A replication of the study 'Adverse effects of spinal manipulation: a systematic review'.
To assess the significance of adverse events after spinal manipulation therapy (SMT) by replicating and critically reviewing a paper commonly cited when reviewing adverse events of SMT as reported by Ernst (J Roy Soc Med 100:330-338, 2007). Replication of a 2007 Ernst paper to compare the details recorded in this paper to the original source material. Specific items that were assessed included the time lapse between treatment and the adverse event, and the recording of other significant risk factors such as diabetes, hyperhomocysteinemia, use of oral contraceptive pill, any history of hypertension, atherosclerosis and migraine. The review of the 32 papers discussed by Ernst found numerous errors or inconsistencies from the original case reports and case series. These errors included alteration of the age or sex of the patient, and omission or misrepresentation of the long term response of the patient to the adverse event. Other errors included incorrectly assigning spinal manipulation therapy (SMT) as chiropractic treatment when it had been reported in the original paper as delivered by a non-chiropractic provider (e.g. Physician).The original case reports often omitted to record the time lapse between treatment and the adverse event, and other significant clinical or risk factors. The country of origin of the original paper was also overlooked, which is significant as chiropractic is not legislated in many countries. In 21 of the cases reported by Ernst to be chiropractic treatment, 11 were from countries where chiropractic is not legislated. The number of errors or omissions in the 2007 Ernst paper, reduce the validity of the study and the reported conclusions. The omissions of potential risk factors and the timeline between the adverse event and SMT could be significant confounding factors. Greater care is also needed to distinguish between chiropractors and other health practitioners when reviewing the application of SMT and related adverse effects.


Room-temperature distance measurements using RIDME and the orthogonal spin labels trityl/nitroxide.
Electron paramagnetic resonance (EPR) based nanometer distance measurements at ambient temperatures are of particular interest for structural biology applications. The nitroxide spin labels commonly used in EPR reveal relatively short transverse relaxation under these conditions, which limits their use for detecting static dipolar interactions. At the same time, the longitudinal relaxation of nitroxide spin labels is still long enough to allow using them as 'pumped' species in the relaxation induced dipolar modulation enhancement (RIDME) experiment where the detection is carried out on the slower relaxing triarylmethyl (TAM) spin labels. In the present study, we report the first demonstration of room-temperature RIDME distance measurements in nucleic acids using TAM as the slow-relaxing detected species and traditional nitroxide as the fast-relaxing partner spin. Two types of immobilizers, glassy trehalose and the modified silica gel Nucleosil, were used for immobilization of the spin-labeled biomolecules. The room-temperature RIDME-based distance distributions are in good agreement with those measured at 80 K by other techniques. Room-temperature RIDME on the spin pairs trityl/nitroxide may become a useful method for the structural characterization of biomacromolecules and biomolecular complexes at near physiological temperatures.


Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.
The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors and ossifying jaw fibromas. The gene causing HPT-JT, HRPT2, is located on chromosome 1q31.2 and consists of 17 exons that encode a 531-amino acid protein, designated parafibromin. We recently identified six Roma families in Portugal with 56 members (11 affected and 45 asymptomatic), who had the HPT-JT syndrome. We postulated that they may have a common ancestor and that the HPT-JT syndrome may be due to a mutation of the HRPT2 gene. Haplotype analysis using 14 chromosome 1q24-q32 polymorphic markers showed that the 11 affected individuals shared a common haplotype defined by seven markers that spanned an approximately 12.5-cM region, flanked centromerically by D1S202 and telomerically by D1S306. DNA sequence analysis identified a 2-bp (TG or GT) frameshift deletion in exon 8, which predicts a truncated parafibromin protein, in all 11 affected individuals. This mutation was also found in 19 unaffected individuals (age range, 12-74 yr) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. Thus, the HPT-JT syndrome in six Roma families from Portugal is due to a novel founder mutation in the HRPT2 gene.


A Qualitative Exploration of Perceptions of a Digital Intervention to Promote Physical Activity in Older Adults.
This study explored participant views of a web-based physical activity intervention for older adults and examined how they resonate with the key principles that guided intervention development. Qualitative interviews were carried out with 52 older adults. A deductive qualitative analysis approach was taken, based around the intervention's key principles. Participants expressed mostly positive views of the intervention features, broadly confirming the appropriateness of the key principles, which were to: (a) encourage intrinsic motivation for physical activity, (b) minimize the risk of users receiving activity suggestions that are inappropriate or unsafe, (c) offer users choice regarding the activities they engage with and build confidence to undertake more activity, and (d) minimize the cognitive load and need to engage with the intervention website. The findings also identified ways in which content could be improved to further increase acceptability. This study illustrates how using the person-based approach has enabled the identification and implementation of features that older adults appreciate.


Oncogenic Ras dominates overexpression of E-cadherin in malignant transformation of intestinal epithelial cells.
Loss of the adherens junction protein E-cadherin is a critical event during Ras-mediated transformation of intestinal epithelial cells. The purpose of our study was to determine if overexpression of E-cadherin prevents Ras-induced malignant transformation and suppresses cell growth. Rat intestinal epithelial cells were constructed with a mutated human Ha-RasVal12 cDNA. In these cells, Ras is constitutively expressed or induced by addition of isopropyl-1-thio-B-D-galactopyranoside. Cells were transfected with a bicistronic retroviral system that expressed green fluorescent protein alone or this protein and human E-cadherin. E-cadherin expression was measured by Western blot analysis, and localization by immunofluorescence. Anchorage-independent growth in soft agar was examined as well as tumor growth in nude mice. After Ras induction, endogenous E-cadherin was downregulated, whereas overexpression of human E-cadherin was sustained. Oncogenic Ras dominated overexpression of E-cadherin by causing malignant transformation and E-cadherin mislocalization. Ras also promoted growth in soft agar and tumors in nude mice despite E-cadherin overexpression. Oncogenic Ras subverts the tumor suppressor activity of E-cadherin in Ras-transformed intestinal epithelial cells by downregulating endogenous E-cadherin and mislocalizing transfected E-cadherin. The role of E-cadherin as a tumor suppressor in intestinal malignancies may be restricted by mutated or overactive Ras.


Suicide trends following the Taiwan earthquake of 1999: empirical evidence and policy implications.
Mental health impact of severe earthquakes on survivors has attracted considerable attention. Suicide represents a terminal outcome of the spectrum of potential major mental health issues spawned by severe earthquakes. This study used time-series analysis to examine the time trends of increased suicide rates after the Chi-Chi earthquake of 1999 in Taiwan in the affected counties. Adult cause of death data were used to study monthly suicide rates per 100,000 adult population in the study and control counties, during January 1995 to December 2001. Box and Tiao's event intervention analysis was used to examine changes in monthly suicide rates before and after the Chi-Chi earthquake. During the post-quake period, October 1999 to December 2001, the mean monthly suicide rate in the affected counties was 1.567 per 100,000, compared with the control counties' rate of 1.297 per 100,000. Mean monthly suicide rate among the high-exposure group was 42% higher during the 26 months following the earthquake than the average for the entire observation period. Examined by time trends, the increased suicide rate registered in the first month following the quake began a monthly gradual decline by 0.7/100,000 thereafter, accounting for a total reduction of 98% in quake-related suicides by the end of 10 months. Suicide rates fell to the baseline level after 10 months. We found that the mean monthly suicide rate for earthquake victims was higher while the low-exposure group remained stable and consistent throughout the observation period, indicating that the impact on the high-exposure group was attributable to the earthquake. This indicates the need for providing strengthened psychiatric services during the first year following major disasters.


Exploring the Genetic Correlation Between Growth and Immunity Based on Summary Statistics of Genome-Wide Association Studies.
The relationship between growth and immune phenotypes has been presented in the context of physiology and energy allocation theory, but has rarely been explained genetically in humans. As more summary statistics of genome-wide association studies (GWAS) become available, it is increasingly possible to explore the genetic relationship between traits at the level of genome-wide summary statistics. In this study, publicly available summary statistics of growth and immune related traits were used to evaluate the genetic correlation coefficients between immune and growth traits, as well as the cause and effect relationship between them. In addition, pleiotropic variants and KEGG pathways were identified. As a result, we found negative correlations between birthweight and immune cell count phenotypes, a positive correlation between childhood head circumference and eosinophil counts (EO), and positive or negative correlations between childhood body mass index and immune phenotypes. Statistically significant negative effects of immune cell count phenotypes on human height, and a slight but significant negative influence of human height on allergic disease were also observed. A total of 98 genomic regions were identified as containing variants potentially related to both immunity and growth. Some variants, such as rs3184504 located in SH2B3, rs13107325 in SLC39A8, and rs1260326 located in GCKR, which have been identified to be pleiotropic SNPs among other traits, were found to also be related to growth and immune traits in this study. Meanwhile, the most frequent overlapping KEGG pathways between growth and immune phenotypes were autoimmune related pathways. Pleiotropic pathways such as the adipocytokine signaling pathway and JAK-STAT signaling pathway were also identified to be significant. The results of this study indicate the complex genetic relationship between growth and immune phenotypes, and reveal the genetic background of their correlation in the context of pleiotropy.


