Multiple benign symmetric lipomatosis--a differential diagnosis of obesity. Is there a rationale for fibrate treatment?

Multiple benign symmetric lipomatosis (MSL) is characterized by a rapid progression of multiple, symmetric nonencapsulated fat masses in the face, neck, and extremities. The lipomas are thought to be the result of defective brown adipose tissue (BAT). In up to 90% MSL is associated with chronic alcohol abuse. Prognosis depends on the concomitant presence of a neuropathy with a mortality of 25.8%. Therapeutic options are limited to alcohol abstinence and surgical interventions. We report here about a 53-year-old MSL patient who increased his body weight by 37 kg over 10 years. Multiple lipectomies were performed, but disease progressed. We treated him with fenofibrates (200 mg/day). Disease progression discontinued and circumferences of abdominal adipose tissue reduced. Fibrates, peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists, are pleiotropic hypolipidemic drugs, and might have worked by suppression of protein expressions involved in the architecture of BAT keeping it in a quiescent state.

Multiple benign symmetric lipomatosis--a differential diagnosis of obesity: is there a rationale for fibrate treatment?

Multiple benign symmetric lipomatosis (MSL) is characterized by a rapid progression of multiple, symmetric nonencapsulated fat masses in face, neck, and extremities. The lipomas are thought to be the result of defective brown adipose tissue (BAT). In up to 90%, MSL is associated with chronic alcohol abuse. Prognosis depends on the concomitant presence of a neuropathy with a mortality of 25.8%. Therapeutic options are limited to alcohol abstinence and surgical interventions. We report here about a 53-year-old MSL patient who increased his body weight by 37 kg over 10 years. Multiple lipectomies were performed but disease progressed. We treated him with fenofibrates (200 mg/day). Disease progression discontinued, and circumferences of abdominal adipose tissue reduced. Fibrates, peroxisome proliferator-activated receptor alpha agonists, are pleiotropic hypolipidemic drugs and might have worked by suppression of protein expressions involved in the architecture of BAT keeping it in a quiescent state.

Statistical methods for detecting genetic interactions: a head and neck squamous-cell cancer study.

Tobacco smoke and occupational exposures to chemicals such as polycyclic aromatic hydrocarbons (PAHs) are, aside from alcohol, the major risk factors for development of head and neck squamous-cell cancer (HNSCC). In this study, new statistical methods were applied. We employ new statistical methods to detect genetic interactions perhaps of higher order, that might play a role in developing HNSCC. The underlying study comprises 312 HNSCC cases and 300 controls. Single-nucleotide polymorphisms (SNPs) of PAH metabolizing and repair enzymes, somatic p53 mutations, and tobacco smoke were examined. Key statistical tools for our analysis are methods of unsupervised and supervised learning. In unsupervised learning, one performs cluster analyses based on well-known and new distance measures to find differences in the SNP patterns of cases and controls, and to understand the role of p53. Our main goal in supervised learning was to identify SNPs and SNP interactions that are likely to alter the susceptibility to HNSCC. Logic regression, a classification method well suited for SNPs, was employed as well as a Bayesian generalization that allows for incorporating additional expert knowledge. These methods detected several important interactions, such as an association between CYP1B1, tobacco smokes and p53 mutations and some interactions between CYP1B1 and glutathione S-transferases in smokers, which included a three-way interaction between CYP1B1, CYP2E1-70G>T, and GSTP1 (exon 5).

Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair.

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.

Pulse wave velocity is increased in patients with transient myocardial ischemia.

OBJECTIVE: We have recently shown that mean pulse pressure is higher in patients with transient myocardial ischemia. Pulse pressure elevation might be an important consequence of increased arterial stiffness. The aim of this study was to prove if arterial stiffness is changed in patients with transient myocardial ischemia who bear a high cardiovascular risk. Additionally we investigated whether arterial stiffness or wave reflection is the best indicator for transient myocardial ischemia. Aortic pulse wave velocity (PWV) is a measure of arterial stiffness, and augmentation index (AIx) an indication of arterial wave reflection. Both are indicators for cardiovascular risk. METHODS: PWV (carotid-femoral) and AIx (SphygmoCor) were assessed in 74 hypertensive patients. Transient myocardial ischemia was detected using an ST-triggered 24-h ambulatory blood pressure monitoring device. RESULTS: ST-segment depressions were recorded in 30 of 74 patients. There were no significant differences with regard to age, mean arterial pressure, systolic blood pressure, diastolic blood pressure or heart rate. PWV was seen to be higher in patients with transient myocardial ischemia (10.6 versus 9.5 m/s, P = 0.036). There was no significant difference in AIx between the two groups. PWV (r = 0.36, P = 0.002) but not AIx correlated with pulse pressure. CONCLUSIONS: PWV is higher in hypertensive individuals (age > 60 years) with transient myocardial ischemia, suggesting that PWV is an indicator of increased cardiovascular risk. Although AIx is known to be associated with several cardiovascular diseases, it was not seen to be associated with silent myocardial ischemia. Our results suggest that the clinical significance of parameters of arterial stiffness and arterial wave reflection change with age, with a higher clinical importance of PWV indicated in patients over the age of 60.

