[Screening study for detection insomnia in general practice. Diagnostic error in every second patient?].
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Adolescent↗
Biomedical subjects
S Winter
Publications and source records attributed to S Winter.
A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13.
We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.
Amino Acids↗
[NISAS-2000: The "Nationwide Insomnia Screening and Awareness Study". Prevalence and interventions in primary care].
AIM: To estimate the point prevalence of insomnia, recognition and prescription behavior in primary care. METHODS: Nationwide sample of 539 primary care settings along with their characterization (stage 1). Standardized assessment of all attenders (N = 19.155 patients) on the NISAS target day using a sleep questionnaire (PSQI) and additional questions to cover psychosocial and additional clinical variables. All patients were evaluated by the primary care doctors using a standardized clinical appraisal questionnaire, including a CGI-rating. RESULTS: Prevalence insomnia according to DSM-IV was 26.5%. Recognition of presence of any clinically significant sleep disorder was 72%, recognition of insomnia was poor 54.3%. 85.6% of insomnia patients were rated as chronic. Close to 50% of all insomnia cases did not receive a specific insomnia therapy. Herbals, followed by hypnotics and sedatives and antidepressants were the three most frequent treatments applied, psychotherapy was only seldomly indicated. DISCUSSION: NISAS provides for the first time nationally representative estimates of interventions for insomnia in primary care. The relatively low treatment rates and the high proportion of chronic patients receiving longterm prescription of benzodiazepines seem to be critical. Priorities for future agenda to improve this situation are discussed.
Adolescent↗
[Prevalence and correlates of generalized anxiety disorders in primary care].
AIM: The investigators evaluated the (target-day) point prevalence and correlates of generalized anxiety and depression in German primary care practices. METHOD: The study used a representative national sample of more than 500 primary care practices. On a target day, all primary care patients were examined by questionnaires (GAS-Q and DSQ). RESULTS: Conservatively estimated, 5.3% of all primary care patients met criteria for generalized anxiety disorder (GAD). Similar prevalence estimations were found for Major Depression. Only 30% of all GAD patients met criteria for depression cross-sectionally. Patients with GAD (whether comorbid with depression or not) were more frequently female, reported an onset of GAD mostly between ages of 25 and 45 years, had increased rates of disability and impairment in major social roles and high utilization rates of all health care resources. They also revealed a predominantly chronic course of illness over a period of several years and an increased suicide rate. The presence of physical illness increased rates of handicap/impairment days in the past month. Associated negative outcomes were found to be similar to those observed in depressive disorders. Patients with GAD reported significantly more frequently sleep, anxiety and depressive problems as primary reasons for contact. CONCLUSION: The GAD-P study highlights the significance of GAD in primary care as a condition that occurs at about the same frequency as major depression. Further, the relatively high proportion of pure GAD suggests that the frequency of depression-comorbidity of GAD has previously been overestimated.
Adolescent↗
["Generalized anxiety and depression in primary care" (GAD-P). Study design and methods].
The aim of the study is to develop a comprehensive clinical-epidemiological description of the prevalence of generalized anxiety disorders and depression among primary care patients along with an assessment of physicians recognition rates and prescription behaviour. The paper describes methods and design of the study and provides background information on the sampling process and instruments used as well as characteristics of doctors and patients. The study is based on a nationally representative sample of 558 primary care physicians and over 20,000 patients, who attended physicians' offices on the target day. The first stage of study involved a comprehensive description of the physicians characteristics in terms of psychosocial qualification, and provider aspects as well as attitudes towards GAD and depression. In the second stage, all the patients completed a diagnostic screening questionnaire for GAD and depression. In the third stage all patients were characterized by their physicians in terms of their diagnostic status and their past and current interventions.
Adolescent↗
Transvenous left ventricular lead implantation with the EASYTRAK lead system: the European experience.
