Crossing boundaries to improve mental health in the Americas: international collaborative authorship.

A nurse anthropologist with a background in international collaborations attended Project LEAD for two years, which enabled her to continue to serve as an advocate for the mentally ill in Belize. The anthropologist collaborated with a psychiatrist from Belize to develop a cross-cultural, cross-discipline publication, "Mental Health in Belize: A National Priority, " which highlights the work of psychiatric nurse practitioners in the country. The researcher learned to collaborate with her peer in Belize through face to face discussions and e-mail and overcame technological difficulties and cultural barriers to produce an international publication. Project LEAD gave the author a sense of self-discovery and self-knowledge, reinforced core values, and developed a frame of reference for leadership. The author also benefited from discussions by local, national, and international leaders on leadership in terms of its key components, contexts, challenges, triumphs, and styles.

Sublocalisation of the X breakpoint in the translocation (X; 18)(p11.2; q11.2) primary change in synovial sarcomas.

A specific translocation between chromosomes X and 18 was identified in synovial sarcomas. From a girl with synovial sarcoma, we isolated two clones with t(X; 18)(p11.2; q11.2) and which had lost the normal X chromosome. Southern blot analysis of DNA from the tumor, the patient and her parents demonstrated that the normal X chromosome, lost in the tumor, was the paternal one. A somatic hybrid cell line was established by fusing tumor cells (after passages on athymic mice) to an HPRT deficient hamster cell line. By cytogenetic, in situ hybridization and molecular analysis, it was found to contain the derivative (X) chromosome in the absence of the der (18) chromosome. To determine the position of the breakpoint on the X chromosome, Southern blots of DNA from this hybrid were hybridized to [32P]-labelled X chromosome probes. DXS146 and DXS255 were retained in the hybrid cell line whereas GAPDP1, the ARAF1 and TIMP proto-oncogenes were not present, indicating that the breakpoint lies proximal to GAPD1, ARAF1 and TIMP and distal to DXS255 and DXS146. Results obtained from other authors are compared. Further studies will be necessary to determine the extent of variation of the breakpoint in different tumors.

Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation.

A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in the DMD gene and discordant for the clinical manifestations of Duchenne muscular dystrophy, were analyzed by molecular studies, in situ hybridization, and methylation pattern of X chromosomes to search for opposite X inactivation as an explanation of their clinical discordance. Results in lymphocytes and skin fibroblast cell lines suggest a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternal deleted X chromosome preferentially active in the affected twin. A review shows that MZ female twins discordant for X-linked diseases are not uncommon. Twinning and X inactivation may be interrelated and could explain the female twins discordant for X-linked traits.

Use of Gen-Probe and Bactec for rapid isolation and identification of mycobacteria. Correlation of probe results with growth index.

Gen-Probe culture confirmation tests (Gen-Probe, San Diego, CA) for Mycobacterium tuberculosis complex and Mycobacterium avium complex were performed on 276 mycobacterial isolates. All 138 M. tuberculosis complex isolates and 79 of 80 M. avium complex isolates were identified correctly. No falsely positive test results were obtained; 58 nontuberculous mycobacteria other than M. avium complex were negative by Gen-Probe. In a second phase of testing, Gen-Probe tests were performed using concentrates from 101 patient Bactec 12B cultures. Positive results by Gen-Probe tests were correlated with the growth index (GI) reading on the day of processing as well as the accumulated GI readings. For those 51 with high (greater than or equal to 999) final GIs, 40/40 (100%) M. tuberculosis complex isolates and 9/11 M. avium complex isolates were positive by Gen-Probe, and six other mycobacteria were negative. Of the 25 with moderate final readings (400 less than or equal to GI less than 999), 12/17 M. tuberculosis complex isolates and 1/1 M. avium complex isolates were correctly identified by Gen-Probe; seven other mycobacteria were negative. Of 25 with low readings (GI less than 400), 8/24 M. tuberculosis isolates were correctly identified by Gen-Probe, and no falsely positive test results were obtained with the other probes. All true negative tests on seven other mycobacteria (not M. tuberculosis complex or M. avium complex) had less than 2% hybridization. Of the 24 falsely negative tests on M. tuberculosis complex isolates or M. avium complex isolates, 22 had greater than 2% hybridization with their respective probes. Thus, percent hybridization greater than 2% may be a useful indicator of the need for retesting.

Chromosome rearrangements and human gene mapping.

The successful mapping of numerous mendelian disorders by chromosome rearrangements turned out to be a key method for positional location of disease genes. We present some personal observations and comments on the interest of cytogenetic studies in human gene mapping.

The Noonan syndrome. The Nancy experience revisited.

