Cystatin C-Creatinine Based Glomerular Filtration Rate Equation in Obese Chronic Kidney Disease Patients: Impact of Deindexation and Gender.
Cystatin C is considered an alternative to creatinine to estimate glomerular filtration rate (GFR). However, studies have reported that increased adiposity is associated with a higher level of circulating cystatin C questioning the performance of estimation of GFR using cystatin C in obese subjects. We prospectively included 166 obese stages 1-5 chronic kidney disease (CKD) patients between 2013 and 2015. GFR was measured with a reference method without (measured GFR [mGFR]) and with adjustment to body surface area (mGFRr) and estimated (eGFR) or de-indexed eGFR using the Chronic Kidney Disease and Epidemiology (CKD-EPI) equation using creatinine (CKD-EPIcreat), cystatin (CKD-EPIcyst) and the combination of cystatin and creatinine (CKD-EPIcyst-creat). The biases between mGFR and de-indexed CKD-EPIcyst-creat were significantly lower than de-indexed CKD-EPIcreat (p = 0.001). Accuracies were significantly better with de-indexed CKD-EPIcyst-creat compared to CKD-EPIcreat and CKD-EPIcyst, respectively (p = 0.04 and 0.03). Bland and Altman plot showed a great dispersion of all formulae when patients had a GFR >60 ml/min. Interestingly, there is a gender difference; biases, precisions and accuracies of de-indexed CKD-EPIcyst-creat were significantly lower in obese women. These results may be related to a difference in the change of body composition during obesity in men versus women and in fact only waist circumference (WC) was positively and significantly correlated with cystatin C (p < 0.0001) whereas body mass index (BMI; p = 0.3) was not; bias for CKD-EPIcyst-creat was related with WC. Cystatin C-creatinine-based GFR equations outperform creatinine-based formula in obese CKD patients especially those with BMI ≥35 and in obese women.


ATP mediates fast synaptic potentials in enteric neurons.
Conventional intracellular electrophysiological methods were used to study fast synaptic transmission in the myenteric plexus of guinea pig ileum in vitro. Fast excitatory postsynaptic potentials (fEPSPs) were evoked in 98 neurons following single stimuli applied to interganglionic connectives. The nicotinic antagonist hexamethonium (100 microM) reduced fEPSPs by 83% in 37 neurons; these fEPSPs were considered to be cholinergic. In 61 neurons, hexamethonium reduced fEPSPs by 33%; fEPSPs recorded in the presence of hexamethonium were considered to be noncholinergic. Similar data were obtained using the nicotinic antagonist mecamylamine (10 microM) to block fEPSPs. Hexamethonium or mecamylamine completely blocked depolarizations caused by acetylcholine (ACh) applied by ionophoresis. The P2 receptor antagonist suramin (1-300 microM) inhibited noncholinergic fEPSPs in 30 cells; the suramin IC50 was 4 microM. Suramin (100 microM) did not block depolarizations caused by ACh or 5-HT, but suramin blocked depolarizations caused by ATP. Hexamethonium did not block ATP-induced depolarizations. The estimated reversal potential for suramin-sensitive fEPSPs and ATP-induced depolarizations was -25 and -16 mV, respectively. ATP responses were reduced in low-sodium (26 mM) extracellular solution, suggesting that ATP activates a cation channel. These data indicate that in myenteric nerves ATP, in addition to ACh, contributes to fast synaptic transmission.


The social determinants of lesbian, gay, bisexual and transgender youth suicidality in England: a mixed methods study.
Lesbian, gay, bisexual and transgender (LGBT) youth have a higher risk of suicidality and self-harm than heterosexual youth populations but little is known about the underlying mechanisms. We aimed to investigate the social determinants of this mental health inequality. A two-stage sequential mixed method study was conducted. Firstly, 29 semi-structured interviews with LGBT youth (aged 13-25 years old) were completed. Data was analysed thematically. Stage 2 involved a self-completed questionnaire employing an online community-based sampling strategy (n = 789). Logistic regression analysis was performed to predict suicidality. Five social determinants explained suicidal risk: (i) homophobia, biphobia or transphobia; (ii) sexual and gender norms; (iii) managing sexual and gender identities across multiple life domains; (iv) being unable to talk; (v) other life crises. Youth who were transgender (OR = 1.50, P < 0.022), disabled (OR = 2.23, P < 0.000), had self-harmed (OR = 7.45, P < 0.000), were affected by abuse (OR = 2.14, P < 0.000), and affected by not talking about their emotions (OR = 2.43, P < 0.044) were most likely to have planned or attempted suicide. Public health universal interventions that tackle bullying and discrimination in schools, and selected interventions that provide specific LGBT youth mental health support could reduce LGBT mental health inequalities in youth suicidality.


Cephalometric measurements and determination of general skull type of Cavalier King Charles Spaniels.
The general skull morphology of the head of the Cavalier King Charles Spaniel (CKCS) was examined and compared with cephalometric indices of brachycephalic, mesaticephalic, and dolichocephalic heads. Measurements were taken from computed tomography images. Defined landmarks for linear measurements of were identified using three-dimensional (3D) models. The calculated parameters of the CKCS were different from all parameters of mesaticephalic dogs but were the same as parameters from brachycephalic dogs. However, the CKCS had a wider braincase in relation to length than in other brachycephalic breeds. Studies of the etiology of the chiari-like malformation in the CKCS should therefore focus on brachycephalic control groups. As Chari-like malformation has only been reported in brachycephalic breeds, its etiology could be associated with a higher grade of brachycephaly, meaning a shorter longitudinal extension of the skull. This has been suggested for other breeds.


Lost in translation: health resource variability in the achievement of optimal performance and clinical outcome.
BACKGROUND- An evidence-practice gap in acute coronary syndromes (ACS) is commonly recognized. System, provider, and patient factors can influence guideline adherence. Through using guideline facilitators in the clinical setting, the uptake of evidence-based recommendations may be increased. We hypothesized that facilitators of guideline recommendations (systems, tools, and workforce) in acute cardiac care were associated with increased guideline adherence and decreased adverse outcome. METHODS AND RESULTS- A cross-sectional evaluation of guideline facilitators was conducted in Australian hospitals. The population was derived from the Acute Coronary Syndrome Prospective Audit (ACACIA) and assessed performance, death, and recurrent myocardial infarction (death/re-MI) at 30 days and 12 months. Thirty-five hospitals and 2392 patients participated. Significant associations with decreased death/re-MI were observed with hospital strategies to facilitate primary percutaneous coronary intervention for ST-elevation MI patients (38/428 [8.9%] versus 30/154 [19.5%], P<0.001) and after adjustment (odds ratio [OR], 0.47 [95% confidence interval (CI), 0.24 to 0.90], P<0.023), electronic discharge checklists (none: 233/1956 [11.9%], integrated; 43/251[17.1%], P=0.069, electronic; 6/124 [4.8%], P<0.001) and after adjustment (integrated versus none: OR, 1.66 [95% CI, 0.98 to 2.80], P=0.057 and electronic versus none: OR, 0.49 [95% CI, 0.35 to 0.68], P<0.001), and intensive cardiac care unit (ICCU) staff-to-patient ratios (neither: 200/1257 (15.9%), CCU: 135/1051 (12.8%), ICCU: 8/84 (9.5%), P=0.049 and after adjustment (CCU versus neither: OR, 0.74 [95% CI, 0.47 to 1.14], P=0.172 and ICCU versus neither: OR, 0.55; [95% CI, 0.38 to 0.81] P=0.003). CONCLUSIONS- Facilitating uptake of evidence in clinical practice may need to consider quality improvement systems, tools and workforce to achieve optimal ACS outcomes.


Dental erosion in asthma: a case-control study from south east Queensland.
Asthma medication places patients at risk of dental erosion by reducing salivary protection against extrinsic or intrinsic acids. But patterns of lesions in asthmatics may differ from patterns in non-asthmatics, because gastro-oesophageal reflux (GOR) is found in 60 per cent of asthmatics. The lesions in 44 asthma cases were compared to those of age and sex match controls with no history of asthma or medications drawn from the dental records of 423 patients referred concerning excessive tooth wear. The subjects were 70 males age range 15 to 55 years and 18 females age range 18 to 45. Anamnestic clinical data were compared between the two groups. Models of all 88 subjects were examined by light microscopy, and wear patterns were recorded on permanent central incisor, canine, premolar and first molar teeth. Clinical differences were a higher incidence of tooth hypersensitivity, xerostomia, salivary gland abnormalities, gastric complaints, and self induced vomiting in the cases. No differences were found between the cases and controls on citrus fruit and acid soft drink consumption. More occlusal erosion sites were found in cases, whereas more attrition sites were found in the controls. There were no significant differences in palatal erosion on maxillary anterior teeth found between cases and controls. Lingual erosion of the mandibular incisors, found only in GOR patients, was not observed. A higher incidence of erosion was found in asthmatics. Gastro-oesophageal reflux symptoms were not associated with the sign of lingual mandibular incisor erosion. The clinical significance is that asthmatics are at risk of dental erosion from extrinsic acid, but GOR does not appear to contribute in a site-specific manner.


