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.

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.

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.

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.

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.

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.

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.

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.

Detection of DNA by tritiated actinomycin D on ultrathin frozen sections.

Ultrathin frozen sections of fresh liver tissue were floated on actinomycin D-(3)H. Quantitative high resolution radioautography was performed to determine the value of the method for detection of DNA by electron microscopy. A complete series of control experiments involving various treatments of frozen sections with enzymes (pronase, DNase) and 0.1 N HCl were also carried out to determine the specificity of the labeling. The results indicate the value of the method for detection of DNA directly on ultrathin frozen sections. Short treatments with pronase followed by DNase reduce the labeling to zero, whereas removal of chromosomal proteins with HCl increases the amount of radioactivity in the nucleus considerably. The results are discussed in view of the future applications opened by ultracryotomy, since radioautographic detection of various macromolecules and cellular components by labeled compound with specific affinities will now be possible.

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.

Molecular cloning of a Bacillus subtilis xylanase gene in Escherichia coli.

A gene coding for xylanase synthesis in Bacillus subtilis was isolated by direct shotgun cloning using Escherichia coli as a host. Following partial digestion of B. subtilis chromosomal DNA with PstI or EcoRI restriction enzymes, fragments ranging from 3 to 7 kb were introduced into the PstI or EcoRI sites of pBR325. Transformed colonies having lost either the ampicillin or chloramphenicol resistance markers were screened directly on 1% xylan plates. Out of 8000 transformants, ten xylanase-positive clones were identified by the clearing zone around lysozyme-treated colonies. Further characterization of one of the clones showed that the xylanase gene was present in a 3.9-kb insert within the PstI site of the plasmid pBR325. Retransformation of E. coli strain with the xylanase-positive hybrid plasmid pRH271 showed 100% transformation to xylanase production. The intracellular xylanase produced by the transformed E. coli was purified by ion exchange and gel permeation chromatography. The electrophoretic mobility of the purified xylanase indicated an Mr of 22 000.

Impact of revaccinating children who initially received measles vaccine before 10 months of age.

Two hundred fifty-four infants who had received measles vaccine at less than 10 months of age were revaccinated at greater than or equal to 15 months of age, and their immune responses were compared with 129 control infants who received their first doses of measles vaccine at greater than or equal to 15 months of age. Sera were collected at the time of revaccination (study infants) or primary vaccination (control infants), 3 weeks, and 8 months later and tested for antibody by hemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA), and cytopathic effect neutralization (CPEN). Of the 121 study infants who were initially HI negative, 116 (95.9%) made HI antibody 3 weeks postrevaccination compared with 126 (99.2%) of 127 control infants (P = 0.19). Of the 63 study infants with no initial detectable antibody by any of the three tests, 14 (22.2%) had a measles-specific IgM response 3 weeks postrevaccination compared with 37 of 50 (74.0%) randomly chosen control infants. By 8 months after revaccination, the 121 initially HI-negative study infants were significantly less likely to have detectable HI antibodies than control infants (52.1% v 97.6%) (P less than .001). However, 96.7% of these 121 study infants had detectable neutralizing antibody 8 months postrevaccination, an antibody thought to correlate best with protection. This study confirms the altered immune response to revaccination in infants first vaccinated prior to 10 months of age; however, the data suggest that most of these infants were successfully primed and are probably protected after revaccination.

Phage typing of Bacillus subtilis and B. thuringiensis.

Phage typing schemes for Bacillus subtilis and B. thuringiensis were constructed using 98 phages and 743 bacterial strains. Most phages were host-species-specific. Phages were classified by electron microscopy. The B. subtilis scheme includes 10 phages and 29 phage types. The B. thuringiensis scheme comprises 8 phages and 25 phage types and can be applied to B. cereus. There is no correlation between H antigen serotypes and phagovars in B. thuringiensis. Characteristics of typing phages are described for identity control.

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.

Long-term clinical and functional results of sleeve lobectomy for primary lung cancer.

