Sex and pubertal variation in reward-related behavior and neural activation in early adolescents.

This study aimed to characterize the role of sex and pubertal markers in reward motivation behavior and neural processing in early adolescence. We used baseline and two-year follow-up data from the Adolescent Brain and Cognitive DevelopmentSM study (15844 observations; 52% from boys; age 9-13). Pubertal development was measured with parent-reported Pubertal Development Scale, and DHEA, testosterone, and estradiol levels. Reward motivation behavior and neural processing at anticipation and feedback stages were assessed with the Monetary Incentive Delay task. Boys had higher reward motivation than girls, demonstrating greater accuracy difference between reward and neutral trials and higher task earnings. Girls had lower neural activation during reward feedback than boys in the nucleus accumbens, caudate, rostral anterior cingulate, medial orbitofrontal cortex, superior frontal gyrus and posterior cingulate. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, although these associations changed when controlling for age. There were no significant associations between pubertal development and neural activation during reward anticipation and feedback. Sex differences in reward-related processing exist in early adolescence, signaling the need to understand their impact on typical and atypical functioning as it unfolds into adulthood.

Sex and pubertal influences on the neurodevelopmental underpinnings of schizophrenia: A case for longitudinal research on adolescents.

Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.

Abnormal liver function tests in acne patients receiving isotretinoin.

BACKGROUND: Isotretinoin is an efficacious treatment option for severe acne. Although isotretinoin often causes mild liver enzyme elevation, how acne patients should be monitored on isotretinoin therapy is not well characterized. OBJECTIVE: The purpose of this study was to assess the management and clinical outcome of acne patients with abnormal aspartate transaminase (AST) and alanine aminotransferase (ALT) when receiving isotretinoin. METHODS: A retrospective chart review was conducted in acne subjects with abnormal AST and ALT levels receiving isotretinoin. Abnormal liver enzymes were graded using the Common Terminology Criteria for Adverse Events version 5. RESULTS: Of 108 subjects with abnormal liver enzymes, 79 subjects were on isotretinoin 80 mg and 23 subjects were on isotretinoin 40 mg. Most abnormalities were during Month 1 of therapy (48). Of the 122 abnormal Grade 1 AST elevations, 40 normalized, 38 remained in Grade 1, and 1 increased into Grade 2 when a healthcare provider maintained the isotretinoin dose. Of the 102 abnormal Grade 1 ALT levels managed by maintaining the isotretinoin dose, 31 normalized and 38 remained persistently elevated. CONCLUSION: Most mild elevations of isotretinoin therapy do not worsen. Acne patients with isotretinoin may not need continued testing when experiencing low-grade liver enzyme abnormalities.

Perfusion and Volume Response of Canine Brain Tumors to Stereotactic Radiosurgery and Radiotherapy.

BACKGROUND: Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) are highly conformal, high-dose radiation treatment techniques used to treat people and dogs with brain tumors. OBJECTIVES: To evaluate the response to SRS- and SRT-treated tumors using volume and perfusion variables and to measure the survival times of affected dogs. ANIMALS: Prospective study of 34 dogs with evidence of brain tumors undergoing stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). METHODS: Computed tomography and MRI imaging were used to calculate tumor volume and perfusion at baseline, and at 3 months and 6 months after treatment. Survival analysis was performed to evaluate treatment efficacy. RESULTS: Mean tumor volume significantly declined from baseline to the first recheck by -0.826 cm(3) (95% CI: -1.165, -0.487) (P < .001); this reduction was maintained at the second recheck. Blood flow and blood volume declined significantly in the tumor after treatment. Median survival was 324 days (95% CI: 292.8, 419.4), and 4 dogs survived longer than 650 days. Neither actual tumor volume (hazard ratio = 1.21, P = .19) nor the change in tumor volume from the baseline (hazard ratio = 1.38, P = .12) significantly affected the hazard of death because of the tumor. CONCLUSIONS AND CLINICAL IMPORTANCE: Stereotactic radiosurgery and SRT are effective treatments for reducing tumor volume, blood flow, and blood volume. Treated dogs surviving for more than 1 year are more likely to die from other causes than of their primary brain tumor. SRS and SRT should be considered for noninvasive treatment of intracranial brain tumors.

Sesame allergy threshold dose distribution.

