Bonebridge implantation for mixed hearing loss in a patient with Kabuki syndrome.
The high prevalence of middle ear disease with related hearing loss in Kabuki syndrome requires the diagnostic and treatment expertise of otologists. This case report describes outcomes and changes in the quality of life of a patient affected by Kabuki syndrome with a history of recalcitrant chronic otitis media and mixed hearing loss who had undergone several unsuccessful surgical procedures before solving his problems by means of subtotal petrosectomy and active middle ear implant.


Joint-specific hand symptoms and self-reported and performance-based functional status in African Americans and Caucasians: The Johnston County Osteoarthritis Project.
To assess associations between joint-specific hand symptoms and self-reported and performance-based functional status. Participants were from the population-based Johnston County Osteoarthritis Project. Symptoms in the distal interphalangeal (DIP), proximal interphalangeal (PIP), first carpometacarpal (CMC), and metacarpophalangeal (MCP) joints were assessed on a 30-joint diagram of both hands. Self-reported function was assessed by Health Assessment Questionnaire (HAQ) and performance-based function by timed repeated chair stands and 8-foot walk time. Separate multiple logistic regression models examined associations between symptoms in specific hand joint groups, symptoms in >/=2 hand joint groups and number of symptomatic hand joints, and functional status measures, controlling for age, race/ethnicity, sex, body mass index, radiographic knee and hip OA, knee and hip symptoms and depressive symptoms. Those with symptomatic hand joint groups were more likely than those without these complaints to report more difficulty and require longer times for performance measures. Those with 2 or more symptomatic hand joint groups were more likely to have higher HAQ scores (OR = 1.97 (1.53 to 2.53)) and require more time to complete 5 chair stands (OR = 1.98 (1.23 to 3.18)) and the 8 foot walk test (OR = 1.49 (1.12 to 1.99)). Joint-specific hand symptoms are associated with difficulty performing upper- or lower-extremity tasks, independent of knee and hip OA and symptoms, suggesting that studies examining functional status in OA should not ignore symptomatic joints beyond the joint site of interest, even when functional measures appear to be specific for the joint site under study.


Severity of labour pain: influence of physical as well as psychologic variables.
The role of physical factors in the severity of labour pain has been neglected. The amount of cervical dilation, the frequency of the contractions, the woman's height and usual weight before the pregnancy and other physical factors were therefore examined in relation to the intensity of labour pain in 141 primiparous and 99 multiparous women. In general, pain increased gradually during labour in both groups of women, though the severity of the pain was lower in the women who had received prepared childbirth training than in those who had not. Although the average pain scores in this study were high, there were striking individual differences, some women having extremely severe pain and others having almost none. The pain scores in both groups of women were significantly correlated with the ratios of the women's usual weight to height. In the multiparous women the scores were also correlated with the woman's usual weight and the baby's weight but not with the woman's weight gain during pregnancy. Thus, the results show that physical as well as psychologic factors contribute to the severity of labour pain.


Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry.
Rett syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the methyl-CpG-binding protein 2 (MeCP2). A major paradox in the pathogenesis of RTT is how mutations in ubiquitously transcribed MECP2 result in a phenotype specific to the central nervous system (CNS) during postnatal development. To address this question, we have used a novel approach for quantitating the level and distribution of wild-type and mutant MeCP2 in situ by immunofluorescence and laser scanning cytometry. Surprisingly, cellular heterogeneity in MeCP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression (MeCP2(hi)) and the remainder exhibiting low expression (MeCP2(lo)). MeCP2 expression was significantly higher in CNS compared with non-CNS tissues of human and mouse by automated quantitation of MeCP2 on multiple tissue arrays. Quantitative localization of MeCP2 expression phenotypes in normal human brain showed a mosaic, but distinct, distribution pattern, with MeCP2(hi) neurons highest in layer IV of the cerebrum and MeCP2(lo )neurons highest in the granular layer of the cerebellum. In female RTT brains, MECP2 mutant-expressing cells were identified as cells negative for the MeCP2 C-terminal epitope. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MeCP2 expression with N-terminal-specific anti-MeCP2. These results demonstrate a CNS-specific cellular phenotype of MeCP2 high expression and suggest that MECP2 mutations in RTT are only manifested in MeCP2(hi) cells. In addition, our results demonstrate the power of laser scanning cytometry in examining complex cellular phenotypes in disease pathogenesis.


Rescue of epithelial HCO3- secretion in murine intestine by apical membrane expression of the cystic fibrosis transmembrane conductance regulator mutant F508del.
This study investigated whether expression of the common cystic fibrosis transmembrane conductance regulator (CFTR) mutant F508del in the apical membrane of enterocytes confers increased bicarbonate secretory capacity on the intestinal epithelium of F508del mutant mice compared to that of CFTR knockout (KO) mice. CFTR KO mice, F508del mutant mice (F508del) and wild-type (WT) littermates were bred on the FVB/N background. F508del isolated brush border membrane (BBM) contained approximately 5-10% fully glycosylated band C protein compared to WT BBM. Similarly, the forskolin (FSK)-induced, CFTR-dependent short-circuit current (I(sc)) of F508del mucosa was approximately 5-10% of WT, whereas the HCO(3)(-) secretory response ( ) was almost half that of WT in both duodenum and mid-colon studied in vitro and in vivo. While WT intestine retained full FSK-induced in the absence of luminal Cl(-), the markedly higher than I(sc) in F508del intestine was dependent on the presence of luminal Cl(-), and was blocked by CFTR inhibitors. The Ste20-related proline-alanine-rich kinases (SPAK/OSR1), which are downstream of the with-no-lysine (K) protein kinases (WNK), were rapidly phosphorylated by FSK in WT and F508del, but significantly more slowly in CFTR KO intestine. In conclusion, the data demonstrate that low levels of F508del membrane expression in the intestine of F508del mice significantly increased FSK-induced HCO(3)(-) secretion mediated by Cl(-)/HCO(3)(-) exchange. However, in WT mucosa FSK elicited strong SPAK/OSR1 phosphorylation and Cl(-)-independent HCO(3)(-) efflux. This suggests that therapeutic strategies which deliver F508del to the apical membrane have the potential to significantly enhance epithelial HCO(3)(-) secretion.


[Ischaemic heart disease as a risk factor for general anaesthesia and surgery].
The risk of myocardial reinfarction in the patient who has suffered a pre-operative infarction is well documented. In a literature search, the cardiovascular risk implied by either asymptomatic or symptomatic ischaemic heart disease (without infarction) to the patient scheduled for anaesthesia and surgery appears to be minimal provided that hypotension, hypoxia, tachyarrythmias and hypertension are avoided. However, a myocardial ischaemic incident prior to surgery seems to warrant the postponement of elective surgical procedures.


[Intracranial aneurysms in autosomal dominant polycystic kidney disease detected by MR angiography: screening and treatment].
The association of intracranial aneurysm with ADPKD is well-known, and patients with ADPKD are at increased risk of subarachnoid hemorrhage from rupture of intracranial aneurysms. We prospectively performed three-dimensional time-of-flight magnetic resonance angiography (MRA) in 30 nonselective adult patients with ADPKD. Sixteen were women and 14 were men with a mean age of 51 yr (range 24 to 79 yr). The diagnosis of ADPKD was made on the basis of abdominal ultrasound or computed tomographic studies. Three patients were on maintenance hemodialysis, 8 patients were nondialysed patients with chronic renal failure (serum creatinine > or = mg/dl) and 25 patients had hypertension (BP > or = 140/90 mmHg). None of these patients have a previous diagnosis of intracranial aneurysm. Unruptured intracranial aneurysms were suspected in 5 patients by MRA, and 8 aneurysms were confirmed in 4 (13.3%) of 30 patients by conventional arteriography. These aneurysms were 3 approximately 10 mm in diameter and 3 aneurysms (3 approximately 4 mm in diameter) were newly detected by cerebral arteriography. After informed consent was obtained, neck clipping of the intracranial aneurysms were performed successfully in all the patients. These results suggest that the prevalence of intracranial aneurysms is about 13% in ADPKD, and that MRA is useful in screening for occult intracranial aneurysms in patients with ADPKD.


Using mitochondrial genome sequences to track the origin of imported Plasmodium vivax infections diagnosed in the United States.
Although the geographic origin of malaria cases imported into the United States can often be inferred from travel histories, these histories may be lacking or incomplete. We hypothesized that mitochondrial haplotypes could provide region-specific molecular barcodes for tracing the origin of imported Plasmodium vivax infections. An analysis of 348 mitochondrial genomes from worldwide parasites and new sequences from 69 imported malaria cases diagnosed across the United States allowed for a geographic assignment of most infections originating from the Americas, southeast Asia, east Asia, and Melanesia. However, mitochondrial lineages from Africa, south Asia, central Asia, and the Middle East, which altogether contribute the vast majority of imported malaria cases in the United States, were closely related to each other and could not be reliably assigned to their geographic origins. More mitochondrial genomes are required to characterize molecular barcodes of P. vivax from these regions.