67 patients with Noonan syndrome seen over the last 29 years were selected preferentially on cardiac involvement. The cardiac anomalies consisted in the association of dysplastic pulmonary stenosis with asymmetric cardiomyopathy. In one patient, a translocation (3;22) was found. The relationship with cardio-facio-cutaneous syndrome and with the group of phacomatoses is discussed. The familial occurrence (10 families) seems compatible with autosomal dominant inheritance. A gene location on chromosome 22 cannot be excluded.

[Familial supravalvular aortic stenosis. Investigation in a family and review of the literature]. / Sténose aortique supravalvulaire familiale. Observation d'une famille et revue de la littérature.

Familial supravalvular aortic stenosis is a rare autosomal dominant condition. It may be distinguished from the Williams-Beuren syndrome by the absence of the characteristic dysmorphic appearances and of mental retardation. The case of a 9-year-old girl with a severe surgical stenosis led to the diagnosis of the same malformation in the mother and two brothers. This family adds to the 121 cases reported in the literature describing the main features of SVAS. Molecular biological advances have shown that familial SVAS and the Williams syndrome are due to mutation of the elastin gene located at 7q11-23. In the Williams syndrome the allele of this gene is completely absent and there is also probably deletion of contiguous genes, which explains involvement of cognitive function. In SVAS, the genetic lesion, mutation or microdeletion is more limited, explaining the usually isolated aortic malformation. Other studies are necessary to confirm these results.

Potential use of BacT/Alert automated blood culture system for antifungal susceptibility testing.

A simple, rapid susceptibility test is needed to determine the possible resistance of yeasts to commonly used antifungal agents. The BacT/Alert automated blood culture system was evaluated as one technology for development of such a test. Yeast nitrogen base was used as the growth medium, and amphotericin B was the test antifungal agent. Isolates of various Candida species, Torulopsis glabrata, Saccharomyces cerevisiae, and Cryptococcus neoformans were evaluated. The results suggest that detection of amphotericin B resistance of yeast isolates within 12 to 14 h after inoculation of test medium is possible.

[Union of 2 carriers of a balanced translocation. Familial study of 3 generations]. / Union de deux porteurs de translocation équilibrée. Etude familiale sur trois générations.

Both unrelated members of a couple are carrier of a balanced translocation, a reciprocal and a Robertsonian translocation, respectively. After reporting on the family investigation of these individuals, the authors analyse the offspring of six other similar couples reported in the literature.

X chromosome inactivation in 30 girls with Rett syndrome: analysis using the probe.

Rett syndrome (RS) is a neurologic disorder with an exclusive incidence in females. A nonrandom X-inactivation could provide insight into the understanding of this disease. We performed molecular analysis based on the differential methylation of the active and inactive X with probe M27 beta, taking into account the parental origin of the two Xs, in 30 control girls, 8 sisters, and 30 RS girls. In 27 control an 31 RS mothers, the inactivation status of the X transmitted to their daughters was also analyzed. The results showed a significantly increased frequency of partial paternal X inactivation (> 65%) in lymphocytes from 16/30 RS compared with 4/30 controls (P = 0.001). These results do not support the hypothesis of a monogenic X-linked mutation but should be taken into account when researching the etiology of this disease.

[Fragile site on chromosome 2 (q11) in a case of familial lymphohistiocytosis]. / Site fragile sur le chromosome 2 (q11) dans un cas de lymphohistiocytose familiale.

After recalling the main studies about the fragile sites, a fra (2) (q11) in a girl with familial lymphohistiocytosis is described. The influence of medicine, inducers, mutagenic agents are analysed.

The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15.

Chamberlain et al. have assigned the gene for Friedreich ataxia (FA), a recessive neurodegenerative disorder, to chromosome 9, and have proposed a regional localization in the proximal short arm (9p22-cen), on the basis of linkage to D9S15 and to interferon-beta (IFNB), the latter being localized in 9p22. We confirmed more recently the close linkage to D9S15 in another set of families but found much looser linkage to IFNB. We also reported another closely linked marker, D9S5. Additional families have now been studied, and our updated lod scores are z = 14.30 at theta = .00 for D9S15-FA linkage and z = 6.30 at theta = .00 for D9S5-FA linkage. Together with the recent data of Chamberlain et al., this shows that D9S15 is very likely within 1 cM of the FA locus. We have found very significant linkage disequilibrium (delta Std = .28, chi 2 = 9.71, P less than .01) between FA and the D9S15 MspI RFLP in French families, which further supports the very close proximity of these two loci. No recombination between D9S5 and D9S15 was found in the FA families or Centre d'Etude du Polymorphisme Humain families (z = 9.30 at theta = .00). Thus D9S5, D9S15, and FA define a cluster of tightly linked loci. We have mapped D9S5 by in situ hybridization to 9q13-q21, and, accordingly, we assign the D9S5, D9S15, and FA cluster to the proximal part of chromosome 9 long arm, close to the heterochromatic region.

[Balanced X-autosomal translocation and mental retardation. Mapping mental retardation linked to X (excluding fragile X)]. / Translocations X-autosomes équilibrées et retard mental. Contribution à la cartographie des retards mentaux liés à l'X (à l'exclusion de l'X-fra).