Confrontation of fibroblasts with cancer cells in vitro: gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth.
There is growing evidence that emerging malignancies in solid tissues might be kept under control by physical intercellular contacts with normal fibroblasts. Here we characterize transcriptional landscapes of fibroblasts that confronted cancer cells. We studied four pairs of in vitro and ex vivo fibroblast lines which, within each pair, differed in their capacity to inhibit cancer cells. The natural process was modeled in vitro by confronting the fibroblasts with PC-3 cancer cells. Fibroblast transcriptomes were recorded by Affymetrix microarrays and then investigated using network analysis. The network enrichment analysis allowed us to separate confrontation- and inhibition-specific components of the fibroblast transcriptional response. Confrontation-specific differences were stronger and were characterized by changes in a number of pathways, including Rho, the YAP/TAZ cascade, NF-kB, and TGF-beta signaling, as well as the transcription factor RELA. Inhibition-specific differences were more subtle and characterized by involvement of Rho signaling at the pathway level and by potential individual regulators such as IL6, MAPK8, MAP2K4, PRKCA, JUN, STAT3, and STAT5A. We investigated the interaction between cancer cells and fibroblasts in order to shed light on the potential mechanisms and explain the differential inhibitory capacity of the latter, which enabled both a holistic view on the process and details at the gene/protein level. The combination of our methods pointed to proteins, such as members of the Rho pathway, pro-inflammatory signature and the YAP1/TAZ cascade, that warrant further investigation via tools of experimental perturbation. We also demonstrated functional congruence between the in vitro and ex vivo models. The microarray data are made available via the Gene Expression Omnibus as GSE57199.


Driving self-restriction and motor vehicle collision occurrence in glaucoma.
To confirm that subjects with primary open-angle glaucoma (POAG) who avoid driving in high-risk situations are less likely to be involved in motor vehicle collisions (MVCs) than those who do not. This study evaluated 252 consecutive Japanese aged between 40 and 85 years with POAG. All participants were requested to answer a questionnaire on their driving habits, including self-restriction in driving at night, in rain, in fog, on freeways, and lane changing, and history of MVCs. Those who reported restricting their driving in one or more ways constituted the self-restriction group, and those who reported no self-restriction made up the no-restriction group. The prevalence of MVCs and the crash rate (number of MVCs/10,000 km driven) were compared between the two groups. The association between prevalence of MVCs and the number of driving self-restrictions was also evaluated. The association between driving self-restriction and MVCs was observed among the male subjects, not among the female subjects. Among the male subjects, the prevalence of MVCs was significantly higher in the no-restriction group than in the self-restriction group (no-restriction group, 33/107 = 30.8%; self-restriction group, 9/66 = 13.6%, p = 0.01). The crash rate was also significantly higher in the no-restriction group (no-restriction group, 1.4 ± 0.8; self-restriction group, 0.4 ± 0.3, average ± SE, p = 0.01). No restriction was significantly associated with MVCs (multivariable-adjusted odds ratios, 2.43 [95% confidence interval, 1.03 to 5.73]). The number of driving self-restrictions was also associated with MVCs (multivariable-adjusted odds ratios, 0.41 [95% confidence interval, 0.18 to 0.99], per one increment of self-restriction). Driving self-restriction may be associated with a reduced prevalence of MVCs in men with POAG.


[Assessment of the management of community-acquired pneumonia in adults outpatients].
There is limited information about the effectiveness of the treatment of community-acquired pneumonia (CAP) in Chilean emergency rooms. To assess the treatment of CAP in emergency rooms at the Viña del Mar Health Service in Chile. Prospective study of immunocompetent adult patients consulting for a CAP in emergency rooms. Those that required hospital admission were considered ineligible. The initial clinical and laboratory assessment, antimicrobial treatment and their condition after 30 days of follow up, were recorded. Three hundred eleven adult patients aged 57+/-22 years (152 males), were evaluated. Patients with class I CAP (40% of cases) were treated with Clarithromycin (71.8%) or Amoxicillin (26.6%) for 10 days. Patients with class II CAP (60%) were treated with Amoxicillin-clavulanate (80.7%) or Levofloxacin (18.2%) for 10 days. Three hundred eight patients (99%) were cured without need of hospital admission; three patients (1%) were subsequently hospitalized because of clinical failure of ambulatory treatment. Overall, three patients (1%) died; all deaths occurred during or immediately after hospitalization and were related to the severity of lung infection but not to the choice of antibiotic treatment. The outpatient management of CAP by general practitioners working at emergency rooms was clinically effective with low rates of hospital admission and mortality.


Do sensorimotor processes have reflexes in sentence syntax as well as sentence semantics?
Predicate logic has proved a very useful tool for the expression of theories of natural language semantics. Hurford's suggestion that predicate-argument structures mirror certain properties of the human sensorimotor architecture can be seen as an explanation of why this is so. Although I support this view, I think that the correspondences that Hurford draws between linguistic and sensorimotor structures not only involve natural language semantics, but include some elements of natural language syntax as well.


DNA-based watermarks using the DNA-Crypt algorithm.
The aim of this paper is to demonstrate the application of watermarks based on DNA sequences to identify the unauthorized use of genetically modified organisms (GMOs) protected by patents. Predicted mutations in the genome can be corrected by the DNA-Crypt program leaving the encrypted information intact. Existing DNA cryptographic and steganographic algorithms use synthetic DNA sequences to store binary information however, although these sequences can be used for authentication, they may change the target DNA sequence when introduced into living organisms. The DNA-Crypt algorithm and image steganography are based on the same watermark-hiding principle, namely using the least significant base in case of DNA-Crypt and the least significant bit in case of the image steganography. It can be combined with binary encryption algorithms like AES, RSA or Blowfish. DNA-Crypt is able to correct mutations in the target DNA with several mutation correction codes such as the Hamming-code or the WDH-code. Mutations which can occur infrequently may destroy the encrypted information, however an integrated fuzzy controller decides on a set of heuristics based on three input dimensions, and recommends whether or not to use a correction code. These three input dimensions are the length of the sequence, the individual mutation rate and the stability over time, which is represented by the number of generations. In silico experiments using the Ypt7 in Saccharomyces cerevisiae shows that the DNA watermarks produced by DNA-Crypt do not alter the translation of mRNA into protein. The program is able to store watermarks in living organisms and can maintain the original information by correcting mutations itself. Pairwise or multiple sequence alignments show that DNA-Crypt produces few mismatches between the sequences similar to all steganographic algorithms.


Market-driven production of biospecimens and the role of NHS hospital-led biobanks.
Biobanks are vital for biospecimen production in research, despite the regulatory, recruitment and commercial difficulties they face. We conducted interviews with clinicians, researchers, volunteers who recruit biobank participants, regulators and NHS managers about the integration of a biobank into an NHS hospital. We show that medical waste collected for biomedical research acquires its socio-ethical and economic value from the level of integration (both technologically and organisationally) of the biobank into the NHS hospital. There is extensive investment in a range of intellectual and commercial relationships and labour among stakeholders involved in the production of biospecimens. It is not only the boundaries of research, clinical care and commercialisation of biospecimens that blur but also those of volunteerism and citizenship. Hospital-led biobanks provide an opportunity to study the intertwining of biomedical innovation and healthcare.


Fine-scale mapping of recombination rate in Drosophila refines its correlation to diversity and divergence.
Regional rates of recombination often correlate with levels of nucleotide diversity, and either selective or neutral hypotheses can explain this relationship. Regional recombination rates also correlate with nucleotide differences between human and chimpanzee, consistent with models where recombination is mutagenic; however, a lack of correlation is observed in the Drosophila melanogaster group, consistent with models invoking natural selection. Here, we revisit the relationship among recombination, diversity, and interspecies difference by generating empirical estimates of these parameters in Drosophila pseudoobscura. To measure recombination rate, we genotyped 1,294 backcross hybrids at 50 markers across the largest assembled linkage group in this species. Genome-wide diversity was estimated by sequencing a second isolate of D. pseudoobscura at shallow coverage. Alignment to the sequenced genome of the closely related species, Drosophila persimilis, provided nucleotide site orthology. Our findings demonstrate that scale is critical in determining correlates to recombination rate: fine-scale cross-over rate estimates are far stronger predictors of both diversity and interspecies difference than broad-scale estimates. The correlation of fine-scale recombination rate to diversity and interspecies difference appears to be genome-wide, evidenced by examination of an X-linked region in greater detail. Because we observe a strong correlation of cross-over rate with interspecies difference, even after correcting for segregating ancestral variation, we suggest that both mutagenic and selective forces generate these correlations, the latter in regions of low crossing over. We propose that it is not cross-overs per se that are mutagenic, but rather repair of DNA double-strand break precursors via crossing over and gene conversion.


