PubMed Health⌕ Search

Biomedical subjects

M Till

Publications and source records attributed to M Till.

At least 19 recordsLinked to original sources
PubMed2006

Six cases of cryptic subtelomeric translocations in four families: the use of subtelomeric FISH probes as a diagnostic tool.

Finding the diagnosis in children with mental retardation and a normal karyotype, whether or not associated with dysmorphic features, is important for defining an eventual syndrome and for genetic counselling of the families. Telomeric re-arrangements may be a common and underestimated-to-date cause of non-syndromic mental retardation. Using a FISH-based approach combining subtelomeric probes, we report the detection of 4 cases of cryptic translocations t(2;10)(p25.3;q26.3), t(4;17)(p16.2;q25), t(4;20)(p16.2;q13) and t(5;7)(p15.3;q36) associated with MR and dysmorphic features. We discuss the usefulness of subtelomeric FISH in children with unexplained delayed psychomotor development, when the genetic cause remains unknown and the karyotype is normal.

Abnormalities, Multiple↗
PubMed2005

Prenatal diagnosis of Aicardi-Goutières syndrome.

OBJECTIVES: Aicardi-Goutières syndrome is an autosomal recessive neurodegenerative disorder inducing cerebral atrophy, intracerebral calcification and developmental arrest. Diagnosis requires the presence of progressive encephalopathy with clinical onset shortly after birth, typical neuroimaging features associated with a raised blood and cerebrospinal fluid interferon-alpha level.A case of prenatal diagnosis of Aicardi-Goutières syndrome is reported. METHODS: An MRI performed at 26 gestational weeks showed bilateral calcifications and white matter abnormalities, cerebral anomalies typically described in this disease. The fetal blood analysis revealed an increase in interferon-alpha. RESULTS: Therefore, the prenatal diagnosis of Aicardi-Goutières syndrome in this fetus was based on the following facts: the familial background with the affected first child and consanguineous parents, a normal pregnancy and normal fetal growth, cerebral anomalies diagnosed on prenatal ultrasound and cerebral MRI, raised interferon-alpha in the fetal serum and no evidence of any infectious etiology. The autopsy performed postdelivery at 28 1/2 weeks' gestation confirmed the diagnosis of Aicardi-Goutières syndrome. CONCLUSION: To the best of our knowledge, this is the first prenatal diagnosis of this syndrome. Such a diagnosis may prove useful for families at risk as long as genetic screening is not available.

Abnormalities, Multiple↗
PubMed2005

[Netherton syndrome: a type of infantile erythroderma with failure to thrive, immune deficiency, rickets. Report of 3 cases].

We report the cases of 2 boys and 1 girl suffering from Netherton syndrome. Both boys presented with a non-bullous congenital erythroderma and were diagnosed early as Netherton syndrome with hair biopsies. Both had severe failure to thrive, signs of atopy, several episodes of bacterial infection, and rickets (with a high blood level of vitamin D in the first boy, and vitamin D deficiency in the second). In the third case, the pilar abnormality appeared at the age of 3 years. The girl had ichtyosis linearis circumflexa, failure to thrive and severe constipation. Netherton syndrome is a rare disorder characterized by severe ichtyosis, signs of atopy, immune deficiency and failure to thrive. The disease is severe and comprises many complications in early infancy. It is due to a genetic disorder of recessive autosomal transmission, and the gene, SPINK5, is located in the chromosome 5. Prenatal diagnosis is possible. Two of our patients had rickets, which has never been described in such patients population.

Carrier Proteins↗
PubMed2005

Extended antiretroviral treatment interruption in HIV-infected patients with long-term suppression of plasma HIV RNA.

OBJECTIVES: Evaluation of extended treatment interruption (TI) in chronic HIV infection among patients successfully treated with antiretroviral therapy. METHODS: An observational analysis of 25 patients in a prospectively followed cohort with chronic HIV infection, viral loads <500 HIV-1 RNA copies/mL for at least 6 months, and an interruption in therapy of >/=28 days duration was carried out. Follow up was divided into 3-month time periods for analysis. The effects of time period, stratification group and stratification group by time period interactions on CD4 counts were tested using a mixed model. Univariate comparisons among patient characteristics and responses were performed using Fisher's exact test or the Wilcoxon rank sum test. RESULTS: At initiation of TI, the median CD4 count was 799 cells/microL. TI duration was a median of 7.1 months. HIV RNA rebounded to a median maximum level of 75 000 copies/mL. Maximum viral rebound was significantly greater in patients who were male, had lipodystrophy and had zenith HIV RNA prior to TI of >/=50 000 copies/mL. Lower CD4 cell counts were observed during TI in patients with lipodystrophy, zenith HIV RNA >/=50 000 copies/mL, history of AIDS, HIV infection >/=5 years and presuppression CD4 count </=350 cells/muL. Patients who reinitiated therapy had shorter TI duration, presuppression CD4 count </=350 cells/microL, previous AIDS diagnosis and lipodystrophy. No patients developed adverse or AIDS-defining events during TI. CONCLUSIONS: Long-term TI resulted in greater immune deterioration in patients with high viral set points or low CD4 cell counts prior to initiation of suppressive antiretroviral therapy.