Destabilization of AT(1) receptor mRNA by calreticulin.

AT(1) receptor activation leads to vasoconstriction, blood pressure increase, free radical release, and cell growth. AT(1) receptor regulation contributes to the adaptation of the renin-angiotensin system to long-term stimulation and serves as explanation for the involvement of the AT(1) receptor in the pathogenesis of cardiovascular disease. The molecular mechanisms involved in AT(1) receptor regulation are poorly understood. Here, we report that angiotensin II accelerates AT(1) receptor mRNA decay in vascular smooth muscle cells. A cognate mRNA region within the 3' untranslated region at bases 2175 to 2195 governs the inducible decay of the AT(1) receptor mRNA. Sequential protein purifications led to the discovery of a novel mRNA binding protein, calreticulin, which mediates destabilization of the AT(1) receptor mRNA. Angiotensin II-caused phosphorylation of calreticulin enables binding of calreticulin to the AT(1) receptor mRNA at bases 2175 to 2195 and propagates calreticulin-induced acceleration of AT(1) receptor mRNA decay. Thus, a novel mRNA binding protein, calreticulin, is discovered, which causes AT(1) receptor mRNA degradation via binding to a distinct mRNA region in the 3' untranslated region. These findings display a novel mechanism of posttranscriptional mRNA processing.

Management of patients with uncontrolled arterial hypertension--the role of electronic compliance monitoring, 24-h ambulatory blood pressure monitoring and Candesartan/HCTZ.

BACKGROUND: Incomplete drug regimen compliance (DRC) and white-coat hypertension are two of several possible causes of uncontrolled hypertension. Therefore the aim of the present study was to compare DRC in hypertensives treated with combination therapy whose blood pressures (BP) were controlled vers. uncontrolled after 4 weeks of self-monitored BP measurement. To observe the consequences in uncontrolled patients of switching one drug of the combination therapy to candesartan/HCTZ (16 mg/12.5 mg) with and without a compliance intervention program. METHODS: Self-and ambulatory-monitoring of BP were done with upper arm oscillometric devices. Patients' dosing histories were compiled electronically (MEMS, AARDEX). Patients with office blood pressure (OBP) >140/90 mmHg despite combination therapy were begun on MEMS monitoring and self BP measurement for 4 weeks of run-in. Of 62 such patients, 18 (29%) patients were normotensive according to self BP measurement and ambulatory BP measurement at 4 weeks (Group A); in the remaining 44 still uncontrolled patients, candesartan/HCTZ was substituted for one of the combination therapy drugs, with half these patients receiving passive compliance monitoring (B) and half a DRC intervention program (C). All groups were then followed for 8 weeks. RESULTS: DRC before week 4 was significantly higher in A than in the uncontrolled patients (B&C). DRC was stable during run-in A, but declined in B and C. DRC after week 4 was not different in the three groups and stayed constant over time. DRC during weekends was lower than during weekdays in all groups. In group A no significant change in blood pressure was observed with all three methods of BP measurements. In groups B and C significant reductions of systolic and diastolic BP were observed for ABPM and SBPM. After the change to candesartan/HCTZ in B&C ambulatory 24-h-BP (ABPM) was normalized in 39% of patients. CONCLUSION: Normalization of BP was associated with superior drug regimen compliance in previously uncontrolled patients treated with a combination drug regimen. Switching still-uncontrolled patients to candesartan/HCTZ significantly improved BP control and stabilized a declining DRC.

Myocardial ischemia during everyday life in patients with arterial hypertension: prevalence, risk factors, triggering mechanism and circadian variability.

