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Childhood obesity is rapidly increasing worldwide and is largely the consequence of adoption of unhealthy diets excessive in calories and salt (NaCl) as well as devoid in pivotal micronutrients such as potassium (K) and magnesium (Mg). Education-based programs aiming to encourage healthy food knowledge and behaviors are crucial at a young age, and for this purpose, convenient ways to assess daily dietary intake are warranted. We therefore attempted to evaluate the dietary intake of Okinawan schoolchildren in Japan by analyzing a series of biomarkers in morning spot urine samples and explore whether these biomarkers correlate with body weight and a series of metabolic parameters. We enrolled 98 third-grade elementary schoolchildren in Okinawa, Japan. Morning spot urine samples were collected and analyzed using high-performance liquid chromatography (HPLC) to assess dietary intake. We found that estimated daily NaCl intake was higher in obese/overweight children as compared to healthy-weight children (p = 0.0001). There was also a significant positive correlation between body mass index (BMI) and NaCl intake (Spearman) (ρ = 0.45, p < 0.0001) and a negative correlation between BMI and Mg/Cr (ρ =  -0.27, p = 0.01). Furthermore, Na/K ratio was higher in samples collected on Monday (weekend) as compared to samples collected on Thursday or Friday (weekday) (p < 0.0001)., Conclusion: Via the use of morning spot urine analyses, our results show that NaCl intake was associated with obesity, and Mg excretion negatively correlated with BMI in Japanese schoolchildren, highlighting the potential role of these micronutrients in maintaining a healthy body weight., What Is Known: •Overweight and obesity are largely due to excessive consumption of calories and positively correlated with salt (NaCl) intake. •Spot urine methods are convenient for assessing the nutritional needs and targeting prevention programs in children., What Is New: •Utilizing morning spot urine analyses, estimated NaCl intake is positively correlated and Mg/Cr negatively correlated with BMI in Okinawan schoolchildren. •As estimated via morning spot urine samples, a greater proportion of children likely exceeds the recommended NaCl intake on the weekend as compared to weekday., (© 2022. The Author(s).)

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1-4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5-8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial 1 . Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins 2 . However, the anatomical and cellular complexity of developing human tissues 3 -particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Empirical data obtained from controlled experiments is necessary to ensure that sound expert opinion evidence is provided regarding transfer and persistence of DNA in criminal proceedings. Knowledge in this area is also required at the outset of criminal investigations, to ensure that the proposed examinations can assist with answering questions that are relevant to forensic investigations. This study aimed to provide such data by examining the relative and absolute quantities of DNA deposited on items that are routinely submitted to the forensic laboratory by a habitual user, defined as someone who used it for ~1 week, and a subsequent one-time user. We found that the quantity of DNA deposited on routine household items spanned a broad range. The habitual user's DNA was detected on most items as the major donor, regardless of whether it was subsequently handled by another person for a short period of time. The one-time, short duration, user's DNA was detected on approximately two thirds of the items, albeit typically at quantities lower than the habitual user. Most of the household items we examined also had detectable DNA deposits from at least one other, unknown individual, typically in low quantities. Attempts to clean non-porous items with readily available household cleaners were partially effective but failed to completely eliminate detectable DNA from a habitual user in most cases., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Introduction: Evaluation of a quality improvement project designed to improve HPV vaccine uptake in a pediatric primary care setting for young adolescents., Method: Three strategies were implemented in one private pediatric practice to promote HPV vaccine uptake for 11- and 12-year-old adolescents. 1) a standardized vaccine policy change was made to include HPV vaccine with other adolescent vaccines, 2) a pre-visit email was sent to parents of teens to provide factual vaccine information in preparation for the visit, and 3) a provider communication initiative was implemented to ensure all providers communicated consistent messages and delivered an effective cancer prevention recommendation for HPV vaccination. A pre/post design was used to compare vaccine rates. Data was obtained via the electronic health records., Results: The post-intervention group demonstrated HPV vaccine rates increased substantially from 17.8% to 63.6%., Discussion: Strategically implementing standardized clinical vaccine policies and presumprive provider communication practices has implications for significantly increasing HPV vaccine uptake among teens and may be key to preventing cancer among future generations., (Copyright © 2021 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes., (© 2021 by the American Diabetes Association and the Canadian Diabetes Association.)