Polyvalent Rev decoys act as artificial Rev-responsive elements.
Interactions between Rev and the Rev-responsive element (RRE) control the order, rate, and extent of gene expression in human immunodeficiency virus type 1. Rev decoys may therefore prove to be useful RNA therapeutics for the treatment of AIDS. To improve upon the current generation of Rev decoys that bind single Rev molecules, it would be useful to generate polyvalent Rev decoys that could bind multiple Rev molecules. J. Kjems and P. A. Sharp (J. Virol. 67:4769-4776, 1993) originally constructed functional polyvalent Rev decoys, but the structural context of these polyvalent decoys remains unclear, and it has been argued that the individual decoys were either structurally discrete (Kjems and Sharp, J. Virol. 67:4769-4776, 1993) or were part of an extended helix (R. W. Zemmel et al., Mol. Biol. 258:763-777, 1996). To resolve the differences between these models, we have designed and synthesized concatemers of Rev-binding elements (RBEs) that fold to form multiple, discrete, high-affinity Rev-binding sites. We find that the concatenated RBEs can facilitate the cytoplasmic transport of viral mRNAs and therefore likely bind multiple Rev molecules. These artificial RREs may simultaneously sequester Rev and hinder access to the cellular transport machinery.


[Neurological phenocopying].
To expand the -supposedly- narrow relationships that exist between genes and clinical syndromes by reflecting on several illustrative examples that disturb current simplistic genotype: phenotype correlations, and to explore a variety of biological mechanisms that account for this emerging phenomenon. Because it is well known that mutations in a single gene can give rise to numerous phenotypes, it would appear, at least intuitively, that the converse relationship might also hold true: that different genotypes may converge on just one single phenotype. Several examples taken from the study of selected neurological diseases illustrate that the latter principle indeed occurs in nature because disparate human genetic anomalies manifest similarly by exhibiting only a relatively limited phenotypic repertoire. This interesting biological phenomenon and vexing clinical problem is best described as phenocopying. Conditions such as spinal muscular atrophy, congenital glycosylation disorders, and mitochondrial diseases are but a few notorious examples of phenocopying. The nervous system is endowed with a limited number of genes and of types of molecules and, especially during development, its functional repertoire, at least from an observable point of view, is also limited. Therefore, ample genotyping capabilities are necessary to avoid erring in the process of diagnostic attribution because of phenocopying.


Hardness Analysis and Empirical Studies of the Relations among Robustness, Topology and Flow in Dynamic Networks.
Network robustness is the ability of a network to maintain performance after disruption, thus it is an important index for network designers to refer to. Every actual network has its own topology structure, flow magnitude (scale) and flow distribution. How the robustness relates to these factors still remains unresolved. To analyze the relations, we first established a robustness problem model, studied the hardness of a special case of the model, and generated a lot of representative network instances. We conducted experiments on these instances, deleting 5% to 50% edges on each instance and found that the robustness of a network has an approximate linearity to its structural entropy and flow entropy, when the correlation coefficient between the structure and flow is fixed. We also found that robustness is unlikely to have a relation to the flow scale and edge scale in our model. The empirical studies thus can provide a way of quickly estimating the robustness of real-world networks by using the regression coefficients we obtained during the experiments. We conducted computation on a real-world dataset and got favorable results, which exhibited the effectiveness of the estimation.


Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis.
We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.


[Violence against the elderly: analysis of the reports made in the health sector--Brazil, 2010].
The scope of this study was to describe reports of violence against the elderly (e" 60 years) reported in the Information System for Notifiable Diseases - net version (Sinan Net) in 2010. We conducted a descriptive, retrospective study with data analyzed by Stata version 11. We estimated proportion ratios (PR) of violence according to selected variables. Of the 3,593 reports of violence against the elderly, 52.3% were against females. Physical violence was significantly more frequent against males (PR=0.82) in the group aged 60 to 69 years, out of the home, committed by offenders who were not sons and were suspected of drinking alcohol. Psychological violence was more common among elderly people (PR=2.17), in the home, inflicted by sons, with suspected chronic alcohol abuse. Negligence was predominant among females (P R=1.24), in the group above 70 years of age, in the home, recurrently perpetrated by sons. Sexual violence was more common against females (PR=5.21), by offenders who were not children, but who consumed alcohol. The knowledge of the different manifestations of violence against the elderly supports actions to combat them, identifying characteristics of vulnerability in which support networks may intervene.


Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters.
Class I molecules of the major histocompatibility complex (MHC) bind and present peptides derived from the degradation of intracellular, often cytoplasmic, proteins, whereas class II molecules usually present proteins from the extracellular environment. It is not known how peptides derived from cytoplasmic proteins cross a membrane before presentation at the cell surface. But certain mutations in the MHC can prevent presentation of antigens with class I molecules. In addition, mutations possibly in the MHC can affect presentation by class II molecules. Here we report the finding of a new gene in the MHC that might have a role in antigen presentation and which is related to the ABC (ATP-binding cassette) superfamily of transporters. This superfamily includes the human multidrug-resistance protein, and a series of transporters from bacteria and eukaryotic cells capable of transporting a range of substrates, including peptides.


Human aldehyde dehydrogenase 3A1 (ALDH3A1) exhibits chaperone-like function.
Aldehyde dehydrogenase 3A1 (ALDH3A1) is a metabolic enzyme that catalyzes the oxidation of various aldehydes. Certain types of epithelial tissues in mammals, especially those continually exposed to environmental stress (e.g., corneal epithelium), express ALDH3A1 at high levels and its abundance in such tissues is perceived to help to maintain cellular homeostasis under conditions of oxidative stress. Metabolic as well as non-metabolic roles for ALDH3A1 have been associated with its mediated resistance to cellular oxidative stress. In this study, we provide evidence that ALDH3A1 exhibits molecular chaperone-like activity further supporting its multifunctional role. Specifically, we expressed and purified the human ALDH3A1 in E. coli and used the recombinant protein to investigate its in vitro ability to protect SmaI and citrate synthase (from precipitation and/or deactivation) under thermal stress conditions. Our results indicate that recombinant ALDH3A1 exhibits significant chaperone function in vitro. Furthermore, over-expression of the fused histidine-tagged ALDH3A1 confers host E. coli cells with enhanced resistance to thermal shock, while ALDH3A1 over-expression in the human corneal cell line HCE-2 was sufficient for protecting them from the cytotoxic effects of both hydrogen peroxide and tert-butyl hydroperoxide. These results further support the chaperone-like function of human ALDH3A1. Taken together, ALDH3A1, in addition to its primary metabolic role in fundamental cellular detoxification processes, appears to play an essential role in protecting cellular proteins against aggregation under stress conditions.


Comparison of the Antimicrobial Efficacy of Various Contact Lens Solutions to Inhibit the Growth of Pseudomonas aeruginosa and Staphylococcus aureus.
Soft contact lenses provide perfect conditions for the breeding of pathogens. The study is a prospective, experimental study, conducted to know the antimicrobial ability of multipurpose contact lens solution against standard strains of Staphylococcus aureus and Pseudomonas aeruginosa by the stand-alone test. The test method is based on the procedures in the ISO 14729 standard primary stand-alone test. Three multipurpose contact lens care solutions commercially available in Mangalore markets, namely, Biotrue (Bausch & Lomb), Opti-Free Replenish (Alcon), and Aquasoft (Stericon Pharma), were tested for its antimicrobial effect in the microbiology lab at Kasturba Medical College, Mangalore. According to this study, the solutions named "Biotrue" and "Aquasoft" met the primary stand-alone and reached the 3log reduction and 5log reduction criteria in the manufacturer recommended time, respectively. No conclusion could be drawn for Opti-Free Replenish since the minimum recommended disinfection time was overnight, whereas it was noted for 6 hr only, and it should have been experimented further. The effectiveness of multipurpose solutions varies against different bacterial species. We have observed that the antimicrobial activity of different solutions varies with respect to time of incubation, and also there was a marked difference in the activity of some solutions against S. aureus and P. aeruginosa. So, it is necessary for the contact lens users to store their lenses in solutions for longer duration of hours. It is also recommended to use solutions that clear the ISO 14729 standards for better health conditions of the eye.


Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.
Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.


Integrated Bottom-Up and Top-Down Proteomics of Patient-Derived Breast Tumor Xenografts.
Bottom-up proteomics relies on the use of proteases and is the method of choice for identifying thousands of protein groups in complex samples. Top-down proteomics has been shown to be robust for direct analysis of small proteins and offers a solution to the "peptide-to-protein" inference problem inherent with bottom-up approaches. Here, we describe the first large-scale integration of genomic, bottom-up and top-down proteomic data for the comparative analysis of patient-derived mouse xenograft models of basal and luminal B human breast cancer, WHIM2 and WHIM16, respectively. Using these well-characterized xenograft models established by the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium, we compared and contrasted the performance of bottom-up and top-down proteomics to detect cancer-specific aberrations at the peptide and proteoform levels and to measure differential expression of proteins and proteoforms. Bottom-up proteomic analysis of the tumor xenografts detected almost 10 times as many coding nucleotide polymorphisms and peptides resulting from novel splice junctions than top-down. For proteins in the range of 0-30 kDa, where quantitation was performed using both approaches, bottom-up proteomics quantified 3,519 protein groups from 49,185 peptides, while top-down proteomics quantified 982 proteoforms mapping to 358 proteins. Examples of both concordant and discordant quantitation were found in a ∼60:40 ratio, providing a unique opportunity for top-down to fill in missing information. The two techniques showed complementary performance, with bottom-up yielding eight times more identifications of 0-30 kDa proteins in xenograft proteomes, but failing to detect differences in certain posttranslational modifications (PTMs), such as phosphorylation pattern changes of alpha-endosulfine. This work illustrates the potency of a combined bottom-up and top-down proteomics approach to deepen our knowledge of cancer biology, especially when genomic data are available.


