Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients having granulomatosis with polyangiitis: results of a study involving 115 patients from a single center.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCAs) are considered a risk factor for granulomatosis with polyangiitis (GPA) exacerbation, especially when staphylococcal superantigens (SAgs) are present in nasal swabs. Their role in monitoring disease activity remains controversial. This study determined the relationship of ANCAs with disease activity and presence of SAgs in GPA patients. METHODS: Among a total of 115 GPA patients hospitalized in the period 2009-2016, we investigated the presence of SAgs and ANCA concentration. Blood samples and nasal swabs were taken at each visit (referred further to as episodes). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: We analyzed 362 episodes. ANCAs were detected in 215 (59.4%), while SAgs were detected in 126 (34.8%) episodes. We found a significant correlation between the presence of ANCAs and disease activity (p = 0.0032), as well as between their level and GPA severity (r = 0.25363, p = 0.000001). We also determined that an ANCA values ≥ 138 Ru/ml were an indicator of active disease with high specificity and low sensitivity (84.4% and 37.3%, respectively). The relationship between ANCA presence and the presence of SAgs was not confirmed; however, when SAgs were analyzed based on the different types, ANCA levels were found to be significantly higher in the group with SAg type B (p = 0.031). CONCLUSIONS: There was no detectable evidence for the association between ANCA level and the presence of SAgs. Although monitoring ANCA levels as a marker of disease activity may be clinically relevant, GPA management cannot proceed on the basis of ANCA levels alone. Key Points • ANCA concentration usually correlates with GPA activity, although in half of patients, ANCAs persist despite effective treatment and clinical remission. • ANCA values of 138 Ru/ml seem to be an indicator of active disease with high specificity, but low sensitivity. • Although there is a relevance for ANCA monitoring as a marker of disease activity, GPA management cannot be based on ANCA levels alone. • The suspected clinical correlation between ANCA formation and SAg presence in nasal swabs is not obvious and requires further investigations.

Hand Function Deficiency in Patients with Dupuytren's Disease and Course of Recovery after Palmar Fasciectomy.

PURPOSE OF THE STUDY To evaluate hand function deficiency in patients with Dupuytren's disease (DD) in addition to assessing the improvement of function after palmar fasciectomy by using different hand-related questionnaires. MATERIAL AND METHODS A total of 121 hands (95 patients) underwent surgery. Disease severity was designated using Tubiana's Staging System. The Tendency of changes of Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH), Patient Evaluation Measure (PEM), and Hand Function Score (HFS) scores of patients with DD undergoing palmar fasciectomy were assessed prior to, 3 months after, and 1 year after the operation. Moreover, total loss of extension (TLoE) was evaluated using a goniometer in the same time intervals. Repeated measure ANOVA Friedman's test were used. Responsiveness to clinical change was calculated by using standardized response means (SRMs). RESULTS The results showed statistically significant improvement of the originally obtained questionnaire results after 3 months for DASH and HFS and 12 months for all forms; only the PEM and DASH score significantly changed between 3 and 12 months. TLoE before surgery was 144.1 o ±99.6 o ; 3-month and 1-year after surgery: 14.3 o ±58.0 o and 19.3 o ±34.7 o respectively. SRMs for 1 year after surgery was large for PEM (1.11) and medium for DASH (0.7) and HFS (0.79). CONCLUSIONS DASH, PEM, and HFS are valuable tools to monitor the hand function of patients with DD after surgery. Key words:hand function, Dupuytren's disease, palmar fasciectomy.

Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates.

AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MATERIALS AND METHODS: MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months. RESULTS: MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys. CONCLUSIONS: Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.

Contribution of regional brain melanocortin receptor subtypes to elevated activity energy expenditure in lean, active rats.

