Cannabidiol and refractory epilepsy: parental and caregiver perspectives of participation in a compassionate access scheme.

BACKGROUND: The Compassionate Access Scheme (CAS) being delivered through the Queensland Children's Hospital is designed to allow access to an investigational purified Cannabidiol oral solution to paediatric patients with severe refractory epilepsy. The objectives of this study were to conduct semi-structured interviews to: 1. Understand families' expectations and attitudes about the use of an investigational cannabinoid product for their child's seizures; 2. Understand families' perceptions of Cannabidiol's efficacy for their child's seizures; and other aspects of their child's behaviour, quality of life and/or cognition. METHODS: Children aged 2-18 years had been enrolled in, or were enrolled in a compassionate access scheme for Cannabidiol at the time of the study. Semi-structured interviews (n = 19) with parents or caregivers (n = 23) of children diagnosed with refractory epilepsy were voice-recorded, transcribed and analysed to generate common themes. RESULTS: Key themes emerged relating to seizure activity, family and school engagement, drug safety and legal access, efficacy, clinical support, social acceptance of the medication and program delivery. The use of Cannabidiol was perceived to have benefits in relation to reducing the severity and frequency of seizure activity for almost a third of patients experiencing refractory epilepsy. Participants described other benefits including improved social engagement, wakefulness and a reduction of side effects related to a reduction of conventional medication dosage. CONCLUSION: This study provided unique perspectives of families' experiences managing untreatable epilepsy, their experiences with conventional and experimental pharmacological treatments and health services. Whilst families' perceptions showed the use of Cannabidiol did not provide a therapeutic reduction in the seizure activity for all patients diagnosed with refractory epilepsy, it's use as an additional pharmacological agent was perceived to provide other benefits by some patient families.

Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer.

AIMS: Although health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. MATERIALS AND METHODS: This was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b-T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. RESULTS: Overall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003-1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.023). CONCLUSION: In a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.

Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy.

AIMS: Several classes of concomitant medications have been shown to affect oncological outcomes in patients with prostate cancer (PCa). We assessed the association between the use of commonly prescribed concomitant medications and biochemical relapse-free survival (bRFS) in patients with localised PCa treated with radiotherapy and androgen deprivation therapy (ADT). MATERIALS AND METHODS: A secondary pooled analysis of two phase III randomised trials was carried out. In the first trial, patients with localised PCa with clinical stage T1b-T3, prostate-specific antigen <30 ng/ml and Gleason score ≤7 were treated with radical radiotherapy and 6 months of ADT starting 4 months before or concomitantly with radiotherapy. In the second trial, patients with high-risk PCa were treated with radical radiotherapy and 36 months of ADT with randomisation to three-dimensional conformal or intensity-modulated radiotherapy. Information on concomitant medications was collected from the medical record. Univariable and multivariable Cox regression was used to identify factors associated with bRFS. RESULTS: Overall, 486 patients were evaluable. The median follow-up was 125 months; 10-year bRFS was 83.7%. On univariable analysis, receipt of metformin was significantly associated with worse bRFS. Ten-year bRFS was 73% and 85% for patients with and without concomitant metformin (adjusted hazard ratio 2.11, 95% confidence interval 1.03-4.33). Similar evidence of an association was observed with sulfonamide-based α1-receptor blockers (adjusted hazard ratio 2.72, 95% confidence interval 1.31-5.66). However, no such association was seen with receipt of quinazoline-based α1-receptor blockers (adjusted hazard ratio 1.09, 95% confidence interval 0.42-2.82). There was no significant association between bRFS and receipt of all other medication classes considered. CONCLUSIONS: In this population of patients with localised PCa treated with radiotherapy and ADT, receipt of concomitant metformin and sulfonamide-based α1-receptor blockers was associated with inferior biochemical outcome. Randomised trials are required to assess the true effect of these medications on oncological outcomes in localised PCa.

Red Propolis and Its Dyslipidemic Regulator Formononetin: Evaluation of Antioxidant Activity and Gastroprotective Effects in Rat Model of Gastric Ulcer.