Pharmacological activation of PPAR-γ: a potential therapy for skin fibrosis.
Skin fibrosis caused by excessive collagen synthesis and deposition in the dermis affects the quality of daily life of hundreds of thousands of people around the world. The skin quality, including its smoothness in young age and wrinkly during the aging process, depends largely on the levels of extracellular matrix proteins such as collagen in skin. As physiological levels of collagen are desirable for skin homeostasis, beauty, and its flexibility, too much collagen deposition in the skin is associated with tight hard skin, loss of adipose layer, and flexibility, the pathological manifestations of skin fibrosis in fibrotic diseases such as scleroderma. To understand the molecular basis of skin fibrosis and in search of its therapy, different cellular, molecular, epigenetic, and preclinical studies have been undertaken to control abnormal excessive synthesis and accumulation of matrix protein collagen. Over the last two decades, numerous phase 1 through 3 clinical trials have been conducted to test the safety and efficacy of a wide variety of compounds in amelioration of skin fibrosis and other pathologies in scleroderma, yet, no effective therapy for skin fibrosis is available. This article solely focuses on the role of a nuclear receptor and transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR-γ), as an anti-skin fibrotic driving force and the potential therapeutic efficacies of PPAR-γ-specific ligands/agonists including antidiabetic drugs and other natural or semi-synthetic compounds derived from cannabis in amelioration of skin fibrosis in scleroderma. The underlying molecular basis of agonist-activated PPAR-γ-mediated suppression of profibrogenic signaling and skin fibrogenesis is also highlighted.


Twin reversed arterial perfusion (TRAP) sequence in association with VACTERL association: a case report.
Twin reversed arterial perfusion (TRAP) sequence is a rare complication of multiple pregnancy caused by defects in early embryogenesis. The pump twin supplies the acardiac recipient twin with blood, and although the pump twin is usually structurally normal, congenital anomalies have sometimes been reported. We report a unique case of twin reversed arterial perfusion sequence with a prenatal diagnosis of VACTERL association in the surviving pump twin. A 24-year-old Caucasian woman presented at 11 weeks' gestation with a monochorionic, monoamniotic twin pregnancy. A reversed arterial flow was noted on a Doppler imaging study coming from the larger, apparently normal twin to the smaller, grossly abnormal twin, and a diagnosis of twin reversed arterial perfusion sequence was made. Cardiac activity was undetectable in the recipient twin by 16 weeks' gestation. Further detailed assessment at 18 weeks' gestation revealed multiple congenital anomalies of the surviving pump twin, in keeping with a diagnosis of VACTERL association. A live infant girl was delivered at 39 weeks by elective cesarean section. She underwent extensive surgery with subsequent normal development at the age of two years. The co-existence of two rare and complex conditions in this unique case raises interesting questions about the role of early defects in embryogenesis and their subsequent effects on fetal development. This case also highlights the importance of prenatal diagnosis of major congenital anomalies to the plan treatment, reduce morbidity and aid the survival of affected children.


Nuts as a replacement for carbohydrates in the diabetic diet.
Fat intake, especially monounsaturated fatty acid (MUFA), has been liberalized in diabetic diets to preserve HDL cholesterol and improve glycemic control, yet the exact sources have not been clearly defined. Therefore, we assessed the effect of mixed nut consumption as a source of vegetable fat on serum lipids and HbA(1c) in type 2 diabetes. A total of 117 type 2 diabetic subjects were randomized to one of three treatments for 3 months. Supplements were provided at 475 kcal per 2,000-kcal diet as mixed nuts (75 g/day), muffins, or half portions of both. The primary outcome was change in HbA(1c). The relative increase in MUFAs was 8.7% energy on the full-nut dose compared with muffins. Using an intention-to-treat analysis (n = 117), full-nut dose (mean intake 73 g/day) reduced HbA(1c) (-0.21% absolute HbA(1c) units, 95% CI -0.30 to -0.11, P < 0.001) with no change after half-nut dose or muffin. Full-nut dose was significantly different from half-nut dose (P = 0.004) and muffin (P = 0.001), but no difference was seen between half-nut dose and muffins. LDL cholesterol also decreased significantly after full-nut dose compared with muffin. The LDL cholesterol reduction after half-nut dose was intermediate and not significantly different from the other treatments. Apolipoprotein (apo) B and the apoB:apoA1 ratio behaved similarly. Nut intake related negatively to changes in HbA(1c) (r = -0.20, P = 0.033) and LDL cholesterol (r = -0.24, P = 0.011). Two ounces of nuts daily as a replacement for carbohydrate foods improved both glycemic control and serum lipids in type 2 diabetes.


A habitable fluvio-lacustrine environment at Yellowknife Bay, Gale crater, Mars.
The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. Carbon, hydrogen, oxygen, sulfur, nitrogen, and phosphorus were measured directly as key biogenic elements; by inference, phosphorus is assumed to have been available. The environment probably had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars.


Clostridium perfringens identifies source of pollution and reference streams in a tropical highland environment.
Clostridium perfringens was analysed in soils from a tropical highland catchment and corresponding headwater streams at baseflow condition in order to understand the contribution of soils to the microbiological quality of stream water and the feasibility of using these streams as surrogate for negative control (reference streams). The concentrations of C. perfringens depended on the sample matrix. C. perfringens concentrations were significantly higher in the catchment soil than in the stream water (P < 0.05, n = 20). In addition, C. perfringens concentrations in the catchment soil remarkably predicted C. perfringens concentrations in the stream water (i.e., 82% of variations in C. perfringens concentrations in water were predicted by C. perfringens concentrations in soil; P < 0.05, n = 20). This suggests that the catchment soils contributed C. perfringens to the stream water. Despite the observed contamination, the concentrations of C. perfringens (geometric mean of 32 cfu/100 cm3) in the stream water was below the recommended safe level for tropical freshwater systems and extremely lower than that detected in anthropogenically influenced rivers. This concentration was defined as an acceptable level of disturbance, and a reference concentration that can serve as surrogate for negative control in the studied tropical environment.


Head orientation and trajectory of locomotion during jumping and walking in domestic chicks.
The relationships between the head orientation of domestic chicks and their trajectory of locomotion were examined in three tasks: jumping over gaps of different depths and widths; walking on surfaces of different slopes; and walking on a level transparent surface above a slope. Head orientation was measured as the angle between the horizontal and a line joining the centre of the eye to the beak tip. At the initiation of a jump, head angle increased with increasing depth of the gap but was not affected by gap width. During walking, head angle increased with increasing downwards slope of the walking surface and decreased with increasing upwards slope. The same effect of a downwards slope was observed when chicks walked on a level transparent surface above a slope, indicating that the effect does not depend on kinaesthetic information. The findings are discussed together with measurements of pigeon head orientation during landing flight. Explanations in terms of specialised retinal areas, binocular visual fields and lower visual field myopia are considered and rejected. It is proposed that the results instead reflect a general role of head orientation as a component in the visual control of locomotion in birds.


Using Deep Learning for Image-Based Plant Disease Detection.
Crop diseases are a major threat to food security, but their rapid identification remains difficult in many parts of the world due to the lack of the necessary infrastructure. The combination of increasing global smartphone penetration and recent advances in computer vision made possible by deep learning has paved the way for smartphone-assisted disease diagnosis. Using a public dataset of 54,306 images of diseased and healthy plant leaves collected under controlled conditions, we train a deep convolutional neural network to identify 14 crop species and 26 diseases (or absence thereof). The trained model achieves an accuracy of 99.35% on a held-out test set, demonstrating the feasibility of this approach. Overall, the approach of training deep learning models on increasingly large and publicly available image datasets presents a clear path toward smartphone-assisted crop disease diagnosis on a massive global scale.


Analysis of the ospC regulatory element controlled by the RpoN-RpoS regulatory pathway in Borrelia burgdorferi.
Outer surface lipoprotein C (OspC) is a key virulence factor of Borrelia burgdorferi. ospC is differentially regulated during borrelial transmission from ticks to rodents, and such regulation is essential for maintaining the spirochete in its natural enzootic cycle. Recently, we showed that the expression of ospC in B. burgdorferi is governed by a novel alternative sigma factor regulatory network, the RpoN-RpoS pathway. However, the precise mechanism by which the RpoN-RpoS pathway controls ospC expression has been unclear. In particular, there has been uncertainty regarding whether ospC is controlled directly by RpoS (sigma(s)) or indirectly through a transactivator (induced by RpoS). Using deletion analyses and genetic complementation in an OspC-deficient mutant of B. burgdorferi, we analyzed the cis element(s) required for the expression of ospC in its native borrelial background. Two highly conserved upstream inverted repeat elements, previously implicated in ospC regulation, were not required for ospC expression in B. burgdorferi. Using similar approaches, a minimal promoter that contained a canonical -35/-10 sequence necessary and sufficient for sigma(s)-dependent regulation of ospC was identified. Further, targeted mutagenesis of a C at position -15 within the extended -10 region of ospC, which is postulated to function like the strategic C residue important for Esigma(s) binding in Escherichia coli, abolished ospC expression. The minimal ospC promoter also was responsive to coumermycin A(1), further supporting its sigma(s) character. The combined data constitute a body of evidence that the RpoN-RpoS regulatory network controls ospC expression by direct binding of sigma(s) to a sigma(s)-dependent promoter of ospC. The implication of our findings to understanding how B. burgdorferi differentially regulates ospC and other ospC-like genes via the RpoN-RpoS regulatory pathway is discussed.