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Extra virgin olive oil (EVOO) and flaxseed oil (FO) contain a variety of constituents beneficial for chronic inflammation and cardio-metabolic derangement. However, little is known about the impact of EVOO and FO on dysbiosis of gut microbiota, intestinal immunity, and barrier. We, therefore, aimed to assess the impact of EVOO and FO on gut microbiota, mucosal immunity, barrier integrity, and metabolic health in mice., Methods: C57BL/6 J mice were exposed to a low-fat (LF), lard (HF), high fat-extra virgin olive oil (HF-EVOO), or high fat-flaxseed oil (HF-FO) diet for 10 weeks. Gut microbiota assessment was undertaken using 16S rRNA sequencing. Levels of mRNA for genes involved in intestinal inflammation and barrier maintenance in the intestine and bacterial infiltration in the liver were measured by qPCR., Results: HF-EVOO or HF-FO mice showed greater diversity in gut microbiota as well as a lower abundance of the Firmicutes phylum in comparison with HF mice (P < 0.05). The qPCR analyses revealed that mRNA level of FoxP3, a transcription factor, and IL-10, an inducer of regulatory T cells, was significantly elevated in the intestines of mice-fed HF-EVOO in comparison with mice-fed HF (P < 0.05). The mRNA level of the antimicrobial peptide, RegӀӀӀγ, was markedly elevated in the intestines of HF-EVOO and HF-FO compared with HF group (P < 0.05)., Conclusions: Our data suggest that the consumption of EVOO or FO can beneficially impact gut microbiota, enhance gut immunity, and assist in the preservation of metabolic health in mice.

The Centre of Forensic Sciences has validated the Precision ID Ancestry Panel on the Ion S5™ Massively Parallel Sequencing instrument for use in forensic casework. The focus of this paper is the development of reporting guidelines for implementation of the biogeographic ancestry inference service based on the Admixture Prediction results produced using the Torrent Suite™ Software (Thermo Fisher Scientific). The Admixture Prediction algorithm estimates the genetic ancestry of a sample using seven root populations (Europe, East Asia, Oceania, America, Africa, South Asia, and Southwest Asia). For individuals that declared a single ancestry, there was a high correlation between the declared ancestry and the ancestry predicted by the algorithm. However, some individuals with declared ancestries of Southern Europe, Southwest Asia, South Asia and Horn of Africa had Admixture Predictions that were composed of two or more root populations at 20% or greater. For individuals with known admixed ancestry, the major component of their declaration was included in their results in all but one case. Based on these results, reporting guidelines were developed and subsequently evaluated using the Admixture Predictions of additional samples. This paper discusses the development and evaluation of these reporting guidelines, along with an implementation plan for forensic casework., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To address sexual assault kit backlogs some laboratories in North America have implemented 'Direct to DNA' (DTD) approaches for the examination of relevant vaginal, oral, rectal and external genitalia swabs from sexual assault examination kits. Using this approach no preliminary serological screening for semen or spermatozoa is performed. Instead, swabs are directly subjected to differential extraction and quantitation using a dual quantification system. Decisions regarding the next steps in processing each sample are typically based on the quantity of male DNA detected, the fraction in which it is detected, and its ratio to the total human DNA in the sample. In the absence of serological results it remains of value in many cases to determine whether spermatozoa are present in the sample and whether the male DNA profile may be attributed to this body fluid. In this study we examine the distribution of male DNA from various body fluids between epithelial and spermatozoa fractions following differential extraction. Based on these results we identified criteria under which a DNA profile can be reliably attributed to spermatozoa. A total of 18 blood samples, 129 saliva samples, and 78 semen samples were processed. The maximum amount of male DNA observed in the sperm fraction of a spermatozoa-free sample was 10.4 ng and the maximum portion of total male DNA observed in the sperm fraction was 7.7%. In contrast, when a sample contained spermatozoa the minimum portion of total male DNA observed in the sperm fraction was 52.6%. This research supports a 50% threshold of male DNA in the sperm fraction following differential extraction as a conservative criterion under which the scientist at the Centre of Forensic Sciences (CFS) may infer that spermatozoa is present in a sample in the absence of serological results. This general threshold is applicable to all sample types (underwear, clothing, swabs, condoms) tested. We further demonstrate that, if the same male DNA profile is represented more prominently in the sperm fraction versus the epithelial fraction, the analyst should not fall into the intuitive trap of inferring the presence of spermatozoa in the sample. Instead, enrichment calculations must be based on the measured quantity of male and total DNA in each fraction and not the male:female DNA ratios observed in the DNA profiles., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Asthma encompasses numerous phenotypes that may require alternate approaches to diagnosis and therapy, particularly for patients whose symptoms remain poorly controlled despite escalating treatment. We describe 3 patients with apparent asthma who demonstrated unusual findings on cryobiopsy by flexible bronchoscopy and responded to therapy directed against autoimmune disease., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

