catenanes. We synthesized a series of different catenated DNA nanostructures, among them symmetric ones containing two 126 or 168 base-pair rings, non-symmetric ones with a 126 and a 168 base-pair ring, and a [3]catenane containing three 126 base-pair rings. Reversible and quantitative on/off switching of the mobility of the rings was demonstrated as a proof-of-concept for the employment of these catenanes as dynamic DNA-nanostructures.


Small noncoding RNA expression during extreme anoxia tolerance of annual killifish (Austrofundulus limnaeus) embryos.
Small noncoding RNAs (sncRNA) have recently emerged as specific and rapid regulators of gene expression, involved in a myriad of cellular and organismal processes. MicroRNAs, a class of sncRNAs, are differentially expressed in diverse taxa in response to environmental stress, including anoxia. In most vertebrates, a brief period of oxygen deprivation results in severe tissue damage or death. Studies on sncRNA and anoxia have focused on these anoxia-sensitive species. Studying sncRNAs in anoxia-tolerant organisms may provide insight into adaptive mechanisms supporting anoxia tolerance. Embryos of the annual killifish Austrofundulus limnaeus are the most anoxia-tolerant vertebrates known, surviving over 100 days at their peak tolerance at 25°C. Their anoxia tolerance and physiology vary over development, such that both anoxia-tolerant and anoxia-sensitive phenotypes comprise the species. This allows for a robust comparison to identify sncRNAs essential to anoxia-tolerance. For this study, RNA sequencing was used to identify and quantify expression of sncRNAs in four embryonic stages of A. limnaeus in response to an exposure to anoxia and subsequent aerobic recovery. Unique stage-specific patterns of expression were identified that correlate with anoxia tolerance. In addition, embryos of A. limnaeus appear to constitutively express stress-responsive miRNAs. Most differentially expressed sncRNAs were expressed at higher levels during recovery. Many novel groups of sncRNAs with expression profiles suggesting a key role in anoxia tolerance were identified, including sncRNAs derived from mitochondrial tRNAs. This global analysis has revealed groups of candidate sncRNAs that we hypothesize support anoxia tolerance.


Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with early rheumatoid arthritis.
To analyze serum concentrations of matrix metalloproteinases (MMP) MMP-1, MMP-3, MMP-9, MMP-13, tissue inhibitors of MMP (TIMP) TIMP-1 and TIMP-2, and MMP/TIMP ratios in patients with early rheumatoid arthritis (RA) before and after 6 months of treatment with methotrexate (MTX). The study group consisted of 30 patients with RA, not treated with disease modifying antirheumatic drugs or corticosteroids, with disease duration < 3 years. Twenty patients with osteoarthritis (OA) served as a control group. Analysis of serum concentrations of MMP and TIMP was based on a quantitative sandwich ELISA. Serum concentrations of MMP-1, MMP-3, MMP-9, and MMP-13 were higher in untreated patients with early RA than in OA patients (p < 0.001 in all cases). Serum levels of TIMP-1 and TIMP-2 dominated in the serum of RA patients compared with controls (p < 0.01 and p < 0.05, respectively). Ratios of MMP to TIMP were significantly higher in patients with early RA versus controls. Six months' treatment with MTX downregulated serum concentrations of MMP-1 (p < 0.001), MMP-3 (p < 0.001), MMP-9 (p < 0.001), MMP-13 (p < 0.01), and TIMP-1 (p < 0.05) in patients with RA. These changes were accompanied by significantly reduced ratios of MMP to TIMP. MTX treatment decreased markers of RA activity such as the number of painful and swollen joints, erythrocyte sedimentation rate, Disease Activity Score, and C-reactive protein. Patients with early RA are characterized by high serum concentrations of tissue-degrading metalloproteinases. Therapy with MTX resulted in clinical improvement and reduced serum MMP levels in patients with RA, confirming effectiveness of MTX in patients in early stages of the disease.


Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms.
Recent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD. Children aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used. There was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task. Our findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.


Bulimic disorders and sociocentric values in north India.
Previous studies have shown low rates of eating disorders in some developing countries. We set out to investigate the prevalence of bulimia in an all-female college population in north India and relate it to sociocentrism of the culture. A total of 504 students in an all-girls private college in an industrial town in north India completed the Hindi translation of the Bulimia Investigatory Test, Edinburgh (BITE). A random sample of 50 students, irrespective of their scores, were interviewed using the DSM-III-R interview for eating disorders; they were also asked about qualitative aspects of their relationship with the family and their own views of their identity. There was no effect of age, social class, religion or height on the distribution of BITE scores. Three key factors emerged; these were related to the constructs of compulsive activity, impulsivity/sociocentric avoidance and associated attitudinal responses and depressive thinking with features of helplessness and feelings of failure. Acculturation was not related to BITE scores. Virtually all interviewees had sociocentric views of theirselves. Sociocentrism and impulsivity account for a significant amount of the variance. The role of sociocentrism in influencing patterns of eating deserves to be studied further.


Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures.
One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating. A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. A maximum temperature rise of 22.4°C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2°C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8°C. Up to a maximum of 22.4°C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner.


