Diagnostic value of lumbar puncture for the etiological assessment of uveitis: a retrospective cohort of 188 patients.

AIM: To assess the relevance of lumbar puncture (LP) for the etiological diagnosis of uveitis and to establish predictive factors associated with its contributory use. METHODS: We performed a retrospective study of patients with de novo uveitis who were referred to our tertiary hospital for etiological diagnosis of uveitis, between January 2003 and July 2018. We included patients who underwent a LP as part of the etiological assessment of uveitis. LP was considered as contributory if it led to the etiological diagnosis or to correct the initially suspected diagnosis. RESULTS: One hundred eighty eight of the 1211 patients referred for evaluation (16%) had an LP, among these patients, 93 (49.4%) had abnormal results including 69 (36.7%) patients with hypercellularity, 69 (36.7%) with hyperproteinorachia, and 28 (14.9%) with oligoclonal bands and/or increased IgG index. LP was considered as contributing to the diagnosis in only 31 (16.4%) cases, among which there were 10 (5.3%) contributions to the etiological diagnosis and 21 (11.2%) modifications in the diagnosis classification. Multivariate analysis established that African ethnicity (p < 0.001), bilateral uveitis (p = 0.01), presence of macular edema or retinal serous detachment (p = 0.048), presence of retinal vasculitis (p < 0.001), presence of neurological signs or symptoms (p = 0.01), and contributing cerebral MRI (p < 0.001) were all significantly associated with a contributory LP. LP did not lead to any therapeutic modification. CONCLUSION: LP direct contribution to the diagnosis was rare and most often detected non-specific abnormalities. LP should be performed only in cases of neurological clinical signs or symptoms, suspicion of multiple sclerosis, Vogt-Koyanagi-Harada, or syphilis.

Relevance of Brain MRI in Patients with Uveitis: Retrospective Cohort on 402 Patients.

AIM: To assess the diagnostic value of brain magnetic resonance imaging (bMRI) for the etiological diagnosis of uveitis and to establish predictive factors associated with its advantageous use. METHODS: Retrospective study on all patients with de novo uveitis who were referred to our tertiary hospital and who underwent a bMRI between 2003 and 2018. RESULTS: bMRI was contributive in 19 out of 402 cases (5%), among patients with a contributive bMRI, 68% had neurological signs. Univariate analysis established that neurological signs (p < .001), granulomatous uveitis (p = .003), retinal vasculitis (p = .002), and intermediate uveitis (p < .001) were all significantly associated with a contributive bMRI. Multivariate analysis confirms the significant association of neurological signs (p < .001) and intermediate uveitis (p = .01). CONCLUSION: bMRI appears to be a relevant exam in specific cases; intermediate/posterior uveitis or panuveitis accompanied by neurological signs, retinal vasculitis, or in patients older than 40, to rule out an oculocerebral lymphoma. ABBREVIATIONS: ACE: Angiotensin-Converting Enzyme; bMRI: Magnetic Resonance Imaging; CBC: Complete Blood cell Count; BMRI: Brain Magnetic Resonance Imaging; CT: Computerized Tomography; MS: Multiple Sclerosis; NS: Neurological Signs; OCL: Oculocerebral Lymphoma; RIS: Radiologically Isolated Syndrome.

Replication of a rare risk haplotype on 1p36.33 for autism spectrum disorder.

Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previously published linkage analyses and follow-up exome sequencing in seven large families with ASDs, implicating 14 rare exome variants. These included rs200195897, which was transmitted to four affected individuals in one family. We attempted replication of those variants in the MSSNG database. MSSNG is a unique resource for replication of ASD risk loci, containing whole genome sequence (WGS) on thousands of individuals diagnosed with ASDs and family members. For each exome variant, we obtained all carriers and their relatives in MSSNG, using a TDT test to quantify evidence for transmission and association. We replicated the transmission of rs200195897 to four affected individuals in three additional families. rs200195897 was also present in three singleton affected individuals, and no unaffected individuals other than transmitting parents. We identified two additional rare variants (rs566472488 and rs185038034) transmitted with rs200195897 on 1p36.33. Sanger sequencing confirmed the presence of these variants in the original family segregating rs200195897. To our knowledge, this is the first example of a rare haplotype being transmitted with ASD in multiple families. The candidate risk variants include a missense mutation in SAMD11, an intronic variant in NOC2L, and a regulatory region variant close to both genes. NOC2L is a transcription repressor, and several genes involved in transcription regulation have been previously associated with ASDs.

Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.

Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Trends in alcohol use during moderate and severe traumatic brain injury: 18 years of neurotrauma in Pennsylvania.

PRIMARY OBJECTIVE: Alcohol is a known risk factor for TBI, yet little is known about how rates of alcohol use at time of injury differ across demographics and the stability of alcohol-related injury over time. Further, findings examining the relationship between alcohol and outcome are mixed. This study aimed to examine changes in alcohol-positive moderate-to-severe traumatic brain injury (+aTBI) over two decades with focus on demographic factors, changes in +aTBI frequency over time, mortality and acute outcome. METHODS: This retrospective study examined data collected from 1992-2009 by the Pennsylvania Trauma Outcome Study (PTOS). RESULTS: Results reveal that the proportion of +aTBI has been generally stable across years. However, there is an interaction of +aTBI incidence with mechanism of injury and age, with a downward trend in +aTBI within MVA and fall and individuals 18-30 and 71+ years. Further, consistent with several findings in the literature, alcohol was associated with higher rates of survival and better FSD scores during acute recovery. CONCLUSIONS: This study discusses findings in the context of a greater literature on TBI-related alcohol and outcome. The injury-alcohol profiles highlighted could be used to inform future allocation of resources toward prevention of, intervention for and care of individuals who sustain TBI.

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

Recurrent de novo mutations implicate novel genes underlying simplex autism risk.

Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.

Identification of rare variants from exome sequence in a large pedigree with autism.

We carried out analyses with the goal of identifying rare variants in exome sequence data that contribute to disease risk for a complex trait. We analyzed a large, 47-member, multigenerational pedigree with 11 cases of autism spectrum disorder, using genotypes from 3 technologies representing increasing resolution: a multiallelic linkage marker panel, a dense diallelic marker panel, and variants from exome sequencing. Genome-scan marker genotypes were available on most subjects, and exome sequence data was available on 5 subjects. We used genome-scan linkage analysis to identify and prioritize the chromosome 22 region of interest, and to select subjects for exome sequencing. Inheritance vectors (IVs) generated by Markov chain Monte Carlo analysis of multilocus marker data were the foundation of most analyses. Genotype imputation used IVs to determine which sequence variants reside on the haplotype that co-segregates with the autism diagnosis. Together with a rare-allele frequency filter, we identified only one rare variant on the risk haplotype, illustrating the potential of this approach to prioritize variants. The associated gene, MYH9, is biologically unlikely, and we speculate that for this complex trait, the key variants may lie outside the exome.

Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal.

CONTEXT AND OBJECTIVE: Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth. PATIENTS AND METHODS: We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts. RESULTS: Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients. CONCLUSION: A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

EEG mu rhythm and imitation impairments in individuals with autism spectrum disorder.

Imitation ability has consistently been shown to be impaired in individuals with autism. A dysfunctional execution/observation matching system has been proposed to account for this impairment. The EEG mu rhythm is believed to reflect an underlying execution/observation matching system. This study investigated evidence of differential mu rhythm attenuation during the observation, execution, and imitation of movements and examined its relation to behaviorally assessed imitation abilities. Fourteen high-functioning adults with autism spectrum disorder (ASD) and 15 IQ- and age-matched typical adults participated. On the behavioral imitation task, adults with ASD demonstrated significantly poorer performance compared to typical adults in all domains of imitation ability. On the EEG task, both groups demonstrated significant attenuation of the mu rhythm when executing an action. However, when observing movement, the individuals with ASD showed significantly reduced attenuation of the mu wave. Behaviorally assessed imitation skills were correlated with degree of mu wave attenuation during observation of movement. These findings suggest that there is execution/observation matching system dysfunction in individuals with autism and that this matching system is related to degree of impairment in imitation abilities.

Assessing immunization coverage in private practice.