Adult↗
PubMed2003

[Hypomelanosis of Ito in a girl with Trisomy 13 mosaicism: a cytogenetic study].

BACKGROUND: Hypomelanosis of Ito was first described by Ito in 1952 as incontinentia pigmenti achromians. The consistent feature of the disease is a characteristic cutaneous hypopigmentation area following the lines of Blaschko, but the clinical manifestations are varied and hypomelanosis of Ito is regarded as a neurocutaneous syndrome. Hypomelanosis of Ito is sporadic but is probably a non-specific expression of chromosomal mosaicism; we report a case with four clones. CASE REPORT: We report the case of a 26 year-old woman with neurocutaneous hypomelanosis of Ito and Trisomy 13 mosaicism. She also exhibited skeletal and ophthalmologic disorders. Immunohistology revealed a PS100 and Melan A decrease in hypopigmented skin. Cytogenetic study of normal and hypopigmented skin fibroblasts showed mosaicism with four clones. DISCUSSION: This is the third case of Trisomy 13 mosaicism associated with hypomelanosis of Ito, although other anomalies on chromosome 13 have been described. Happle published "phylloid" pigmented cases, which are mainly associated with Trisomy 13. This is the first observation of four-clone mosaicism and can be explained by successive mutations during embryogenesis. Anomalies on chromosomes 5,6 and 21 have never been described. The definition of hypomelanosis of Ito is not well established and the disease is presently included in a group of "pigmentary dysplasia" with genetic mosaicism.

Adult↗
PubMed2001

Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures.

Hirschsprung disease (HSCR) is a common malformation of neural-crest-derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest-derived cells and of CNS but also in the development of midline structures in humans.

Abnormalities, Multiple↗
PubMed2001

Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase.

Ventricular cardiomyocytes and cardiac tissue of lean and genetically obese (fa/fa) Zucker rats were used 1) to study the role of the p85 regulatory subunit isoforms p85 alpha and p85 beta for insulin signaling through the phosphatidylinositol (PI) 3-kinase pathway, and 2) to elucidate the implications of these mechanisms for cardiac insulin resistance. Western blot analysis of cardiomyocyte lysates revealed expression of p85 alpha and p85 beta but no detectable amounts of the splice variants of p85 alpha. Essentially no p85 alpha subunit of PI 3-kinase was found to be associated with insulin receptor substrate (IRS)-1 or IRS-2 in basal and insulin-stimulated (5 min) cardiomyocytes. Instead, insulin produced a twofold increase in p85 beta associated with IRS-1, leading to a three- to fourfold increase in p85 beta-associated PI 3-kinase activity. This response was significantly reduced in obese animals. Comparable results were obtained in the intact heart after in vivo stimulation. In GLUT-4-containing vesicles, an increased abundance (3.7 +/- 0.7-fold over basal) of p85 alpha was observed after insulin stimulation of lean animals, with no significant effect in the obese group. No p85 beta could be detected in GLUT-4-containing vesicles. Recruitment of the p110 catalytic subunit of PI 3-kinase and a twofold increase in enzyme activity in GLUT-4-containing vesicles by insulin was observed only in lean rats. We conclude that, in the heart, p85 alpha recruits PI 3-kinase activity to GLUT-4 vesicles, whereas p85 beta represents the main regulator of IRS-1- and IRS-2-mediated PI 3-kinase activation. Furthermore, multiple defects of PI 3-kinase activation, involving both the p85 alpha and the p85 beta adaptor subunits, may contribute to cardiac insulin resistance.

Animals↗
PubMed2000

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus [FGS2]?

FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.

Abnormalities, Multiple↗
PubMed2000

Molecular mechanisms of contraction-regulated cardiac glucose transport.

Insulin and contraction are the most important regulators of glucose utilization in cardiac muscle. In contrast with insulin, the intracellular signalling elements of contraction have remained unexplored. In the present studies, adult rat ventricular cardiomyocytes were electrically stimulated to perform rhythmic contractions to permit the determination of potential sites of convergence of contraction and insulin signalling to glucose transport. The participation of phosphoinositide 3-kinase (PI-3K) in Ca(2+)- and contraction-stimulated 3-O-methylglucose transport was suggested by the great sensitivity of this process towards the PI-3K inhibitors wortmannin and LY294002 and by the presence of PI-3K activity in anti-phosphotyrosine immunoprecipitates from contracted cells. Initial signalling events of insulin action, including receptor kinase activation, the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and the recruitment of PI-3K to IRS-1 and IRS-2, were found not to be involved in contraction-mediated signalling. However, immunoprecipitation of p85alpha revealed a markedly enhanced tyrosine phosphorylation of an unknown co-precipitated 200 kDa protein in response to both stimuli. It is concluded that contraction-regulated cardiac glucose transport involves the activation of PI-3K in response to upstream signalling pathways different from that of insulin.

