The interplay of autophagy and ß-Catenin signaling regulates differentiation in acute myeloid leukemia.

The major feature of leukemic cells is an arrest of differentiation accompanied by highly active proliferation. In many subtypes of acute myeloid leukemia, these features are mediated by the aberrant Wnt/ß-Catenin pathway. In our study, we established the lectin LecB as inducer of the differentiation of the acute myeloid leukemia cell line THP-1 and used it for the investigation of the involved processes. During differentiation, functional autophagy and low ß-Catenin levels were essential. Corresponding to this, a high ß-Catenin level stabilized proliferation and inhibited autophagy, resulting in low differentiation ability. Initiated by LecB, ß-Catenin was degraded, autophagy became active and differentiation took place within hours. Remarkably, the reduction of ß-Catenin sensitized THP-1 cells to the autophagy-stimulating mTOR inhibitors. As downmodulation of E-Cadherin was sufficient to significantly reduce LecB-mediated differentiation, we propose E-Cadherin as a crucial interaction partner in this signaling pathway. Upon LecB treatment, E-Cadherin colocalized with ß-Catenin and thereby prevented the induction of ß-Catenin target protein expression and proliferation. That way, our study provides for the first time a link between E-Cadherin, the aberrant Wnt/ß-Catenin signaling, autophagy and differentiation in acute myeloid leukemia. Importantly, LecB was a valuable tool to elucidate the underlying molecular mechanisms of acute myeloid leukemia pathogenesis and may help to identify novel therapy approaches.

All-cause mortality and serum insulin-like growth factor I in primary care patients.

OBJECTIVE: Previous population-based studies provided conflicting results regarding the association of total serum insulin-like growth factor I (IGF-I) and mortality. The aim of the present study was to assess the relation of IGF-I levels with all-cause mortality in a prospective study. DESIGN: DETECT (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment) is a large, multistage, and nationally representative study of primary care patients in Germany. The study population included 2463 men and 3603 women. Death rates were recorded by the respective primary care physician. Serum total IGF-I levels were determined by chemiluminescence immunoassays and categorized into three groups (low, moderate, and high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS: Adjusted analyses revealed that men with low [hazard ratio (HR) 1.70 (95% confidence interval [CI] 1.05-2.73), p=0.03] and high [HR 1.76 (95% CI 1.09-2.85), p=0.02] IGF-I levels had higher risk of all-cause mortality compared to men with moderate IGF-I levels. The specificity of low IGF-I and high IGF-I levels increased with lower and higher cut-offs, respectively. No such association became apparent in women. CONCLUSIONS: The present study revealed a U-shaped relation between IGF-I and all-cause mortality in male primary care patients.

[Evaluation of a new disposable insulin pen and injection habits of diabetes patients in everyday clinical practice]. / Bewertungeines neuen Insulin-Fertigpens und Injektionsgewohnheiten von Diabetikern in der täglichen Praxis. Ergebnisse zweierAnwendungsbeobachtungen in Deutschland.

UNLABELLED: Evaluation of a new disposable insulin pen and injection habits of diabetes patients in everyday clinical practice BACKGROUND: Injection devices (pens) for insulin application play a major role in treatment acceptance and adherence in insulin-treated diabetes patients. The mechanical disposable pen SoloStar containing the insulin analogs glargine or glulisine (each 100 IE/ml) provides modern design with user-friendly handling features. METHODS: In two independent, non-interventional, observational studies conducted nation-wide between April and December 2007 in outpatient practices, patients with diabetes newly instructed on how to use the pen were interviewed by their trainers (physicians, diabetes consultants) after approx. 6-8 weeks of pen use to give feedback on technical deficiencies, handling problems with the pen, injection habits, as well as on pen properties. Trainers were also asked to assess pen properties and particularly to document the time required for pen training. The evaluation applied a grading system similar to that used in German schools (1: very good; 6: very insufficient/failed). Furthermore, trainers were asked to retrospectively record any adverse events occurring during the observational period. RESULTS: A total of 2,412 trainers from 1,626 centres and 8,428 patients (80% type 2) participated in the studies. In each study 0.5% of patients reported 41 and 19 technical problems with the pen, respectively. Similarly 3% of patients from each study reported handling problems. Recommended changes of needles and safety checks of the pen before each injection were performed by 40% and max. 25% of the patients, respectively. The features of the new disposable pen were all rated "very good" to "good" by the majority of patients and trainers. The best rated features were usability, dose adjustment and the low effort for the dose release. Pen training of patients were rated as "very simple" or "simple" by the training staff and average instruction time was reported not to exceed more than 10 minutes for the majority of patients. In 19 patients (0.2%) a total of 34 adverse events were documented. CONCLUSION: The results of these two observational studies showed no relevant technical deficiencies and handling problems associated with the new disposable pen in everyday clinical practice. Ease of use and little time required for pen training may contribute to a high acceptance and satisfaction by the patients and training staff. Injection habits, however, indicated that patients did not well comply with recommendations given for needle changes and safety tests.

