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Background Patients with Crohn’s disease (CD) can develop complications including stricturing and penetrating disease [1, 2]. Although reliable baseline predictors of disease progression are urgently needed to inform management strategies, few studies have comprehensively explored the phenotypic and genetic determinants of disease progression in a sufficiently powered cohort. Methods We used data from 13,926 patients with CD in the UK IBD BioResource to investigate the effects of clinical phenotypes and genetics on CD progression. Median follow-up was 10.6 years and total follow-up was 193,033 patient-years. We applied the Montreal classification system to define disease as B1 (inflammatory), B2 (stricturing) and B3 (penetrating). Patients with B2 or B3 disease (N = 5,185) were compared to patients with B1 disease (N = 8,471) in a multivariate model fitted with both phenotype data and a polygenic score that we developed. Associations with q-values (false discovery rate adjusted p-values) less than 0.05 were defined as statistically significant. Results CD progression occurred over time from diagnosis (Figure 1). Consistent with previous findings, we confirmed factors including smoking, disease location and perianal disease were associated with disease progression [3] (Table 1). The impact of a genetic influence on disease progression was confirmed and shown to be independent of genetic effects on disease location [4]. Early prescription of medications showed a protective effect on disease progression: Infliximab, adalimumab and thiopurines significantly reduced the chance of B2/B3 progression when prescribed within two years of diagnosis. Additionally, we observed a decreased progression to B2/B3 disease in patients diagnosed recently (between 2012–2020) compared to those diagnosed before 2012. This finding persisted after conditioning on exposure to biologics and correcting for follow-up time and interval to first thiopurine prescription, and thus may be indicative of other improvements in standards of care in recent years. Conclusion Using a large, well-characterised cohort we confirm the importance of disease location, smoking status and genetics on disease progression. We highlight the positive impact of early medication prescription on disease progression and discover an independent signal relating to potential improvements in the standard of care in CD over time. These results create the framework for reliable predictors of CD progression that may better guide future CD management strategies. References

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P

Maltreatment-related childhood adversity is the leading preventable risk factor for mental illness and substance abuse. Although the association between maltreatment and psychopathology is compelling, there is a pressing need to understand how maltreatment increases the risk of psychiatric disorders. Emerging evidence suggests that maltreatment alters trajectories of brain development to affect sensory systems, network architecture and circuits involved in threat detection, emotional regulation and reward anticipation. This Review explores whether these alterations reflect toxic effects of early-life stress or potentially adaptive modifications, the relationship between psychopathology and brain changes, and the distinction between resilience, susceptibility and compensation.

SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

The amygdala is vulnerable to stress-dependent disruptions in neural development. Animal models have shown that stress increases dendritic arborization leading to larger amygdala volumes. Human studies of early stress and amygdala volume, however, remain inconclusive. This study compared amygdala volume in adults with childhood maltreatment to that in healthy controls. Eighteen participants from a longitudinal cohort and 33 cross-sectional controls (17 M/34 F, 25.5±3.1 years) completed a structural magnetic resonance imagining scan and the Maltreatment and Abuse Chronology of Exposure scale. Random forest regression with conditional trees was used to assess relative importance of exposure to adversity at each age on amygdala, thalamic or caudate volume. Severity of exposure to adversity across age accounted for 27% of the variance in right amygdala volume. Peak sensitivity occurred at 10-11 years of age, and importance of exposure at this time was highly significant based on permutation tests (p=0.003). The regression model showed that exposure during this sensitive period resulted in steep dose-response function with maximal response to even modest levels of exposure. Subjects in the highest exposure quartile (MACE-11, range=11-54) had a 9.1% greater right amygdala volume than subjects in the lowest exposure quartile (MACE-11, ≤3.5). No associations emerged between age of exposure and volume of the left amygdala or bilateral caudate or thalamus. Severity of adversity experienced at age 10-11 contributed to larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental sensitive period in preadolescence.