Patterns of association with host and habitat: antibody reactive with Sin Nombre virus in small mammals in the major biotic communities of the southwestern United States.
The distribution and prevalence of antibody reactive with Sin Nombre virus were determined in mammals in biotic communities of the southwestern United States. Small mammals (n = 3,069) of 69 species were trapped in nine communities from lower Sonoran desert to alpine tundra. Antibody was found in rodents from all communities (overall prevalence = 6.3%); prevalence was lowest at the altitudinal and climatic extremes (0.4% in desert and 2.0% in alpine tundra). Antibody occurred in 11% of 928 deer mice, 20% of 355 brush mice, 23% of 35 western harvest mice, and 12% of 24 Mexican voles. No infected deer mice were found in desert habitat; prevalence varied from 4% in chaparral to 17% in pinyon-juniper. Brush mice were frequently infected in chaparral and montane forest (25%). Seropositivity was higher in males and in heavier animals, suggesting horizontal transmission among adult males. Decreasing prevalence with age among the youngest deer mice suggests that infected dams confer passive immunity to pups.


Engineering iridium-based metal organic frameworks towards electrocatalytic water oxidation.
Intensive efforts have been made towards designing water oxidation catalysts using homogeneous metal complexes. However, poor stability, caused by structure collapse and strong oxidants, prohibits further application of these catalysts. Therefore, the fabrication of stable and efficient water oxidation catalysts with robust structures and mild driving forces is in high demand. In this paper, we demonstrate the heterogeneous, porous and stable structure of Ir-doped metal organic frameworks (MOFs) by functionalizing bipyridine-incorporated MOFs with [IrCp*Cl(μ-Cl)]2 complexes. The resultant Ir-doped MOFs were immobilized on the surface of a glassy carbon electrode to drive the water oxidation process directly by electricity. Through the condition optimization, the enhanced electrocatalytic activity with an onset potential of 0.87 V versus the normal hydrogen electrode (NHE) towards oxygen evolution reaction with the highest Faradaic efficiency of 99% could be obtained. Moreover, it maintains high activity with no apparent loss for at least 3600 s. The excellent electrochemical performance may be ascribed to the unique MOFs structure, which not only protects the molecular catalyst from collapse, but also facilitates uniform distribution of active sites and efficient electron transfer through the channel.


Physeal sparing reconstruction of the anterior cruciate ligament in skeletally immature prepubescent children and adolescents. Surgical technique.
The management of anterior cruciate ligament injuries in skeletally immature patients is controversial. Conventional adult reconstruction techniques risk potential iatrogenic growth disturbance due to physeal damage. The purpose of this study was to evaluate the results of a physeal sparing, combined intra-articular and extra-articular reconstruction technique in prepubescent skeletally immature children. Between 1980 and 2002, forty-four skeletally immature prepubescent children and adolescents who were in Tanner stage 1 or 2 (with a mean chronological age of 10.3 years) underwent physeal sparing, combined intra-articular and extra-articular reconstruction of the anterior cruciate ligament with use of an autogenous iliotibial band graft. Twenty-seven patients had additional meniscal surgery. Functional outcome, graft survival, radiographic outcome, and growth disturbance were evaluated at a mean of 5.3 years after surgery. Two patients underwent a revision reconstruction for graft failure at 4.7 and 8.3 years postoperatively. In the remaining forty-two patients, the mean International Knee Documentation subjective knee score (and standard deviation) was 96.7 +/- 6.0 points, and the mean Lysholm knee score was 95.7 +/- 6.7 points. The results of the Lachman examination for anterior cruciate ligament integrity were normal for twenty-three patients, nearly normal for eighteen patients, and abnormal for one patient. The results of the pivot-shift examination were normal for thirty-one patients and nearly normal for eleven patients. Four of the twenty-three patients who underwent concurrent meniscal repair had a repeat arthroscopic meniscal repair or partial meniscectomy. The mean growth in total height from the time of surgery to the final follow-up evaluation was 21.5 cm. No patient had an angular deformity measured radiographically or a discrepancy in the length of the lower extremities measured clinically. Physeal sparing, combined intra-articular and extra-articular reconstruction of the anterior cruciate ligament with use of an autogenous iliotibial band graft in skeletally immature prepubescent children and adolescents provides excellent functional outcome with a low revision rate and a minimal risk of growth disturbance.


The research potential of practice nurses.
Little is known about the research aspirations and experiences of practice nurses. The study discussed in the present paper had three main aims: (1) to assess the level of research interest among practice nurses working in Essex and East London, UK; (2) to identify practice nurses' research priorities; and (3) to explore factors which facilitate and impede the development of practice nursing research. All practice nurses (n = 1,054) in the above areas were sent a questionnaire, and a total of 40% (n = 426) responded after two follow-up letters. Fifty-five respondents who volunteered for further participation were interviewed, either individually or in focus groups. About half (n = 207) of the survey respondents expressed an interest in undertaking research. One-third (n = 145) reported previous participation in research, and 20% (n = 85) had initiated their own research. Logistic regression showed that practice nurses educated to graduate level, and those working in practices with nurse training or participation in external research, were most likely to want to undertake research. Working in a medical training practice was found to be a negative predictor of research interest. Respondents prioritised research into long-term health problems with a high prevalence in the local population; for example, diabetes. Their reasons for wishing to engage in research included improving the service, career development, making work more interesting and reducing isolation. The main barriers identified were lack of time, lack of support from some general practitioners and poor access to higher education resources outside formal courses. The development of practice nurse research would provide a distinctive perspective on health need and service provision. It would contribute to the achievement of the national strategic objective of improving the quality of primary care, enhance the status of the profession, utilise the enthusiasm of individuals, increase job satisfaction and staff retention, and answer real questions.