Isolation and characterization of a novel ribonucleoprotein particle: large structures contain a single species of small RNA.
Rat liver coated vesicle preparations were frequently found to contain small ovoid bodies, which resembled coated vesicles in morphology. We have purified these bodies to homogeneity using sucrose density gradients and preparative agarose gel electrophoresis. When negatively stained and viewed by electron microscopy, the purified structures display a very distinct and complex morphology, resembling the multiple arches which form cathedral vaults. They measure 35 X 65 nm and are therefore considerably larger than ribosomes. When subjected to SDS PAGE, these structures, which we refer to as vaults, appear to contain several minor and five major species: Mr 210,000, 192,000, 104,000, 54,000, and 37,000. One of these (Mr 104,000) greatly predominates, accounting for greater than 70% of the total Coomassie Brilliant Blue-staining protein. Another major species of Mr 37,000 has been identified as a species of small RNA of unusual base composition (adenosine 12.0%, guanosine 29.7%, uridine 30.9%, and 27.4% cytidine), which migrates as a single species in urea PAGE between the 5S and 5.8S ribosomal standards, containing approximately 140 bases. Although the RNA constitutes only 4.6% of the entire structure, the large size of the particle requires that each one contains approximately 9 molecules of this RNA. Antibodies prepared against the entire particle are largely specific for the major (Mr 104,000) polypeptide species. Although they do not directly react with the RNA constituent on Western blots, these antibodies immunoprecipitate a 32P-labeled RNA of identical size from metabolically-labeled rat hepatoma cells. Vaults are observed in partially purified fractions from human fibroblasts, murine 3T3 cells, glial cells, and rabbit alveolar macrophages. It therefore appears that these novel ribonucleoprotein structures are broadly distributed among different cell types. The function of vaults is at present unknown.


Developing a community-based neonatal care intervention: a health facility assessment to inform intervention design.
Community-based interventions are an important way of improving health in low-income countries. A necessary prerequisite for the design of such interventions is an understanding of the local health system. This will inform intervention design, help ensure the community-intervention forms part of a continuum of care, and provide information about health system strengthening activities that may be necessary for success. Such formative research processes, however, are seldom reported in the literature. We present the results of a health facility assessment used in the design stage of Newhints, a community-based intervention to improve neonatal survival in rural Ghana. We illustrate the methodology, findings and how these were used to inform the design and implementation of Newhints. The assessment involved key informant interviews with staff members at seven health facilities within the study area, including a brief inventory of available drugs and equipment. The key informant interviews identified that practices and health promotion messages at the health facilities were not consistent with one of the key target behaviours of the Newhints intervention - thermal care through delayed infant bathing. Health workers were bathing neonates soon after delivery and also advising women to do the same, which is a potential cause of hypothermia for the newborn. We found that health centres other than large district hospitals were ill-equipped to treat serious complications of labour or illness in the newborn, which had implications for advice on health seeking behaviour within the intervention. As a result of the health facility assessment, it was deemed necessary to undertake both health worker training and sensitisation activities. We demonstrate that important information can be yielded from a relatively simple health facility assessment involving key informant interviews.


Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate.
Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D(4)) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [(18)F]2-fluoro-2-deoxy-D-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D(4). Images were analyzed using a novel automated image registration procedure. Baseline D(4)(-/-) mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D(4)(+/+) and D(4)(+/-) mice; when given MP, D(4)(-/-) mice increased metabolism in the PFC and decreased it in the CBV, whereas in D(4)(+/+) and D(4)(+/-) mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D(4) polymorphisms.


Vancomycin pharmacokinetic-pharmacodynamic parameters to optimize dosage administration in critically ill children.
Critically ill children may present changes in pharmacokinetic parameters and may not reach effective concentrations of vancomycin with current dosages. The objective of this study is to calculate vancomycin pharmacokinetic parameters in critically ill children and to estimate area under the curve at 24 hrs/minimal inhibitory concentration reached for Staphylococcus aureus. Children treated with vancomycin, hospitalized in the Intensive Care Unit of the Pediatric Hospital-Centro Hospitalario Pereira Rossell, were included. Samples to determine vancomycin serum concentration were obtained on first and third days of treatment, 1 hr after the end of the third daily dose administration (maximum drug concentration) and 15 mins before the fourth (minimum drug concentration). Half-life elimination, volume of distribution, clearance, and area under the curve at 24 hrs were estimated. Vancomycin concentration values of 20-40 μg/mL (maximum drug concentration) and 5-10 μg/mL (minimum drug concentration) were considered therapeutic. Twenty-two children were included. On day 1, seven of 18 children for maximum drug concentration and 16 of 22 for minimum drug concentration reached concentrations in therapeutic range; on day 3, seven of 16 children for maximum drug concentration and 11 of 17 for minimum drug concentration did. Mean values of maximum drug concentration and minimum drug concentration were higher in children with negative water balance. Mean value of half-life elimination increased from day 1 to day 3. Considering a value of minimal inhibitory concentration for S. aureus of 1 μg/mL, nine of 18 children reached a relationship area under the curve at 24 hrs/minimal inhibitory concentration >400 on day 1 and seven of 15 on day 3. Considering a minimal inhibitory concentration of 2 μg/mL, one child reached it on day 1 and one on day 3. Critically ill children show changes in pharmacokinetic parameters. Serum concentration monitorization is necessary for dosage individualization. Most children do not reach an area under the curve at 24 hrs/minimal inhibitory concentration >400 with current dosage.


Developing a culture of safety in a reluctant audience.
To describe the injury pattern of skateboarding injuries today. The pattern of injuries, circumstances, and severity were investigated in a study of 139 people injured in skateboarding accidents during 1995 through 1998 inclusive and admitted to the University Hospital of Umeå, Umeå, Sweden. This is the only hospital in the area, serving a population of 135,000. Of the 139 injured, 3 were pedestrians hit by a skateboard rider; the rest were riders. The age range was 7 to 47 years (mean, 16.0). The severity of the injuries was minor (Abbreviated Injury Scale 1) to moderate (Abbreviated Injury Scale 2); fractures were classified as moderate. The annual number of injuries increased during the study period. Fractures were found in 29% of the casualties, and four children had concussion. The most common fractures were of the ankle and wrist. Older patients had less severe injuries, mainly sprains and soft tissue injuries. Most children were injured while skateboarding on ramps and at arenas; only 12 (9%) were injured while skateboarding on roads. Some 37% of the injuries occurred because of a loss of balance and 26% because of a failed trick attempt. Falls caused by surface irregularities resulted in the highest proportion of the moderate injuries. Skateboarding should be restricted to supervised skateboard parks, and skateboarders should be required to wear protective gear. These measures would reduce the number of skateboarders injured in motor vehicle collisions, the personal injuries among skateboarders, and the number of pedestrians injured in collisions with skateboarders.


Trends in the treatment of lumbar spine fractures in the United States: a socioeconomics perspective: clinical article.
The objective of this study was to investigate a national health care database and analyze demographics, hospital charges, and treatment trends of patients diagnosed with lumbar spine fractures in the US over a 5-year period. Clinical data were derived from the Nationwide Inpatient Sample (NIS) for the years 2003 through 2007. The NIS is maintained by the Agency for Healthcare Research and Quality and represents a 20% random stratified sample of all discharges from nonfederal hospitals within the US. Patients with lumbar spine fractures were identified using the appropriate ICD-9-CM code. Data on the number of vertebral body augmentation procedures were also retrieved. National estimates of discharges, hospital charges, discharge patterns, and treatment with spinal fusion trends were retrieved and analyzed. More than 190,000 records of patients with lumbar spine fractures were abstracted from the database. During the 5-year period, there was a 17% increase in hospitalizations for lumbar spine fractures. This was associated with a 27% increase in hospital charges and a 55% increase in total national charges (both adjusted for inflation). The total health care bill associated with lumbar spine fractures in 2007 exceeded 1 billion US dollars. During this same time period, there was a 24% increase in spinal fusions for lumbar fractures, which was associated with a 15% increase in hospital charges. The ratio of spinal fusions to hospitalizations (surgical rate) during this period, however, was stable with an average of 7.4% over the 5-year period. There were an estimated 13,000 vertebral body augmentation procedures for nonpathological fractures performed in 2007 with a total national bill of 450 million US dollars. An increasing trend of hospitalizations, surgical treatment, and charges associated with lumbar spine fractures was observed between 2003 and 2007 on a national level. This trend, however, does not appear to be as steep as that of surgical utilization in degenerative spine disease. Furthermore, the ratio of spinal fusions to hospitalizations for lumbar fractures appears to be stable, possibly indicating no significant changes in indications for surgical intervention over the time period studied.