The Kastle-Meyer (KM) test is a quick and easy chemical test for blood used in forensic analyses. Two practical variations of this test are the KM-rub (indirect) test and the more sensitive KM-direct test, the latter of which is performed by applying reagents directly to a suspected blood stain. This study found that sodium hydroxide present in the KM reagents eliminated the potential to generate a DNA profile when applied directly to small quantities of blood. A modified approach to the KM-rub test that increases its sensitivity is presented as a method to replace destructive KM-direct testing., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Background: Patients with failed endoscopic retrograde cholangiopancreatography (ERCP) are conventionally offered percutaneous transhepatic biliary drainage (PTBD). While PTBD is effective, it is associated with catheter-related complications, pain, and poor quality of life. Endoscopic ultrasound-guided biliary drainage (EUS-BD) is a minimally invasive endoscopic option increasingly offered as an alternative to PTBD. We compare outcomes of EUS-BD and PTBD in patients with biliary obstruction at a single tertiary care center., Methods: A retrospective review was performed in patients with biliary obstruction who underwent EUS-BD or PTBD after failed ERCP from June 2010 through December 2014 at a single tertiary care center. Patient demographics, procedural data, and clinical outcomes were documented for each group. The aim was to compare efficacy and safety of EUS-BD and PTBD and evaluate predictors of success., Results: A total of 60 patients were included (mean age 67.5 years, 65 % male). Forty-seven underwent EUS-BD, and thirteen underwent PTBD. Technical success rates of PTBD and EUS-BD were similar (91.6 vs. 93.3 %, p = 1.0). PTBD patients underwent significantly more re-interventions than EUS-BD patients (mean 4.9 versus 1.3, p < 0.0001), had more late (>24-h) adverse events (53.8 % vs. 6.6 %, p = 0.001) and experienced more pain (4.1 vs. 1.9, p = 0.016) post-procedure. In univariate analysis, clinical success was lower in the PTBD group (25 vs. 62.2 %, p = 0.03). In multivariable logistic regression analysis, EUS-BD was the sole predictor of clinical success and long-term resolution (OR 21.8, p = 0.009)., Conclusion: Despite similar technical success rates compared to PTBD, EUS-BD results in a lower need for re-intervention, decreased rate of late adverse events, and lower pain scores, and is the sole predictor for clinical success and long-term resolution. EUS-BD should be the treatment of choice after a failed ERCP.

