The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

Extreme temperament and diagnosis. A study in a psychiatric sample of consecutive children.

We report on an epidemiological-clinical study of the New York (NY) Longitudinal Study temperament model in a consecutive sample of children (N = 814) referred to a child psychiatric center. Temperament comparisons in this clinical population were made by using temperament normative values obtained in previous random samples of the general population in the greater Quebec City (Canada) area. Different clinical diagnostic groups (externalized disorders, developmental delays, and mixed disorders) were derived from a review of the entire hospital charts in which the interrater reliability was tested and performed "blind" to temperament scores. The diagnostic groups were confirmed through discriminant function analyses. The results (1) replicated, in this child psychiatric population, two factors of temperament similar to those previously found in random samples of our general population; (2) showed, in the psychiatric population of children, an overproportion of difficult temperaments on both factors; (3) confirmed conversely that a large proportion of children referred for a disorder did not present with an extreme temperament, and, therefore, an extreme temperament and a clinical disorder were not equivalent; and (4) suggested a specificity in the relationship between particular temperament factors and the type of clinical problem. Temperament factor 1 (withdrawal from new stimuli, low adaptability, high intensity, and negative mood) was found to be more associated with externalized disorders (opposition, conduct, or attention-deficit disorders), whereas temperament factor 2 (low persistence, high sensory threshold, and high mobility) was found to be more associated with specific developmental delays. The findings provided leads for future clinical research on temperament, family functioning, and child psychiatric diagnoses.

Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.

A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

Temperament and intellectual development: a longitudinal study from infancy to four years.

Using three temperamentally different subgroups from a large birth cohort, the authors undertook a longitudinal study of the association between temperament measured in children at 4 and 8 months and IQ assessed at 4.7 years. The data suggested a strong effect of extreme temperament traits on IQ development in middle and upper socioeconomic classes and in families with superior functioning in terms of communication. The temperamentally difficult group unexpectedly displayed higher IQs, and the well-replicated effect of socioeconomic status on IQ development was observed mainly in this group. These data support the hypothesis that difficult infants activate special family resources, which stimulates intellectual development over the years.

Psychiatric status of adolescents who had extreme temperaments at age 7.

Two temperamentally extreme (extremely easy and extremely difficult) subgroups of children were selected at the age of 7 years from a large random sample of the general population of Quebec City. The clinical status, family functioning, IQ, and academic performance of these children were reassessed at 12 and 16 years of age. Findings suggest that extreme temperament at age 7 predicts psychiatric status in preadolescence and adolescence only when family functioning is also taken into account. The adolescents who had been temperamentally difficult children and who were living in families with dysfunctional behavior control displayed more clinical disorders.

Value of difficult temperament among 7-year-olds in the general population for predicting psychiatric diagnosis at age 12.

The authors assessed the predictive value of "difficult" temperament, as defined in the New York Longitudinal Study, in 12-year-old children from the general population of Quebec City whose temperaments had been determined to be difficult or easy at age 7. The difficult and easy temperament groups were balanced for age, sex, and socioeconomic status. The authors used many convergent measuring devices and were blind to the temperament scores of the children at age 7. Temperamentally difficult children had more clinical disorders at age 12 that qualified for a DSM-III diagnosis. An association with family dysfunction in terms of behavior control seemed to increase this risk: there was a lower rate of clinical disorders among children in superior functioning families than among those in dysfunctional families.

Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure.

OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure were examined, and factors associated with reliability were determined. METHOD: The subjects were 134 members of large multigenerational pedigrees densely affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses were derived: first, by a research psychiatrist and research assistant unblind to the relatives' diagnoses; second, by two blind independent psychiatrists; third, by a panel of four blind psychiatrists. The subjects were characterized on several clinical and methodological variables, which were used to compare the agreements of two types of best-estimate diagnoses with the disagreements. RESULTS: There was satisfactory agreement between the unblind and blind consensus best-estimate diagnoses and between the two blind independent psychiatrists. Latent class analyses revealed that limited sensitivity was the main source of imperfect reliability. Confusability analyses revealed that the most problematic diagnostic distinctions involved schizoaffective disorder, which was confused with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness significantly affected diagnostic outcome in latent class analyses. Moreover, for diagnostic disagreements, unblind diagnoses had greater continuity with the most predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic disagreements were associated with the presence of mixed affective and psychotic symptoms, less diagnostic certainty, and shorter duration of illness. CONCLUSIONS: These results suggest that it is possible to identify cases that are more likely to lead to diagnostic disagreements in family and epidemiological studies and that blind diagnoses may help to prevent false positive diagnoses, which may be particularly detrimental to genetic linkage analyses.

Screening for distal sensory peripheral neuropathy in HIV-infected persons in research and clinical settings.

OBJECTIVE: To determine the accuracy of a screening examination for distal sensory peripheral neuropathy (DSPN) performed by nonphysician clinicians and to explore the associations between DSPN and clinical features in HIV-infected persons. METHODS: A case-control study of a volunteer sample of 226 HIV-infected individuals was performed. An interview, focusing on risks and symptoms of DSPN, and a screening neurologic examination were performed. RESULTS: Compared with the neurologist's examinations, the clinicians' examination was sensitive (92 to 95%) but not as specific (71 to 84%) for the diagnosis of DSPN. After excluding 27 patients with confounders, 42 of 199 patients (21%) had DSPN. This was associated significantly with neurotoxic nucleoside antiretroviral use and with more advanced HIV disease. Of the 42 patients with DSPN, 30 (71%) had no neuropathy symptoms. CONCLUSIONS: A brief examination performed by trained nonphysician clinicians can be used to screen for DSPN in HIV-infected persons. Asymptomatic DSPN is common in these individuals.

Chemiluminescent and colorimetric enzymatic assays for the detection of PCR-amplified Salmonella sp. products in microplates.

To improve Salmonella detection, we developed nonradioactive hybridization assays of amplified products from pure Salmonella cultures. Biotin-labeled PCR products were trapped by internal probes covalently bound to CovaLink-NH MicroWells and detected by colorimetric or chemiluminescent enzymatic reactions. The sensitivities of colorimetric assays using peroxidase and alkaline phosphatase were similar to those obtained with an ethidium bromide-stained agarose gel; both procedures allow the detection of 50 Salmonella cells. Chemiluminescence was 10-fold more sensitive than colorimetry.

Rapid SNP allele frequency determination in genomic DNA pools by pyrosequencing.

Individual genotyping of single nucleotide polymorphisms (SNPs) remains expensive, especially for linkage disequilibrium mapping strategies involving high-throughput SNP genotyping. On one hand, current methods may suit scientific and laboratory needs in regard to accuracy, reproducibility/robustness, and large-scale application. On the other hand, a cheaper and less time-consuming alternative to individual genotyping is the use of SNP allelefrequencies determined in DNA pools. We have developed an accurate and reproducible protocol for allele frequency determination using Pyrosequencing technology in large genomic DNA pools (374 individuals). The measured correlation (R2) in large DNA pools was 0.980. In the context of disease-associated SNPs studies, we compared the allele frequencies between the disease (e.g., type 2 diabetes and obesity) and control groups detected by either individual genotyping or Pyrosequencing of DNA pools. In large pools, the variation between the two methods was 1.5 +/- 0.9%. It may be concluded that the allele frequency determination protocol could reliably detect over 4% differences between populations. The method is economical in regard to amounts of DNA, PCR, and primer extension reagents required. Furthermore, it allows the rapid determination of allelefrequency differences in case/control groups for association studies and susceptibility gene discovery in complex diseases.

Genetics of human obesity.

Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.

Anticipation in schizophrenia and bipolar disorder controlling for an information bias.