Propolis has various pharmacological properties of clinical interest, and is also considered a functional food. In particular, hydroalcoholic extracts of red propolis (HERP), together with its isoflavonoid formononetin, have recognized antioxidant and anti-inflammatory properties, with known added value against dyslipidemia. In this study, we report the gastroprotective effects of HERP (50-500 mg/kg, p.o.) and formononetin (10 mg/kg, p.o.) in ethanol and non-steroidal anti-inflammatory drug-induced models of rat ulcer. The volume, pH, and total acidity were the evaluated gastric secretion parameters using the pylorus ligature model, together with the assessment of gastric mucus contents. The anti-Helicobacter pylori activities of HERP were evaluated using the agar-well diffusion method. In our experiments, HERP (250 and 500 mg/kg) and formononetin (10 mg/kg) reduced (p < 0.001) total lesion areas in the ethanol-induced rat ulcer model, and reduced (p < 0.05) ulcer indices in the indomethacin-induced rat ulcer model. Administration of HERP and formononetin to pylorus ligature models significantly decreased (p < 0.01) gastric secretion volumes and increased (p < 0.05) mucus production. We have also shown the antioxidant and anti-Helicobacter pylori activities of HERP. The obtained results indicate that HERP and formononetin are gastroprotective in acute ulcer models, suggesting a prominent role of formononetin in the effects of HERP.

Pre-operative versus post-operative radiosurgery for brain metastasis: Effects on treatment volume and inter-observer variability.

PURPOSE/OBJECTIVES: Compared to post-operative whole brain radiotherapy, resection cavity radiosurgery reduces impact on neuro-cognitive function and improves quality-of-life. However, coverage of the operative tract, in addition to tumour bed, may lead to large treatment volumes and inter-observer variability. We hypothesized that pre-operative radiosurgery reduces target volume size and inter-observer variability compared to post-operative radiosurgery. MATERIALS/METHODS: We identified 10 consecutive patients, with solitary brain metastasis, treated with post-operative cavity radiosurgery.Pre- and post-operative axial T1 contrast MRI were co-registered with the planning CT scans. Three radiation oncologists independently contoured the target volumes on the pre- and post-operative imaging. A 2mm-PTV margin was utilized for both strategies and radiosurgery treatment plans were generated. The following parameters were evaluated in the 2 plans: Mean target volume (cc), 50% isodose volume (cc), Inter-observer variability (Jaccard Index JI) and Conformity Index (CI). RESULTS: There was no significant difference in the mean target volume, nor 50% isodose volume, between pre- and post-operative strategies. (17.6 (95% CI 9.98 - 25.22) versus 19.4 (95% CI 10.11 - 28.69) cc, P=0.80; 61.7 (95% CI 38.4 - 85.0) vs 77.7 (95% CI 34.94 - 120.46) cc, P=0.65). There was significantly less inter-observer variability and improved conformity in the pre-operative group (Mean JI 0.84(95% CI 0.82 - 0.86) versus 0.70 (95% CI 0.62 - 0.78), P = 0.005; Mean CI 1.32 (95% CI 1.26 - 1.38) vs 1.45 (95% CI 1.36 - 1.54), P= 0.01). Planned subgroup analysis did not reveal any significant difference (between pre- vs post-op) in the mean volume of cystic versus non-cystic metastasis. Deep lesions (>2.5cm from dura) had a larger post-operative target volume (25.8 (95% CI 15.1 - 36.5) vs 12.3 (95% CI 6.54 - 18.06) cc, P=0.06) compared to superficial lesions. CONCLUSION: Pre-operative radiosurgery has less inter-observer variability and improved plan conformity. However, there was no difference in mean target volume between the pre- versus post-operative radiation. Contouring guidelines, and peer review, may help to reduce inter-observer variability for cavity radiosurgery.

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV-Infected Subjects With Aging Biomarkers.

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.

Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci.

BACKGROUND: Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. METHOD: We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. RESULTS: Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. CONCLUSIONS: The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.

p16INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects.

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Effects of Diamide Insecticides on Predators in Soybean.

