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Biomedical subjects

D Stephan

Publications and source records attributed to D Stephan.

At least 19 recordsLinked to original sources
PubMed2006

KATP channel openers of the benzopyran type reach their binding site via the cytosol.

BACKGROUND AND PURPOSE: ATP-sensitive K+ (KATP) channels are composed of pore-forming subunits (Kir6.x) and of sulphonylurea receptors (SUR). Both sulphonylureas and K(ATP) channel openers act by binding to SUR. Sulphonylureas reach their binding site from the cytosol but it remains unknown whether this holds for openers too. EXPERIMENTAL APPROACH: A poorly membrane-permeant sulphonic acid derivative of the benzopyran-type opener, bimakalim, was synthesized, descyano-bimakalim-6-sulphonic acid (BMSA). Binding of BMSA and bimakalim was compared in membranes and intact cells expressing the Kir6.2/SUR2B channel and channel opening was compared in inside-out patches and whole cells. KEY RESULTS: In membranes, bimakalim and BMSA bound to Kir6.2/SUR2B with Ki values of 61 nM and 4.3 microM, showing that the negative charge decreased affinity 69-fold. In intact cells, however, binding of BMSA was much weaker than in membranes (75-fold) whereas that of bimakalim was unchanged. The Ki value of BMSA decreased with increasing incubation time. In inside-out patches, bimakalim (1 microM) and BMSA (100 microM) opened the Kir6.2/SUR2B channel closed by MgATP to a similar degree whereas in whole-cell experiments, only bimakalim was effective. CONCLUSIONS AND IMPLICATIONS: Despite its negative charge, BMSA is an effective channel opener. The fact that BMSA binds and acts more effectively when applied to the inner side of the cell membrane shows that benzopyran openers reach their binding site at SUR from the cytosol. This suggests that the binding pocket of SUR is only open on the cytoplasmic side.

Benzopyrans↗
PubMed2006

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels.

AIMS/HYPOTHESIS: Sulfonylureas and glinides close beta cell ATP-sensitive K(+) (K(ATP)) channels to increase insulin release; the concomitant closure of cardiovascular K(ATP) channels, however, leads to complications in patients with cardiac ischaemia. The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K(ATP) channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K(ATP) channels may be overstated. We therefore re-examined repaglinide's potency at and affinity for the recombinant pancreatic, myocardial and vascular K(ATP) channels in comparison with glibenclamide. METHODS: K(ATP) channel subunits (i.e. inwardly rectifying K(+) channels [Kir6.x] and sulfonylurea receptors [SURx]) were expressed in intact human embryonic kidney cells and assayed in whole-cell patch-clamp and [(3)H]glibenclamide binding experiments at 37 degrees C. RESULTS: Repaglinide and glibenclamide, respectively, were >or=30 and >or=1,000 times more potent in closing the pancreatic than the cardiovascular channels and they did not lead to complete inhibition of the myocardial channel. Binding assays showed that the selectivity of glibenclamide was essentially based on high affinity for the pancreatic SUR, whereas binding of repaglinide to the SUR subtypes was rather non-selective. After coexpression with Kir6.x to form the assembled channels, however, the affinity of the pancreatic channel for repaglinide was increased 130-fold, an effect much larger than with the cardiovascular channels. This selective effect of coexpression depended on the piperidino substituent in repaglinide. CONCLUSIONS/INTERPRETATION: Repaglinide and glibenclamide show higher potency and efficacy in inhibiting the pancreatic than the cardiovascular K(ATP) channels, thus supporting their clinical use.

ATP-Binding Cassette Transporters↗
PubMed2006

[Spontaneous dissection of the carotid artery].

Spontaneous dissection of the carotid artery is a rare cause of stroke. A 54-year-old man was hospitalized for transient ischemic attack. Duplex ultrasound of cervical arteries showed indirect signs of a dissection of the carotid. Magnetic resonance angiography showed a dissection of the post bulbar segment of the right carotid artery and a right ischemic stroke. Angiography confirmed the diagnosis. The anti-coagulant treatment initialized as soon as the diagnosis of dissection was suspected, was stopped because of a massive cerebral infarct. The course was unfavorable with a persistent hemiplegia.

Anticoagulants↗
PubMed2006

[The best of vascular medicine in 2005].