Physical activity and non-exercise activity thermogenesis (NEAT) are crucial factors accounting for individual differences in body weight, interacting with genetic predisposition. In the brain, a number of neuroendocrine intermediates regulate food intake and energy expenditure (EE); this includes the brain melanocortin (MC) system, consisting of MC peptides as well as their receptors (MCR). MC3R and MC4R have emerged as critical modulators of EE and food intake. To determine how variance in MC signaling may underlie individual differences in physical activity levels, we examined behavioral response to MC receptor agonists and antagonists in rats that show high and low levels of physical activity and NEAT, that is, high- and low-capacity runners (HCR, LCR), developed by artificial selection for differential intrinsic aerobic running capacity. Focusing on the hypothalamus, we identified brain region-specific elevations in expression of MCR 3, 4, and also MC5R, in the highly active, lean HCR relative to the less active and obesity-prone LCR. Further, the differences in activity and associated EE as a result of MCR activation or suppression using specific agonists and antagonists were similarly region-specific and directly corresponded to the differential MCR expression patterns. The agonists and antagonists investigated here did not significantly impact food intake at the doses used, suggesting that the differential pattern of receptor expression may by more meaningful to physical activity than to other aspects of energy balance regulation. Thus, MCR-mediated physical activity may be a key neural mechanism in distinguishing the lean phenotype and a target for enhancing physical activity and NEAT.

Prevalence, severity and underdiagnosis of COPD in the primary care setting.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease with a steadily increasing prevalence and mortality. However, recent epidemiological estimates differ depending on the population studied and methods used. AIM: To investigate the prevalence, severity and burden of COPD in a primary care setting. METHODS: From 4730 patients registered in a single primary care practice, all 2250 patients aged 40 years or more were invited to participate. Participants completed a questionnaire on smoking, respiratory symptoms, education and social status. A physical examination was followed by pre- and post-bronchodilator (BD) spirometry. RESULTS: Of the eligible patients, 1960 (87%) participated. 92% of spirometric tests met the ATS criteria. Airflow limitation was demonstrated in 299 (15%) of the participants pre-BD and in 211 (11%) post-BD. COPD was diagnosed in 183 patients (9.3%). Of these patients, the degree of post-BD airflow limitation was mild in 30.6%, moderate in 51.4%, severe in 15.3% and very severe in 2.7%. Only 18.6% of these patients had previously been diagnosed with COPD; almost all of these had severe or very severe airflow limitation. As a result of the study, a diagnosis of asthma was made in 122 patients. CONCLUSIONS: The prevalence and underdiagnosis of COPD in adult patients in this primary care setting made case finding worthwhile. Large numbers of newly detected patients were symptomatic and needed treatment. Limiting investigations to smokers would have reduced the number of COPD diagnoses by 26%.

Blockade of MCH1 receptor signalling ameliorates obesity and related hepatic steatosis in ovariectomized mice.

BACKGROUND AND PURPOSE: Melanin-concentrating hormone (MCH) is a cyclic orexigenic neuropeptide predominantly expressed in the lateral hypothalamus. We investigated the roles of MCH1 receptor signalling in ovariectomy (OVX)-induced obesity in female C57BL/6J mice, an animal model of postmenopausal obesity. EXPERIMENTAL APPROACH: The effects of blocking signalling via the MCH1 receptor on OVX-induced obesity was investigated by using Mch1r deficient (KO) mice and chronic treatment with a selective MCH1 receptor antagonist. KEY RESULTS: OVX induced body weight gain and increases in the weight of visceral fat and of liver; these effects were attenuated following OVX in Mch1r KO mice. OVX-induced triglyceride (TG) accumulation and elevated expression of lipogenic genes were significantly ameliorated in the liver of Mch1r KO mice. In agreement with these results, chronic i.c.v. infusion of a selective MCH1 receptor antagonist significantly reduced body weight gain, visceral fat and liver weights in OVX mice, and hepatic TG contents and lipogenic gene expression levels were normalized. CONCLUSION AND IMPLICATIONS: Our results indicate that MCH1 receptor signalling is involved in the development of fatty liver, as well as obesity, in OVX mice, and suggest a therapeutic potential for MCH1 receptor antagonists in the treatment of obesity and fatty liver.