Monolithic and assembled polymer-ceramic composites for bone regeneration.
The rationale for the use of polymer-ceramic composites for bone regeneration stems from the natural composition of bone, with collagen type I and biological apatite as the main organic and inorganic constituents, respectively. In the present study composite materials of PolyActive™ (PA), a poly(ethylene oxide terephthalate)/poly(butylene terephtalate) co-polymer, and hydroxyapatite (HA) at a weight ratio of 85:15 were prepared by rapid prototyping (RP) using two routes. In the first approach pre-extruded composite filaments of PA-HA were processed using three-dimensional fibre deposition (3DF) (conventional composite scaffolds). In the second approach PA scaffolds were fabricated using 3DF and combined with HA pillars produced inside stereolithographic moulds that fitted inside the pores of the PA three-dimensional structure (assembled composite scaffolds). Analysis of calcium and phosphate release in a simulated physiological solution, not containing calcium or phosphate, revealed significantly higher values for the HA pillars compared with other scaffolds. Release in simulated body fluid saturated with respect to HA did not show significant differences among the different scaffolds. Human mesenchymal stromal cells were cultured on polymer (3DF), conventional composite (3DF-HA) and assembled composite (HA assembled in 3DF) scaffolds and assessed for morphology, metabolic activity, DNA amount and gene expression of osteogenic markers using real time quantitative polymerase chain reaction (PCR). Scanning electron microscopy images showed that the cells attached to and infiltrated all the scaffolds. Assembled composites had a higher metabolic activity compared with 3DF-HA scaffolds while no significant differences were observed in DNA amounts. Gene expression of osteopontin in the assembled composite was significantly higher compared with the conventional composites. The strategy of composite fabrication by assembly appears to be a promising alternative to the conventional composite fabrication route for scaffolds for bone regeneration.


Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjögren's syndrome and systemic lupus erythematosus.
To analyse B cell activating factor (BAFF) receptor (BAFF-R) expression on peripheral lymphocytes from patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells from 20 patients with pSS, 19 patients with SLE and 15 controls were examined by flow cytometry to investigate BAFF-R mean fluorescence intensity (MFI) on lymphocytes. BAFF-R mRNA level from isolated blood B cells of nine patients with pSS and eight controls was assessed by real-time quantitative reverse transcription-PCR. BAFF serum level was determined by ELISA. In all subjects, BAFF-R was expressed on all naïve CD27- and memory CD27+ B-cells and was present on <0.5% of T cells. The expression of BAFF-R on B cells was significantly decreased in patients with pSS as compared with controls (MFI = 7.8 vs 10.6, p = 0.001), and was intermediate in patients with SLE (MFI = 9.5). Serum BAFF level was inversely correlated with BAFF-R MFI (p = 0.007), but not because of competition between endogenous BAFF (at observed concentrations in patients) and the monoclonal antibody (11C1) detecting BAFF-R. BAFF-R mRNA levels did not differ between patients with pSS and controls (p = 0.48). BAFF-R MFI decreased after overnight culture with recombinant human BAFF (from 32.5 to 25.4, p = 0.03). Contrary to the serum BAFF level, BAFF-R expression was correlated with extraglandular involvement in pSS and SLE Disease Activity Index. BAFF-R expression is reduced on peripheral B cells of patients with pSS and SLE. This down-regulation occurs through a post-transcriptional mechanism and could be the consequence of chronic increase in BAFF. BAFF-R levels on B cells could be a novel activity biomarker in autoimmune diseases.


Effects of glucose-dependent insulinotropic polypeptide receptor knockout and a high-fat diet on cognitive function and hippocampal gene expression in mice.
It has been previously demonstrated that compromise of glucose-dependent insulinotropic polypeptide receptor (GIPR) action and chronic consumption of a high-fat diet can independently impair memory and learning ability, however, the underlying pathology remain to be elucidated. The present study investigated the effects of GIPR knockout (KO), alone and in combination with a high-fat diet, on aspects of cognitive function and hippocampal gene expression in mice. In object recognition tests, normal mice exhibited effective memory, preferring to investigate the novel over the familiar object. However, wild-type (WT) mice fed a high-fat diet and GIPR KO mice fed a standard or high-fat diet demonstrated no such discrimination, suggesting the impairment of memory function. This decline in cognitive function was associated with marked changes in the expression levels of hippocampal genes involved in memory and learning. The chronic consumption of a high-fat diet decreased the hippocampal gene expression levels of mammalian target of rapamycin (mTOR), neurotrophic tyrosine kinase receptor type 2 (NTRK2) and synaptophysin. Notably, the GIPR KO mice fed a high-fat diet exhibited no reduction in the hippocampal expression of synaptophysin expression, however, the GIPR KO mice fed a standard rodent maintenance diet exhibited reduced hippocampal expression of mTOR compared with the WT controls. These data highlighted the importance of intact GIPR signalling and dietary composition in modulating memory and learning, and hippocampal pathways involved in the maintenance of synaptic plasticity, including mTOR and NTRK2, appear to be key in this regard.


Scapular fixation in muscular dystrophy.
Winging of the scapula is caused by weakness of the thoracoscapular muscles, which allows the scapula to lift off the chest wall during shoulder movements. In facioscapulohumeral muscular dystrophy (and occasionally in other muscular dystrophies) there is selective weakness of the thoracoscapular muscles which may spare other shoulder muscles such as the deltoid muscle. This imbalance results in significant winging and loss of shoulder function. Historically, a number of different surgical and non-surgical interventions have been used to achieve scapular stability. This review examines the evidence available for the use of all scapular fixation techniques in muscular dystrophy, especially facioscapulohumeral muscular dystrophy. To examine the evidence for the relative efficacy of scapular fixation techniques in muscular dystrophy (especially facioscapulohumeral muscular dystrophy) in improving upper limb function. We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (20 July 2009), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009) Medline (1966 to July 2009) and EMBASE (1980 to July 2009) for randomised trials. We also contacted authors of trials and other experts in the field. All reports of scapular fixation for muscular dystrophy, including quasi-randomised or randomised controlled trials, comparing any form of scapular fixation (surgical and non-surgical) in people (of all ages and of all severity) with scapular winging due to muscular dystrophy. Our primary outcome measure was objective improvement in shoulder abduction. Our secondary outcome measures were: patient-perceived improvement in performance of activities of daily living, cosmetic results, subjective improvement in pain and proportion of patients with significant postoperative complications. We collated and summarised studies on the treatment of scapular winging in muscular dystrophy. No randomised trials were identified. We therefore present a review of the non-randomised literature available. There is no evidence from randomised trials to support the suggestion from observational studies that operative interventions produce significant benefits. However, these have to be balanced against postoperative immobilisation, need for physiotherapy and potential complications. We conclude that a randomised trial would be difficult, but a register of cases and the use of a standardised assessment protocol would allow more accurate comparison of the disparate techniques.


Circulating microRNA-214 and -126 as potential biomarkers for canine neoplastic disease.
Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human and canine species. We performed RT-qPCR to obtain the profiles of circulating plasma microRNA-214 and -126 in total 181 cases of canine neoplastic diseases and healthy controls. MicroRNA-214 levels were high in 2 epithelial tumours (thyroid and mammary carcinomas) and 4 non-epithelial tumours (osteosarcoma, histiocytic sarcoma, chondrosarcoma, and hemangiosarcoma). In contrast, microRNA-126 levels were high in 6 epithelial tumours (mammary, hepatocellular, squamous cell, thyroid, transitional cell carcinomas, and adenocarcinoma) and 4 non-epithelial tumours (osteosarcoma, mast cell tumour, melanoma, and hemangiosarcoma). The diagnostic potential of microRNA-214 was relatively high in sarcomas, whereas that of microR-126 was high in most types of the tumours. MicroRNA-214 and -126 were prognostic predictors in 2 groups (adenocarcinoma and non-epithelial tumours except for osteosarcoma) and 3 groups (epithelial tumours, adenocarcinoma, and melanoma), respectively. Additionally, the microRNA levels did not show a strong correlation with the other clinical parameters. In conclusion, circulating microRNA-214 and -126 have the potential to be diagnostic and prognostic biomarkers for canine neoplastic diseases. Furthermore, their profiles may be key references as well for exploring novel biomarkers for human cancers.


A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.
Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).


