[The P.M.S.I. and maxillofacial surgery].
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Dental Service, Hospital↗
Biomedical subjects
M Frank
Publications and source records attributed to M Frank.
rMAL is a glycosphingolipid-associated protein of myelin and apical membranes of epithelial cells in kidney and stomach.
rMAL, the rat myelin and lymphocyte protein, is a small hydrophobic protein of 17 kDa with four putative transmembrane domains and is expressed in oligodendrocytes and Schwann cells, the myelinating cells of the nervous system. In addition, transcript expression has been found in kidney, spleen, and intestine. Confocal microscopy and immunoelectron microscopy with an affinity-purified antibody localized rMAL to compact myelin in a pattern similar to the structural myelin proteins: myelin basic protein and proteolipid protein. In kidney and stomach epithelia, rMAL is located almost exclusively on the apical (luminal) membranes of the cells lining distal tubuli in kidney and the glandular part of the stomach. Biochemical analysis of plasma membranes isolated from spinal cord and kidney demonstrated that rMAL is a proteolipid that is present in detergent insoluble complexes typical for proteins associated with glycosphingolipids. Lipid and protein analysis showed a co-enrichment of glycosphingolipids and rMAL protein within these complexes, indicating a close association of rMAL to glycosphingolipids in myelin and in kidney in vivo. We conclude that specific rMAL-glycosphingolipid interactions may lead to the formation and maintenance of stable protein-lipid microdomains in myelin and apical epithelial membranes. They may contribute to specific properties of these highly specialized plasma membranes.
Animals↗
Safety and cost effectiveness of a 10 x 10(9)/L trigger for prophylactic platelet transfusions compared with the traditional 20 x 10(9)/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia.
In 105 consecutive patients with de novo acute myeloid leukemia (French-American-British M3 excluded), we compared prospectively the risk of bleeding complications, the number of platelet and red blood cell transfusions administered, and the costs of transfusions using two different prophylactic platelet transfusion protocols. Two hundred sixteen cycles of induction or consolidation chemotherapy and 3,843 days of thrombocytopenia less than 25 x 10(9)/L were evaluated. At the start of the study, each of the 17 participating centers decided whether they would use a 10 x 10(9)/L prophylactic platelet transfusion trigger (group A/8 centers) or a 20 x 10(9)/L trigger (group B/9 centers). Bleeding complications (World Health Organization grade 2-4) during treatment cycles were comparable in the two groups: 20 of 110 (18%) in group A and 18 of 106 (17%) in group B (P = .8). Serious bleeding events (grade 3-4) were generally not related to the patient's platelet count but were the consequence of local lesions and plasma coagulation factor deficiencies due to sepsis. Eighty-six percent of the serious bleeding episodes occurred during induction chemotherapy. No patient died of a bleeding complication. There were no significant differences in the number of red blood cell transfusions administered between the two groups, but there were significant differences in the number of platelet transfusions administered per treatment cycle: pooled random donor platelet concentrates averaged 15.4 versus 25.4 (P < .01) and apheresis platelets averaged 3.0 versus 4.8 (P < .05) for group A versus group B, respectively. This resulted in the cost of platelet therapy being one third lower in group A compared with group B without any associated increase in bleeding risk.
Acute Disease↗
Cryogenic high-resolution X-ray spectrometers for SR-XRF and microanalysis.
Experimental results are presented obtained with a cryogenically cooled high-resolution X-ray spectrometer based on a 141 x 141 micro m Nb-Al-Al(2)O(3)-Al-Nb superconducting tunnel junction (STJ) detector in an SR-XRF demonstration experiment. STJ detectors can operate at count rates approaching those of semiconductor detectors while still providing a significantly better energy resolution for soft X-rays. By measuring fluorescence X-rays from samples containing transition metals and low-Z elements, an FWHM energy resolution of 6-15 eV for X-rays in the energy range 180-1100 eV has been obtained. The results show that, in the near future, STJ detectors may prove very useful in XRF and microanalysis applications.