BACKGROUND: Sesame is a relevant food allergen in France. Compared to other allergens there is a lack of food challenge data and more data could help sesame allergy risk management. The aim of this study is to collect more sesame challenge data and investigate the most efficient food challenge method for future studies. METHOD: Records of patients at University Hospital in Nancy (France) with objective symptoms to sesame challenges were collected and combined with previously published data. An estimation of the sesame allergy population threshold was calculated based on individual NOAELs and LOAELs. Clinical dosing schemes at Nancy were investigated to see if the optimal protocol for sesame is currently used. RESULTS: Fourteen patients (10 M/4 F, 22 ± 14.85 years old) with objective symptoms were added to previously published data making a total of 35 sesame allergic patients. The most sensitive patient reacted to the first dose at challenge of 1.02 mg sesame protein. The ED05 ranges between 1.2 and 4.0 mg of sesame protein (Log-Normal, Log-Logistic, and Weibull models) and the ED10 between 4.2 and 6.2 mg. The optimal food challenge dosing scheme for sesame follows semi-log dose increases from 0.3 to 3000 mg protein. CONCLUSION: This article provides a valuable update to the existing clinical literature regarding sesame NOAELs and LOAELs. Establishment of a population threshold for sesame could help in increasing the credibility of precautionary labelling and decrease the costs associated with unexpected allergic reactions. Also, the use of an optimal dosing scheme would decrease time spent on diagnostic and thereafter on the economic burden of sesame allergy diagnosis.

Effect of screening abdominal ultrasound examination on the decision to pursue advanced diagnostic tests and treatment in dogs with neurologic disease.

BACKGROUND: Abdominal ultrasound examinations (AUS) are commonly performed before advanced neurodiagnostics to screen for diseases that might affect diagnostic plans and prognosis. OBJECTIVES: Describe the type and frequency of abnormalities found by AUS in dogs presenting with a neurological condition, identify risk factors associated with abnormalities, and evaluate treatment decisions based on findings. ANIMALS: Seven hundred and fifty-nine hospitalized dogs. METHODS: Retrospective study. Medical records of dogs presented from 2007 to 2009 for neurologic disease were searched for signalment, neuroanatomic localization, and AUS findings. Whether dogs had advanced neurodiagnostics and treatment was analyzed. RESULTS: Fifty-eight percent of dogs had abnormal findings on AUS. Probability of abnormalities increased with age (P < 0.001). Nondachshund breeds had higher probability of abnormal AUS than dachshunds (odds ratio [OR] = 1.87). Eleven percent of dogs did not have advanced neurodiagnostics and in 1.3%, this was because of abnormal AUS. Dogs with ultrasonographic abnormalities were less likely than dogs without to have advanced neurodiagnostics (OR = 0.3 [95% confidence interval [CI]: 0.17, 0.52]), however, the probability of performing advanced diagnostics was high regardless of normal (OR = 0.95 [95% CI: 0.92, 0.97]) or abnormal (OR = 0.85 [95% CI: 0.81, 0.88]) AUS. Treatment was more often pursued in small dogs and less often in dogs with brain disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Findings from screening AUS had a small negative effect on the likelihood of pursuing advanced neurodiagnostics. Although it should be included in the extracranial diagnostic workup in dogs with significant history or physical examination abnormalities, AUS is considered a low-yield diagnostic test in young dogs and dachshunds.

Unintended allergens in precautionary labelled and unlabelled products pose significant risks to UK allergic consumers.

BACKGROUND: Allergens in food may pose a risk to allergic consumers. While there is EU regulation for allergens present as an ingredient, this is not the case for unintended allergen presence (UAP). Food companies use precautionary allergen labels to inform allergic individuals of a potential risk from UAPs. This study investigates the risk of an allergic reaction within the milk-, wheat-, hazelnut- and peanut-allergic populations when ingesting UK foods across multiple product categories with and without precautionary allergen labelling. METHODS: Allergen risk assessment using probabilistic techniques enables the estimation of the residual risk after the consumption of a product that unintentionally contains an allergen. RESULTS: Within this selection of UK products, the majority that tested positive for an allergen contained a concentration of allergen predicted to cause a reaction in >1% of the allergic population. The concentrations of allergens measured were greater than the VITAL(®) 2.0 action levels and would trigger precautionary allergen labelling. This was found for products both with and without precautionary allergen labelling. CONCLUSIONS: The results highlight the need for the food industry and regulators to adopt a transparent, risk-based approach for the communication of the risk associated with potential cross-contact that could occur in the processing facility or production chain.