Background Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. Methods One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. Results Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43 % cases, 0.11 % controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13 % cases, 0.01 % controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22 % carriers among cases, 0.03 % carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. Conclusion Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0289-z) contains supplementary material, which is available to authorized users.

Previous studies have reported cerebellar abnormalities or static ataxia associated with risk for chronic use of alcohol and drugs. Adverse childhood experience is another strong risk factor for later substance abuse. We therefore sought to ascertain the relationship between morphological phenotypes of the lingula (lobule I) of the anterior cerebellar vermis, and exposure to emotional (EM) versus physical (PM) maltreatment, on the degree of ongoing alcohol or drug use. The study design consisted of a cross-sectional in vivo neuroimaging study, utilizing retrospective assessment of maltreatment history and self-reports of alcohol and substance use. Study participants were 153 subjects (54 M/99F, 21.9 +/- 2.2 years) selected for imaging from a database of 1,402 community participants 18-25 years of age, who completed a detailed online screening instrument and met rigorous inclusion/exclusion criteria. Subjects were exposed to only physical abuse or harsh corporal punishment (HCP; PM group, n = 37) and parental verbal abuse and/or witnessing domestic violence (EM group, n = 58) or had no history of maltreatment or axis I disorders (n = 58). The main outcome measures consisted of the gray matter volume of lobule I as measured by manual tracing, number and type of alcoholic beverages consumed during a drinking session, number of sessions per month, and monthly drug use, along with family history of drug and alcohol abuse. Lingula thickness was not attenuated by alcohol use or maltreatment history. However, increased lingula thickness was associated with greater consumption of drugs and hard liquor, particularly in physically maltreated subjects who consumed 2.5- and 2.7-fold more alcohol and used drugs 6.1- and 7.8-fold more frequently than controls or EM subjects, respectively. In conclusion, physical maltreatment was observed to interact with cerebellar morphology resulting in a strong association with alcohol and substance use. Lingula thickness may represent a novel, experientially sensitive, phenotypic risk factor for enhanced alcohol and drug use that perhaps modulates sensitivity to these agents.

In contrast to the classic signal transduction of D1 dopamine receptors in striatum or molecular expression systems, it has been reported that D1 receptor agonists do not stimulate adenylate cyclase in homogenates of microdissected nuclei of the amygdaloid complex. This article examines this phenomenon in detail to determine if lack of cAMP signaling in the amygdaloid complex is an experimental artifact, or an indication of a marked difference from the well-studied basal ganglia terminal fields. Thus, whereas dopamine agonists failed to increase cAMP synthesis in the amygdala, forskolin, guanine nucleotides, or Mg2+ were able to stimulate adenylate cyclase activity in the same preparations. Under several different conditions, caudate preparations responded more robustly than amygdaloid preparations, while amygdala homogenates exhibited higher basal production of cAMP. Whereas the beta-adrenergic agonist isoproterenol was able to stimulate cAMP efflux in membranes from both the caudate and amygdala under a variety of tested conditions, neither dopamine nor fenoldopam (D1 agonist) could stimulate adenylate cyclase in the amygdala. Additionally, while manipulation of Ca2+ and calmodulin affected the differential actions of dopamine in the caudate, no change in these parameters restored sensitivity to dopamine in the amygdala. Together, these data challenge the commonly accepted notion that cAMP is a mandatory signaling pathway for D1 receptors. Because it is now proven that G protein-coupled receptors can signal promiscuously, elucidation of the non-cAMP-dependent signaling mechanisms resulting from D1 activation is clearly critical in understanding how this important receptor functions in situ.

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.