Predicting young adult social functioning from developmental trajectories of externalizing behaviour.
The long-term consequences of child and adolescent externalizing problems often involve a wide spectrum of social maladaptation in adult life. The purpose of this study was to describe the predictive link of child and adolescent externalizing developmental trajectories to social functioning in adulthood. Social functioning was predicted from developmental trajectories of parent-reported aggression, opposition, property violations and status violations that were defined in a longitudinal multiple birth cohort study of 2,076 males and females aged 4-18 years. Social functioning was assessed using self-reports by young adults aged 18-30 years. Linear and logistic regression analyses were used to describe the extent to which developmental trajectories are prospectively related to social functioning. Children with high-level trajectories of opposition and status violations reported more impaired social functioning as young adults than children with high-level trajectories of aggression and property violations. Young adults who showed onset of problems in adolescence reported overall less impaired social functioning than individuals with high-level externalizing problems starting in childhood. Overall, males reported more impaired social functioning in adulthood than females. However, females with persistent high-level externalizing behaviour reported more impairment in relationships than males with persistent high-level externalizing behaviour. The long-term consequences of high levels of opposition and status violations in childhood to serious social problems during adulthood are much stronger than for individuals who show only high levels of aggressive antisocial behaviours.


Intravenous ephedrine abolished suspected bronchoconstriction during general anesthesia in a patient undergoing beta-adrenergic blocker therapy for hypertension.
We report a case of intravenous ephedrine administration that abolished suspected bronchoconstriction during general anesthesia in a patient undergoing beta-adrenergic blocker therapy for hypertension and who was subsequently diagnosed postoperatively as having bronchial asthma. A 54-year-old man who had childhood asthma was scheduled for laparoscopic cholecystectomy at our institution. The preanesthetic interview suggested full resolution of his childhood asthma. His capnogram showed an airway obstructive pattern immediately after the initiation of mechanical ventilation. However, after administration of ephedrine due to low blood pressure during surgery, his obstructive capnogram reverted to normal. On postoperative day 3, he was diagnosed as having bronchial asthma. Furthermore, we found that small airway obstruction as indicated in his preoperative pulmonary function test (PFT) had been overlooked. Two important points arise from this case. First, the use of beta-blockers for the treatment of hypertension in patients potentially having obstructive lung disease should be avoided. Second, clinicians should carefully check the preoperative PFT results in detail to ensure that nothing has been overlooked.


Deciphering the complex role of thrombospondin-1 in glioblastoma development.
We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.


Pancreatic Head Resection Following Roux-en-Y Gastric Bypass: Operative Considerations and Outcomes.
This study aimed to identify optimal management decisions for surgeons preforming pancreatic head resection on patients with altered anatomy due to a previous Roux-en-Y gastric bypass (RYGB). A multi-national (4), multi-center (28) collaborative of 55 pancreatic surgeons who have performed pancreatoduodenectomy or total pancreatectomy following RYGB for obesity (2005-2018) was created. Demographics, operative details, and perioperative outcomes from this cohort were analyzed and compared in a propensity-score matched analysis with a multi-center cohort of 5533 pancreatoduodenectomies without prior RYGB. Ninety-six patients with a previous RYGB undergoing pancreatic head resection were assembled. Pathologic indications between the RYGB and normal anatomy cohorts did not differ. Propensity score matching of RYGB vs. patients with unaltered anatomy demonstrated no differences in major postoperative outcomes. In total 20 distinct reconstructions were employed (of 37 potential options); the three most frequent reconstructions accounted for 52.1%, and none demonstrated superior outcomes. There were no differences in outcomes observed between original biliopancreatic limb use (66.7%) and those where a secondary Roux limb was created for biliopancreatic reconstruction. Remnant stomachs were removed in 54.7% of cases, with no outcome differences between resected and retained stomachs. Venting gastrostomy tubes were used in 36.2% of retained stomachs without obvious outcome benefits. Jejunostomy tubes were used infrequently (11.7%). Pancreatic head resection after RYGB is an infrequently encountered, unique and challenging scenario for any given surgeon. These patients do not appear to suffer higher morbidity than those with unaltered anatomy. Various technical reconstructive options do not appear to confer distinct benefits.


Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease.
Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.


Dual origin and segmental organisation of the avian scapula.
Bones of the postcranial skeleton of higher vertebrates originate from either somitic mesoderm or somatopleural layer of the lateral plate mesoderm. Controversy surrounds the origin of the scapula, a major component of the shoulder girdle, with both somitic and lateral plate origins being proposed. Abnormal scapular development has been described in the naturally occurring undulated series of mouse mutants, which has implicated Pax1 in the formation of this bone. Here we addressed the development of the scapula, firstly, by analysing the relationship between Pax1 expression and chondrogenesis and, secondly, by determining the developmental origin of the scapula using chick quail chimeric analysis. We show the following. (1) The scapula develops in a rostral-to-caudal direction and overt chondrification is preceded by an accumulation of Pax1-expressing cells. (2) The scapular head and neck are of lateral plate mesodermal origin. (3) In contrast, the scapular blade is composed of somitic cells. (4) Unlike the Pax1-positive cells of the vertebral column, which are of sclerotomal origin, the Pax1-positive cells of the scapular blade originate from the dermomyotome. (5) Finally, we show that cells of the scapular blade are organised into spatially restricted domains along its rostrocaudal axis in the same order as the somites from which they originated. Our results imply that the scapular blade is an ossifying muscular insertion rather than an original skeletal element, and that the scapular head and neck are homologous to the 'true coracoid' of higher vertebrates.


Genomic drift and copy number variation of chemosensory receptor genes in humans and mice.
Recent studies about the structural variation of genomic sequences have shown that there is a large amount of copy number variations (CNVs) of genes within species. Analyzing Redon et al.'s (2006) crude data on copy number variable regions (CNVRs), we previously showed that CNVs are particularly high for chemosensory receptor genes in human populations. In this paper, we reanalyzed the CNVs of these genes using more refined data by Perry et al. (2008). The results showed that the extent of CNVs is somewhat lower in this dataset than in the previous one, but that the extent is still substantial for olfactory receptor (OR), vomeronasal receptor (VR), and taste receptor (TR) genes. We also studied the CNVs for chemosensory receptor genes in mice, using CNVR data obtained from inbred strains. It was found that the extent of CNVs is quite substantial but is lower than that for human populations. However, because the mouse data came from inbred strains and might be biased, this conclusion should be regarded as tentative. Despite this reservation, the distribution of gene copy number for the OR gene family was approximately normal in both humans and mice, suggesting that genomic drift caused by random duplication and deletion of genes plays important roles in determining the evolutionary change of chemosensation.


CD200R1 supports HSV-1 viral replication and licenses pro-inflammatory signaling functions of TLR2.
The CD200R1:CD200 axis is traditionally considered to limit tissue inflammation by down-regulating pro-inflammatory signaling in myeloid cells bearing the receptor. We generated CD200R1(-/-) mice and employed them to explore both the role of CD200R1 in regulating macrophage signaling via TLR2 as well as the host response to an in vivo, TLR2-dependent model, herpes simplex virus 1 (HSV-1) infection. CD200R1(-/-) peritoneal macrophages demonstrated a 70-75% decrease in the generation of IL-6 and CCL5 (Rantes) in response to the TLR2 agonist Pam(2)CSK(4) and to HSV-1. CD200R1(-/-) macrophages could neither up-regulate the expression of TLR2, nor assemble a functional inflammasome in response to HSV-1. CD200R1(-/-) mice were protected from HSV-1 infection and exhibited dysfunctional TLR2 signaling. Finally, both CD200R1(-/-) mice and CD200R1(-/-) fibroblasts and macrophages showed a markedly reduced ability to support HSV-1 replication. In summary, our data demonstrate an unanticipated and novel requirement for CD200R1 in "licensing" pro-inflammatory functions of TLR2 and in limiting viral replication that are supported by ex vivo and in vivo evidence.


Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes.
Previous studies have shown that intravenous immunoglobulin (IVIg) therapy is useful prophylaxis against infection in patients with secondary hypogammaglobulinaemia due to a low-grade lymphoproliferative disease. This randomized double-blind study was undertaken to determine prospectively the dose regime required. 34 such patients received IVIg at either 500 or 250 mg/kg every 4 weeks for 1 year. There was no significant difference in the rates of serious infections between the two groups of patients, which were well matched for disease and laboratory parameters. The rates of infection seen were similar to those in IVIg groups of previous studies and strikingly different from those in the placebo group in the previously randomized placebo-controlled study.