Lanthanum from a modified clay used in eutrophication control is bioavailable to the marbled crayfish (Procambarus fallax f. virginalis).
To mitigate eutrophication in fresh standing waters the focus is on phosphorus (P) control, i.e. on P inflows to a lake as well as a lake's sediment as internal P source. The in-lake application of the lanthanum (La) modified clays - i.e. La modified bentonite (Phoslock) or La modified kaolinite, aim at dephosphatising the water column and at reducing the release of P from a lake's sediment. Application of these clays raises the question whether La from these clays can become bioavailable to biota. We investigated the bioavailability of La from Phoslock in a controlled parallel groups experiment in which we measured the La in carapace, gills, ovaries, hepatopancreas and abdominal muscle after 0, 14 and 28 days of exposure to Phoslock. Expressing the treatment effect as the difference of the median concentration between the two treatment groups (Phoslock minus control group) yield the following effects, the plus sign (+) indicating an increase, concentrations in µg g(-1) dry weight: Day 14: carapace +10.5 µg g(-1), gills +112 µg g(-1), ovaries +2.6 µg g(-1), hepatopancreas +32.9 µg g(-1) and abodminal muscle +3.2 µg g(-1). Day 28: carapace +17.9 µg g(-1); gills +182 µg g(-1); ovaries +2.2 µg g(-1); hepatopancreas +41.9 µg g(-1) and abdominal muscle +7.6 µg g(-1), all effects were statistically significant. As La from Phoslock is bio-available to and taken up by the marbled crayfishes (Procambarus fallax f. virginalis), we advocate that the application of in-lake chemical water treatments to mitigate eutrophication should be accompanied by a thorough study on potential side effects.


Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature.
Forces generated by blood flow are known to contribute to cardiovascular development and remodeling. These hemodynamic forces induce molecular signals that are communicated from the endothelium to various cell types. The cardiovascular system consists of the heart and the vasculature, and together they deliver nutrients throughout the body. While heart valves and blood vessels experience different environmental forces and differ in morphology as well as cell types, they both can undergo pathological remodeling and become susceptible to calcification. In addition, while the plaque morphology is similar in valvular and vascular diseases, therapeutic targets available for the latter condition are not effective in the management of heart valve calcification. Therefore, research in valvular and vascular pathologies and treatments have largely remained independent. Nonetheless, understanding the similarities and differences in development, calcific/fibrous pathologies and healthy remodeling events between the valvular and vascular systems can help us better identify future treatments for both types of tissues, particularly for heart valve pathologies which have been understudied in comparison to arterial diseases.


Task-dependent variations in parkinsonian motor impairments.
Studies of visually-guided arm movements in patients with Parkinson's disease (PD) have suggested a relationship between slowness of movement and a reduction in the ratio of movement amplitude and peak velocity. Recent studies indicate, however, that PD impairments may be different for well-learned, natural movements performed without visual guidance, or movements associated with sequential motor behaviours such as speech. To address this issue, PD subjects and age/sex-matched controls were compared on the performance of three tasks, all of which required lowering the jaw: (1) single, rapid, visually-guided movements; (2) equivalent movements associated with a single speech syllable (inherently without visual guidance), and (3) well-learned speech movements produced in a natural sequence. PD subjects manifested similar deficits for visually-guided jaw lowering as those previously reported for arm movements, namely reduced velocity/amplitude ratios and increased movement durations. By contrast, analogous jaw movements during the sequential speech tasks were unimpaired on these measures. These results suggest that PD motor impairments are influenced by a variety of factors, including the degree to which tasks are familiar and natural, and the availability of visual information.


Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review.
In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.


Source identification and assessment of sediment contamination of trace metals in Kogarah Bay, NSW, Australia.
The distribution of trace metals (spatial and temporal) and sedimentary fractions were investigated to identify the concentrations and sources of trace metals within Kogarah Bay, NSW, Australia. A total of 59 surface sediments and six subsurface samples from core of the sediment were collected. The contamination factor and pollution load index indices used to evaluate environmental effects of trace metals. The study area was found to be uncontaminated with Cr and Ni, moderately contaminated with As and considerably contaminated with Cu, Zn and Pb. The concentrations of Cr and Ni were below both effect range low and effect range median, while As, Cu, Zn and Pb were slightly above effect range low. The highest concentrations of these trace metals such as Cu, Zn and Pb were found in the north, northwest and southeast of the bay, close to discharge points, stormwater outlets and around boatyards and watercrafts. The spatial distributions of metals were strongly related to muddy particles and organic matter. The temporal sediments of metals declined with increased sediment depth, which reflects accumulation of trace metals since European settlement in this area. Furthermore, the source of the trace metals was found to be stormwater outlets, gasoline fumes, boatyards and other human activities.


Challenges and insights in implementing coordinated care between oncology and primary care providers: a Canadian perspective.
We report here on the current state of cancer care coordination in Canada and discuss challenges and insights with respect to the implementation of collaborative models of care. We also make recommendations for future research. This work is based on the findings of the Canadian Team to Improve Community-Based Cancer Care Along the Continuum (canimpact) casebook project. The casebook project identified models of collaborative cancer care by systematically documenting and analyzing Canadian initiatives that aim to improve or enhance care coordination between primary care providers and oncology specialists. The casebook profiles 24 initiatives, most of which focus on breast or colorectal cancer and target survivorship or follow-up care. Current key challenges in cancer care coordination are associated with establishing program support, engaging primary care providers in the provision of care, clearly defining provider roles and responsibilities, and establishing effective project or program planning and evaluation. Researchers studying coordinated models of cancer care should focus on designing knowledge translation strategies with updated and refined governance and on establishing appropriate protocols for both implementation and evaluation.


Pollinator Behavior Drives Sexual Specializations in the Hermaphrodite Flowers of a Heterodichogamous Tree.
Dioecy, the specialization of individuals into either male-only or female-only sexual function, has multiple evolutionary origins in plants. One proposed ancestral mating system is heterodichogamy, two morphs of cross-fertilizing hermaphrodite flowers that differ in their timing of flowering. Previous research suggested that small specializations in these morphs' functional genders could facilitate their evolution into separate sexes. We tested the possible role of pollinators in driving such specializations. Ziziphus spina-christi is an insect-pollinated heterodichogamous tree with self-incompatible flowers and two sympatric flowering morphs. We compared the flower development patterns, floral food rewards, pollinator visits, and fruit production between the two morphs. Male-phase flowers of Z. spina-christi's "Early" and "Late" morphs open before dawn and around noon, respectively, and transition into female-phase 7-8 h later. Flowers of both morphs contain similar nectar and pollen rewards, and receive visits by flies (their ancestral pollinators) at similar rates, mostly during the morning. Consequently, the Early morph functions largely as pollen donor. The Late morph, functioning as female in the morning, produces more fruit. We developed an evolutionary probabilistic model, inspired by Z. spina-christi's reproductive system, to test whether pollinator visit patterns could potentially play a role in an evolutionary transition from heterodichogamy towards dioecy. The model predicts that reproductive incompatibility within flowering morphs promotes their evolution into different sexes. Furthermore, the pollinators' morning activity drives the Early and Late morphs' specialization into male and female functions, respectively. Thus, while not required for transitioning from heterodichogamy to dioecy, pollinator-mediated selection is expected to influence which sexual specialization evolves in each of the flowering morphs.


Molecular self-assembly at bare semiconductor surfaces: cooperative substrate-molecule effects in octadecanethiolate monolayer assemblies on GaAs(111), (110), and (100).
The structures of self-assembled monolayers formed by chemisorption of octadecanethiol onto the surfaces of GaAs(001), (110), (111-A)-Ga, and (111-B)-As have been characterized in detail by a combination of X-ray photoelectron, near-edge X-ray absorption fine structure, and infrared spectroscopies and grazing incidence X-ray diffraction. In all cases, the molecular lattices are ordered with hexagonal symmetry, even for the square and rectangular intrinsic substrate (001) and (110) lattices, and the adsorbate lattice spacings are all incommensurate with their respective intrinsic substrate lattices. These results definitively show that the monolayer organization is driven by intermolecular packing forces to assemble in a hexagonal motif, such as would occur in the approach to a limit for an energetically featureless surface. The accompanying introduction of strain into the soft substrate surface lattice via strong S substrate bonds forces the soft substrate lattice to compliantly respond, introducing quasi-2D strain. A notably poorer organization for the (111-A)-Ga case compared to the (111-B)-As and other faces indicates that that the Ga-terminated surface lattice is more resistant to adsorbate packing-induced stress. Overall, the results show that surface molecular self-assembly must be considered as a strongly cooperative process between the substrate surface and the adsorbate and that inorganic substrate surfaces should not be considered as necessarily rigid when strong intermolecular adsorbate packing forces are operative.


