ADGRE1 (EMR1, F4/80) Is a Rapidly-Evolving Gene Expressed in Mammalian Monocyte-Macrophages.
The F4/80 antigen, encoded by the Adgre1 locus, has been widely-used as a monocyte-macrophage marker in mice, but its value as a macrophage marker in other species is unclear, and has even been questioned. ADGRE1 is a seven transmembrane G protein-coupled receptor with an extracellular domain containing repeated Epidermal Growth Factor (EGF)-like calcium binding domains. Using a new monoclonal antibody, we demonstrated that ADGRE1 is a myeloid differentiation marker in pigs, absent from progenitors in bone marrow, highly-expressed in mature granulocytes, monocytes, and tissue macrophages and induced by macrophage colony-stimulating factor (CSF1) treatment in vivo. Based upon these observations, we utilized RNA-Seq to assess the expression of ADGRE1 mRNA in bone marrow or monocyte-derived macrophages (MDM) and alveolar macrophages from 8 mammalian species including pig, human, rat, sheep, goat, cow, water buffalo, and horse. ADGRE1 mRNA was expressed by macrophages in each species, with inter-species variation both in expression level and response to lipopolysaccharide (LPS) stimulation. Analysis of the RNA-Seq data also revealed additional exons in several species compared to current Ensembl annotations. The ruminant species and horses appear to encode a complete duplication of the 7 EGF-like domains. In every species, Sashimi plots revealed evidence of exon skipping of the EGF-like domains, which are highly-variable between species and polymorphic in humans. Consistent with these expression patterns, key elements of the promoter and a putative enhancer are also conserved across all species. The rapid evolution of this molecule and related ADGRE family members suggests immune selection and a role in pathogen recognition.


Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator.
In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares. Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n=76); or SC rilonacept 320 mg at baseline plus oral placebo (n=75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0=none; 4=extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments. Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean±SD age of 50.3±10.6 years. All treatment groups reported within-group pain reductions from baseline (P<0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55±0.92) relative to indomethacin alone (-1.40±0.96), the difference was not statistically significant (P=0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69±0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness. Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare. ClinicalTrials.gov registration number NCT00855920.


The impact of chronic pain in the community.
Chronic pain is known to be very common in the community. Less is known about the epidemiology of more significant or severe chronic pain. The impact of chronic pain in the community, in terms of general health, employment and interference with daily activity, has not been quantified. The aim of this study was to describe the prevalence and distribution in the community of chronic pain defined as 'significant' and 'severe', and to explore the impact of chronic pain on health and activity. A questionnaire survey was carried out of a sample drawn from the general population in the Grampian region of SCOTLAND: Questionnaires were sent to a random sample of 4611 individuals aged 25 years and over, stratified for age and gender, selected from the practice lists of 29 general practices (total practice population 136,383). The study instrument included a case definition questionnaire, from which were identified individuals with 'any chronic pain' (pain of at least 3 months duration). The instrument also included a level of expressed need questionnaire and the chronic pain grade questionnaire, from which were derived definitions for 'significant chronic pain' (based on the reported need for treatment and professional advice) and 'severe chronic pain' (based on reported intensity and pain-related disability). The SF-36 general health questionnaire and demographic questions were also included. Of the sample, 14.1% reported 'significant chronic pain', and this was more prevalent among women and older age groups. A total of 6.3% reported 'severe chronic pain', and this was more common in older age groups. On multiple logistic regression modelling, female gender, housing tenure, employment category and educational attainment were found to be independently associated with both 'significant' and 'severe' chronic pain. The presence of 'any', 'significant' and 'severe' chronic pain had progressively more marked adverse associations with employment, interference with daily activities and all measured dimensions of general health. Comparison of the epidemiology of 'significant chronic pain' and 'severe chronic pain' with 'any chronic pain' allows an understanding of the more clinically important end of the chronic pain spectrum. These results support the suggestion that chronic pain is multidimensional, both in its aetiology and in its effects, particularly at this end of the spectrum. This must be addressed in management and in further research.


Pharmacological and molecular characterization of ATP-sensitive K(+) conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus.
The role of hypothalamic ATP-sensitive potassium channels in the maintenance of energy homeostasis has been extensively explored. However, how these channels are incorporated into the neuronal networks of the arcuate nucleus remains unclear. Whole-cell patch-clamp recordings from rat arcuate nucleus neurons in hypothalamic slice preparations revealed widespread expression of functional ATP-sensitive potassium channels within the nucleus. ATP-sensitive potassium channels were expressed in orexigenic neuropeptide Y/agouti-related protein (NPY/AgRP) and ghrelin-sensitive neurons and in anorexigenic cocaine-and-amphetamine regulated transcript (CART) neurons. In 70% of the arcuate nucleus neurons recorded, exposure to glucose-free bathing medium induced inhibition of electrical excitability, the response being characterized by membrane hyperpolarization, a reduction in neuronal input resistance and a reversal potential consistent with opening of potassium channels. These effects were reversible upon re-introduction of glucose to the bathing medium or upon exposure to the ATP-sensitive potassium channel blockers tolbutamide or glibenclamide. The potassium channel opener diazoxide, but not pinacidil, also induced a tolbutamide and glibenclamide-sensitive inhibition of electrical excitability. Single-cell reverse transcription-polymerase chain reaction revealed expression of mRNA for sulfonylurea receptor 1 but not sulfonylurea receptor 2 subunits of ATP-sensitive potassium channels. Thus, rat arcuate nucleus neurons, including those involved in functionally antagonistic orexigenic and anorexigenic pathways express functional ATP-sensitive potassium channels which include sulfonylurea receptor 1 subunits. These data indicate a crucial role for these ion channels in central sensing of metabolic and energy status. However, further studies are needed to clarify the differential roles of these channels, the organization of signaling pathways that regulate them and how they operate in functionally opposing cell types.


Evaluating monitoring methods to guide adaptive management of a threatened amphibian (Litoria aurea).
Prompt detection of declines in abundance or distribution of populations is critical when managing threatened species that have high population turnover. Population monitoring programs provide the tools necessary to identify and detect decreases in abundance that will threaten the persistence of key populations and should occur in an adaptive management framework which designs monitoring to maximize detection and minimize effort. We monitored a population of Litoria aurea at Sydney Olympic Park over 5 years using mark-recapture, capture encounter, noncapture encounter, auditory, tadpole trapping, and dip-net surveys. The methods differed in the cost, time, and ability to detect changes in the population. Only capture encounter surveys were able to simultaneously detect a decline in the occupancy, relative abundance, and recruitment of frogs during the surveys. The relative abundance of L. aurea during encounter surveys correlated with the population size obtained from mark-recapture surveys, and the methods were therefore useful for detecting a change in the population. Tadpole trapping and auditory surveys did not predict overall abundance and were therefore not useful in detecting declines. Monitoring regimes should determine optimal survey times to identify periods where populations have the highest detectability. Once this has been achieved, capture encounter surveys provide a cost-effective method of effectively monitoring trends in occupancy, changes in relative abundance, and detecting recruitment in populations.


Evolution of Force Sensing Technologies.
In order to Improve the procedural success and long-term outcomes of catheter ablation techniques for atrial fibrillation (AF), an Important unfulfilled requirement is to create durable electrophysiologically complete lesions. Measurement of contact force (CF) between the catheter tip and the target tissue can guide physicians to optimise both mapping and ablation procedures. Contact force can affect lesion size and clinical outcomes following catheter ablation of AF. Force sensing technologies have matured since their advent several years ago, and now allow the direct measurement of CF between the catheter tip and the target myocardium in real time. In order to obtain complete durable lesions, catheter tip spatial stability and stable contact force are important. Suboptimal energy delivery, lesion density/contiguity and/or excessive wall thickness of the pulmonary vein-left atrial (PV-LA) junction may result in conduction recovery at these sites. Lesion assessment tools may help predict and localise electrical weak points resulting in conduction recovery during and after ablation. There is increasing clinical evidence to show that optimal use of CF sensing during ablation can reduce acute PV re-conduction, although prospective randomised studies are desirable to confirm long-term favourable clinical outcomes. In combination with optimised lesion assessment tools, contact force sensing technology has the potential to become the standard of care for all patients undergoing AF catheter ablation.