Predatory arthropods can be important for preventing insect pests from reaching damaging levels in soybean. However, the predator community can be compromised when pest control strategies include the application of broad-spectrum insecticides. The use of selective insecticides such as diamides could conserve predators while still providing necessary pest control. We evaluated two selective diamide insecticides, chlorantraniliprole and flubendiamide, and a broad-spectrum insecticide, lambda-cyhalothrin in combination with chlorantraniliprole, for impact on predators in soybean. We applied insecticides to field plots and documented predator abundance prior to and up to 3 wk postapplication using sticky card, beat sheet, and sweep net sampling methods. In sweep net samples, total predator abundance in plots treated with the selective insecticides was not significantly different from untreated control plots. For beat sheet samples, there were no significant differences in the abundance of total predators on any day postapplication between the selective diamide insecticides or the untreated control, but abundance decreased after application of lambda-cyhalothrin + chlorantraniliprole and did not recover. For sticky cards, there were no differences in predator abundance among treatments on any day postapplication. Over all, results showed that there were no significant differences in the abundance of total predators, Anthocoridae, Araneae, or Geocoridae after application of flubendiamide or chlorantraniliprole compared with the untreated control for up to 3 wk after application. All insecticides significantly decreased populations of lepidopteran pests compared with the untreated control, but only lambda-cyhalothrin + chlorantraniliprole reduced predatory arthropod abundance.

Quality and accuracy of publicly accessible cancer-related physical activity information on the Internet: a cross-sectional assessment.

In this study, we assessed the quality of publicly available cancer-related physical activity (PA) information appearing on reputable sites from Canada and other English-speaking countries. A cross-sectional Internet search was conducted on select countries (Canada, USA, Australia, New Zealand, UK) using Google to generate top 50 results per country for the keywords "'physical activity' AND 'cancer'". Top results were assessed for quality of PA information based on a coding frame. Additional searches were performed for Canadian-based sites to produce an exhaustive list. Results found that many sites offered cancer-related PA information (94.5%), but rarely defined PA (25.2%). Top 50 results from each country did not differ on any indicator examined. The exhaustive list of Canadian sites found that many sites gave information about PA for survivorship (78.3%) and prevention (70.0%), but rarely defined (6.7%) or referenced PA guidelines (28.3%). Cancer-related PA information is plentiful on the Internet but the quality needs improvement. Sites should do more than mention PA; they should provide definitions, examples and guidelines. With improvements, these websites would enable healthcare providers to effectively educate their patients about PA, and serve as a valuable resource to the general public who may be seeking cancer-related PA information.

Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester.

Physiological changes during pregnancy can affect drug pharmacokinetics. Here we present a population pharmacokinetic model to describe the longitudinal change of unbound lopinavir/ritonavir (LPV/RTV) PK parameters with gestational age, and to predict unbound LPV concentrations under different dosing regimens. The changes in apparent intrinsic clearances of LPV and RTV during pregnancy are described using an exponential function of gestational age. The unbound fractions of LPV/RTV are not significantly different between pregnancy and postpartum. Simulation reveals that despite increases in LPV intrinsic clearance, effective LPV inhibitory quotient (IQ) values are predicted with the standard dosing (400/100 mg b.i.d.) in >90% of simulations, with ≤4-fold increase in viral IC50. As viral susceptibility decreases, higher doses increase the likelihood of efficacy. With ≥40-fold increases in IC50, IQs suggest alternate regimens be considered. This approach refines previous LPV PK reports, and supports that standard dosing is effective with susceptible virus.

Multiparametric MRI of the anterior prostate gland: clinical-radiological-histopathological correlation.

Anterior prostate cancer (APC) is defined as a tumour in which more than half of malignant tissue is located anterior to the urethra. APCs are increasingly recognized as clinically important, particularly in patients undergoing active surveillance and for patients with negative non-targeted systematic transrectal ultrasound (TRUS)-guided biopsies but with persistent clinical suspicion of cancer. Multiparametric (mp) MRI has a crucial role for the diagnosis of anterior tumours, eventual histological sampling of suspicious lesions using image-guided targeted biopsy techniques, and potentially, to improve local staging of disease. mpMRI is accurate for the detection of APC and for differentiation of tumour from other anterior prostatic structures including benign prostatic hyperplasia (BPH) and the anterior fibromuscular stroma (AFMS). Characterization and reporting of APC should rely on the recently revised Prostate Imaging and Data Reporting System (PI-RADS) version 2.0 document. T2-weighted (T2W) imaging is emphasized as the determining sequence for assessment of the anterior prostate and specific features for APC on T2W imaging include: ill-defined/spiculated margin, lenticular shape, anterior/inferior location, and growth pattern (invasion of urethra or AFMS and crossing midline). Functional imaging, mainly with diffusion-weighted imaging, is also contributory and improves the sensitivity for detection of APC compared to T2W imaging alone. APCs commonly show positive surgical margins after radical prostatectomy and staging of disease extent using conventional clinical parameters is limited. mpMRI may have a future role to improve local staging of APC. This review illustrates the importance of mpMRI in APC using a clinical-radiological-histopathological approach.