Parent, partner and individual contexts of very early first sex experiences among young men and their links to subsequent reproductive health outcomes.
Research indicates that upwards to 30% of US urban Black male adolescents report first sex younger than age 13; however, there is limited literature on the sexual and reproductive health outcomes and contexts of these early first sex experiences. This exploratory study described sexual and reproductive health histories and explored personal, partner and parent contextual factors associated with first sex experiences occurring at 13 years or younger among a sample of US urban young men aged 15-24. Participants were assessed on their demographics and sexual health histories and a subset of young men were assessed on the contextual factors related to their first sex experience. Pearson chi-squared tests examined factors associated with early first sex and Fisher's exact tests examined associated contextual factors. First sex at 13 years or younger was reported by 29% of young men. A higher proportion of young men who had first sex at 13 or younger than those who had sex onset at 14 or older reported having got someone pregnant, having a "much older" first partner, and relationship satisfaction with their mother (16%) and father (12%). Study findings highlight the need to better understand urban young men's early first sex experiences, including the support needed to promote their healthy sexual development.


In vivo chemical and structural analysis of plant cuticular waxes using stimulated Raman scattering microscopy.
The cuticle is a ubiquitous, predominantly waxy layer on the aerial parts of higher plants that fulfils a number of essential physiological roles, including regulating evapotranspiration, light reflection, and heat tolerance, control of development, and providing an essential barrier between the organism and environmental agents such as chemicals or some pathogens. The structure and composition of the cuticle are closely associated but are typically investigated separately using a combination of structural imaging and biochemical analysis of extracted waxes. Recently, techniques that combine stain-free imaging and biochemical analysis, including Fourier transform infrared spectroscopy microscopy and coherent anti-Stokes Raman spectroscopy microscopy, have been used to investigate the cuticle, but the detection sensitivity is severely limited by the background signals from plant pigments. We present a new method for label-free, in vivo structural and biochemical analysis of plant cuticles based on stimulated Raman scattering (SRS) microscopy. As a proof of principle, we used SRS microscopy to analyze the cuticles from a variety of plants at different times in development. We demonstrate that the SRS virtually eliminates the background interference compared with coherent anti-Stokes Raman spectroscopy imaging and results in label-free, chemically specific confocal images of cuticle architecture with simultaneous characterization of cuticle composition. This innovative use of the SRS spectroscopy may find applications in agrochemical research and development or in studies of wax deposition during leaf development and, as such, represents an important step in the study of higher plant cuticles.


Human MAIT Cell Activation In Vitro.
Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T cell subset in humans, enriched in mucosal tissues and the liver. MAIT cells express a semi-invariant T cell receptor (TCR) and recognize microbial-derived riboflavin metabolites presented on the MHC Class I-like molecule MR1. In addition to activation via the TCR, MAIT cells can also be activated in response to cytokines such as IL-12 and IL-18, in contrast to conventional T cells. Here we describe TCR-dependent and -independent methods for MAIT cell activation. The TCR-dependent approaches include stimulation with microbead- or plate-bound anti-CD3/anti-CD28 antibodies, and with 5-OP-RU or paraformaldehyde (PFA)-fixed E. coli in the presence of antigen-presenting cells (APCs). The latter method includes a combination of TCR- and cytokine-mediated stimulation. The TCR-independent methods include direct stimulation with the recombinant cytokines IL-12 and IL-18, and indirect stimulation with TLR-4/TLR-8 agonists or influenza A virus in the presence of APCs. Finally, we outline a protocol to analyze activated MAIT cells using flow cytometry.


Efficacy and safety of therapeutic nutrition products for home based therapeutic nutrition for severe acute malnutrition a systematic review.
Severe acute malnutrition (SAM) in children is a significant public health problem in India with associated increased morbidity and mortality. The current WHO recommendations on management of SAM are based on facility based treatment. Given the large number of children with SAM in India and the involved costs to the care-provider as well as the care-seeker, incorporation of alternative strategies like home based management of uncomplicated SAM is important. The present review assesses (a) the efficacy and safety of home based management of SAM using therapeutic nutrition products or ready to use therapeutic foods (RUTF); and (b) efficacy of these products in comparison with F-100 and home-based diet. Electronic database (Pubmed and Cochrane Controlled Trials Register) were scanned using keywords severe malnutrition, therapy, diet, ready to use foods and RUTF. Bibliographics of identified articles, reviews and books were scanned. The information was extracted from the identified papers and graded according to the CEBM guidelines. Eighteen published papers (2 systematic reviews, 7 controlled trials, 7 observational trials and 2 consensus statements) were identified. Systematic reviews and RCTs showed RUTF to be at least as efficacious as F-100 in increasing weight (WMD=3.0 g/kg/day; 95% CI -1.70, 7.70) and more effective in comparison to home based dietary therapies. Locally made RUTFs were as effective as imported RUTFs (WMD=0.07 g/kg/d; 95% CI=-0.15, 0.29). Data from observational studies showed the energy intake with RUTF to be comparable to F-100. The pooled recovery rate, mortality and default in treatment with RUTF was 88.3%, 0.7% and 3.6%, respectively with a mean weight gain of 3.2 g/kg/day. The two consensus statements supported the use of RUTF for home based management of uncomplicated SAM. The use of therapeutic nutrition products like RUTF for home based management of uncomplicated SAM appears to be safe and efficacious. However, most of the evidence on this promising strategy has emerged from observational studies conducted in emergency settings in Africa. There is need to generate more robust evidence, design similar products locally and establish their efficacy and cost-effectiveness in a non-emergency setting, particularly in the Indian context.


Adverse-event-reporting practices by US hospitals: results of a national survey.
Little is known about hospitals' adverse-event-reporting systems, or how they use reported data to improve practices. This information is needed to assess effects of national patient-safety initiatives, including implementation of the Patient Safety and Quality Improvement Act of 2005 (PSQIA). This survey generated baseline information on the characteristics of hospital adverse-event-reporting systems and processes, for use in assessing progress in improvements to reporting. The Adverse Event Reporting Survey, developed by Westat, was administered in September 2005 through January 2006, using a mixed-mode (mail/telephone) survey with a stratified random sample of 2050 non-federal US hospitals. Risk managers were the respondents. An 81% response rate was obtained, for a sample of 1652 completed surveys. Virtually all hospitals reported they have centralised adverse-event-reporting systems, although characteristics varied. Scores on four performance indexes suggest that only 32% of hospitals have established environments that support reporting, only 13% have broad staff involvement in reporting adverse events, and 20-21% fully distribute and consider summary reports on identified events. Because survey responses are self-reported by risk managers, these may be optimistic assessments of hospital performance. Survey findings document the current status of hospital adverse-event-reporting systems and point to needed improvements in reporting processes. PSQIA liability protections for hospitals reporting data to patient-safety organisations should also help stimulate improvements in hospitals' internal reporting processes. Other mechanisms that encourage hospitals to strengthen their reporting systems, for example, strong patient-safety programmes, also would be useful.


Ideal target for psoriatic arthritis? Comparison of remission and low disease activity states in a real-life cohort.
Psoriatic arthritis (PsA) recommendations state that the target of treatment should be remission or low disease activity (LDA). We used a real-life dataset to compare different potential targets. 250 patients with PsA considered in an acceptable disease state according to their rheumatologist were included. Targets for remission were the Disease Activity Index for Psoriatic Arthritis (DAPSA) and clinical DAPSA (cDAPSA) remission (≤4), very low disease activity (VLDA) and Psoriatic Arthritis Disease Activity Score ≤1.9. LDA targets analysed were the DAPSA ≤14, cDAPSA ≤13, minimal disease activity (MDA) and adjusted MDA targets: MDAjoints with both tender joint count (TJC) and swollen joint count (SJC) mandated, MDAskin (psoriasis area and severity index (PASI) mandated) and MDAjoints&skin with TJC, SJC and PASI mandated. Comparison of the several candidate targets demonstrates that VLDA is achieved by the lowest proportion of patients and includes patients with the lowest residual disease activity compared with the other remission targets. The modified MDA measures are the most stringent targets for LDA in terms of residual disease on joints, psoriasis and enthesitis within patients achieving the target. In both remission and LDA, the inclusion of C reactive protein did not show an added value. The exclusion of a skin domain, as in the DAPSA measures, resulted in negligence of skin disease and a negative impact on the quality of life in some patients. The different remission and LDA targets show us significant overlap between measures, but these measures targeting the same definition do differ in terms of allowance of residual disease. Inclusion of laboratory markers seems unnecessary, although exclusion of a skin domain may result in psoriasis not being assessed resulting in residual impactful skin disease.


Xanthomonas Leaf Spot of Catnip: A New Disease Caused by a Pathovar of Xanthomonas campestris.
Xanthomonas leaf spot is a new disease that has occurred on catnip (Nepeta cataria). Catnip is grown commercially in California for use as herbs, seasonings, and tea. This disease has developed recently on catnip transplants that are produced in enclosed greenhouses. Symptoms consist of small brown flecks that are visible from both sides of a leaf. The flecks later develop into larger, dark brown, angular leaf spots. Severe infection reduced the quality and marketability of the transplants. Xanthomonas campestris, as identified by biochemical, physiological, and molecular tests, was consistently isolated from symptomatic plants, and selected strains caused similar symptoms when inoculated onto catnip test plants. However, catnip strains failed to cause any symptoms when inoculated onto nine other plants in the Lamiaceae family and five other hosts of known X. campestris pathovars. Catnip plants showed no symptoms when inoculated with X. campestris pvs. campestris, carotae, and vesicatoria. Catnip also was not susceptible to the X. campestris pathogen isolated from lavender. This is the first report of a bacterial disease of catnip caused by a Xanthomonas pathogen, and the catnip strains may be a new and distinct pathovar of X. campestris.