It is illusory to think that one year is long enough to establish all the truths that will guide our clinical practice in vascular medicine. On the contrary, one year was long enough to contradict what the preceding twelve months had set out to demonstrate. Consequently, promising trials in the treatment of abdominal aortic aneurysms by endoprostheses have been the object of contradictory debate with regards to the long-term benefits. In fundamental research, circulating progenitors of endothelial cells have been shown to be a marker of atherosclerosis, but is it a better marker than LDL-cholesterol values? The demonstration that these progenitors are of value in the treatment of essential ischaemia of the lower limbs is awaited. Finally, ximelagatran, a direct thrombin antagonist, seemed to have all the qualities of an ideal anticoagulant: easy to use, safe... until the report of raised hepatic enzymes, the clinical relevance of which remains to be determined. In the good news section: the Systolic Pressure Index, an unquestioned marker of arterial disease. Its reduction was known to be correlated with the prevalence of cardiovascular complications. However, it has now been shown that an increase in the index is also associated with cardiovascular complications, a real U-shaped curve. Renal arterial stenosis should be considered in patients with left ventricular failure presenting with flash pulmonary oedema. In the absence of cardiac pathology, BNP would seem to be a good biological marker of haemodynamically significant renal arterial stenosis. Finally, should superficial femoral artery stenosis be treated by an active stent. To date, there is no formal proof.

Angiogenesis Inhibitors↗
PubMed2005

On-line tracking of the coating of nanoscaled silica with titania nanoparticles via zeta-potential measurements.

Nanoscaled spherical silica particles were directly coated with the titania nanoparticles by means of a heterogenic coagulation. Silica was prepared by the Stöber method, titania by a hydrolysis-condensation reaction of tetrapropylorthotitanate under acidic conditions. The on-line tracking of the coating process was performed by measuring the change in zeta potential during the gradual addition of a titania sol to the spherical silica particles. Silica particles of various sizes were used to determine the consumption of the titania sol in the dependence upon the particle size. The coated and uncoated particles were characterized by zeta-potential measurements, acoustic attenuation spectroscopy, dynamic light scattering, and scanning electron microscopy.

Journal Article↗
PubMed2005

[The best of vascular medicine in 2004].

The wealth of information in vascular pathology merits close examination. The French Cardiology Society vascular group turned its attention to arteries, veins, hypertension and a more fundamental investigation to analyse the results from some illuminating studies which appeared in 2004, despite some pertinent therapeutic doubts. Examination of the trials discussed here shows the importance, as much in vascular pathology as elsewhere, of founding our practice on evidence based medicine.

Humans↗
PubMed2004

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation.

BACKGROUND: A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1. OBJECTIVE: To determine if this disorder among the Agarwals is due to mutations in MLC1 by a mutation screening study conducted on affected Agarwal patients. METHODS: Genomic DNA from these Indian leukodystrophy patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the MLC1 gene. RESULTS: Thirty-three affected individuals whose clinical and imaging presentations were consistent with MLC were screened. All were from northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous for A157E. No mutation in the coding region was found in the non-Agarwal patient. CONCLUSIONS: Indian patients with megalencephaly and MRI changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. Members of the Agarwal ethnic group affected with the disorder present with a mildly progressive course and show a common mutation (320insC) in the MLC1 gene, suggesting a founder effect.

Adolescent↗
PubMed2004

[Puffy hand in long-term intravenous drug users].

Narcotic addiction may induce systemic and local complications. Intravenous injections of drugs can cause venous thrombosis, and septic or embolic complications. The puffy hand sign is a more uncommon complication of hard-core injection addicts. Three long-term intravenous drug users, two males, one female, mean age 30.6 years (26-37) presented puffy hands. These patients had been drug addicts for four to twelve years (mean duration 7.3 years) and had stopped heroin injections for 3-5 years (mean 4.6), participating in a buprenorphine substitution program. The edema appeared several years after drug cessation (1.5-5, mean 2.3). Typically the puffiness was bilateral, the hands swollen from the proximal segments of the fingers to the wrist. In one patient, the edema was localized both in the hands and in the feet. The edema was not pitting and unaffected by elevation. Duplex ultrasound examination of the extremities was normal. Lymphangiography performed in one patient was consistent with deep lymphatic destruction. Puffy hand syndrome appears to be the end result of lymphatic obstruction. Repeated injections of drugs in or outside the veins destroy the lymphatics. Buprenorphine may play an important role in the puffy hand sign. Although it is supposed to be administered orally, many drug addicts use it as an i.v. solution. Because buprenorphine is poorly soluble, it causes lymphatic obstruction. This type of hand for which no therapy exists must be differentiated from deep palmar space infection with dorsal edema which requires incision and drainage.

Adult↗
PubMed2003

Hypereosinophilia-induced digital necrosis in a smoking patient.

Raynaud's phenomenon and digital necrosis of the fingers are rare complications of hypereosinophilia. We report a case of a smoking male who developed Raynaud's phenomenon and digital necrosis of the fingers associated with idiopathic hypereosinophilia with angiographically documented occlusion of small and medium arteries of the extremities. The eosinophils may play a thrombotic role in vascular pathology and eosinophil blood count should be checked when investigating patients with digital gangrene.