Aim: To explore the experience of serious mental illness and cancer from the perspective of patients, significant others and healthcare professionals involved in their care., Background: Serious mental illness is associated with poorer cancer outcomes. Those suffering from this comorbidity receive fewer specialist interventions and die earlier than the general population. Prior qualitative research in this area has comprised of a single study focussing on healthcare professionals and there is little evidence regarding the experiences of patients and caregivers., Design: A qualitative exploration using approximately 36 semi-structured interviews., Methods: Semi-structured digitally recorded interviews conducted with: adults living with serious mental illness and diagnosed with cancer; those providing them with informal support and care; and healthcare professionals. Questions will focus on the experience of having cancer and serious mental illness or caring for someone with this comorbidity, experiences of healthcare and priorities for patients and carers. Framework analysis will be used. Research Ethics Committee and Trust Research & Development approval was obtained. A steering group comprising six people with experience of either cancer or mental illness provided feedback and ratified the patient information sheets and interview schedules., Discussion: There is a paucity of research addressing stakeholder perspectives on the experience of cancer and of cancer services for people with serious mental illness. Dissemination of findings will inform practice relating to the care of an often neglected population, informing better support for their significant others and the professionals involved in their care., (© 2015 John Wiley & Sons Ltd.)

Background: High-risk patients with cholecystitis have conventionally been offered percutaneous gallbladder drainage (PGBD) for treatment. A growing experience of endoscopic gallbladder drainage (EGBD) has been reported to be effective and safe., Objective: To compare the short- and long-term outcomes of EGBD and PGBD., Design: A retrospective review., Setting: Single academic tertiary care center., Patients: Inpatients diagnosed with cholecystitis., Interventions: Any patient deemed a nonsurgical candidate and who has undergone either PGBD or EGBD was included in the analysis., Main Outcome Measurements: Patient demographics along with procedural and clinical outcomes were recorded for each group., Results: Forty-three patients underwent PGBD and 30 underwent EGBD (24 transpapillary, 6 transmural). Technical (97.6% vs 100%) and clinical (97.6% vs 86.7%) success rates of PGBD and EGBD were similar. However, postprocedure hospital length of stay (16.3 vs 7.6 days), time to clinical resolution (4.6 vs 3.0 days), adverse event rate (39.5% vs 13.3%), number of sessions (2.0 vs 1.0), number of repeat interventions (53.4% vs 13.3%), and postprocedure pain scores (3.8 vs 2.1) were significantly higher for PGBD than EGBD., Limitations: Retrospective analysis., Conclusion: Although EGBD has similar technical and clinical success compared with PGBD, it uses fewer hospital resources and results in fewer adverse events, improved pain scores, and decreased need for repeat gallbladder drainage. EGBD may provide a less-invasive, safer, cost-effective option for gallbladder drainage than PGBD with improved clinical outcomes., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background/aims: Surgery is the mainstay of treatment for cholecystitis. However, gallbladder stenting (GBS) has shown promise in debilitated or high-risk patients. Endoscopic transpapillary GBS and endoscopic ultrasound-guided GBS (EUS-GBS) have been proposed as safe and effective modalities for gallbladder drainage., Methods: Data from patients with cholecystitis were prospectively collected from August 2004 to May 2013 from two United States academic university hospitals and analyzed retrospectively. The following treatment algorithm was adopted. Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and cystic duct stenting was initially attempted. If deemed feasible by the endoscopist, EUS-GBS was then pursued., Results: During the study period, 139 patients underwent endoscopic gallbladder drainage. Among these, drainage was performed in 94 and 45 cases for benign and malignant indications, respectively. Successful endoscopic gallbladder drainage was defined as decompression of the gallbladder without incidence of cholecystitis, and was achieved with ERCP and cystic duct stenting in 117 of 128 cases (91%). Successful endoscopic gallbladder drainage was also achieved with EUS-guided gallbladder drainage using transmural stent placement in 11 of 11 cases (100%). Complications occurred in 11 cases (8%)., Conclusions: Endoscopic gallbladder drainage techniques are safe and efficacious methods for gallbladder decompression in non-surgical patients with comorbidities.