Rapid coma resolution with artemether in Malawian children with cerebral malaria.
Artemisinin compounds clear parasitaemia more rapidly than other drugs do in both mild and severe malaria, but no advantage in clinical efficacy has been shown. We have compared artemether treatment with standard quinine treatment in Malawian children with cerebral malaria. 65 unconscious children were randomly allocated to intravenous quinine (n = 37) or intramuscular artemether (n = 28) treatment. The two groups were well matched for various prognostic features. Median parasite clearance times were shorter in the artemether group (28 [interquartile range 18-34] vs 40 [36-44] h in the quinine group, p = 0.0002). Coma resolution times were also shorter with artemether than with quinine (8 [4-15] vs 14 [10-36] h, p = 0.01).


Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB.
Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.


Single genome retrieval of context-dependent variability in mutation rates for human germline.
Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.


Flanking Variation Influences Rates of Stutter in Simple Repeats.
It has been posited that the longest uninterrupted stretch (LUS) of tandem repeats, as defined by the number of exactly matching repeating motif units, is a better predictor of rates of stutter than the parental allele length (PAL). While there are cases where this hypothesis is likely correct, such as the 9.3 allele in the TH01 locus, there can be situations where it may not apply as well. For example, the PAL may capture flanking indel variations while remaining insensitive to polymorphisms in the repeat, and these haplotypic changes may impact the stutter rate. To address this, rates of stutter were contrasted against the LUS as well as the PAL on different flanking haplotypic backgrounds. This study shows that rates of stutter can vary substantially depending on the flanking haplotype, and while there are cases where the LUS is a better predictor of stutter than the PAL, examples to the contrary are apparent in commonly assayed forensic markers. Further, flanking variation that is 7 bp from the repeat region can impact rates of stutter. These findings suggest that non-proximal effects, such as DNA secondary structure, may be impacting the rates of stutter in common forensic short tandem repeat markers.


Clinical results of AutoNRT, a completely automatic ECAP recording system for cochlear implants.
AutoNRT is the completely automatic electrically evoked compound action potential (ECAP) measuring algorithm in the recently released Nucleus Freedom cochlear implant system. AutoNRT allows clinicians to automatically record T-NRT profiles that in turn can be used as a guide for initial fitting. The algorithm consists of a pattern recognition part that judges if the traces contain an ECAP and an intelligent flow that optimizes the measurement parameters and finds the ECAP threshold (T-NRT). The objective of this study was to determine how accurate, reliable, and fast the automatic measurements are. Data on more than 400 electrodes were collected as part of the multicenter clinical trial of the Nucleus Freedom cochlear implant system. T-NRT values determined by the algorithm were compared with T-NRT determinations on the same data by different human observers. Also, the time the measurements took was analyzed. In 90% of the cases, the absolute difference between the AutoNRT and the human observer determined T-NRT was less than 9 CL; the median absolute difference was 3 CL. A second experiment, in which a group of human observers were asked to analyze NRT data, showed high variability in T-NRT; in some cases, two experienced clinicians disagreed by more than 30 current levels. Compared with the group, AutoNRT performed as well as the "average" clinician, with the advantage that the AutoNRT threshold determinations are objective. Analysis of the timing data showed an average intraoperative measurement time of less than 20 sec per electrode with a standard deviation of 5 sec, suggesting that the total array of 22 electrodes can be measured intraoperatively in about 7 minutes on average. AutoNRT provides comparable accuracy to an average clinician but with the added benefit of significant time savings over manual recordings. This makes it a valuable tool for clinical measurement of ECAP threshold in cochlear implant recipients.


Causes of death and expected years of life lost among treated opioid-dependent individuals in the United States and Taiwan.
This study compared the cause-specific standardized mortality ratios (SMRs) and expected years of life lost (EYLL) among opioid-dependent individuals in the United States and Taiwan. Survival data came from two cohorts followed until 2014: The U.S. data were based on a randomized trial of 1267 opioid-dependent participants enrolled between 2006 and 2009; the Taiwan data were from a study of 983 individuals that began in 2006, when opioid agonist treatment (OAT) was implemented in Taiwan. SMRs were calculated for each national cohort and compared. Kaplan-Meier estimation was performed on the survival data, then lifespans were extrapolated to 70 years (840 months) to estimate life expectancy using a semi-parametric method. EYLLs for both cohorts were estimated by subtracting their life expectancies from the age- and gender-matched referents within the general population of their respective country. Compared with age- and gender-matched referents, the SMRs were 3.2 for the U.S. sample and 7.8 for the Taiwan sample; the EYLLs were 7.7 and 16.4 years, respectively. Half of decedents died of unnatural causes in both cohorts; overdose deaths predominated in the U.S. and suicide in Taiwan. Our study identified differences by country in EYLL and causes of deaths. These findings suggest that intervention strategies to reduce mortality risk by overdose (particularly in the U.S.) and suicide (particularly in Taiwan) are urgently needed in these countries.


Capacity building in global mental health research.
Research-generated information about mental disorders is crucial in order to establish the health needs in a given setting, to propose culturally apt and cost-effective individual and collective interventions, to investigate their implementation, and to explore the obstacles that prevent recommended strategies from being implemented. Yet the capacity to undertake such research in low- and middle-income countries is extremely limited. This article describes two methods that have proved successful in strengthening, or that have the potential to strengthen, mental health research capacity in low-resource settings. We identify the central challenges to be faced, review current programs offering training and mentorship, and summarize the key lessons learned. A structured approach is proposed for the career development of research staff at every career stage, to be accompanied by performance monitoring and support. A case example from the Mental Health and Poverty Project in sub-Saharan Africa illustrates how this approach can be put into practice-in particular, by focusing upon training in core transferrable research skills.


Effect of environmental fluctuations on invasion fronts.
We determine the density profile and velocity of invasion fronts in one-dimensional infinite habitats in the presence of environmental fluctuations. The population dynamics is reformulated in terms of a stochastic reaction-diffusion equation and is reduced to a deterministic equation that incorporates the systematic contributions of the noise. We obtain analytical expressions for the front profile and velocity by constructing a variational principle. The effect of the noise differs, depending on whether it affects the density-independent growth rate, the intraspecific competition term or the Allee threshold. Fluctuations in the density-independent growth rate increase the invasion velocity and the population density of the invaded area. Fluctuations in the competition term also change the population density of the invaded area, but modify the invasion velocity only for certain initial conditions. Fluctuations in the Allee threshold can induce pulled or pushed invasion fronts as well as invasion failure. We compare our analytical results with numerical solutions of the stochastic partial differential equations and show that our procedure proves useful in dealing with reaction-diffusion equations with multiplicative noise.


Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model.
Prediction of metabolic clearance in extreme individuals rather than the 'average human' is becoming an attractive tool within the pharmaceutical industry. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CL(int)) data from in vitro metabolic data and back-calculation from in vivo clearance data. Second, the sensitivity of predicted in vivo variability to changes in variability for physiological parameters (e.g. liver weight, haematocrit, CYP3A abundance). Finally, reported estimates of variability in hepatic CYP3A4 abundance (coefficient of variation (CV) 95%) were refined by separating experimental from interindividual variability using a repeat measurement protocol in 52 human liver samples. Using in vitro metabolic data, predicted clearances were within 2-fold of observed for triazolam and midazolam. Clearance of alprazolam was overpredicted by 2.0- to 3.7-fold. Use of in vivo CL(int) values improved prediction of intravenous clearance to within 2-fold of observed for all drugs. Initially, the variability in clearance was overestimated for all drugs (by 1.8- to 3.6-fold). Use of a reduced hepatic CYP3A4 CV of 41%, representative of interindividual variability alone improved predictions of variability in clearance for all drugs to within 2-fold of observed.


Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study.
Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the β-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz β band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing.