Fifteen subjects evaluated while wearing, in random order, four pairs of glasses, two limiting vision to either the left or right lateral visual field (LVF) and two monocular glasses (MGs) limiting vision to either eye, manifested significant differences in laterality indices in the predicted direction for the theta electroencephalogram (EEG) (P < .003) and ear canal temperature (P < .02) between the LVF glasses, but not the MGs. There was a significant correlation between lateral shifts in the theta EEG and ear canal temperature (r2 = .47 F(1,10) = 8.72, P < .015). The LVF glasses induced an absolute difference in anxiety greater (P < .05) than that induced by the MGs. LVF glasses appear to induce a shift in affect and hemispheric dominance.

Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

M.A. van Leeuwen1, S. Veenbergen1, R. Kersseboom2, L.F. de Ruiter1, H. Raatgeep1, D.J. Lindenbergh-Kortleve1, Y. SimonsOosterhuis1, L. de Ridder1, G.J.A. Driessen3, J.C. Escher1, J.N. Samsom1 *. 1Erasmus Medical Centre Sophia Children’s Hospital, Dept. of Paediatric Gastroenterology, Rotterdam, 2Erasmus Medical Centre, Dept. of Clinical Genetics, Rotterdam, 3Erasmus Medical Centre, Dept. of Paediatric Infectious Disease and Immunology, Rotterdam, Netherlands

Background: The advent of biologic agents that bind to tumor necrosis factor (TNF) has revolutionized therapy of inflammatory bowel disease (IBD). However, these agents carry a unique set of adverse effects, including development of a lupus-like syndrome termed antiTNF induced lupus (ATIL). This adverse effect often leads to cessation of the anti-TNF agent. The clinical manifestations and criteria for ATIL are incompletely defined in patients with IBD. We explored aspects of ATIL in a series of IBD patients. Methods: Patients from the University of Calgary IBD clinic in whom ATIL was diagnosed by the treating physician were included (N=10). Ethics approval was obtained from the Conjoint Health Research Ethics Board at the University of Calgary. Charts were reviewed for pertinent clinical data. Blood was drawn and sent for serology including anti-nuclear antibody (ANA) and extractable nuclear antigens (ENA), by the Mitogen Advanced Diagnostics Laboratory (mitogen.ca, Calgary, AB). DNA was sent to the Sanger Institute (Cambridge, UK) for whole-exome sequencing (analysis pending). Results: The cohort consisted of largely females (8/10) with Crohn's disease (CD) (7/10). In CD patients, disease location was mainly ileocolonic (6/7), while all UC patients had left-sided disease (3/3). Median age at diagnosis was 39 (range 19-62). Seven patients developed ATIL on infliximab, and 3 on adalibumab. Reported manifestations included rash (70%), and arthritis (50%) or arthralgias (40%). Antinuclear antibody (ANA) was positive in 9 patients. The most common pattern was speckled (7/9) and homogenous (5/9), with a median titer of 1:320. No patients were ENA positive. All patients had thiopurine exposure, and 50% had a previous adverse reaction to thiopurines (2 hepatotoxicity, 2 leukopenia, and 1 pancreatitis). Of patients who developed ATIL on adalibumab, 2/3 had a history of infusion reaction to infliximab. Six patients who developed ATIL on infliximab subsequently received adalibumab, 3/6 developing recurrent ATIL symptoms. Conclusions: In the present study we sought to characterize ATIL in a series of IBD patients. There was a predominance of ileocolonic CD patients treated with infliximab; this may purely reflect historical predominance of infliximab use. However, a putative mechanism of ATIL is via anti-cellular immunity against cells expressing membrane-bound anti-TNF, and it is possible that the chimeric infliximab induces more avid epitope spreading, and thus predisposes to ATIL. There was a high prevalence of previous adverse reaction to thiopurines, suggesting a possible association with development of ATIL. Introduction of another anti-TNF agent was possible in some without recurrent ATIL. Understanding characteristics of ATIL may help in early recognition and development of predictive markers of this important adverse effect.