Gastroprotective effects of thymol on acute and chronic ulcers in rats: The role of prostaglandins, ATP-sensitive K(+) channels, and gastric mucus secretion.

Thymol, a monoterpene phenol derivative of cymene, is found in abundance in the essential oils of Thymus, Origanum, and Lippia species. The present study investigated the gastroprotective actions of thymol (10, 30, and 100 mg/kg, p.o.) in the acute (ethanol- and nonsteroidal anti-inflammatory drug-induced ulcers) and chronic (acetic acid-induced ulcers) ulcer models in rats. Some of the mechanisms underlying to the gastroprotective effect of thymol were investigated in the ethanol-induced ulcer model. Gastric secretion parameters (volume, pH, and total acidity) were also evaluated by the pylorus ligature model, and the mucus in the gastric content was determined. The anti-Helicobacter pylori activity of thymol was performed using the agar-well diffusion method. Thymol (10, 30, and 100 mg/kg) produced dose dependent reduction (P < 0.01) on the total lesion area in the ethanol-induced ulcer model. The gastroprotective response caused by thymol (30 mg/kg) was significantly attenuated (P < 0.001) by intraperitoneal treatment of rats with indomethacin (a non-selective inhibitor of cyclo-oxygenase, 10 mg/kg) and glibenclamide (ATP-sensitive K(+) channel blocker, 10 mg/kg), but not by DL-Propargylglycine (PAG, a cystathionine-γ-lyase inhibitor, 25 mg/kg) and Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME, a non-selective inhibitor of nitric oxide synthase, 70 mg/kg). Thymol (30 and 100 mg/kg) also reduced the ulcer index (P < 0.05) and the total lesion area (P < 0.001) in the indomethacin- and acetic-acid-induced ulcer models, respectively. In the model pylorus ligature, the treatment with thymol failed to significantly change the gastric secretion parameters. However, after treatment with thymol (30 and 100 mg/kg), there was a significant increase (P < 0.01) in mucus production. Thymol no showed anti-H. pylori activity in vitro. Collectively, the present results provide convincing evidence that thymol displays gastroprotective actions on the acute and chronic ulcer models through mechanisms that involve increased in the amount of mucus, prostaglandins, and ATP-sensitive K(+) channels.

Isolated brain metastases as first site of recurrence in prostate cancer: case report and review of the literature.

Fewer than 2% of patients with metastatic prostate cancer (pca) develop brain metastases. Autopsy series have confirmed the rarity of brain metastases. When present, brain metastases occur in end stage, once the pca is castrate-resistant and spread to other sites is extensive. Here, we present a rare case of a patient with pca who developed a solitary parenchymal brain metastasis as first site of relapse 9 years after radical therapy. The patient underwent craniotomy and excision of the tumour. A second recurrence was also isolated to the brain. In the literature, pca patients with brain metastases have a poor mean survival of 1-7.6 months. The patient in our case report experienced a relatively favourable outcome, surviving 19 months after his initial brain relapse.

Occurrence of Brown Marmorated Stink Bug (Hemiptera: Pentatomidae) on Wild Hosts in Nonmanaged Woodlands and Soybean Fields in North Carolina and Virginia.

Nonmanaged plants occurring along forest edges and in suburban settings were sampled for brown marmorated stink bug, Halyomorpha halys (Stål), in North Carolina (NC) and Virginia (VA) over the course of three growing seasons. Commercial soybeans (Glycine max), an attractive cultivated host, were also sampled in 2014 in NC and in VA from 2010-2014. Very few H. halys were found on nonmanaged plants or soybean fields in the coastal plain region of either state, but substantial populations were recorded in the piedmont and mountain regions. From 2011 to 2013, H. halys comprised from 51 to 97% of all stink bug species observed on nonmanaged plants in the piedmont and mountain regions. In VA, the distribution expanded from detection in 12 counties in 2010 to 53 counties in 2014, with economically damaging levels occurring in the piedmont region. During these studies, H. halys were observed to complete one and a partial second generation per year in western NC and southwestern VA, similar to that previously observed in regions farther north. Several plants were identified as preferred hosts, with tree of heaven, catalpa, yellowwood, paulownia, cherry, walnut, redbud, and grape having consistently high numbers of H. halys. Knowing that these plants are preferred by H. halys during certain stages of the insects' development will aid in the search for H. halys in new areas, as well as serve as one predictor of the likelihood of a certain area to attract and sustain large H. halys populations.