Nods and 'intracellular' innate immunity.
Innate immunity relies on the detection of microbial invaders by two distinct systems. One system comprises a family of membrane-bound receptors, termed the Toll-like receptors, while the other family, termed the nucleotide-binding site/leucine-rich repeat (NBS/LRR) proteins, consists of molecules that are found in the cytoplasmic compartment. These two detection systems recognize conserved molecular components of microbes including such structural motifs as lipopolysaccharide from the Gram-negative bacterial cell wall and peptidoglycan (PGN) found in the cell wall of both Gram-negative and Gram-positive bacteria. This review focuses on two members of the NBS/LRR family of proteins, Nod1 and Nod2. Recently, the microbial motifs sensed by these two molecules have been characterized. Both Nod1 and Nod2 recognize PGN, however, each requires distinct molecular motifs to attain sensing. Nod1 recognizes a naturally occurring muropeptide of PGN that presents a unique amino acid at its terminus called diaminopilemic acid (DAP). This amino acid is found mainly in the PGN of Gram-negative bacteria designating Nodl as a sensor of Gram-negative bacteria. In contrast, Nod2 can detect the minimal bioactive fragment of PGN, called muramyl dipeptide. Thus Nod2 is a general sensor of bacterial PGN. Since mutations in the gene encoding Nod2 were recently shown to be associated with the chronic inflammatory disease, Crohn's disease, these results are discussed in the context of how disrupting the interplay between host detection and bacterial aggression may lead to inflammatory diseases.


Large historical growth in global terrestrial gross primary production.
Growth in terrestrial gross primary production (GPP)-the amount of carbon dioxide that is 'fixed' into organic material through the photosynthesis of land plants-may provide a negative feedback for climate change. It remains uncertain, however, to what extent biogeochemical processes can suppress global GPP growth. As a consequence, modelling estimates of terrestrial carbon storage, and of feedbacks between the carbon cycle and climate, remain poorly constrained. Here we present a global, measurement-based estimate of GPP growth during the twentieth century that is based on long-term atmospheric carbonyl sulfide (COS) records, derived from ice-core, firn and ambient air samples. We interpret these records using a model that simulates changes in COS concentration according to changes in its sources and sinks-including a large sink that is related to GPP. We find that the observation-based COS record is most consistent with simulations of climate and the carbon cycle that assume large GPP growth during the twentieth century (31% ± 5% growth; mean ± 95% confidence interval). Although this COS analysis does not directly constrain models of future GPP growth, it does provide a global-scale benchmark for historical carbon-cycle simulations.


Determination of protein deposits on RGP lenses by X-ray photoelectron spectroscopy.
To establish a novel and objective screening method for evaluating the cleaning efficacy of contact lens care solutions for removal of protein deposits on single rigid gas permeable (RGP) lenses. New and unworn RGP lenses containing no nitrogen atoms were incubated in a standard tear protein test solution. Protein deposition on lenses was determined by X-ray photoelectron spectroscopy (XPS) before and after standardized cleaning with commercially available care solutions (daily cleaners A, B) and a wetting/soaking solution or with 0.1w/v% sodium dodecyl sulfate (SDS) as a control. Cleaning efficacy was calculated based on the percentage of nitrogen atoms present in the total elements of the measured XPS scan spectrum. Nitrogen atoms originating from residual protein deposits on RGP lenses after cleaning were determined by XPS. The cleaning efficacy of the wetting/soaking solution was lower (74%) than that of daily cleaners A and B (95%) or SDS (96%) controls. XPS determination of residual protein deposits is a novel and direct evaluation method for determining the cleaning efficacy of RGP lens care solutions for single lenses.


Risk of Carotid Stroke after Chiropractic Care: A Population-Based Case-Crossover Study.
Chiropractic manipulation is a popular treatment for neck pain and headache, but may increase the risk of cervical artery dissection and stroke. Patients with carotid artery dissection can present with neck pain and/or headache before experiencing a stroke. These are common symptoms seen by both chiropractors and primary care physicians (PCPs). We aimed to assess the risk of carotid artery stroke after chiropractic care by comparing association between chiropractic and PCP visits and subsequent stroke. A population-based, case-crossover study was undertaken in Ontario, Canada. All incident cases of carotid artery stroke admitted to hospitals over a 9-year period were identified. Cases served as their own controls. Exposures to chiropractic and PCP services were determined from health billing records. We compared 15,523 cases to 62,092 control periods using exposure windows of 1, 3, 7, and 14 days prior to the stroke. Positive associations were found for both chiropractic and PCP visits and subsequent stroke in patients less than 45 years of age. These associations tended to increase when analyses were limited to visits for neck pain and headache-related diagnoses. There was no significant difference between chiropractic and PCP risk estimates. We found no association between chiropractic visits and stroke in those 45 years of age or older. We found no excess risk of carotid artery stroke after chiropractic care. Associations between chiropractic and PCP visits and stroke were similar and likely due to patients with early dissection-related symptoms seeking care prior to developing their strokes.


Reducing Medication Costs to Prevent Cardiovascular Disease: A Community Guide Systematic Review.
Hypertension and hyperlipidemia are major cardiovascular disease risk factors. To modify them, patients often need to adopt healthier lifestyles and adhere to prescribed medications. However, patients' adherence to recommended treatments has been suboptimal. Reducing out-of-pocket costs (ROPC) to patients may improve medication adherence and consequently improve health outcomes. This Community Guide systematic review examined the effectiveness of ROPC for medications prescribed for patients with hypertension and hyperlipidemia. We assessed effectiveness and economics of ROPC for medications to treat hypertension, hyperlipidemia, or both. Per Community Guide review methods, reviewers identified, evaluated, and summarized available evidence published from January 1980 through July 2015. Eighteen studies were included in the analysis. ROPC interventions resulted in increased medication adherence for patients taking blood pressure and cholesterol medications by a median of 3.0 percentage points; proportion achieving 80% adherence to medication increased by 5.1 percentage points. Blood pressure and cholesterol outcomes also improved. Nine studies were included in the economic review, with a median intervention cost of $172 per person per year and a median change in health care cost of -$127 per person per year. ROPC for medications to treat hypertension and hyperlipidemia is effective in increasing medication adherence, and, thus, improving blood pressure and cholesterol outcomes. Most ROPC interventions are implemented in combination with evidence-based health care interventions such as team-based care with medication counseling. An overall conclusion about the economics of the intervention could not be reached with the small body of inconsistent cost-benefit evidence.


Cancer stem cells: at the headwaters of tumor development.
According to the cancer stem cell hypothesis, only a subpopulation of cells within a cancer has the capacity to sustain tumor growth. This subpopulation of cells is made up of cancer stem cells, which are defined simply as the population of cells within a tumor that can self-renew, differentiate, and regenerate a phenocopy of the cancer when injected in vivo. Cancer stem cells have now been prospectively isolated from human cancers of the blood, breast, and brain, and putative cancer stem cells have been identified from human skin, bone, and prostate tumors and from multiple established mammalian cancer cell lines. Furthermore, researchers are actively seeking cancer stem cells in every human cancer type. We present the current scientific evidence supporting the cancer stem cell hypothesis and discuss the experimental and therapeutic implications of the discovery of human cancer stem cells.


Quantifying Possible Routes for SpnF-Catalyzed Formal Diels-Alder Cycloaddition.
The Diels-Alder reaction is a cornerstone of modern organic synthesis. Despite this, it remains essentially inaccessible to biosynthetic approaches. Only a few natural enzymes catalyze even a formal [4 + 2] cycloaddition, and it remains uncertain if any of them proceed via the Diels-Alder mechanism. In this study, we focus on the [4 + 2] cycloaddition step in the biosynthesis of spinosyn A, a reaction catalyzed by SpnF enzyme, one of the most promising "true Diels-Alderase" candidates. The four currently proposed mechanisms (including the Diels-Alder one) for this reaction in water (as a first-order approximation of the enzymatic reaction) are evaluated by an exhaustive quantum mechanical search for possible transition states (728 were found in total). We find that the line between the recently proposed bis-pericyclic [J. Am. Chem. Soc. 2016, 138 (11), 3631] and Diels-Alder routes is blurred, and favorable transition states of both types may coexist. Application of the Curtin-Hammett principle, however, reveals that the bis-pericyclic mechanism accounts for ∼83% of the reaction flow in water, while the classical Diels-Alder mechanism contributes only ∼17%. The current findings provide a route for modeling this reaction inside the SpnF active site and inferring the catalytic architecture of possible Diels-Alderases.


