Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Adherence to clozapine vs. other antipsychotics in schizophrenia.

BACKGROUND: To date, there have been no studies evaluating adherence to clozapine with electronic adherence monitoring (EAM) such as the Medication Event Monitoring System (MEMS® ). METHODS: In outpatients with schizophrenia, we conducted a 3-month prospective study investigating antipsychotic adherence with EAM (eCAP® ). Participants were treated with different oral antipsychotics, including clozapine, and blind to EAM monitoring; all were on antipsychotic monotherapy administered once daily. Outcome measures included adherence rate, missed dose, and medication gap. Adherence trajectory patterns were also analyzed for clozapine vs. other antipsychotics collectively. RESULTS: A total of 111 patients were included in the study; 33 and 78 patients received clozapine or other antipsychotics, respectively. Adherence rates, defined as proportion of days that the subject took the medication at the prescribed time ± 3 h and proportion of subjects with ≥80% adherence, were numerically higher in patients receiving clozapine vs. other antipsychotics (72.0% vs. 65.1%, P = 0.10; 49.5% vs. 35.7%, P = 0.11, respectively). Along similar lines, some of the missed dose and medication gap outcomes were significantly better in patients receiving clozapine vs. other antipsychotics. Three adherence trajectory patterns were identified for both clozapine and other antipsychotics, with two shared by both groups (i.e., low adherence with a slight decrease over time; high and stable adherence). CONCLUSION: Findings suggest that in patients with schizophrenia clozapine adherence is at least comparable, if not slightly better, compared with other antipsychotics.

Biological and molecular characterization of two Anticarsia gemmatalis multiple nucleopolyhedrovirus clones exhibiting contrasting virulence.

Baculovirus natural populations are known to be genetically heterogeneous and such genotypic diversity could have implications in the performance of biocontrol agents. The Anticarsia gemmatalis nucleopolyhedrovirus (AgMNPV) has been widely used to control the velvetbean caterpillar, Anticarsia gemmatalis, in Brazil. In the present work, morphological and molecular analyses as well as the biological activity of AgMNPV genotypes derived from a Brazilian field isolate (AgMNPV-79) were carried out. The existence of genotypic variants in the population was confirmed by DNA restriction analysis. Although difference in virulence was observed among the variants, the most (Ag79-01) and the least (AgL-16) virulent clones do not show any morphological and cytopathological changes when compared to the most studied isolate (AgMNPV-2D). The complete genome analysis of the two viral clones showed the presence of single open reading frames (ORFs) of the pe-38 and he65 genes, which contrasts with the two split ORFs present in the genome of the AgMNPV-2D isolate. The viral clone AgL-16 has many variations in the ie-2 and pe-38 genes, which are transcription regulatory genes responsible for the regulation of viral early gene expression during insect cell infection. Furthermore, other genes showed alterations like the odv-e56, which have an essential role in the maturation and envelopment of the ODVs, and bro-a and bro-b genes which were fused to form a single ORF. For the Ag79-01, although the total number of single nucleotide variants (SNVs) was more prominent in the pe-38 gene, its genome showed very few modifications in comparison to the AgMNPV-2D genome.

Organogenesis and foetal haemodynamics during the normal gestation of healthy black-rumped agoutis (Dasyprocta prymnolopha, Wagler, 1831) bred in captivity.

The objective of this study was to define the patterns of organogenesis and foetal haemodynamics during the normal gestation of healthy agoutis (Dasyprocta prymnolopha) kept in captivity. Thirty pregnant agoutis that ranged in size from small to medium and weighed between 2.5 and 3 kg underwent B-mode and Doppler ultrasonography for the biometric evaluation of the foetal organs. The foetal aortic blood flow proved to be predominantly systolic, and the measured flow velocity was 78.89 ± 2.95 cm/s, with a maximum pressure gradient of 2.12 ± 0.27 mmHg. The liver was characterized by its large volume, occupying the entire cranial aspect of the abdominal cavity, and it was associated cranially with the diaphragm and caudally with the stomach. The flow velocity in the portal vein was estimated to equal 12.17 ± 2.37 cm/s, with a resistivity index of 0.82 ± 0.05. The gallbladder was centrally located and protruded cranially towards the diaphragm. The spleen was visualized as an elongated structure with tapered cranial and caudal extremities, and the foetal kidneys were visualized bilaterally in the retroperitoneal region, with the right kidney positioned slightly more cranially than the left. The morphological characterization and hemodynamic analysis of the foetal organs of black-rumped agoutis via B-mode and Doppler ultrasonography allow determination of the vascular network and of reference values for the blood flow required for perfusing the anatomical elements essential for maintaining the viability of foetuses at different gestational ages.

Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59.

Changes in the corpus callosum in women with late-stage bipolar disorder.