Double balloon enteroscopy procedure in patients with surgically altered bowel anatomy: analysis of a large prospectively collected database.
Patients with surgically altered bowel anatomy frequently undergo the double balloon enteroscopy (DBE) procedure to evaluate various small bowel diseases. There are limited data on the diagnostic yield and safety of DBE in these patients. We evaluated the diagnostic yield and complication rates of DBE in patients with surgical altered bowel anatomy. We also evaluated the success rate of DBE in achieving complete examination of the excluded segment of the small bowel and excluded stomach in these patients. Our study was a single-center retrospective analysis of a large prospectively collected DBE database. Patients with a history of surgically altered bowel anatomy who had a DBE procedure performed between January 2006 and August 2011 were included in the study analysis. Patients' demographics, procedure indications, findings, endoscopic interventions, and postprocedural recovery data were recorded. We used frequency statistics to calculate the diagnostic yield and complication rates of DBE in these patients. In total, 1215 DBEs were performed at our institution during the study period. Sixty-two patients with a history of altered bowel anatomy underwent 53 DBEs and 11 DBE-assisted endoscopic retrograde cholangiopancreatographies (ERCPs). The overall diagnostic yield of DBE was 61%, and that of DBE-assisted ERCP was 64%. No serious early or delayed DBE-associated complications were identified. In patients with surgically altered bowel anatomy containing excluded small bowel and excluded stomach, DBE success rate to achieve their complete examination was 92% (n=46). DBE including DBE-assisted ERCP is feasible, safe, and associated with reasonably high diagnostic yield in patients with surgically altered bowel anatomy.


Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients.
Young age has been reported as a negative prognostic factor for pituitary adenomas (PAs). They are very uncommon in children and adolescents; therefore, surgical outcomes are poorly described. To report results of microsurgical transsphenoidal approach (MTSA) in pediatric PAs. The study retrospectively analyzed 3040 PAs treated in our institute, according to the adenoma subtype and then divided into pediatric (≤18 yr) and adult groups (>18 yr). The average follow-up after surgery was 58 mo (n = 2906). In the pediatric group, the majority of adenomas were hormone-secreting (89.5%) with a female sex prevalence (78%) in prolactinomas and nonfunctioning pituitary adenomas (NFPAs); the maximum diameter of growth hormone (GH)-secreting adenomas was greater (28.1 ± 4.1 mm) than in adults (18 ± 0.3 mm, P = .002). Surgical remission rate at 6 mo was similar in both groups for all adenoma subtypes: 72.1% and 76% in pediatric and adult Cushing's disease, 69.3% and 59.3% in prolactinomas, 55.6% and 61% in gigantism or acromegaly, 55.6% and 61.5% in NFPAs. Recurrences after remission occurred more frequently in pediatric GH-secreting adenomas compared to adults (40.0% vs 5.3%, P = .028) despite similar follow-up (38 ± 17 and 48.1 ± 2.2 mo, P = .7). Mortality was zero in the pediatric and 0.2% in the adult group (P = .7); major morbidity was 2.4% and 2.2%, respectively (P = .8). MTSA was safe and effective in children and adolescents as in adults, with the only exception of higher recurrence rate in pediatric GH-secreting adenomas. No complications related to young age appeared.


Anemia and erythropoiesis-stimulating agent administration in patients with non-Hodgkin lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone ± rituximab chemotherapy: results from an observational study.
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) ± rituximab [(± R)CHOP] is the current standard of care for aggressive non-Hodgkin lymphoma (NHL). Anemia resulting from chemotherapy can be treated with erythropoiesis-stimulating agents (ESAs). As part of the observational IMPACT NHL study, data were collected on ESA use and anemia-related outcomes in 1829 adults receiving (± R)CHOP-14 or (± R)CHOP-21. Overall, 33% of patients were anemic during chemotherapy. Older age, lower baseline hemoglobin (Hb), worse performance status, more advanced disease stage, and use of CHOP-14 were significant predictors of transfusion and anemia in logistic regression models. ESAs were received by 404 patients, usually in response to low or declining Hb levels. Most patients (65%) had Hb 9-11 g/dL at ESA initiation, and 89% (Kaplan-Meier percentage) achieved Hb 10-12 g/dL. In conclusion, two-thirds of anemic patients with NHL receiving (± R)CHOP initiated ESA treatment at Hb 9-11 g/dL, and most achieved target Hb levels (10-12 g/dL).


The use of feathers in monitoring bioaccumulation of metals and metalloids in the South African endangered African grass-owl (Tyto capensis).
Few studies have quantified metals in South African species and no published data on residues specifically in South African owl feathers exist. Tyto capensis is listed as vulnerable within South Africa, making it preferable to use a non-invasive technique to determine metal bioaccumulation for this species. Comparisons are made with the cosmopolitan T. alba to determine whether this species could be used as a surrogate. Concentrations of various metals were thus determined in feathers of the two species and compared with liver and muscle samples. Samples were taken from 119 owls collected as road kill along a national road. A comparison of concentrations in feathers revealed similarly higher concentrations of aluminium, antimony, lead, nickel, and strontium, whereas concentrations of chromium, copper, iron, manganese, selenium, titanium and zinc were similarly higher in internal tissues for both species. Metal concentrations of owls were comparable to those reported in literature and below toxic levels, suggesting that these metals were not likely to impact the owls. Further regressions between feathers and corresponding livers were examined to determine if feathers were indicative of internal metal burdens. Significant positive relationships were found for aluminium, copper, lead, nickel and vanadium in T. alba and nickel, manganese and vanadium in T. capensis. Preliminary results support the feasibility of using feathers as non-destructive indicators of environmental contamination in T. capensis although caution needs to be taken when interpreting the results.


Combination of bone marrow stromal cell transplantation with mobilization by granulocyte-colony stimulating factor promotes functional recovery after spinal cord transection.
Spinal cord injury (SCI) results in severe neurological deficit. However, the functional recovery following SCI is very poor due to the neural lost and limited axonal regeneration. To date, there was no effective treatment. Recent studies have shown that bone marrow stromal cells (BMSCs) transplantated into the central nervous system (CNS) can survive and differentiate into neuronal-like cells. Additionally, granulocyte colony-stimulating factor (G-CSF) can mobilize hematopoietic stem cells and inhibit neural cell apoptosis. Thus, we aimed to evaluate the combined effect of BMSC transplantation and G-CSF administration on rats with traverse spinal cord injury. BMSCs were cultured in vitro, labeled with Hoechst33342, and then transplanted into the lesion site with or without G-CSF administration (50 microg/kg/day) for 5 subsequent days. The groups included an untreated control, along with treatment by G-CSF alone, BMSCs alone, and G-CSF + BMSCs. In this study, by the end of eighth week after SCI injury, the animals in group treated with G-CSF + BMSCs showed higher BBB scores than the other two groups. Morphometric assessment showed that the lesion areas in the rats of the G-CSF + BMSCs group were much smaller. Compared with the control, BMSC, and G-CSF groups, less expression of apoptosis cells and more neural-cell markers around the spinal cord injury were found in rats treated with G-CSF + BMSCs. The animals with the combination treatment achieved a better functional and morphologic recovery, although partial. This synergistic effect between BMSCs and G-CSF may be attributed to extrinsic and endogenous neurogenesis in the traverse spinal cord injury.


Surviving Siblings' Illnesses, Treatments/Health Services over 13 Months after a Sibling's Death.
Two million children experience sibling death annually and have problems that require clinical intervention although few receive such help. Effects on surviving siblings' mental health has been well documented, however their physical health has not. This study described surviving siblings' illnesses, treatments/health services at 2, 4, 6, and 13 months post-sibling death. The 132 children (76 girls, 56 boys, M 10.6 years, SD 3.43); 30% Hispanic, 51% Black, 26% White were recruited via hospital ICUs and published obituaries. Using a longitudinal design, parents reported types and numbers of surviving siblings' illnesses, treatments/health services, and dates post-sibling death. Most of the 207 illnesses and 674 treatments/health services occurred in the first 6 months post-sibling death. While girls had more illnesses (131) than boys (76) and Hispanic children had more illnesses than White or Black children, these differences were not statistically significant. Girls accounted for 66% of the treatments/health services and boys 34%. There was no significant difference in treatments/health service use by gender of the children (F = 1.00, p = .32). Hispanic children had significantly more treatments/health service use than Black children (F = 6.81, p = .002). Sibling death affects surviving siblings' physical health. Study data document the importance of monitoring the health, treatments and health service use of surviving siblings especially in the first 6 months after a sibling death, regardless of the child' s gender. On average, Hispanic children had greater health service use, which may warrant greater attention.


What, Where, and How to Collect Real-World Data and Generate Real-World Evidence to Support Drug Reimbursement Decision-Making in Asia: A reflection Into the Past and A Way Forward.
Globally, there is increasing interest in the use of real-world data (RWD) and real-world evidence (RWE) to inform health technology assessment (HTA) and reimbursement decision-making. Using current practices and case studies shared by eleven health systems in Asia, a non-binding guidance that seeks to align practices for generating and using RWD/RWE for decision-making in Asia was developed by the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) Working Group, addressing a current gap and needs among HTA users and generators. The guidance document was developed over two face-to-face workshops, in addition to an online survey, a face-to-face interview and pragmatic search of literature. The specific focus was on what, where and how to collect RWD/ RWE. All 11 REALISE member jurisdictions participated in the online survey and the first in-person workshop, 10 participated in the second in-person workshop, and 8 participated in the in-depth face-to-face interviews. The guidance document was iteratively reviewed by all working group members and the International Advisory Panel. There was substantial variation in: (a) sources and types of RWD being used in HTA, and (b) the relative importance and prioritization of RWE being used for policy-making. A list of national-level databases and other sources of RWD available in each country was compiled. A list of useful guidance on data collection, quality assurance and study design were also compiled. The REALISE guidance document serves to align the collection of better quality RWD and generation of reliable RWE to ultimately inform HTA in Asia.


