Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.

Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.

Cloning and mapping of 5' exons from the gene encoding chicken beta nerve growth factor.

An NGF cDNA containing the 5' exons of the nerve growth factor (NGF) messenger was obtained from chicken heart mRNA using the anchored polymerase chain reaction technique. Alignment of the chicken with the corresponding murine and human sequences reveals interspecies similarities. A sequence corresponding to an exon found only in the NGF messenger, which is abundant in the submaxillary gland of the male mouse, is present in the chicken NGF cDNA. The first non-coding exons of the NGF gene are much less conserved between chicken and mouse or human than the region of the last exon encoding the mature protein. After the cloning of the chicken NGF gene from a cosmid library, the chicken NGF exons have been located within 20 kb of DNA. The chicken NGF gene is therefore shorter than its murine counterpart which spans more than 43 kb. Furthermore, the organization of the chicken and murine NGF genes markedly differs in their 5' portion.

Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12.

Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1-12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin-Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.

Recurrent intracerebral hemorrhage.

Between 1984 and 1994, of the 375 patients admitted to our department for intracerebral hemorrhage (ICH), 24 (6.4%) had a recurrent ICH. There were 15 women and nine men and the mean age of the patients was 64.7 +/- 9.4 years (range 49-81) at the first bleeding episode and 68.7 +/- 7.5 years (range 57-83) at the second. The mean interval between the two bleeding episodes was 47.5 +/- 30.5 months (range 3 months to 14.8 years). Nine patients presented with more than one recurrence of ICH. Seventy-one percent of the patients were hypertensive. The site of the first hemorrhage was lobar in 17 patients, ganglionic (putamen, thalamus, or caudate nucleus) in six patients, and subdural in one. The recurrent hemorrhage occurred at a different location from the previous ICH. The most common pattern of recurrence was "lobar-lobar" (14 patients) and more rarely "ganglionic-ganglionic" (five patients), which was always observed in hypertensive patients. The outcome after the recurrent hemorrhage was usually poor, with severe cognitive impairment. By comparison with 81 patients followed up to 24 months (47.9 +/- 22.2 months) with isolated ICH without recurrence, only lobar hematoma and a younger age were risk factors for recurrences whereas sex and previous hypertension were not. The mechanisms of recurrence of ICH were multiple (hypertension, cerebral amyloid angiopathy). Control of blood pressure after the first hemorrhage may prevent ICH recurrences.

Menarche and the onset of depression and anxiety in Victoria, Australia.

STUDY OBJECTIVE: Psychiatric disorder often begins at adolescence. This study aimed to examine the associations between puberty and social circumstances and the adolescent rise in depression and anxiety. DESIGN: A two stage cluster sampling procedure was used to identify a representative group of Australian secondary school students in years 7 (age 12-13 years), 9 (14-15 years), and 11 (16-17 years) of 45 Victorian schools. The computerised clinical interview schedule (CIS) was used to evaluate psychiatric morbidity. MAIN RESULTS: A total of 2525 subjects completed the survey - an overall participation rate of 83%. Levels of depression and anxiety increased with the secondary school years and girls had significantly higher rates at each school year level. For boys, the clearest independent associations with depression and anxiety were rising school year level and high parental educational achievement. For girls menarchal status emerged as the strongest predictor. Associations with age and school year level, evident on univariate analysis, did not persist when the recency of menarche was taken into account. After addition of measures of perceived social stress to a multivariate model, a significant association between depression/anxiety and parental divorce disappeared but the association with menarche persisted. CONCLUSIONS: Menarche marks a transition in the risk of depression and anxiety in girls. The pattern of findings is consistent with a biological mediation of this association.

The self-image of adolescents with cystic fibrosis.