Diabetes Mellitus in German Primary Care: quality of glycaemic control and subpopulations not well controlled - results of the DETECT study.

INTRODUCTION: The quality of glycaemic control of patients with T1D and T2D can be assessed with HbA (1c) levels. We aimed to assess the quality of glycaemic control and the prevalence of inadequately controlled diabetes in German primary care, and to determine simple patient and treatment related factors associated with poor control. MATERIAL AND METHODS: Using a nationwide probability sample of 3 188 general practices (response rate 50.6%), a total of 55,518 patients were assessed in DETECT, a cross-sectional and prospective multistage epidemiological study. Diabetes diagnoses were based on physician assessment. HbA (1c) values were taken from the patient charts. RESULTS: The quality of metabolic control was unsatisfactory on the whole in the 277 people with T1D (e.g. mean HbA (1c)=7.4%+/-1.4%). The 8 188 people with T2D had a mean HbA (1c) of 6.89%+/-1.2%. 38.8% of individuals had an HbA (1c)>/=7.0%. The situation was less favourable in subjects with a longer history of diabetes - in many cases in those with diabetes for 5-9 years, but generally in those with a plus-10-year history of diabetes - and also in younger men with a shorter disease history. Patients with a short T2D history, especially older subjects had more favourable values. With regard to age, a higher percentage of patients had an HbA (1c)>/=7.0% (42.0% and 40.6%) in the 45-54 and 55-64 year olds. With respect to the correlation between HbA (1c) and treatment modality, we identified the best metabolic control in T2D patients without drug therapy for diabetes, and the worst in patients on combination regimens (OAD/insulin). The average duration of diabetes in the various treatment groups differs substantially. The average duration was highest (12.1 y) in the insulin group. Oral treatment was the predominant treatment modality in all HbA (1c) categories. CONCLUSION: T1D treatment needs to be improved overall. The situation as regards T2D is less clear-cut. When people with T2D start requiring more intensive and complex treatment in response to disease progression, the treatment efforts of patients and physicians evidently fail to keep up with the actual pace of metabolic deterioration. Early and strict alignment with approximately normal HbA (1c) targets is essential. Close attention should be paid to T2 diabetics with a 5-9-year diabetes history, with the aim of preventing any loss of metabolic control. Likewise, patients aged 45-64 y and younger men require more attention.

Unmet needs in the diagnosis and treatment of dyslipidemia in the primary care setting in Germany.

OBJECTIVES AND METHODS: DETECT is a cross-sectional study of 55,518 unselected consecutive patients in 3188 representative primary care offices in Germany. In a random subset of 7519 patients, an extensive standardized laboratory program was undertaken. The study investigated the prevalence of cardiovascular disease, known risk factors (such as diabetes, hypertension and dyslipidemia and their co-morbid manifestation), as well as treatment patterns. The present analysis of the DETECT laboratory dataset focused on the prevalence and treatment of dyslipidemia in primary medical care in Germany. Coronary artery disease (CAD), risk categories and LDL-C target achievement rates were determined in the subset of 6815 patients according to the National Cholesterol Education Program (NCEP) ATP III Guidelines. RESULTS: Of all patients, 54.3% had dyslipidemia. Only 54.4% of the NCEP-classified dyslipidemic patients were diagnosed as 'dyslipidemic' by their physicians. Only 27% of all dyslipidemic patients (and 40.7% of the recognized dyslipidemic patients) were treated with lipid-lowering medications, and 11.1% of all dyslipidemic patients (41.4% of the patients treated with lipid-lowering drugs) achieved their LDL-C treatment goals. In conclusion, 80.3% of patients in the sample with dyslipidemia went undiagnosed, un-treated or under-treated.