OBJECTIVE: This study investigated the differences in corpus callosum (CC) volumes between women with early-stage and late-stage bipolar I (BP I) disorder using the criteria previously described in the literature. METHOD: We compared women with early- and late-stage BP I using criteria described in the Staging Systems Task Force Report of the International Society for Bipolar Disorders. We included 20 patients with early stage and 21 patients with late-stage BP I and a group of 25 healthy controls. Patients and controls underwent structural magnetic resonance imaging. Information on the clinical features of bipolar disorder was collected using a standardized questionnaire. Anatomical volumes of five regions of CC were compared between the three groups. RESULTS: Women with late-stage BP I disorder had reduced posterior CC volumes compared with early-stage bipolar I patients and controls (F = 6.05; P = 0.004). The difference was significant after controlling for age, comorbidity with post-traumatic stress disorder, psychotic symptoms during mood episodes, and current use of medication. CONCLUSION: The posterior CC was significantly decreased in volume in women with late-stage bipolar disorder. These findings suggest that CC may be an anatomical target of neuroprogression in the course of bipolar disorder in women.

Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Successful co-infection of two different baculovirus species in the same cell line reveals a potential strategy for large in vitro production.

Baculoviruses have been applied for biocontrol of agricultural pests, such as velvetbean caterpillar (Anticarsia gemmatalis) and fall armyworm (Spodoptera frugiperda). Cell culture is an interesting approach for large-scale production of these viruses. Co-infection of a host cell with two distinct viruses can contribute to reduce costs due to saving cell culture media, bioreactor space and the resulting co-occluded polyhedra may help to reduce final biopesticide costs. The baculovirus Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) and Spodoptera frugiperda multiple nucleopolyhedrovirus (SfMNPV) were chosen to test a model for in vitro co-infection in SF21 cells. Different proportions of SfMNPV/AgMNPV were evaluated along three in vitro passages by optical microscopy analysis of cells and real-time PCR (qPCR) of DNA obtained from budded viruses (BVs) and occlusion bodies (OBs). The kinetics of viral protein synthesis was carried out for analysis of the co-infection in first passage and bioassays with the resulting OBs were performed against A. gemmatalis and S. frugiperda larvae. The results demonstrated successful co-infection in these cells. The quantity of SfMNPV and AgMNPV in supernatants and sediments tends to be maintained stable during the three passages, although the amount of AgMNPV was higher than SfMPNV in most of the experiments. Analysis of the kinetics of radiolabed proteins showed that the cell protein synthesis was shut off and two distinct bands of about 30 kDa, regarded to be the polyhedrin of each virus, were strongly detected at 48 and 72 hp.i. Although the pathogenicity of the produced viruses was not completely satisfactory, the bioassays confirmed occurrence of co-infected larvae with disproportional amount of each virus.

Atlantic and Mediterranean populations of the widespread serpulid Ficopomatus enigmaticus: Developmental responses to carbon nanotubes.

Ficopomatus enigmaticus was adopted as model species for ecotoxicological bioassay, with its larval development as endpoint. Two different populations of the same species, collected in areas far from each other (Mediterranean Sea and Atlantic Ocean), were exposed to multi-walled carbon nanotubes, a class of emerging pollutants with a constantly increasing relevance in the landscape of nanomaterials production. Moreover, a molecular analysis based on Cyt b amplification and sequencing, was carried out to confirm that both populations belong to the same species. The aim of the present work was to strengthen existing results about F. enigmaticus relevance in ecotoxicological bioassays, adding the variable of population effect. For both populations the concentration-response curve of effect at different toxicant concentrations was similar and, at certain concentrations, overlapping, confirming the ecological relevance of the assay. These results posed an interesting acceptance on the introduction of this species as model in ecotoxicological bioassay scenery, underlining the relevance of a widespread wild species to compare effects of chemicals and environmental samples over large distances using the same bioassay.

Impulsivity and bipolar disorder.

Impulsivity is frequently associated with bipolar disorder (BD) during manic episodes, but may also be present in euthymic bipolar patients. Aggression is an impulsivity-related behavior also found during manic episodes. The objective of this review is to further clarify the relationship between impulsivity and BD. A search in Medline and Psycinfo databases, combined with a manual search of selected references, was conducted to identify available literature on BD and impulsivity-related features. Although few studies have directly measured impulsivity in BD, available findings suggest that impulsivity is not only state-related, but also a trait component of BD, which could represent a core feature of the illness. Further research exploring the neurobiology of the impulsivity/BD relationship may contribute to elucidate the pathophysiology and to improve the diagnosis and treatment of this severe illness.

Trait impulsivity in patients with mood disorders.