INTRODUCTION: The objective of the present study was to investigate the prevalence, the risk factors, the hemodynamic triggering mechanisms, the circadian variability of ST segment depression (ST depression) and the effect of day and night fall in blood pressure on the prevalence of ST depression in hypertensive patients. MATERIALS AND METHODS: In a multicentric study in Germany, 1,244 CardioTens registrations (combined 24-h ambulatory blood pressure measurement/electrocardiography with ST segment triggering; Meditech, Budapest, Hungary) from patients with arterial hypertension were consecutively monitored and evaluated centrally at the University of Bonn. Inclusion criterion was treated or untreated arterial hypertension. The ST segment was measured in accordance with the "1 : 1 : 1 rule" (horizontal or descending ST depression by 1 mm, 1 min duration, 1 min interval from the previous episode). RESULTS: ST segment depression was observed in 250 (20.1%) patients; 90.3% of the transient ST-segment depression was silent (without angina pectoris). Ambulatory 24-h blood pressure measurement, but not office-based blood pressure measurement, was predictive for the occurrence of ST-segment depression. Risk factors for ST-segment depression were the Sokolow index > or =3.5 mV, smoking status, severity of coronary heart disease, use of diuretics, reduced left ventricular function, pulse pressure > or =60 mmHg and increase of double product (1,000 mmHg/min). A significant rise of the systolic/diastolic blood pressure (+8+ or -18/+7+ or -10 mmHg), of the heart rate (+12+ or -13/min) and of the double product (+2,471+ or -2,517 mmHg/min) was found during the transient ST depression as compared with the corresponding 24-h ambulatory blood pressure measurement mean values (P<0.0001 for all parameters specified). In most intermittent ST depressions, a rise of the double product was seen (n=789 episodes), and in the remaining 239 ST depressions, a fall of the double product was observed. ST depressions with fall of the double product showed a circadian distribution with a peak in the late evening. ST depression accompanied by a rise in double product showed two peaks (one in the early morning and one in the late evening). The prevalence of ST depression was significantly higher (28.6%) in extreme dippers than in dippers (18.2%), risers (21.8%) and non-dippers (19.6%). CONCLUSIONS: ST depressions have a high prevalence of 20.1% in hypertensive patients. Clinical predictors for the occurrence of ST-segment depression were classical risk factors and cardiac target organ damage. Office-based blood pressure measurement was not a useful measuring tool for forecasting the likelihood of ST-segment depression. ST depressions were triggered inter alia by variations of blood pressure and the heart rate. The circadian variability of the ST depressions is crucially affected by the pressure double product characteristics on which the ST depression is based.

Relationship between the frequency of blood pressure self-measurement and blood pressure reduction with antihypertensive therapy : results of the OLMETEL (OLMEsartan TELemonitoring blood pressure) study.

OBJECTIVES: This subanalysis of the OLMETEL (OLMEsartan TELemonitoring blood pressure) study in patients with essential hypertension assessed the relationship between the frequency of blood pressure self-measurement (BPSM) and the response to blood pressure (BP)-lowering therapy with olmesartan medoxomil, and the number of BP readings per week necessary to detect a mean systolic or diastolic BP reduction > or =5mm Hg. METHODS: A total of 53 patients with essential hypertension received treatment with olmesartan medoxomil 10, 20 or 40 mg daily for 12 weeks. BPSM was performed for the first 9 weeks using a TensioPhone TP2 device. Patients were instructed to measure BP at least twice daily (morning and evening). RESULTS: After the first 9 weeks of the 12-week treatment period, the extent of BP reduction correlated with the number of BPSMs. Systolic/diastolic BP reductions in patients with a 100% adherence to at least two BP measurements daily were -16.6/-8.0mm Hg compared with -0.2/-3.3mm Hg in patients with only a 75% adherence to at least one BP measurement daily. Obtaining five home BP readings per week resulted in a sensitivity of 94.8% and a specificity of 90.0% to detect a BP reduction of > or =5mm Hg. CONCLUSION: Patients adhering to the instructions for BPSM (at least two measurements daily) had a better response to antihypertensive treatment with olmesartan medoxomil. Whether BPSM per se resulted in an improved adherence to therapy or whether the number of recordings was an indicator of already existing adherence remains to be determined. Obtaining at least five home BP readings per week was identified as the threshold for correctly predicting response to olmesartan medoxomil treatment.

A novel component of the ubiquitin pathway, ubiquitin carboxyl extension protein 1 is overexpressed in prostate cancer.

Prostate cancer is among the most common tumors in industrialized nations. However, little is known about the molecular events underlying its development. In the present study we used suppressive subtraction hybridization (SSH) in combination with laser-assisted microdissection in order to compare gene expression between prostate carcinoma and the normal prostate proper. Both are mixed tissues which consist of an epithelial and a stromal compartment. We first compared mRNA (cDNA) expression by SSH and then used real-time quantitative RT-PCR analysis of microdissected tissue probes in order to verify differential expression of subtracted cDNA clones. We also used differentially expressed cDNAs for the synthesis of radiolabelled riboprobes in order to attribute differential expression to specific cell types in tissue sections by in situ hybridization. Using this approach we found an up-regulation of ubiquitin carboxyl extension protein 1 (UBCEP-1) mRNA in prostate carcinoma cells compared to the normal glandular epithelium of the prostate proper. UBCEP-1 mediated ubiquitin chain elongation may promote prostate carcinoma development by increasing via the proteasome pathway the degradation of proteins which are involved in growth inhibition or apoptosis.