Hyperlipoproteinemia is common in patients with renal disease, but increased lipids are only one of several risk factors frequently identified for coronary artery disease. Before treatment options are instituted, renal disease status, current medications, and possible interactions between drugs must be considered. Hypertriglyceridemia is common in patients with renal failure; therapeutic options are influenced by the levels of serum triglycerides and high-density lipoprotein cholesterol. If nonsteroidal drugs improve renal function and decrease proteinuria in patients with renal disease, hyperlipidemia frequently abates. Interactions between drugs are important considerations when lipid-lowering drug treatment is prescribed in recipients of renal transplants.

Endometriosis is a common gynaecological disease associated with severe pelvic pain and sub-fertility. There is considerable debate whether different endometriosis stages represent disease progression, or whether moderate-severe (rAFS III/IV) disease is pathological and minimal-mild (rAFS I/II) an epiphenomenon. We conducted a genome-wide association study using 540 082 SNPs in 3194 surgically confirmed endometriosis cases and 7060 controls from Australia and the UK. We used novel statistical methods to estimate the proportion of common variation explained by all markers and performed polygenic predictive modelling for disease stage, both showing significantly increased genetic loading among the 42% of cases with moderate-severe endometriosis. The strongest signals of association were also observed for moderate-severe disease. We subsequently genotyped 72 SNPs in an independent US dataset comprising 2392 endometriosis cases and 1646 controls. An association with rs7798431 on 7p15.2 for moderate-severe endometriosis (P = 6.0 × 10–8, OR = 1.34 (1.21–1.49)) was replicated, reaching combined genome-wide significance (P = 1.7 × 10–9; OR = 1.26 (1.17–1.35)). The implicated inter-genic region involves a 48 kb segment of high LD upstream of plausible candidate genes NFE2L3 and HOXA10. This locus is the first to be robustly implicated in the aetiology of endometriosis, with evidence of association limited to moderate-severe disease.

Hyperlipoproteinemia is common in recipients of renal allografts. In this study, serum lipids and some possible contributing factors--weight gain, weight relative to ideal body weight, daily dose of prednisone, serum creatinine, 24-hour urinary protein, and diabetes mellitus--were assessed in 100 patients. At the end of the first year after transplantation, 57 of the 100 patients had total serum cholesterol concentrations of 240 mg/dl or more--40 of 75 patients without diabetes and 17 of 25 with diabetes. The mean values for weight gain (11.2 kg) and actual weight relative to ideal body weight (19.4 kg) were significantly greater (P = 0.029 and P = 0.01, respectively) in the subgroup of patients without diabetes who had total serum cholesterol values of 240 mg/dl or more at 1 year after transplantation than in those with values of less than 240 mg/dl. The daily dose of prednisone and the serum creatinine levels were similar in these two subgroups. The 24-hour urinary protein measurements were greater at 1 month than at 1 year in both patients with and those without diabetes. Perhaps the initial dietary advice for patients who have undergone renal transplantation should emphasize control of total caloric intake; subsequently, intake of cholesterol and fat can be modified in those patients who have persistent hyperlipoproteinemia.

We received requested follow-up information from 105 (73%) of our 144 kidney donors who had undergone unilateral nephrectomy 10 to 20 years previously. Five donors had died of unrelated causes 6 or more years postoperatively. Studies in the remaining 100 donors showed that the current mean serum creatinine concentration was 1.2 mg/dl and the mean 24-hour urinary protein value was 89 mg. Hypertension (defined as 160 mm Hg or more systolic, 95 mm Hg or more diastolic, or both) was present in 19% of the donors. In a subgroup of 66 donors who had had serial serum creatinine determinations, the renal function, as estimated on the basis of these serum creatinine values, had not deteriorated with time. Thus, we consider unilateral nephrectomy in this group of patients relatively safe. Subsequent evaluation will be necessary to ascertain whether these findings prevail.