Framework to evaluate ecological and social outcomes of collaborative management: lessons from implementation with a northern Arizona collaborative group.
As collaborative groups gain popularity as an alternative means for addressing conflict over management of public lands, the need for methods to evaluate their effectiveness in achieving ecological and social goals increases. However, frameworks that examine both effectiveness of the collaborative process and its outcomes are poorly developed or altogether lacking. This paper presents and evaluates the utility of the holistic ecosystem health indicator (HEHI), a framework that integrates multiple ecological and socioeconomic criteria to evaluate management effectiveness of collaborative processes. Through the development and application of the HEHI to a collaborative in northern Arizona, the Diablo Trust, we present the opportunities and challenges in using this framework to evaluate the ecological and social outcomes of collaborative adaptive management. Baseline results from the first application of the HEHI are presented as an illustration of its potential as a co-adaptive management tool. We discuss lessons learned from the process of selecting indicators and potential issues to their long-term implementation. Finally, we provide recommendations for applying this framework to monitoring and adaptive management in the context of collaborative management.


Biomechanical Assessment of Locking Plate Fixation of Comminuted Proximal Olecranon Fractures.
To determine if mean ultimate strength or failure mechanism differed between comminuted olecranon fractures created at the proximal 25% or 50% of the trochlear notch and fixed with precontoured posterior locking plates (PLPs). Comminuted osteotomies were created in 10 matched pairs of cadaveric upper extremities at either the proximal 25% or 50% of the trochlear notch after quantitative computed tomography scans were performed to evaluate bone mineral density. Variable-angle olecranon PLPs were fixed to the specimens. The triceps tendon of each specimen was loaded cyclically and then to failure. Comparison of mean force at failure (displacement >2 mm) was performed using the 2-tailed t test. There were no significant differences in specimen bone mineral density within matched pairs. Nineteen specimens failed by olecranon bisection fracture in the sagittal plane. Specimens in the 25% osteotomy group failed at lower ultimate forces of 808 N (SD ± 474 N) versus 1058 N (SD ± 480 N) in the 50% osteotomy group (P = 0.044). The ultimate strength of comminuted olecranon fracture fixation with a PLP decreases significantly if the fracture is proximal to the midpoint of the trochlear notch. Fractures proximal to the midpoint of the trochlear notch may benefit from supplemental fixation or suture augmentation to prevent failure, particularly at force ranges higher than those experienced during active elbow range of motion.


Intravenous drug preparation: the infection risks.
The preparation of intravenous drugs is a common yet inherently dangerous nursing procedure. Potential errors associated with this procedure include incorrect drugs, doses and routes of administration. As a consequence of these recognized risks, a variety of checks are used to optimize safety. This paper explores the literature around infusate contamination, which can cause infusate-related bloodstream infection (IR-BSI). In addition, this paper will discuss the mechanisms of infusate contamination, as well as details of the types of microorganisms that cause contamination and the types of drugs that enable proliferation of microorganisms. Deficits within current guidance are revealed. The paper concludes that IR-BSI is a significant but under-recognized risk to patients. As microbial contamination sufficient to cause IR-BSI is not detectable to the naked eye, those who prepare intravenous drugs must be more aware of contamination risks and how to reduce them.


Caring for the dying patient in the ICU--the past, the present and the future.
The aim of this paper is to present the state of the science concerning issues in end-of-life (EOL) care which have an impact on intensive care nurses possibilities to provide nursing care for dying patients and their families. The perspective of families is also illuminated and finally ethical challenges in the present and for the future are discussed. The literature review revealed that the problem areas nurses report concerning EOL care have been the same over three decades. Most problems are related to inter-disciplinary collaboration and communication with the medical profession about the transition from cure to comfort care. Nurses need enhanced communication skills in their role as the patient's advocate. Education in EOL care and a supportive environment are prerequisites for providing EOL care. Losing a loved one in the ICU is a stressful experience for close relatives and nursing care has a profound impact on families' memories of the EOL care given to their loved ones. It is therefore important that ICU nurses are aware of families' needs when a loved one is dying and that follow-up services are appreciated by bereaved family members. Ethical challenges are related to changed sedation practices, organ donation, globalisation and cultural sensitivity.


Carbon and Nitrogen Uptake of Calcareous Benthic Foraminifera along a Depth-Related Oxygen Gradient in the OMZ of the Arabian Sea.
Foraminifera are an important faunal element of the benthos in oxygen-depleted settings such as Oxygen Minimum Zones (OMZs) where they can play a relevant role in the processing of phytodetritus. We investigated the uptake of phytodetritus (labeled with (13)C and (15)N) by calcareous foraminifera in the 0-1 cm sediment horizon under different oxygen concentrations within the OMZ in the eastern Arabian Sea. The in situ tracer experiments were carried out along a depth transect on the Indian margin over a period of 4 to 10 days. The uptake of phytodetrital carbon within 4 days by all investigated species shows that phytodetritus is a relevant food source for foraminifera in OMZ sediments. The decrease of total carbon uptake from 540 to 1100 m suggests a higher demand for carbon by species in the low-oxygen core region of the OMZ or less food competition with macrofauna. Especially Uvigerinids showed high uptake of phytodetrital carbon at the lowest oxygenated site. Variation in the ratio of phytodetrital carbon to nitrogen between species and sites indicates that foraminiferal carbon and nitrogen use can be decoupled and different nutritional demands are found between species. Lower ratio of phytodetrital carbon and nitrogen at 540 m could hint for greater demand or storage of food-based nitrogen, ingestion, or hosting of bacteria under almost anoxic conditions. Shifts in the foraminiferal assemblage structure (controlled by oxygen or food availability) and in the presence of other benthic organisms are likely to account for observed changes in the processing of phytodetritus in the different OMZ habitats. Foraminifera dominate the short-term processing of phytodetritus in the OMZ core but are less important in the lower OMZ boundary region of the Indian margin as biological interactions and species distribution of foraminifera change with depth and oxygen levels.


Occurrence of Triatoma costalimai (Hemiptera: Reduviidae) in different environments and climatic seasons: a field study in the Brazilian savanna.
Trypanosoma cruzi-infected specimens of Triatoma costalimai have been detected in domiciliary units of Central Brazil, thereby maintaining the potential risk of vectorial transmission of Chagas disease. The aim of this study was to determine the occurrence and natural infection of T. costalimai in different environments (gallery forest, dry forest and peridomicile) and climatic seasons (wet and dry), in the municipality of Mambaí, State of Goiás, Brazil. Triatomines were captured in October 2010 and in June 2011, employing two different methods (manual capture and mouse-baited adhesive traps). The insects were later separated by sex and nymphal stage, counted and examined parasitologically by abdominal compression and microscopic analysis of feces. Triatoma costalimai was found in three environments and in the two seasons studied. Overall, capture success of 900 traps and 60 blocks of rocks inspected was 5.8% and 11.7%, respectively. The occurrence of T. costalimai was higher among rocks in the peridomicile, where 97% of the 131 specimens were captured. The proportion of nymphs (98%) was much higher than that of adults, which were only detected in peridomicile. Most (95%) insects were captured during the wet season, with predominance of early-stage nymphs. None of the 43 specimens examined were infected by trypanosomatids. The results indicate a greater occurrence of T. costalimai in peridomiciliary environments and during the wet season in Mambaí, Goiás, highlighting the synanthropic behavior of this triatomine species in one area of the Brazilian savanna and the importance of entomological surveillance.


Berlin statement on legacy and emerging contaminants in polar regions.
Polar regions should be given greater consideration with respect to the monitoring, risk assessment, and management of potentially harmful chemicals, consistent with requirements of the precautionary principle. Protecting the vulnerable polar environments requires (i) raising political and public awareness and (ii) restricting and preventing global emissions of harmful chemicals at their sources. The Berlin Statement is the outcome of an international workshop with representatives of the European Commission, the Arctic Council, the Antarctic Treaty Consultative Meeting, the Stockholm Convention on Persistent Organic Pollutants (POPs), environmental specimen banks, and data centers, as well as scientists from various international research institutions. The statement addresses urgent chemical pollution issues in the polar regions and provides recommendations for improving screening, monitoring, risk assessment, research cooperation, and open data sharing to provide environmental policy makers and chemicals management decision-makers with relevant and reliable contaminant data to better protect the polar environments. The consensus reached at the workshop can be summarized in just two words: "Act now!" Specifically, "Act now!" to reduce the presence and impact of anthropogenic chemical pollution in polar regions by. •Establishing participatory co-development frameworks in a permanent multi-disciplinary platform for Arctic-Antarctic collaborations and establishing exchanges between the Arctic Monitoring and Assessment Program (AMAP) of the Arctic Council and the Antarctic Monitoring and Assessment Program (AnMAP) of the Scientific Committee on Antarctic Research (SCAR) to increase the visibility and exchange of contaminant data and to support the development of harmonized monitoring programs. •Integrating environmental specimen banking, innovative screening approaches and archiving systems, to provide opportunities for improved assessment of contaminants to protect polar regions.