Journal Article↗
Agonist regulation of human beta2-adrenergic receptor mRNA stability occurs via a specific AU-rich element.
Prolonged agonist stimulation of beta2-adrenergic receptors results in receptor down-regulation, which is closely associated with a reduction of the corresponding mRNA, an effect mediated in part by changes in mRNA stability. Transfection experiments with human beta2-adrenergic receptor cDNAs bearing or lacking the untranslated regions suggested that the essential agonist sensitivity of the mRNA resides within the 3'-untranslated region. The importance of this region was further confirmed in gel shift experiments; cytosolic preparations from agonist-stimulated DDT1-MF2 smooth muscle cells caused a shift of beta2-adrenergic receptor mRNAs containing the 3'-untranslated region. Progressive 3'-terminal truncations of the receptor cDNA led to the identification of an AU-rich element at positions 329-337 of the 3'-untranslated region as the responsible cis-acting element. Substitution of this motif by cytosine residues almost completely abolished mRNA down-regulation and inhibited the formation of the RNA-protein complex. Even though the beta2-adrenergic receptor AU-rich element showed two U --> A transitions compared with the recently proposed AU-rich element consensus sequence, it revealed an almost identical destabilizing potency. Fusion of the beta2-adrenergic receptor 3'-untranslated region to the beta-globin coding sequence dramatically reduced the half-life of the chimeric transcript in an agonist- and cAMP-dependent manner. This suggests that the agonist-induced beta2-adrenergic receptor mRNA destabilization is regulated by cAMP-dependent RNA-binding protein(s) via a specific AU-rich element.
Adrenergic beta-2 Receptor Agonists↗
Changes of creatine kinase gene expression in rat heart post-myocardial infarction.
Creatine kinase (CK) plays a crucial role in cardiac energy transduction. During chronic cardiac stress conditions leading to hypertrophy and/or heart failure, the profile of CK isoenzyme activities changes towards a fetal pattern with increases of BB- and MB-CK and decreases of MM-CK and mito-CK. Changes of myocardial CK gene expression are only indirectly reflected by measurements of CK activities. The purpose of this work was, therefore, to determine myocardial expression of B-, M- and sarcomeric mito-CK genes in an animal model of heart failure where hemodynamic alterations and CK system changes are well defined, that is, in the rat heart post-myocardial infarction. Intact residual left ventricular myocardium was harvested 2 months following infarction (MI; n = 7) or sham operation (sham; n = 6) after in vivo left-ventricular end-diastolic pressure (LVEDP) was recorded. Total CK activity was measured spectrophotometrically, CK isoenzyme distribution with agarose gel electrophoresis. Steady state mRNA levels coding for B-, M- and mito-CK genes were measured with quantitative PCR and were normalized for GAPDH expression. Total CK activity tended to be reduced in MI (5.51 +/- 0.62 IU/mg protein) compared to sham (6.77 +/- 0.24; P = 0.55). CK isoenzyme distribution showed an increase of fetal BB- + MB-CK (MI 22.0 +/- 3.1%, sham 15.1 +/- 1.0%; P < 0.05), no change of MM-CK and a decrease of mito-CK (27.0 +/- 1.5% sham, 20.8 +/- 2.0% MI: P < 0.05). Relative B-CK mRNA levels increased (sham 0.46 +/- 0.06, MI 1.03 +/- 0.09; P < 0.05) and M-CK mRNA levels decreased (sham 1.06 +/- 0.08. MI 0.66 +/- 0.09; P < 0.05) significantly post-MI. The increase of B-CK mRNA (r = 0.72; P = 0.009) and the decrease of M-CK mRNA (r = 0.76; P = 0.003) correlated significantly with in vivo LVEDP. Mito-CK mRNA levels remained unchanged after MI (sham 0.94 +/- 0.16, MI 0.98 +/- 0.09). Intact residual left-ventricular myocardium post-MI is characterized by increased B-CK-mRNA and reduced M-CK-mRNA expression.
Animals↗
Diameter of the common bile duct in the elderly patient: measurement by ultrasound.