Sprouting of brainstem-spinal tracts in response to unilateral motor cortex stroke in mice.
After a stroke to the motor cortex, sprouting of spared contralateral corticospinal fibers into the affected hemicord is one mechanism thought to mediate functional recovery. Little is known, however, about the role of the phylogenetically old, functionally very important brainstem-spinal systems. Adult mice were subjected to a unilateral photothrombotic stroke of the right motor cortex ablating 90% of the cross-projecting corticospinal cells. Unilateral retrograde tracing from the left cervical spinal hemicord devoid of its corticospinal input revealed widespread plastic responses in different brainstem nuclei 4 weeks after stroke. Whereas some nuclei showed no change or a decrease of their spinal projections, several parts of the medullary reticular formation as well as the spinally projecting raphe nuclei increased their projections to the cortically denervated cervical hemicord by 1.2- to 1.6-fold. The terminal density of corticobulbar fibers from the intact, contralesional cortex, which itself formed a fivefold expanded connection to the ipsilateral spinal cord, increased up to 1.6-fold specifically in these plastic, caudal medullary nuclei. A second stroke, ablating the originally spared motor cortex, resulted in the reappearance of the deficits that had partially recovered after the initial right-sided stroke, suggesting dependence of recovered function on the spared cortical hemisphere and its direct corticospinal and indirect corticobulbospinal connections.


Attitudes of house physicians concerning various antibiotic-use control programs.
Medical and surgical house physicians at three teaching hospitals with different antibiotic control programs (ACPs) were surveyed to determine their attitudes about and preferences for these programs. Questionnaires were mailed to resident physicians who had trained at all three hospitals. One hospital had no antibiotic prescribing policy (open prescribing), one employed an infectious-disease physician consultant who discussed antibiotic orders for certain reserved drugs with prescribing physicians but did not otherwise restrict access to the drugs (educational ACP), and the third hospital required approval of an infectious-disease physician for dispensing of reserved drugs by the pharmacy department (restrictive ACP). The survey response was 77% after one follow-up mailing to nonrespondents. Regardless of hospital type, physicians preferred the educational ACP to either open prescribing or the restrictive ACP. Based on personal experiences, significantly fewer physicians encountered patient-care problems with the educational ACP than with either open antibiotic prescribing or the restrictive ACP. Significantly more physicians perceived that the educational ACP was more beneficial for patient antibiotic therapy and will be more beneficial for future antibiotic prescribing than the restrictive ACP. Most respondents believed that ACPs save hospitals money, that ACPs can be implemented without compromising either patient care or physician performance, and that they would encounter similar ACPs in the future. Educational ACPs should be considered at teaching hospitals with interested infectious-disease consultants.


A quantum-mechanical perspective on linear response theory within polarizable embedding.
We present a derivation of linear response theory within polarizable embedding starting from a rigorous quantum-mechanical treatment of a composite system. To this aim, two different subsystem decompositions (symmetric and nonsymmetric) of the linear response function are introduced and the pole structures as well as residues of the individual terms are discussed. In addition to providing a thorough justification for the descriptions used in polarizable embedding models, this theoretical analysis clarifies which form of the response function to use and highlights complications in separating out subsystem contributions to molecular properties. The basic features of the presented expressions and various approximate forms are illustrated by their application to a composite model system.


Differences in Parkinson's Disease Risk with Caffeine Intake and Postmenopausal Hormone Use.
Caffeine intake has been associated with a lower risk of Parkinson's disease (PD). This association is robust in men, but inconsistent in women due to a possible interaction with post-menopausal hormone (PMH) use. To (1) evaluate the association between caffeine intake and PD risk and (2) assess potential effect modification of the association by PMH use among women. We examined associations between caffeine intake and incident PD risk in the Nurses' Health Study (NHS) (N = 121,701 women) and the Health Professionals Follow-up Study (HPFS) (N = 51,529 men). Dietary data on coffee and caffeine from other sources were collected every four years using a validated semi-quantitative food frequency questionnaire for both cohorts. Information on lifestyle and incident PD diagnosis was updated biennially and PD diagnoses were confirmed by medical record review. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models. We documented a total of 1,219 PD cases over the follow-up period. The multivariable-adjusted HR comparing the highest to lowest quintile of caffeine intake was 0.50 (95% CI: 0.37, 0.68; Ptrend<0.0001) in the HPFS. Among women, there was a suggestion of an interaction between coffee intake and PMH use (P = 0.08). In the pooled analyses combining men and women who have never used PMH, the risk of PD was lower as coffee intake increased (Ptrend<0.001). Our results support previous findings that increased caffeine intake may be associated with a decreased PD risk in men and women who have never used PMH.


Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package.
Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance.


Ligand specificity of nicotinic acetylcholine receptors in rat spinal cord: studies with nicotine and cytisine.
Administration of nicotinic agonists to the spinal cord leads to a variety of cardiovascular and behavioral responses. The discrete localization of afferent and efferent fibers presents a system in which occupation of nicotinic receptor subtypes might be correlated with specific pharmacologic responses. To this end, we examined [3H]cytisine and [3H]nicotine binding to membranes isolated from regions of the rat spinal cord. [3H]Cytisine showed saturable, noncooperative (nH congruent to 1) binding to a single-class of sites with a Kd of 0.44 +/- 0.01 nM and total saturable sites of 19.9 +/- 0.9 fmol/mg of protein. [3H]Cytisine binding to membranes from intermediolateral cell column and dorsal and ventral sections of the lumbosacral regions each revealed a single class of binding sites with virtually identical Kd values. However, the dorsal sections of the lumbar spinal cord contained a higher number of total binding sites than ventral lumbar or intermediolateral sections. The rank order potencies of the nicotinic agonists competing for [3H]cytisine binding was cytisine > I-nicotine > N-methylcarbamylcholine > dimethylphenylpiperazinium > acetylcholine > d-nicotine > carbamylcholine. Competitive antagonists also competed with high affinities (Ki as low as nanomolar) with the order of potencies being alpha-lobeline > or = dihydro-beta-erythroidine >> methyllycaconitine, whereas the channel blockers, mecamylamine and hexamethonium, only competed at concentrations > or = 100 microM. Competitive ganglionic blockers such as d-tubocurarine or trimethaphan and neurotoxins such as alpha-bungarotoxin, alpha-cobratoxin or neuronal bungarotoxin had weak affinities for cytisine sites. Similar to [3H]cytisine, [3H]nicotine also revealed a saturable single class of binding sites, but of lower affinity. The rank order of Ki values of the agonists, antagonists and neurotoxins for competing with [3H]nicotine binding was similar to the order for [3H]cytisine. Nicotinic receptors in the spinal cord membrane show a specificity for both agonists and antagonists that differ from neuronal receptors in the ganglia or the regions of the brain characterized to date. These findings, when correlated with the pharmacological responses documented in the comparison article suggests that the spinal nicotinic receptors may define a new member of the neuronal nicotinic receptor family.


Childhood cancers in a referral hospital in Kenya: a review.
Following the outbreak of human immune deficiency virus (HIV) infection in the early 1980's, there has been an increase in reported cases of Kaposi's sarcoma, among other childhood malignancies, from the East and Central African region. To assess the status of childhood cancers at Kenyatta National Hospital during the AIDS epidemic period and to compare the findings with those obtained before the outbreak, relevant data were extracted from ward admission registers for all children admitted in the paediatric wards and in whom a diagnosis of a malignant disease was confirmed. The data were summarised in tables and bar charts. The hospital based prevalence for malignant diseases was 1.27% (CI = 1.23,1.31). Lymphoma (51.3%), leukaemia (21.3%), nephroblastoma (8.5%) and rhabdomyosarcoma (5.2%) are the most common childhood cancers. Compared with earlier studies, the frequency of acute lymphoblastic leukaemia, Hodgkin's disease and rhabdomyosarcoma appear to have increased. Despite the AIDS epidemic, there has been no obvious increase in number of cases of Kaposi's sarcoma.