Androstadienes↗
PubMed2000

Treatment of cervical carcinoma in situ in HIV positive women.

OBJECTIVES: To evaluate the safety and effectiveness of hysterectomy vs. cone biopsy in HIV seropositive patients with carcinoma in situ of the cervix (CIS). METHODS: We performed a retrospective case-control study of all HIV seropositive patients diagnosed with carcinoma in situ of the cervix from 1989 to 1995. A control group of HIV(-) women with CIS was also ascertained matched for date of diagnosis of CIS, race and age. RESULTS: There were 439 patients with CIS, of which 45 were HIV seropositive (10.3%). Nine were treated by hysterectomy, 30 by cone biopsy, and six remained untreated. Overall, 63% of HIV(+) patients did not receive any follow-up Pap smear (44% of hysterectomy patients, 50% of cone biopsy patients, and 83% of untreated patients; chi(2) P=0.41). According to Pap smear results, 67% (10/15) cone biopsy patients and 60% (3/5) hysterectomy patients had an abnormal Pap smear after treatment (P=0.9). Median time to recurrence was 12 months in hysterectomy patients vs. 14 months in cone biopsy patients. Deaths occurred in 22% of hysterectomy patients, 17% of cone biopsy patients, and 50% of untreated patients, none due to cervical cancer. Median time to death from presentation was 27.5 months for hysterectomy patients, 11 months for cone biopsy patients, and 7 months for untreated patients (P<0.05). There were no complications in the hysterectomy group, however, two patients were readmitted after cone biopsy for bleeding. When compared to HIV(-) women with CIS, HIV(+) patients were more likely to be treated by hysterectomy (chi(2) P=0.01). CONCLUSION: All patients diagnosed with CIS should be counseled regarding HIV prevention and testing because of a significant seropositive rate. Compliance with gynecologic follow-up is very poor in this patient population. Special efforts should be made to enhance compliance. Cone biopsy and hysterectomy appear to be equally safe and effective in the treatment of CIS. CIS in HIV patients is a poor prognostic indicator for death from any cause.

Adolescent↗
PubMed1999

Potency of various polycyclic aromatic hydrocarbons as inducers of CYP1A1 in rat hepatocyte cultures.

A number of highly toxic environmental pollutants including certain polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and 'dioxin-like' polychlorinated biphenyls (PCB) are among the most potent agonists of the aryl hydrocarbon receptor (AHR). Induction of cytochrome P4501A1 (CYP1A1) in mammalian cell culture is widely used as a functional parameter for AHR activation providing an estimate for 'dioxin-like' inducing equivalents in extracts from environmental samples. Since a number of polycyclic aromatic hydrocarbons (PAHs) also act as AHR-agonists, the CYP1A1-inducing potencies, measured as induction of 7-ethoxyresorufin O-deethylase (EROD) activity in rat hepatocyte cultures were analyzed for 16 PAHs frequently present in environmental samples. Among these, seven PAHs including benzo[a]pyrene were relatively potent inducers allowing the determination of Induction Equivalency Factors (IEF). For three PAHs including benzo[k]fluoranthene which acted as weak inducers, IEFs were estimated, while six PAHs including acenaphthylene were classified as inactive. Based on different efficacies the concentration-response characteristics of CYP1A1 induction were analyzed in more detail for benzo[a]pyrene, benzo[k]fluoranthene, and acenaphthylene. Benzo[k]fluoranthene was markedly less effective than benzo[a]pyrene as inducer of EROD activity but even more effective than benzo[a]pyrene as inducer of CYP1A1 protein and mRNA. Acenaphthylene was highly more effective on the level of mRNA than on the levels of protein or EROD activity. Further analysis revealed that the low efficacy of acenaphthylene as inducer of CYP1A1 protein and EROD activity is due to its marked cytotoxicity while no clear-cut explanation was found for the differences in efficacy between benzo[k]fluoranthene and benzo[a]pyrene. The EROD-inducing potency of a mixture of 16 PAH was about 2-fold higher than that calculated on the basis of IEFs of the individual constituents of the mixture.

Animals↗
PubMed1999

Trisomy 17 mosaicism in amniotic fluid cells not found at birth in blood but present in skin fibroblasts.

This article describes a case of fetal trisomy 17 mosaicism found in amniotic fluid cells in one of two bichorial biamniotic twins without any sonographic anomaly. The extra chromosome 17 was absent from cord blood cells at birth but present on karyotype and in situ hybridization in cultured fibroblasts from skin biopsy. Clinical examination showed a few mild dysmorphic features and a moderate neurological involvement which may rather be related to prematurity. It therefore seemed important to obtain the karyotype on fibroblasts when a trisomic cell line was found in amniocentesis and not confirmed on blood lymphocytes, even in the absence of dysmorphic features. This should help to differentiate a real mosaic from a mosaic restricted to extra-fetal tissues.

Amniotic Fluid↗