Adult↗
PubMed2002

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.

Adenine Nucleotides↗
PubMed2001

[In vitro determination of the cytotoxic activity of saliva samples of smokers].

BACKGROUND: The question arised whether saliva can be included in populations monitoring of high risk groups for the development of head and neck squamous cell carcinomas. Cytotoxic mechanisms strongly influence the carcinogenesis of squamous cell carcinomas. PATIENTS AND METHODS: Saliva specimen of 131 abusing and non-abusing probands were tested on their biological (cytotoxic) effects to draw conclusions on the individual cancer risk. To determine the cytotoxic activity of saliva, we used the "plating efficiency index" of lungfibroblasts of the chinese hamster. RESULTS: We found significantly increased cytotoxic effects in the saliva of smoking probands (p < 0.002). Regularly combined smoking and drinking of alcohol led to a highly significant increased risk of cytotoxic saliva in the tested persons (odds ratio: 17.4; p < 0.005). CONCLUSIONS: Including patients with head and neck squamous cell carcinomas, ongoing studies must prove the practical relevance of this biomarker for estimating the relative cancer risk in the upper aerodigestive tract.

Adult↗
PubMed2001

[Ames test as biomarker].

BACKGROUND AND OBJECTIVE: The incidence of squamous cell carcinomas in the upper aerodigestive tract has increased worldwide. The main risk factors are chronic tobacco and alcohol consumption. The detection of high-risk persons is important because early diagnosis of these tumors provides a good chance for permanent healing. Biomonitoring programs may help to give precise information about the individual cancer risk among smoking and drinking persons. The aim of this study was to evaluate the Ames test as a biomarker to detect the genotoxicity of saliva. PATIENTS AND METHODS: Saliva specimens of 131 probands were investigated for their genotoxic effects using the Ames test. RESULTS: Our results showed an increased trend of genotoxic activity in the saliva of smokers. A highly significant additional increase of genotoxicity was measured in smoking and drinking individuals. CONCLUSIONS: Our study shows that the Ames test could be used to show genotoxic effects in saliva specimens. In combination with other biomarkers, this test may help to develop a valid concept for detecting cancer-endangered people.

Adult↗
PubMed2001

[Altered heart rate variability but preserved temporal relationship with sleep stages in a patient with primary aldosteronism].

OBJECTIVE: In a previous study, we found oscillations in the autonomic nervous system activity--as estimated by spectral analysis of R-R intervals--strongly linked to the non-rapid-eye movement (NREM)--REM sleep cycles, with low sympathetic activity during NREM sleep and predominant sympathetic activity during REM sleep. In the present study we established the 5-min nighttime profiles in various measures of heart rate variability (HRV) in one patient with primary aldosteronism before and after successful surgery of Conn adenoma. METHODS: One patient (female, 36 years old) with primary aldosteronism underwent two experimental nights a few weeks before and after surgery by coeliscopy in which sleep and cardiac recordings were made. Power spectral analysis was performed on ectopic-free R-R intervals with a fast Fourier transform. We calculated also the standard deviation of normal R-R intervals (SDNN) and the root mean square difference among successive R-R intervals (RMSSD). RESULTS: While removal of adenoma resulted in a rapid complete normalization of blood pressure and classical signs and biological symptoms of aldosterone hypersecretion, HRV profile did not changed a few weeks after surgery. The overnight SDNN was low although not abnormal at 38 and 33 ms before and after surgery respectively vs 58 +/- 15 ms (33 to 83) in normal female controls. RMSSD was low although not abnormal at 33 and 31 ms before and after surgery respectively vs 60 +/- 20 ms (20 to 105). The total spectrum power was low although not abnormal at 2.3 and 1.8 ms2 before and after surgery, respectively vs 3.2 +/- 1.1 ms2 (1.4 to 4.9). One out of the 8 controls had comparable or lower SDNN (33 ms), RMSSD (20 ms) and total power (1.4 ms2) values. While LF/HF ratio was comparable, the VLF (0.003-0.04 Hz) and LF (0.04-0.15 Hz) relative power were decreased and increased respectively in the patient compared in controls. Despite this reduced HRV, the normal temporal relationship of spectral parameters with specific sleep stages was preserved. CONCLUSION: Altered HRV with normal temporal relationships with specific sleep stages was observed in a patient with primary hyperaldosteronism. This HRV profile did not changed 20 weeks after successful surgery i.e. complete remission of classical signs and symptoms of aldosterone hypersecretion.

Adenoma↗
PubMed2000

Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.

Aged↗