Effects of olive oil and its minor phenolic constituents on obesity-induced cardiac metabolic changes.
Olive oil and its minor constituents have been recommended as important dietary therapeutic interventions in preventive medicine. However, a question remains to be addressed: what are the effects of olive oil and its phenolic compounds on obesity-induced cardiac metabolic changes? Male Wistar rats were divided into two groups (n = 24/group): (C) receiving standard-chow; (Ob) receiving hypercaloric-chow. After 21 days C and Ob groups were divided into four subgroups (n = 6/group):(C) standard-chow and saline; (C-Olive)standard-chow and olive-oil (3.0 g/kg.day); (C-Oleuropein)standard-chow and oleuropein (0.023 mg/kg/day); (C-Cafeic) standard-chow and cafeic-acid (2.66 mg/kg/day); (Ob)receiving hypercaloric-chow and saline;(Ob-Olive) hypercaloric-chow and olive-oil;(Ob-Oleuropein) hypercaloric-chow and oleuropein;(Ob-Cafeic) hypercaloric-chow and cafeic-acid. Treatments were given twice a week during 21 days. After 42 days, obesity was evidenced in Ob rats from enhanced body-weight, surface-area, and body-mass-index. Energy-expenditure, oxygen consumption(VO2) and fat-oxidation were lower in Ob-group than in C. Despite no morphometric changes, Ob-Olive, Ob-Oleuropein and Ob-Cafeic groups had higher VO2, fat-oxidation, myocardial beta-hydroxyacyl coenzyme-A dehydrogenase and lower respiratory-quotient than Ob. Citrate-synthase was highest in Ob-Olive group. Myocardial lipid-hydroperoxide(LH) and antioxidant enzymes were unaffected by olive-oil and its compounds in obesity condition, whereas LH was lower and total-antioxidant-substances were higher in C-Olive and C-Oleuropein than in C. The present study demonstrated for the first time that olive-oil, oleuropein and cafeic-acid enhanced fat-oxidation and optimized cardiac energy metabolism in obesity conditions. Olive oil and its phenolic compounds improved myocardial oxidative stress in standard-fed conditions.


Antimicrobial breakpoints for gram-negative aerobic bacteria based on pharmacokinetic-pharmacodynamic models with Monte Carlo simulation.
This study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key gram-negative aerobic bacteria. A 10,000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was > or = 90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies. PK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested--with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (< or = 10%) differences in the percentages susceptible. In contrast, large (> 15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii. Breakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.


Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase.
Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM). Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death. Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies. Trial registration ID NCT01770353.


Electrostatic effects and binding determinants in the catalysis of prolyl oligopeptidase. Site specific mutagenesis at the oxyanion binding site.
Prolyl oligopeptidase, a member of a new family of serine peptidases, plays an important role in memory disorders. Earlier x-ray crystallographic investigations indicated that stabilization of the tetrahedral transition state of the reaction involved hydrogen bond formation between the oxyanion of the tetrahedral intermediate and the OH group of Tyr(473). The contribution of the OH group was tested with the Y473F variant using various substrates. The charged succinyl-Gly-Pro-4-nitroanilide was hydrolyzed with a much lower k(cat)/K(m) compared with the neutral benzyloxycarbonyl-G1y-Pro-2-naphthylamide, although the binding modes of the two substrates were similar, as shown by x-ray crystallography. This suggested that electrostatic interactions between Arg(643) and the succinyl group competed with the productive binding mechanism. Unlike most enzyme reactions, catalysis by the wild-type enzyme exhibited positive activation entropy. In contrast, the activation entropy for the Y473F variant was negative, suggesting that the tyrosine OH group is involved in stabilizing both the transition state and the water shell at the active site. Importantly, Tyr(473) is also implicated in the formation of the enzyme-substrate complex. The nonlinear Arrhenius plot suggested a greater significance of the oxyanion binding site at physiological temperature. The results indicated that Tyr(473) was more needed at high pH, at high temperature, and with charged substrates exhibiting "internally competitive inhibition."


Antibody-catalyzed porphyrin metallation.
An antibody elicited to a distorted N-methyl porphyrin catalyzed metal ion chelation by the planar porphyrin. At fixed Zn2+ and Cu2+ concentrations, the antibody-catalyzed reaction showed saturation kinetics with respect to the substrate mesoporphyrin IX (2) and was inhibited by the hapten, N-methylmesoporphyrin IX (1). The turnover number of 80 hour-1 for antibody-catalyzed metallation of 2 with Zn2+ compares with an estimated value of 800 hour-1 for ferrochelatase. The antibody also catalyzed the insertion of Co2+ and Mn2+ into 2, but it did not catalyze the metallation of protoporphyrin IX (3) or deuteroporphyrin IX (4). The antibody has high affinity for several metalloporphyrins, suggesting an approach to developing antibody-heme catalysts for redox or electron transfer reactions.


Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis in human immunodeficiency virus-negative patients: retrospective analysis of 83 cases. French Cryptococcosis Study Group.
We retrospectively analyzed clinical outcome of meningeal and extrameningeal cryptococcosis in HIV-negative patients treated with amphotericin B (43 patients) or fluconazole (40 patients). Amphotericin B and fluconazole were prescribed equally to patients with neoplastic diseases and no risk factor, but organ transplant recipients and patients with other diseases were mostly given fluconazole and amphotericin B, respectively. Patients with more severe infections (i.e., meningitis, neurological disorders, or higher levels of antigen in cerebrospinal fluid) were more frequently treated with amphotericin B. A cure rate of > 70% was achieved regardless of the initial treatment and the severity of the infection. A Cox regression analysis showed that age of > 60 years, neoplastic disease, abnormal mental status, disseminated infection at the time of diagnosis, and therapeutic failure were independent predictors of death. Although fluconazole appears to be as effective as amphotericin B, only a prospective multicenter study will determine the best treatment regimen for patients with cryptococcal meningitis who do not have AIDS.


Impact of intensive care practices on short-term and long-term outcomes for extremely preterm infants: comparison between the British Isles and France.
The objective of this study was to compare practices of care and outcomes of infants who were born between 23 and 25 weeks' gestation in 1995 in the British Isles and in 1997-1998 in France. We examined 2 population-based cohorts in the British Isles (1892 births included) and in France (456 births): the EPICure and EPIPAGE studies. The rate of follow-up was 90% at 30 months and 86% at 2 years. At 5 to 6 years, the cognitive function of 64% of the children without severe disability was assessed in the EPICure study and 57% in the EPIPAGE study. The mortality rate of live-born infants was lower in the EPICure study (25%) than in the EPIPAGE study (34%) before admission to a NICU but higher in the NICU (45% vs 29%, respectively), such that there was no difference in the proportions of survivors at discharge after adjustment for gestational age. The risk for severe brain lesions was 24% among infants who were admitted to a NICU in both studies, 41% in the EPICure study versus 67% in the epidemiologic study on great prematurity (EPIPAGE) among infants who died after discontinued treatment in NICU, and 17% vs 11% among survivors at discharge. The risk for cerebral palsy at 24 to 30 months was 20% in the EPICure study versus 16% in the EPIPAGE study, whereas the risk for overall cognitive score of <70 at 5 to 6 years was 10% vs 14%, respectively. Despite apparent differences in the modalities of limitation of intensive care, the outcomes of infants who were born at 23 to 25 weeks' gestation in the EPICure and EPIPAGE studies were not significantly different.


A systematic review of reported cases involving psychotic symptoms worsened by aripiprazole in schizophrenia or schizoaffective disorder.
Numerous case reports have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia. We reviewed reported cases which have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia and evaluated each regarding quality of the causal relationship. A systematic literature search was conducted on August 18, 2012, using the PubMed and the EMBASE. Twenty-two cases met the following inclusion criteria: (1) diagnosis of schizophrenia or schizoaffective disorder, (2) worsening of psychotic symptoms associated with aripiprazole, and (3) aripiprazole dose ≤ 30 mg/day. Information about the causal relationship between aripiprazole and increased psychotic symptoms was extracted. The quality of the causal relationship was evaluated according to the modified guidelines for evaluation of drug-associated events and classified as "questionable," "moderately suggestive," or "highly suggestive." Patients were chronic in at least 15 cases, and prior antipsychotic dose exceeded recommended guidelines in 19 cases. Psychotic symptoms worsened after simply adding aripiprazole to the current regimen in eight cases. Besides psychotic symptoms, increasing agitation (nine cases), aggression (11 cases), and/or activation (seven cases) were reported. Clinical resolution occurred after aripiprazole discontinuation in eight cases. Regarding causal relationship, 11 cases were classified as "highly suggestive," three as "moderately suggestive," and eight as "questionable". Clinicians should be vigilant when adding aripiprazole to patients with chronic schizophrenia also receiving relatively high doses of other antipsychotics, and discontinuation of aripiprazole should be considered if psychotic symptoms and/or agitation/aggression/activation increase.


