Telerehabilitation for chronic respiratory disease.
Pulmonary rehabilitation is a proven, effective intervention for people with chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and bronchiectasis. However, relatively few people attend or complete a program, due to factors including a lack of programs, issues associated with travel and transport, and other health issues. Traditionally, pulmonary rehabilitation is delivered in-person on an outpatient basis at a hospital or other healthcare facility (referred to as centre-based pulmonary rehabilitation). Newer, alternative modes of pulmonary rehabilitation delivery include home-based models and the use of telehealth. Telerehabilitation is the delivery of rehabilitation services at a distance, using information and communication technology. To date, there has not been a comprehensive assessment of the clinical efficacy or safety of telerehabilitation, or its ability to improve uptake and access to rehabilitation services, for people with chronic respiratory disease. To determine the effectiveness and safety of telerehabilitation for people with chronic respiratory disease. We searched the Cochrane Airways Trials Register, and the Cochrane Central Register of Controlled Trials; six databases including MEDLINE and Embase; and three trials registries, up to 30 November 2020. We checked reference lists of all included studies for additional references, and handsearched relevant respiratory journals and meeting abstracts. All randomised controlled trials and controlled clinical trials of telerehabilitation for the delivery of pulmonary rehabilitation were eligible for inclusion. The telerehabilitation intervention was required to include exercise training, with at least 50% of the rehabilitation intervention being delivered by telerehabilitation. We used standard methods recommended by Cochrane. We assessed the risk of bias for all studies, and used the ROBINS-I tool to assess bias in non-randomised controlled clinical trials. We assessed the certainty of evidence with GRADE. Comparisons were telerehabilitation compared to traditional in-person (centre-based) pulmonary rehabilitation, and telerehabilitation compared to no rehabilitation. We analysed studies of telerehabilitation for maintenance rehabilitation separately from trials of telerehabilitation for initial primary pulmonary rehabilitation. We included a total of 15 studies (32 reports) with 1904 participants, using five different models of telerehabilitation. Almost all (99%) participants had chronic obstructive pulmonary disease (COPD). Three studies were controlled clinical trials. For primary pulmonary rehabilitation, there was probably little or no difference between telerehabilitation and in-person pulmonary rehabilitation for exercise capacity measured as 6-Minute Walking Distance (6MWD) (mean difference (MD) 0.06 metres (m), 95% confidence interval (CI) -10.82 m to 10.94 m; 556 participants; four studies; moderate-certainty evidence). There may also be little or no difference for quality of life measured with the St George's Respiratory Questionnaire (SGRQ) total score (MD -1.26, 95% CI -3.97 to 1.45; 274 participants; two studies; low-certainty evidence), or for breathlessness on the Chronic Respiratory Questionnaire (CRQ) dyspnoea domain score (MD 0.13, 95% CI -0.13 to 0.40; 426 participants; three studies; low-certainty evidence). Participants were more likely to complete a program of telerehabilitation, with a 93% completion rate (95% CI 90% to 96%), compared to a 70% completion rate for in-person rehabilitation. When compared to no rehabilitation control, trials of primary telerehabilitation may increase exercise capacity on 6MWD (MD 22.17 m, 95% CI -38.89 m to 83.23 m; 94 participants; two studies; low-certainty evidence) and may also increase 6MWD when delivered as maintenance rehabilitation (MD 78.1 m, 95% CI 49.6 m to 106.6 m; 209 participants; two studies; low-certainty evidence). No adverse effects of telerehabilitation were noted over and above any reported for in-person rehabilitation or no rehabilitation. This review suggests that primary pulmonary rehabilitation, or maintenance rehabilitation, delivered via telerehabilitation for people with chronic respiratory disease achieves outcomes similar to those of traditional centre-based pulmonary rehabilitation, with no safety issues identified. However, the certainty of the evidence provided by this review is limited by the small number of studies, of varying telerehabilitation models, with relatively few participants. Future research should consider the clinical effect of telerehabilitation for individuals with chronic respiratory diseases other than COPD, the duration of benefit of telerehabilitation beyond the period of the intervention, and the economic cost of telerehabilitation.


A method for detection of doxorubicin-induced cardiotoxicity: Flow-mediated vasodilation of the brachial artery.
The cardiotoxicity of anthracyclin antibiotics such as doxorubicin (DOX) is a serious side effect in cancer therapy. Reduced antioxidant capacity may be a factor responsible for DOX-induced oxidative damage to the heart. The endothelial dysfunction that results from excessive free radicals can be easily detected by flow-mediated vasodilation (FMD) of the brachial artery. To determine the change in endothelial function after intravenous DOX bolus; to determine the change in biochemical parameters, reflecting increased activity of free radicals or decreased endogenous antioxidant capacity, after intravenous DOX bolus; and to determine the relation between alteration of en-dothelial function after the first DOX bolus and the change in left ventricular function during follow-up. Twenty-two patients, with either non-Hodgkin's lymphoma (18 patients) or Hodgkin's disease (four patients) were enrolled for the study (seven women and 15 men), with a mean age of 37.3+/-13.7 years. Each patient was treated with a DOX-containing regimen. The actual mean dose of DOX was 33+/-12 mg/m(2). FMD was evaluated before and after DOX administration. In nine patients more frequent measures were taken to determine the time course of change in FMD after DOX administration. FMD was measured 6, 12, 24 and 48 h after DOX. On average each patient was followed up for 18.6+/-8.1 months following the first DOX administration. The mean cumulative DOX dose was 229+/-112 mg/m(2) by the end of the follow-up period. Left ventricular ejection fraction was determined regularly during and at the end of the study. FMD was normal (more than 5%) at baseline in each patient but decreased significantly after DOX bolus (9.9+/-4.4% versus 6.1+/-4.6%, P<0.02). Marked individual differences were found in FMD changes after DOX. Patients who had a more than 5% decrease in FMD after DOX bolus were pretreated with 1000 mg of vitamin C intravenously, just before the next intravenous bolus of DOX was given. The decrease in FMD was prevented. Stepwise multiple regression analysis showed that the decrease in left ventricular ejection fraction during follow-up significantly and independently correlated with the cumulative DOX dose and the value of FMD alteration after the first DOX bolus administration. FMD in the brachial artery was significantly impaired after the first DOX bolus. The marked individual differences suggest different antioxidant capacities in these patients. The results suggest that alterations in FMD after DOX allows for detection of patients with insufficient antioxidant capacity and patients at a higher risk of DOX-induced cardiotoxicity.


Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents.
Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.


Comparative genomic analyses of 17 clinical isolates of Gardnerella vaginalis provide evidence of multiple genetically isolated clades consistent with subspeciation into genovars.
Gardnerella vaginalis is associated with a spectrum of clinical conditions, suggesting high degrees of genetic heterogeneity among stains. Seventeen G. vaginalis isolates were subjected to a battery of comparative genomic analyses to determine their level of relatedness. For each measure, the degree of difference among the G. vaginalis strains was the highest observed among 23 pathogenic bacterial species for which at least eight genomes are available. Genome sizes ranged from 1.491 to 1.716 Mb; GC contents ranged from 41.18% to 43.40%; and the core genome, consisting of only 746 genes, makes up only 51.6% of each strain's genome on average and accounts for only 27% of the species supragenome. Neighbor-grouping analyses, using both distributed gene possession data and core gene allelic data, each identified two major sets of strains, each of which is composed of two groups. Each of the four groups has its own characteristic genome size, GC ratio, and greatly expanded core gene content, making the genomic diversity of each group within the range for other bacterial species. To test whether these 4 groups corresponded to genetically isolated clades, we inferred the phylogeny of each distributed gene that was present in at least two strains and absent in at least two strains; this analysis identified frequent homologous recombination within groups but not between groups or sets. G. vaginalis appears to include four nonrecombining groups/clades of organisms with distinct gene pools and genomic properties, which may confer distinct ecological properties. Consequently, it may be appropriate to treat these four groups as separate species.


Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2.
The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients. Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy.