This study was designed to evaluate the effects of soy fiber, a natural source of dietary fiber that consists of both cellulosic and noncellulosic dietary fiber, on human plasma lipoprotein lipids and glucose tolerance in patients with primary hyperlipidemia. Supplementing 25 g of soy fiber per day provided a significant additional reduction of plasma total-cholesterol by 13 mg/dl (P less than 0.04) and LDL cholesterol by 12 mg/dl (P less than 0.05) beyond that previously achieved by treatment with an NIH Type II-A low-fat, low-cholesterol diet for 12 weeks in Type II-A hypercholesterolemic patients. There were no effects on HDL cholesterol or apoprotein A-I and A-II levels. The hypocholesterolemic effect was greater than in the hyperlipidemic patients with impaired glucose tolerance. Soy fiber supplementation also significantly reduced insulin responses to oral glucose challenge by 20% in Type II-A hypercholesterolemic and by 16.5% in Type IV hypertriglyceridemic patients. Results from this study suggest that supplementing the diet with soy fiber may be beneficial in dietary management of hyperlipidemia in patients with hypercholesterolemia and particularly in hyperlipidemic patients with hyperinsulinemia and impaired glucose tolerance.

Two immunosuppressive regimens-cyclosporine plus prednisone and azathioprine plus prednisone-were compared in 78 renal transplantation patients (39 in each treatment group) who were successfully managed for more than 15 months. In patients who received cyclosporine, the dosage was adjusted to achieve trough whole blood concentrations of 100 to 250 ng/ml measured by liquid chromatography. A greater number of haplotypes matched in the azathioprine-treated group than in the cyclosporine-treated group (P less than 0.026). Graft survival was similar in patients who received azathioprine (95%) and those given cyclosporine (94%). The azathioprine group had a higher mortality (7%) than the cyclosporine group (2%). In a comparison of the two treatment groups, no statistically significant difference was found in posttransplant renal function, based on either serum creatinine or iothalamate clearance. We conclude that renal toxicity due to cyclosporine can be minimized to statistical nonsignificance by using cyclosporine dosages that provide trough whole blood concentrations in the range of 150 to 250 ng/ml during the first 4 months of therapy and 80 to 200 ng/ml thereafter.

Dialysis and transplantation are now standard treatments for end-stage renal failure. Often, neurologists are consulted regarding the neurological complications of these therapeutic procedures. In addition to previously reported complications, neurovascular disease is being recognized as a cause of mortality and morbidity in these patients. We report two cases of apparent thromboembolic stroke in young patients with renal failure -- one treated by dialysis and the other by renal transplantation. The risk factors of both dialysis and transplant are identified and data from the American College of Surgeons/National Institutes of Health Transplant Registry are reviewed.

The value of preoperative nutritional assessment in predicting postoperative morbidity and mortality is controversial. To evaluate the predictive value of preoperative nutritional status, the courses of 100 consecutive patients undergoing colorectal operations were studied prospectively. Subnormal findings for triceps-skin-fold thickness (TSF) and percentage of ideal body weight were associated with a significantly higher complication rate, but occurred so infrequently in our patients that the routine use of these tests is not recommended. Subnormal values for commonly obtained nutritional variables may not justify delay of operation for nutritional repletion.

The present study mapped the topographic distribution of, and the effect of neuropharmacologically distinct antipsychotic drugs on, the concentration of neurotensin (NT) in the rat brain at the level of discrete nuclei or areas. The chronic administration of either haloperidol or clozapine increased the concentration of NT-like immunoreactivity (NT-LI) in the nucleus accumbens and decreased it in the medial prefrontal and cingulate cortex and in the interstitial (bed) nucleus of the stria terminalis. In contrast, the prolonged administration of haloperidol, but not clozapine, increased the concentration of NT-LI in the anterior caudate nucleus and posterior caudate-putamen. The concentration of NT-LI in the great majority of the rat brain nuclei examined was unaffected by the chronic administration of either antipsychotic drug. This pattern of pharmacological response distinguishes NT from all other neuropeptides which have been shown to be influenced by prolonged antipsychotic drug administration. These findings suggest that the functional information imparted to NT-containing cells by neuronal dopamine (DA) release, as inferred from the consequences of receptor blockade, varies remarkably between different populations of DA neurons and further implicate NT as a neuroanatomically-selective neurochemical substrate of the adaptive responses mediating the therapeutic and motoric side effects of antipsychotic drugs.