When a forensic DNA sample cannot be associated directly with a previously genotyped reference sample by standard short tandem repeat profiling, the investigation required for identifying perpetrators, victims, or missing persons can be both costly and time consuming. Here, we describe the outcome of a collaborative study using the Identitas Version 1 (v1) Forensic Chip, the first commercially available all-in-one tool dedicated to the concept of developing intelligence leads based on DNA. The chip allows parallel interrogation of 201,173 genome-wide autosomal, X-chromosomal, Y-chromosomal, and mitochondrial single nucleotide polymorphisms for inference of biogeographic ancestry, appearance, relatedness, and sex. The first assessment of the chip's performance was carried out on 3,196 blinded DNA samples of varying quantities and qualities, covering a wide range of biogeographic origin and eye/hair coloration as well as variation in relatedness and sex. Overall, 95 % of the samples (N = 3,034) passed quality checks with an overall genotype call rate >90 % on variable numbers of available recorded trait information. Predictions of sex, direct match, and first to third degree relatedness were highly accurate. Chip-based predictions of biparental continental ancestry were on average ~94 % correct (further support provided by separately inferred patrilineal and matrilineal ancestry). Predictions of eye color were 85 % correct for brown and 70 % correct for blue eyes, and predictions of hair color were 72 % for brown, 63 % for blond, 58 % for black, and 48 % for red hair. From the 5 % of samples (N = 162) with <90 % call rate, 56 % yielded correct continental ancestry predictions while 7 % yielded sufficient genotypes to allow hair and eye color prediction. Our results demonstrate that the Identitas v1 Forensic Chip holds great promise for a wide range of applications including criminal investigations, missing person investigations, and for national security purposes.

Unlabelled: Objectives. Radiofrequency ablation (RFA) has replaced photodynamic therapy for premalignant and malignant lesions of the esophagus. However, there is limited experience in the bile duct. The objective of this pilot study was to assess the safety and efficacy of RFA in malignant biliary strictures., Methods: Twenty patients with unresectable malignant biliary strictures underwent RFA with stenting between June 2010 and July 2012. Diameters of the stricture before and after RFA, immediate and 30 day complications and stent patency were recorded prospectively. Results. A total of 25 strictures were treated. Mean stricture length treated was 15.2 mm (SD = 8.7 mm, Range = 3.5-33 mm). Mean stricture diameter before RFA was 1.7 mm (SD = 0.9 mm, Range = 0.5-3.4 mm) while the mean diameter after RFA was 5.2 mm (SD = 2 mm, Range = 2.6-9 mm). There was a significant increase of 3.5 mm (t = 10.8, DF = 24, P value = <.0001) in the bile duct diameter post RFA. Five patients presented with pain after the procedure, but only one developed mild post-ERCP pancreatitis and cholecystitis., Conclusions: Radiofrequency ablation can be a safe palliation option for unresectable malignant biliary strictures. A multicenter randomized controlled trial is required to confirm the long term benefits of RFA and stenting compared to stenting alone.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It has been proposed that the polymorphism encoding Y402H (T1277C) in the complement factor H gene (CFH) is one of the main determinants of disease. We genotyped the polymorphism at a number of loci in the region encompassing the Regulators of Complement Activation (RCA) on chromosome 1, including T1277C SNP, in 187 patients and 146 controls. Haplotypes have been classified as protective (P) or susceptible (S) with respect to AMD. This included the identification of an S haplotype with a T at 1277. The results show that no single locus should be assumed to be directly responsible for AMD, but rather argue for the existence of RCA haplotypes, which can be assigned meaningful predictive values for AMD. We conclude that the critical sequences are within a region 450 kb centromeric to 128 kb telomeric of CFH., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes., Design: Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes., Results: GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100 μg) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1β-induced inflammatory mediators such as nitric oxide (NO) [mean NO (μM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004)., Conclusions: These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses., Perspective: This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses.