Several independent studies suggest that resynchronization therapy--achieved by left- or biventricular pacing--improves hemodynamics in heart failure patients with interventricular conduction disturbances. Delivery of this new therapy in an effective and minimally invasive manner presents technical challenges, as transvenous access to the left ventricle is required. Since 1999, a novel over-the-wire approach combining standard pacing lead and angioplasty technology has been evaluated in several European countries. This new left ventricular lead, the EASYTRAK system (Guidant, St. Paul, MN), has been clinically evaluated in 2 phases. The first phase was a clinical investigation to obtain the CE-mark (i.e. European Commission approval). The second phase, which started immediately after the CE-mark was obtained, consisted of a postmarket surveillance called the European registry. This article reports on the results of the pre-CE-mark clinical investigation and the preliminary results of the European registry (first 150 patients). During the pre-CE-mark clinical investigation of the EASYTRAK system, lead performance was assessed in 36 successfully implanted patients. The patients had indications for VVI-pacing, symptoms of heart failure and significant left ventricular dysfunction. The left ventricular lead was implanted in conjunction with a conventional right ventricular lead and a new heart failure device (CONTAK TR, Guidant, Brussels, Belgium). Lead measurements (threshold, sensing, and impedance) were performed at implant and subsequent follow-ups. The stimulation thresholds at 0.5 msec impulse width were acceptable, although (as expected) slightly higher than with standard right ventricular pacing leads: 1.39 +/- 1.15 V at implant, 1.72 +/- 1.26 V at predischarge, 1.54 +/- 0.88 V at 2 weeks, 1.38 +/- 0.80 V at 6 weeks, and 1.24 +/- 0.73 V at 12 weeks. R-wave and impedance measurements were stable over time. A revision of the EASYTRAK lead was required in 3 patients. No perforations were observed. During the second phase of the European registry, 150 implants were attempted in 63 centers from November 1999 to January 2000. The EASYTRAK was implanted with a pulse generator offering, in addition to resynchronization therapy, either tachycardia monitoring (CONTAK TR) or implantable cardioverter defibrillator therapy (CONTAK CD), depending on the patient indication. Over half of the centers involved had not previously implanted the EASYTRAK system. Total implant success rate was 83% (135/150), skin-to-skin duration of the implant was 169 +/- 81 minutes (range, 53-480 minutes), with a clear learning curve. Once the coronary sinus was found, the implant success rate was 92%. One lead dislodgment and 2 cases of phrenic nerve stimulation were reported. We conclude that the new EASYTRAK lead design for transvenous left ventricular lead implantation seems to be a suitable and safe tool for delivering resynchronization therapy to heart failure patients.
Aged↗
On the significance of telomerase activity in human malignant glioma cells.
Telomerase is critical for tumor cell immortalization and is a novel target for cancer chemotherapy. Here, we examined whether telomerase is expressed in glioma cell lines, whether telomerase activity is regulated by bcl-2 or p53, and whether telomerase activity predicts response to chemotherapy. Further, we characterized the effects of a candidate telomerase inhibitor, penclomedine, in glioma cells. All 12 human malignant glioma cell lines examined were telomerase positive. Telomerase activity was not modulated during cell cycle progression, did not correlate with p53 status or bcl-2 family protein expression, and did not predict drug sensitivity, except for an association with resistance to carmustine. Ectopic bcl-2 expression did not enhance telomerase activity. Wild-type p53 reduced telomerase activity in cell lines retaining p53 activity but not in p53-mutant cell lines. Penclomedine killed glioma cells via an apoptotic, but death receptor-, bcl-2- and caspase-independent pathway, but did not inhibit telomerase and did not act synergistically with cytotoxic drugs. We conclude that telomerase activity does not account for the differential chemosensitivity of human glioma cells and that penclomedine kills glioma cells via a telomerase-independent pathway.
Animals↗
Glutathione S-transferase and drug sensitivity in malignant glioma.
Malignant gliomas are largely resistant to current approaches of adjuvant chemotherapy. Gluthatione S-transferases (GST) have been attributed a role in the resistance of cancer cells, e.g., to nitrosoureas. Here, we assessed the expression levels of GST-pi and GST-mu RNA and protein as well as total GST activity in a panel of 12 human glioma cell lines and correlated these data with p53 status, BCL-2 family protein expression and drug sensitivity in these cells. Neither GST protein levels nor GST activity correlated with genetic or functional p53 status or with the expression of various BCL-2 family proteins. No evidence for GST-mediated protection from chemotherapeutic drugs became apparent. In contrast, high levels of GST-pi protein, probably the major source of GST activity in glioma cells, and of total GST activity correlated with enhanced sensitivity to vincristine-induced clonogenic cell death. Expression of GST-pi in human glioblastomas in vivo was confirmed by immunohistochemistry. Neither total, nor cytoplasmic or nuclear, GST-pi immunoreactivity correlated with the response to adjuvant radiotherapy or radiochemotherapy. A comparative analysis of primary and recurrent tumors showed that GST expression was not enhanced by radiochemotherapy in vivo. We conclude that GST does not account for the differential chemosensitivity of glioma cell lines in vitro and does not accumulate in glioma subpopulations that form recurrent tumors after radiochemotherapy in vivo.