Assessing the Influence of Vegan, Vegetarian and Omnivore Oriented Westernized Dietary Styles on Human Gut Microbiota: A Cross Sectional Study.
Diet and lifestyle have a strong influence on gut microbiota, which in turn has important implications on a variety of health-related aspects. Despite great advances in the field, it remains unclear to which extent the composition of the gut microbiota is modulated by the intake of animal derived products, compared to a vegetable based diet. Here the specific impact of vegan, vegetarian, and omnivore feeding type on the composition of gut microbiota of 101 adults was investigated among groups homogeneous for variables known to have a role in modulating gut microbial composition such as age, anthropometric variables, ethnicity, and geographic area. The results displayed a picture where the three different dietetic profiles could be well distinguished on the basis of participant's dietetic regimen. Regarding the gut microbiota; vegetarians had a significantly greater richness compared to omnivorous. Moreover, counts of Bacteroidetes related operational taxonomic units (OTUs) were greater in vegans and vegetarians compared to omnivores. Interestingly considering the whole bacterial community composition the three cohorts were unexpectedly similar, which is probably due to their common intake in terms of nutrients rather than food, e.g., high fat content and reduced protein and carbohydrate intake. This finding suggests that fundamental nutritional choices such as vegan, vegetarian, or omnivore do influence the microbiota but do not allow to infer conclusions on gut microbial composition, and suggested the possibility for a preferential impact of other variables, probably related to the general life style on shaping human gut microbial community in spite of dietary influence. Consequently, research were individuals are categorized on the basis of their claimed feeding types is of limited use for scientific studies, since it appears to be oversimplified.


The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence.
Evidence of LRRK2 haplotypes associated with Parkinson's disease (PD) risk was recently found in the Chinese population from Singapore, and a common LRRK2 missense variant, Gly2385Arg, was independently detected as a putative risk factor for PD in the Chinese population from Taiwan. To test the association between the Gly2385Arg variant in a large case-control sample of Chinese ethnicity from Singapore, and to perform functional studies of the wild type and Gly2385Arg LRRK2 protein in human cell lines. In a case-control study involving 989 Chinese subjects, the frequency of the heterozygous Gly2385Arg genotype was higher in PD compared to controls (7.3 vs. 3.6%, odds ratio = 2.1, 95% CI: 1.1-3.9, P = 0.014); these values yield an estimated population attributable risk (PAR) of approximately 4%. In a multivariate logistic regression analysis with the disease group (PD vs. controls) as the dependent variable and the genotype as an independent factor with adjustments made for the effect of age and gender, the heterozygous Gly2385Arg genotype remained associated with an increased risk of PD compared to wild type genotype (odds ratio = 2.67, 95% CI: 1.43-4.99, P = 0.002). The glycine at position 2385 is a candidate site for N-myristoylation, and the Gly2385Arg variant replaces the hydrophobic glycine with the hydrophilic arginine, and increases the net positive charge of the LRRK2 WD40 domain. In transfection studies, we demonstrated that both the wild type and Gly2385Arg variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under condition of oxidative stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis. Our study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the Chinese population. Our bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant is biologically relevant and it might act through pro-apoptotic mechanisms.


Characterization and comparison of extended-spectrum β-lactamase (ESBL) resistance genotypes and population structure of Escherichia coli isolated from Franklin's gulls (Leucophaeus pipixcan) and humans in Chile.
We investigated the general level of antibiotic resistance with further analysis of extended-spectrum beta-lactamase (ESBL) prevalence, as well as the population structure of E. coli in fecal flora of humans and Franklin's gulls (Leucophaeus pipixcan) in central parts of Chile. We found a surprisingly high carriage rate of ESBL-producing E. coli among the gulls 112/372 (30.1%) as compared to the human population 6/49 (12.2%.) Several of the E. coli sequence types (STs) identified in birds have previously been reported as Multi Drug Resistant (MDR) human pathogens including the ability to produce ESBLs. This means that not only commensal flora is shared between birds and humans but also STs with pathogenic potential. Given the migratory behavior of Franklin's gulls, they and other migratory species, may be a part of ESBL dissemination in the environment and over great geographic distances. Apart from keeping the antibiotic use low, breaking the transmission chains between the environment and humans must be a priority to hinder the dissemination of resistance.


Zipf's, Heaps' and Taylor's Laws are Determined by the Expansion into the Adjacent Possible.
Zipf's, Heaps' and Taylor's laws are ubiquitous in many different systems where innovation processes are at play. Together, they represent a compelling set of stylized facts regarding the overall statistics, the innovation rate and the scaling of fluctuations for systems as diverse as written texts and cities, ecological systems and stock markets. Many modeling schemes have been proposed in literature to explain those laws, but only recently a modeling framework has been introduced that accounts for the emergence of those laws without deducing the emergence of one of the laws from the others or without ad hoc assumptions. This modeling framework is based on the concept of adjacent possible space and its key feature of being dynamically restructured while its boundaries get explored, i.e., conditional to the occurrence of novel events. Here, we illustrate this approach and show how this simple modeling framework, instantiated through a modified Pólya's urn model, is able to reproduce Zipf's, Heaps' and Taylor's laws within a unique self-consistent scheme. In addition, the same modeling scheme embraces other less common evolutionary laws (Hoppe's model and Dirichlet processes) as particular cases.


Oxidative stress and mitochondrial-mediated apoptosis in dopaminergic cells exposed to methylcyclopentadienyl manganese tricarbonyl.
Methylcyclopentadienyl manganese tricarbonyl (MMT), an organic manganese-containing gasoline additive, was investigated to determine whether MMT potentially causes dopaminergic neurotoxic effects. MMT is acutely cytotoxic and dopamine-producing cells (PC-12) seemed to be more susceptible to cytotoxic effects than nondopaminergic cells (striatal gamma-aminobutyric acidergic and cerebellar granule cells). MMT also potently depleted dopamine apparently by cytoplasmic vesicular release to the cytosol, a neurochemical change resembling other dopaminergic neurotoxicants. Generation of reactive oxygen species (ROS), an early effect in toxicant-induced apoptosis, occurred within 15 min of MMT exposure. MMT caused a loss of mitochondrial transmembrane potential (DeltaPsim), a likely source of ROS generation. The ROS signal further activated caspase-3, an important effector caspase, which could be inhibited by antioxidants (Trolox or N-acetyl cysteine). Predepletion of dopamine by using alpha-methyl-p-tyrosine (tyrosine hydroxylase inhibitor) treatment partially prevented caspase-3 activation, denoting a significant dopamine and/or dopamine by-product contribution to initiation of apoptosis. Genomic DNA fragmentation, a terminal hallmark of apoptosis, was induced concentration dependently by MMT but completely prevented by pretreatment with Trolox, deprenyl (monoamine oxidase-B inhibitor), and alpha-methyl-p-tyrosine. A final set of critical experiments was performed to verify the pharmacological studies using a stable Bcl-2-overexpressing PC-12 cell line. Bcl-2-overexpressing cells were significantly refractory to MMT-induced ROS generation, caspase-3 activation, and loss of DeltaPsim and were completely resistant to MMT-induced DNA fragmentation. Taken together, the results presented herein demonstrate that oxidative stress plays an important role in mitochondrial-mediated apoptotic cell death in cultured dopamine-producing cells after exposure to MMT.


People, pets, and parasites: one health surveillance in southeastern Saskatchewan.
Residents of remote and Indigenous communities might experience higher exposure to some zoonotic parasites than the general North American population. Human sero-surveillance conducted in two Saulteaux communities found 113 volunteers exposed as follows: Trichinella (2.7%), Toxocara canis (4.4%), Echinococcus (4.4%), and Toxoplasma gondii (1.8%). In dogs, 41% of 51 fecal samples were positive for at least one intestinal parasite, 3% of 77 were sero-positive for Borrelia burgdorferi, and 21% of 78 for T. gondii. Echinococcus exposure was more likely to occur in non-dog owners (odds ratio [OR]: 11.4, 95% confidence interval [CI]: 1.2-107, P = 0.03); while T. canis was more likely to occur in children (ages 4-17) (OR: 49, 95% CI: 3.9-624; P = 0.003), and those with a history of dog bites (OR: 13.5, 95% CI: 1.02-179; P = 0.048). Our results emphasize the use of dogs as sentinels for emerging pathogens such as Lyme disease, and the need for targeted surveillance and intervention programs tailored for parasite species, cultural groups, and communities.


The relationship between heartbeat counting and heartbeat discrimination: A meta-analysis.
Interoception concerns the perception of the body's internal state. Despite the importance of this ability for health and aspects of higher-order cognition, its measurement remains problematic. Most studies of interoception employ one of two tasks: the heartbeat counting or heartbeat discrimination task. These tasks are thought to index common abilities, an assertion often used to justify the use of a single measure of cardiac interoception. However, mixed findings regarding the relationship between performance on these tasks raises the question of whether they can be used interchangeably to assess interoceptive accuracy, confidence and awareness ('metacognition'). The present study employed a meta-analytical approach to assess the association between these tasks. Pooled findings from 22 studies revealed a small relationship between accuracy scores on the measures. Additional analyses demonstrated a moderate relationship between confidence ratings but no association between measures of interoceptive awareness. These findings question the interchangeable use of the two tasks.