Immunogenicity of fractional doses of tetravalent a/c/y/w135 meningococcal polysaccharide vaccine: results from a randomized non-inferiority controlled trial in Uganda.
Neisseria meningitidis serogroup A is the main causative pathogen of meningitis epidemics in sub-Saharan Africa. In recent years, serogroup W135 has also been the cause of epidemics. Mass vaccination campaigns with polysaccharide vaccines are key elements in controlling these epidemics. Facing global vaccine shortage, we explored the use of fractional doses of a licensed A/C/Y/W135 polysaccharide meningococcal vaccine. We conducted a randomized, non-inferiority trial in 750 healthy volunteers 2-19 years old in Mbarara, Uganda, to compare the immune response of the full dose of the vaccine versus fractional doses (1/5 or 1/10). Safety and tolerability data were collected for all subjects during the 4 weeks following the injection. Pre- and post-vaccination sera were analyzed by measuring serum bactericidal activity (SBA) with baby rabbit complement. A responder was defined as a subject with a > or =4-fold increase in SBA against a target strain from each serogroup and SBA titer > or =128. For serogroup W135, 94% and 97% of the vaccinees in the 1/5- and 1/10-dose arms, respectively, were responders, versus 94% in the full-dose arm; for serogroup A, 92% and 88% were responders, respectively, versus 95%. Non-inferiority was demonstrated between the full dose and both fractional doses in SBA seroresponse against serogroups W135 and Y, in total population analysis. Non-inferiority was shown between the full and 1/5 doses for serogroup A in the population non-immune prior to vaccination. Non-inferiority was not shown for any of the fractionate doses for serogroup C. Safety and tolerability data were favourable, as observed in other studies. While the advent of conjugate A vaccine is anticipated to largely contribute to control serogroup A outbreaks in Africa, the scale-up of its production will not cover the entire "Meningitis Belt" target population for at least the next 3 to 5 years. In view of the current shortage of meningococcal vaccines for Africa, the use of 1/5 fractional doses should be considered as an alternative in mass vaccination campaigns. ClinicalTrials.gov NCT00271479.


Incidence of sacral fractures and in-hospital postoperative complications in the United States: an analysis of 2002-2011 data.
Retrospective study of an administrative database. To estimate the incidence of sacral fractures in the United States and report short-term outcomes after their surgical management. The incidence of sacral fractures in the United States is currently unknown, and these lesions have been associated with significant morbidity after their surgical management. This study used the Nationwide Inpatient Sample database for the years 2002-2011. All patients with a primary discharge diagnosis of a sacral fracture with and without a neurological injury were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients with a diagnosis of osteoporosis or pathological fracture were excluded. A stepwise multivariate logistic regression analysis was performed to identify factors associated with an in-hospital complication. During the study period, 10,177 patients with a nonosteoporotic sacral fracture were identified, of whom 1002 patients underwent surgery. Between 2002 and 2011, the estimated incidence of sacral fractures increased from 0.67 per 100,000 persons to 2.09 (P < 0.001). Similarly, the rate of surgical treatment for sacral fractures increased from 0.05 per 100,000 persons in 2002 to 0.24 per 100,000 in 2011 (P < 0.001). Complications occurred in 25.95% of patients and remained steady over time (P = 0.992). Average length of stay significantly decreased from 11.93 days to 9.66 days in the 10-year period (P = 0.023). The independent factors associated with an in-hospital complication were congestive heart failure (odds ratio, 3.65; 95% confidence interval, 1.18-11.26), coagulopathy (odds ratio, 3.58; 95% confidence interval, 1.88-6.81), and electrolyte abnormalities (odds ratio, 3.28; 95% confidence interval, 2.14-5.02). During the examined 10-year period, both the incidence of nonosteoporotic sacral fractures and the surgical treatment of these lesions increased in the United States. Between 2002 and 2011, although patient comorbidity increased, in-hospital complication rates remained stable and length of stay significantly decreased over time. 4.


Male primer endocrine responses to preovulatory female cyprinids under natural conditions in Sweden.
This study investigated two related aspects of male-female reproductive interactions in the family Cyprinidae: (1) whether ovulating female rudd Scardinius erythrophthalmus (subfamily Leuciscinae) induce endocrine and gonadal priming responses in conspecific males, a phenomenon which has been described only in species from the subfamily Cyprininae such as goldfish, Carassius auratus, crucian carp Carassius carassius and common carp, Cyprinus carpio and (2) whether the stimuli mediating these responses are species-specific. Field studies of three sympatric European cyprinids, two leuciscins (S. erythrophthalmus and white bream Blicca bjoerkna) and one cyprinin (C. carassius), were conducted on fishes captured in Sweden in the spawning season and held in net pens under natural conditions. As previously reported in C. carassius, male S. erythrophthalmus increased milt (sperm and seminal fluid) volume and plasma concentrations of the sperm maturation hormone 4-pregnen-17,20β-diol-3-one (17,20β-P) when they were held with female S. erythrophthalmus induced to ovulate by injection of Ovaprim (GnRH analogue plus dopamine antagonist). Male S. erythrophthalmus had larger milt volumes than male C. carassius prior to and following exposure to ovulatory conspecifics, but exhibited a smaller proportional milt increase in response to stimulation, suggesting species differences in sperm allocation at spawning. The presence of female S. erythrophthalmus and B. bjoerkna did not affect milt volumes of C. carassius under two experimental conditions: (1) ovulating S. erythrophthalmus and B. bjoerkna did not increase the milt volumes of C. carassius and (2) S. erythrophthalmus and B. bjoerkna did not interfere with the milt volume increase induced in male C. carassius by ovulating conspecifics. These results suggest that, as in C. auratus, C. carassius and C. carpio (subfamily Cyprininae), female S. erythrophthalmus (subfamily Leuciscinae) release a preovulatory pheromone that exerts priming effects on male hormones and sperm allocation. The findings also indicate that C. carassius discriminate between the reproductive odours of conspecifics and heterospecifics.


Clinical classification of itch: a position paper of the International Forum for the Study of Itch.
Chronic itch is a common and distressing symptom that arises from a variety of skin conditions and systemic diseases. Despite this, there is no clinically based classification of pruritic diseases to assist in the diagnosis and cost-effective medical care of patients with pruritus. The proposed classification focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. Three groups of conditions are proposed: pruritus on diseased (inflamed) skin (group I), pruritus on non-diseased (non-inflamed) skin (group II), and pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis (group III). The next part classifies the underlying diseases according to different categories: dermatological diseases, systemic diseases including diseases of pregnancy and drug-induced pruritus, neurological and psychiatric diseases. In some patients more than one cause may account for pruritus (category "mixed") while in others no underlying disease can be identified (category "others"). This is the first version of a clinical classification worked out by the members of the International Forum for the Study of Itch. It is intended to serve as a diagnostic route for better evaluation of patients with chronic pruritus and aims to improve patients' care.


Assessment of inhibitory potential of essential oils on natural mycoflora and Fusarium mycotoxins production in wheat.
In the last years essential oils from different plants were used in the prevention of fungi and mycotoxins accumulation in cereals. The most attractive aspect derived from using of essential oils as seed grains protectants is due to their non-toxicity. This study was focused on assessment the inhibitory effect of some essential oils: Melissa officinalis (O1), Salvia officinalis (O2), Coriandrum sativum (O3), Thymus vulgaris (O4) Mentha piperita (O5) and Cinnamomum zeylanicum (O6) against natural mycoflora and Fusarium mycotoxins production correlated with their antioxidants properties. All essential oils showed inhibitory effect on fungal contamination of wheat seeds. This ability was dose-dependent. The highest inhibitory effect on Fusarium and Aspergillus fungi was recorded after 5 days of treatment. Fungi such as yeast (Pichia, Saccharomyces and Hyphopichia) were predominantly on seeds mycoflora after 22 days. Each treatment had a selective inhibitory effect on frequency of fungus genera. After 5 days of treatment the most fungicidal effect was recorder for O4, followed by O1. In terms of essential oils effect on mycotoxins development, the best control on fumonisins (FUMO) production was recorded for O6. The antioxidant properties of essential oils decreased in order: O4 > O1 > O6 > O5 > O2 > O3. Also, our data suggested that there is a significant negative correlation between antioxidant properties and seed contamination index (SCI), but there was not recorded a good correlation between antioxidant properties and FUMO content. Based on proven antifungal and antimycotoxin effects as well as their antioxidant properties, the essential oils could be recommended as natural preservatives for stored cereals. The highest inhibition of fungal growth was noted after 5 days of treatment and decreased after 22 days.


Aerosol production and aerosol droplet size distribution during mechanical ventilation (IPPV) with a new ultrasonic nebulizer.
Administration of drugs via the airway is increasingly practiced in ICU- and surgical patients. For this purpose, aerosols may be produced by either jet nebulization or ultrasonic droplet generation. In mechanically ventilated patients, aerosol delivery is often insufficient. The influence of the ventilatory pattern on nebulizer efficacy is poorly understood. In the present in vitro study we determined the efficacy of a new ultrasonic nebulizer in delivering aerosolized epoprostenol using defined ventilator settings. We determined aerosol delivery rates, the aerosol droplet size distribution and the impact of the connection tubing on drug delivery, applying adult and infant ventilation patterns. Aerosol production rates ranged from 0.28 to 0.57 ml per minute. Using an adult ventilator setting volume controlled ventilation (CMV) led to a higher aerosol production rate than pressure controlled ventilation (PCV) at identical tidal volumes and mean airway pressures (0.57 ml/min,CMV vs 0.39 ml/min, PCV). With an infant ventilator setting, nebulizer rates were lower than those found for the adult ventilator setting, but did not differ substantially between CMV and PCV mode (0.29 ml/min, CMV vs 0.28 ml/min, PCV). Aerosol delivery rates distal to the endotracheal tube changed according to aerosol production rates (adult mode: 0.18 ml/min, CMV vs 0.10 ml/min, PCV; infant mode: 0.03 ml/min, both CMV and PCV). In the infant ventilation mode, a higher percentage of the aerosol was trapped in the catheter mount as compared to the adult ventilation mode. Mass median droplet diameters for each of the four ventilator settings were almost identical (4.63 to 5.09 micron) and smaller than indicated in the product specifications (8 micron). Delivery rates and sizes of droplets delivered by the new ultrasonic nebulizer SUN 345(R) agree well with previously reported data from comparable settings using diverse nebulizer devices.