[Cardiovascular high-risk constellations in primary care. DETECT Study 2003]. / Kardiovaskuläre Hochrisikokonstellationen in der primärärztlichen Versorgung. DETECT-Studie 2003

DETECT is a nationwide epidemiological cross-sectional and longitudinal study program in a random probability sample of 3,795 primary care settings (response rate: 60.2%). Based on a target day total assessment of n=55,518 consecutive patients (RR 93.5%) in these settings all patients underwent standardized diagnostic assessment, using self-reporting, clinical interview and laboratory measures. DETECT aims at describing the point prevalence and comorbidity of coronary heart disease (CHD), hyperlipidaemia, arterial hypertension and diabetes mellitus and at identifying the behavioural, clinical, laboratory and psychological risk factors associated with these conditions. A random subset of patients (n=7,519) also completed an extensive standardized laboratory screening program and a 12-month follow-up investigation. Findings reveal a high prevalence of hypertension (36.3%), dyslipidaemia (29.1%), diabetes mellitus (14.6%) and CHD (12.4%) in primary care as well as their close association among each other. The study describes for the first time in greater detail the prevalence of specific disorders and the frequency of high-risk constellations in primary care and allows for the evaluation of various risk scores.

Cardiovascular risk factors in primary care: methods and baseline prevalence rates--the DETECT program.

OBJECTIVES: DETECT is an epidemiological study in primary care to examine (a) the prevalence rates and comorbidity of diabetes mellitus, hypertension, hyperlipidaemia and coronary heart disease (CHD), and associated conditions; (b) the frequency of behavioural and clinical risk factors for onset and progression; (c) the 12-month course and outcome; and (d) the met and unmet needs for these patients. METHODS: Three-stage, cross-sectional clinical-epidemiological study with a prospective-longitudinal component in a nationally representative sample of N = 3795 primary care settings [response rate (RR): 60.2%] and N = 55518 patients (RR: 95.5%). Patients completed a standardized assessment, including questionnaires for patients and the physician and diagnostic screening measures (i.e. blood pressure, heart rate, body mass index and waist circumference assessments). A subsample of patients (N = 7519) also completed a standardized laboratory screening program and was followed-up after 12 months. Data were weighted to adjust for non-response, regional distribution and attrition. RESULTS: (1) Doctors and patients sample can be regarded as representative for primary care settings in Germany. (2) The clinician-rated point prevalence of hypertension is highest (35.5%), followed by hyperlipidaemia (29.1%), diabetes (14.1%) and CHD (12.1%); prevalence rates of each disorder as well as their co-incidence rates increase markedly with age. (3) The vast majority (78%) of all patients revealed multiple (3+) behavioural and clinical risk factors. CONCLUSION: The findings of DETECT underline the considerable burden for primary care doctors in managing a highly morbid patient population, with predominantly complex risk factor constellations, in routine care. Our data provide, in unprecedented detail, a basis for calculating age-, gender- and risk-group-adjusted risk-factor profiles in routine care.

[Prevalence and pharmacotherapy of diabetes mellitus in primary care]. / Prävalenz und Pharmakotherapie des Diabetes mellitus in der primärärztlichen Versorgung.

