IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.     

Conservation laws and shock waves in the theory of relaxation heat transfer

A set of divergent forms of heat-transfer equations are presented. New laws are established that govern the behavior of the temperature field behind the front of a strong discontinuity. Comparison of theoretical and experimental data on the propagation of nonlinear waves in a sapphire crystal and liquid helium is carried out. Translated from Inzhenerno-Fizicheskii Zhurnal, Vol. 70, No. 2, pp. 318–325, March–April 1997.     

Experimental peri-implant tissue breakdown around hydroxyapatite-coated implants

Factor V Leiden mutation was initially detected in thrombophilic patients and relatives by PCR RFLP (Restriction Fragment Length Polymorphism) according to Bertina (1). This technique presents some drawbacks and the current trend is to simplify the diagnosis. We describe a technique of Allele Specific Amplification (ASA) which is optimized in terms of reliability: an additional mismatch in antepenultimate position enables to obtain the same specificity as PCR RFLP. Furthermore, coamplification of internal control warrants an optimal sensitivity. All the PCR have been simplified: the DNA extraction improvement allows to analyse the genotype with only a few microliters of whole blood whatever the anticoagulant and the procedure of preservation (freezing, dried blood spots, storage at +4 degrees C for several days). This technique saves time. Moreover, full automation of the ASA technique may be shortened thanks to the lack of extraction and the positive/negative reading of the PCR signal.     

The relationship between umbilical artery Doppler findings, fetal biophysical score and placental inflammation in cases of premature rupture of membranes

BACKGROUND: To assess the relationship between placental inflammation, umbilical artery Doppler waveforms and fetal biophysical profile score, umbilical artery Doppler studies and fetal biophysical evaluations were performed in 24 preterm pregnants with premature rupture of membranes (PPROM). SUBJECTS: After delivery, the placentas were microscopically examined and two subgroups were formed including noninflamed or inflamed placentas. RESULTS: In the first group, which includes 14 cases with no histological signs of placental inflammation, we found increased systolic/diastolic ratio only in one patient, whereas in the second group including ten cases with microscopically proven inflammation, nine were found to have increased systolic/diastolic ratios (p < 0.05). Mean systolic/diastolic ratio in the first and the second groups were 2.74 +/- 0.18 and 4.64 +/- 0.93 respectively (p < 0.001). Mean biophysical profile score was 9 +/- 1.04 in the first group and 7 +/- 1.05 in the second group (p < 0.001). CONCLUSION: Abnormal biophysical profile scores along with increased arterial systolic/diastolic ratios have been shown to be the markers of impending clinical infection.     

Rapid and selective depletion of CD4+ T lymphocytes and preferential loss of memory cells on interaction of mononuclear cells with HIV-1 glycoprotein-expressing cells

Apigenin is a plant flavonoid that has been shown to significantly inhibit ultraviolet-induced mouse skin tumorigenesis when applied topically and may be an alternative sunscreen agent for humans. A long-term goal of our laboratory is to elucidate the molecular mechanism or mechanism by which apigenin inhibits skin tumorigenesis. In a previous publication, we characterized the mechanism by which apigenin induced G2/M arrest in keratinocytes. More recent studies in our laboratory have provided evidence that apigenin can induce G1 arrest in addition to arresting cells at G2/M. Here we describe the mechanism of the apigenin-induced G1 arrest in human diploid fibroblasts (HDF). Treatment of asynchronous HDF for 24 h with 10-50 microM apigenin resulted in dose-dependent cell-cycle arrest at both the G0/G1 and G2/M phases as measured by flow cytometry. The G0/G1 arrest was more clearly defined by using HDF that were synchronized in G0 and then released from quiescence by replating at subconfluent densities in medium containing 10-70 microM apigenin. The cells were analyzed for cell-cycle progression or cyclin D1 expression 24 h later. A dose of apigenin as low as 10 microM reduced the percentage of cells in S phase by 20% compared with control cultures treated with solvent alone. Western blot analysis of apigenin-treated HDF indicated that cyclin D1 was expressed at higher levels than in untreated cells, which signifies that they were arrested in G1 phase rather than in a G0 quiescent state. The G1 arrest was further studied by cyclin-dependent kinase 2 (cdk2) immune complex-kinase assays of apigenin-treated asynchronous HDF, which demonstrated a dose-dependent inhibition of cdk2 by apigenin. Inhibition of cdk2 kinase activity in apigenin-treated cells was associated with the accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein as measured by western blot analysis. The cdk inhibitor p21/WAF1 was also induced in a dose-dependent manner, with a 22-fold induction of p21/WAF1 in 70 microM apigenin-treated cells. In conclusion, apigenin treatment produced a G1 cell-cycle arrest by inhibiting cdk2 kinase activity and the phosphorylation of Rb and inducing the cdk inhibitor p21/WAF1, all of which may mediate its chemopreventive activities in vivo. To our knowledge this is the first report of a chemopreventive agent inducing p21/WAF1, a known downstream effector of the p53 tumor suppressor protein.     

Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.     

Parallel, self-organizing, hierarchical neural networks. II

For pt.I see IEEE Trans. Neural Networks, vol.1, p.167-78 (1990). Parallel, self-organizing, hierarchical neural networks (PSHNNs) involve a number of stages with error detection at the end of each stage, i.e., rejection of error-causing vectors, which are then fed into the next stage after a nonlinear transformation. The stages operate in parallel during testing. Statistical properties and the mechanisms of vector rejection of the PSHNN are discussed in comparison to the maximum likelihood method and the backpropagation network. The PSHNN is highly fault tolerant and robust against errors in the weight values due to the adjustment of the error detection bounds to compensate errors in the weight values. These properties are exploited to develop architectures for programmable implementations in which the programmable parts are reduced to on-off or bipolar switching operations for bulk computations and attenuators for pointwise operations     

False aneurysm of the left ventricle and coronary aneurysms in Beh?et disease

A false left ventricular aneurysm and coronary artery aneurysm were discovered in a 29 year old patient with Beh?et's syndrome. The operation under cardiopulmonary bypass consisted of closing the neck of the false aneurysm by an endo-aneurysmal approach with a Gore-Tex patch. The coronary artery aneurysms were respected. There were no postoperative complications. Cardiac involvement is rare in Beh?et's syndrome (6%). The originality of this case is the association of two aneurysmal pathologies: the coronary and ventricular aneurysms due to the angiitis and the myocardial fragility induced by ischaemia.