PURPOSE: The changing expectations, therapies and outcomes for young people with cystic fibrosis (CF) necessitate a re-evaluation of the impact of this chronic illness on adolescent development. The aim of this study was to assess the psychological well-being and adjustment of contemporary adolescents with CF. METHODS: Forty-nine adolescents with CF (24 males, 25 females) aged 14-18 years were enrolled from the Royal Children's Hospital CF Clinic, Melbourne, Australia. The Offer Self-Image Questionnaire was administered to participating subjects whose growth and pubertal developmental and pulmonary function was assessed. RESULTS: The mean (SD) FEV1% was 82 (21), and mean (SD) National Institute of Health clinical score was 81 (12). There were no significant differences between males and females in pulmonary function or clinical scores, but growth and pubertal development were delayed in both sexes. Females, but not males, with CF were less well-adjusted than their healthy peers. Two-way analysis of variance was performed and showed significant sex differences in sub-scales of the Offer questionnaire numbers I, II, III, VI, VIII, IX, as well as in the total score. Age was significant only for scales II and VIII, and only scale II displayed an interaction between sex and age. CONCLUSIONS: This study suggests that adjustment and self-esteem are less than ideal in young people with CF, especially females.

Development of a scale to measure discomfort during pregnancy.

During pregnancy fundamental changes occur in a woman's body that make physical discomforts almost unavoidable. Extensive literature searches revealed that there was no psychometrically acceptable tool available to assess accurately maternal physical discomfort. This paper presents the procedures undertaken to develop the Maternal Physical Discomfort Scale (MPDS), an assessment instrument designed to quantify the type and number of maternal physical discomforts. The MPDS, a scale consisting of 36 items, was developed and psychometrically evaluated using factor analysis, item response theory and reliability measures. The initial version of the scale was validated by a sample of 307 pregnant women. Based on the result from this sample, the MPDS was modified to 33 items and validated by a further sample of 125 pregnant women. The MPDS developed in this study was demonstrated to have content and construct validity and to be reliable.

Left hemispheric reductions of regional cerebral blood flow (rCBF) correlate with measures of dementia severity in patients with Alzheimer's disease: a SPECT study.

Regional cerebral blood flow (rCBF) values were measured by single photon emission computed tomography (SPECT) in different regions of the brain in 27 patients with DAT. Significant correlations were found between rCBF in left parieto-temporooccipital regions and psychometric test scores. Patients with hemisphere asymmetry in SPECT performed worse on psychometric tests. SPECT did not permit prediction of or differentiation between depressive and psychotic symptoms.

[Bilateral medial medullary infarction]. / Infarctus bulbaire médian bilatéral.

We report a case of a 42-year old man with a bilateral medial medullary stroke (MMS) with favorable outcome. First described by Spiller in 1908, the MMS accounts for less than 0,5% of all cerebral infarcts. It may be unilateral or more rarely bilateral, and may often be the consequence of the atherosclerosis. The clinical features of MMS classically associate contralateral hemiparesis and lemniscal hypoesthesia accompanied by ipsilateral lingual palsy and sometimes oculomotor disturbances (upbeat nystagmus). With the advent of magnetic resonance imaging, some restricted or unusual clinical manifestations can be attributed to this localization. The benign form of MMS seems much more common than MMS with poor prognosis.

[Pathological laughter after the brainstem infarction]. / Fou rire prodromique d'une occlusion du tronc basilaire.

We report a case of 'fou rire prodromique' heralding a brainstem infarct with favorable prognosis after thrombolysis. Different clinical forms of pathological laughter, the pathophysiological mechanisms and clinico-anatomical correlations of this rare phenomenon are discussed.

[Crossed aphasia disclosed by central auditory disorder]. / Aphasie croisée révélée par un trouble central de l'audition.

A 80-year-old woman, right-handed, suddenly felt the impression to be deaf. Besides, she presented language disorders of aphasic type relating to a sensorial transcortical aphasia. The case meets the diagnostic criteria for crossed aphasia. The magnetic resonance imaging showed a right temporo-parietal infarct. There was no sensorial or peripheral auditive disorder and no auditory agnosia of non verbal modality. During the evolution, the aphasic symptoms diminished partially and the subjective auditory deficit of the left ear continued. The integrated auditory evaluation (neuroacoustic test, study of auditory gnosia, dichotic listening test, evoked cortical auditory potentials) allowed the evidence of the characteristic disturbances of a right hemianacousia: loss of left hear in dichotic audition, decrease of amplitude of evoked right cortical auditory potentials. In the light of theories concerning auditory integration, one can explain this evolution. The initial aphasic comprehension disturbance expresses the alteration of the linguistic treatment of auditory information of the dominant hemisphere, here the right hemisphere. Subsequently, the linguistic disturbance regresses largely, letting persist the change of general auditory treatment. The representation of this general auditory treatment is hemispheric bilateral, the only right hemispheric damage shall result in hemianacousia.