Production of 3-O-xylosyl quercetin in Escherichia coli.
Quercetin, a flavonol aglycone, is one of the most abundant flavonoids with high medicinal value. The bioavailability and pharmacokinetic properties of quercetin are influenced by the type of sugars attached to the molecule. To efficiently diversify the therapeutic uses of quercetin, Escherichia coli was harnessed as a production factory by the installation of various plant and bacterial UDP-xylose sugar biosynthetic genes. The genes encoding for the UDP-xylose pathway enzymes phosphoglucomutase (nfa44530), glucose-1-phosphate uridylyltransferase (galU), UDP-glucose dehydrogenase (calS8), and UDP-glucuronic acid decarboxylase (calS9) were overexpressed in E. coli BL21 (DE3) along with a glycosyltransferase (arGt-3) from Arabidopsis thaliana. Furthermore, E. coli BL21(DE3)/∆pgi, E. coli BL21(DE3)/∆zwf, E. coli BL21(DE3)/∆pgi∆zwf, and E. coli BL21(DE3)/∆pgi∆zwf∆ushA mutants carrying the aforementioned UDP-xylose sugar biosynthetic genes and glycosyltransferase and the galU-integrated E. coli BL21(DE3)/∆pgi host harboring only calS8, calS9, and arGt-3 were constructed to enhance whole-cell bioconversion of exogeneously supplied quercetin into 3-O-xylosyl quercetin. Here, we report the highest production of 3-O-xylosyl quercetin with E. coli BL21 (DE3)/∆pgi∆zwf∆ushA carrying UDP-xylose sugar biosynthetic genes and glycosyltransferase. The maximum concentration of 3-O-xylosyl quercetin achieved was 23.78 mg/L (54.75 μM), representing 54.75 % bioconversion, which was an ~4.8-fold higher bioconversion than that shown by E. coli BL21 (DE3) with the same set of genes when the reaction was carried out in 5-mL culture tubes with 100 μM quercetin under optimized conditions. Bioconversion was further improved by 98 % when the reaction was scaled up in a 3-L fermentor at 36 h.


Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization.
The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.


Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes.
Ubiquitin (Ub) and ubiquitin-like proteins (Ubls) are conjugated to their targets by specific cascades involving three classes of enzymes, E1, E2, and E3. Each E1 adenylates the C terminus of its cognate Ubl, forms a E1 approximately Ubl thioester intermediate, and ultimately generates a thioester-linked E2 approximately Ubl product. We have determined the crystal structure of yeast Uba1, revealing a modular architecture with individual domains primarily mediating these specific activities. The negatively charged C-terminal ubiquitin-fold domain (UFD) is primed for binding of E2s and recognizes their positively charged first alpha helix via electrostatic interactions. In addition, a mobile loop from the domain harboring the E1 catalytic cysteine contributes to E2 binding. Significant, experimentally observed motions in the UFD around a hinge in the linker connecting this domain to the rest of the enzyme suggest a conformation-dependent mechanism for the transthioesterification function of Uba1; however, this mechanism clearly differs from that of other E1 enzymes.


Magnetic orientation and navigation in marine turtles, lobsters, and molluscs: concepts and conundrums.
The Earth's magnetic field provides a pervasive source of directional information used by phylogenetically diverse marine animals. Behavioral experiments with sea turtles, spiny lobsters, and sea slugs have revealed that all have a magnetic compass sense, despite vast differences in the environment each inhabits and the spatial scale over which each moves. For two of these animals, the Earth's field also serves as a source of positional information. Hatchling loggerhead sea turtles from Florida responded to the magnetic fields found in three widely separated regions of the Atlantic Ocean by swimming in directions that would, in each case, facilitate movement along the migratory route. Thus, for young loggerheads, regional magnetic fields function as navigational markers and elicit changes in swimming direction at crucial geographic boundaries. Older turtles, as well as spiny lobsters, apparently acquire a "magnetic map" that enables them to use magnetic topography to determine their position relative to specific goals. Relatively little is known about the neural mechanisms that underlie magnetic orientation and navigation. A promising model system is the marine mollusc Tritonia diomedea, which possesses both a magnetic compass and a relatively simple nervous system. Six neurons in the brain of T. diomedea have been identified that respond to changes in magnetic fields. At least some of these appear to be ciliary motor neurons that generate or modulate the final behavioral output of the orientation circuitry. These findings represent an encouraging step toward a holistic understanding of the cells and circuitry that underlie magnetic orientation behavior in one model organism.


Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS.
To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety. Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions. In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup (p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning (r = -0.950, p = 0.001) and memory (r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex. In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations.


Thoughts on the development, structure and evolution of the mammalian and avian telencephalic pallium.
Various lines of evidence suggest that the development and evolution of the mammalian isocortex cannot be easily explained without an understanding of correlative changes in surrounding areas of the telencephalic pallium and subpallium. These are close neighbours in a common morphogenetic field and are postulated as sources of some cortical neuron types (and even of whole cortical areas). There is equal need to explain relevant developmental evolutionary changes in the dorsal thalamus, the major source of afferent inputs to the telencephalon (to both the pallium and subpallium). The mammalian isocortex evolved within an initially small dorsal part of the pallium of vertebrates, surrounded by other pallial parts, including some with a non-cortical, nuclear structure. Nuclear pallial elements are markedly voluminous in reptiles and birds, where they build the dorsal ventricular ridge, or hypopallium, which has been recently divided molecularly and structurally into a lateral pallium and a ventral pallium. Afferent pallial connections are often simplified as consisting of thalamic fibres that project either to focal cell aggregates in the ventral pallium (predominant in reptiles and birds) or to corticoid areas in the dorsal pallium (predominant in mammals). Karten's hypothesis, put forward in 1969, on the formation of some isocortical areas postulates an embryonic translocation into the nascent isocortex of the ventropallial thalamorecipient foci and respective downstream ventropallial target populations, as specific layer IV, layers II- III, or layers V-VI neuron populations. This view is considered critically in the light of various recent data, contrasting with the alternative possibility of a parallel, separate evolution of the different pallial parts. The new scenario reveals as well a separately evolving tiered structure of the dorsal thalamus, some of whose parts receive input from midbrain sensory centres (collothalamic nuclei), whereas other parts receive oligosynaptic 'lemniscal' connections bypassing the midbrain (lemnothalamic nuclei). An ampler look into known hodological patterns from this viewpoint suggests that ancient collothalamic pathways, which target ventropallial foci, are largely conserved in mammals, while some emergent cortical connections can be established by means of new collaterals in some of these pathways. The lemnothalamic pathways, which typically target ancestrally the dorsopallial isocortex, show parallel increments of relative size and structural diversification of both the thalamic cell populations and the cortical recipient areas. The evolving lemnothalamic pathways may interact developmentally with collothalamic corticopetal collaterals in the modality-specific invasion of the emergent new areas of isocortex.


Acute effects of physical exercise in type 2 diabetes: A review.
The literature has shown the efficiency of exercise in the control of type 2 diabetes (T2D), being suggested as one of the best kinds of non-pharmacological treatments for its population. Thus, the scientific production related to this phenomenon has growing exponentially. However, despite its advances, still there is a lack of studies that have carried out a review on the acute effects of physical exercise on metabolic and hemodynamic markers and possible control mechanisms of these indicators in individuals with T2D, not to mention that in a related way, these themes have been very little studied today. Therefore, the aim of this study was to organize and analyze the current scientific production about the acute effects of physical exercise on metabolic and hemodynamic markers and possible control mechanisms of these indicators in T2D individuals. For such, a research with the following keywords was performed: -exercise; diabetes and post-exercise hypotension; diabetes and excess post-exercise oxygen consumption; diabetes and acute effects in PUBMED, SCIELO and HIGHWIRE databases. From the analyzed studies, it is possible to conclude that, a single exercise session can promote an increase in the bioavailability of nitric oxide and elicit decreases in postexercise blood pressure. Furthermore, the metabolic stress from physical exercise can increase the oxidation of carbohydrate during the exercise and keep it, in high levels, the post exercise consumption of O², this phenomenon increases the rate of fat oxidation during recovery periods after exercise, improves glucose tolerance and insulin sensitivity and reduces glycemia between 2-72 h, which seems to be dependent on the exercise intensity and duration of the effort.