Anticipation was investigated in schizophrenia (SZ) and bipolar disorder (BP) while addressing several biases in 18 large families (154 subjects) from Eastern Québec densely affected by SZ, BP, or both over three generations. In particular, we controlled for an information bias using a measure of quality and quantity of clinical information (QOI) concerning the subjects' illness. Otherwise, spurious anticipation could have arisen because we found that QOI varied with the generations as well as with the severity of illness. Although anticipation was investigated separately for SZ and BP, both disorders were also included in one analysis that tested anticipation under the unitary hypothesis that the SZ and the BP spectrums represent a continuum of severity of the same disease. Age of onset (AOO) and five indices of severity were tested for anticipation. Two statistics were used: the difference in the mean AOO or severity between two successive generations, and the mean difference in parent-offspring pairs (POP). The study led to four main findings: 1) the choice of the statistics greatly influenced the results, POP yielding systematically greater biased estimates; 2) for SZ and BP, the evidence for anticipation with the five severity indices vanished after controlling for QOI; 3) as regards AOO a decrease of 8.6 years, p = 0.0001, and 5.3 years, p = 0.009 in AOO was found for SZ between Generations 1-2, and 2-3, respectively, despite controlling for QOI and addressing all biases; and 4) conversely for BP, anticipation with AOO may be due to censoring. Findings suggest that future anticipation studies should also control for QOI. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:61-68, 2000.

6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

Follow-up of a randomized trial for oat cell carcinoma evaluating the efficacy of peripheral intravenous nutrition (PIVN) as adjunct treatment.

A randomized trial was initiated to compare the effects of peripheral i.v. nutrition (PIVN)-associated chemotherapy (adriamycin, vincristine, VP-16-213, and cyclophosphamide) versus a chemotherapy control group in patients with oat cell lung carcinoma. Thirty-nine evaluable patients were randomized. The test group included 19 patients, whereas 20 were followed in the control group. PIVN was scheduled each day the patient underwent chemotherapy. Each patient received 1,550 kcal day which included 10% glucose, 20% lipids, and amino acids which may or may not have been mixed in the same infusion bottle. The results show ten PIVN patients presently in complete remission at the end of three courses of treatment, compared to nine over the same time period in the chemotherapy control group. Thirty-three percent of patients are still alive after 15 months after the beginning of treatment. There was no significant difference in either general health or side effects, frequency or duration of complete remission, or survival time. After 1 year of treatment, 8 of 19 PIVN patients are still in complete remission, compared to 7 of 20 patients in the control groups.

Genetics of pathways regulating body weight in the development of obesity in humans.

Although rapid globalization of the Westernized way of life is responsible for the large rise in the number of obesity cases (about 1 billion individuals are now overweight or frankly obese), obesity is a typical common multifactorial disease in that environmental and genetic factors interact, resulting in a disease state. There is strong evidence for a genetic component to human obesity: e.g., the familial clustering (the relative risk among siblings being 3-7) and the high concordance of body composition in monozygotic twins. However, the role of genetic factors in many human obesities (referred to as "common obesity" in this review) is complex, being determined by interaction of several genes (polygenic), each of which may have relatively small effects (i.e., they are "susceptibility" genes and work in combination with each other as well as with environmental factors such as nutrients, physical activity, and smoking).

Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.

BACKGROUND: Clinical presentation and natural history of diabetes are somewhat different in Black Africans compared to Caucasians. This peculiar disease course could be at least partly related to a specific genetic profile that has not been studied in this population. METHODS: Medical backgrounds, anthropometric and biologic parameters were obtained from 69 diabetic subjects in Dakar, Senegal, in 1998. Blood anti GAD and Islet Cell Antibodies were studied, using RIA and immunofluorescence assay. The HNF-1alpha gene was sequenced searching the Gly574Ser mutation, previously described in MODY 3. RESULTS: Among these 69 diabetic patients, 11 (16%) were found to have the G574S mutation affecting the HNF-1alpha. These 11 patients carrying the mutation were compared respectively with the 58 non carriers. Mean age (57.5 yr. +/- 11 vs 51.1 yr. +/- 15) and duration of diabetes (11.9 vs 6.7 yr), were similar in the two groups. BMI was not different in patients with the mutation (26.3 vs 23.3, p=0.06). Metabolic control (Glycosylated hemoglobin) was poor in the two groups (9.5% vs 9.2%). Chronic complications were equally found in the patients, but no mutation carrier had macroangiopathy. None of the anti GAD positive or ICA positive patients had the mutation. CONCLUSIONS: The HNF-1alpha Gly574Ser mutation was found in 16% of cases in a 69 diabetic patients group in Senegal. Diabetes was as severe as in non carriers of mutation. This mutation has been implicated in atypical diabetes of Afro-American children. The study confirms its prevalence in Africans with diabetes.