BACKGROUND AND OBJECTIVE: So far only incomplete epidemiological data on the management of diabetes mellitus have been available for the Federal Republic of Germany. It was the aim of this study to obtain such information from a representative cross-section of patients. PATIENTS AND METHODS: 43549 consecutive, unselected patients (52.6% females; mean age 64.9 +/- 11.7 years) of general practitioners and internists in private practice were included in this study which was based on data provided by the general practitioners or internists during September 2001. They recorded prevalence of diabetes, hypertension and 22 other diseases, and the patients' current treatment. Also recorded were associations of other patient-related variables (age, gender, associated or resulting diseases, hypertension, micro- and macrovascular complications, obesity), with medical practitioner-related variables (medical training, use of guidelines, regional factors) and with the frequency of antidiabetic treatment (total and differentiated by class of drug). RESULTS: The prevalence of diabetes mellitus in this cohort was 15.6% (18.5% for males and 13.7% for females). 67.6% of the diabetics received antidiabetic medication. There was little difference, between the different age groups and between males and females, with regard to which of the various drugs were prescribed. Patients with macrovascular complications were more intensively treated with antidiabetics than those with exclusively microvascular ones. There was hardly any correlation between patterns of prescription and various practitioner characteristics (medical training, use of guidelines, regional factors). CONCLUSION: There was little differentiation in the prescription of antidiabetic medication by general practitioners/internists among an unselected patient cohort.

Recognition and management of overweight and obesity in primary care in Germany.

BACKGROUND: In contrast to the well-documented high prevalence of overweight and obesity in the general population, the prevalence, recognition rates and management by primary care physicians--as the core gatekeeper in the health care system--remains poorly studied. PURPOSE OF THE STUDY: To examine (1) the point prevalence of overweight (BMI 25.0-29.9 kg/m(2)) and obesity (BMI> or =30 kg/m(2)) in primary care patients, (2) prevalence patterns in patients with high-risk constellations (diabetes, hypertension, cardiovascular disease, etc.), (3) doctors' recognition and interventions, as well as patients' use and perceived effectiveness of weight-loss interventions and (4) factors associated with non-treatment. METHODS: Cross-sectional point prevalence study of 45 125 unselected consecutive primary care attendees recruited from a representative nationwide sample of 1912 primary care practices. MEASURES: (1) standardized clinical appraisal of each patient by the physician (diagnostic status and recognition, severity, comorbidity, current and past interventions). (2) Patient self-report questionnaire: height and weight, illness history, past and current treatments and their perceived effectiveness, health attitudes and behaviors. RESULTS: (1) In all, 37.9% of all primary care attendees were overweight, 19.4% obese. (2) Rates for overweight and obesity were highest in patients with diabetes (43.6 and 36.7%) and hypertension (46.1 and 31.3%), followed by patients with cardiovascular disorders. Rates of overweight/obesity increased steadily by the number of comorbid conditions. (3) Doctors' recognition of overweight (20-30%) and obesity (50-65%) was low, patients' actual use of weight control interventions even lower (past 12 months: 8-11%, lifetime: 32-39%). Patient success rates were quite limited. (4) Co- and multimorbidity in particular as well as other patient and illness variables were identified as predictors for recognition, but prediction of patients' actual use of weight loss interventions was limited. CONCLUSIONS: Primary care management of overweight and obesity is largely deficient, predominantly due to four interrelated factors: doctors' poor recognition of patients' weight status, doctors' inefficient efforts at intervention, patients' poor acceptance of such interventions and dissatisfaction with existing life-style modification strategies.

Diabetes and cardiovascular risk evaluation and management in primary care: progress and unresolved issues - rationale for a nationwide primary care project in Germany.

This review highlights established and more recently recognized risk factors for coronary heart disease (CHD) relevant for patients seen in primary care, emphasizing the key role of diabetes mellitus type 2. Recent trends in risk factor research as well as current methods of risk stratification, and new systemic markers are discussed. Beyond the need for more forceful public health strategies to improve early recognition and intervention, the necessity of an integrated comprehensive investigation of the overall characteristics of cardiovascular disease, especially in primary care patients as a prerequisite for future concerted actions is pointed out. Based on this, a large-scale epidemiological investigation focusing on CHD and diabetes in the primary care sector is suggested.

Desensitization of neuronal nicotinic acetylcholine receptors conferred by N-terminal segments of the beta 2 subunit.