Immunocytochemical localization of the GABA transporter in rat brain.
Polyclonal antibodies were raised against the GABA transporter (GABA-Tp) purified from rat brain tissue (Radian et al., 1986) and used for immunocytochemical localization of the antigen in several rat brain areas, including the cerebellum, hippocampus, substantia nigra, and cerebral cortex. Light microscopic studies with the peroxidase-antiperoxidase and biotin-avidin-peroxidase techniques suggested that GABA-Tp is localized in the same types of axons and terminals that contain endogenous GABA, as judged by comparison with parallel sections incubated with antibodies against glutaraldehyde-conjugated GABA. However, as expected from biochemical results, different neurons differed in their relative contents of GABA-Tp and GABA; thus, GABA-Tp was relatively low in striatonigral and Purkinje axon terminals and relatively high in nerve plexus around the bases of cerebellar Purkinje cells and hippocampal pyramidal and granule cells. The GABA-Tp antiserum did not produce detectable labeling of nerve cell bodies. Electron microscopic studies supported the light microscopic observations and provided direct evidence of cellular co-localization of GABA-Tp and GABA (as visualized by the peroxidase-antiperoxidase technique and postembedding immunogold labeling, respectively). The ultrastructural studies indicated the presence of GABA-Tp also in glial processes but not in glial cell bodies. The relative intensity of the neuronal and glial staining varied among regions: glial staining predominated over neuronal staining in the substantia nigra, whereas the converse was true in the cerebellum and hippocampus. The present immunocytochemical data demonstrate directly what has previously been inferred from biochemical and autoradiographic evidence: that the mechanisms for high-affinity GABA uptake is selectively and differentially localized in GABAergic neurons and in glial cells.


The costs of negative affect attributable to alcohol consumption in later life: A within-between random longitudinal econometric model using UK Biobank.
Research demonstrates a negative relationship between alcohol use and affect, but the value of deprecation is unknown and thus cannot be included in estimates of the cost of alcohol to society. This paper aims to examine this relationship and develop econometric techniques to value the loss in affect attributable to alcohol consumption. Cross-sectional (n = 129,437) and longitudinal (n = 11,352) analyses of alcohol consumers in UK Biobank data were undertaken, with depression and neuroticism as proxies of negative affect. The cross-sectional relationship between household income, negative affect and alcohol consumption were analysed using regression models, controlling for confounding variables, and using within-between random models that are robust to unobserved heterogeneity. The differential in household income required to offset alcohol's detriment to affect was derived. A consistent relationship between depression and alcohol consumption (β = 0.001, z = 7.64) and neuroticism and alcohol consumption (β = 0.001, z = 9.24) was observed in cross-sectional analyses, replicated in within-between models (depression β = 0.001, z = 2.32; neuroticism β = 0.001, z = 2.33). Significant associations were found between household income and depression (cross sectional β = -0.157, z = -23.86, within-between β = -0.146, z = -9.51) and household income and neuroticism (cross sectional β = -0.166, z = -32.02, within-between β = -0.158, z = -7.44). The value of reducing alcohol consumption by one gram/day was pooled and estimated to be £209.06 (95% CI £171.84 to £246.27). There was a robust relationship between alcohol consumption and negative affect. Econometric methods can value the intangible effects of alcohol use and may, therefore, facilitate the fiscal determination of benefit.


Initial and Long-term Retention of Robotic Technical Skills in an Otolaryngology Residency Program.
To objectively assess the initial and long-term retention of robotic surgical skills of otolaryngology residents. This study was performed in an academic otolaryngology residency training program. Between October 2015 and November 2016, residents were invited to complete a prospective, multiphase robotic surgical skills training course: 1) online da Vinci Surgical System Assessment and didactic, 2) faculty-supervised robotic simulator training, 3) robotic docking and draping training, 4) robotic dry-lab exercises. To optimize surgical skill retention, the training laboratory was repeated 2 weeks after the initial training session. Twenty otolaryngology residents were included. Primary outcome was measured as robotic skill assessment scores on three tasks: camera targeting, peg board, and needle targeting. Skill assessments were completed prior to training, between the two training sessions, and at 1 month and 6 months after training. Residents were also asked to complete a self-assessment questionnaire. Camera targeting scores were improved at midtraining (P < .001) and 1-month posttraining (P = .010). Peg board scores were improved at 1 month training (P = .043). Needle targeting scores were improved at midtraining (P = .002), 1 month (P = .002), and 6 months posttraining (P < .001). Resident self-assessment scores demonstrating comfort with using the robotic console (P < .01) and docking/draping (P < .01) improved significantly following the training. Following a multiphase robotic training program, otolaryngology residents demonstrated significant, objective skill acquisition and retention at 1 month and 6 months follow-up. Although the proposed training strategy may be considered an important step in otolaryngology residency training, additional innovations are being designed toward a formal robotic training curriculum. NA Laryngoscope, 129:1380-1385, 2019.


Development and validation of an alternative ankylosing spondylitis disease activity score when patient global assessment is unavailable.
To develop an alternative Ankylosing Spondylitis Disease Activity Score (ASDAS) to be used in research settings in axial SpA (axSpA) when Patient Global Assessment (PGA) is unavailable in databases. Longitudinal data from four axSpA cohorts and two randomized controlled trials were combined. Observations were randomly split in a development (N = 1026) and a validation cohort (N = 1059). Substitutes of PGA by BASDAI total score, single or combined individual BASDAI questions, and a constant value, were established in the development cohort. Conversion factors for each substitute were defined by Generalized Estimating Equations, obtaining seven 'alternative' formulae. Validation was performed in the validation cohort according to the OMERACT filter, taking into consideration: (i) truth (agreement with original-ASDAS in the continuous score, by intraclass correlation coefficient and in disease activity states, by weighted kappa); (ii) discrimination [standardized mean difference of ASDAS scores between high/low disease activity states defined by external anchors, e.g. Patient Acceptable Symptom State; agreement (kappa) in the percentage of patients reaching ASDAS improvement criteria according to alternative vs original formulae]; and (iii) feasibility. Comparing various options, alternative-ASDAS using BASDAI total as PGA replacement proved to be: truthful (intraclass correlation coefficient = 0.98, kappa = 0.90), discriminative [ASDAS scores between Patient Acceptable Symptom State no/yes: standardized mean difference = 1.37 (original-ASDAS standardized mean difference = 1.43); agreement with original-ASDAS in major improvement/clinically important improvement criteria: kappa = 0.93/0.88] and feasible (BASDAI total often available, as questions required for the ASDAS; conversion coefficient ≈ 1). Alternative-ASDAS using BASDAI total score as PGA replacement is the most truthful, discriminative and feasible instrument.


The Plant Hormone Cytokinin Confers Protection against Oxidative Stress in Mammalian Cells.
Modulating key dynamics of plant growth and development, the effects of the plant hormone cytokinin on animal cells gained much attention recently. Most previous studies on cytokinin effects on mammalian cells have been conducted with elevated cytokinin concentration (in the μM range). However, to examine physiologically relevant dose effects of cytokinins on animal cells, we systematically analyzed the impact of kinetin in cultured cells at low and high concentrations (1nM-10μM) and examined cytotoxic and genotoxic conditions. We furthermore measured the intrinsic antioxidant activity of kinetin in a cell-free system using the Ferric Reducing Antioxidant Power assay and in cells using the dihydroethidium staining method. Monitoring viability, we looked at kinetin effects in mammalian cells such as HL60 cells, HaCaT human keratinocyte cells, NRK rat epithelial kidney cells and human peripheral lymphocytes. Kinetin manifests no antioxidant activity in the cell free system and high doses of kinetin (500 nM and higher) reduce cell viability and mediate DNA damage in vitro. In contrast, low doses (concentrations up to 100 nM) of kinetin confer protection in cells against oxidative stress. Moreover, our results show that pretreatment of the cells with kinetin significantly reduces 4-nitroquinoline 1-oxide mediated reactive oxygen species production. Also, pretreatment with kinetin retains cellular GSH levels when they are also treated with the GSH-depleting agent patulin. Our results explicitly show that low kinetin doses reduce apoptosis and protect cells from oxidative stress mediated cell death. Future studies on the interaction between cytokinins and human cellular pathway targets will be intriguing.


Scaling Laws in Directional Spreading of Droplets on Wettability-Confined Diverging Tracks.
Spontaneous pumpless transport of droplets on wettability-confined tracks is important for various applications, such as rapid transport and mixing of fluid droplets, enhanced dropwise condensation, biomedical devices, and so forth. Recent studies have shown that on an open surface, a superhydrophilic track of diverging width, laid on a superhydrophobic background, facilitates the transport of water from the narrower end to the wider end at unprecedented rates (up to 40 cm/s) without external actuation. The spreading behavior on such surfaces, however, has only been characterized for water. Keeping in mind that such designs play a key role for a diverse range of applications, such as handling organic liquids and in point-of-care devices, the importance of characterizing the spreading behavior of viscous liquids on such surfaces cannot be overemphasized. In the present work, the spreading behavior on the aforementioned wettability-patterned diverging tracks was observed for fluids of different viscosities. Two dimensionless variables were identified, and a comprehensive relationship was obtained. Three distinct temporal regimes of droplet spreading were established: I), a Washburn-type slow spreading, II) a much faster Laplace pressure-driven spreading, and III), a sluggish density-augmented Tanner-type film spreading. The results offer design guidance for tracks that can pumplessly manage fluids of various viscosities and surface tensions.