BACKGROUND: Impulsivity is a key component of the manic behavior of bipolar disorder and is reported to occur in bipolar patients as a stable characteristic, i.e. a trait. Nevertheless, impulsivity has not been widely studied in depressed bipolar patients. We assessed impulsivity in depressed and euthymic bipolar and unipolar patients and healthy controls. We hypothesized that bipolar subjects would have higher levels of trait impulsivity than the comparison groups. METHODS: Twenty-four depressed bipolar, 24 depressed unipolar, 12 euthymic bipolar, and 10 euthymic unipolar patients, as well as 51 healthy subjects were evaluated with the Barratt Impulsiveness Scale (BIS). Analysis of covariance with age and sex as covariates was used to compare mean group differences. RESULTS: Depressed bipolar, euthymic bipolar, and depressed unipolar patients did not differ, and showed greater impulsivity than healthy controls on all of the BIS scales. Euthymic unipolar patients scored higher than healthy controls only on motor impulsivity. LIMITATIONS: Higher number of past substance abusers in the bipolar groups, and no control for anxiety and personality disorders, as well as small sample sizes, limit the reach of this study. CONCLUSIONS: This study replicates prior findings of stable trait impulsivity in bipolar disorder patients, and extends them, confirming that this trait can be demonstrated in depressed patients, as well as manic and euthymic ones. Trait impulsivity may be the result of repeated mood episodes or be present prior to their onset, either way it would influence the clinical presentation of bipolar disorder.

Morphometric analysis of a population of diplopods of the genus Rhinocricus Karsch, 1881.

Diplopods belonging to the subclass Helminthomorpha may present one or both leg pairs of the seventh diplosegment modified into structures that aid copulation, called gonopods. These structures are used as a taxonomic trait for the description of most species. In the genus Rhinocricus these structures are closely similar, so that it is difficult to distinguish species only on the basis of this trait. Two species, R. padbergi and R. varians, are found in the same habitat and present gonopods practically identical in shape; together they present a broad colour gradient, ranging from dark brown to light beige. Morphometric data for individuals of the experimental group were submitted to ANOVA and MANOVA, using Hotelling-Lawley Trace and generalized Mahalanobis distances (D2) tests. The results demonstrated a relationship between size and colour, with darker individuals being larger. On the basis of this preliminary analysis, we may suggest that the two species are distinct since dark individuals are distant from medium- and light-coloured individuals according to the D2 values. This seems to indicate a possible polymorphism of individuals belonging to R. padbergi which present close proximity in the values obtained. In all analyses, we observed that the main variables were diameter, length and telson size.

Overdoses among cocaine users in Brazil.

AIMS: A survey of cocaine users was undertaken to study (i) the frequency of reported drug overdoses among cocaine users; and (ii) the frequency of witnessing drug overdoses in the same population. DESIGN AND SETTING: A cross-sectional study as part of the World Health Organization (WHO) Multi-city Study among injecting drug users (IDUs), phase II, was conducted in Santos Metropolitan Region, State of São Paulo, Brazil, in 1999. PARTICIPANTS: Three hundred and ninety-six exclusive users of cocaine in the Santos Metropolitan Region, São Paulo State, Brazil were surveyed concerning their past experience with drug overdoses. FINDINGS: Eighty (20%) of the cocaine users reported having experienced one or more overdoses, and 50% reported that they knew one or more other cocaine users who had died of an overdose. On multivariate analysis, being female and having spent time in jail were associated with an increased likelihood of having had one or more overdoses. CONCLUSION: Cocaine overdoses are an important and under-recognized health problem in the Santos Metropolitan Region, and possibly in other areas of Brazil.

Lichen planus and chronic hepatitis C: exacerbation of the lichen under interferon-alpha-2a therapy.

A 51-year-old man was treated for histologically proven chronic hepatitis C with 3 MU of recombinant interferon-alpha-2a three times a week. Before interferon therapy, a mild lichen planus (hypertrophic variant) had been diagnosed, which exacerbated within 6 weeks of treatment to a severe erosive oral form. Then interferon therapy was stopped because local measures did not improve oral lesions. However, the patient tolerated interferon therapy well, and the initially four-fold elevated aminotransferase levels returned to normal. Nine weeks after discontinuation of interferon therapy, nearly all the buccal mucous membrane lesions had disappeared. But 8 weeks after withdrawal of interferon, aminotransferase levels rose again to six times the normal range. Treating physicians should know that a pre-existing lichen planus would potentially exacerbate, as a side effect of interferon-alpha-2a therapy of chronic hepatitis. However, further observations are needed to decide its clinical relevance.

Antibiotic prophylaxis and prosthetic valve endocarditis.