Adult↗
Nuclear coactivator protein p100 is present in endoplasmic reticulum and lipid droplets of milk secreting cells.
We have identified the p100 protein, previously known as a novel cellular coactivator, as a constituent of endoplasmic reticulum and cytosolic lipid droplets from milk secreting cells. Cytosolic lipid droplets of terminally differentiated mammary epithelial cells are secreted as milk lipid globules. However, milk lipid globules did not have detectable amounts of p100 protein. The p100 protein was found also in cytosol from lactating mammary gland, in storage lipid droplets from mouse adipocytes, and in endoplasmic reticulum from liver. Immunofluorescence microscopy of mammary epithelial cells confirmed the presence of p100 in non-nuclear regions of these cells. Partial sequence analysis of tryptic peptides from p100 from cow mammary gland showed extensive homology with the reported sequence of p100 determined from a human cDNA. Antibodies against a peptide synthesized to duplicate a sequence in human p100 recognized a protein of the size of p100 in cow, mouse and rat cell fractions.
Adipocytes↗
Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.
Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.
Benzamides↗
Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo.
Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Aetiology of childhood vision impairment, metropolitan Atlanta, 1991-93.
Data from the population-based Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) were used to describe the underlying causes of vision impairment (VI; corrected visual acuity in the better eye of 20/70 or worse) in young children (n = 228) in metropolitan Atlanta in 1991-93. Children with VI were identified through record review at multiple educational and medical sources. Children were categorised as having isolated VI or multiple disabilities (i.e. VI plus one or more of four additional developmental disabilities) and as having low vision (visual acuity 20/70-20/400) or blindness (visual acuity worse than 20/400). Medical conditions abstracted from MADDSP sources were reviewed to determine the probable aetiology of a child's VI. Aetiologies were assigned to one of three developmental time periods: prenatal, perinatal, or postnatal. Prenatal aetiologies were identified in 43% of the children; 38% of the prenatal aetiologies were genetic. Perinatal aetiologies were found in 27% of the children. Postnatal aetiologies were rare. Prenatal aetiologies were more common in children with isolated VI; perinatal and postnatal aetiologies were more common in children with multiple disabilities. Children with prenatal aetiologies tended to have less severe vision loss than did children with perinatal or postnatal aetiologies. The distribution varied by birthweight, but did not differ significantly by sex or race.
Abnormalities, Multiple↗
Mobilization with etoposide and granulocyte colony-stimulating factor can replace bone marrow harvesting in patients with malignant lymphoma who previously failed to mobilize sufficient stem cells with cyclophosphamide and G-CSF.
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Adult↗
[Pacemaker in therapy of heart failure--biventricular stimulation].
The management of congestive heart failure remains a therapeutic challenge despite recent advances in drug therapy, including ACE inhibitors, beta blockade and spironolacton treatment. Patients affected with the disease still have a restricted quality of life and a poor prognosis in the long run. Epidemiologically, the incidence and prevalence are increasing due to improved survival from both coronary artery disease and arterial hypertension. A subgroup of patients presents with marked prolongation of the QRS-complex in the surface ECG, mostly with a left bundle branch block pattern. This acts as a marker for interventricular conduction abnormality and specifically indicates a reduced left ventricular systolic function. Biventricular pacing tries to resynchronize the abnormal activation pattern by actively influencing diastolic filling and systolic function. The mechanisms involved are supposed to be restoration of left ventricular septal mechanical synchrony, reduction in presystolic mitral regurgitation and optimization of diastolic function with the maximization of diastolic filling time. In this article the current role and future directions of biventricular pacing are discussed.
Animals↗
Selective potentiation of drug cytotoxicity by NSAID in human glioma cells: the role of COX-1 and MRP.
Here, we report that nonsteroidal anti-inflammatory drugs (NSAID) enhance the cytotoxic effects of doxorubicin and vincristine in T98G human malignant glioma cells. The cytotoxicity of BCNU, cisplatin, VM26, camptothecin, and cytarabine is unaffected by NSAID. No free radical formation is induced by doxorubicin or vincristine in the absence or presence of NSAID. Doxorubicin and vincristine cytotoxicity in the absence or presence of NSAID are unaffected by free radical scavengers. Functional inhibitors of phospholipase A2 (PLA2), such as dexamethasone and quinacrine, do not mimick the effects of NSAID. T98G cells, but not LN-18, LN-229, LN-308, or A172 glioma cells, express cyclooxygenase (COX-1) and NSAID do not modulate drug cytotoxicity in the other cell lines, except T98G. Thus, augmentation of doxorubicin and vincristine cytotoxicity by NSAID correlates with COX-1 expression. However, ectopic expression of COX-1 in LN-229 cells does not induce the phenotype of T98G cells, indicating that COX-1 inhibition does not mediate the effects of NSAID on drug cytotoxicity. In contrast, a multidrug resistance (MDR) phenotype due to expression of the multidrug resistance-associated protein (MRP) is most prominent in T98G cells and is amenable to modulation by indomethacin, suggesting that inhibition of MRP is at least in partly responsible for the potentiation of doxorubicin and vincristine cytotoxicity by NSAID.