[Papillary fibroelastoma. A rare etiology of strokes in young patients]. / Fibroélastome papillaire. Une étiologie rare des accidents vasculaires cérébraux du sujet jeune.

BACKGROUND: The papillary fibroelastomas are cardiac lesions, which typically occur on the cardiac valves, but rarely on the endocardium. The incidence of these benign primitive tumors varies from 0.002 to 0.33% and increases with advancing age. METHODS: We report two cases of stroke, one in a 31-year-old man and the other in a 48-year-old woman, both admitted to the same stroke center. RESULTS: The diagnostic studies were normal in these two patients, except for the echocardiography. The first showed an echogenic mass on the mitral valve on transthoracic echocardiography (TTE), confirmed by the transesophageal echocardiography (TEE). The second demonstrated a mass on the sigmoid aortic valve on TEE, but the TTE was normal. For these two patients, a surgical excision was carried out and pathologic examination concluded to a papillary fibroelastoma. After surgery, no recurrence was observed. CONCLUSIONS: The papillary fibroelastomas are usually asymptomatic and easily detected by TEE. However, it can be revealed by stroke, myocardial infarction and lower limbs ischemia. These cardiac tumors should be surgically removed, since their complete excision remains the only means of avoiding a recurrence of embolism.

[Cerebral ischemic disorders in the young subject. Epidemiologic and prognostic data]. / Accidents ischémiques cérébraux du sujet jeune. Données épidémiologiques et pronostiques.

A COMMON EVENT: Cerebral vascular events in young subjects account for 5 to 15% of all such cases admitted to specialized services. The incidence of cerebral vascular events in young subjects varies from 3 to 40 per 100,000 depending on the study period (incomplete explorations in early studies), the study site (industrialized or developing country) and the ethnic background of the population. A HETEROGENEOUS GROUP: Although cerebral vascular events are defined as those occurring in subjects aged 18 to 45 years, the population is nevertheless quite heterogeneous due to rising incidence after 35 years and variable frequency of age-dependent and site-dependent underlying causes. RELATIVELY GOOD PROGNOSIS: Early mortality is relatively low (approximately 5%) and two-thirds of the subjects suffer minor or mild sequellae. However, depression, which is frequent, and the impossibility to return to normal work activities have an important impact on quality of life.

[Procedural learning and neurological disorders]. / Aprendizajes procedimentales y enfermedades neurológicas.

INTRODUCTION AND DEVELOPMENT: We review the current state of learning procedures in six neurological conditions: amnesia, Alzheimer-type dementia, Huntington's disease, Parkinson's disease, progressive supranuclear paralysis and cerebellar pathology. In each condition the conservation or deterioration of different types of ability is specified: motor and percepto-motor abilities were evaluated using different tests such as following a rotating disk or signal, the labyrinth test, percepto-motor adaptation test or tests using paradigms of time of serial reaction; percepto-cognitive abilities evaluated by 'mirror-reading' and cognitive abilities evaluated by the Tower of Hanoi, of Toronto, or of London. CONCLUSION: Most of the papers published describe conservation of learning procedures in amnesic syndromes, relatively conserved in Alzheimer's disease and relatively deteriorated in Huntington's disease, in progressive supranuclear paralysis and in cerebellar dysfunction.

Assessment of the severity of asthma in a family practice.