Family history of cognitive disabilities in first-degree relatives of autistic and mentally retarded children.

We compared with a family history method the rate of cognitive disabilities (CD) in 156 first-degree relatives of 49 autistic (AU) probands to that found in 55 first-degree relatives of 18 mentally retarded (MR) probands. Broadly defined CD were found in, respectively, 17 and 16% of the relatives of the AU and MR probands. However, the characteristics of the probands associated with a family history of CD are different in AU and MR: Female and low IQ AU probands have more first-degree relatives with CD. Our findings suggest that a positive family history of CD is not specific to autism when compared to mental retardation. The observation that female and low IQ probands have higher family history of CD may suggest heterogeneity within autistic children and provides leads for future family studies.

Surgical pathology of the intervertebral disc. Is routine examination necessary?

A retrospective review of 508 charts of patients undergoing laminectomy for all reasons was carried out with special attention to the preoperative diagnosis, postoperative diagnosis, pathologic diagnosis, and discharge diagnosis. The elimination of routine pathologic examination of surgical discectomy specimens would not have lowered the standard of care; the pathologist's report had no discernible influence on patient management. Unusual clinical features will continue to require careful examination of surgical specimens by the pathologist. Millions of healthcare dollars can be saved by eliminating this routine examination, which is based on outmoded routines. Hospital medical staffs who wish to change this practice must revise their hospital bylaws in keeping with the standards of the The Joint Commission on Accreditation of Healthcare Organizations (JCAHO).

Use of and attitudes about alternative and complementary therapies among outpatients and physicians at a municipal hospital.

OBJECTIVES: To survey outpatients and physicians about their use of, knowledge of, and interest in alternative therapies. DESIGN: Anonymous self-administered survey. SETTINGS/LOCATION: Outpatient clinics at a major municipal medical center. SUBJECTS: Outpatients visiting clinics and staff physicians. INTERVENTIONS: Patient survey about overall use of 7 categories and 19 types of alternative therapies, and their desire to have specific therapies offered at the institution. Survey to physicians about whether their patients used the same categories and types of alternative therapies, whether they provided or recommended their use, and their interest in having them available at the institution. OUTCOME MEASURES: Frequency of use of different alternative therapies by gender and race. Frequency of patient use of alternative therapies according to their physicians and frequency of physicians who provide or recommend alternative therapies. RESULTS: A total of 567 outpatients completed questionnaires during the survey week. When given a list of alternative therapies, 85% of patients acknowledged use of one or more alternative therapies. When Diet/Nutrition was excluded, 42% reported use of alternative therapies. No differences in overall use were seen by age, sex, or race; but when Diet/Nutrition was excluded, women were more likely to use alternative therapies, and use of Manual Healing and Herbal Medicine differed by race. Of the 85 responding physicians, 86% reported that their ambulatory patients used alternative therapies. Similar proportions (35%-38%) of patients and physicians wanted Manual Healing and Mind/Body Control therapies to be available. CONCLUSIONS: Frequency of use of alternative therapies was high, and similar according to patients and physicians. Overall use did not differ by gender and race, except when Diet/Nutrition was excluded. Patients and physicians had similar interests in having alternative therapies provided, and both were hampered by lack of information about many therapies.