We wanted to assess the width of the common bile duct (CBD) in an asymptomatic elderly (> 75 years) population, since no previous report has particularly considered the important age-related increase in CBD diameter for this patient group. CBD width of 92 asymptomatic people over 75 years of age (mean 84.7 years, range 75-96 years) without clinical or laboratory evidence for biliary, hepatocellular or pancreatic disease was measured by real-time high-resolution ultrasound of the upper abdomen. All examinations were performed by one experienced radiologist. Mean values were calculated for three groups: patients with and without cholecystolithiasis and after cholecystectomy. Statistical analysis was carried out by analysis of variance. Considering the measurements of all patients, the mean width (+/- SD) of the CBD was calculated as 6.5 +/- 2.5 mm. The difference between patients without cholecystolithiasis (6.2 +/- 2.3 mm) and patients after cholecystectomy (8.7 +/- 2.9 mm) was statistically significant (P < 0.0001). Cholecystolithiasis (6.0 +/- 1.6 mm) proves not to be an additional factor for CBD widening in comparison with patients without stone disease. The CBD of these very elderly subjects shows a considerable increase in comparison with the recommended borderline values in the ultrasound literature. An upper limit of 10 mm seems reasonable for patients with and without cholecystolithiasis. A significant increase in CBD width after cholecystectomy was found and measurements up to 14 mm may occur. Measurements have to be correlated with clinical and laboratory findings.
Aged↗
Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria.
Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial defect of the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD). PBGD is encoded by two distinct mRNA species expressed in a tissue-specific manner from a single gene. One transcript is expressed in erythroid tissues, while the housekeeping transcript is expressed in all tissues. In classical AIP (95% of cases) the housekeeping and the erythroid-specific enzymes both have half-normal activity in erythroid and non-erythroid tissues, whereas in the variant non-erythroid form of the disease the enzymatic defect is present only in non-erythroid cells. A large allelic heterogeneity of mutations (n>135) has been demonstrated in classical AIP, but to date only three different mutations have been characterized in the non-erythroid variant form of AIP. We describe the molecular abnormalities responsible for the non-erythroid variant form of AIP in two French and two German unrelated AIP patients with normal PBGD activity in the erythrocytes. Three different splicing defects located in the intron 1 donor splice site were identified: a 33+1 g-->a mutation, previously described in a Dutch family, was found in two patients; two novel mutations (33+2 t-->a, 33+5 c-->g) affected the two remaining patients. All the mutations resulted in the activation of a cryptic splice site 67 bp downstream in intron 1, leading to a frameshift and a premature stop codon in exon 4. Mutations in the exon 1 donor splice site are involved in eight of the nine non-erythroid variant AIP families reported in the literature. These data show that most mutations causing the non-erythroid variant AIP are exon 1 splice defects, in contrast with classical AIP, where missense mutations are chiefly involved. Moreover, the allelic heterogeneity of PBGD gene defects causing the non-erythroid variant AIP is demonstrated, with five different mutations identified. These mutations could be easily detected by a single denaturing gradient gel electrophoresis which also allows the presymptomatic detection of gene carriers in the affected families.
Adult↗
Initial urinary albumin excretion determines the progression of microalbuminuria in patients with type-2 diabetes and normotensive blood pressure values despite improved metabolic control.