The objective of this study was to evaluate clinical history and self-perception of severity as predictors of asthma severity. A short-term longitudinal study was conducted in a family practice in Melbourne, Australia, utilizing peak flow monitoring, medication diary, and self-administered asthma severity questionnaire. Seventy-two asthmatic subjects with a positive bronchodilator or exercise test, aged between 6 and 79 years, were studied. Symptom and treatment items were correlated with peak flow variability and minimal peak expiratory flow rate (PEFR). An asthma severity scale was generated using the partial credit version of Item Response Theory and the participants' severity scores were validated against lung function tests and medication usage. Quantitative modeling procedures were used to investigate the interrelationships of factors associated with peak flow variability. Severity scores demonstrated significant relationships with peak flow variability (partial r = 0.34) and treatment items. Self-perceived severity of asthma in the preceding 2 weeks showed significant association with peak flow variability (partial rho = 0.46) and minimal PEFR (rho = -0.41). The severity module of the Monash Respiratory Questionnaire is a valid and reliable instrument. The most important symptoms appear to be the frequency of use of bronchodilator and frequency of nocturnal attacks. A carefully structured clinical history in conjunction with the peak flow criteria of variability and minimal peak flow rate would be appropriate in the evaluation of asthma severity. Patients' self-perception of the severity of their asthma needs further evaluation.

Computer administration of a school-based adolescent health survey.

OBJECTIVE: To examine the utility of notebook computers in the collection of data in large scale surveys. METHODOLOGY: A notebook computer administered survey of health in adolescents was conducted in 1992 using a multi-instrument questionnaire. Students in school years 7, 9 and 11 in private and government schools in Melbourne and rural Victoria participated. RESULTS: Parental consent was obtained with an 83% response rate. Each student answered questions directly onto the computer taking an average of 68 min to complete the highly branched confidential but not anonymous questionnaire. Students were presented with on average 33% of the 897 possible questions. Over 90% of students reported enjoying using the computer. Those who reported answering the questions honestly all the time ranged from 68 to 85%, increasing with grade level. CONCLUSIONS: The use of computers in survey research provides many advantages in data collection including exposure only to relevant questions and the opportunity of asking sensitive questions.

Regional assignment of 68 new human gene transcripts on chromosome 11.

We have tested 80 expressed sequence-tagged site (eSTS) markers assigned to human chromosome 11 by the Genexpress program on a panel of somatic cell hybrids containing parts of this chromosome, characterized by cytogenetic data, reference markers, and with respect to the Généthon microsatellite genetic map. Sixty-eight new gene transcripts have been assigned to 25 subregions, one of which was newly defined by five of the eSTS markers. The markers are distributed on the short and long arms in agreement with their physical length. The genic map thus obtained has been integrated with the cytogenetic, genetic, and disease maps. Two eSTS markers have been further mapped with respect to a yeast artificial chromosome (YAC) contig close to the brain-derived neurotrophic factor (BDNF) gene and thus provide potential candidate genes for the mental retardation phenotype of WAGR (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation) syndrome. Altogether, the 68 new gene transcripts localized here represent more than a threefold increase in the number of unknown regionalized genes that could reveal potential candidate genes for the numerous orphan pathologies associated with chromosome 11.

Morbidity, medication and trigger factors in a community sample of adults with asthma.

OBJECTIVES: To determine asthma morbidity, use of medications and trigger factors for asthma attacks in an adult community sample. METHODS: Follow-up questionnaires were sent to respondents indicating a history of asthma or any respiratory symptom on a screening questionnaire. A new scale to measure asthma severity was developed. RESULTS: Questionnaires were returned by 74% (589/795). Respondents with diagnosed asthma had more frequent symptoms and more disruption to lifestyle than those with non-specific respiratory symptoms. Inhaled beta-agonist and oral theophylline preparations were used by 61% and 16% of asthmatics, respectively. Preventive medications such as inhaled corticosteroids and cromoglycate were used daily by only 15% and 4%, respectively. The most frequently reported trigger factors were viral upper respiratory tract infections, cigarette smoke, house dust, smog and other non-specific irritants. Twenty per cent of asthmatics reported occupational exacerbation of symptoms. CONCLUSIONS: There is substantial morbidity from asthma in Victorian adults, which could be reduced by greater use of preventive medications, avoidance of trigger factors, peak flow monitoring and action plans. The asthma severity scale proved to be reliable and valid.