Aggregation makes a protein allergenic at the challenge phase of basophil-mediated allergy in mice.
A hapten is a small molecule that is not immunogenic on its own but can stimulate the production of antibodies at the sensitization phase when conjugated to carrier proteins. The hapten then reacts specifically with the antibodies generated against it to elicit an immune or allergic response at the challenge phase. Here, we compared various carrier proteins conjugated with the same hapten in their ability to induce hapten-specific IgE-mediated allergic responses in vitro and in vivo, and characterized the nature of carrier proteins that determines the magnitude of response at the challenge phase of allergic reactions. Hapten 2,4,6-trinitrophenol (TNP)-conjugated ovalbumin (TNP-OVA) and bovine serum albumin (TNP-BSA) elicited TNP-specific, mast cell-dependent, immediate-type allergic reactions at a comparable level in mice that had been passively sensitized with TNP-specific IgE. In contrast, TNP-OVA but not TNP-BSA efficiently induced a basophil-dependent, IgE-mediated chronic allergic inflammation (IgE-CAI), even though both proteins could stimulate basophils in vitro at a comparable level. By comparing different carrier proteins and structurally modifying them, we found that the formation of large aggregates is crucial for TNP-conjugated carrier proteins to efficiently elicit IgE-CAI, regardless of the type of protein. Thus, the aggregation status of carrier proteins appears to determine the magnitude of allergic response at the challenge phase of hapten-specific IgE-CAI. Our findings suggest that the allergenicity of substances is a matter of importance not only at the sensitization but also at the challenge phase in a certain type of allergy including a basophil-mediated allergic inflammation.


The epidemiology of firearm violence in the twenty-first century United States.
This brief review summarizes the basic epidemiology of firearm violence, a large and costly public health problem in the United States for which the mortality rate has remained unchanged for more than a decade. It presents findings for the present in light of recent trends. Risk for firearm violence varies substantially across demographic subsets of the population and between states in patterns that are quite different for suicide and homicide. Suicide is far more common than homicide and its rate is increasing; the homicide rate is decreasing. As with other important health problems, most cases of fatal firearm violence arise from large but low-risk subsets of the population; risk and burden of illness are not distributed symmetrically. Compared with other industrialized nations, the United States has uniquely high mortality rates from firearm violence.


Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated with Programmed Cell Death 1 Inhibitors.
The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with treatment response in non-melanoma malignancies. We conducted a retrospective study of patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan-Meier curves with log-rank tests and Cox regression models were used for the comparison of TTNTD and OS. Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%) were treated on a clinical trial. Immune-related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non-trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low-grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune-related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13). We demonstrate several positive associations between the development of irAEs and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required. This study evaluated whether the development of immune-related adverse events in non-melanoma patients treated with programmed cell death 1 checkpoint inhibitors correlates with improved clinical outcomes. The results indicate that for a subset of patients, in particular those with low-grade immune-related adverse events, immune-related adverse events predicted for an improved response rate and longer time to next therapy or death.


Identifying high-risk pregnant drinkers: biological and behavioral correlates of continuous heavy drinking during pregnancy.
To determine whether women who continued to drink during pregnancy could be differentiated from women who discontinued alcohol use during their second trimester of pregnancy based on biological, social and behavioral data collected during a prenatal interview, 267 women receiving prenatal care at Grady Memorial Hospital, a large metropolitan hospital in Atlanta, were interviewed antepartum, assessing current drug and alcohol use as well as other demographic information. Postpartum interviews were conducted during the first 3 days following delivery to determine any changes in drug use or alcohol consumption that occurred after the first interview. Women who continued to drink throughout pregnancy and women who stopped drinking were similar on most demographic variables examined, including age, marital status, ethnic group, income, obstetrical complications risk score, amount of alcohol consumed per week and use of other drugs. Discriminant analysis was used to determine whether drinking-group membership could be predicted from self-reported drinking behaviors or biological and other demographic variables. The best predictors of drinking throughout pregnancy were the length of drinking history, reported tolerance to alcohol, a history of alcohol-related illness and drinking by siblings. In addition, women who continued to drink throughout pregnancy were more likely to report that they drank most often with other family members. Of the subjects who continued to drink, 81% were correctly classified based on this discriminant function. These findings suggest that women who continue to drink during pregnancy may be experiencing more chronic and severe alcohol-related problems than women who discontinue alcohol use and may thus be identified and targeted for intensive prevention effects.


Telehealth and the Re-Design of Emergency Medical Services.
As patient numbers continue to rise Emergency Department's (ED's) are struggling to not only control patient wait times but also to maintain the quality of patient care. Improving patient flow through the ED has been a priority for many years with techniques such as Lean Six-Sigma being implemented specifically to help alleviate the problem. The Institute for Healthcare Improvement recently stated that the best opportunities to improving patient flow relate to the front-end of the ED, namely triage. This contribution examines the use of Telehealth initiatives at the front-end of the ED, specifically tele-consultation, to reduce patient loading, provide timelier healthcare (with improved patient outcomes) and reduce costs.