Impact of Clinical Pharmacist-led Interventions in Turkey
Detecting drug-related problems (DRPs) is important in pharmaceutical care in for better therapeutic outcomes. Clinical pharmacists-led comprehensive medication management plays a crucial role in the rational use of drugs by preventing, identifying, and resolving DRPs. In this review, we aimed to determine the effect of interventions on patient outcomes performed by clinical pharmacists in Turkey. A systematic literature search was performed on PubMed, Google Scholar, EMBASE, Cochrane Library, and Turkish databases (ULAKBIM, Dergipark). The main categories were "clinical pharmacist", "intervention", and "Turkey". Two reviewers reviewed each article independently. Two independent reviewers screened all records and extracted data; disagreements were resolved through a consensus. Randomized controlled studies, pre- to post-intervention comparison studies, and cross-sectional studies including pharmacist-led interventions were included in the review. This review included 15 articles evaluating clinical pharmacist interventions. Ten studies (66.7%) focused on DRPs and pharmacist interventions to these problems, while the remaining 5 (33.3%) studies focused on patient education and adherence issues. Studies were conducted in oncology (33.3%), geriatrics (20.0%), chest diseases (13.3%), psychiatry (6.7%), cardiology (6.7%), and infectious diseases (6.7%) clinics. When results of studies are reviewed, most of the interventions were made at the prescriber level followed by the drug level and patient level. Problems were solved in 54.2-93.2% of DRPs, and adherence, patient knowledge, or skills were improved in most of the studies. Most of the studies were carried out within the scope of a postgraduate or doctorate thesis and yet various positive outcomes such as the prevention of side effects, increased quality of life, and decreased duration of hospital stay were observed with high positive rates of interventions, which indicate that other healthcare workers are ready to collaborate with the clinical pharmacists in Turkey.


Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach.
Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.


Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice.
Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.


Increase in antidepressant medication in the US adult population between 1990 and 2003.
The rate of antidepressant treatment in the US has significantly increased in the past decade. There are, however, concerns about undertreatment among traditionally underserved groups and overtreatment in less severely ill individuals. This study examines trends in the prevalence of antidepressant drug treatment in two US general population surveys. The prevalence of antidepressant treatment within a 12-month period was compared in the US National Comorbidity Survey (1990-1992) and the National Comorbidity Survey-Replication (2001-2003). Variations in trends across groups were examined using bivariate and multivariate logistic regression models. The rate of antidepressant drug treatment increased more than four times between early 1990s and early 2000s. The trend was similar across sociodemographic groups. Younger adults, men and racial/ethnic minorities continued to receive antidepressant treatment at a lower rate compared to middle-aged adults, women and non-Hispanic whites, respectively. The rate of antidepressant treatment increased more in the group of less severely ill individuals than in those with more severe psychopathology. Sociodemographic disparities in antidepressant treatment persisted over the last decade in the US, lending support to concerns about undertreatment among traditionally underserved groups, whereas the greater increase in the rate of antidepressant treatment in the less severely ill group lends support to concerns about antidepressant overtreatment in this population.


Top-down modulation of human early visual cortex after stimulus offset supports successful postcued report.
Modulations of sensory processing in early visual areas are thought to play an important role in conscious perception. To date, most empirical studies focused on effects occurring before or during visual presentation. By contrast, several emerging theories postulate that sensory processing and conscious visual perception may also crucially depend on late top-down influences, potentially arising after a visual display. To provide a direct test of this, we performed an fMRI study using a postcued report procedure. The ability to report a target at a specific spatial location in a visual display can be enhanced behaviorally by symbolic auditory postcues presented shortly after that display. Here we showed that such auditory postcues can enhance target-specific signals in early human visual cortex (V1 and V2). For postcues presented 200 msec after stimulus termination, this target-specific enhancement in visual cortex was specifically associated with correct conscious report. The strength of this modulation predicted individual levels of performance in behavior. By contrast, although later postcues presented 1000 msec after stimulus termination had some impact on activity in early visual cortex, this modulation no longer related to conscious report. These results demonstrate that within a critical time window of a few hundred milliseconds after a visual stimulus has disappeared, successful conscious report of that stimulus still relates to the strength of top-down modulation in early visual cortex. We suggest that, within this critical time window, sensory representation of a visual stimulus is still under construction and so can still be flexibly influenced by top-down modulatory processes.


Cognitive disorders in patients with chronic kidney disease: specificities of clinical assessment.
Neurocognitive disorders are frequent among chronic kidney disease (CKD) patients. Identifying and characterizing cognitive impairment (CI) can help to assess the ability of adherence to CKD risk reduction strategy, identify potentially reversible causes of cognitive decline, modify pharmacotherapy, educate the patient and caregiver and provide appropriate patient and caregiver support. Numerous factors are associated with the development and progression of CI in CKD patients and various conditions can influence the results of cognitive assessment in these patients. Here we review clinical warning signs that should lead to cognitive screening; conditions frequent in CKD at risk to interfere with cognitive testing or performance, including specificities of cognitive assessment in dialysis patients or after kidney transplantation; and available tests for screening and observed cognitive patterns in CKD patients.


The determination of importance of sequences neighboring the Psi sequence in lentiviral vector transduction and packaging efficiency.
A number of lentiviral vector systems have been developed for gene delivery and therapy by eliminating and/or modifying viral genetic elements. However, all lentiviral vector systems derived from HIV-1 must have a viral packaging signal sequence, Psi (Ψ), which is placed downstream of 5' long terminal repeat in a transgene plasmid to effectively package and deliver transgene mRNA. In this study, we examined feasible regions or sequences around Psi that could be manipulated to further modify the packaging sequence. Surprisingly, we found that the sequences immediately upstream of the Psi are highly refractory to any modification and resulted in transgene vectors with very poor gene transduction efficiency. Analysis around the Psi region revealed that there are a few sites that can be used for manipulation of the Psi sequence without disturbing the virus production as well as the efficiency of transgene RNA packaging and gene transduction. By exploiting this new vector system, we investigated the requirement of each of four individual stem-loops of the Psi sequence by deletion mapping analysis and found that all stem-loops, including the SL4 region, are needed for efficient transgene RNA packaging and gene delivery. These results suggest a possible frame of the lentiviral vector that might be useful for further modifying the region/sequence around the packaging sequence as well as directly on the Psi sequence without destroying transduction efficiency.


X-ray diffraction and computation yield the structure of alkanethiols on gold(111).
The structure of self-assembled monolayers (SAMs) of long-chain alkyl sulfides on gold(111) has been resolved by density functional theory-based molecular dynamics simulations and grazing incidence x-ray diffraction for hexanethiol and methylthiol. The analysis of molecular dynamics trajectories and the relative energies of possible SAM structures suggest a competition between SAM ordering, driven by the lateral van der Waals interaction between alkyl chains, and disordering of interfacial Au atoms, driven by the sulfur-gold interaction. We found that the sulfur atoms of the molecules bind at two distinct surface sites, and that the first gold surface layer contains gold atom vacancies (which are partially redistributed over different sites) as well as gold adatoms that are laterally bound to two sulfur atoms.


Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway.
Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted.


Mining the apollo and amor asteroids.
Earth-approaching asteroids could provide raw materials for space manufacturing. For certain asteroids the total energy per unit mass for the transfer of asteroidal resources to a manufacturing site in high Earth orbit is comparable to that for lunar materials. For logistical reasons the cost may be many times less. Optical studies suggest that these asteroids have compositions corresponding to those of carbonaceous and ordinary chondrites, with some containing large quantities of iron and nickel; others are thought to contain carbon, nitrogen, and hydrogen, elements that appear to be lacking on the moon. The prospect that several new candidate asteroids will be discovered over the next few years increases the likelihood that a variety of asteroidal resource materials can be retrieved on low-energy missions.