Genetic diversity of peanut (Arachis hypogaea L.) and its wild relatives based on the analysis of hypervariable regions of the genome.
The genus Arachis is native to a region that includes Central Brazil and neighboring countries. Little is known about the genetic variability of the Brazilian cultivated peanut (Arachis hypogaea, genome AABB) germplasm collection at the DNA level. The understanding of the genetic diversity of cultivated and wild species of peanut (Arachis spp.) is essential to develop strategies of collection, conservation and use of the germplasm in variety development. The identity of the ancestor progenitor species of cultivated peanut has also been of great interest. Several species have been suggested as putative AA and BB genome donors to allotetraploid A. hypogaea. Microsatellite or SSR (Simple Sequence Repeat) markers are co-dominant, multiallelic, and highly polymorphic genetic markers, appropriate for genetic diversity studies. Microsatellite markers may also, to some extent, support phylogenetic inferences. Here we report the use of a set of microsatellite markers, including newly developed ones, for phylogenetic inferences and the analysis of genetic variation of accessions of A. hypogea and its wild relatives. A total of 67 new microsatellite markers (mainly TTG motif) were developed for Arachis. Only three of these markers, however, were polymorphic in cultivated peanut. These three new markers plus five other markers characterized previously were evaluated for number of alleles per locus and gene diversity using 60 accessions of A. hypogaea. Genetic relationships among these 60 accessions and a sample of 36 wild accessions representative of section Arachis were estimated using allelic variation observed in a selected set of 12 SSR markers. Results showed that the Brazilian peanut germplasm collection has considerable levels of genetic diversity detected by SSR markers. Similarity groups for A. hypogaea accessions were established, which is a useful criteria for selecting parental plants for crop improvement. Microsatellite marker transferability was up to 76% for species of the section Arachis, but only 45% for species from the other eight Arachis sections tested. A new marker (Ah-041) presented a 100% transferability and could be used to classify the peanut accessions in AA and non-AA genome carriers. The level of polymorphism observed among accessions of A. hypogaea analyzed with newly developed microsatellite markers was low, corroborating the accumulated data which show that cultivated peanut presents a relatively reduced variation at the DNA level. A selected panel of SSR markers allowed the classification of A. hypogaea accessions into two major groups. The identification of similarity groups will be useful for the selection of parental plants to be used in breeding programs. Marker transferability is relatively high between accessions of section Arachis. The possibility of using microsatellite markers developed for one species in genetic evaluation of other species greatly reduces the cost of the analysis, since the development of microsatellite markers is still expensive and time consuming. The SSR markers developed in this study could be very useful for genetic analysis of wild species of Arachis, including comparative genome mapping, population genetic structure and phylogenetic inferences among species.


A Large-Scale Comparative Metagenomic Study Reveals the Functional Interactions in Six Bloom-Forming Microcystis-Epibiont Communities.
Cyanobacterial blooms are worldwide issues of societal concern and scientific interest. Lake Taihu and Lake Dianchi, two of the largest lakes in China, have been suffering from annual Microcystis-based blooms over the past two decades. These two eutrophic lakes differ in both nutrient load and environmental parameters, where Microcystis microbiota consisting of different Microcystis morphospecies and associated bacteria (epibionts) have dominated. We conducted a comprehensive metagenomic study that analyzed species diversity, community structure, functional components, metabolic pathways and networks to investigate functional interactions among the members of six Microcystis-epibiont communities in these two lakes. Our integrated metagenomic pipeline consisted of efficient assembly, binning, annotation, and quality assurance methods that ensured high-quality genome reconstruction. This study provides a total of 68 reconstructed genomes including six complete Microcystis genomes and 28 high quality bacterial genomes of epibionts belonging to 14 distinct taxa. This metagenomic dataset constitutes the largest reference genome catalog available for genome-centric studies of the Microcystis microbiome. Epibiont community composition appears to be dynamic rather than fixed, and the functional profiles of communities were related to the environment of origin. This study demonstrates mutualistic interactions between Microcystis and epibionts at genetic and metabolic levels. Metabolic pathway reconstruction provided evidence for functional complementation in nitrogen and sulfur cycles, fatty acid catabolism, vitamin synthesis, and aromatic compound degradation among community members. Thus, bacterial social interactions within Microcystis-epibiont communities not only shape species composition, but also stabilize the communities functional profiles. These interactions appear to play an important role in environmental adaptation of Microcystis colonies.


Endometrial hyperplasia and apoptosis following neonatal diethylstilbestrol exposure and subsequent estrogen stimulation in both host and transplanted hamster uteri.
Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes morphogenetic alterations and neoplasia in the human reproductive tract. In the hamster, neonatal DES exposure alters early uterine morphogenesis and induces endometrial adenocarcinomas in adults. We now demonstrate that the preneoplastic stages of this phenomenon in the hamster reflect an abnormal uterotropic response to estrogen that is characterized by hyperplastic lesions in the endometrial epithelium and includes an immune and/or inflammatory component. Interestingly, biochemical and in situ analysis revealed that the hyperplastic epithelium is also an active site of cell death by apoptosis. To further probe the mechanism of this phenomenon, uteri from 7-day-old control or DES-exposed donors were transplanted into the cheek pouches of control or neonatally DES-exposed adult hosts, and both host groups were treated to provide high circulating levels of estradiol. Among the four ectopic scenarios, histopathological lesions (epithelial hyperplasia, dysplasia, and apoptosis), segregated almost exclusively to the two that consisted of neonatally DES-exposed uteri. The virtual absence of lesions in control uteri transplanted to DES hosts eliminated host systemic factors as causative agents. Therefore, we conclude that DES or its metabolites alter the cellular physiology and/or composition of the developing uterus (initiating event) in such a way that it thereafter responds abnormally to estrogenic stimulation (promoting event). These observations serve to further define a unique experimental system for probing: (a) various aspects of the clinical "DES Syndrome"; (b) how estrogen regulates normal uterine growth and morphogenesis; and (c) how this process can degenerate to the unregulated neoplastic state.


A Meta-Analysis of Universal School-Based Prevention Programs for Anxiety and Depression in Children.
Anxiety and depression are among the most common mental health issues experienced in childhood. Implementing school-based prevention programs during childhood, rather than adolescence, is thought to provide better mental health outcomes. The present meta-analysis aimed to investigate the efficacy of universal school-based prevention programs that target both anxiety and depression in children (aged 13 years or below), and examine three moderators (i.e., program type, primary target of program, and number of sessions) on prevention effects. PsycINFO, PubMED, and Google Scholar were systematically searched for relevant articles published up to and including January 2018. Fourteen randomised controlled trials, consisting of 5970 children, met eligibility criteria. Prevention programs led to significantly fewer depressive symptoms at post-program (g = 0.172) and at long-term follow-up periods (g = 0.180), but not at short-term follow-up. Programs were not found to prevent anxiety symptoms across any time point. Considerable heterogeneity was observed for all effects. Program type and length were found to moderate the relationship between prevention program and outcomes. Prevention programs were effective in preventing depressive symptoms at post-program and long-term follow-up, while no significant preventative effect on anxiety symptoms was observed. The FRIENDS Program and programs which contained a greater number of sessions showed beneficial effects on anxiety and depressive symptoms. Universal programs aimed at preventing both anxiety and depression in children are limited. Future research should investigate the long-term evaluation of school-based prevention programs for anxiety and depression in children.


Translational challenges of animal models in Chagas disease drug development: a review.
Chagas disease, or American trypanosomiasis, caused by Trypanosoma cruzi parasite infection is endemic in Latin America and presents an increasing clinical challenge due to migrating populations. Despite being first identified over a century ago, only two drugs are available for its treatment, and recent outcomes from the first clinical trials in 40 years were lackluster. There is a critical need to develop new drugs to treat Chagas disease. This requires a better understanding of the progression of parasite infection, and standardization of animal models designed for Chagas disease drug discovery. Such measures would improve comparison of generated data and the predictability of test hypotheses and models designed for translation to human disease. Existing animal models address both disease pathology and treatment efficacy. Available models have limited predictive value for the preclinical evaluation of novel therapies and need to more confidently predict the efficacy of new drug candidates in clinical trials. This review highlights the overall lack of standardized methodology and assessment tools, which has hampered the development of efficacious compounds to treat Chagas disease. We provide an overview of animal models for Chagas disease, and propose steps that could be undertaken to reduce variability and improve predictability of drug candidate efficacy. New technological developments and tools may contribute to a much needed boost in the drug discovery process.


Performance of BRCA1/2 mutation prediction models in Asian Americans.
There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II. We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model. BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers. Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.