Opportunities for nurses to support recovery after pediatric injury: Relationships among posttraumatic stress, hope, and quality of life.
Nurses are at the forefront of children's postinjury recovery; this unique role provides an opportunity for nurses to recognize and screen for symptoms that may interfere with children's quality of life (QOL). As such, aims of the present investigation were to explore selected variables (e.g., posttraumatic stress symptoms [PTSS], hope) that have the potential to impact QOL after pediatric injury, with a larger goal of contributing to recommendations for nursing practice to support children's full (physical and emotional) recovery during the peritrauma period following injury. Sixty children (aged 7-13) completed measures of PTSS, hope, and QOL while receiving injury treatment. PTSS significantly predicted concurrent QOL, β = -0.42, p = 0.001. Exploratory results demonstrated that specific PTSS clusters (re-experiencing [ β = -0.39; p = 0.003), avoidance [ β = -0.35; p = 0.009], arousal [ β = -0.34; p = .012]) all significantly predicted QOL. Specific PTSS were explored. Hope (overall, domains of pathways, general agency, goal setting) did not significantly predict concurrent QOL. While this study is exploratory and more research is needed, current results suggest that nurses' awareness of PTSS (including symptoms of re-experiencing, avoidance, arousal) may help medical teams in identifying children that are at risk for impaired functional recovery (e.g., QOL) during the peritrauma period. Nurses may want to consider advocating for the integration of PTSS screeners into standard medical care. In addition, nurses have the opportunity to serve as key medical professionals in the delivery of trauma-informed medical care (which aims to minimize further trauma or re-traumatization). Nursing leadership may want to consider offering training in how nurses can identify and respond to children who have experienced an injury (such as trauma-informed care).


Dopaminergic correlates of metabolic network activity in Parkinson's disease.
Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss.


Supramolecular Organization of Collagen Fibrils in Healthy and Osteoarthritic Human Knee and Hip Joint Cartilage.
Cartilage matrix is a composite of discrete, but interacting suprastructures, i.e. cartilage fibers with microfibrillar or network-like aggregates and penetrating extrafibrillar proteoglycan matrix. The biomechanical function of the proteoglycan matrix and the collagen fibers are to absorb compressive and tensional loads, respectively. Here, we are focusing on the suprastructural organization of collagen fibrils and the degradation process of their hierarchical organized fiber architecture studied at high resolution at the authentic location within cartilage. We present electron micrographs of the collagenous cores of such fibers obtained by an improved protocol for scanning electron microscopy (SEM). Articular cartilages are permeated by small prototypic fibrils with a homogeneous diameter of 18 ± 5 nm that can align in their D-periodic pattern and merge into larger fibers by lateral association. Interestingly, these fibers have tissue-specific organizations in cartilage. They are twisted ropes in superficial regions of knee joints or assemble into parallel aligned cable-like structures in deeper regions of knee joint- or throughout hip joints articular cartilage. These novel observations contribute to an improved understanding of collagen fiber biogenesis, function, and homeostasis in hyaline cartilage.


Stability Analysis of Mathematical Model including Pathogen-Specific Immune System Response with Fractional-Order Differential Equations.
In this study, the mathematical model examined the dynamics between pathogen and specific immune system cells (memory T cells) for diseases such as chronic infection and cancer in which nonspecific immune system cells are inadequate to destroy the pathogen and has been suggested by using a system of the fractional-order differential equation with multi-orders. Qualitative analysis of the proposed model reveals the equilibrium points giving important ideas about the proliferation of the pathogen and memory T cells. According to the results of this analysis, the possible scenarios are as follows: the absence of both pathogen and memory T cells, only the existence of pathogen, and the existence of both pathogen and memory T cells. The qualitative analysis of the proposed model has expressed the persistent situations of the disease where the memory T cells either do not be able to respond to the pathogen or continue to exist with the disease-causing pathogen in the host. Results of this analysis are supported by numerical simulations. In the simulations, the time-dependent size of the tumor population under the pressure of the memory T cells was tried to be estimated.


Reduced breast cancer mortality in women under age 50: updated results from the Malmö Mammographic Screening Program.
This article provides additional follow-up data of two cohorts from the Malmö Mammographic Screening Trial (MMST). The first cohort, MMST I, contained 7,984 women under age 50 at entry into MMST who were born between 1927 and 1932. Half were assigned to a control group and were not invited for examination until four years after the code was broken in the MMST in 1988. The second cohort, MMST II, contained 17,786 women born between 1933 and 1945. Fifty four percent of these women were randomly invited to screening between 1978 and 1990. The remaining 46%--the control group--was invited to screening between 1991 and 1994. Nine screening rounds were completed in MMST I, and a mean of five rounds were completed in MMST II; the screening interval ranged from 18 to 24 months. The effect of screening on breast cancer mortality was assessed by pooling the two cohorts. At the end of follow-up--December 1993 for MMST I and December 1995 for MMST II--there was a statistically significant 36% reduction in breast cancer mortality in the intervention groups (relative risk = 0.64; 95% CI: 0.45-0.89; P = 0.009). A harm-benefit analysis showed, however, that for every two breast cancer deaths prevented, one clinically insignificant cancer was diagnosed; for each breast cancer death prevented, 63 cancer-free women had been called back for further examinations; and for every 20 lives saved, one radiation-induced breast cancer death may have occurred. Recommendations for screening must therefore weigh mortality benefits against these negative effects.


Implementation of a new undergraduate radiology curriculum: experience at the University of British Columbia.
The purpose of this study was to review and revise the undergraduate radiology curriculum at the University of British Columbia to improve radiology education to medical students and to meet the needs of a medical program with province-wide distribution. We identified the radiology content of the curriculum from the Curriculum Management and Information Tool online database, from personal interviews with curriculum heads, and from published information. Undergraduates' and recent graduates' opinions were solicited by means of surveys. Information on radiology curricula at medical schools across Canada was gathered from email surveys and personal contacts with members of the Canadian Heads of Academic Radiology (CHAR). Review of our curriculum indicated that lack of a unified syllabus resulted in redundant content, gaps in knowledge, and lack of continuity in the curriculum. Results from the survey of programs across Canada indicated that most schools also lacked a formal radiology curriculum for medical students. By adapting the guidelines from the Association of Medical Student Education in Radiology, we revised our undergraduate radiology curriculum to emphasize integration and self-learning. The modified curriculum includes a combination of instructional technology, focused lectures in preclinical years, and in-context seminars in clerkship rotations. Most medical schools in Canada do not have a formal radiology curriculum for medical students. A structured curriculum is required to improve the quality of radiology teaching for medical students.


Effects of repeated hypoglycemia on cognitive function: a psychometrically validated reanalysis of the Diabetes Control and Complications Trial data.
To test the conclusion that there is no association between multiple episodes of severe hypoglycemia and cognitive decrements by reanalyzing the data from the Diabetes Control and Complications Trial (DCCT) with psychometrically validated cognitive factors and to conduct a novel analysis of the association between individual differences in baseline cognitive ability and episodes of severe hypoglycemia documented after baseline. The factor structure of cognitive ability in the neuropsychological data from the DCCT study was derived. Four cognitive factors (spatial ability, processing speed, memory, and verbal ability) were extracted. Changes in patients' cognitive scores for each year of follow-up were obtained, and paired comparisons of these change scores were performed between groups experiencing zero and five or more hypoglycemic episodes. The association between cognitive ability at baseline and number of subsequent episodes of severe hypoglycemia was also examined. Repeated episodes of hypoglycemia were found not to be associated with cognitive decline in any of the validated cognitive factors. No significant association was found between prospectively documented numbers of severe hypoglycemic episodes and baseline cognitive ability level. Repeated episodes of hypoglycemia were not related to cognitive decrement, and initial mental ability level was not associated with eventual numbers of hypoglycemic episodes in this group of patients.