Influence of catastrophizing on treatment outcome in patients with nonspecific low back pain: a systematic review.
Systematic review. The aim of this study was to assess the effect of catastrophizing on treatment efficacy and outcome in patients treated for low back pain. Psychological factors including catastrophizing thoughts are thought to increase the risk for chronic low back pain. The influence of catastrophizing is debated. In September 2012, the following databases were searched: BIOSIS, CINAHL, Cochrane Library, EMBASE, OTseeker, PeDRO, PsycINFO, MEDLINE, Scopus, and Web of Science. For 50 of 706 references, full text was assessed. Results based on 11 studies were included in this analysis. In the 11 studies, a total of 2269 patients were included. Seven studies were of good and 4 of moderate methodological quality. Heterogeneity in study settings, treatments, outcomes, and patient populations impeded meta-analysis. Catastrophizing at baseline was predictive for disability at follow-up in 4 studies and for pain in 2 studies. Three studies found no predictive effect of catastrophizing. A mediating effect was found in all studies (n = 5) assessing the impact of a decrease in catastrophizing during treatment. A greater decrease was associated with better outcome. Most studies that investigated the moderating effects on treatment efficacy found no effect (n = 5). However, most studies did not look for a direct interaction between the treatment and catastrophizing thoughts. No study investigated the influence of catastrophizing on work-related outcomes including return to work. Catastrophizing predicted degree of pain and disability and mediated treatment efficacy in most studies. The presence of catastrophizing should be considered in patients with persisting back pain. Limited evidence was found for the moderating effects on treatment efficacy. Future research should aim to clarify the role of catastrophizing as a moderator of outcome and investigate its importance for work-related outcomes. 1.


How important is thermal history? Evidence for lasting effects of developmental temperature on upper thermal limits in Drosophila melanogaster.
A common practice in thermal biology is to take individuals directly from the field and estimate a range of thermal traits. These estimates are then used in studies aiming to understand broad scale distributional patterns, understanding and predicting the evolution of phenotypic plasticity, and generating predictions for climate change risk. However, the use of field-caught individuals in such studies ignores the fact that many traits are phenotypically plastic and will be influenced by the thermal history of the focal individuals. The current study aims to determine the extent to which estimates of upper thermal limits (CTmax), a frequently used measure for climate change risk, are sensitive to developmental and adult acclimation temperatures and whether these two forms of plasticity are reversible. Examining a temperate and tropical population of Drosophila melanogaster we show that developmental acclimation has a larger and more lasting effect on CTmax than adult acclimation. We also find evidence for an interaction between developmental and adult acclimation, particularly when flies are acclimated for a longer period, and that these effects can be population specific. These results suggest that thermal history can have lasting effects on estimates of CTmax. In addition, we provide evidence that developmental and/or adult acclimation are unlikely to contribute to substantial shifts in CTmax and that acclimation capacity may be constrained at higher temperatures.


FEM-PrEP: adherence patterns and factors associated with adherence to a daily oral study product for pre-exposure prophylaxis.
Several clinical trials have demonstrated the safety and effectiveness of oral tenofovir disoproxil fumarate (TDF), with or without emtricitabine (FTC), as pre-exposure prophylaxis (PrEP) for reducing the risk of HIV acquisition. Adherence to the study product was insufficient to demonstrate the effectiveness of FTC/TDF in 2 PrEP clinical trials conducted among women (FEM-PrEP and the Vaginal and Oral Interventions to Control the Epidemic study), but further analyses of adherence in these studies may inform PrEP demonstration projects and future HIV prevention clinical trials. We randomly selected a subcohort of 150 participants randomized to FTC/TDF in 3 FEM-PrEP sites (Bondo, Kenya; Bloemfontein, South Africa; and Pretoria, South Africa) to examine adherence levels over time and to assess factors associated with adherence, based on plasma tenofovir and intracellular tenofovir diphosphate drug concentrations in specimens collected at 4-week visit intervals. We observed drug concentrations consistent with good adherence in 28.5% of all visit intervals when drug was available to use, but only 12% of participants achieved good adherence throughout their study participation. In multivariate analysis, the Bloemfontein site [odds ratio (OR): 2.43; 95% confidence interval (CI): 1.32 to 4.48] and liking the pill color (OR: 2.93; 95% CI: 1.18 to 7.27) were positively associated with good adherence, whereas using oral contraceptive pills at enrollment was negatively associated with good adherence (OR: 0.37; 95% CI: 0.18 to 0.74). Most participants did not regularly adhere to the study product throughout their trial participation, although a small minority did. Few factors associated with good adherence to the study product were identified in FEM-PrEP.


Nano- and microscale holes modulate cell-substrate adhesion, cytoskeletal organization, and -beta1 integrin localization in SV40 human corneal epithelial cells.
Human corneal epithelial cells (HCECs) interface with a basement membrane in vivo that possesses complex nanoscale topographic features. We report that synthetic substrates patterned with nano- and microscale holes differentially modulate the proliferation, shape and adhesion of SV40 human corneal epithelial cells (SV40-HCECs) as a function of feature size: 1) Cell proliferation was inhibited on nanoscale features (features size less than 800 nm in pitch) compared to microscale features or planar substrates in identical culture conditions. 2) Cells on nanoscale holes had a stellate morphology compared to those on microscale features that were more evenly spread. 3) Cells adhered more to nanoscale features than to microscale features when exposed to shear stress in a laminar flow chamber. Transmission electron microscopy showed that cells cultured on the 400 nm pitch patterns had longer and more numerous filopodia and retraction fibers than cells cultured on the 1600 nm pitch patterns. Immunogold labeling of -beta1 integrins revealed that these receptors were localized at the cell periphery and in the aforementioned cytoskeletal elements. Our findings indicate that surface discontinuities and the activation of mechanochemical cell signaling mechanisms may contribute to the observed responses exhibited by SV40-HCECs cultured on nano- and microscale topography.


The distribution of GABAergic cells, fibers, and terminals in the monkey amygdaloid complex: an immunohistochemical and in situ hybridization study.
The primate amygdaloid complex is a prominent structure in the medial temporal lobe that comprises a variety of cytoarchitectonically distinct nuclei and cortical regions. The present study employed immunohistochemical and in situ hybridization techniques to determine the distribution of GABAergic cells, fibers, and terminals in the macaque monkey amygdala. Using a monoclonal antibody to GABA, immunoreactive neurons were observed throughout the amygdaloid complex (constituting approximately 20% of the neurons in the lateral nucleus), with higher densities located in the intercalated nuclei, amygdalohippocampal area, and posterior cortical nucleus. The lowest densities of labeled cells were observed in the central and medial nuclei. Interestingly, despite the low number of GABA-immunoreactive neurons, the terminal density in the central nucleus was among the highest in the amygdala. The GABAergic neurons in the amygdala were heterogeneous in morphology, and three general classes of immunopositive aspiny cells were observed. Using mRNA probes for glutamic acid decarboxylase (GAD: GAD65 and GAD67), in situ hybridization demonstrated distributions of labeled cells that generally replicated the immunohistochemical findings. One exception was in the central nucleus where, in contrast to the low number of immunohistochemically labeled cells, both GAD probes labeled large numbers of neurons. These studies on the organization of GABAergic circuits in the primate amygdala are significant because alterations of function in the human amygdala have been implicated in the pathogenesis of temporal lobe epilepsy and in the etiology of affective and other behavioral disorders. The present study provides baseline information with which to evaluate the role of GABAergic systems in amygdala-mediated behaviors and the potential contribution of GABAergic dysfunction in amygdala-associated disorders.


Response of a patient with pleural and peritoneal mesothelioma after second-line chemotherapy with lipoplatin and gemcitabine.
We report the case of a 56-year-old patient with malignant pleural mesothelioma of epithelial type, who responded to second-line chemotherapy with lipoplatin plus gemcitabine. Diagnosis and staging of the disease was done by medical thoracoscopy with biopsies of the right pleura in December 2003, when he was treated with talc pleurodesis. Eighteen months later, he presented with pleural effusion of the left side and underwent first-line chemotherapy with cisplatin plus vinorelbine. After 8 cycles, the patient presented renal toxicity limiting further cisplatinum chemotherapy and disease progression with peritoneal invasion of the tumor and ascites. Treatment with lipoplatin-gemcitabine was decided on in November 2006, and the patient showed important improvement in the clinical status and peritoneal effusion. He survived for 36 weeks, with symptom-free survival of 34 weeks.


Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model.
Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand- puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model. Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 µM) for 6 hours. AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262). Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated "cytokine storm", coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.


Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation.
Invasive aspergillosis (IA) is a life-threatening complication among allogeneic hematopoietic stem cell transplant (alloSCT) recipients. Despite well known risk factors and different available assays, diagnosis of invasive aspergillosis remains challenging. 103 clinical variables from patients with hematological malignancies and subsequent alloSCT were collected. Associations between collected variables and patients with (n = 36) and without IA (n = 36) were investigated by applying univariate and multivariable logistic regression. The predictive power of the final model was tested in an independent patient cohort (23 IA cases and 25 control patients). Findings were investigated further by in vitro studies, which analysed the effect of etanercept on A. fumigatus-stimulated macrophages at the gene expression and cytokine secretion. Additionally, the release of C-X-C motif chemokine ligand 10 (CXCL10) in patient sera was studied. Low monocyte concentration (p = 4.8 × 10-06), severe GvHD of the gut (grade 2-4) (p = 1.08 × 10-02) and etanercept treatment of GvHD (p = 3.5 × 10-03) were significantly associated with IA. Our studies showed that etanercept lowers CXCL10 concentrations in vitro and ex vivo and down-regulates genes involved in immune responses and TNF-alpha signaling. Our study offers clinicians new information regarding risk factors for IA including low monocyte counts and administration of etanercept. After necessary validation, such information may be used for decision making regarding antifungal prophylaxis or closely monitoring patients at risk.


Photoacoustic ultrasound spectroscopy for assessing red blood cell aggregation and oxygenation.
Red blood cell (RBC) aggregation and oxygenation are important markers for a variety of blood disorders. No current technique is capable of simultaneously measuring aggregation/oxygenation levels noninvasively. We propose using photoacoustic ultrasound spectroscopy (PAUS) for assessing both phenomena. This technique relies on frequency-domain analysis of the PA signals by extracting parameters such as the ultrasound spectral slope and the midband fit. To investigate the effect of hematocrit, aggregation, and oxygenation levels on PAUS parameters, a Monte Carlo-based theoretical model and an experimental protocol using porcine RBCs were developed. The samples were illuminated at 750 and 1064 nm and changes in the PAUS parameters were compared to the oxygen-dependent optical absorption coefficients to assess the oxygenation level. Good agreement between the theoretical and experimental spectral parameters was obtained for the spectral slope of the nonaggregated spectra (≈ 0.3 dB/MHz). The experimental midband fit increased by ≈ 5 dB for the largest aggregate size. Based on the analysis of the PA signals, the oxygen saturation level of the most aggregated sample was >20% greater than the nonaggregated sample. The results provide a framework for using PA signals' spectroscopic parameters for monitoring the aggregation and oxygenation levels of RBCs.


[A "pulseless" woman with proteinuria!].
Takayasu arteritis, also called pulseless women disease, is a chronic vasculitis of unknown aetiology, which primarily involves the aorta, its branches and coronary and pulmonary arteries. It is an uncommon disease with a variety of presentations and most frequently found in Asia than in Europe. We report a case of a 52-year-old woman, suffering from Takayasu arteritis for 19 years. She was admitted to the hospital for diffuse pain and oedema. Biological tests pointed out proteinuria with renal failure, which was confirmed by a renal biopsy. The association of Takayasu arteritis and renal failure is unusual. This review focuses on the biological manifestations of Takayasu arteritis and on the link between this disease and the renal failure observed in this case.


Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.
Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.


Association of the K153R polymorphism in the myostatin gene and extreme longevity.
The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n = 156; 132 women, age range 100-111 years) and younger adults (controls, n = 384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1%) than in controls (2.7%) (P = 0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 (95% confidence interval 1.67-7.28, P = 0.001), compared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, n = 79 (40 women), age range 100-104 years; younger controls, n = 316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6%) compared to controls (3.0%) (P = 0.004) was independently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity.


The role of long-range connections on the specificity of the macaque interareal cortical network.
We investigated the influence of interareal distance on connectivity patterns in a database obtained from the injection of retrograde tracers in 29 areas distributed over six regions (occipital, temporal, parietal, frontal, prefrontal, and limbic). One-third of the 1,615 pathways projecting to the 29 target areas were reported only recently and deemed new-found projections (NFPs). NFPs are predominantly long-range, low-weight connections. A minimum dominating set analysis (a graph theoretic measure) shows that NFPs play a major role in globalizing input to small groups of areas. Randomization tests show that (i) NFPs make important contributions to the specificity of the connectivity profile of individual cortical areas, and (ii) NFPs share key properties with known connections at the same distance. We developed a similarity index, which shows that intraregion similarity is high, whereas the interregion similarity declines with distance. For area pairs, there is a steep decline with distance in the similarity and probability of being connected. Nevertheless, the present findings reveal an unexpected binary specificity despite the high density (66%) of the cortical graph. This specificity is made possible because connections are largely concentrated over short distances. These findings emphasize the importance of long-distance connections in the connectivity profile of an area. We demonstrate that long-distance connections are particularly prevalent for prefrontal areas, where they may play a prominent role in large-scale communication and information integration.


Nasopharyngeal carriage of resistant pneumococci in young South Indian infants.
Streptococcus pneumoniae is the leading bacterial cause of life-threatening infections in infants. Although antibiotic resistance affects management of pneumococcal infections, few data on patterns of resistance are available for India. We examined nasopharyngeal carriage of antibiotic-resistant pneumococci in 464 South Indian infants between 2 and 6 months. Newly acquired serotypes were screened for susceptibility to cotrimoxazole, erythromycin and penicillin using disk diffusion. Cumulative prevalence of pneumococcal carriage rose from 53.9% at 2 months to 70.2% at 6 months. The prevalence of strains that were not susceptible to penicillin, cotrimoxazole and erythromycin was 34, 81.1 and 37.2%, respectively. Carriage of erythromycin non-susceptible strains declined significantly between ages 4 months and 6 months (44.1 vs. 10.7%). More than 87% of the isolates screened were non-susceptible to > or = 1 antibiotic. Serogroups/types that were most frequently non-susceptible to 1 or more antibiotics were 6, 9, 14, 19 and 23. Less than 1% of the isolates were multi-drug resistant. Widespread use of antibiotics in South India has resulted in S. pneumoniae becoming non-susceptible to some commonly used antibiotics. Monitoring trends in antibiotic susceptibility and making antibiotics available only through prescription from a health care worker may slow the spread of resistant pneumococci and improve management of pneumococcal infections in South India.


Persistent Incisional Pain after Noncardiac Surgery: An International Prospective Cohort Study.
The purpose of this study was to determine the incidence, characteristics, impact, and risk factors associated with persistent incisional pain. The hypothesis was that patient demographics and perioperative interventions are associated with persistent pain. This was a secondary analysis of an international prospective cohort study from 2012 to 2014. This study included patients who were 45 yr of age or older who underwent major inpatient noncardiac surgery. Data were collected perioperatively and at 1 yr after surgery to assess for the development of persistent incisional pain (pain present around incision at 1 yr after surgery). Among 14,831 patients, 495 (3.3%; 95% CI, 3.1 to 3.6) reported persistent incisional pain at 1 yr, with an average pain intensity of 3.6 ± 2.5 (0 to 10 numeric rating scale), with 35% and 14% reporting moderate and severe pain intensities, respectively. More than half of patients with persistent pain reported needing analgesic medications, and 85% reported interference with daily activities (denominator = 495 in the above proportions). Risk factors for persistent pain included female sex (P = 0.007), Asian ethnicity (P < 0.001), surgery for fracture (P < 0.001), history of chronic pain (P < 0.001), coronary artery disease (P < 0.001), history of tobacco use (P = 0.048), postoperative patient-controlled analgesia (P < 0.001), postoperative continuous nerve block (P = 0.010), insulin initiation within 24 h of surgery (P < 0.001), and withholding nonsteroidal anti-inflammatory medication or cyclooxygenase-2 inhibitors on the day of surgery (P = 0.029 and P < 0.001, respectively). Older age (P < 0.001), endoscopic surgery (P = 0.005), and South Asian (P < 0.001), Native American/Australian (P = 0.004), and Latin/Hispanic ethnicities (P < 0.001) were associated with a lower risk of persistent pain. Persistent incisional pain is a common complication of inpatient noncardiac surgery, occurring in approximately 1 in 30 adults. It results in significant morbidity, interferes with daily living, and is associated with persistent analgesic consumption. Certain demographics, ethnicities, and perioperative practices are associated with increased risk of persistent pain.


Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells.
To define the extent of involvement of chromosome 9p in breast carcinogenesis, we performed microsatellite length polymorphism analysis of markers spanning this region. Of 24 primary breast carcinomas analyzed, we observed a high frequency (58%) of loss of heterozygosity or allelic imbalance affecting subregion 9p21-22. Mutational analysis of CDKN2 (p16) was performed to determine whether this gene was the target of such alterations. Of 21 tumors analyzed, only 1 showed a mutation of probable consequence, suggesting that CDKN2 appears not to be the target of loss of heterozygosity and indicating the possible existence of another tumor suppressor gene within this region. Additionally, since it has been suggested that some CDKN2 deletions and mutations could be due to an in vitro phenomenon, four immortal breast cell lines derived from normal epithelium, MCF10F, MCF12F, 184A1, and 184B5, were examined for loss or mutation of CDKN2. Two lines (MCF10F and MCF12F) showed homozygous deletions of CDKN2, and one (184A1) revealed a hemizygous deletion and a nonsense mutation in the remaining allele. This could imply an important role of CDKN2 in the control of immortalization or in vitro adaptation and is the first evidence of such in nontumor-derived cell lines. Additionally, this is the first report of frequent loss of heterozygosity in the 9p21-22 chromosome subregion of uncultured primary breast tumors.


Dual-Task Costs of Quantitative Gait Parameters While Walking and Turning in People with Parkinson's Disease: Beyond Gait Speed.
There is a lack of recommendations for selecting the most appropriate gait measures of Parkinson's disease (PD)-specific dual-task costs to use in clinical practice and research. We aimed to identify measures of dual-task costs of gait and turning that best discriminate performance in people with PD from healthy individuals. We also investigated the relationship between the most discriminative measures of dual-task costs of gait and turning with disease severity and disease duration. People with mild-to-moderate PD (n = 144) and age-matched healthy individuals (n = 79) wore 8 inertial sensors while walking under single and dual-task (reciting every other letter of the alphabet) conditions. Outcome measures included 26 objective measures within four gait domains (upper/lower body, turning and variability). The area under the curve (AUC) from the receiver-operator characteristic plot was calculated to compare discriminative ability of dual-task costs on gait across outcome measures. PD-specific, dual-task interference was identified for arm range of motion, foot strike angle, turn velocity and turn duration. Arm range of motion (AUC = 0.73) and foot strike angle (AUC = 0.68) had the largest AUCs across dual-task costs measures and they were associated with disease severity and/or disease duration. In contrast, the most commonly used dual-task gait measure, gait speed, showed an AUC of only 0.54. Findings suggest that people with PD rely more than healthy individuals on executive-attentional resources to control arm swing, foot strike, and turning, but not gait speed. The dual-task costs of arm range of motion best discriminated people with PD from healthy individuals.


Renal osteodystrophy: neurosurgical considerations and challenges.
Dialysis-associated destructive spondyloarthropathy (DSA) is the major bony complication of end-stage renal disease, most commonly found in the lower cervical region. The risk factors for developing dialysis-associated DSA include duration of hemodialysis and patient age. Patients with DSA have a higher incidence of osteoporosis and poor bone mineral density, which may place them at greater risk of atraumatic fractures, instrumentation failure, and neurologic compromise. We describe a case of cervical radiculopathy due to dialysis-associated DSA atraumatic vertebral body fractures with a postoperative course that was complicated by instrumentation failure. We reviewed the literature regarding all 138 published cases, presenting the complications, surgical treatment options, and outcomes. A 44-year-old dialysis-dependent man presented with acute neck pain, radiculopathy, and weakness due to atraumatic fracture of C5 and C6 vertebral bodies. He underwent anterior C5 and C6 corpectomies, reconstruction with mesh cage and plate, and supplemental posterior instrumentation (C4-T1). Six weeks later, a computed tomography scan revealed anterior translation across the instrumented area with failure of the posterior instrumentation. He subsequently underwent traction, revision reinstrumentation from C2 to T5, and placement of external halo ring/jacket for 6 months. At 18 months later, he remains ambulatory without evidence of construct failure. Patients with renal osteodystrophy present a challenge for the spine surgeon due to compromised bone density. Hardware failure at the bone-construct interface is common in these patients, with revision surgery needed in 22% of published cases. Longer constructs with circumferential instrumentation and halo immobilization may minimize the risk of pseudoarthrosis and construct pull-out.


Clinical and laboratory features of chronic idiopathic urticaria in the elderly.
There are few data regarding epidemiology and clinical features of urticarial diseases in the elderly population. The aim of the study was to determine the clinical and laboratory characteristics of chronic idiopathic urticaria (CIU) in the geriatric population. Electronic medical records of outpatient allergy consultations due to a diagnosis of CIU were retrospectively reviewed to collect demographic data, urticaria activity score, results of autologous serum skin test (ASST), and laboratory workup. From 1598 patients with chronic urticaria, there were 1319 (82.5%) adult (adult CIU group) and 124 (9.4%) elderly subjects (elderly CIU group). The elderly CIU group was characterized by lower prevalence (46.7%) of women compared to the adult CIU group (69.2%; P = 0.022); fewer wheals (1.4 ± 0.5) vs. (2.3 ± 0.7; P < 0.001); lower rates of concomitant symptomatic dermographism 2 (2.2%) vs. 121 (12.6%; P = 0.003); and lower rates of angioedema, 3 (14.1%) vs. 362 (37.8%; P < 0.001). Fewer elderly patients with CIU (18.1%) than adult patients with CIU (44.7%; P = 0.019) demonstrated a positive ASST. There were no differences in laboratory data between the study groups. CIU in the elderly population is nearly equally distributed in both sexes and is characterized by fewer wheals, lower rates of concomitant symptomatic dermographism, lower rates of angioedema, and lower ASST positivity.


Moving towards a complete molecular framework of the Nematoda: a focus on the Enoplida and early-branching clades.
The subclass Enoplia (Phylum Nematoda) is purported to be the earliest branching clade amongst all nematode taxa, yet the deep phylogeny of this important lineage remains elusive. Free-living marine species within the order Enoplida play prominent roles in marine ecosystems, but previous molecular phylogenies have provided only the briefest evolutionary insights; this study aimed to firmly resolve internal relationships within the hyper-diverse but poorly understood Enoplida. In addition, we revisited the molecular framework of the Nematoda using a rigorous phylogenetic approach in order to investigate patterns of early splits amongst the oldest lineages (Dorylaimia and Enoplia). Morphological identifications, nuclear gene sequences (18S and 28S rRNA), and mitochondrial gene sequences (cox1) were obtained from marine Enoplid specimens representing 37 genera. The 18S gene was used to resolve deep splits within the Enoplia and evaluate the branching order of major clades in the nematode tree; multiple phylogenetic methods and rigorous empirical tests were carried out to assess tree topologies under different parameters and combinations of taxa. Significantly increased taxon sampling within the Enoplida resulted in a well-supported, robust phylogenetic topology of this group, although the placement of certain clades was not fully resolved. Our analysis could not unequivocally confirm the earliest splits in the nematode tree, and outgroup choice significantly affected the observed branching order of the Dorylaimia and Enoplia. Both 28S and cox1 were too variable to infer deep phylogeny, but provided additional insight at lower taxonomic levels. Analysis of internal relationships reveals that the Enoplia is split into two main clades, with groups consisting of terrestrial (Triplonchida) and primarily marine fauna (Enoplida). Five independent lineages were recovered within the Enoplida, containing a mixture of marine and terrestrial species; clade structure suggests that habitat transitions have occurred at least four times within this group. Unfortunately, we were unable to obtain a consistent or well-supported topology amongst early-branching nematode lineages. It appears unlikely that single-gene phylogenies using the conserved 18S gene will be useful for confirming the branching order at the base of the nematode tree-future efforts will require multi-gene analyses or phylogenomic methods.