A simple physiologic algorithm for managing hemodynamics using stroke volume and stroke volume variation: physiologic optimization program.
Intravascular volume status and volume responsiveness continue to be important questions for the management of critically ill or injured patients. Goal-directed hemodynamic therapy has been shown to be of benefit to patients with severe sepsis and septic shock, acute lung injury and adult respiratory distress syndrome, and for surgical patients in the operating room. Static measures of fluid status, central venous pressure (CVP), and pulmonary artery occlusion pressure (PAOP) are not useful in predicting volume responsiveness. Stroke volume variation and pulse pressure variation related to changes in stroke volume during positive pressure ventilation predict fluid responsiveness and represent an evolving practice for volume management in the intensive care unit (ICU) or operating room. Adoption of dynamic parameters for volume management has been inconsistent. This manuscript reviews some of the basic physiology regarding the use of stroke volume variation to predict fluid responsiveness in the ICU and operating room. A management algorithm using this physiology is proposed for the critically ill or injured in various settings.


Direct inhibition of RNAse T2 expression by the HTLV-1 viral protein Tax.
Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP) assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development.


Changes in auditory P300 with clinical remission in schizophrenia: effects of facial-affect stimuli.
The auditory P300 is affected by arousal and emotion. We examined the effect of drawings expressing sadness or pleasure on auditory event-related potentials (ERP) during recovery from schizophrenia. Oddball-paradigm auditory ERP were recorded while presenting one of these drawings to nine patients with paranoid schizophrenia and seven patients with other types of schizophrenia during the acute stage and again during remission. P300 parameters (amplitude, area, and latency), reaction time, and symptom scores were evaluated. P300 amplitude and area were significantly greater in the recovery than in the acute phase. Increases were larger when viewing drawings that expressed sadness than when viewing drawings that expressed pleasure. In paranoid-type patients, P300 when viewing pleasurable drawings was similar to that when viewing sad drawings during the acute phase; in remission, P300 was significantly larger when viewing sad drawings than when viewing pleasurable drawings. In non-paranoid patients, P300 while viewing pleasurable drawings was significantly larger than that while viewing sad drawings during the acute phase; this difference disappeared during recovery. P300 latency and reaction time were not influenced by facial-affect stimuli or recovery. A significant negative correlation was noted between amplitude and negative symptom scores. P300 amplitude and area may be useful state markers during recovery in schizophrenic patients. Effects involving attention resources and emotional arousal are also involved.


Derivation of a mouse model for conditional inactivation of Pax9.
Pax9 is required for the formation of a variety of organs during mouse development. The function of Pax9 at postnatal stages is unknown since homozygosity of the null allele (Pax9(lacZ)) causes neonatal lethality. Recently, we have generated a hypomorphic Pax9 allele, Pax9(neo), which contains a removable neomycin resistance cassette (neo) and loxP sites flanking the first two exons of Pax9. Here we show that FLP-mediated in vivo excision of neo generates phenotypically normal Pax9(flox) mice. Crossing Pax9(flox) mice to PGK-Cre mice leads to efficient recombination of loxP sites and neonatal lethality in the resulting Pax9(del/del) offspring. Inactivation of Pax9 using Wnt1-Cre mice causes cleft secondary palate and tooth agenesis and reveals that the Pax9 expressing mesenchymal cells of the nose, palate, and teeth are derived from neural crest cells. The conditional Pax9 allele will be a valuable tool to study Pax9 function in specific tissues of adult mice.


Cytokine gene polymorphisms in acute pancreatitis.
Pro-inflammatory and regulatory cytokines play a key role in the pathogenesis of acute pancreatitis. Genetic loci encoding cytokines have been shown to be polymorphic, in some cases influencing protein expression. To investigate if TNF and IL-10 gene loci are associated with the occurrence or severity of acute pancreatitis. Acute surgical unit within large district hospital serving a population of 500,000. METHODS, Three TNF microsatellite loci (TNFa, TNFb, TNFc), the TNF-308 polymorphism, the IL-10.G microsatellite locus, and 3 i-allelic polymorphisms in the IL-10 5' region were typed using PCR in 135 acute pancreatitis patients and ethnically matched normal controls (n=107). Aetiology of disease was determined and patients grouped according to disease severity by assigning an organ failure score or classification according to the Atlanta system. Allelic frequency of polymorphic loci in patients with different aetiology and disease course in acute pancreatitis. No difference was noted in allelic frequency of any of the cytokine gene loci between groups stratified according to disease severity. When aetiology was studied again there was no significant difference in allelic frequency. The cytokine gene polymorphisms studied play no part in determination of disease severity or susceptibility to acute pancreatitis.


Evolutionary genomics of dog domestication.
We review the underlying principles and tools used in genomic studies of domestic dogs aimed at understanding the genetic changes that have occurred during domestication. We show that there are two principle modes of evolution within dogs. One primary mode that accounts for much of the remarkable diversity of dog breeds is the fixation of discrete mutations of large effect in individual lineages that are then crossed to various breed groupings. This transfer of mutations across the dog evolutionary tree leads to the appearance of high phenotypic diversity that in actuality reflects a small number of major genes. A second mechanism causing diversification involves the selective breeding of dogs within distinct phenotypic or functional groups, which enhances specific group attributes such as heading or tracking. Such progressive selection leads to a distinct genetic structure in evolutionary trees such that functional and phenotypic groups cluster genetically. We trace the origin of the nuclear genome in dogs based on haplotype-sharing analyses between dogs and gray wolves and show that contrary to previous mtDNA analyses, the nuclear genome of dogs derives primarily from Middle Eastern or European wolves, a result more consistent with the archeological record. Sequencing analysis of the IGF1 gene, which has been the target of size selection in small breeds, further supports this conclusion. Finally, we discuss how a black coat color mutation that evolved in dogs has transformed North American gray wolf populations, providing a first example of a mutation that appeared under domestication and selectively swept through a wild relative.


Archaeological assessment reveals Earth's early transformation through land use.
Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth's transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.


Application of immunosignatures for diagnosis of valley fever.
Valley fever (VF) is difficult to diagnose, partly because the symptoms of VF are confounded with those of other community-acquired pneumonias. Confirmatory diagnostics detect IgM and IgG antibodies against coccidioidal antigens via immunodiffusion (ID). The false-negative rate can be as high as 50% to 70%, with 5% of symptomatic patients never showing detectable antibody levels. In this study, we tested whether the immunosignature diagnostic can resolve VF false negatives. An immunosignature is the pattern of antibody binding to random-sequence peptides on a peptide microarray. A 10,000-peptide microarray was first used to determine whether valley fever patients can be distinguished from 3 other cohorts with similar infections. After determining the VF-specific peptides, a small 96-peptide diagnostic array was created and tested. The performances of the 10,000-peptide array and the 96-peptide diagnostic array were compared to that of the ID diagnostic standard. The 10,000-peptide microarray classified the VF samples from the other 3 infections with 98% accuracy. It also classified VF false-negative patients with 100% sensitivity in a blinded test set versus 28% sensitivity for ID. The immunosignature microarray has potential for simultaneously distinguishing valley fever patients from those with other fungal or bacterial infections. The same 10,000-peptide array can diagnose VF false-negative patients with 100% sensitivity. The smaller 96-peptide diagnostic array was less specific for diagnosing false negatives. We conclude that the performance of the immunosignature diagnostic exceeds that of the existing standard, and the immunosignature can distinguish related infections and might be used in lieu of existing diagnostics.


Potential of porous silicon nanoparticles as an emerging platform for cancer theranostics.
Currently, nanoscience is a major part of biomedical research, due to material advances that aid the development of new tools and techniques to replace traditional methods. To this end, the potential of porous silicon nanoparticles (pSiNPs) has been examined, especially in areas of cancer treatment and diagnosis. The properties of pSiNPs such as their porous structure, high surface area and porous volume, biocompatibility and biodegradability offer real opportunities for focal therapies that can avoid the side effects caused by conventional methods. This review is focused on pSiNPs and their potential application in targeted anticancer drug delivery, and photodynamic and thermal therapies. In addition, the luminescence properties of pSiNPS are useful in bioimaging and diagnosis. Hence, the theranostic potential of pSiNPs is discussed herein.