From personal observations and reported cases of translocation X-Autosome, a study of the breakpoint showed that Xp11 is more frequently associated to mental retardation. This finding is in agreement with linkage analysis in families with X-linked mental retardation non X-fra.

Hypomagnesemia with secondary hypocalcemia in a female with balanced X;9 translocation: mapping of the Xp22 chromosome breakpoint.

Magnesium-dependent hypocalcaemia (HSH), a rare inherited disease, is caused by selective disorders of magnesium absorption. Both X-linked and autosomal recessive modes of inheritance have been reported for HSH; this suggests a genetically heterogeneous condition. A balanced de novo t(X;9)(p22;q12) translocation has been reported in a female manifesting hypomagnesemia with secondary hypocalcemia. In a lymphoblastoid cell line, derived from this patient, the normal X chromosome is preferentially inactivated, suggesting that the patient's phenotype is caused by disruption of an HSH gene in Xp22. In an attempt to define more precisely the position of the X breakpoint, we have constructed a hybrid cell line retaining the der(X)(Xqter-Xp22.2::9q12-9qter) in the absence of the der(9) and the normal X chromosome. Southern blot analysis of this hybrid and in situ hybridization on metaphase chromosomes have localized the breakpoint between DXS16 and the cluster (DXS207, DXS43), in Xp22.2. Thus, if a gene involved in HSH residues at or near the translocation breakpoint, our findings should greatly facilitate its isolation.

Physical mapping of DNA markers in the q13-q22 region of the human X chromosome.

DNA probe screening of somatic cell hybrids derived from females with X;autosome translocations has enabled us to define eight new breakpoints within the Xq13-q22 region. Together with other X-chromosome rearrangements that have been described earlier, these breakpoints subdivide the Xq21-q22 region into 20 intervals. Our panel refines the physical assignment of 40 probes in the Xq21-q22 segment. Thus, these X-chromosome rearrangements are useful tools for ordering X-linked markers and genes on the proximal long arm of the human X chromosome.

Prenatal exclusion of X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence using closely linked DNA markers.

X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence (H-SAS, MIM number 307,000) is a rare genetic disorder characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, mental retardation, and cerebral malformations. This regularly lethal condition is usually diagnosed at birth or prenatally by ultrasound, but hydrocephalus may be moderate or even undetectable on fetal ultrasound examination. Moreover, since heterozygous women are asymptomatic, carrier detection is at present impossible before the birth of an affected son. Therefore, mapping the H-SAS locus to distal Xq (Xq28) was of primary importance for genetic counselling and prenatal diagnosis. Here, we report prenatal exclusion of H-SAS with a probability of 97.6 per cent in two male fetuses with a 50 per cent a priori risk of being affected using closely linked Xq28 DNA markers.

Monosomy 21q: two cases of del(21q) and review of the literature.

We report on two cases of partial monosomy 21 and review cases with a partial or an apparently full monosomy 21. In situ hybridization and/or molecular studies appear to be necessary tools to study imbalance in such a small chromosome and to perform further genotype-phenotype correlations. The segregation mode in cases with a translocation is adjacent 1, adjacent 2, and 3:1 in about 1/4, 1/4 and 1/2 of the cases, respectively.

Mosaic tetrasomy 12p.

Mosaic tetrasomy 12p is a dysmorphic syndrome which has been described under the name of Pallister mosaic syndrome and Teschler-Nicola/Killian syndrome and has sometimes been incorrectly interpreted as tetrasomy 21. Here we report the first case to be diagnosed prenatally and confirmed by enzyme assays, and we summarize the clinical and biological characteristics of all the cases reported so far under various names.

Interstitial deletion of the long arm of chromosome 6.

A de novo interstitial deletion of 6q21 was observed in a male baby with moderate microcephaly, facial dysmorphism, and psychomotor retardation. In situ hybridization with a c-myb probe showed that the gene was conserved on the deleted chromosome.

De novo methylation of tumour suppressor genes CDKN2A and CDKN2B is a rare finding in B-cell chronic lymphocytic leukaemia.

De novo methylation of the 5'CpG island has been recently reported as an alternative mechanism of inactivation for the tumour suppressor genes CDKN2A and CDKN2B. We examined CDKN2A methylation status at diagnosis in 42 B-cell chronic lymphocytic leukaemia (CLL) patients, in 19 cases the CDKN2B methylation status was also analysed. No homozygous CDKN2A/2B deletion was detected, but four patients (9%) displayed an aberrant CDKN2A methylation status and only one had hypermethylated CDKN2B. De novo methylation was associated with silencing of gene expression. These results confirm that CDKN2A/2B inactivation by deletion is a rare event in CLL and suggest that aberrant methylation could be an alternative way of inactivation very rarely involved in the development of some CLL.