Precautionary allergen labelling: perspectives from key stakeholder groups.

Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present.

Dietary management of peanut and tree nut allergy: what exactly should patients avoid?

Peanut and tree nut allergies are the commonest cause of life-threatening food-allergic reactions and significantly affect quality of life in children and their families. Dietary nut avoidance and provision of emergency medication is currently the mainstay of treatment. Nut avoidance has consequences on both quality of life and nutrition. We review the terminology that may cause confusion and lead to unnecessary dietary restrictions. In peanut or tree nut-allergic children, introduction of specific nuts to which the child is not allergic may improve quality of life and should be considered in patients with multiple foods allergies, vegan or ethnic-specific diets, in whom nuts are an important source of protein. Nut-allergic consumers do not just need to avoid foods containing nuts as an ingredient, but also contend with pre-packed foods which frequently have precautionary allergen labelling (PAL) referring to possible nut contamination. Although the published rate of peanut contamination in 'snack' foods with PAL (see Box ) ranges from 0.9-32.4%, peanut contamination in non-snack items with PAL is far less common. We propose that in some peanut-allergic patients (depending on history of reactivity to trace levels of peanut, reaction severity, other medical conditions, willingness to always carry adrenaline, etc.), consideration may be given to allow the consumption of non-snack foods containing PAL following discussion with the patient's (and their family's) specialist. More work is needed to provide consumers with clearer information on the risk of potential nut contamination in pre-packed food. We also draw attention to the change in legislation in December 2014 that require mandatory disclosure of allergens in non-pre-packed foods.

Identification and characterization of intestinal lactobacilli strains capable of degrading immunotoxic peptides present in gluten.

AIM: Identify and characterize bacteria from the proximal gastrointestinal tract of pigs capable of degrading immunogenic gluten peptides. METHODS AND RESULTS: Bacteria were cultured from the small intestine of pigs fed a 20% gluten diet and from an enrichment media with the 18-mer peptide LQLQPFPQPQLPYPQPQL. Isolates were screened for the production of specialized proteolytic enzymes and the ability to degrade and remove metastable peptides from α-gliadin (16-mer and 33-mer) and ω-gliadin (17-mer), with established roles in the aetiology of coeliac disease. Degradation was determined by ELISA and mass spectrometry (UHPLC-MS/MS in MRM mode), and hydrolysis fragments were characterized by LC-MS/MS. Four strains from the species Lactobacillus ruminis, Lactobacillus johnsonii, Lactobacillus amylovorus and Lactobacillus salivarius showed the highest peptide-degrading activities. Strains displayed different degradation rates and cleavage patterns that resulted in reduction but not complete removal of immunotoxic epitopes. CONCLUSIONS: We employed a unique enrichment process to select for bacteria adapted to the conditions of the proximal gastrointestinal tract with the ability to partially detoxify well-characterized peptides involved in coeliac disease. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a basis for the selection of Lactobacillus strains for probiotic applications aimed to reduce epitope-containing gluten peptides before reaching the epithelium of the small intestine of patients with coeliac disease.

Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.

We aimed to determine the incidence of Clostridium difficile infection (CDI), the molecular epidemiology of circulating C. difficile strains and risk factors for CDI among hospitalised children in the Auckland region. A cross-sectional study was undertaken of hospitalised children <15 years of age in two hospitals investigated for healthcare-associated diarrhoea between November 2011 and June 2012. Stool specimens were analysed for the presence of C. difficile using a two-step testing algorithm including polymerase chain reaction (PCR). C. difficile was cultured and PCR ribotyping performed. Demographic data, illness characteristics and risk factors were compared between children with and without CDI. Non-duplicate stool specimens were collected from 320 children with a median age of 1.2 years (range 3 days to 15 years). Forty-six patients (14 %) tested met the definition for CDI. The overall incidence of CDI was 2.0 per 10,000 bed days. The percentage of positive tests among neonates was only 2.6 %. PCR ribotyping showed a range of strains, with ribotype 014 being the most common. Significant risk factors for CDI were treatment with proton pump inhibitors [risk ratio (RR) 1.74, 95 % confidence interval (CI) 1.09-5.59; p = 0.002], presence of underlying malignancy (RR 2.71, 95 % CI 1.65-4.62; p = 0.001), receiving chemotherapy (RR 2.70, 95 % CI 1.41-4.83; p = 0.003) and exposure to antibiotics (RR 1.17, 95 % CI 0.99-1.17; p = 0.03). C. difficile is an important cause of healthcare-associated diarrhoea in this paediatric population. The notion that neonatal populations will always have high rates of colonisation with C. difficile may not be correct. Several risk factors associated with CDI among adults were also found to be significant.