Identification of QTLs for arsenic accumulation in maize (Zea mays L.) using a RIL population.
The Arsenic (As) concentration in different tissues of maize was analyzed using a set of RIL populations derived from an elite hybrid, Nongda108. The results showed that the trend of As concentration in the four measured tissues was leaves>stems>bracts>kernels. Eleven QTLs for As concentration were detected in the four tissues. Three QTLs for As concentration in leaves were mapped on chromosomes 1, 5, and 8, respectively. For As concentration in the bracts, two QTLs were identified, with 9.61% and 10.03% phenotypic variance. For As concentration in the stems, three QTLs were detected with 8.24%, 14.86%, and 15.23% phenotypic variance. Three QTLs were identified for kernels on chromosomes 3, 5, and 7, respectively, with 10.73%, 8.52%, and 9.10% phenotypic variance. Only one common chromosomal region between SSR marker bnlg1811 and umc1243 was detected for QTLs qLAV1 and qSAC1. The results implied that the As accumulation in different tissues in maize was controlled by different molecular mechanism. The study demonstrated that maize could be a useful plant for phytoremediation of As-contaminated paddy soil, and the QTLs will be useful for selecting inbred lines and hybrids with low As concentration in their kernels.


Synthesis and evaluation of silica hydride-based fluorinated stationary phases.
Two novel silica hydride-based fluorinated bonded phases have been synthesized using a hydrosilation procedure to test combined fluorine and hydride selectivity. The bonded moieties were characterized by elemental and spectral analysis. Chromatographic testing was done using hydrophilic analytes in the aqueous normal phase mode. At higher amounts of the nonpolar solvent in the mobile phase, there should be increased retention for solutes such as acids, bases and other polar compounds, whereas nonpolar solutes can be retained when water is increased as in RP chromatography. The synergistic effects of the fluorinated phase selectivity and aqueous normal phase retention on a hydride surface have been explored for small polar molecules. The stability and repeatability of the hydride-based fluorinated stationary phases were evaluated. The use of acetone as the organic component in the mobile phase was also tested.


Evaluation of human papillomavirus-consensus primers for HPV detection by the polymerase chain reaction.
Cervical cancer is one of the most frequently found cancers in women and appears to have a viral aetiology. Substantial evidence points to the human papillomaviruses (HPV) as the infectious agents and there is considerable interest in identifying and accurately typing the viruses. Since HPVs now comprise more than 100 different HPV types, the polymerase chain reaction (PCR) has been the preferred methodology for virus identification and typing on isolated DNA. In that context, five commonly employed PCR consensus primers have been evaluated for the detection and typing of HPV. The five consensus primer pairs were derived from the consensus sequences of either the L1 and E1 open reading frames. All primers exhibited approximately equal sensitivity, as defined by the ability to detect HPV DNA, on a series of standard HPV DNA-containing preparations. However, the five primer pairs performed differently on 24 HPV-positive and 34 HPV-negative samples obtained from cervical scrapes which had been typed by type-specific PCR for HPV 6/11, 16, 18 and 33. The values for agreement between identification of samples by a HPV type-specific PCR and the consensus primer PCR were 78, 84, 91, 93 and 98%. Three samples, which were positive with only one of the five consensus primer pairs and were negative with the PCR for HPV types 6/11, 16, 18 and 33, contained other HPV sequences or HPV-related sequences as determined by DNA sequence analysis. To our knowledge, this report represents the first extensive comparison of five different consensus primers in a polymerase chain reaction for the detection of HPV. Our results suggest that PCR typing for human papillomaviruses requires more than one consensus primer pair to identify all HPV-infected samples.


Optical Coherence Tomography Angiography Features in Melanocytoma of the Optic Nerve.
Optic disc melanocytoma (ODM) is a pigmented tumor with malignant potential characterized clinically as a dark brown to black lesion with feathery margins. The authors report a case of ODM and describe the utility of optical coherence tomography angiography (OCTA) in detecting superficial tumor vascularization. This case report demonstrated the ability of OCTA to reveal the fine abnormal retinal vasculature on the surface of the lesion, a characteristic of ODM, which has been previously correlated with tumor growth. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:364-366.].


Early functional disability predicts both all-cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register.
To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all-cause and cardiovascular disease (CVD) mortality. 1010 subjects with new-onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all-cause and CVD) per 1000 person-years were calculated by HAQ stratum (HAQ scores<1, 1-2 and>or=2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years. By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all-cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup. Our data show that at 1 year of follow-up, HAQ score is an important independent predictor of subsequent all-cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.


Polarization effects in flow cytometric DNA sizing.
We have investigated the influence of the polarization direction of excitation light on DNA sizing results obtained by a flow cytometric technique. We found strong fluorescence anisotropy of the fluorescent signal from lambda DNA stained with the bis-intercalating dye TOTO-1. Small fragments of DNA are less sensitive to polarization than larger pieces. This effect is more pronounced at faster flow speeds. These observations show a noticeable orientation of the DNA molecules introduced by the shear forces in the flow system. The data are consistent with an angle between the transition moment of fluorescence of TOTO-1, and the long axis of DNA is approximately 62 degrees .