Quantitative studies of prostatic secretion. III. Simultaneous measurement of size and secretion of the canine prostate and the interaction of androgenic and estrogenic substances thereon.
The prostate of the dog was relocated permanently in the perineum where its size could be measured and correlated with the output of prostatic secretion during many months. The secretion of a submaxillary gland obtained through a fistula was utilized as an internal biologic standard of the effects of pilocarpine, the secretory stimulus employed, because the amount and route of administration of the alkaloid are critical factors in inducing secretion. Prostatic secretion was found to be profoundly affected by androgenic and estrogenic compounds, in contrast to salivation. The curves of the secretory response of the prostate and submaxillary glands to pilocarpine proved to be similar and a mathematical formula has been constructed to represent them. When testosterone propionate was administered in increasing quantities for periods of weeks at each level, the volume of the prostate increased in a series of flattened curves. This volume, under the conditions mentioned, was found to stand in a simple arithmetic relationship to the amount of testosterone propionate administered. Moderate quantities of testosterone propionate masked the effects of small amounts of stilbestrol on the prostate. The reverse was also true and the critical amounts of these compounds were defined. The amounts of stilbestrol were determined which lowered the quantity of prostatic secretion resulting from the simultaneous administration of moderate amounts of testosterone propionate in castrate dogs, the result being a level and flat secretory curve which was maintained for many weeks. We designate this effect the plateau phenomenon. When this amount of estrogen was continued, and the dosage of testosterone propionate greatly augmented, the prostatic secretion did not increase in volume. Very slight increases above the critical amount of stilbestrol, however, caused the secretory curve to fall to new and still lower levels though the secretion was never completely suppressed. The acid phosphatase content of the prostatic secretion in the regions of secretory plateaus was similar to that of castrate dogs injected with androgen alone. The plateau phenomenon is due to simultaneous physiologic action of androgenic and estrogenic compounds on the prostatic cells. The depression of prostatic secretion resulting in the plateau phenomenon is due to both functional and structural changes in the prostatic epithelium. They are best explained on the assumption that differences in steroid threshold exist in groups of cells within the prostate, those of the anterior rim of the gland being least susceptible to estrogenic activity.


Case study: auditory brain responses in a minimally verbal child with autism and cerebral palsy.
An estimated 30% of individuals with autism spectrum disorders (ASD) remain minimally verbal into late childhood, but research on cognition and brain function in ASD focuses almost exclusively on those with good or only moderately impaired language. Here we present a case study investigating auditory processing of GM, a nonverbal child with ASD and cerebral palsy. At the age of 8 years, GM was tested using magnetoencephalography (MEG) whilst passively listening to speech sounds and complex tones. Where typically developing children and verbal autistic children all demonstrated similar brain responses to speech and nonspeech sounds, GM produced much stronger responses to nonspeech than speech, particularly in the 65-165 ms (M50/M100) time window post-stimulus onset. GM was retested aged 10 years using electroencephalography (EEG) whilst passively listening to pure tone stimuli. Consistent with her MEG response to complex tones, GM showed an unusually early and strong response to pure tones in her EEG responses. The consistency of the MEG and EEG data in this single case study demonstrate both the potential and the feasibility of these methods in the study of minimally verbal children with ASD. Further research is required to determine whether GM's atypical auditory responses are characteristic of other minimally verbal children with ASD or of other individuals with cerebral palsy.


An Exploratory Analysis of the Smoking and Physical Activity Outcomes From a Pilot Randomized Controlled Trial of an Exercise Assisted Reduction to Stop Smoking Intervention in Disadvantaged Groups.
Economically disadvantaged smokers not intending to stop may benefit from interventions aimed at reducing their smoking. This study assessed the effects of a behavioral intervention promoting an increase in physical activity versus usual care in a pilot randomized controlled trial. Disadvantaged smokers who wanted to reduce but not quit were randomized to either a counseling intervention of up to 12 weeks to support smoking reduction and increased physical activity (n = 49) or usual care (n = 50). Data at 16 weeks were collected for various smoking and physical activity outcomes. Primary analyses consisted of an intention to treat analysis based on complete case data. Secondary analyses explored the impact of handling missing data. Compared with controls, intervention smokers were more likely to initiate a quit attempt (36 vs. 10%; odds ratio 5.05, [95% CI: 1.10; 23.15]), and a greater proportion achieved at least 50% reduction in cigarettes smoked (63 vs. 32%; 4.21 [1.32; 13.39]). Postquit abstinence measured by exhaled carbon monoxide at 4-week follow-up showed promising differences between groups (23% vs. 6%; 4.91 [0.80; 30.24]). No benefit of intervention on physical activity was found. Secondary analyses suggested that the standard missing data assumption of "missing" being equivalent to "smoking" may be conservative resulting in a reduced intervention effect. A smoking reduction intervention for economically disadvantaged smokers which involved personal support to increase physical activity appears to be more effective than usual care in achieving reduction and may promote cessation. The effect does not appear to be influenced by an increase in physical activity.


Effect of cytosolic pH on inward currents reveals structural characteristics of the proton transport cycle in the influenza A protein M2 in cell-free membrane patches of Xenopus oocytes.
Transport activity through the mutant D44A of the M2 proton channel from influenza virus A was measured in excised inside-out macro-patches of Xenopus laevis oocytes at cytosolic pH values of 5.5, 7.5 and 8.2. The current-voltage relationships reveal some peculiarities: 1. "Transinhibition", i.e., instead of an increase of unidirectional outward current with increasing cytosolic H(+) concentration, a decrease of unidirectional inward current was found. 2. Strong inward rectification. 3. Exponential rise of current with negative potentials. In order to interpret these findings in molecular terms, different kinetic models have been tested. The transinhibition basically results from a strong binding of H(+) to a site in the pore, presumably His37. This assumption alone already provides inward rectification and exponential rise of the IV curves. However, it results in poor global fits of the IV curves, i.e., good fits were only obtained for cytosolic pH of 8.2, but not for 7.5. Assuming an additional transport step as e.g. caused by a constriction zone at Val27 resulted in a negligible improvement. In contrast, good global fits for cytosolic pH of 7.5 and 8.2 were immediately obtained with a cyclic model. A "recycling step" implies that the protein undergoes conformational changes (assigned to Trp41 and Val27) during transport which have to be reset before the next proton can be transported. The global fit failed at the low currents at pHcyt = 5.5, as expected from the interference of putative transport of other ions besides H(+). Alternatively, a regulatory effect of acidic cytosolic pH may be assumed which strongly modifies the rate constants of the transport cycle.


Current efforts in research of pleural mesothelioma-An analysis of the ClinicalTrials.gov registry.
Currently there are many uncertainties in the optimal treatment of malignant pleural mesothelioma (MPM), this is reflected in discrepancies between current guidelines. Our aim was to evaluate the current status of prospective interventional clinical trials within the ClinicalTrials.gov registry in MPM in order to predict a potential impact on MPM management in the next years. The records of 263.832 clinical trials registered were searched in December 2017. Trials starting between 2005 and 2017 (n = 262) were selected for further manual review. Trials including other tumour entities or mesothelioma originating outside the pleura (n = 94) were excluded, as well as trials where the primary endpoint has already been published (n = 22). In total, 91 clinical trials were identified and selected for further analysis. Most trials had a single arm design, were in phase I, and were non-randomized. Academic centres were recorded as primary sponsors in the majority of trials (56%), followed by industry in 21%. Most studies investigated targeted (n = 42) or cytotoxic therapies (n = 39). Ten studies investigated different genetic therapies. In 67% of the trials (n = 61) targeted and/or cytotoxic therapies were involved. Treatments involving surgery were investigated in 12 trials (13%), radiotherapy in 10 trials (11%). Only five studies (6%) were phase 3 studies and one was a phase 2/3 study. Four of these five phase 3 trials investigated targeted therapies, while one trial investigated prophylactic radiotherapy of operative tracts. Currently running trials in MPM are mostly in early phases and dominated by systemic therapies. Very few trials evaluate loco-regional therapeutic approaches. The current controversy surrounding the use of surgery and radiotherapy within multimodal therapy strategies will not be answered by these trials in the coming years.


Drinking Water Sodium and Elevated Blood Pressure of Healthy Pregnant Women in Salinity-Affected Coastal Areas.
Coastal areas in Southeast Asia are experiencing high sodium concentrations in drinking water sources that are commonly consumed by local populations. Salinity problems caused by episodic cyclones and subsequent seawater inundations are likely (partly) related to climate change and further exacerbated by changes in upstream river flow and local land-use activities. Dietary (food) sodium plays an important role in the global burden of hypertensive disease. It remains unknown, however, if sodium in drinking water-rather than food-has similar effects on blood pressure and disease risk. In this study, we examined the effect of drinking water sodium on blood pressure of pregnant women: increases in blood pressure in this group could severely affect maternal and fetal health. Data on blood pressure, drinking water source, and personal, lifestyle, and environmental confounders was obtained from 701 normotensive pregnant women residing in coastal Bangladesh. Generalized linear mixed regression models were used to investigate association of systolic and diastolic blood pressure of these-otherwise healthy-women with their water source. After adjustment for confounders, drinkers of tube well and pond water (high saline sources) were found to have significantly higher average systolic (+4.85 and +3.62 mm Hg) and diastolic (+2.30 and +1.72 mm Hg) blood pressures than rainwater drinkers. Drinking water salinity problems are expected to exacerbate in the future, putting millions of coastal people-including pregnant women-at increased risk of hypertension and associated diseases. There is an urgent need to further explore the health risks associated to this understudied environmental health problem and feasibility of possible adaptation strategies.