ATP-Binding Cassette Transporters↗
Glutathione depletion and neuronal cell death: the role of reactive oxygen intermediates and mitochondrial function.
Glutathione (GSH) levels are supposed to determine the vulnerability of many cells towards a wide array of insults. We investigated the effects of chronic inhibition of GSH synthesis and acute depletion of GSH on cerebellar granule neurons in vitro and determined cytoplasmic and mitochondrial GSH with relation to mitochondrial function and generation of reactive oxygen intermediates (ROI). l-buthionine sulfoximine (BSO), which irreversibly blocks gamma-glutamyl-cysteine synthase, led to a time- and concentration-dependent loss of cytoplasmic GSH, while mitochondrial GSH was relatively preserved. No increased generation of ROI was detected over 48 h and the mitochondrial membrane potential was largely maintained. Neuronal degeneration occurred when mitochondrial GSH levels had fallen below 50% of control after 24-36 h. In contrast, direct conjugation of mitochondrial and cytoplasmic GSH with etacrynic acid (EA), resulted in immediate loss of mitochondrial GSH, a large increase of ROI within 2 h, subsequent collapse of the mitochondrial membrane potential and complete cell death within 4-8 h. Electron microscopy studies revealed an as yet unknown change of the chromatin structure to a homogeneous granular pattern after BSO, while EA resulted in typical necrotic changes. No typical features of apoptosis, i.e., no chromatin condensation or DNA fragmentation were detected after GSH depletion after BSO or EA treatment.
Animals↗
Flt3 ligand can promote survival and macrophage development without proliferation in myeloid progenitor cells.
Flt3 ligand elicits a variety of effects on early hemopoietic progenitors by occupying its cognate receptor, Flt3, a member of the type III tyrosine kinase receptor family. The cytokines macrophage colony-stimulating factor (M-CSF) and stem cell factor (SCF) bind to related members of this tyrosine kinase receptors family, c-fms and c-kit, respectively. The relative effects of the cytokines M-CSF, SCF, and Flt3L on the proliferation and development of the late myeloid progenitors granulocyte-macrophage colony-forming cells (GM-CFC) were investigated. Distinct biologic responses were stimulated by ligand binding to these different tyrosine kinase receptors in enriched GM-CFC. M-CSF stimulated GM-CFC to proliferate and develop into macrophages. SCF, on the other hand, stimulated GM-CFC to develop into neutrophils. Flt3 ligand had a relatively small proliferative effect on enriched GM-CFC compared to SCF and M-CSF and had no ability to either stimulate colony formation or synergize with these two cytokines in promoting DNA synthesis, colony formation, or expansion in liquid culture. Flt3 ligand, however, was capable of maintaining the clonogenic potential of GM-CFC and acted as an anti-apoptotic agent as assessed using the Annexin-V apoptosis assay. GM-CFC cultured in Flt3 ligand eventually formed macrophages and neutrophils in liquid culture. Labeling with the membrane-associated cell tracker dye PKH26 indicated that the majority of the enriched GM-CFC responded to Flt3 ligand by undergoing limited proliferation and macrophage development, whereas other cells survived but did not proliferate and differentiate into macrophages. Thus, Flt3 ligand promoted survival and stimulated development without proliferation in primary-enriched myeloid progenitor cells.
Animals↗
Detection of the DeltaF508 mutation in the CFTR gene by means of time-resolved fluorescence methods.
A rapid recognition in the base sequence of nucleic acids is an important prerequisite toward the diagnosis of genetic diseases and their carrier states. We have developed a hybridisation method in which a fluorescently labeled oligonucleotide is used to detect point mutations in a target by a simple fluorescence lifetime analysis of the emission of the fluorescent label. We applied this method to detect the deltaF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a model system and with biologically derived PCR product and discuss the potential generality of this method.
Base Sequence↗