Vendor-based restrictions on pesticide sales to prevent pesticide self-poisoning - a pilot study.
In South Asia, up to 20% of people ingesting pesticides for self-poisoning purchase the pesticide from a shop with the sole intention of self-harm. Individuals who are intoxicated with alcohol and/or non-farmers represent 72% of such high-risk individuals. We aimed to test the feasibility and acceptability of vendor-based restrictions on pesticide sales for such high-risk individuals. We conducted a pilot study in 14 (rural = 7, urban = 7) pesticide shops in Anuradhapura District of Sri Lanka. A two-hour training program was delivered to 28 pesticide vendors; the aim of the training was to help vendors recognize and respond to customers at high risk of pesticide self-poisoning. Knowledge and attitudes of vendors towards preventing access to pesticides for self-poisoning at baseline and in a three month follow-up was evaluated by questionnaire. Vendors were interviewed to explore the practice skills taught in the training and their assessment of the program. The scores of knowledge and attitudes of the vendors significantly increased by 23% (95% CI 15%-32%, p < 0.001) and by 16% (95% CI 9%-23%, p < 0.001) respectively in the follow-up. Fifteen (60%) vendors reported refusing sell pesticides to a high-risk person (non-farmer or intoxicated person) in the follow-up compared to three (12%) at baseline. Vendors reported that they were aware from community feedback that they had prevented at least seven suicide attempts. On four identified occasions, vendors in urban shops had been unable to recognize the self-harming intention of customers who then ingested the pesticide. Only 2 (8%) vendors were dissatisfied with the training and 23 (92%) said they would recommend it to other vendors. Our study suggests that vendor-based sales restriction in regions with high rates of self-poisoning has the potential to reduce access to pesticides for self-poisoning. A large-scale study of the effectiveness and sustainability of this approach is needed.


Metabolic Relations between Methylxanthines and Methyluric Acids in Coffea L.
Metabolism of purine alkaloids in the leaves of Coffea dewevrei De Wild et Durand var excelsa Chev, Coffea liberica Bull ex Hiern and Coffea abeokutae Cramer was studied by analyzing leaf discs collected during vegetative development and by feeding the following radioactive tracers: [(14)C]theobromine, [(14)C]caffeine, and [(14)C]theacrine (1,3,7,9-tetramethyluric acid). Their principal metabolites were quantitatively and qualitatively determined. All three species convert the precursors to the same radioactive products, and proceed through the same four maturity stages characterized by the alkaloid accumulation pattern and by a particular transformation potency: (stage 1) young plant accumulating caffeine, transforms theobromine to caffeine; (stage 2) caffeine is gradually replaced by theacrine, theobromine and caffeine are converted to theacrine; (stage 3) theacrine disappears whereas liberine (O(2), 1,9-thrimethyluric acid) accumulates, theacrine is metabolized to liberine; (stage 4) branched-out plant containing liberine but no theacrine, caffeine is converted rapidly to liberine via theacrine. Methylliberine (O(2),1,7,9-tetramethyluric acid), presumably the direct precursor of liberine, is occasionally found in low concentrations at stage 3 and 4.The collective term ;liberio-excelsoid' introduced by geneticists for the numerous races or species of Pachycoffea is in accordance with the phytochemical equality found in this work.


Graft weight/recipient weight ratio: how well does it predict outcome after partial liver transplants?
Partial graft liver recipients with graft weight/recipient weight (GW/RW) ratios < 0.8% are thought to have a higher incidence of postoperative complications, including small-for-size syndrome (SFSS). We analyzed a cohort of such recipients and compared those with GW/RW < 0.8% to those with GW/RW >or= 0.8%. Between 1999 and 2008, 107 adult patients underwent partial graft liver transplants: 76 from live donors [living donor liver transplantation (LDLT)] and 31 from deceased donors [split liver transplantation (SLT)]. Of these, 22 had GW/RW < 0.8% (12 with LDLT and 10 with SLT), and 85 had GW/RW >or= 0.8% (64 with LDLT and 21 with SLT). The baseline demographics and median length of follow-up were similar. SFSS developed in 3 recipients with GW/RW < 0.8% (13.6%) and in 8 recipients with GW/RW >or= 0.8% (9.4%; P = not significant). Other early complications were similar between the 2 groups. Inflow modification with splenic artery occlusion was performed in 13 recipients: 7 with GW/RW < 0.8% and 6 with GW/RW >or= 0.8%. Graft survival at 1 year post-transplant did not differ (91% versus 92%; P = not significant). In conclusion, GW/RW did not appear to be the only determinant of outcome after partial liver transplantation. Using techniques such as inflow modification may help to prevent some of the problems seen with smaller grafts.


Soil bacterial communities are shaped by temporal and environmental filtering: evidence from a long-term chronosequence.
Soil microbial communities are abundant, hyper-diverse and mediate global biogeochemical cycles, but we do not yet understand the processes mediating their assembly. Current hypothetical frameworks suggest temporal (e.g. dispersal limitation) and environmental (e.g. soil pH) filters shape microbial community composition; however, there is limited empirical evidence supporting this framework in the hyper-diverse soil environment, particularly at large spatial (i.e. regional to continental) and temporal (i.e. 100 to 1000 years) scales. Here, we present evidence from a long-term chronosequence (4000 years) that temporal and environmental filters do indeed shape soil bacterial community composition. Furthermore, nearly 20 years of environmental monitoring allowed us to control for potentially confounding environmental variation. Soil bacterial communities were phylogenetically distinct across the chronosequence. We determined that temporal and environmental factors accounted for significant portions of bacterial phylogenetic structure using distance-based linear models. Environmental factors together accounted for the majority of phylogenetic structure, namely, soil temperature (19%), pH (17%) and litter carbon:nitrogen (C:N; 17%). However, of all individual factors, time since deglaciation accounted for the greatest proportion of bacterial phylogenetic structure (20%). Taken together, our results provide empirical evidence that temporal and environmental filters act together to structure soil bacterial communities across large spatial and long-term temporal scales.


Satisfying America's Fruit Gap: Summary of an Expert Roundtable on the Role of 100% Fruit Juice.
The 2015 to 2020 Dietary Guidelines for Americans (DGAs) recognize the role of 100% fruit juice in health and in helping people meet daily fruit recommendations and state that 100% fruit juice is a nutrient-dense beverage that should be a primary choice, along with water and low-fat/fat-free milk. The DGAs note that children are consuming 100% fruit juice within recommendations (that is, 120 to 180 mL/d for children aged 1 to 6 y and 236 to 355 mL/d for children aged 7 to 18 y). Evidence shows that compared to nonconsumers, those who consume 100% fruit juice come closer to meeting daily fruit needs and have better diet quality. In children, 100% fruit juice is associated with increased intakes of nutrients such as vitamin C, folate, and potassium. When consumed within the DGA recommendations, 100% fruit juice is not associated with overweight/obesity or childhood dental caries and does not compromise fiber intake. Preliminary data suggest that polyphenols in some 100% fruit juices may inhibit absorption of naturally occurring sugars. Given its role in promoting health and in helping people meet fruit needs, experts participating in a roundtable discussion agreed that there is no science-based reason to restrict access to 100% fruit juice in public health nutrition policy and programs such as the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Reducing or eliminating 100% fruit juice could lead to unintended consequences such as reduced daily fruit intake and increased consumption of less nutritious beverages (for example, sugar-sweetened beverages).


Mapping multiple components of malaria risk for improved targeting of elimination interventions.
There is a long history of considering the constituent components of malaria risk and the malaria transmission cycle via the use of mathematical models, yet strategic planning in endemic countries tends not to take full advantage of available disease intelligence to tailor interventions. National malaria programmes typically make operational decisions about where to implement vector control and surveillance activities based upon simple categorizations of annual parasite incidence. With technological advances, an enormous opportunity exists to better target specific malaria interventions to the places where they will have greatest impact by mapping and evaluating metrics related to a variety of risk components, each of which describes a different facet of the transmission cycle. Here, these components and their implications for operational decision-making are reviewed. For each component, related mappable malaria metrics are also described which may be measured and evaluated by malaria programmes seeking to better understand the determinants of malaria risk. Implementing tailored programmes based on knowledge of the heterogeneous distribution of the drivers of malaria transmission rather than only consideration of traditional metrics such as case incidence has the potential to result in substantial improvements in decision-making. As programmes improve their ability to prioritize their available tools to the places where evidence suggests they will be most effective, elimination aspirations may become increasingly feasible.


Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats.
Diabetic retinopathy is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. We hypothesized that eriodictyol, one of the most abundant dietary flavonoids, could be effective against diabetic retinopathy, which involves significant oxidative stress and inflammation. The aim of the present study was to investigate the effects of eriodictyol in early retinal and plasma changes of streptozotocin-induced diabetic rats. The effect of eriodictyol treatment (0.1, 1, 10 mg/kg daily for 10 days) was evaluated by TNF-α, ICAM-1, VEGF, and eNOS protein levels measurement in the retina, plasma lipid peroxidation, and blood-retinal barrier (BRB) integrity. Increased amounts of cytokines, adhesion molecule, and nitric oxide synthase were observed in retina from diabetic rats. Eriodictyol treatment significantly lowered retinal TNF-α, ICAM-1, VEGF, and eNOS in a dose-dependent manner. Further, treatment with eriodictyol significantly suppressed diabetes-related lipid peroxidation, as well as the BRB breakdown. These data demonstrated that eriodictyol attenuates the degree of retinal inflammation and plasma lipid peroxidation preserving the BRB in early diabetic rats.