Persistent increased urinary albumin excretion rate (UAER) is associated with increased cardiovascular mortality in type-2 diabetes, however, there are no conclusive data about the progression of advanced UAER in these patients. The present study has investigated the effect of metabolic intervention on the progression in UAER in relation to initial UAER levels. A total of 20 patients with type-2 diabetes and secondary failure to sulfonylurea were observed during 1 year (age, 60 +/- 8 years; HbA1c, 10.8 +/- 1.4%; and duration of diabetes, 17 +/- 10 years) and divided into two groups: group 1 (n = 10; UAER: 51 +/- 35 mg/24 h); and group 2 (n = 10; UAER: 191 +/- 175 mg/24 h). Despite a significant improvement of metabolic control by insulin treatment in both groups (HbA1c: group 1: 11 +/- 1.5 vs. 7.9 +/- 1.2%; group 2: 10.6 +/- 0.9 vs. 9.1 +/- 1.3%, P < 0.001), a progression of UAER was observed in group 2 (191 +/- 175 vs. 331 +/- 237 mg/24 h, P < 0.02), but not in group 1 (51 +/- 35 vs. 41 +/- 24 mg/24 h). Still serum creatinine levels remained normal in all patients during the observation period. The 24 h blood pressure (RR) values in the two groups remained normal under antihypertensive therapy throughout the study (group 1: RR syst: 130 vs. 136 mmHg; RR diast: 80 vs. 81 mmHg, mean arterial pressure (MAD): 89 vs. 93 mmHg; group 2: RR syst: 139 vs. 134 mmHg; RR diast: 78 vs. 75 mmHg, MAD: 97 vs. 90 mmHg). The data shows that in type-2 diabetic patients with normotensive blood pressure values the initial urinary albumin excretion levels determine the progression of UAER. When metabolic control is improved incipient UAER remains constant, but advanced UAER shows progression.
Aged↗
Superconducting Tunnel Junction Array Development for High-Resolution Energy-Dispersive X-ray Spectroscopy.
: Cryogenic energy-dispersive X-ray detectors are being developed because of their superior energy resolution (10 eV FWHM for keV X-rays) compared to that achieved in semiconductor energy-dispersive spectrometry (EDS) systems. So far, their range of application is limited because of their comparably small size and low count rate. We present data on the development of superconducting tunnel junction (STJ) detector arrays to address both of these issues. A single STJ detector has a resolution of around 10 eV below 1 keV and can be operated at count rates of the order 10,000 counts/sec. We show that the simultaneous operation of several STJ detectors does not dimish their energy resolution significantly, and it increases the detector area and the maximum count rate by a factor given by the total number of independent channels.
Journal Article↗
Immunohistochemical analysis and clinical course of high-malignant composite endocrine-acinar cell carcinoma: a case report.
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Carcinoma, Acinar Cell↗
Hepatic complications of erythropoietic protoporphyria.
A quarter of patients with erythropoietic protoporphyria develop mild to severe cholestatic liver disease. The determination of early indicators of hepatobiliary involvement are of pivotal importance to select patients for choleretic therapy. Porphyrin parameters were studied during ursodeoxycholic acid treatment in eight patients with protoporphyrin-associated liver disease and eight patients with liver failure before and after liver transplantation. The patients with intrahepatic cholestasis exhibited excessive protoporphyrinemia (27 mumol/l) compared with controls (normal < 0.64 mumol/l). Fecal protoporphyrin excretion decreased in patients with deterioration of liver function, whereas urinary coproporphyrin increased up to 2290 nmol/24 h (normal < 119 nmol/24 h). Coproporphyrin isomer I proportion increased to 71 +/- 10% (mean +/- SD, n = 8) in patients with terminal liver failure (normal < 31%). During therapy with ursodeoxycholic acid biochemical improvement occurred but without clinical remission in most cases. Eight patients underwent liver transplantation between 1987 and 1997. One patient died of liver failure. Two transplant recipients are in a good condition since 8 and 9 years, respectively. All explanted livers revealed micronodular cirrhosis and high protoporphyrin levels of about 25,000-fold (mean, n = 3). Immediately after liver transplantation protoporphyrin in erythrocytes decreased to 46-96% of pre-operative values. Coproporphyrin remained moderately elevated due to post-operative cholestasis. A post-operative rise in fecal protoporphyrin elimination reflected sufficient biliary clearence of protoporphyrin by the transplant. In conclusion, moderate coproporphyrinuria with isomer I is the earliest sign of liver complications in erythropoietic protoporphyria. Progression of protoporphyrin induced toxic liver injury is indicated by excessive protoporphyrinemia and coproporphyrinuria with an isomer I proportion > 71 +/- 10%, and reduction of fecal protoporphyrin excretion. Results suggest that therapy of intrahepatic cholestasis with ursodeoxycholic acid is only effective in the initial stages of liver disease in erythropoietic protoporphyria. In patients with severe cholestatic hepatic failure, liver transplantation is the treatment of choice.