False positive detection of peanut residue in liquid caramel coloring using commercial ELISA kits.

Initial food industry testing in our laboratory using enzyme-linked immunosorbent assay (ELISA) methods indicated that the darkest caramel color (class IV) unexpectedly contained traces of peanut protein, a potential undeclared allergen issue. Caramel production centers on the heating of sugars, often glucose, under controlled heat and chemical processing conditions with other ingredients including ammonia, sulfite, and/or alkali salts. These ingredients should not contain any traces of peanut residue. We sought to determine the reliability of commercially available peanut allergen ELISA methods for detection of apparent peanut residue in caramel coloring. Caramel color samples of classes I, II, III, and IV were obtained from 2 commercial suppliers and tested using 6 commercially available quantitative and qualitative peanut ELISA kits. Five lots of class IV caramel color were spiked with a known concentration of peanut protein from light roasted peanut flour to assess recovery of peanut residue using a spike and recovery protocol with either 15 ppm or 100 ppm peanut protein on a kit-specific basis. A false positive detection of peanut protein was found in class IV caramel colors with a range of 1.2 to 17.6 parts per million recovered in both spiked and unspiked liquid caramel color samples. ELISA kit spike/recovery results indicate that false negative results might also be obtained if peanut contamination were ever to actually exist in class IV caramel color. Manufacturers of peanut-free products often test all ingredients for peanut allergen residues using commercial ELISA kits. ELISA methods are not reliable for the detection of peanut in class IV caramel ingredients and their use is not recommended with this matrix.

Challenges in testing genetically modified crops for potential increases in endogenous allergen expression for safety.

Premarket, genetically modified (GM) plants are assessed for potential risks of food allergy. The major risk would be transfer of a gene encoding an allergen or protein nearly identical to an allergen into a different food source, which can be assessed by specific serum testing. The potential that a newly expressed protein might become an allergen is evaluated based on resistance to digestion in pepsin and abundance in food fractions. If the modified plant is a common allergenic source (e.g. soybean), regulatory guidelines suggest testing for increases in the expression of endogenous allergens. Some regulators request evaluating endogenous allergens for rarely allergenic plants (e.g. maize and rice). Since allergic individuals must avoid foods containing their allergen (e.g. peanut, soybean, maize, or rice), the relevance of the tests is unclear. Furthermore, no acceptance criteria are established and little is known about the natural variation in allergen concentrations in these crops. Our results demonstrate a 15-fold difference in the major maize allergen, lipid transfer protein between nine varieties, and complex variation in IgE binding to various soybean varieties. We question the value of evaluating endogenous allergens in GM plants unless the intent of the modification was production of a hypoallergenic crop.

Parvalbumin in fish skin-derived gelatin: is there a risk for fish allergic consumers?

The major allergen parvalbumin was purified from cod muscle tissues, and polyclonal antibodies were raised towards it. The antibodies were tested for specificity and an enzyme-linked immunosorbent assay (ELISA) was developed using these antibodies. The ELISA was applied to measure parvalbumin in cod skin, the starting material for fish gelatin made from deep sea, wild fish. The ELISA was sufficiently sensitive (LLOQ = 0.8 ng ml(-1) in extracts, corresponding to 0.02 µg of parvalbumin per g of tissue), and did not cross-react with common food constituents. Fish gelatin, wine and beer, matrices for the potential use of this ELISA, did not cause disturbance of the assay performance. The data show that the parvalbumin content in cod muscle tissue is 6.25 mg g(-1), while the skins contained considerably less, 0.4 mg g(-1). Washing of the skins, a common industrial procedure during the manufacturing of fish gelatin, reduced the level of parvalbumin about 1000-fold to 0.5 µg g(-1), or 0.5 ppm. From 95 commercial lots of fish gelatin it is shown that 73 are below 0.02 µg g(-1) parvalbumin. From the other 22 lots, the one with the highest concentration contained 0.15 µg g(-1) of parvalbumin. These levels are generally assumed to be safe for fish-allergic individuals.