Complex allosteric modulation of cardiac muscarinic receptors by protamine: potential model for putative endogenous ligands.
A large number of diverse pharmacological agents bind to a secondary domain on the muscarinic receptor, to influence allosterically the interaction of ligands at the primary binding site. Based on common structural features of these antagonists, we examined the interaction of protamine, an endogenous polycationic peptide, and of polyamines with muscarinic receptors in rat heart. Our results provide several lines of qualitative evidence that protamine allosterically modulates the conformation of muscarinic receptors, in a marked negatively cooperative manner. It decelerated the dissociation of N-[3H]methylscopolamine ([3H] NMS) initiated by atropine, in a concentration-dependent fashion. Inhibition by protamine of [3H]NMS binding at equilibrium showed a distinct plateau, which increased in magnitude at higher ligand concentrations. Scatchard analysis of saturation isotherms of [3H]NMS binding in the absence and presence of protamine indicated that protamine did not alter Bmax in a statistically significant fashion, although there was a trend of a concentration-dependent increase in this parameter. On the other hand, it caused a marked concentration-dependent decrease in the affinity of [3H]NMS, and this effect reached a ceiling limit. However, there were marked quantitative deviations of the interaction of protamine from a simple ternary allosteric model. Some of these discrepancies could be explained by the tendency of protamine to increase Bmax. The allosteric actions of protamine demonstrated in kinetic and equilibrium experiments were selective for m1 and m2 muscarinic receptors, compared with m3, m4, and m5 receptors, as studied in Chinese hamster ovary cells transfected with the genes of the different muscarinic receptors. Arginine residues play an important role in the allosteric interaction of protamine, inasmuch as poly-L-arginine qualitatively mimicked the effects of protamine. In contrast, no effects of the polyamines spermine, spermidine, and putrescine were observed on [3H]NMS binding. This is the first report on the allosteric modulation of muscarinic receptors by an endogenous peptide.


New perspectives on the relationship between mandibular and statural growth.
Condylar and somatic growth have similar growth curves. The aim of this study was to compare both growth curves in untreated subjects at different ages and investigate if a correlation factor (CF) could be established. Semi-longitudinal records (cephalograms and body height) of 418 untreated, healthy children (193 girls and 225 boys) from a craniofacial growth study were analyzed. Incremental changes of three mandibular measurements from articulare and three from condylion were compared to statural growth changes separately. Based on the assumption that mandibular and somatic growth both follow a parallel line, a CF was postulated and checked for validity and reliability. Mandibular growth spurt could be observed in all six different mandibular measurements, but distances from condylion were more informative. Gonial measurements were not as indicative as symphyseal distances. Mandibular growth did not coincide with somatic growth precisely, and condylar peak velocity preceded statural peak velocity in boys and was slightly delayed in girls. CF was close to the value of 0.4, and its validity could be ascertained when using the condylion-gnathion distance for all ages in girls and up to the age of 12 in boys. Reliability, however, proved to be poor owing to heterogeneity of the sample. Although the relationship between mandibular and statural growth increments can be expressed as a CF with some degree of adequacy, the variance rendered CF unreliable. When evaluating growth-related changes, condylion should be preferred as condylar reference, and symphyseal landmarks should be favoured over gonion.


Using the PHQ-9 for depression screening and treatment monitoring for Chinese Americans in primary care.
Because Chinese Americans are known to underutilize mental health services, routine screening for depression in primary care clinics has been advocated as a means of identifying Chinese-American patients with depression and initiating appropriate treatment. This analysis evaluated the utility of the nine-item depression module of the Patient Health Questionnaire (PHQ-9) for depression screening and monitoring treatment outcomes among Chinese Americans at a primary health care setting. A total of 3,417 patients who presented for an initial or annual physical examination with their primary care providers were screened for depression between January and October 2003 at the Charles B. Wang Community Health Center, a primary health care center in New York City serving primarily low-income Chinese Americans. The depression screen was a two-tier process: if patients endorsed one or more of three initial questions on an abridged version of the PHQ-9, they were then administered the PHQ-9. A total of 141 individuals (4.1 percent) had clinically significant depressive symptoms (PHQ-9 score of 10 or higher). Women were more likely to have significant levels of depressive symptoms than men (17.3 percent compared with 11.6 percent). A total of 114 of the 141 patients with clinically significant depressive symptoms received treatment plans initiated by their primary care provider. Forty (35.1 percent) responded to treatment (50 percent decrease in PHQ-9 score) by eight weeks of treatment. The PHQ-9 can be used to screen for depression as well as guide depression treatment planning among Chinese Americans in primary care. Screening for major depression with the PHQ-9 in primary care settings should be considered for appropriate identification and treatment of depression for Chinese-American patients.


Cross-cultural differences in drivers' speed choice.
The aim of the present study was to examine if there are any cross-cultural differences between Swedish and Turkish drivers' rating of the variables in the theory of planned behaviour (TPB) with regard to complying with the speed limit. A sample of 219 Swedish and 252 Turkish drivers completed a questionnaire including questions based on the theory of planned behaviour (i.e. regarding attitude, subjective norm, perceived behavioural control, intention and behaviour). The results show that country differences in drivers' intention to comply with the speed limit as well as their self-reported compliance could be explained by differences found in their attitude, subjective norm and perceived behavioural control. Furthermore, drivers who live in a country with fewer road traffic fatalities (i.e. Sweden), compared with drivers who live in a country with more road traffic fatalities (i.e. Turkey), reported a more positive attitude towards complying with the speed limit, a more positive subjective norm, a higher perceived behavioural control, a higher intention and a larger proportion of the time spent complying.


Romosozumab in postmenopausal women with low bone mineral density.
Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).


First Report of Broad bean wilt virus 2 in Echinacea purpurea in China.
Field-grown Echinacea purpurea plants showing necrosis, leaf roll, yellow mosaic, and mosaic symptoms in leaves were collected in June 2010 in Huairou, Beijing, China. ELISAs of extracts of four samples showed that one sample with mosaic symptoms had a positive reaction with Broad bean wilt virus 2 (BBWV-2) monoclonal antibody provided by Professor X. P. Zhou (1). The monoclonal antibody recognized the 44.7 kD coat protein subunit of BBWV-2. We used Chenopodium quinoa as an assay species to isolate the virus by sap transmissions and to maintain the virus strain. Sap from infected C. quinoa, when inoculated onto indicator plant species, induced the following symptoms: C. quinoa: local lesions in inoculated leaves, systemic chlorotic mottle in upper leaves, deformation, and apical necrosis; C. amaranticolor: chlorotic local lesions, systemic mosaic and leaf distortion; Nicotiana benthamiana: systemic mosaic; Gomphrena globosa: local purple spots in inoculated leaves and systemic infection in upper leaves; Tetragonia expansa: local lesions, but no symptoms of systemic infection; Physalis floridana: systemic mosaic. No symptoms were observed on Capsicum annuum, Datura stramonium, N. glutinosa, or N. tabacum cv. White Burley. To confirm BBWV-2 infection, total RNAs extracted from infected C. quinoa leaves were reverse transcripted to cDNA using oligo-dT primer (T17V). The primer pair Fab5'R1F (5'-AAATATTAAAACAAACAGCTTTCGTT-3') and Fab5'R1R (5'-TTCAAAGCTCGTGCCATNTYATTKGC-3') for specific detection of the Fabavirus genus (2) was used for PCR analysis. The amplified fragment is between the 5'-terminal non-translatable region (NTR) and the beginning of the coding region of RNA1. Amplicons of approximately the expected size (~391 bp) were produced from the virus-infected C. quinoa and a BBWV-2 positive control (ATCC PV131, PV0537). Amplicons of approximately the expected size (~350 bp) were produced from the BBWV-1 positive control (ATCC PV132). However, no such amplicons were observed from healthy C. quinoa plants and water control. The 391-bp amplicons of RNA1 obtained from the infected C. quinoa were cloned and sequenced. Comparison with sequences of other BBWV-2 isolates showed that the isolate we obtained (No. JX070674) had approximately 99% nt identity (98% amino acid identity) with Chinese BBWV-2 isolate BC (No. FJ485686.1) (3). As an ornamental and medicinal plant, E. purpurea is widely cultivated in northern China. Up until now, Tomato ring spot virus, Tobacco rattle virus, Cucumber mosaic virus, and Tomato spotted wilt virus have been detected or isolated from E. purpurea in the world (4). To our knowledge, this is the first report of BBWV-2 infecting E. purpurea in China. BBWV-2-infected E. purpurea may have less secondary metabolites, which could influence the quality and therapeutic efficacy of this herbal medicine. References: (1) L. Qing et al. Acta Microbiologica Sinica 40:166, 2000. (2) R. M. Ferrer et al. J. Virol. Methods 144:156, 2007. (3) C. Sui et al. Plant Dis. 93:844, 2009. (4) B. Dikova. Bulgarian J. Agric. Sci. 17:306, 2011.


Acute nicotine reduces and repeated nicotine increases spontaneous activity in male and female Lewis rats.
The Lewis (LEW) strain of rat appears more sensitive to nicotine than other strains in self-administration, conditioned place preference, and drug discrimination behavioral studies. The present study sought to further evaluate the behavioral effects of chronic nicotine treatment in the LEW strain by assessing spontaneous activity, which has consistently revealed sensitization to chronic nicotine administration in Sprague Dawley (SD) rats. High active and low active male and female LEW rats (N=8 per group) were treated twice daily with either nicotine (0.4 mg/kg, sc) or vehicle for 14 consecutive days. Regardless of baseline activity level or sex, spontaneous activity was significantly decreased, compared to saline-treated rats, after a single nicotine injection. However, spontaneous activity increased in both low- and high-activity rats (both sexes) over the two weeks of nicotine administration to levels that were significantly higher than saline-treated rats. Based on these findings, acute and chronic nicotine administration had greater suppressive and enhancing effects on spontaneous activity in LEW rats compared to other strains of rats previously studied. These results further clarify the behavioral sensitivity of the LEW strain of rat to nicotine exposure and lend credence to the role of genetics in the individual susceptibility to nicotine dependence.