Early onset prosthetic valve endocarditis is one of the most lethal complications after valve replacement. During the first year of operation of our new cardiac surgical program, we observed 10 cases of prosthetic valve endocarditis, the majority being caused by staphylococci, making an incidence of 10.6%. Subsequent investigations uncovered a very high prevalence of methicillin-resistant strains which led to a radical change in the antibiotic prophylaxis, from a cephalosporin-based protocol to a two drug regime of vancomycin and netilmicin. There were no cases of prosthetic infection among the 138 patients operated on in the one year period following the institution of this protocol. Because there were no other changes, either in the types of prostheses used or the techniques of implantation, the eradication of prosthetic valve endocarditis can be related only to this alteration in the prophylaxis. Therefore, we may conclude that the inter-institutional transfer of protocols is not adequate before a thorough investigation of the prevalent hospital pathogens and their sensitivity to antibiotics is carried out. We have not registered resistances to vancomycin and this drug remains the most important antimicrobial agent, both in the prophylaxis and in the treatment of prosthetic valve endocarditis.

Iatrogenic bile duct injuries.

BACKGROUND: The real incidence of bile duct injury (BDI) during laparoscopic cholecystectomy (LC) is not known. METHODS: Using questionnaires, we analyzed 91,232 LC performed by 170 surgical units in Brazil between 1990 and 1997. RESULTS: A total of 167 BDI occurred (0.18%); the most frequent were Bismuth type 1 injuries (67.7%). Most injuries (56.8%) occurred at the hands of surgeons who had surpassed the learning curve (50 operations). However, the incidence dropped with increasing experience; it was 0.77% at surgical departments with <50 operations vs 0.16% at departments with >500 operations. The diagnosis was made intraoperatively in 67.7%, but it was based on intraoperative cholangiography in only 19.5%. The procedure was converted to open surgery in 85.8% when the diagnosis of injury occurred intraoperatively, and laparotomy was performed in 90.7% when the injury was diagnosed postoperatively. The mean hospitalization time was 7.6 +/- 5.9 days, the major complications were stenosis and fistulas, and the mortality rate was 4.2%. CONCLUSION: The incidence of BDI after LC is similar to that reported for the open procedure. BDI increases mortality and morbidity and prolongs hospitalization; therefore, all efforts should be made to reduce its incidence.

Preservation of the pulmonary annulus in total correction of tetralogy of Fallot. Decreasing transannular gradients in the early follow-up period.

The integrity of the pulmonary annulus was preserved in 21 of 22 children consecutively subjected to total correction of tetralogy of Fallot. There was one early death (4.8%). The 20 survivors were studied prospectively and constitute the basis of this report. Mean age was 59.3 +/- 35.3 months (range 6 months-12 years). Eight patients (40%) had previous Blalock-Taussig shunts and 3 (15%) had associated cardiac anomalies. Two-dimensional Doppler echocardiography had demonstrated right ventricle to main pulmonary artery peak systolic gradients of 75.4 +/- 12.7 mmHg (range 50-104 mmHg). Ventricular infundibulectomy was carried out in all patients but one, who had abnormal coronary anatomy. Extensive incision or resection of hypertrophied or abnormal muscle bands was performed. Pulmonary valve commissurotomy was performed in 14 patients (70%), 10 (50%) had autologous pericardium supravalvular enlargement of the pulmonary trunk and one (5%) had an infundibular bovine pericardial patch. Intraoperative, postrepair right/left ventricular pressure ratios were 0.67 +/- 0.18 (range 0.41-1.0). All ratios were accepted, because all patients were haemodynamically well and only two required inotropic (dopamine) support. There was no late mortality. During the early follow-up period (mean 13.0 +/- 5.4 months, range 7-25 months), all patients had two-dimensional Doppler echocardiography measured gradients at discharge (mean 44.2 +/- 22.6 mmHg, range 10-86 mmHg; p less than 0.001 vs. preoperative values), at 3 months (mean 31.1 +/- 14.5 mmHg, range 8-64 mmHg; p less than 0.011 vs. values at discharge) and at 6 months (mean 28.5 +/- 14.3 mmHg, range 12-57 mmHg; p = 0.009 vs. values at discharge). A similar favourable evolution of the diameters of the pulmonary annulus and of the right pulmonary artery was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Guess what! Porokeratosis of Mibelli.

A 72-year-old man had noticed, in his early forties, the appearance of well-defined papulous hyperkeratotic lesions, with increasing growth, located on both sides of his feet. After twenty-five years he consulted a dermatologist for the first time. Physical examination showed annular papules and rose-coloured plaques with atrophic centres, some of them hypopigmented, with higher and irregular borders, separated from the surrounding skin by longitudinal and well-defined furrows. The lesions presented variable sizes and shapes, some of them punctate, involving exclusively and in a bilateral form, both sides, back and sole of the feet (Figs. 1 and 2). The patient did not report any subjective symptoms. He was immunocompetent and did not remember that any relative had the same disease, nor had he been subjected to radiation treatment.