Anatomical accuracy of standard-practice tractography algorithms in the motor system - A histological validation in the squirrel monkey brain.
For two decades diffusion fiber tractography has been used to probe both the spatial extent of white matter pathways and the region to region connectivity of the brain. In both cases, anatomical accuracy of tractography is critical for sound scientific conclusions. Here we assess and validate the algorithms and tractography implementations that have been most widely used - often because of ease of use, algorithm simplicity, or availability offered in open source software. Comparing forty tractography results to a ground truth defined by histological tracers in the primary motor cortex on the same squirrel monkey brains, we assess tract fidelity on the scale of voxels as well as over larger spatial domains or regional connectivity. No algorithms are successful in all metrics, and, in fact, some implementations fail to reconstruct large portions of pathways or identify major points of connectivity. The accuracy is most dependent on reconstruction method and tracking algorithm, as well as the seed region and how this region is utilized. We also note a tremendous variability in the results, even though the same MR images act as inputs to all algorithms. In addition, anatomical accuracy is significantly decreased at increased distances from the seed. An analysis of the spatial errors in tractography reveals that many techniques have trouble properly leaving the gray matter, and many only reveal connectivity to adjacent regions of interest. These results show that the most commonly implemented algorithms have several shortcomings and limitations, and choices in implementations lead to very different results. This study should provide guidance for algorithm choices based on study requirements for sensitivity, specificity, or the need to identify particular connections, and should serve as a heuristic for future developments in tractography.


Liquid biomarkers in melanoma: detection and discovery.
A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.


Microbial endoxylanases: effective weapons to breach the plant cell-wall barrier or, rather, triggers of plant defense systems?
Endo-beta-1,4-xylanases (EC 126.96.36.199) are key enzymes in the degradation of xylan, the predominant hemicellulose in the cell walls of plants and the second most abundant polysaccharide on earth. A number of endoxylanases are produced by microbial phytopathogens responsible for severe crop losses. These enzymes are considered to play an important role in phytopathogenesis, as they provide essential means to the attacking organism to break through the plant cell wall. Plants have evolved numerous defense mechanisms to protect themselves against invading pathogens, amongst which are proteinaceous inhibitors of cell wall-degrading enzymes. These defense mechanisms are triggered when a pathogen-derived elicitor is recognized by the plant. In this review, the diverse aspects of endoxylanases in promoting virulence and in eliciting plant defense systems are highlighted. Furthermore, the role of the relatively recently discovered cereal endoxylanase inhibitor families TAXI (Triticum aestivum xylanase inhibitor) and XIP (xylanase inhibitor protein) in plant defense is discussed.


Measurement of calcium ion concentrations in the lateral line cupulae of Xenopus laevis.
1. Ion selective microelectrodes were used to measure the distribution of Ca2+ in the cupulae of Xenopus laevis, and to observe the effects of the Ca2+ blocker, La3+, and a Ca2+ chelating agent (EGTA) on the endocupular potential and K+ concentration. 2. Measurements of the endocupular Ca2+ and potential were found to be in the range of 2-30 muM and 55-10 mV respectively, and their relationship indicates that Ca2+ is passively distributed in the cupula. 3. The concentration of endocupular K+ and endocupular potential was found not to be influenced by addition of either 1 mM EGTA or 100 muM-La3+ to the bathing solution.


Role of intracellular calcium as a priming signal for the induction of nitric oxide synthesis in murine peritoneal macrophages.
Because the role of intracellular Ca2+ in the two-signal process for the induction of nitric oxide (NO) synthesis is controversial, this study was undertaken to examine the role of Ca2+ in the transcriptional regulation of inducible NO synthase (iNOS) in murine peritoneal macrophages. Treatment of the cells with thapsigargin (TG) or 2,5-di-(t-butyl)-1,4-benzodihydroquinone (tBuBHQ), which are the specific and potent Ca(2+)-ATPase inhibitors of endoplasmic reticulum (ER), showed modest effects on tumoricidal function, whereas TG or tBuBHQ in combination with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed marked effects on tumoricidal function of the cells. The tumoricidal effects of the activated macrophages were correlated with the amount of NO synthesis, and totally abrogated by the use of NOS inhibitor, NG-monomethyl-L-arginine (NGMMA). The increases in NO synthesis was reflected as increased amounts of iNOS mRNA by Northern blotting. To confirm that iNOS induction was due to the changes in the intracellular Ca2+ level, the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular Ca2+ chelator, was used. Blocking the increase of cytosolic free Ca2+ significantly decreased the induction of NO synthesis. To demonstrate that intracellular Ca2+ acts as a 'priming' signal rather than a 'triggering' signal on the induction of NO synthesis by murine peritoneal macrophages, we designed several experiments. When the cells were treated with TG 6 hr after the treatment with IFN-gamma, there was no increase in NO synthesis. In addition, when the cells were treated with TG or LPS 6 hr after treatment with tBuBHQ, a synergistic increase on NO synthesis was shown only in the case of LPS. When phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, was added to the cells 6 hr after the treatment with TG, there was a marked co-operative induction of NO synthesis, even though PMA alone has no effect. Based on the results obtained in this study, we suggest that cytosolic Ca2+ might be enough for the expression of iNOS gene as a priming signal and PKC might be involved in the induction of NO synthesis as a triggering signal by post-transcriptional modification of iNOS mRNA or iNOS itself in the activated murine peritoneal macrophages.


Autocrine BDNF-TrkB signalling within a single dendritic spine.
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal's learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF-TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR-CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.


Age-related increase of baseline frequencies of sister chromatid exchanges, chromosome aberrations, and micronuclei in human lymphocytes.
Intra- and interindividual variations of baseline frequencies of cytogenetic end points in lymphocytes of human populations have been reported by various authors. Personal characteristics seem to account for a significant proportion of this variability. Several studies investigating the role of age as a confounding factor in cytogenetic biomonitoring found an age-related increase of micronucleus (MN) frequency, whereas contradictory results were reported for chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs). We have quantitatively evaluated the effect of age on SCE, CA, and MN through the analysis of a population sample that included data from several biomonitoring studies performed over the last few decades in 12 Italian laboratories. The large size of the data set, i.e., more than 2000 tests for each end point, allowed us to estimate the independent effect of age, taking into account other covariates, such as sex, smoking habits, occupational exposure, and inter- and intralaboratory variability. A greater frequency of the mean standardized values by increasing of age was observed for all of the end points. A leveling off was evident in the last age classes in the trend of MN frequencies. Frequency ratios (FRs), which express the increase of the cytogenetic damage with respect to the first age classes, i.e., 1-19 years, were estimated using Poisson regression analysis after adjustment for the potential confounding factors and confirmed the increasing trend by age class for all three end points. The most dramatic increase was observed for MN, with a FR that approaches the value of 2 at the age class 50-59 (FR, 1.97; 95% confidence interval, 1.43-2.71) and remains substantially unchanged thereafter. The trend of FRs for CA is more homogeneous, with a constant rise even in the older classes, whereas the frequency of SCE increases with age to a lesser extent, reaching a plateau in the age class 40-49 and the maximum value of FR in the age class over 70 (FR, 1.14; 95% confidence interval, 1.07-1.23). In conclusion, our results point to an age-related increase of the chromosome damage in lymphocytes and emphasize the need to take into account the potential confounding effect of this variable in the design of biomonitoring studies based on chromosome damage.