Cardiac Troponin I and Incident Stroke in European Cohorts: Insights From the BiomarCaRE Project.
Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce. High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries. Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021). Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.


Global gene expression and systems biology analysis of bovine monocyte-derived macrophages in response to in vitro challenge with Mycobacterium bovis.
Mycobacterium bovis, the causative agent of bovine tuberculosis, is a major cause of mortality in global cattle populations. Macrophages are among the first cell types to encounter M. bovis following exposure and the response elicited by these cells is pivotal in determining the outcome of infection. Here, a functional genomics approach was undertaken to investigate global gene expression profiles in bovine monocyte-derived macrophages (MDM) purified from seven age-matched non-related females, in response to in vitro challenge with M. bovis (multiplicity of infection 2:1). Total cellular RNA was extracted from non-challenged control and M. bovis-challenged MDM for all animals at intervals of 2 hours, 6 hours and 24 hours post-challenge and prepared for global gene expression analysis using the Affymetrix® GeneChip® Bovine Genome Array. Comparison of M. bovis-challenged MDM gene expression profiles with those from the non-challenged MDM controls at each time point identified 3,064 differentially expressed genes 2 hours post-challenge, with 4,451 and 5,267 differentially expressed genes detected at the 6 hour and 24 hour time points, respectively (adjusted P-value threshold ≤ 0.05). Notably, the number of downregulated genes exceeded the number of upregulated genes in the M. bovis-challenged MDM across all time points; however, the fold-change in expression for the upregulated genes was markedly higher than that for the downregulated genes. Systems analysis revealed enrichment for genes involved in: (1) the inflammatory response; (2) cell signalling pathways, including Toll-like receptors and intracellular pathogen recognition receptors; and (3) apoptosis. The increased number of downregulated genes is consistent with previous studies showing that M. bovis infection is associated with the repression of host gene expression. The results also support roles for MyD88-independent signalling and intracellular PRRs in mediating the host response to M. bovis.


Semi-field evaluation of the cumulative effects of a "Lethal House Lure" on malaria mosquito mortality.
There is growing interest in the potential to modify houses to target mosquitoes with insecticides or repellents as they search for human hosts. One version of this 'Lethal House Lure' approach is the In2Care® EaveTube, which consists of a section of polyvinyl chloride (PVC) pipe fitted into a closed eave, with an insert comprising electrostatic netting treated with insecticide powder placed inside the tube. Preliminary evidence suggests that when combined with screening of doors and windows, there is a reduction in entry of mosquitoes and an increase in mortality. However, the rate of overnight mortality remains unclear. The current study used a field enclosure built around experimental huts to investigate the mortality of cohorts of mosquitoes over multiple nights. Anopheles gambiae sensu lato mosquitoes were collected from the field as larvae and reared through to adult. Three-to-five days old adult females were released inside an enclosure housing two modified West African style experimental huts at a field site in M'be, Côte d'Ivoire. Huts were either equipped with insecticide-treated tubes at eave height and had closed windows (treatment) or had open windows and open tubes (controls). The number of host-seeking mosquitoes entering the huts and cumulative mortality were monitored over 2 or 4 days. Very few (0-0.4%) mosquitoes were able to enter huts fitted with insecticide-treated tubes and closed windows. In contrast, mosquitoes continually entered the control huts, with a cumulative mean of 50-80% over 2 to 4 days. Baseline mortality with control huts was approximately 2-4% per day, but the addition of insecticide-treated tubes increased mortality to around 25% per day. Overall cumulative mortality was estimated to be up to 87% over 4 days when huts were fitted with tubes. Only 20-25% of mosquitoes contacted insecticide-treated tubes or entered control huts in a given night. However, mosquitoes continue to host search over sequential nights, and this can lead to high cumulative mortality over 2 to 4 days. This mortality should contribute to community-level reduction in transmission assuming sufficient coverage of the intervention.


Characterization of Enterobacteriaceae isolates obtained from a tertiary care hospital in Mexico, which produces extended-spectrum β-lactamase.
The prevalence and genetic characteristics of Escherichia coli and Klebsiella pneumoniae clinical isolates producing extended-spectrum β-lactamase (ESBL) were examined. Between October 2010 and March 2011, E. coli (n=460) and K. pneumoniae (n=78) isolates were collected at a tertiary care hospital in Guadalajara, Mexico. The minimum inhibitory concentration (MIC) for each isolate was determined using a broth microdilution method, and ESBL production was assayed. The presence of β-lactamase genes, blaSHV, blaCTX-M, and blaTLA-1, was detected by PCR and confirmed with sequencing. Only ESBL-producing isolates were further subjected to pulsed-field gel electrophoresis (PFGE) and plasmid profiling. All of the ESBL isolates were multidrug resistant and 75/460 (16.3%) E. coli isolates and 21/78 (26.9%) K. pneumoniae isolates were found to produce ESBL. For the E. coli isolates, >95% susceptibility to amikacin, meropenem, fosfomycin, imipenem, and nitrofurantoin was observed. For K. pneumoniae, similar results were obtained, with discrepancies observed for gentamicin and nitrofurantoin. PFGE further identified eleven pulsotypes for E. coli and three clusters of K. pneumoniae. CTX-M-15 was detected in 85% of ESBL-producing E. coli and in 76% of ESBL-producing K. pneumoniae. In contrast, SHV-5 ESBL was identified in 17% of E. coli isolates and in 86% of K. pneumoniae isolates. The bla-TLA-1 gene was not detected in any of the 96 isolates analyzed. Overall, CTX-M-15 and SHV-5 were found to have a high rate of spread throughout the hospital and were associated with strong multidrug resistance.


Effects of structured exercise programmes on physiological and psychological outcomes in adults with inflammatory bowel disease (IBD): A systematic review and meta-analysis.
Exercise has been suggested to counteract specific complications of inflammatory bowel disease (IBD). However, its role as a therapeutic option remains poorly understood. Therefore, we conducted a systematic review and meta-analysis on the effects of exercise in IBD. Five databases (MEDLINE, Embase, CINAHL, CENTRAL and SPORTDiscus) and three registers (Clinicaltrials.gov, WHO ICTRP and ISRCTN) were searched from inception to September 2022, for studies assessing the effects of structured exercise of at least 4 weeks duration on physiological and/or psychological outcomes in adults with IBD. Two independent reviewers screened records, assessed risk of bias using the Cochrane Risk of Bias (RoB 2.0) and ROBINS-I tools, and evaluated the certainty of evidence using the GRADE method. Data were meta-analysed using a random-effects model. From 4,123 citations, 15 studies (9 RCTs) were included, comprising of 637 participants (36% male). Pooled evidence from six RCTs indicated that exercise improved disease activity (SMD = -0.44; 95% CI [-0.82 to -0.07]; p = 0.02), but not disease-specific quality of life (QOL) (IBDQ total score; MD = 3.52; -2.00 to 9.04; p = 0.21) when compared to controls. Although meta-analysis could not be performed for other outcomes, benefits were identified in fatigue, muscular function, body composition, cardiorespiratory fitness, bone mineral density and psychological well-being. Fourteen exercise-related non-serious adverse events occurred. The overall certainty of evidence was low for disease activity and very low for HRQOL as a result of downgrading for risk of bias and imprecision. Structured exercise programmes improve disease activity, but not disease-specific QOL. Defining an optimal exercise prescription and synthesis of evidence in other outcomes, was limited by insufficient well-designed studies to ascertain the true effect of exercise training. This warrants further large-scale randomised trials employing standard exercise prescription to verify this effect to enable the implementation into clinical practice. This systematic review was prospectively registered in an international database of systematic reviews in health-related research (CRD42017077992; https://www.crd.york.ac.uk/prospero/).


Dementia associated with infectious diseases.
At the turn of the last century, infectious diseases represented an important cause of health morbidity and behavioral changes. Neurosyphilis, for example, was relatively common at the time and often led to the development of cognitive impairment and dementia. With the advent of effective antibiotic treatment, the association between infectious diseases and dementia became increasingly less frequent, although a resurgence of interest in this area has taken place during the past 15 years with the emergence of acquired immunodeficiency syndrome (AIDS) and variant Creutzfeldt-Jakob disease (vCJD). This paper reviews the most frequent infectious causes of dementia, including prion diseases, as well as infections caused by herpes virus, human immunodeficiency virus (HIV), toxoplasmosis, cryptococcus, cytomegalovirus, syphilis, borrelia and cysticercosis.


A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).
Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.