Desensitization is a general property of ligand-gated ion channels. Because of a wide array of available subunit combinations, it generates different time constants for channel closure, thereby modulating the processing of information in the brain. Within the family of neuronal nicotinic acetylcholine receptors (nAChRs), alpha 3 beta 2 and alpha 3 beta 4 receptors display contrasting properties of desensitization. When measured using two-electrode voltage-clamp in Xenopus oocytes, desensitization results in current decreases 2 s after initiation of acetylcholine application by 94% for alpha 3 beta 2 receptors, but only by 6% in the case of alpha 3 beta 4 receptors. Desensitization was analyzed by inserting different portions of the beta2 into the beta 4 subunit. Residues 1--212 of the beta2 subunit were able to confer 78% desensitization in 2 s, while smaller chimeras revealed desensitization in 2 s conferred by residues 1--42 alone to a level of 50%, by residues 72--89 to a level of 74%, and by residues 96--212 to a level of 77%. Some long-term (25 min) effects of desensitization driven by acetylcholine were found to rely partially on the same elements, including an enhancement mediated by residues 1--95 and 96--212 of the beta 2 subunit individually. Our results reveal that desensitization relies independently on diverse portions of the extracellular domain of the beta 2 subunit. Phenotype of alpha 3 beta 4 involves, in contrast, complex structural requirements involving residues dispersed throughout the entire N-terminal domain of the beta 4 subunit.

Betaxolol versus carvedilol in chronic heart failure (BETACAR study). Rationale and design.

The use of beta-blockers in heart failure for a long time was regarded as contra-indicated because of their negative inotropic effects. Nevertheless, there is growing evidence that beta-blockers slow down the progression of left ventricular dilatation that characterizes heart failure. In addition changes in left ventricular ejection fraction after several months of beta-blocker treatment appears to have predictive value for survival. This beneficial effect of beta-blockade in chronic heart failure needs to be assessed further. The presumed benefit of beta-blockade with betaxolol (CAS 63659-18-7), a highly selective beta-blocker with long duration of action in chronic heart failure (CHF) will be assessed in BETACAR, a comparative study versus carvedilol (CAS 72956-09-3). The design of this study is provided in this article.

Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors.

To identify the molecular determinants underlying the pharmacological diversity of neuronal nicotinic acetylcholine receptors, we compared the alpha7 homo-oligomeric and alpha4beta2 hetero-oligomeric receptors. Sets of residues from the regions initially identified within the agonist binding site of the alpha4 subunit were introduced into the alpha7 agonist binding site, carried by the homo-oligomeric alpha7-V201-5HT3 chimera. Introduction of the alpha4 residues 183-191 into alpha7 subunit sequence (chimera C2) selectively increased the apparent affinities for equilibrium binding and for ion channel activation by acetylcholine, resulting in a receptor that no longer displays differences in the responses to acetylcholine and nicotine. Introduction of the alpha4 residues 151-155 (chimera B) produced a approximately 100-fold increase in the apparent affinity for both acetylcholine and nicotine in equilibrium binding measurements. In both cases electrophysiological recordings revealed a much smaller increase (three- to sevenfold) in the apparent affinity for activation, but the concentrations required to desensitize the mutant chimeras parallel the shifts in apparent binding affinity. The data were fitted by a two-state concerted model, and an alteration of the conformational isomerization constant leading to the desensitized state accounts for the chimera B phenotype, whereas alteration of the ligand binding site accounts for the chimera C2 phenotype. Point mutation analysis revealed that several residues in both fragments contribute to the phenotypes, with a critical effect of the G152K and T183N mutations. Transfer of alpha4 amino acids 151-155 and 183-191 into the alpha7-V201-5HT3 chimera thus confers physiological and pharmacological properties typical of the alpha4beta2 receptor.

[Metabolism of L-thiazolidine-4-carboxylic acid]. / Metabolismus der L-Thiazolidincarbonsäure-(4).

L-thiazolidine-(4)-carboxylic acid (TAC) has proven to be a good substrate for long-term parenteral nutrition. In this study the metabolism of TAC in the rat is examined at subcellular level. TAC is oxidized by mitochondrial proline oxidase of liver and kidney to L-thiazoline-(4)-carboxylic acid, which then is hydrolyzed to N-formyl-cysteine (FCYS). FCYS is hydrolyzed to cysteine and formic acid by a cytosolic enzyme.

