The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon.

The ABCA subfamily of ATP-binding cassette (ABC) transporters includes eleven members to date. In this study, we describe a new, unusually large gene on chromosome 7p12.3, ABCA13. This gene spans over 450 kb and is split into 62 exons. The predicted ABCA13 protein consists of 5,058 ami- no acid residues making it the largest ABC protein described to date. Like the other ABCA subfamily members, ABCA13 contains a hydrophobic, predicted transmembrane segment at the N-terminus, followed by a large hydrophilic region. In the case of ABCA13, the hydrophilic region is unexpectedly large, more than 3,500 amino acids, encoded by 30 exons, two of which are 4.8 and 1.7 kb in length. These two large exons are adjacent to each other and are conserved in the mouse Abca13 gene. Tissue profiling of the major transcript reveals the highest expression in human trachea, testis, and bone marrow. The expression of the gene was also determined in 60 tumor cell lines and the highest expression was detected in the SR leukemia, SNB-19 CNS tumor and DU-145 prostate tumor cell lines. ABCA13 has high similarity with other ABCA subfamily genes which are associated with human inherited diseases: ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders. The ABCA13 gene maps to chromosome 7p12.3, a region that contains an inherited disorder affecting the pancreas (Shwachman-Diamond syndrome) as well as a locus involved in T-cell tumor invasion and metastasis (INM7), and therefore is a positional candidate for these pathologies.

Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34.

The ABCA subfamily of ABC transporters includes ten members to date. In this study, we describe an additional gene, ABCA12. Four full-length cDNA sequences have been obtained from human placenta that contain two different polyadenylation sites and two splicing forms, coding for ABCA12 isoforms of 2,595 and 2,516 amino acid residues. Both isoforms are predicted to have two ATP-binding domains (nucleotide binding domain, NBD) and two transmembrane (TM) domains, features shared by all other ABCA subfamily proteins. ABCA12 is most closely related to ABCA1, with an amino acid similarity of 47%. Northern blot analysis demonstrates that a 9.5-kb transcript is mainly expressed in the stom- ach. ABCA12 was mapped to human chromosome 2q34. Two other genes from ABCA subfamily are associated with human inherited diseases, ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders. The ABCA12 gene is located in a region of chromosome 2q34 that harbors the genes for lamellar ichthyosis, polymorphic congenital cataract, and insulin-dependent diabetes mellitus (IDDM13), and therefore is a positional candidate for these pathologies.

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.

Comparative analysis of the promoter structure and genomic organization of the human and mouse ABCA7 gene encoding a novel ABCA transporter.

We report here the genomic and transcriptional characterization in mouse and man of a novel transporter of the ABCA subclass, named ABCA7. As it is the case for other ABCA genes, the predicted protein encoded by ABCA7 is a full symmetric transporter, highly conserved across species. The ABCA7 gene maps to human chromosome 19 and to the homologous region at band B4-C1 on mouse chromosome 10. The preferential expression of ABCA7 in the spleen, thymus, and fetal liver is consistent with the finding, in both human and mouse promoter, of sites targeted by lymphomyeloid-specific transcription factors. This suggests that ABCA7 may play a pivotal role in the developmental specification of hematopoietic cell lineages.

Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter.

The ABCA1 gene, a member of the ATP-binding cassette A (ABCA1) transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. Mutations in ABCA1 lead to familial high density lipoprotein deficiency and Tangier disease. We report the complete human ABCA1 gene sequence, including 1,453 bp of the promoter, 146,581 bp of introns and exons, and 1 kb of the 3' flanking region. The ABCA1 gene spans 149 kb and comprises 50 exons. Sixty-two repetitive Alu sequences were identified in introns 1-49. The transcription start site is 315 bp upstream of a newly identified initiation methionine codon and encodes an ORF of 6,783 bp. Thus, the ABCA1 protein is comprised of 2,261 aa. Analysis of the 1,453 bp 5' upstream of the transcriptional start site reveals multiple binding sites for transcription factors with roles in lipid metabolism. Comparative analysis of the mouse and human ABCA1 promoter sequences identified specific regulatory elements, which are evolutionarily conserved. The human ABCA1 promoter fragment -200 to -80 bp that contains binding motifs for SP1, SP3, E-box, and AP1 modulates cellular cholesterol and cAMP regulation of ABCA1 gene expression. These combined findings provide insights into ABCA1-mediated regulation of cellular cholesterol metabolism and will facilitate the identification of new pharmacologic agents for the treatment of atherosclerosis in humans.