Leptin measurement in urine is a reliable method of monitoring its secretion in patients with obstructive sleep apnea syndrome.

Leptin is believed to play a significant role in the pathogenesis of obstructive sleep apnea syndrome (OSAS) as well as progression of OSAS-related obesity. It is also known that other factors such as gender and diurnal variations in serum strongly affect the measurement results making repeated blood sampling necessary for leptin precise monitoring. Since renal metabolism and urine secretion are the main elimination mechanism for leptin, in this study we evaluated urine relevance for leptin secretion monitoring. Serum and urine (collected during the day and overnight) sampled from 169 OSAS patients and 41 controls were assayed by immunoenzymatic method specific for human leptin. Only 5 (17%) controls and 10 (5.8%) OSAS patients had undetectable urine leptin. We observed significant relationships between serum and urinary leptin in both day-time (r=0.656, P<0.001) and night-time (r=0.518, P<0.001) samples and between day and night-time urine leptin (r=0.811, P<0.001). Significance values did not alter when urinary leptin levels were expressed as the ratio to urinary creatinine. Gender-related differences in leptin concentrations were present both in serum (P<0.001) and overnight urine (P<0.01) in the OSAS group. However, mean night-time urine leptin was lower in the OSAS patients (P<0.05) and their subgroups stratified according to disease severity (P<0.01), while serum leptin levels were comparable in both groups. We conclude that assaying leptin in urine by immunoenzymatic method is a reliable and useful non-invasive alternative for its serum measurement. However, night-time urine leptin levels better reflect differences in its turnover due to gender and OSAS severity.

Obstructive sleep apnea and the quality of life.

Patients suffering from obstructive sleep apnea (OSA) are unaware of clinical symptoms, such as cessation of breathing during sleep, decrease in blood oxygen levels, severe sleep fragmentation, and excessive daytime sleepiness. Equally worrying is a low level of knowledge among physicians, psychiatrists, and psychologists of the intellectual and emotional impact of OSA. The illness may lead to anxiety, depression, psychosis, and other pathological symptoms. The aim of the present study was to evaluate relationships among OSA, quality of life, and psychological performance. STAI, UMACL, the Beck Depression Inventory, the Framingham Type A Scale, the Courtauld Emotional Control Scale (CECS), the Life Orientation Test - Revised (LOT-R), and the Satisfaction With Life Scale (SWLS) were applied. The tests were used to describe the well-being and pathological symptoms, such as depression or anxiety, in a clinical group (newly-diagnosed, untreated OSA patients) in comparison with a control group (healthy volunteers). The results of the tests failed to substantiate the presence of significant differences between the clinical and control groups. We put forward a hypothesis that the rather unexpected lack of psychological differences might stem from a rapid mood improvement in OSA patients on anticipation of being diagnosed and taken care of in the hospital setting. Followed-up studies in the same patients are required to confirm this hypothesis.

Effect of interferon alfa and ribavirin treatment on hepatitis C virus RNA in serum and peripheral blood mononuclear cells in children with chronic hepatitis C.