The genomic region encompassing complement factor H (CFH) is thought to be important in determining susceptibility to inflammatory diseases such as age-related macular degeneration, but only limited polymorphism has been described. After applying the genomic matching technique to three-generation families and an ethnically diverse reference panel we have demonstrated that the polymorphism resembles that found in the major histocompatibility complex. The different ancestral haplotypes carry either T or C at T1277C but also other more polymorphic alleles over a region of 2 Mb. Thus the association between age-related macular degeneration and T1277 or Y402 actually reflects multiple linked polymorphisms including an indel that cannot be dissected from any direct effect of Y402 and may be more important. We show for the first time that simple algorithms can identify genomic sequence elements that appear to be more useful haplospecific markers than single nucleotide polymorphism or microsatellites.

Targeting of many polytopic proteins to the inner membrane of prokaryotes occurs via an essential signal recognition particle-like pathway. FtsY, the Escherichia coli homolog of the eukaryotic signal recognition particle receptor alpha-subunit, binds to membranes via its amino-terminal AN domain. We demonstrate that FtsY assembles on membranes via interactions with phosphatidylethanolamine and with a trypsin-sensitive component. Both interactions are mediated by the AN domain of FtsY. In the absence of phosphatidylethanolamine, the trypsin-sensitive component is sufficient for binding and function of FtsY in the targeting of membrane proteins. We propose a two-step mechanism for the assembly of FtsY on the membrane similar to that of SecA on the E. coli inner membrane.

Occupational sensitization to lactase is reported in workers formulating and packaging this consumer product, which is used for the relief of gastrointestinal symptoms caused by intolerance to lactose. Allergic rhinitis, conjunctivitis, and some cases of asthma were noted. There was suggestive evidence that atopic individuals may be at greater risk of sensitization. Lactase should be added to the list of potential occupational respiratory sensitizers.

A partnership between corporate worksites, a community-based prevention agency, and families in those worksites is described. Its primary goals were the reduction of family risk and enhancement of family protective factors that predispose children and youth to substance abuse and related social and emotional difficulties. A related goal of the program is to reduce family stress levels and attitudes that may influence the parents' levels of risk for substance abuse and related disorder. The program delivery strategy is conceived of as part of the necessart efforts of prevention programs to reach target populations in host settings in which they may naturally participate, thereby reducing obstacles and barriers to participation that often impede prevention efforts. Evaluation revealed that the program was generally better able to retain parents for a fairly lengthy period, and with high rates of attendance. Program attendance was also not affected by parental background characteristics that, in other delivery approaches, are often associated with poor attendance and high drop-out levels. Results also indicated that levels of program exposure (dosage) do make a significant difference in the efficacy of such efforts as those parents in the program who participated in higher percentages and numbers of sessions (i.e. more than 80% of sessions) showed both short-term and longer-term (i.e. across 18 month follow-ups) gains in their ratings of the target child's behavior problems and strengths, substance abuse resistance related knowledge and attitudes, reduced parental stress, depression and irritability, and increased utilization of social support. By contrast, parents who received a low program exposure exhibited a more restricted set of short-term gains. The findings are discussed in terms of their importance for consideration of program dosage for prevention programs, and the need to attend to the context in which programming is offered as it may facilitate or impede efforts to provide levels of dosage and fidelity to create enduring impacts.

Psychiatrists' axis III diagnoses of physical illnesses in 357 psychiatric patients were compared with diagnoses by a physician's assistant using a standardized medical history form. The physician's assistant detected nearly three times as many physical illnesses as the psychiatrists. The psychiatrists were significantly more likely to miss diagnoses among older patients and women. Patients who met criteria for depressive disorders appeared to be at greatest risk for undetected illnesses, followed by patients with bipolar disorders and schizophrenia. Patients with a secondary diagnosis of substance abuse had significantly more undetected illness than those who did not abuse substances. The authors suggest that current axis III guidelines are inadequate and that a systematic review of physical health problems should be part of the psychiatric diagnostic assessment.