Variation in manuka oil lure efficacy for capturing Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae), and cubeb oil as an alternative attractant.
Redbay ambrosia beetle, Xyleborus glabratus Eichoff, is an exotic species to North America vectoring a deadly vascular wilt disease of redbay [Persea borbonia (L.) Spreng], swampbay [P. palustris (Raf.) Sarg.], avocado (P. americana Mill.), and sassafras [Sassafras albidum (Nutt.) Nees]. Xyleborus glabratus is attracted to manuka oil lures, which are commercially available, and phoebe oil. Variable efficacy of manuka oil lures and insufficient availability of phoebe oil prompted us to investigate the reasons behind changes in manuka oil lure efficacy and to test cubeb oil, a readily available essential oil from Piper cubeba L. seeds, as an alternative attractant. Attraction, release rates and durations, and volatile composition of manuka oil lures manufactured in 2008 were compared with manuka oil lures manufactured in 2012, and to whole and a distilled fraction of cubeb oil. Manuka oil lures from 2008 were more attractive to X. glabratus than controls for 8 wk, whereas lures from 2012 were attractive for only 2 wk. Cubeb oil and the distilled fraction of it were as attractive as or more attractive than manuka oil in three trials. In gravimetric studies, manuka oil lures from 2008 and cubeb oil lures continued to release volatiles for 57 d, whereas lures from 2012 stopped after 16 d. The chemical composition of volatiles released from new manuka oil lures from 2008 was similar to 2012; however, a preservative (butylated hydroxytoluene) was detected in the 2008 lures. Cubeb oil was an effective attractant for X. glabratus that lasted 8-9 wk when released from bubble lures.


The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial.
One of the proposed causes of obesity and metabolic syndrome is the excessive intake of products containing added sugars, in particular, fructose. Although the ability of excessive intake of fructose to induce metabolic syndrome is mounting, to date, no study has addressed whether a diet specifically lowering fructose but not total carbohydrates can reduce features of metabolic syndrome. A total of 131 patients were randomized to compare the short-term effects of 2 energy-restricted diets-a low-fructose diet vs a moderate natural fructose diet-on weight loss and metabolic syndrome parameters. Patients were randomized to receive 1500, 1800, or 2000 cal diets according to sex, age, and height. Because natural fructose might be differently absorbed compared with fructose from added sugars, we randomized obese subjects to either a low-fructose diet (<20 g/d) or a moderate-fructose diet with natural fruit supplements (50-70 g/d) and compared the effects of both diets on the primary outcome of weight loss in a 6-week follow-up period. Blood pressure, lipid profile, serum glucose, insulin resistance, uric acid, soluble intercellular adhesion molecule-1, and quality of life scores were included as secondary outcomes. One hundred two (78%) of the 131 participants were women, mean age was 38.8 ± 8.8 years, and the mean body mass index was 32.4 ± 4.5 kg/m(2). Each intervention diet was associated with significant weight loss compared with baseline. Weight loss was higher in the moderate natural fructose group (4.19 ± 0.30 kg) than the low-fructose group (2.83 ± 0.29 kg) (P = .0016). Compared with baseline, each intervention diet was associated with significant improvement in secondary outcomes. Reduction of energy and added fructose intake may represent an important therapeutic target to reduce the frequency of obesity and diabetes. For weight loss achievement, an energy-restricted moderate natural fructose diet was superior to a low-fructose diet.


Targeted sequencing of plasmacytoid urothelial carcinoma reveals frequent TERT promoter mutations.
Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. Although the cadherin 1 (CDH1) gene is commonly mutated in the clinically aggressive plasmacytoid variant of urothelial carcinoma (PUC), little is known about their TERT promoter mutation status. A retrospective search of our archives for PUC and UC with plasmacytoid and/or signet ring cell features (2007-2014) was performed. Ten specimens from 10 patients had archived material available for DNA analysis and were included in the study. Intratumoral areas of nonplasmacytoid histology were also evaluated when present. Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform. TERT promoter mutations were detected in specimens with pure and focal plasmacytoid features (6/10). Similar to conventional UC, the predominant mutation identified was g.1295228C>T. In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas. Co-occurring mutations in tumor protein p53 (TP53, 2 cases) and kirsten rat sarcoma (KRAS) viral proto-oncogene (1 case) were also detected. TERT promoter mutations are frequently present in PUC, which provides further evidence that TERT promoter mutations are common events in bladder cancer, regardless of histologic subtype, and supports their inclusion in any liquid biopsy assay for bladder cancer.


von Willebrand disease in the RIIIS/J mouse is caused by a defect outside of the von Willebrand factor gene.
An animal model for human type I von Willebrand disease (vWD) has been previously described in the inbred mouse strain RIIIS/J. Murine vWD is characterized by a prolonged bleeding time, normal von Willebrand factor (vWF) multimer distribution, autosomal dominant inheritance, and proportionately decreased plasma vWF antigen, ristocetin cofactor, and factor VIII (FVIII) activities. To study the molecular genetics of murine vWD, a portion of the vWF gene surrounding exon 28 was cloned, sequenced, and used to develop two informative DNA sequence polymorphisms for rapid genotyping by DNA polymerase chain reaction. RIIIS/J mice were crossed with PWK/Ph mice, an inbred line of Mus musculus musculus, and the F1 progeny backcrossed to the parental PWK/Ph strain. vWF antigen levels in F1 mice were not significantly different from the parental RIIIS/J strain but were markedly decreased compared with the parental PWK/Ph mice. Genetic linkage analysis of 104 backcross progeny showed no correlation between vWF antigen level and vWF genotype. These data indicate that murine vWD is caused by a defect at a novel genetic locus, distinct from the murine vWF gene. The distribution of vWF antigen levels among backcross progeny suggests the presence of one major dominant vWD gene in the RIIIS/J mouse with possible modifying contributions from one or more additional minor loci. These observations may provide new insights into the molecular basis and variable expressivity of human vWD.