UNLABELLED: The correlations between the severity of hepatic lesions, age, gender, HBV co-infection and negativisation of HCV-RNA from serum and peripheral blood mononuclear cells (PBMC) after treatment of chronic hepatitis C (CHC) were analysed. 41 children (11 F/ 30 M), aged 5-16 years (mean 10 +/- 2.8), were treated with IFN-alpha and ribavirin for 12 months. Sustained negativisation of HCV-RNA from serum was achieved in 25 patients (61%), in 3 (7%) it reappeared after treatment, and in 13 (32%) it was ineffective. Clearance of HCV did not correlate with age (p = 0.65), sex (p = 0.13), past HBV infection (n = 22 anti-HBc +) (p = 0.24), maximum pre-treatment ALT activity (p = 0.06), grade of inflammation (p = 0.33) or stage of fibrosis (p = 0.9) in liver biopsy. It was achieved in 6/16 children previously resistant to IFN-a monotherapy and in 19/25 naive (p = 0.017). HCV-RNA was detected in PBMC in 9/24 (37%) seronegative children and in 1/21 (5%) in comparative group of seronegative adults; p = 0.004. Persistence of HCV-RNA in PBMC after combined treatment occurred in 5/10 (50%) patients resistant to previous IFN-alpha monotherapy, 6/35 (20%) of them cleared HCV from PBMC (p = 0.04). CONCLUSIONS: Age and gender, infection route, history of HBV infection or severity of histopathologic liver lesions had no influence on the efficacy of treatment with IFN-alpha and ribavirin. Clearance of HCV from serum and from PBMC occurs less frequently in patients previously resistant to IFN-alpha. Children with CHC require longitudinal observation after successful antiviral treatment as in 37% of those considered to be free from the virus by ordinary measures, HCV-RNA was found in PBMC.

Smokers with airway obstruction are more likely to quit smoking.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is one of the leading causes of morbidity and mortality. Smoking cessation at an early stage of the disease usually stops further progression. A study was undertaken to determine if diagnosis of airway obstruction was associated with subsequent success in smoking cessation, as advised by a physician. METHODS: 4494 current smokers (57.4% men) with a history of at least 10 pack-years of smoking were recruited from 100 000 subjects screened by spirometric testing for signs of airway obstruction. At the time of screening all received simple smoking cessation advice. 1177 (26.2%) subjects had airway obstruction and were told that they had COPD and that smoking cessation would halt rapid progression of their lung disease. No pharmacological treatment was proposed. After 1 year all subjects were invited for a follow up visit. Smoking status was assessed by history and validated by exhaled carbon monoxide level. RESULTS: Nearly 70% attended a follow up visit (n = 3077): 61% were men, mean (SD) age was 52 (10) years, mean (SD) tobacco exposure 30 (17) pack-years, and 33.3% had airway obstruction during the baseline examination. The validated smoking cessation rate in those with airway obstruction was 16.3% compared with 12.0% in those with normal spirometric parameters (p = 0.0003). After correction for age, sex, nicotine dependence, number of cigarettes smoked daily, and lung function, success in smoking cessation was predicted by lower lung function, lower nicotine dependence, and lower tobacco exposure. CONCLUSIONS: Simple smoking cessation advice combined with spirometric testing resulted in good 1 year cessation rates, especially in subjects with airway obstruction.

Increasing COPD awareness.

Early diagnosis and smoking cessation are the only available methods to stop the progression of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the effects of early detection of airflow limitation (AL) in a population with high risk for COPD, using spirometric screening. Smokers aged 40 yrs with a smoking history of 10 pack-yrs were invited to visit a local outpatient chest clinic for simple spirometry (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Smoking history was recorded, followed by smoking cessation advice relating the results of spirometry to the smoking behaviour. Subjects who did not fulfil the above criteria (younger and/or nonsmokers) were also screened. A total 110,355 subjects were investigated; they were aged 53.5+/-11.5 yrs and 58.2% were males. Of the total amount of subjects, 64% were current smokers, 25.1% were former smokers and 10.9% were lifelong nonsmokers. Spirometry tests were within normal values for 70.3%, and 20.3% showed signs of AL: this was mild in 7.6%, moderate in 6.7% and severe in 5.9%. The remaining 8.3% of subjects presented with a restrictive pattern of ventilatory impairment. Airflow limitation was found in 23% of smokers aged 40 yrs with a history of 10 pack-yrs. This study concluded that large-scale voluntary spirometry screening of the population with high risk for COPD detects a large number of subjects with AL.

1H NMR structural analysis of human ghrelin and its six truncated analogs.