Corynebacterium diphtheriae endocarditis: a case series and review of the treatment approach.

OBJECTIVES: Infective endocarditis due to non-toxigenic Corynebacterium diphtheriae is uncommon; we report 10 cases occurring over a 14-year period in Auckland, New Zealand and review the approach for treatment. CASE SERIES: Eight of the 10 patients had known prosthetic valves or homografts in situ. Three patients required surgical intervention for infective endocarditis. Seven patients were treated with a combination of ß-lactam and aminoglycoside, and one each was treated with a combination of vancomycin and an aminoglycoside, a ß-lactam alone, and vancomycin alone. All patients survived and none relapsed. REVIEW OF LITERATURE: The antibiotic treatment of 46 previously reported cases was reviewed; patients treated with a ß-lactam and aminoglycoside (n=25), and without the addition of an aminoglycoside (n=11) were compared. The differences in length of treatment within each group make the comparison of outcome (mortality, need for surgical intervention, disease and treatment complications) difficult. However, regardless of the length of treatment, there was no difference in mortality or need for surgical intervention between the two groups in the currently published cases. CONCLUSIONS: Current evidence suggests that endocarditis of either native or prosthetic valves, caused by penicillin-susceptible C. diphtheriae, demonstrates a favorable outcome when treated with either a ß-lactam alone or in combination with an aminoglycoside. Patient-specific factors will determine which approach is more appropriate for each individual patient.

Complete globozoospermia associated with PLCζ deficiency treated with calcium ionophore and ICSI results in pregnancy.

Globozoospermia is an infrequent pathology in which spermatozoa lack acrosomes. Patients are considered sterile without IVF augmented with intracytoplasmic sperm injection (ICSI), as fertilization is impaired due to absence of oocyte activation. As far as is known, this is the first study to report results of a comprehensive approach to the treatment of the semen parameters, sperm DNA fragmentation, aneuploidy, transmission electron microscopy, Western blotting and immunofluorescence for detection of phospholipase C zeta (PLCzeta), as well as ICSI outcome, of an affected patient. Morphological evaluation and transmission electron microscopy revealed complete globozoospermia with significant duplicate heads and tails. Analysis for DNA damage revealed fragmentation rates of approximately 80% in semen and 15-23% in swim-up fractions. PLCzeta was not detected by immunofluorescence or Western blotting. Aneuploidy rates were within normal ranges. ICSI followed by oocyte activation with calcium ionophore resulted in high rates of fertilization, and an ongoing pregnancy was established after transfer of cryopreserved-thawed embryos.

Health behaviour models: a framework for studying adherence in children with atopic dermatitis.

Atopic dermatitis (AD) is a common problem of childhood causing considerable distress. Effective topical treatments exist, yet poor adherence often results in poor outcomes. A framework is needed to better understand adherence behaviour. To provide a basis for this framework, we reviewed established models used to describe health behaviour. Structural elements of these models informed the development of an adherence model for AD that can be used to complement empirical AD treatment trials. Health behaviour models provide a means to describe factors that affect adherence and that can mediate the effects of different adherence interventions. Models of adherence behaviour are important for promoting better treatment outcomes for children with AD and their families. These models provide a means to identify new targets to improve adherence and a guide for refining adherence interventions.

Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis.

The small intestine and liver express high levels of cytochrome P450 3A (CYP3A), an enzyme subfamily that contributes significantly to drug metabolism. In patients with cirrhosis, reduced metabolism of drugs is typically attributed to decreased liver function, but it is unclear whether drug metabolism in the intestine is also compromised. In this study, we compared CYP3A protein expression and in vitro midazolam hydroxylation in duodenal mucosal biopsies from subjects with normal liver function (controls; n = 20) and subjects with various levels of severity of cirrhosis (n = 23). In samples from subjects with cirrhosis, duodenal CYP3A expression and total midazolam hydroxylation were lower by 47 and 34%, respectively, as compared with samples from controls. Greater decreases in CYP3A expression were seen in subjects with more severe cirrhosis. Therefore, patients with advanced cirrhosis may have greater drug exposure following oral dosing as a result of both impaired liver function and decreased intestinal CYP3A expression and activity.