Energetically favoured defects in dense packings of particles on spherical surfaces.
The dense packing of interacting particles on spheres has proved to be a useful model for virus capsids and colloidosomes. Indeed, icosahedral symmetry observed in virus capsids corresponds to potential energy minima that occur for magic numbers of, e.g., 12, 32 and 72 identical Lennard-Jones particles, for which the packing has exactly the minimum number of twelve five-fold defects. It is unclear, however, how stable these structures are against thermal agitation. We investigate this property by means of basin-hopping global optimisation and Langevin dynamics for particle numbers between ten and one hundred. An important measure is the number and type of point defects, that is, particles that do not have six nearest neighbours. We find that small icosahedral structures are the most robust against thermal fluctuations, exhibiting fewer excess defects and rearrangements for a wide temperature range. Furthermore, we provide evidence that excess defects appearing at low non-zero temperatures lower the potential energy at the expense of entropy. At higher temperatures defects are, as expected, thermally excited and thus entropically stabilised. If we replace the Lennard-Jones potential by a very short-ranged (Morse) potential, which is arguably more appropriate for colloids and virus capsid proteins, we find that the same particle numbers give a minimum in the potential energy, although for larger particle numbers these minima correspond to different packings. Furthermore, defects are more difficult to excite thermally for the short-ranged potential, suggesting that the short-ranged interaction further stabilises equilibrium structures.


Lycopene's Effects on Cancer Cell Functions within Monolayer and Spheroid Cultures.
Lycopene, a compound that blocks the action of free radicals and oxygen molecules, is found in tomatoes and tomato-based products and linked to a reduced incidence of cancer. Increasing willingness of patients to maintain a healthy lifestyle by supplemental intake of nutrients and acceptance of alternative therapeutics has boosted research into nutraceuticals. The potential of lycopene to prevent or treat cancer has been investigated, but outcomes are inconsistent and its mode of action is still unknown. Further studies are needed to understand the role of lycopene in cancer prevention and treatment. The impact of lycopene on viability, proliferation, migration, and invasion of five different cancer cell lines was determined using monolayer and spheroid cultures. Cell viability was significantly reduced upon lycopene treatment at physiologically attainable concentrations. Cell proliferation, migration, and invasion did not change upon lycopene treatment. Ovarian cancer spheroids initially showed a decreased proliferation and after 14 days increased cell viability upon lycopene treatment, confirming the potential of lycopene to reduce cancer cell growth in short-term cultures and also indicate enhanced cell viability over prolonged exposure. This study cannot substantiate that lycopene inhibits cell functions associated with tumor growth, even in a 3D cancer model that mimics the natural tumor microenvironment.


Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.
A HIC1-SIRT1-p53 circular loop in which hypermethylation in cancer 1 (HIC1) represses the transcription of SIRT1 that deacetylates and inactivates p53 thus leading to HIC1 inactivation has been identified in cell and animal models. However, the alteration and prognostic effects of HIC1-SIRT1-p53 circular loop have never been demonstrated in human cancer patients. We examine the HIC1-SIRT1-p53 alterations in 118 lung cancer patients to define their etiological roles in tumorigenesis. We found that patients with lung squamous cell carcinoma with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation of HIC1-SIRT1-p53 circular loop in the clinical model. Interestingly, the expression of deleted in breast cancer 1 (DBC1), which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in patients with lung adenocarcinoma. However, epigenetic alteration of HIC1 promoter by posttranslational modifications of histones and promoter hypermethylation favoring the compacted chromatin production attenuated the transcriptional induction by acetylated p53. Importantly, lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis. Our data show the first valid clinical evidence of the deregulation of HIC1-SIRT1-p53 loop in lung tumorigenesis and prognosis. Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma.


Effects of exchanging lactose for fat in milk replacer on ad libitum feed intake and growth performance in dairy calves.
The recent trend in the dairy industry toward ad libitum feeding of young calves merits reconsideration of calf milk replacer (CMR) formulations. Additionally, feed intake regulation in young calves provided with ad libitum milk and solid feeds is insufficiently understood. This study was designed to determine the effect of exchanging lactose for fat in CMR on voluntary feed intake and growth performance. Lactose was exchanged for fat on a weight/weight basis, resulting in different energy contents per kilogram of CMR. Thirty-two male calves (1.7 ± 0.12 d of age, 47.6 ± 0.83 kg of body weight) were assigned to 1 of 16 blocks based on arrival date. Within each block, calves were randomly assigned to 1 of 2 treatments. The experimental period was divided into 4 periods. In period 1, until 14 ± 1.7 d of age, calves were individually housed, restricted-fed their assigned CMR treatments at 2.5 to 3 L twice daily, and provided with unlimited access to water, chopped straw, and starter. In period 2, calves were group-housed with 8 calves per pen and received ad libitum access to their assigned CMR treatments, starter feed, chopped wheat straw, and water. During period 3, from 43 until 63 d of age, calves were weaned by restricting CMR allowance in 2 steps, maintaining access to all other feeds. All calves were completely weaned at d 64 of age and were monitored until 77 d of age (period 4). Measurements included the intake of all dietary components, body weight gain, and a selection of blood traits. Increasing fat content at the expense of lactose decreased CMR intake by 10%, whereas total calculated metabolizable energy intake and growth remained equal between treatments. Total solid feed (starter and straw) consumption was not affected by CMR composition. These data indicate that calves fed ad libitum regulate their CMR intake based on energy content. High-fat CMR increased plasma phosphate, nonesterified fatty acids, triglycerides, and bilirubin, whereas plasma glucose remained unchanged. Despite the limited animal numbers in the present experiment, there was a significant decrease in the total number of health events (mainly respiratory) requiring therapeutic intervention and in the total number of therapeutic interventions in calves fed high-fat CMR. Calves appeared to consume CMR based on energy content, with a difference in ad libitum intake proportional to the difference in energy content of the CMR, maintaining equal body weight gain and solid feed intake.


Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.
The fetal brain is highly plastic and is not only receptive to but requires cues from its environment to develop properly. Based on an understanding of evolutionary biology, developmental plasticity, and life history theory, one can predict that stressors are an important environmental condition that may influence brain development. In fact, the available empirical evidence appears to support the notion that exposure to excess stress in intrauterine life has the potential to adversely affect short- and long-term neurodevelopmental outcomes with implications for altered susceptibility for mental health disorders in childhood and adult life. In this presentation, we provide a rationale for proposing that endocrine and inflammatory stress mediators are key candidate pathways for programming brain development. These mediators are responsive to a diverse set of intrauterine perturbations and alter key signaling pathways critical for brain development, including but not limited to mammalian target of rapamycin, Wnt (wingless), Sonic hedgehog, and reelin signaling. We suggest that recent advances in neuroimaging and other methods now afford us an unprecedented opportunity to advance our understanding of this important topic. Additionally, we provide empirical evidence from two recently published papers for fetal programming of human brain development. We conclude by suggesting some future directions for expanding this field of research.


Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease.
Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear. To determine the relative effects of inhaled corticosteroids (ICS) compared to long-acting beta(2)-agonists (LABA) on clinical outcomes in patients with stable chronic obstructive pulmonary disease. We searched the Cochrane Airways Group Specialised Register of trials (latest search August 2011) and reference lists of articles. We included randomised controlled trials comparing inhaled corticosteroids and long-acting beta(2)-agonists in the treatment of patients with stable chronic obstructive pulmonary disease. Three authors independently assessed trials for inclusion and then extracted data on trial quality, study outcomes and adverse events. We also contacted study authors for additional information. We identified seven randomised trials (5997 participants) of good quality with a duration of six months to three years. All of the trials compared ICS/LABA combination inhalers with LABA and ICS as individual components. Four of these trials included fluticasone and salmeterol monocomponents and the remaining three included budesonide and formoterol monocomponents. There was no statistically significant difference in our primary outcome, the number of patients experiencing exacerbations (odds ratio (OR) 1.22; 95% CI 0.89 to 1.67), or the rate of exacerbations per patient year (rate ratio (RR) 0.96; 95% CI 0.89 to 1.02) between inhaled corticosteroids and long-acting beta(2)-agonists. The incidence of pneumonia, our co-primary outcome, was significantly higher among patients on inhaled corticosteroids than on long-acting beta(2)-agonists whether classified as an adverse event (OR 1.38; 95% CI 1.10 to 1.73) or serious adverse event (Peto OR 1.48; 95% CI 1.13 to 1.93). Results of the secondary outcomes analysis were as follows. Mortality was higher in patients on inhaled corticosteroids compared to patients on long-acting beta(2)-agonists (Peto OR 1.17; 95% CI 0.97 to 1.42), although the difference was not statistically significant. Patients treated with beta(2)-agonists showed greater improvements in pre-bronchodilator FEV(1) compared to those treated with inhaled corticosteroids (mean difference (MD) 18.99 mL; 95% CI 0.52 to 37.46), whilst greater improvements in health-related quality of life were observed in patients receiving inhaled corticosteroids compared to those receiving long-acting beta(2)-agonists (St George's Respiratory Questionnaire (SGRQ) MD -0.74; 95% CI -1.42 to -0.06). In both cases the differences were statistically significant but rather small in magnitude. There were no statistically significant differences between ICS and LABA in the number of hospitalisations due to exacerbations, number of mild exacerbations, peak expiratory flow, dyspnoea, symptoms scores, use of rescue medication, adverse events, all cause hospitalisations, or withdrawals from studies. Placebo-controlled trials have established the benefits of both long-acting beta-agonist and inhaled corticosteroid therapy for COPD patients as individual therapies. This review, which included trials allowing comparisons between LABA and ICS, has shown that the two therapies confer similar benefits across the majority of outcomes, including the frequency of exacerbations and mortality. Use of long-acting beta-agonists appears to confer a small additional benefit in terms of improvements in lung function compared to inhaled corticosteroids. On the other hand, inhaled corticosteroid therapy shows a small advantage over long-acting beta-agonist therapy in terms of health-related quality of life, but inhaled corticosteroids also increase the risk of pneumonia. This review supports current guidelines advocating long-acting beta-agonists as frontline therapy for COPD, with regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations.