Human ghrelin, the first recognized natural ligand of growth hormone secretagogue growth hormone secretagogue receptors (GHS-Rs) (M. Kojima, H. Hosada, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, Nature, 1999, Vol. 402, pp. 656-660), consists of 28 amino acids of which Ser3 is modified by n-octanoylation. This new peptide hormone has been implicated not only in regulation of the GH secretion but also in regulation of food intake. The discovery of ghrelin opens up more opportunities to study the relationship of ghrelin with metabolic diseases. Until now, only mass spectometry analysis has been reported on the structure of ghrelin. NMR analysis is a suitable way to study if any tertiary structure of unbound ghrelin is present in solution. NMR studies were carried out on human ghrelin and its five truncated analogs. The full-length ghrelin and its fragments exhibited random coil behavior in aqueous solution. Additional studies were carried out on the shortest active segment of human ghrelin, which consists of the first five amino acids of the ghrelin sequence (M. A. Bednarek, S. D. Feighner, S.-S. Pong, K. K. McKee, D. L. Hreniuk, M. V. Silva, V. A. Warrem, A. D. Howard, L. H. Y. Van der Ploeg, and J. V. Heck, Journal of Medical Chemistry, 2000, Vol. 43, pp. 4370-4376), to compare the spectral features with their counterparts in the full-length ghrelin. The NMR data showed behavior similar to ghrelin except for two additional nuclear Overhauser effects (NOEs) between the Phe4 NH and the protons of the beta-methylene of Ser3. CD on human ghrelin and its short active analog in water were indicative of random coil peptides. Molecular modeling based on NMR data was carried out to probe which structural features were similar to growth hormone-releasing peptide-6 (GHRP-6), a hexapeptide that binds to GHS-R releasing GH and stimulating food intake. Modeling suggested some similarities, but they were not of a nature to account for binding properties of these compounds.

Selective, high affinity peptide antagonists of alpha-melanotropin action at human melanocortin receptor 4: their synthesis and biological evaluation in vitro.

Peptide Ac-Nle(4)-cyclo(5beta-->10epsilon)(Asp(5)-His(6)-D-(2')Nal(7)-Arg(8)-Trp(9)-Lys(10))-NH(2), compound 1, a cyclic derivative of alpha-melanotropin, is a nonselective high affinity antagonist at human melanocortin receptors 3 and 4, and an agonist at melanocortin receptors 1 and 5. To differentiate between the physiological functions of these receptors, antagonists with improved receptor selectivity are needed. In this study, analogues of compound 1 without Ac-Nle(4) or His(6) and/or the amino group of Asp(5) were prepared and tested in binding assays and in functional assays on CHO cells expressing hMC3-5R. Several of these peptides were to be selective, high affinity hMC-4R antagonists. The most interesting was compound 10, named MBP10, cyclo(6beta-->10epsilon)(succinyl(6)-D-(2')Nal(7)-Arg(8)-Trp(9)-Lys(10))-NH(2), an antagonist (IC(50) = 0.5 nM) with 125-fold selectivity over hMC-3R (and of >300-fold selectivity over MC-1RB). This compound had no agonist activity at hMC-3R or hMC-4R and only weak agonist activity at hMC-5R. Examination of the sequences of these new peptides revealed that the D-(2')Nal(7)-Arg(8)-Trp(9) segment of peptide 1 forms the "essential core" required for high affinity and high selectivity of analogues of peptide 1 at hMC-4R, but the "extended core", His(6)-D-(2')Nal(7)-Arg(8)-Trp(9), is necessary for the maximum affinity for hMC-3R and hMC-5R.

[Snoring and excessive daytime somnolence and risk of cardiovascular diseases]. / Chrapanie i nadmierna sennosc dzienna a ryzyko chorób sercowo-naczyniowych.