Endonasal endoscopic dacryocystorhinostomy: our experience.
To study the outcome of endonasal endoscopic dacryocystorhinostomy (DCR) with or without mucosal flap preservation, without mitomycin local application, silicon tube stenting or laser assistance. To determine the duration of the surgical procedure of DCR, influence of simultaneously performed endonasal endoscopic procedures for concomitant sinonasal diseases. Combined retrospective and prospective study in our tertiary referral center. 24 patients with chronic dacryocystitis underwent 25 standard endonasal endoscopic DCR procedures, 10 with and 15 without mucosal flap preservation. 6 of these had concomitant sinonasal diseases for which they underwent septoplasty or functional endoscopic sinus surgery (FESS) or both, simultaneously or as staged procedures. Relief from epiphora and patency of the nasolacrimal fistula was assessed by nasal endoscopy and syringing of the lacrimal apparatus at 1 week, 3 weeks and 3 months postoperatively. Out of 18 patients who underwent only DCR, 17 patients (94.44%) had complete relief from epiphora. Out of 6 patients who underwent 7 DCRs with concomitant sinonasal surgery, 5 patients (85.71%) had complete relief from epiphora. Overall 23 out of 25 DCRs (92%) had complete relief. In 15 of the 25 procedures, mucosal flap was excised completely. In remaining 10 procedures, flap was trimmed, repositioned to cover exposed bone around the newly created nasolacrimal fistula. In either situation, only one patient each had partial block of the nasolacrimal fistula. Average duration of the surgical procedure of DCR was 18 min. Endonasal endoscopic DCR is a viable alternative to external DCR, co-existing sinonasal diseases can be managed simultaneously, as may be required in 25% of cases. It can be performed under 20 min without mucosal flap preservation, mitomycin local application, silicon tube stenting or laser assistance and can still provide a good success rate (92%) with less complications.


Individual Positive End-expiratory Pressure Settings Optimize Intraoperative Mechanical Ventilation and Reduce Postoperative Atelectasis.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Intraoperative lung-protective ventilation has been recommended to reduce postoperative pulmonary complications after abdominal surgery. Although the protective role of a more physiologic tidal volume has been established, the added protection afforded by positive end-expiratory pressure (PEEP) remains uncertain. The authors hypothesized that a low fixed PEEP might not fit all patients and that an individually titrated PEEP during anesthesia might improve lung function during and after surgery. Forty patients were studied in the operating room (20 laparoscopic and 20 open-abdominal). They underwent elective abdominal surgery and were randomized to institutional PEEP (4 cm H2O) or electrical impedance tomography-guided PEEP (applied after recruitment maneuvers and targeted at minimizing lung collapse and hyperdistension, simultaneously). Patients were extubated without changing selected PEEP or fractional inspired oxygen tension while under anesthesia and submitted to chest computed tomography after extubation. Our primary goal was to individually identify the electrical impedance tomography-guided PEEP value producing the best compromise of lung collapse and hyperdistention. Electrical impedance tomography-guided PEEP varied markedly across individuals (median, 12 cm H2O; range, 6 to 16 cm H2O; 95% CI, 10-14). Compared with PEEP of 4 cm H2O, patients randomized to the electrical impedance tomography-guided strategy had less postoperative atelectasis (6.2 ± 4.1 vs. 10.8 ± 7.1% of lung tissue mass; P = 0.017) and lower intraoperative driving pressures (mean values during surgery of 8.0 ± 1.7 vs. 11.6 ± 3.8 cm H2O; P < 0.001). The electrical impedance tomography-guided PEEP arm had higher intraoperative oxygenation (435 ± 62 vs. 266 ± 76 mmHg for laparoscopic group; P < 0.001), while presenting equivalent hemodynamics (mean arterial pressure during surgery of 80 ± 14 vs. 78 ± 15 mmHg; P = 0.821). PEEP requirements vary widely among patients receiving protective tidal volumes during anesthesia for abdominal surgery. Individualized PEEP settings could reduce postoperative atelectasis (measured by computed tomography) while improving intraoperative oxygenation and driving pressures, causing minimum side effects.


Academic-Practice Partnership in Public Health Nursing: Working with Families in a Village-Based Collaboration.
The purpose of this program development and evaluation project was to promote healthy families and communities by creating academic-practice partnerships, educating BSN students and building family-nursing student partnerships that were supported by a "village" of interconnected resources. A mixed-methods design was used for the project. Data were collected from a convenience sample of vulnerable families, BSN students engaged in PHN practica, and partner members. Nine tools were developed to capture data over two semesters including a GIS mapping strategy. One hundred and seventy-five home visits were completed with 20 families, 14 of whom needed interpreter assistance. Families reported satisfaction with the quality of home visits, education, and assistance toward health goals. Fifty-three students provided 202 educational interventions, 39 community resource connections, and 46 care transitions. Students reported linking theory with practice and valued the PHN practicum experience. Academic-practice partners identified opportunities for program development and sustainability. GIS mapping illustrated complex family linkages to community resources. Results suggest that young, vulnerable families benefit from public health nursing (PHN) home visits, but sustaining home visit programs is challenging. Academic-practice partnerships can guide students and families partnered in a reciprocal relationship with "village" resources.


[2.2]Paracyclophane derived bisphosphines for the activation of hydrogen by FLPs: application in domino hydrosilylation/hydrogenation of enones.
The heterolytic splitting of hydrogen by two types of [2.2]paracyclophane derived bisphosphines (1, 2a and 2b) in combination with tris(pentafluorophenyl)borane (3) at room temperature is described. The corresponding frustrated Lewis pairs (FLPs) exhibit different behavior in the activation of hydrogen. This results from diverse steric and electronic properties of the bisphosphines. The reactivity of the frustrated Lewis pairs was exploited in the first diastereoselective domino hydrosilylation/hydrogenation reaction catalyzed by FLPs.


High-throughput mammographic-density measurement: a tool for risk prediction of breast cancer.
Mammographic density (MD) is a strong, independent risk factor for breast cancer, but measuring MD is time consuming and reader dependent. Objective MD measurement in a high-throughput fashion would enable its wider use as a biomarker for breast cancer. We use a public domain image-processing software for the fully automated analysis of MD and penalized regression to construct a measure that mimics a well-established semiautomated measure (Cumulus). We also describe measures that incorporate additional features of mammographic images for improving the risk associations of MD and breast cancer risk. We randomly partitioned our dataset into a training set for model building (733 cases, 748 controls) and a test set for model assessment (765 cases, 747 controls). The Pearson product-moment correlation coefficient (r) was used to compare the MD measurements by Cumulus and our automated measure, which mimics Cumulus. The likelihood ratio test was used to validate the performance of logistic regression models for breast cancer risk, which included our measure capturing additional information in mammographic images. We observed a high correlation between the Cumulus measure and our measure mimicking Cumulus (r = 0.884; 95% CI, 0.872 to 0.894) in an external test set. Adding a variable, which includes extra information to percentage density, significantly improved the fit of the logistic regression model of breast cancer risk (P = 0.0002). Our results demonstrate the potential to facilitate the integration of mammographic density measurements into large-scale research studies and subsequently into clinical practice.


Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.
BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. METHODS Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. FINDINGS The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95 percent CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90 percent of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons...


Exclusive breastfeeding and incident atopic dermatitis in childhood: a systematic review and meta-analysis of prospective cohort studies.
Breastfeeding is undisputedly preferable to formula feeding for infant nutrition because of its nutritional, immunological and psychological benefits. However, studies on the association between breastfeeding and development of atopic dermatitis (AD) have shown inconsistent results. To examine the association between exclusive breastfeeding for at least 3 months after birth and the development of AD in childhood. An electronic literature search of MEDLINE (January 1966-May 2008) and EMBASE (1980-May 2008) was conducted. Prospective cohort studies that met the predetermined criteria were independently assessed by three reviewers. The pooled effect estimate was calculated by random effects model. Heterogeneity across the studies was investigated by meta-regression analysis. Twenty-one studies with 27 study populations were included for meta-analysis. The summary odds ratio (OR) for the effect of exclusive breastfeeding on the risk of AD was 0.89 (95% confidence interval, CI 0.76-1.04). Heterogeneity was found across the studies (chi(2) = 83.6, d.f. = 26; P < 0.001). Breastfeeding was associated with a decreased risk of AD (OR 0.70; 95% CI 0.50-0.99) when analysis was restricted to the studies comparing breastfeeding with conventional formula feeding. The pooled OR for study populations with atopic heredity was 0.78 (95% CI 0.58-1.05). There is no strong evidence of a protective effect of exclusive breastfeeding for at least 3 months against AD, even among children with a positive family history.