Relationship between testosterone, estradiol and circulating PCSK9: Cross-sectional and interventional studies in humans.

BACKGROUND: Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9. METHODS: We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels. RESULTS: In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (1) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9. CONCLUSIONS: We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. The studies were registered with ClinicalTrials.gov NCT00848276.

Understanding the relative contributions of direct environmental effects and passive genotype-environment correlations in the association between familial risk factors and child disruptive behavior disorders.

BACKGROUND: Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect (a) the direct effects of familial environment and (b) a passive gene-environment correlation (r(GE)), wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive r(GE) by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. METHOD: Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict and divorce; offspring DBDs included attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD). Mixed-level regressions estimated the main effects of familial environment, adoption status and the familial environment by adoption status interaction term, which tested for the presence of passive r(GE). RESULTS: There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive r(GE). CONCLUSIONS: Many familial risk factors affected children equally across genetically related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive r(GE), where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children.

Management of penoscrotal extramammary Paget disease: case series and review of the literature.

Extramammary Paget disease (empd) is a rare, slow-growing neoplasm, considered to be an adenocarcinoma of the apocrine glands. In men, the penoscrotal region is the most commonly affected area. The disease can present as carcinoma in situ or as invasive disease that can subsequently metastasize to lymph nodes and distant sites. Because of the rarity of empd, the medical literature available to guide management of the disease is limited, particularly in patients with metastases. In addition, metastatic disease may pose a diagnostic challenge, because invasive cancer of the genitourinary or gastrointestinal tract can occur in association with empd. In the present case series, we describe our experience in treating penoscrotal empd with multimodality therapy, and we review the existing literature concerning its diagnosis and management.

Gastroprotective activity of the ethanol extract from the inner bark of Caesalpinia pyramidalis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia pyramidalis Tul. (Fabaceae), known as "catingueira", has been used in folk medicine in the treatment of various disorders such as gastritis, heartburn, indigestion, and stomach ache. However, the gastroprotective properties of this species have not yet been studied. MATERIALS AND METHODS: The ethanol extract of Caesalpinia pyramidalis inner bark was used in rats via oral route, at the doses of 30, 100, and 300 mg/kg. The antiulcer assays were performed using the ethanol- and nonsteroidal anti-inflammatory drug-induced ulcer models. Gastric secretion parameters (volume, pH, and total acidity) were also evaluated by the pylorus ligated model, and the mucus in the gastric content was determined. The anti-Helicobacter pylori activity of the ethanol extract of Caesalpinia pyramidalis was performed using the agar-well diffusion and broth microdilution methods. RESULTS: The ethanol extract (30, 100, and 300 mg/kg) produced dose dependent inhibition (P<0.01) on the ulcer lesion index, the total lesion area, and the percentage of lesion area in the ethanol-induced ulcer model. The ethanol extract (30, 100, and 300 mg/kg) also reduced (P<0.001) the ulcer index in the indomethacin-induced ulcer model. In the model ligature pylorus, the treatment with Caesalpinia pyramidalis ethanol extract failed to significantly change the gastric secretion parameters. However, after treatment with the ethanol extract of Caesalpinia pyramidalis (30, 100, and 300 mg/kg), there was a significant increase (P<0.05) in mucus production. The ethanol extract showed anti-Helicobacter pylori activity, with inhibition halos of 12.0 ± 1.7 mm at 10,000 µg/mL. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the ethanol extract were of 625 and 10,000 µg/mL, respectively. CONCLUSIONS: Collectively, the present results suggest that the ethanol extract of Caesalpinia pyramidalis displays gastroprotective actions, supporting the folkloric usage of the plant to treat various gastrointestinal disturbances.

Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study.

OBJECTIVES: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. METHODS: HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population. RESULTS: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. CONCLUSIONS: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.