Snoring and excessive daytime somnolence (EDS) are very common in middle-age adults. The goal of the investigation was to assess links between those symptoms and risk for cardiovascular diseases (CVD). The population studied included 1186 inhabitants of Warsaw (mean age 52 years), participants of the international multicentre study of cardiovascular disease MONICA II, who completed the sleep disordered breathing (SDB) questionnaire. Snoring was reported by 78% of males (48% habitual and 30% occasional) and 59% of females (27% habitual and 32% occasional). Every fourth (26.8%) subject declared observed apnoeas, in 9.2% apnoeas were observed every night. EDS was declared by 28.7% of studied sample. The results of the questionnaire were compared to the results of MONICA study. Snorers had significantly higher systolic and diastolic blood pressure (133.2 +/- 23/84.6 +/- 13 mm Hg) compared to non-snorers (126.4 +/- 22/80.4 +/- +/- 12 mm Hg) (p < 0.0001). The high total serum cholesterol (> or = 200 mg%) and triglycerides (> or = 200 mg%) concentration, and also obesity (BMI > or = 30 kg/m2) were more prevalent in snorers. Subjects reporting apnoeas more often had coronary artery disease (p < 0.001) or history of stroke (p = 0.002) compared to non-apnoeics. There was no relationship between EDS and risk of cardiovascular disorders, and also between diabetes and SDB. In conclusion, snoring was strongly associated with hyperlipidaemia, obesity or hypertension, well known risk factors for development of cardiovascular disorders. Reported apnoeas were related to risk of coronary artery disease.

Phthalic esters in the indoor environment--test chamber studies on PVC-coated wallcoverings.

Phthalic acid esters are important additives in polyvinyl chloride (PVC) products. Since PVC plastisoles for the production of wallcoverings contain about 30% phthalic acid esters, it is a crucial question whether these products can contribute to the pollution of the indoor environment. In this study, the emission of several technically relevant phthalates from PVC-coated wallcoverings were measured in emission test chambers under standard room conditions. During a 14-day test period, both the chamber air concentrations and the condensation on a cooled plate (fogging) were determined. In the chamber air, maximum concentrations of 5.1 micrograms/m3 for di-n-butylphthalate (DBP), 2.08 micrograms/m3 for di-pentylphthalate (DPP) and 0.94 microgram/m3 for di-(2-ethylhexyl)phthalate (DEHP) were found. After 14 days of exposure, up to 60.4 micrograms DEHP and 17.7 micrograms DPP could be quantified on the cooled plates of the fogging apparatus. The amounts of DBP and DIBP were significantly lower. A simple exposure calculation indicated no specific risk of an increased phthalate exposure in rooms with PVC wallcoverings.

Short segment of human melanin-concentrating hormone that is sufficient for full activation of human melanin-concentrating hormone receptors 1 and 2.

Human melanin-concentrating hormone (hMCH) is a potent but nonselective agonist at human melanin-concentrating hormone receptors 1 and 2 (hMCH-1R and hMCH-2R, respectively). To determine the structural features of this neuropeptide which are necessary for efficient binding to and activation of the receptors, Ala-substituted, open-chain, and truncated analogues were synthesized and tested in the binding assays in CHO cells expressing hMCH-1R and hMCH-2R, and in functional assays measuring the level of intracellular calcium mobilization in human HEK-293 cells expressing these receptors. A compound consisting merely of the cyclic core of hMCH with the Arg attached to the N-terminus of the disulfide ring was found to activate both hMCH-1R and hMCH-2R about as effectively as full-length hMCH. Thus, the sequence Arg-cyclo(S-S)(Cys-Met-Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys) appears to constitute the "active core" that is necessary for agonist potency at hMCH-1R and hMCH-2R. A potent and approximately 4-fold more selective agonist at hMCH-1R than at hMCH-2R is also reported.