Developmental trajectory of purpose identification during adolescence: Links to life satisfaction and depressive symptoms.
Whereas evidence has shown that a sense of purpose is linked to optimal adjustment, longitudinal work investigating the development of purpose identification as well as its effect on psychological functioning among non-Western samples during adolescence is needed. Three hundred and eighty-seven senior high school students (253 female, 65.37%; mean age = 15.76 years at the first investigation) from Taiwan completed surveys four times beginning in the fall of tenth grade and ending in the spring of eleventh grade with a six-month interval. Using self-ratings, purpose identification was evaluated in all four assessments and psychological functioning was examined through life satisfaction and depressive symptoms in the first and the last survey. Growth curve analyses revealed an increased slope in purpose identification over the first two years of high school, and such a trajectory was similar across boys and girls. Additionally, increases in purpose identification predicted enhanced life satisfaction and reduced depressive symptoms among both boys and girls. There was only one gender difference: The negative association between purpose identification trajectory and depressive symptoms was stronger for girls than for boys. There is an increase in the development of identified purpose during middle adolescence among high school students in Taiwan. Such change not only promotes life satisfaction in adolescents but is also preventive of adolescent depression. As such, the current findings highlight the significance for adolescents to discover and commit to a purpose.


Retrieving radius, concentration, optical depth, and mass of different types of aerosols from high-resolution infrared nadir spectra.
We present a sophisticated radiative transfer code for modeling outgoing IR radiation from planetary atmospheres and, conversely, for retrieving atmospheric properties from high-resolution nadir-observed spectra. The forward model is built around a doubling-adding routine and calculates, in a spherical refractive geometry, the outgoing radiation emitted by the Earth and the atmosphere containing one layer of aerosol. The inverse model uses an optimal estimation approach and can simultaneously retrieve atmospheric trace gases, aerosol effective radius, and concentration. It is different from existing codes, as most forward codes dealing with multiple scattering assume a plane-parallel atmosphere, and as for the retrieval, it does not rely on precalculated spectra, the use of microwindows, or two-step retrievals. The simultaneous retrieval on a broad spectral range exploits the full potential of current state-of-the-art hyperspectral IR sounders, such as AIRS and IASI, and should be particularly useful in studying major pollution events. We present five example retrievals of IASI spectra observed in the range from 800 to 1200 cm(-1) above dust, volcanic ash, sulfuric acid, ice particles, and biomass burning aerosols.


Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome.
Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.


Right phrenic nerve injury in orthotopic liver transplantation.
Right hemidiaphragm paralysis has been previously documented in patients after orthotopic liver transplantation (OLT) and it may contribute to the development of postoperative pulmonary problems. It has been postulated that a crush injury to the right phrenic nerve during OLT is the cause of dysfunction of the right hemidiaphragm. To assess the incidence and effect of right phrenic nerve injury after OLT, we prospectively studied 48 adult liver recipients. Twelve patients who underwent liver resection (LR), in whom the suprahepatic vena cava was not clamped, were used as a comparison group. Diaphragm excursion by ultrasound and pulmonary function were performed preoperatively and postoperatively; transcutaneous phrenic nerve conduction studies were performed postoperatively. Right phrenic nerve injury and hemidiaphragm paralysis occurred in 79% and 38% of the liver recipients but not after LR. Conduction along the right phrenic nerve was absent in 53% and reduced in another 26%. Left phrenic nerve conduction and left hemidiaphragm excursion were normal in both liver recipients and the patients who had LR. Liver recipients with no conduction in the right phrenic nerve had a significantly greater decrease in vital capacity in the supine position (29 +/- 9.8%) compared with those with some conduction (14 +/- 6.9%, P < 0.001). However, neither the time on the ventilator nor the hospital stay was significantly different in the latter two groups. Complete recovery of phrenic nerve conduction and diaphragm function took until nine months in some patients. Right phrenic nerve injury is common after OLT and it is the cause of right hemidiaphragm dysfunction.


Higher frequency of social learning in China than in the West shows cultural variation in the dynamics of cultural evolution.
Cultural evolutionary models have identified a range of conditions under which social learning (copying others) is predicted to be adaptive relative to asocial learning (learning on one's own), particularly in humans where socially learned information can accumulate over successive generations. However, cultural evolution and behavioural economics experiments have consistently shown apparently maladaptive under-utilization of social information in Western populations. Here we provide experimental evidence of cultural variation in people's use of social learning, potentially explaining this mismatch. People in mainland China showed significantly more social learning than British people in an artefact-design task designed to assess the adaptiveness of social information use. People in Hong Kong, and Chinese immigrants in the UK, resembled British people in their social information use, suggesting a recent shift in these groups from social to asocial learning due to exposure to Western culture. Finally, Chinese mainland participants responded less than other participants to increased environmental change within the task. Our results suggest that learning strategies in humans are culturally variable and not genetically fixed, necessitating the study of the 'social learning of social learning strategies' whereby the dynamics of cultural evolution are responsive to social processes, such as migration, education and globalization.


Assessing the impacts of the first year of rotavirus vaccination in the United Kingdom.
The United Kingdom (UK) added rotavirus (RV) vaccine (Rotarix GlaxoSmithKline) to the national vaccine schedule in July 2013. During the 2012-2014 rotavirus seasons, children presenting to the Bristol Royal Hospital for Children Emergency Department with gastroenteritis symptoms had stool virology analysis (real-time PCR) and clinical outcome recorded. Nosocomial cases were identified as patients with non-gastroenteritis diagnosis testing positive for rotavirus > 48h after admission. In comparison to average pre-vaccine seasons, in the first year after vaccine introduction there were 48% fewer attendances diagnosed with gastroenteritis, 53% reduction in gastroenteritis admissions and a total saving of 330 bed-days occupancy. There was an overall reduction in number of rotavirus-positive stool samples with 94% reduction in children aged under one year and a 65% reduction in those too old to have been vaccinated. In the first year after the introduction of universal vaccination against rotavirus we observed a profound reduction in gastroenteritis presentations and admissions with a substantial possible herd effect seen in older children. Extrapolating these findings to the UK population we estimate secondary healthcare savings in the first year of ca £7.5 (€10.5) million. Ongoing surveillance will be required to determine the long-term impact of the RV immunisation programme.


Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin.
Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells' growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.


Effect of vitamin D deficiency on sarcoplasmic reticulum function and troponin C concentration of rabbit skeletal muscle.
1. Weanling rabbits were made rachitic either by a vitamin D-deficient diet or by parenteral administration of ethane 1-hydroxy-1,1-diphosphonate (EHDP) in amounts sufficient in other species to block the formation of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. 2. The uptake of calcium into the isolated sarcoplasmic reticulum from mixed striated quadriceps muscle, and the amount of troponin C (the calcium-binding component of the troponin complex) in relation to other proteins from the same muscle, were measured. 3. In muscle from animals made rachitic by a dietary deficiency of vitamin D, the rate of uptake of calcium by the sarcoplasmic reticulum and the troponin C concentration were both significantly less (P less than 0.02) than in control littermates. In EHDP-treated animals no significant differences from controls were found. 4. These results show that dietary deficiency of vitamin D in such animals can affect muscle physiology. Since no changes are found in animals made rachitic with EHDP, who presumably have a selective deficiency of 1,25-(OH)2D3, it is possible that the effect of vitamin D on muscle is mediated through metabolites other than 1,25-(OH)2D3 such as 25-hydroxycholecalciferol.


The presence of liver auto-antibodies induced by Entamoeba histolytica in the sera from both naturally infected humans and immunized rabbits.
Auto-antibodies against normal human liver have been detected in the sera of humans with highly positive indirect hemagglutination (IHA) amebiasis titers and with clinically-proven amebic liver abscess. Sera of amebiasis patients and rabbits immunized with killed Entamoeba histolytica were tested for anti-amebic antibodies by the IHA test and for auto-antibodies by the complement fixation test, using the antigens prepared from extracts of human liver and rabbit liver. A direct correlation was found to exist between high anti-Entamoeba antibody titers and the presence of anti-liver antibody in the serum. It is proposed that, in addition to direct parasite damage to host tissue, immunological damage could result from the attachment of circulating antigen to the cell surfaces of host tissues such as the liver.


An Inner Barrier to Career Development: Preconditions of the Impostor Phenomenon and Consequences for Career Development.
The impostor phenomenon (IP) is increasingly recognized as an important psychological construct for career development, yet empirical research on how it functions in this domain is sparse. We investigated in what way impostor feelings are related to the fear of failure, fear of success, self-esteem, and the career-development aspects career planning, career striving, and the motivation to lead. We conducted two studies with independent samples of university students (N = 212) in a laboratory study and working professionals (N = 110) in an online study. In both samples, impostor feelings were fostered by fear of failure, fear of success, and low self-esteem and they decreased career planning, career striving, and the motivation to lead. A path analysis showed that impostor feelings had the most negative effects on career planning and career striving in students and on the motivation to lead in working professionals. The results suggest that the IP is relevant to career development in different ways at different career stages. Practical implications and interventions to reduce the negative effects of impostor feelings on career development are discussed.