To achieve national health objectives of eliminating most childhood vaccine-preventable diseases by the year 2010, all health care providers will have to improve the immunization rates of their patients. Currently, immunization rates of children 19 to 35 months of age are less than national objectives, suggesting a need for optimized immunization services. A key strategy for improving age-appropriate immunization coverage by health care providers is the assessment of immunization coverage. Because most (62%), immunization services in the United States are delivered in the private sector, a concerted effort in private practice is critical to improving immunization rates. Assessment of immunization coverage of patients enrolled in private practice serves 1) to measure the overall performance of the practice in providing the standard of care, 2) to identify strategies for improving coverage, and 3) to document the quality of health services delivered (report card). Assessment of immunization coverage has been demonstrated in several practice settings to be highly effective in improving immunization rates. All types of physicians should benefit from assessing immunization coverage of their patients. Simple assessment tools are available at no cost to the public and can be obtained by contacting the Centers for Disease Control and Prevention. These tools include a manual self-assessment or a computerized software package (CASA) to fit the needs of the practice.

Reviews of evidence regarding interventions to improve vaccination coverage in children, adolescents, and adults. The Task Force on Community Preventive Services.

This paper presents the results of systematic reviews of the effectiveness, applicability, other effects, economic impact, and barriers to use of selected population-based interventions intended to improve vaccination coverage. The related systematic reviews are linked by a common conceptual approach. These reviews form the basis for recommendations by the Task Force on Community Preventive Services (the Task Force) regarding the use of these selected interventions. The Task Force recommendations are presented on pp. 92-96 of this issue.

An autosomal genomic screen for autism. Collaborative linkage study of autism.

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:609-615, 1999.

Antiplatelet and lipid-lowering therapies for the secondary prevention of cardiovascular disease: are we doing enough?

OBJECTIVE: To evaluate whether current recommendations with respect to the treatment of dyslipidemias and the use of antiplatelet agents are being applied in the secondary prevention of cardiovascular disease in primary care settings. DESIGN: Descriptive study based on data from the FAMUS (FAmily Medicine, Université de Sherbrooke) primary care register. SETTING AND PARTICIPANTS: Two-hundred and thirty-three physicians participating in the FAMUS project contributed information from nonpregnant patients over 20 years of age consulting for a periodic health examination between 1992 and 1996. INTERVENTIONS: Data from patients in secondary prevention (those with or having had angina, a previous myocardial infarction, bypass surgery, coronary angioplasty or peripheral vascular disease) were extracted and analyzed. MAIN RESULTS: Of the 52,505 patients in the register, 4315 (8%) were identified as being in secondary prevention. Overall, 53% were noted as receiving an antiplatelet agent while 4% were taking warfarin therapy. Only 64% (2780) had a complete lipid profile on record while 38% were being treated with a hypolipidemic agent. In the treated group, only 30% had a low density lipoprotein cholesterol level below 3.0 mmol/L compared with 22% in the untreated group. CONCLUSIONS: A large number of patients identified as being in secondary prevention were not screened for dyslipidemias, and, of those who were, the majority were undertreated according to current recommendations. Antiplatelet agents were more widely prescribed but potentially underused.

Mycobacterium tuberculosis mannose-capped lipoarabinomannan can induce NF-kappaB-dependent activation of human immunodeficiency virus type 1 long terminal repeat in T cells.

Tuberculosis has emerged as an epidemic, extended by the large number of individuals infected with human immunodeficiency virus type 1 (HIV-1). The major goal of this study was to determine whether the mycobacterial cell wall component mannose-capped lipoarabinomannan (ManLAM) of Mycobacterium tuberculosis (M. tuberculosis) could activate transcription of HIV-1 in T cells with the use of an in vitro cell culture system. These experiments are of prime importance considering that CD4-expressing T lymphocytes represent the major virus reservoir in the peripheral blood of infected individuals. Using the 1G5 cell line harbouring the luciferase reporter gene under the control of the HIV-1 LTR, it was first found that culture protein filtrates (CFP) from M. tuberculosis or purified ManLAM could activate HIV-1 LTR-dependent gene expression unlike similarly prepared CFP extracts devoid of ManLAM. The implication of protein tyrosine kinase(s), protein kinase A and/or protein kinase C was highlighted by the abrogation of the ManLAM-mediated activation of HIV-1 LTR-driven gene expression using herbimycin A and H7. It was also determined, using electrophoresis mobility shift assays, that M. tuberculosis ManLAM led to the nuclear translocation of the transcription factor NF-kappaB. M. tuberculosis ManLAM resulted in clear induction of the luciferase gene placed under the control of the wild-type, but not the kappaB-mutated, HIV-1 LTR region. Finally, the ManLAM-mediated activation of HIV-1 LTR transcription was found to be independent of the autocrine or paracrine action of endogenous TNF-alpha. The results suggest that M. tuberculosis can upregulate HIV-1 expression in T cells and could thus have the potential to influence the pathogenesis of HIV-1 infection.