Potent and selective peptide agonists of alpha-melanotropin action at human melanocortin receptor 4: their synthesis and biological evaluation in vitro.

alpha-Melanotropin (alphaMSH) and several of its derivatives are potent but not selective agonists at melanocortin receptors 3, 4, and 5 present in the brain (MC3-5R). To differentiate between the physiological role of hMC-4R (believed to be involved in regulation of energy balance) from those of melanocortin receptors 3 and 5, potent and receptor-specific agonists are needed. Therefore, the cyclic derivatives of alphaMSH of a general structure, cyclo(X-His-d-Phe-Arg-Trp-Y)-NH(2), where X is succinic acid or an omega-amino-carboxylic acid, and Y is an alpha,omega-di-amino-carboxylic acid or an omega-carboxy-alpha-amino acid, were prepared and tested in binding assays and in cAMP assays on CHO cells expressing hMC3-5R. Several of the 21-membered or larger lactams turned out to be potent and hMC-4R-selective agonists. For instance, cyclo(CO-CH(2)-CH(2)-CO-His-d-Phe-Arg-Trp-Dab)-NH(2) (Dab: 2,4-di-amino-butyric acid) was a potent agonist at hMC-4R (EC(50) = 4 nM) with 55-fold selectivity over hMC-3R and greater than 1000-fold selectivity over hMC-5R. Another potent and selective compound was cyclo(NH-CH(2)-CH(2)-CO-His-d-Phe-Arg-Trp-Glu)-NH(2): EC(50) about 1 nM at hMC-4R, with 90-fold selectivity over hMC-3R and greater than 2000-fold selectivity over hMC-5R.

Early detection of COPD in a high-risk population using spirometric screening.

STUDY OBJECTIVES: To evaluate the efficacy of mass spirometry use for the detection of airflow obstruction in a high-risk population. DESIGN: Free spirometry was offered to smokers who were > 39 years of age with a smoking history of > 10 pack-years. Action was preceded by the dissemination of information on the causes and symptoms of COPD in the local mass media. SETTING: Pulmonary outpatient clinics in 12 large cities of Poland. PARTICIPANTS: Eleven thousand twenty-seven subjects with the following characteristics were screened: mean (+/- SD) age, 51.8 +/- 12.5 years; men, 57%; current or ex-smokers, 80%; and mean smoking history, 26.1 +/- 16.8 pack-years. INTERVENTIONS: Smoking history, simple spirometry (FVC and FEV(1)), and an antismoking advice. RESULTS: Spirometric signs of airway obstruction were found in 24.3% of the subjects who were screened. Of those subjects, mild obstruction was found in 9.5%, moderate obstruction was found in 9.6%, and severe obstruction was found in 5.2%. In smokers aged > or = 40 years who had a smoking history of > 10 pack-years, airway obstruction was found in 30.6%. Airway obstruction was present in 8.3% of smokers < 40 years of age who had a smoking history of < 10 pack-years. Of the 2,200 subjects who had never smoked in their lives, airway obstruction was found in 14.4%. CONCLUSIONS: Mass spirometry in high-risk groups is an effective and easy method for the early detection of COPD.

[Clinical value of polymesam recording in diagnosis of obstructive sleep apnea. Can we replace polysomnography with polymesam?]. / Ocena kliniczna ograniczonego badania aparatem Polymesam w rozpoznawaniu obturacy jnego bezdechu sennego. Czy polisomnografie mozna zastapic badaniem polymesam?

UNLABELLED: Polymesam (PM) recordings was performed in 320 patients admitted to Sleep Laboratory with suspicion of OSA. OSA was diagnosed in 179 of them (55.9%), group (PM-Ch). These patients were obese (BMI--34.3 +/- 6.7 kg/m2) and had moderately-severe OSA (RDI--41.5 +/- 19.9 and ODI--43.7 +/- 21.5). They suffered from excessive daytime sleepiness (ESS = 12.2 +/- 5.5). PM was negative in 141 person (44.1%), (PM-Z). Subjects PM-Z had significantly lower BMI and rarely suffered from excessive daytime sleepiness. In 38 subjects PM-Z a full PSG was performed. In 12 PSG confirmed OSA (AHI--31.6 +/- 19.9). Both studies (PM and PSG) were negative in 26 subjects. In 10 obese subjects PM-Ch full PSG confirmed diagnosis. CONCLUSIONS: PM recording can replace full PSG in majority of patients suspected of OSA. Patients with typical symptoms of OSA and negative PM require PSG.