[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.

Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred.

Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins. ABC1, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human ABC1 gene and the identification of a mutation in the ABC1 gene from the original Tangier disease kindred. The organization of the human ABC1 gene is similar to that of the mouse ABC1 gene and other related ABC genes. The ABC1 gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a Mnl1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human ABC1 gene and identify a frameshift mutation in the ABC1 gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the ABC1 gene and the analysis of additional ABC1 mutations in patients with Tangier disease.

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.

[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.

[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.

[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.

Functional recovery and social outcome after cerebral infarction in young adults.

This study was designed to assess the return to work, the poststroke depression and the quality of life after a cerebral infarction in young adults and was conducted on 71 consecutive young patients (aged 15-45 years) affected by a cerebral infarct who were hospitalized for the first time and discharged at least 1 year before the study. Data about risk factors, etiology, side and territory of stroke, social characteristics of the patient (age, sex, profession, educational level, family situation), poststroke seizures, recurrent stroke, other vascular events, and deaths were collected. Neurological deficits were graded with the National Institutes of Health (NIH) Stroke Scale. Poststroke depression (PSD) was quantified using the DSM-IIIR criteria and the Montgomery Asberg Depression Rating Scale. Outcomes were rated with the Ranking Scale, the Barthel Index and the Glasgow Outcome Scale. Quality of life was assessed with the Sickness Impact Profile. Follow-up information was obtained by interview and neurological examination. Follow-up information was obtained in 65 patients at a mean of 31.7 +/- 13.0 (range 12-59) months, as 2 patients died and 4 were lost to follow-up and were thus excluded from this study. Poststroke seizures occurred in 7 patients (10.8%) and recurrent strokes in 4 patients (6.2%), but none were fatal. The outcome after stroke among survivors was usually good, since more than two-thirds of the patients (69.8%) reported no problem, 11.1% moderate handicap and one-fifth major handicap. Forty-six patients (73%) returned to work: the time period ranging from several days after stroke to 40 months, with a mean of 8 months. However, adjustments in their occupation were necessary for 12 patients (26.1%). PSD was common, since 48.31% of the patients were classified as depressed. PSD was associated with the localization of the infarct (carotid territory), a severe disability, a bad general outcome, and an absence of return to work. Their opinion about their quality of life was negative among approximately 30% of the patients, especially in emotional and alertness behaviors. social interaction, recreation and pastimes. The general outcome after cerebral infarct in young adults is usually good. However, the risk of a PSD is high, and only half of the patients had returned to their previous work. A remaining psychosocial handicap and depression of sexual activity impaired the quality of life. In multivariate analysis, a low NIH score at admission is a significant predictor for return to work, the absence of PSD, and a good quality of life.

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.

Adolescent dieting: healthy weight control or borderline eating disorder?

Dieting in adolescent girls is ubiquitous but its health significance is uncertain. On the one hand it might be seen as promoting healthy weight control and on the other it might be considered as a risk factor for eating disorders. Dieting levels were systematically assessed in a representative group of 2525 Australian teenagers and classified using item response theory. In this group, 38% of girls and 12% of boys were categorised as intermediate dieters; 7% of girls and 1% of boys fell into a group of extreme dieters. Body mass carried a strong positive association with intermediate dieting. Most female dieters, nevertheless, fell within a normal weight range. Psychiatric morbidity was the clearest factor associated with extreme dieting and 62% of extreme dieters reported high levels of depression and anxiety. Extreme dieting might reasonably be viewed as lying on a spectrum with clinical eating disorders. Most dieting is unjustified on the grounds of appropriate weight control and appears to reflect a widespread striving of teenage girls towards body shapes at the lower end of age-adjusted norms.

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.

[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.

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.

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.