Cardiovascular disease. Physician attitudes toward prevention and treatment.

OBJECTIVE: Survey of physician attitudes toward practising cardiovascular disease prevention. DESIGN: Questionnaire administered via telecommunication from 1992 through 1994. SETTING: The FAMUS (Family Medicine, University of Sherbrooke) project, between 1992 and 1996, used weekly telecommunication to collect data from 200 general practitioners throughout the province of Quebec on cardiovascular disease risk factors and their treatment. PARTICIPANTS: Of 200 physicians contributing to the FAMUS project, 156 completed questionnaires (response rate 78%). MAIN OUTCOME MEASURES: Variations in attitudes to prevention policy and risk factor interventions. RESULTS: Survey results revealed physicians knew important risk factors for cardiovascular disease but differed in attitudes toward efficacy of treatment. Intervention to control cholesterol was thought to be very effective by 21.2% (95% confidence interval [CI] 21.2 +/- 6.4) and without effect by 10.3% (95% CI 10.3 +/- 4.8). Intervention to improve dietary habits was considered ineffective by 48.1% (95% CI 48.1 +/- 7.8). Confidence in managing risk factors varied; most respondents described themselves as only moderately skilled. A few practitioners (30.1%; 95% CI 30.1 +/- 7.2) acknowledged practice guidelines as an important source of information on which to base preventive interventions. Only 14.7% (95% CI 14.7 +/- 5.6) of those surveyed included remuneration as contributing to their implementation of prevention activities in practice. CONCLUSIONS: Variations in physician attitudes could influence risk factor intervention. Interventions to change lifestyle are associated with uncertainty about patient compliance, efficacy of treatment, and ability to effect lifestyle changes.

The lipophosphoglycan of Leishmania donovani up-regulates HIV-1 transcription in T cells through the nuclear factor-kappaB elements.

We have recently demonstrated that the parasite Leishmania donovani and its surface molecule, lipophosphoglycan (LPG), can activate HIV-1 replication in monocytoid cells. Our present interest was to determine whether LPG could also up-regulate HIV-1 transcription in T cells. Using a CD4-positive human lymphoid T cell line (1G5) containing a stably integrated HIV-1 long terminal repeat (LTR)-luciferase construct, we found that LPG is a potent inducer of HIV-1 LTR activity. Treatment of 1G5 cells with signaling antagonists revealed that protein tyrosine kinase- and protein kinase A-dependent pathways were actively participating in the LPG-induced enhancement of HIV-1 LTR-driven activity. Transfection of Jurkat E6.1 cells with plasmids containing wild-type and nuclear factor-kappaB (NF-kappaB)-mutated HIV-1 LTR-luciferase constructs has suggested a role for NF-kappaB binding sites in the LPG-mediated induction of HIV-1 LTR activity. An LPG-induced binding factor specific to the NF-kappaB consensus sequences could be observed using electrophoretic mobility shift assay. Finally, transfection experiments performed with a vector containing HIV-1 kappaB binding sites only showed similar LPG-mediated induction, which was abrogated by sodium salicylate, a known NF-kappaB inhibitor. We thus demonstrate that the LPG-mediated induction of HIV-1 LTR activity in T cells involves several second messengers culminating in activation of HIV-1 LTR-driven transcription via NF-kappaB-binding consensus sequences. In conclusion, these results reinforce the idea that L. donovani is a putative cofactor in HIV-1 pathogenesis.