This paper describes a system of care and the clinical issues that are central to the delivery of alcoholism and for substance abuse services to adolescents. Adolescent services can be provided in a variety of settings. Criteria are identified which can distinguish which level of care is most appropriate for the presenting clinical condition of the adolescent.

Corticotropin releasing factor (CRF) may regulate endocrine, autonomic, and behavioral responses to stress. Evidence indicates that CRF-like immunoreactivity (CRF-LI) is widely distributed throughout the CNS. In this study, the distribution of CRF-LI was determined in 36 rat brain regions by combined radioimmunoassay-micropunch dissection techniques and the effect of stress on CRF-LI was investigated, using a chronic stress model that induces endocrine changes in rats similar to those seen in depressed humans. A control group of rats was handled daily. An acute stress group was subjected to 3 hr of immobilization at 4 degrees C, while a chronic stress group was exposed to unpredictable stressors. Thirty-six brain regions were microdissected by the technique of Palkovits and assayed for CRF-LI, using a specific antiserum to ovine CRF. CRF-LI was detected in most regions. In controls, the highest concentrations were found in the arcuate nucleus/median eminence, the hypothalamic paraventricular (PVN) nucleus, and the periventricular nucleus. The next highest levels were found in the raphe nuclei and dorsal vagal complex. CRF-LI was well represented in the locus coeruleus (LC); in the central, cortical, and medial amygdaloid nuclei; and in the bed nucleus of the stria terminalis. Low concentrations occurred in the hippocampus and cerebrocortical regions. Appreciable concentrations were detected in midbrain and brain stem regions. Acute stress reduced CRF-LI in the arcuate nucleus/median eminence (ME) (by 52%) and in the median preoptic (MPO) nucleus (by 32%) and doubled its concentration in the locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)

A study was designed to compare platelet deposition between knitted and woven Dacron grafts in the same patient. Twenty patients received aortoiliac or aortofemoral bifurcated Dacron grafts, each composed of one woven and one double-velour knitted limb. External nuclear graft imaging was carried out after injection of autologous platelets labeled with indium 111. The patients were studied postoperatively in time periods ranging from 6 days to 42 months. Platelet accumulation was almost identical in knitted and woven limbs in all patients. This study appears to indicate that there is no difference in thrombogenicity between knitted and woven bifurcated Dacron grafts in the aortoiliac or aortofemoral positions measured by platelet accumulation.

Forty patients with Type I membranoproliferative glomerulonephritis were treated for one year with dipyridamole, 225 mg per day, and aspirin, 975 mg per day, in a prospective, randomized, double-blind, placebo-controlled study. At the base line, the half-life of 51Cr-labeled platelets was reduced in 12 of 17 patients. The platelet half-life became longer and renal function stabilized in the treated group, as compared with the placebo group, suggesting a relation between platelet consumption and the glomerulopathy. The glomerular filtration rate, determined by iothalamate clearance, was better maintained in the treated group (average decrease, 1.3 ml per minute per 1.73 m2 of body-surface area per 12 months) than in the placebo group (average decrease, 19.6). Fewer patients in the treated group than in the placebo group had progression to end-stage renal disease (3 of 21 after 62 months as compared with 9 of 19 after 33 months). The data suggest that dipyridamole and aspirin slowed the deterioration of renal function and the development of end-stage renal disease.

Six patients (five men and one woman) with Alport's syndrome underwent successful renal transplantation (four received kidneys from cadaver donors and two received allografts from living, related donors). One patient who had received a cadaver kidney had substantial hearing improvement and the others had stabilization of hearing. Hearing loss in Alport's syndrome is progressive. The reversal of deafness in one of our patients and stabilization in the others made us wonder whether an inherited enzymopathy had been reversed, which then mitigated the deafness.