Adolescent↗
Defining quality of care for children and adolescents with type 1 diabetes.
Recent years have seen an increase in awareness of the need to improve the quality of diabetes care for children and adolescents, as detailed in the Declaration of Kos, for example. This paper addresses some quality-of-care principles and evaluates specific examples of current management. The meaning of the terms quality of care, evidence-based medicine and cost-containment are examined, and the features central to the development and evaluation of quality health care (structure, process and outcome) are explored. The practical aspects of diabetes care are reviewed in terms of the causes and prevention of early mortality, ambulatory vs inpatient care, the value of measuring HbA1c, other metabolic control criteria (including the effect of patient selection, cultural, socioeconomic and biological differences) and clinical practice guidelines. It is concluded that a multidisciplinary team provides the optimum context for diabetes management and that care must be family centred and multidimensional (i.e. not focusing on HbA 1c levels alone). The task of improving diabetes care is massive and operates at all levels (individual, family, healthcare providers, national and international bodies), but offers significant improvements in quality and cost-effectiveness.
Adolescent↗
Lectin ligands: new insights into their conformations and their dynamic behavior and the discovery of conformer selection by lectins.
The mysteries of the functions of complex glycoconjugates have enthralled scientists over decades. Theoretical considerations have ascribed an enormous capacity to store information to oligosaccharides. In the interplay with lectins sugar-code words of complex carbohydrate structures can be deciphered. To capitalize on knowledge about this type of molecular recognition for rational marker/drug design, the intimate details of the recognition process must be delineated. To this aim the required approach is garnered from several fields, profiting from advances primarily in X-ray crystallography, nuclear magnetic resonance spectroscopy and computational calculations encompassing molecular mechanics, molecular dynamics and homology modeling. Collectively considered, the results force us to jettison the preconception of a rigid ligand structure. On the contrary, a carbohydrate ligand may move rather freely between two or even more low-energy positions, affording the basis for conformer selection by a lectin. By an exemplary illustration of the interdisciplinary approach including up-to-date refinements in carbohydrate modeling it is underscored why this combination is considered to show promise of fostering innovative strategies in rational marker/drug design.
Crystallography↗
Familial hairy cell leukemia.
Familial hairy cell leukemia (HCL) occurs rarely, and HCL occurring in association with other hematologic malignancies is even rarer. We describe two cases of familial HCL syndromes: a mother and son with HCL, and a HCL patient whose aunt developed Hodgkin's Disease (HD). This is the first reported familial association of HCL with HD.
Aged↗
5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up.
5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients' enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. After this therapy both urinary 5-aminolevulinic acid (ALA) and total porphyrins were diminished to 65% in patient B. In patient H, ALA was decreased to 80%, and total porphyrins were reduced to 15% after treatment with heme arginate and glucose. The patients remained free of symptoms after this therapy. Family studies of patient B showed cross-reactive immunological material (CRIM), in which the maternal mutation is CRIM(+), whereas the paternal mutation is CRIM(-). Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced porphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.
Adolescent↗
Advances in Charcot-Marie-Tooth disease research: cellular function of CMT-related proteins, transgenic animal models, and pathomechanisms. The European CMT Consortium.
The First Workshop of the European Consortium on Charcot-Marie-Tooth (CMT) disease brought together neuroscientists, molecular and cell biologists, neuropathologists, neurologists, and geneticists with a common interest in the understanding of the fundamental mechanisms that underlie the pathogenesis of CMT. The interdisciplinary group of 25 expert scientists discussed recent advances in (i) molecular genetics and histopathology of CMT, (ii) development of suitable animal models, (iii) understanding of the cellular function of CMT-related proteins, and (iv) studies using nerve biopsies from CMT patients. In this minireview, we summarize the key findings presented and discuss their impact on CMT research.
Animals↗
Quality in HIV/AIDS care.
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Clinical Competence↗