What causes the insulin resistance underlying obesity?
The association between obesity and insulin resistance is an area of much interest and enormous public health impact, with hundreds of articles being published in the last year focused on the possible mechanisms that underlie this association. The purpose to this review is to highlight some of the key recent literature with emphasis on emerging concepts. The specific link between visceral adipose tissue accumulation and insulin resistance continues to be discerned. Visceral adiposity is correlated with accumulation of excess lipid in liver, and results in cell autonomous impairment in insulin signaling. Visceral adipose tissue is also prone to inflammation and inflammatory cytokine production, which also contribute to impairment in insulin signaling. The expansion of visceral adipose tissue and excess lipid accumulation in liver and muscle may result from limited expandability of subcutaneous adipose tissue, due to the properties of its extracellular matrix and capacity for capillary growth. Recent studies underscore the need to better understand the mechanisms linking visceral adiposity with liver fat accumulation, the mechanisms by which ectopic fat accumulation cause insulin resistance, and the mechanisms by which the size of adipose tissue depots is determined.


Effects of Coffee Consumption on Insulin Resistance and Sensitivity: A Meta-Analysis.
Coffee is widely consumed worldwide and impacts glucose metabolism. After a previous meta-analysis that evaluated the effects of coffee consumption on insulin resistance and sensitivity, additional randomized controlled trials (RCTs) were conducted. This meta-analysis aimed to evaluate the effects of coffee consumption on insulin resistance or sensitivity. We selected RCTs that evaluated the effects of coffee consumption for seven days or more on insulin sensitivity or resistance using surrogate indices (homeostasis model assessment for insulin resistance (HOMA-IR) and Matsuda index). The fixed-effects or random-effects model was used according to heterogeneity. Four studies with 268 participants were analyzed in this meta-analysis. Coffee consumption significantly decreased HOMA-IR compared to control (mean difference (MD) = -0.13; 95% CI = -0.24--0.03; p-value = 0.01). However, the significance was not maintained in the sensitivity analysis (MD = -0.04; 95% CI = -0.18-0.10; p-value = 0.55) after excluding data from the healthy, young, normal-weight group. Matsuda index was not significantly different between coffee and control groups (standardized mean difference (SMD) = -0.33; 95% CI = -0.70-0.03; p-value = 0.08). In conclusion, long-term coffee consumption has a nonsignificant effect on insulin resistance and sensitivity. More studies evaluating the effects of coffee consumption in the healthy, young, and normal-weight individuals are needed.


Arguments for the choice of surgical treatments in patients with lumbar spinal stenosis - a systematic appraisal of randomized controlled trials.
Lumbar spinal stenosis is the most common reason for spinal surgery in elderly patients. However, the surgical management of spinal stenosis is controversial. The aim of this review was to list aspects a surgeon considers when choosing a specific type of treatment. Appraisal of arguments reported in randomized controlled trials (RCTs) included in systematic reviews published or indexed in the Cochrane library studying surgical treatments in patients with spinal stenosis. Eight out of nine RCTs listed arguments for the choice of their treatments under investigation. The argument for decompression alone was the high success rate, the argument against was a potential increase in vertebral instability. The argument for decompression and fusion without instrumentation was that it is a well-established technique with a high fusion success rate, the argument against it was that the indication for fusion in spinal stenosis has remained unclear. The argument for decompression and fusion with instrumentation was an increased fusion rate compared to decompression and fusion without instrumentation, the argument against this was that the invasive procedure is associated with more complications. The main argument identified in this appraisal for and against decompression alone in patient with lumbar spinal stenosis was whether or not instability should be treated with (instrumented) fusion procedures. However, there is disagreement on how instability should be defined. In a first step it is important that researchers and clinicians agree on definitions for important key concepts such as instability and reoperations.


Combination of cannabidiol with low‑dose naltrexone increases the anticancer action of chemotherapy in vitro and in vivo.
We previously reported that both cannabidiol (CBD) and low‑dose naltrexone (LDN) exhibit complex effects on G‑protein coupled receptors, which can impact the expression and function of other members of this superfamily. These receptors feed into and interact with central signalling cascades that determine the ease by which cells engage in apoptosis, and can be used as a way to prime cancer cells to other treatments. The present study was designed to investigate the effect of combining these two agents on cancer cell lines in vitro and in a mouse model, and focused on how the sequence of administration may affect the overall action. The results showed both agents had minimal effect on cell numbers when used simultaneously; however, the combination of LDN and CBD, delivered in this specific sequence, significantly reduced the number of cells, and was superior to the regimen where the order of the agents was reversed. For example, there was a 35% reduction in cell numbers when using LDN before CBD compared to a 22% reduction when using CBD before LDN. The two agents also sensitised cells to chemotherapy as significant decreases in cell viability were observed when they were used before chemotherapy. In mouse models, the use of both agents enhanced the effect of gemcitabine, and crucially, their use resulted in no significant toxicity in the mice, which actually gained more weight compared to those without this pre‑treatment (+6.5 vs. 0%). Overall, the results highlight the importance of drug sequence when using these drugs. There is also a need to translate these observations into standard chemotherapy regimens, especially for common tumour types where treatment is often not completed due to toxicities.