This study assessed the effects of fenofibrate on lipoprotein levels and lipoprotein compositions in a subgroup of patients who participated in a multicenter fenofibrate study. Eleven men and 10 women aged 29 to 63 were studied, 12 with type II A and nine with type II B hyperlipoproteinemia. Fasting blood samples were obtained every four to six weeks. Lipoprotein lipids were quantified by procedures of the Lipid Research Clinics, and apolipoproteins by radioimmunoassay. Fenofibrate decreased mean triglyceride and cholesterol levels of the type II A patients from 130 to 99 and from 286 to 237 mg/dl, respectively. Levels of very low-density lipoprotein triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol decreased and high-density lipoprotein cholesterol levels rose. Apolipoprotein B and apolipoprotein E levels decreased, whereas apolipoprotein AI and apolipoprotein AII levels rose. The mean very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratio and low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratio decreased. The low-density lipoprotein cholesterol:apolipoprotein B ratio and high-density lipoprotein cholesterol: apolipoprotein AII ratio decreased as did the apolipoprotein AI:apolipoprotein AII ratio. In patients with type II B hyperlipoproteinemia, triglyceride and cholesterol levels decreased with fenofibrate therapy with most of the decrease in triglyceride levels due to very low-density lipoprotein triglycerides, whereas the decrease in total cholesterol levels was due to decreases in very low-density lipoprotein and low-density lipoprotein cholesterol. High-density lipoprotein cholesterol levels rose. The decrease in low-density lipoprotein cholesterol levels was not significant in this group. Apolipoprotein E levels decreased and apoliprotein AI and apolipoprotein AII levels rose. Indices of composition in type II B patients were similar to those in type II A patients but the changes were less dramatic. Very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratios decreased significantly, but low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratios did not change significantly with treatment. The mean low-density lipoprotein cholesterol:apolipoprotein B ratio, high-density lipoprotein cholesterol:apolipoprotein AII ratio, and apolipoprotein AI:apolipoprotein AII ratio all were lowered by therapy. Thus, very low-density lipoprotein and low-density lipoprotein lost cholesterol in response to fenofibrate therapy and high-density lipoprotein particles became enriched in cholesterol.

The microscopic pathology of the epiphyseal cartilage plates and adjacent bone in seven patients with dwarfism and skeletal deformities has been reported. In two of the patients the clinical picture is clearly that of Morquio's syndrome; in two others, the picture resembles dysplasia epiphysalis multiplex; and in the remaining three there are some of the roentgenographic criteria of both of these conditions. Similar pathological changes were present in the epiphyseal cartilage plate in all seven cases. The essential defect is in the epiphyseal chondrocytes which fail to reach the zone of ossification in adequate numbers or in a fully developed hypertrophic condition, resulting in defective enchondral ossification. Deficient metaphyseal osteogenesis results from inadequate chondrocyte proliferation and maturation. Cystic amid mucoid degeneration of cartilage matrix and areas of aberrant epiphyseal ossification are also noted. None of the storage phenomena of Hurler's syndrome are present. The pathological findings in dysplasia epiphysalis multiplex, Morquio's disease, and achondroplasia relate directly to epiphyseal chondrocyte dysfunction. These conditions might therefore be grouped together under the term chondrogenic dwarfism to indicate their common pathological relationship. The epiphyseal cartilage changes in these coniditions are readily distinguished from those usually associated with dietary deficiencies and endocrine disorders in human subjects.

The collagen, mucopolysaccharides, sulphur, non-protein nitrogen, and non-collagenous protein content were determined in the articular cartilage of joints of the lower extremity its sixty patients. The results were analyzed with relation to the ages of the patients, the sites from which the cartilag