1 The effects of two doses of delta 9THC (2.5 and 10 mg), delivered by paced smoking of herbal cigarettes, on CNV magnitude, subjective mood ratings and heart rate were studied in 20 subjects. 2 There were highly significant interactions between drug dosage and Extraversion and Neuroticism scores, so that the direction and degree of response to the different doses of delta 9THC depended on the personality characteristics of the subjects. 3 The effects of 9 mg delta 9THC and placebo, delivered in herbal cigarettes smoked naturally, on smoking behaviour, subjective mood ratings, measures of autonomic activity and auditory and visual cortical evoked responses were compared in 12 subjects. 4 Smoking behaviour, subjective 'high' rating and elevation of heart rates were the most significant discriminators between drug and placebo. The latency of some of the components of the visual evoked responses was also increased by delta 9THC. 5 There was a significant correlation between the effects of delta 9THC on skin conductance reactivity and the basal (pre-drug) level, reactivity increasing after drug in subjects with low basal reactivity and decreasing in those with high basal levels. 6 Both experiments provided clear evidence of dose-dependent biphasic stimulant and depressant actions of delta 9THC on both subjective and objective measures, and these effects were influenced by the personality and the starting state of the subjects.

The ability of several idealized tibial anchorage systems to resist distractive relative motion between the substrate and the component when subjected to eccentric loads was assessed using mechanical tests employing a urethane foam as a bone substitute and finite element models. Eccentric loads had to be placed within 30-35% of the edge of the tibial plate for separation to occur between an unanchored plate and the substrate. The finite element model predicted that a 90%/10% medial/lateral load distribution was required to maintain compressive vertical stresses beneath the unanchored plate. An anchorage system with four pegs each 10 mm in diameter and 20 mm long and an anchorage system with four cancellous bone screws each 6.5 mm in diameter were loaded eccentrically, and both systems prevented distraction of greater than 76 microns when mounted on urethane foam. Shorter pegs (10 mm) or a single central peg allowed distractions of 150 microns or greater to occur. These data are relevant to the design and testing of tibial components for total knee arthroplasty.

Subsequent to the repair of a true aneurysm from the posteromedial-basal aspect of the left ventricle, a 58 year old man developed a draining wound at the site of the sternotomy. Two-dimensional echocardiography revealed recurrence of the aneurysm at the site of the previous aneurysm repair. This aneurysm had a wide neck and looked similar in appearance to the previous true aneurysm. However, at surgery the patient was found to have a ventricular pseudoaneurysm with a cardiocutaneous fistula.

Some central and peripheral effects of orally administered propranolol (60 mg), diazepam (5 mg) and placebo were compared in normal subjects. The central effects measured were changes in magnitude of the contingent negative variation (CNV) and subjective anxiety ratings; the peripheral effects were changes in heart rate, blood pressure, galvanic skin response and hand steadiness. After diazepam there was a decrease in CNV magnitude and in the level of subjective anxiety; there was a slight fall in blood pressure but little change in heart rate. After propranolol, on the other hand, there was no significant change in CNV magnitude or anxiety rating, but a significant fall in heart rate and systolic blood pressure. It is concluded that, at the dosage used, propranolol, unlike diazepam, does not affect the central mechanisms determining CNV magnitude or subjective anxiety. The relationship of this finding to the use of beta-adrenergic receptor blockers in clinical anxiety states is discussed.

1 The effects in normal subjects of a single oral dose of Motival (one tablet, containing fluphenazine 0.5 mg and nortriptyline 10 mg) on the contingent negative variation (CNV), reaction time, heart rate, blood pressure and self-rating scales for alertness, anxiety, tension, detachment and depression were compared with those of diazepam (5 mg and 7.5 mg) and placebo or propranolol (60 mg). 2 After diazepam (5 mg: twelve subjects and 7.5 mg: seven subjects) there was a significant decrease in CNV magnitude while after Motival (twelve subjects) there was no significant alteration in CNV magnitude compared to placebo. 3 After diazepam (7.5 mg: seven subjects) there was also a fall in subjective ratings for alertness and tension; this fall was significantly greater than the changes after Motival which did not reduce subjective ratings for alterness or tension below "average" levels. Anxiety ratings did not differ significantly between the two drugs. Changes after propranolol were intermediate in all scales. 4 It is concluded that under these conditions diazepam caused central nervous system depression while Motival did not.