Prevalence of asymptomatic bacteriuria among pregnant women in Benin City, Nigeria.
A semi-quantitative screening for asymptomatic bacteriuria was carried out in the first trimester of 500 consecutive pregnant women in Benin City. The purpose was to provide baseline data and rational therapy for asymptomatic bacteriuria in pregnant women. Of the 500 women screened, 433 clinical specimens showed significant bacteriuria, representing an incidence of 86.6%. Of this number, 38 (7.4%) were of mixed bacterial colonies while 395 (91%) were of single bacterial colonies. Staphylococcus aureus (29.8%), Escherichia coli (29.1%) and Klebsiella pneumoniae (21.5%) were the most frequently isolated pathogens. The high incidence of asymptomatic bacteriuria in pregnancy correlated significantly (P < 0.05) with the observed high proportion of pyuria. On average, sensitivity of the pathogens was ciprofloxacin 99.7%; ceftazidime 81.6%; co-trimoxazole 79.4%; augmentin 71.4%; nalidixic acid 61.7%; nitrofurantoin 61.%; gentamycin 56.9% and ampicillin 25.4%. S. aureus was most sensitive, while Proteus mirabilis was least sensitive among the pathogens. Rational therapy of asymptomatic bacteriuria in pregnant women may prevent associated risks such as pyelonephritis and pre-eclampsia.


Estimating mortality and disability in Peru before the COVID-19 pandemic: a systematic analysis from the Global Burden of the Disease Study 2019.
Estimating and analyzing trends and patterns of health loss are essential to promote efficient resource allocation and improve Peru's healthcare system performance. Using estimates from the Global Burden of Disease (GBD), Injuries, and Risk Factors Study (2019), we assessed mortality and disability in Peru from 1990 to 2019. We report demographic and epidemiologic trends in terms of population, life expectancy at birth (LE), mortality, incidence, prevalence, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by the major diseases and risk factors in Peru. Finally, we compared Peru with 16 countries in the Latin American (LA) region. The Peruvian population reached 33.9 million inhabitants (49.9% women) in 2019. From 1990 to 2019, LE at birth increased from 69.2 (95% uncertainty interval 67.8-70.3) to 80.3 (77.2-83.2) years. This increase was driven by the decline in under-5 mortality (-80.7%) and mortality from infectious diseases in older age groups (+60 years old). The number of DALYs in 1990 was 9.2 million (8.5-10.1) and reached 7.5 million (6.1-9.0) in 2019. The proportion of DALYs due to non-communicable diseases (NCDs) increased from 38.2% in 1990 to 67.9% in 2019. The all-ages and age-standardized DALYs rates and YLLs rates decreased, but YLDs rates remained constant. In 2019, the leading causes of DALYs were neonatal disorders, lower respiratory infections (LRIs), ischemic heart disease, road injuries, and low back pain. The leading risk factors associated with DALYs in 2019 were undernutrition, high body mass index, high fasting plasma glucose, and air pollution. Before the COVID-19 pandemic, Peru experienced one of the highest LRIs-DALYs rates in the LA region. In the last three decades, Peru experienced significant improvements in LE and child survival and an increase in the burden of NCDs and associated disability. The Peruvian healthcare system must be redesigned to respond to this epidemiological transition. The new design should aim to reduce premature deaths and maintain healthy longevity, focusing on effective coverage and treatment of NCDs and reducing and managing the related disability.


Albuminuria and decline in cognitive function: The ONTARGET/TRANSCEND studies.
Microvascular disease of the kidney (manifesting as albuminuria) and of the brain (manifesting as cognitive decline) may share a common pathogenesis. Gaining an understanding of the concomitant history of these 2 conditions may inform clinical practice and lead to novel prevention and treatment approaches. A total of 28 384 participants with vascular disease or diabetes mellitus were examined. At baseline and year 5, participants underwent a Mini-Mental State Examination (MMSE) and urine testing for albumin excretion. Multivariable logistic regression was used to determine the association between albumin excretion and MMSE score, cross-sectionally and prospectively, and whether angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker use modified the association. Compared with participants with normoalbuminuria, those with microalbuminuria (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.11-1.44]) and macroalbuminuria (1.49; 1.20-1.85) were more likely to have a reduced MMSE score (<24). On follow-up, participants with baseline albuminuria had increased odds of cognitive decline (decrease in MMSE score ≥3 points) compared with those with normoalbuminuria (microalbuminuria: OR, 1.22; 95% CI, 1.07-1.38; macroalbuminuria: 1.21; 0.94-1.55). Participants who developed new albuminuria had increased odds of cognitive decline during follow-up compared with those who remained normoalbuminuric (new microalbuminuria: OR, 1.30; 95% CI, 1.12-1.52; new macroalbuminuria: 1.77; 1.24-2.54). Participants with baseline macroalbuminuria treated with an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker had lower odds of MMSE decline than participants treated with placebo. Factors that contribute to albuminuria may contribute to cognitive decline, supporting the notion that both conditions share a common microvascular pathogenesis. Trial Registration clinicaltrials.gov Identifier: NCT00153101.


Cell therapy using tolerogenic dendritic cells in transplantation.
Organ transplantation is the main alternative to the loss of vital organ function from various diseases. However, to avoid graft rejection, transplant patients are treated with immunosuppressive drugs that have adverse side effects. A new emerging approach to reduce the administration of immunosuppressive drugs is to co-treat patients with cell therapy using regulatory cells. In our laboratory, as part of a European project, we plan to test the safety of tolerogenic dendritic cell (TolDC) therapy in kidney transplant patients. In this mini-review, we provide a brief summary of the major protocols used to derive human TolDC, and then focus on the granulocyte macrophage-TolDC generated by our own team. Proof of safety of TolDC therapy in the clinic has already been demonstrated in patients with diabetes. However, in transplantation, DC therapy will be associated with the administration of immunosuppressive drugs, and interactions between drugs and DC are possible. Finally, we will discuss the issue of DC origin, as we believe that administration of autologous TolDC is more appropriate, as demonstrated by our experiments in animal models.


Comparison of a limiting dilution assay and ELISpot for detection of memory B-cells before and after immunisation with a protein-polysaccharide conjugate vaccine in children.
In the present study, the limiting dilution assay (LDA) and the ELISpot are compared in their ability to detect serogroup C meningococcal (MenC)-specific memory B-cells in peripheral blood of 12month old children, after 3-dose priming with serogroup C meningococcal conjugate vaccine (MenCV) in infancy. At 12 months of age, MenC-memory B-cells were detected by ELISpot in 61% of children and in 5% by LDA. In contrast, carrier-specific memory B-cells were measurable in 36% of children by LDA and 78% by ELISpot. One month after a booster dose of MenCV given at 12 months of age, MenC-specific memory B-cells were detected in 89% of children by ELISpot and 65% of children by LDA, while diphtheria toxoid-specific memory B-cells were detected in 88% of children by ELISpot and in 74% of children by LDA. Two statistical methods were applied to enumerate memory B-cells with the LDA assay; the Poisson method allowed determination of very low frequencies that could not be determined by the Reed and Muench method. These data are examples of alternative methods to assess long-term protection after protein-polysaccharide conjugate vaccines, through direct measurement of memory B-cells in peripheral blood shortly after immunisation.


Insilico analysis of three different tag polypeptides with dual roles in scFv antibodies.
Single chain fragment variable (scFv) antibodies are composed of variable heavy (VH) and variable light (VL) domains that are joined by a polypeptide linker. Typically, [(Gly4Ser) n] sequence is used as a linker to retain the integrity of the antigen-binding domain. Due to its low immunogenicity, this sequence cannot be used as a tag for scFv detection and purification. Several evidences have shown that the addition of an N or C-terminal tag for scFv detection and purification will result in the decreased expression and binding capacity of this antibody fragment. In this study, we substituted the traditional linker (GGGGS) with His-tag, C-myc or E-tag sequences through molecular modeling. Stability and integrity of all models were assessed by molecular dynamic (MD) simulation. Based on MD simulation analysis, the model containing E-tag sequence as a linker indicated more stability compared to other molecules. The results suggest that E-tag not only can be substituted for the traditional linker, also eliminates the necessity of using additional tag for scFv detection and purification.