[The use of different cysteine derivatives in longterm parenteral nutrition]. / Verwertbarkeit vershiedener Cysteinderivate bei langfristiger parenteraler Ernährung.

Utilization of cysteine derivatives for parenteral nutrition was established by means of nitrogen balance of growing rats. N,N-bis-acetylcystine and bisacetyl-glycyl-cystine were not utilized as substrates. N-acetylcysteine, glutathione disulfide, and L-thiazolidine-(4)-carboxylic acid gave evidence as suitable cysteine sources for parenteral nutrition.

[The significance of cysteine and its derivatives in parenteral nutrition]. / Zur Bedeutung des Cysteins und seiner Derivate für die parenterale Ernährung.

Data on l-cysteine (CYS) concentrations obtained by automated amino acid analysis are in fact cystine measurements. The necessity of a uniform use of nomenclature is discussed. The importance of a CYS supply during parenteral nutrition (PN) is pointed out by several studies. The presently available CYS derivatives and their potential use as CYS source in PN are discussed.

[L-thiazolidine-4-carboxylic acid as a source of cysteine in parenteral nutrition]. / L-Thiazolidincarbonsäure-(4) als Cysteinquelle in der parenteralen Ernährung.

In this study we investigated, whether L-thiazolidine-4-carboxylic acid (TAC), a cysteine derivative analogous to proline, may provide a useful nutrient in parenteral nutrition. Young male Sprague-Dawley rats were maintained entirely by parenteral nutrition for 15 days. Weight gain, nitrogen balance, taurine and cystine concentrations of the various body fluids and tissues were the criteria for establishing the availability of cysteine from TAC.

[Cysteine in parenteral nutrition: comparative study of N-acetyl-cysteine and N,N-diacetylcystine in the rat model]. / Cystein in der parenteralen Ernährung: Vergleichende Studien über N-Acetylcystein und N,N-Diacetylcystin am Modell der Ratte.

In this study the question of whether N-N-diacetylcystine (DAC), which is more stable than N-acetylcysteine (AcCYS), may provide a useful cysteine source for parenteral nutrition was investigated. In in vitro studies the release of cysteine from DAC was measured. The Michaelis, constant and maximum velocity were compared with the corresponding results for AcCYS. In in vivo studies 3 groups of growing rats were maintained entirely by parenteral nutrition low in methionine for 15 days. Group I (n = 4) received a solution containing AcCYS, and group II (n = 6) was supplied with a corresponding amount of DAC. In the solution given to group III (n = 6) the CYS derivative was replaced by an isonitrogeneous amount of glycine. Utilization of the respective CYS derivatives was judged from weight gain, nitrogen balance, plasma amino acid pattern, and urinary excretion of free amino acids. The results from both the in vitro and in vivo studies indicate that DAC is not a suitable substitute for AcCYS in parenteral nutrition.

[Infusion solution with a high concentration of branched-chain amino acids and a high-percentage amino acid solution in an experimental animal model]. / Infusionslösung mit hohem Anteil an verzweitkettigen Aminosäuren (VKAS) und hochprozentige Aminosäurenlösung im experimentellen Tiermodell.

Young male rats are randomized into two groups and maintained by total parenteral nutrition with an isocaloric and isonitrogenous regimen for 6 days. Group I receives a 15% amino acid solution containing 17% branched chain amino acids while group II is given a 10% amino acid solution containing 26.6% branched chain amino acids. By this regimen group I receives 1.02 g and group II 1.77 g branched chain amino acids/kg B.W./day. No significant differences are observed in weight gain, nitrogen balance, amino acid excretion and amino acid concentrations in muscle. The higher supply with branched chain amino acids is simply reflected in significant augmented plasma concentrations of these amino acids. Simultaneously there is a significant increase of glycine and threonine in plasma. The infusion of the concentrated amino acid solution is well tolerated by the animals and results in a decreased urinary volume.