Calcium dynamics and vasomotion in arteries subject to isometric, isobaric, and isotonic conditions.
In vitro, different techniques are used to study the smooth muscle cells' calcium dynamics and contraction/relaxation mechanisms on arteries. Most experimental studies use either an isometric or an isobaric setup. However, in vivo, a blood vessel is neither isobaric nor isometric nor isotonic, as it is continuously submitted to intraluminal pressure variations arising from heart beat. We use a theoretical model of the smooth muscle calcium and arterial radius dynamics to determine whether results may be considerably different depending on the experimental conditions (isometric, isobaric, isotonic, or cyclic pressure variations). We show that isobaric conditions appear to be more realistic than isometric or isotonic situations, as the calcium dynamics is similar under cyclic intraluminal pressure variations (in vivo-like situation) and under a constant pressure (isobaric situation). The arterial contraction is less pronounced in isotonic than in isobaric conditions, and the vasoconstrictor sensitivity higher in isometric than isobaric or isotonic conditions, in agreement with experimental observations. Interestingly, the model predicts that isometric conditions may generate artifacts like the coexistence of multiple stable states. We have verified this model prediction experimentally using rat mesenteric arteries mounted on a wire myograph and stimulated with phenylephrine.


Heterotrimeric G protein signaling functions with dynein to promote spindle positioning in C. elegans.
Proper orientation and positioning of the mitotic spindle is essential for the correct segregation of fate determinants during asymmetric cell division. Although heterotrimeric G proteins and their regulators are essential for spindle positioning in many cell types, their mechanism of action remains unclear. In this study, we show that dyrb-1, which encodes a dynein light chain, provides a functional link between heterotrimeric G protein signaling and dynein activity during spindle positioning in Caenorhabditis elegans. Embryos depleted of dyrb-1 display phenotypes similar to a weak loss of function of dynein activity, indicating that DYRB-1 is a positive regulator of dynein. We find that the depletion of dyrb-1 enhances the spindle positioning defect of weak loss of function alleles of two regulators of G protein signaling, LIN-5 and GPR-1/2, and that DYRB-1 physically associates with these two proteins. These results indicate that dynein activity functions with regulators of G protein signaling to regulate common downstream effectors during spindle positioning in the early C. elegans embryo.


Frequency of and risk factors associated with catastrophic musculoskeletal injuries in Quarter Horses at two Midwestern racetracks: 67 cases (2000-2011).
To determine the incidence and anatomic location of and potential risk factors for catastrophic musculoskeletal injuries (CMIs) in racing Quarter Horses. Retrospective matched case-control study. 67 racing Quarter Horse racehorses euthanized because of CMIs and 134 matched controls. Data for Quarter Horses that sustained CMIs and the total number of race starts for each year were obtained from 2 Midwestern racing jurisdictions from 2000 through 2011. Information for each horse with a CMI and for 2 randomly selected control horses that ran in the same race but did not incur a CMI were obtained from race records, past performance reports, and video analysis. There were 61,797 race starts and 82 CMIs from 2000 through 2011 at the 2 racetracks studied, for an overall CMI incidence of 1.33 CMIs/1,000 starts. Sixty-seven horses with CMIs for which complete data were available and 134 matched control horses were included in the study. There was no difference in the incidence of CMIs between the 2 racetracks or over the years studied. The right forelimb was injured in 38 of the 67 (56.7%) horses. Injures to the carpus (24/67 [35.8%]) and metacarpophalangeal joint (fetlock joint; 23/67 [34.3%]) occurred most frequently. Case-control data indicated that the horses with a CMI had fewer starts, were more likely to have stumbled at the break, had a more erratic stride, were fatigued, and trailed in the race, compared with matched controls from the same races. Irrespective of race distance, most of the horses (47/67 [70.1%]) were injured after or within 10 yards before the finish line. The results of the present study may aid in the identification of racing Quarter Horses at risk for CMIs. The cluster of injuries near the finish line provides a specific focus for future research into methods of injury prevention in this population of racehorses.


Total and acid-soluble fluoride content of infant cereals, beverages and biscuits from Brazil.
Total fluoride (TF) and HCl 0.01 M ('gastric juice')-soluble fluoride (SF) were analysed in infant foods, beverages and calcium-rich biscuits. Samples were divided into seven categories: children cereals (A), chocolate-flavoured milk (B), soy beverages (C), filled biscuits (D), non-filled biscuits (E), wafer biscuits (F) and corn starch biscuits (G). Mean TF concentrations +/- SD (amplitude, unit microgram F ml-1 or microgram F g-1) were: (A) 4.25 +/- 3.04 (0.20-7.84, n = 6); (B) 0.34 +/- 0.47 (0.05-1.27, n = 6); (C) 0.15 +/- 0.07 (0.09-0.29, n = 8); (D) 8.44 +/- 1.76 (7.65-10.47, n = 4); (E) 12.41 +/- 1.15 (10.69-13.68, n = 4); (F) 0.35 +/- 0 (0.34-0.36, n = 4) and (G) 7.77 +/- 1.12 (6.86-8.68, n = 2). Five samples of cereals, one sample of chocolate-flavoured milk and 10 samples of biscuits were analysed for SF. In cereals analysed for SF, all fluoride was soluble, while for the chocolate-flavoured milk, approximately 50% of TF was soluble. Regarding the biscuits analysed for SF approximately 20% of TF was soluble. It was observed that some of the cereals and beverages, and most of the biscuits analysed, might be important contributors to total daily fluoride intake. When consumed just once per day, cereals and beverages might supply up to 25% of the maximum recommended daily fluoride intake (0.07 mg F kg-1 body weight) for a 2-year-old child (12 kg). For the filled, non-filled and corn starch biscuits, when 3, 32 or 20 units of them, respectively, are consumed just once per day, they may supply up to 16% of the maximum recommended daily fluoride intake. However, only approximately 25% of fluoride absorption occurs from the stomach and 75% from the small intestine. Therefore, a higher fluoride bioavailability is possible.


Assessment of Depression in a Primary Care Setting in Nigeria using the PHQ-9.
Mental disorders are major contributors to the burden of diseases all over the world. In general practice, which provides essentially primary care, depression is the most common mental disorder seen and often goes unrecognized. The aims of the study were to determine the prevalence of depression, the variables associated with depression, and the degree of recognition by the Physician in family medicine unit. A cross-sectional descriptive survey of consecutive patients who presented at the general medical out-patient unit of the State University Teaching Hospital, Ado-Ekiti, Nigeria was done. Data were collected using a questionnaire incorporating sociodemographic variables and primary diagnosis made by attending Physician. Depression was assessed with the PHQ-9. Two hundred and seventy two patients were interviewed during the period of the study. Participants were mostly of 45 years or older (51.2%), female (59.9%), married (68.4%), and educated (85.7%). One hundred and thirty (47.8%) of the respondents had significant depressive symptoms with majority (49.2%) being classified as mild. Statistical analysis revealed significant association between depression and age, gender, marital status, and clinical diagnoses (P < 0.05). Over a quarter (28.7%) were presented with infectious diseases, other diagnoses made included cardiovascular disorders (15.8%), endocrine disorders (8.8%), psychiatric disorders other than depression (2.9%) and none had depression as primary diagnosis. The prevalence of depression among patients attending the general medical out-patient clinics is high and highly under-recognised.


GHRH antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro.
We investigated the effect of a GHRH antagonist, MIA-602on the metastatic cascade in vitro of three human cancers, DBTRG-05 glioblastoma, MDA-MB-468 estrogen-independent breast, and ES-2 clear cell ovarian cancer. GHRH receptors and their main splice variant, SV1 were detected on all three cell lines. After treatment with MIA-602, the cell viability decreased significantly, significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased. The attachment of cancer cells to fibronectin and matrigel was severely hindered. Wound-healing experiments demonstrated a reduced cellular motility in all three cell lines. The upregulation of caveolin-1 and E-cadherin,and thepowerful downregulation of NF-kappaB and beta-catenin was detected. Our study suggests that the clinical application of highly potent GHRH antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well.


A phase III skin cancer chemoprevention study of DFMO: long-term follow-up of skin cancer events and toxicity.
Decreasing the incidence of nonmelanoma skin cancer (NMSC) is of great importance in regards to future healthcare services. Given the previously reported preventive effects of α-difluoromethylornithine (DFMO) in skin and colon cancer trials, we determined appropriate cause to update the clinical data on the subjects from the recently reported randomized, double-blind, placebo-controlled phase III skin cancer prevention study of DFMO. Our intention was to retrospectively assess the further incidence of skin cancer, other malignancies, and adverse events of patients accrued to our phase III skin cancer prevention study of DFMO. Clinical records of 209 University of Wisconsin (UW) Health subjects were reviewed, and 2,092.7 person years of on study (884.3 person years) and poststudy (1,208.4 person years) follow-up for these patients were assessed for new NMSC events and recurrence rates from the on study period, the poststudy period, and the two study periods combined. No evidence of increased significant diagnoses or serious adverse events was observed in the DFMO participants. The initially observed, marginally significant reduction (P = 0.069) in NMSC rates for DFMO subjects relative to placebo continued without evidence of rebound. Event rates after discontinuation from study for total NMSCs (DFMO 0.236 NMSC/person/year, placebo 0.297, P = 0.48) or the subtypes of basal cell carcinomas (BCC; DFMO 0.179 BCC/person/year, placebo 0.190, P = 0.77) and squamous cell carcinomas (SCC; DFMO 0.057 SCC/person/year, placebo 0.107, P = 0.43) are listed. Follow-up data revealed a persistent but insignificant reduction in new NMSCs occurring in DFMO subjects without evidence of latent or cumulative toxicity relative to placebo subjects.