Health status and satisfaction of patients receiving ambulatory care at osteopathic training clinics.
Little is known about the health status and level of satisfaction of patients receiving care at osteopathic training clinics. Previous studies report favorable responses to medical student participation in ambulatory clinics. The health status and level of satisfaction for 2700 patients attending six family medicine training clinics at a college of osteopathic medicine were measured from 1996 through 1998. Clinic response rates ranged from 74% to 98%. Data from the Medical Outcomes Study 36-Item Short Form (SF-36) were used to compute standardized scores in the following eight health scales for English- and Spanish-speaking patients: physical functioning, role limitations because of physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations because of emotional problems, and mental health. Patients at these osteopathic training clinics reported poorer health than the general population on all eight scales (P < .001). Patients who were English speakers reported significantly better health than their Spanish-speaking counterparts on four of the eight health scales, although the Spanish-speaking patients reported greater vitality. There were significant differences in patient health across clinics. More than 92% of patients at these six osteopathic training clinics reported that they were satisfied or very satisfied with their healthcare. This study suggests that osteopathic medical students are well accepted in ambulatory clinic encounters and that these students may encounter differing levels of patient health depending on where they receive their training.


Activation by divalent cations of a Ca2+-activated K+ channel from skeletal muscle membrane.
Several divalent cations were studied as agonists of a Ca2+-activated K+ channel obtained from rat muscle membranes and incorporated into planar lipid bilayers. The effect of these agonists on single-channel currents was tested in the absence and in the presence of Ca2+. Among the divalent cations that activate the channel, Ca2+ is the most effective, followed by Cd2+, Sr2+, Mn2+, Fe2+, and Co2+. Mg2+, Ni2+, Ba2+, Cu2+, Zn2+, Hg2+, and Sn2+ are ineffective. The voltage dependence of channel activation is the same for all the divalent cations. The time-averaged probability of the open state is a sigmoidal function of the divalent cation concentration. The sigmoidal curves are described by a dissociation constant K and a Hill coefficient N. The values of these parameters, measured at 80 mV are: N = 2.1, K = 4 X 10(-7) mMN for Ca2+; N = 3.0, K = 0.02 mMN for Cd2+; N = 1.45, K = 0.63 mMN for Sr2+; N = 1.7, K = 0.94 mMN for Mn2+; N = 1.1, K = 3.0 mMN for Fe2+; and N = 1.1 K = 4.35 mMN for Co2+. In the presence of Ca2+, the divalent cations Cd2+, Co2+, Mn2+, Ni2+, and Mg2+ are able to increase the apparent affinity of the channel for Ca2+ and they increase the Hill coefficient in a concentration-dependent fashion. These divalent cations are only effective when added to the cytoplasmic side of the channel. We suggest that these divalent cations can bind to the channel, unmasking new Ca2+ sites.


In vivo pharmacological evaluations of novel olanzapine analogues in rats: a potential new avenue for the treatment of schizophrenia.
Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4'-methylpiperazin-1'-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4'-methyl-1',4'-diazepan-1'-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis.


Giardia lamblia RNA cap guanine-N2 methyltransferase (Tgs2).
Tgs1 is the enzyme responsible for converting 7-methylguanosine RNA caps to the 2,2,7-trimethylguanosine cap structures of small nuclear and small nucleolar RNAs. Whereas budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe encode a single Tgs1 protein, the primitive eukaryote Giardia lamblia encodes two paralogs, Tgs1 and Tgs2. Here we show that purified Tgs2 is a monomeric enzyme that catalyzes methyl transfer from AdoMet (K(m) of 6 microm) to m(7)GDP (K(m) of 65 microm; k(cat) of 14 min(-1)) to form m(2,7)GDP. Tgs2 also methylates m(7)GTP (K(m) of 30 microm; k(cat) of 13 min(-1)) and m(7)GpppA (K(m) of 7 microm; k(cat)) of 14 min(-1) but is unreactive with GDP, GTP, GpppA, ATP, CTP, or UTP. We find that the conserved residues Asp-68, Glu-91, and Trp-143 are essential for Tgs2 methyltransferase activity in vitro. The m(2,7)GDP product formed by Tgs2 can be converted to m(2,2,7)GDP by S. pombe Tgs1 in the presence of excess AdoMet. However, Giardia Tgs2 itself is apparently unable to add a second methyl group at guanine-N2. This result implies that 2,2,7-trimethylguanosine caps in Giardia are either synthesized by Tgs1 alone or by the sequential action of Tgs2 and Tgs1. The specificity of Tgs2 raises the prospect that some Giardia mRNAs might contain dimethylguanosine caps.


Psychedelics as Medicines: An Emerging New Paradigm.
Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.


Hypoxia-inducible factors: key regulators of myeloid cells during inflammation.
Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. In this review, we will summarize our current understanding of the role of HIF-αs in shaping macrophage and neutrophil functions in the pathogenesis and progression of multiple inflammatory diseases.


Differential roles for parietal and occipital cortices in visual working memory.
Visual working memory (VWM) is known as a highly capacity-limited cognitive system that can hold 3-4 items. Recent studies have demonstrated that activity in the intraparietal sulcus (IPS) and occipital cortices correlates with the number of representations held in VWM. However, differences among those regions are poorly understood, particularly when task-irrelevant items are to be ignored. The present fMRI-based study investigated whether memory load-sensitive regions such as the IPS and occipital cortices respond differently to task-relevant information. Using a change detection task in which participants are required to remember pre-specified targets, here we show that while the IPS exhibited comparable responses to both targets and distractors, the dorsal occipital cortex manifested significantly weaker responses to an array containing distractors than to an array containing only targets, despite that the number of objects presented was the same for the two arrays. These results suggest that parietal and occipital cortices engage differently in distractor processing and that the dorsal occipital, rather than parietal, activity appears to reflect output of stimulus filtering and selection based on behavioral relevance.


Using Virtual Pets to Promote Physical Activity in Children: An Application of the Youth Physical Activity Promotion Model.
A virtual pet was developed based on the framework of the youth physical activity promotion model and tested as a vehicle for promoting physical activity in children. Children in the treatment group interacted with the virtual pet for three days, setting physical activity goals and teaching tricks to the virtual pet when their goals were met. The virtual pet became more fit and learned more sophisticated tricks as the children achieved activity goals. Children in the control group interacted with a computer system presenting equivalent features but without the virtual pet. Physical activity and goal attainment were evaluated using activity monitors. Results indicated that children in the treatment group engaged in 1.09 more hours of daily physical activity (156% more) than did those in the control group. Physical activity self-efficacy and beliefs served as mediators driving this increase in activity. Children that interacted with the virtual pet also expressed higher intentions than children in the control group to continue physical activity in the future. Theoretical and practical potentials of using a virtual pet to systematically promote physical activity in children are discussed.


Renal localization and regulation of 15-hydroxyprostaglandin dehydrogenase.
Tissue prostaglandin levels are determined by both biosynthesis and catabolism. The current studies report the expression and localization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin catabolism in the kidneys. We also investigated potential interactions between 15-PGDH and cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis. Both 15-PGDH mRNA and protein levels were significantly higher in kidney cortex than in papilla, which is opposite to the expression pattern of COX-2. In situ hybridization indicated that 15-PGDH mRNA was mainly localized to the tubular epithelial cells in kidney cortex and outer medulla but not in the glomerulus or papilla. Dual immunofluorescent staining indicated that 15-PGDH was expressed in the proximal tubule, cortical, and outer medullary thick ascending limb and collecting duct but not in the macula densa or papilla. 15-PGDH levels were significantly lower in a macula densa cell line (MMDD1) than in a proximal tubule cell line. Although a high-salt diet decreased COX-2 expression in macula densa, it increased macula densa 15-PGDH expression in both mouse and rat kidneys. In MMDD1 cells, a COX-2 inhibitor increased 15-PGDH, whereas a COX-1 inhibitor had no effect. Furthermore, intense 15-PGDH immunofluorescent staining was found in both macula densa and glomerulus in COX-2 knockout mice. The intrarenal distribution of 15-PGDH and its interactions with COX-2 suggest that differential regulation of COX-2 and 15-PGDH may play an important role in determining levels of prostaglandins involved in regulation of salt, volume, and blood pressure homeostasis.


Axonal PPARγ promotes neuronal regeneration after injury.
PPARγ is a ligand-activated nuclear receptor best known for its involvement in adipogenesis and glucose homeostasis. PPARγ activity has also been associated with neuroprotection in different neurological disorders, but the mechanisms involved in PPARγ effects in the nervous system are still unknown. Here we describe a new functional role for PPARγ in neuronal responses to injury. We found both PPAR transcripts and protein within sensory axons and observed an increase in PPARγ protein levels after sciatic nerve crush. This was correlated with increased retrograde transport of PPARγ after injury, increased association of PPARγ with the molecular motor dynein, and increased nuclear accumulation of PPARγ in cell bodies of sensory neurons. Furthermore, PPARγ antagonists attenuated the response of sensory neurons to sciatic nerve injury, and inhibited axonal growth of both sensory and cortical neurons in culture. Thus, axonal PPARγ is involved in neuronal injury responses required for axonal regeneration. Since PPARγ is a major molecular target of the thiazolidinedione (TZD) class of drugs used in the treatment of type II diabetes, several pharmaceutical agents with acceptable safety profiles in humans are available. Our findings provide motivation and rationale for the evaluation of such agents for efficacy in central and peripheral nerve injuries.