Sleeve lobectomy is a lung-saving operation in which a portion of main bronchus is removed in continuity with the involved lobe to preserve distal parenchyma. Current controversies relate to indication and safety of the procedure, adequacy as a cancer operation, and contribution of the reimplanted lobe to overall remaining lung function. Between 1975 and 1985, sleeve lobectomy was done electively in 72 patients with lung cancer. There were no operative deaths, but major complications occurred in 10% of patients. Most resected carcinomas were squamous (65/72). Complete resection was performed in all but five patients. A minimum of 1 year's follow-up information was available for all patients. For patients with N0 disease (n = 34) the cumulative 5 year survival rate was 67%, and for patients with N1 status (n = 34) it was 60%. Although postoperative pulmonary function studies at 5 years (n = 19) show subnormal values, they were not severely altered with regard to percent of predicted (forced vital capacity, 85.9% +/- 17.5%; forced expiratory volume in 1 second, 74.9% +/- 19.4%). Regional function was determined by ventilation/perfusion isotope scanning methods. For 15 patients with right lung bronchoplasties, perfusion ratios were 41.1% right lung/58.9% left lung. For four patients with left sleeve operations, these ratios were 29.3% left lung/51.7% right lung. Washout curves show comparable ventilation between the reimplanted lobe and the contralateral lung. The data show that sleeve lobectomy is a safe and adequate operation for patients with resectable lung cancer. The reimplanted lobe or lobes contribute significantly to the overall remaining lung function.

Immunization of young infants with Edmonston-Zagreb measles vaccine.

Recently studies conducted in several countries using Edmonston-Zagreb vaccine administered subcutaneously to infants younger than 9 months of age have shown high seroconversion rates, approaching or equaling those routinely achieved at 9 months of age with the more widely used Schwarz vaccine. These results have raised expectations that the Edmonston-Zagreb vaccine can play an important role in helping to prevent measles in young infants in highly endemic areas. Because of the implications of changing the measles vaccine recommendations, vaccine advisory groups and vaccine manufacturers will require additional studies to confirm the preliminary findings and to answer new questions which have been raised. The needed data will probably be collected over the next year or two in studies already under way or being planned in the hope that a more effective vaccine for young infants can be introduced before the end of this decade.

Diagnosis and long-term follow-up of major bronchial disruptions due to nonpenetrating trauma.

From 1966 through 1978, 13 patients were treated for major bronchial disruptions due to nonpenetrating trauma. In 10 patients the diagnosis was made early, and operation was carried out in all of them. Four of the 6 patients with main bronchus avulsion had primary repair and all 4 patients with lobar rupture underwent lobectomy. One patient had a pneumonectomy. There was 1 operative death. In 3 patients the diagnosis was made more than a month after the injury. A bronchoplastic repair was done in every patient. All 7 patients who had repair of a transected main bronchus were assessed 2 to 14 years after operation (average, 7 1/2 years). Flow-volume curves on air and air-helium were normal, indicating no major airway obstruction; this finding was confirmed by clinical and bronchoscopic examinations. Pulmonary diffusing capacity for carbon monoxide was also normal in all patients. Volume measurements by closed circuit method and by body plethysmography showed restriction in 1 patient but no major air trapping. Perfusion/ventilation scans showed homogeneous distribution of air and blood flow in the lung.

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.

Effect of occlusive pressure patching on the rate of epithelial wound healing after photorefractive keratectomy.

PURPOSE: This study measured the effect of pressure patching on the rate of epithelial wound healing in 41 myopic patients after photorefractive keratectomy (PRK). METHODS: On day 0, mechanical debridement was done to remove the central 6.5 mm diameter of epithelium. Subsequently, a 5.0 mm diameter photoablation was performed, the depth of ablation being proportional to the degree of myopia (-1.0 to -6.0 diopters). The patients were discharged with an application of antibiotic/steroid ointment (A/S) followed by pressure patching. On day 1, the epithelial defects were stained with fluorescein and photographed. The patients were then randomized prospectively into two groups: Group 1 was pressure patched after application of A/S ointment; Group 2 received A/S ointment twice a day without patching. A photograph of the remaining epithelial defect was taken on day 2. The area of the epithelial defect was measured with a computerized image analyzer. Wound diameter (radius) was used to calculate the epithelial healing rate (EHR). RESULTS: Between days 1 and 2, the mean EHR in Group 1 was 0.072 +/- 0.005 mm/hr and in Group 2, 0.056 +/- 0.004 mm/hr (P < 0.05). There was no correlation between the EHR and patient gender or the degree of myopia. However, a correlation was noted between patient age and wound size on day 1. CONCLUSION: Pressure patching significantly accelerated the EHR following PRK.

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.