Acute effects of acylated and unacylated ghrelin on total and high molecular weight adiponectin inmorbidly obese subjects.

BACKGROUND: Energy homeostasis and body weight are regulated by a highly complex network involving the brain, the digestive tract, and white adipose tissue (WAT). Knowledge about signaling pathways connecting digestive tract and WAT is limited. Gut hormone ghrelin and adipokine adiponectin are both decreased in obesity and they share a potent effect on insulin sensitivity: both adiponectin and the combination of acylated (AG) and unacylated ghrelin (UAG) improve insulin sensitivity. AIM: In the present study, we evaluated whether acute administration of UAG alone or combined with AG affects adiponectin concentrations. SUBJECTS AND METHODS: Eight morbidly obese non-diabetic subjects were treated with either UAG 200 µg, UAG 100 µg + AG 100 µg (Comb), or placebo in 3 episodes in a double blind randomized cross-over design. Study medication was administered as single iv bolus injections at 09:00 h after an overnight fast. High molecular weight (HMW) and total adiponectin, glucose, insulin, and total ghrelin and AG were measured up to 1 h after administration. RESULTS: HMW and total adiponectin concentrations did not change after administration of either UAG or Comb, nor were they different from placebo. Insulin concentrations decreased significantly after acute administration of Comb, reaching a minimum at 20 min: 58.2 ± 3.9% of baseline. CONCLUSIONS: Acute iv administration of UAG and the combination of UAG and AG in morbidly obese non-diabetic subjects without overt diabetes does not affect total or HMW adiponectin concentrations, neither directly nor indirectly by changing insulin concentrations.

Optimization of insulin-mediated creatine retention during creatine feeding in humans.

The aim of this study was to determine whether creatine ingested in combination with relatively small quantities of essential amino acids, simple sugars, and protein would stimulate insulin release and augment whole-body creatine retention to the same extent as a large bolus of simple sugars. Seven young, healthy males underwent three randomized, 3-day experimental trials. Each day, 24-h urine collections were made, and on the second day participants received 5 g creatine + water (creatine trial), 5 g creatine + approximately 95 g dextrose (creatine + carbohydrate) or 5 g creatine + 14 g protein hydrolysate, 7 g leucine, 7 g phenylalanine, and 57 g dextrose (creatine + protein, amino acids, and carbohydrate) via naso-gastric tube at three equally spaced intervals. Blood samples were collected at predetermined intervals after the first and third naso-gastric bolus. After administration of the first and third bolus, serum insulin concentration was increased by 15 min (P < 0.05) in the creatine + carbohydrate and creatine + protein, amino acids, and carbohydrate trials compared with creatine alone, and plasma creatine increased more following creatine alone (15 min, P < 0.05) than in the creatine + carbohydrate and creatine + protein, amino acids, and carbohydrate trials. Urinary creatine excretion was greater with creatine alone (P < 0.05) than with creatine + carbohydrate and creatine + protein, amino acids, and carbohydrate. Administration of creatine + protein, amino acids, and carbohydrate can stimulate insulin release and augment whole-body creatine retention to the same extent as when larger quantities of simple sugars are ingested.

Lipopolysaccharide modifies amiloride-sensitive Na+ transport processes across human airway cells: role of mitogen-activated protein kinases ERK 1/2 and 5.

Bacterial lipopolysaccharides (LPS) are potent inducers of proinflammatory signaling pathways via the activation of nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK), causing changes in the processes that control lung fluid homeostasis and contributing to the pathogenesis of lung disease. In human H441 airway epithelial cells, incubation of cells with 15 microg ml(-1) LPS caused a significant reduction in amiloride-sensitive I (sc) from 15 +/- 2 to 8 +/- 2 microA cm(-2) (p = 0.01, n = 13) and a shift in IC(50) amiloride of currents from 6.8 x 10(-7) to 6.4 x 10(-6) M. This effect was associated with a decrease in the activity of 5 pS, highly Na(+) selective, amiloride-sensitive <1 microM channels (HSC) and an increase in the activity of approximately 18 pS, nonselective, amiloride-sensitive >10 microM cation channels (NSC) in the apical membrane. LPS decreased alphaENaC mRNA and protein abundance, inferring that LPS inhibited alphaENaC gene expression. This correlated with the decrease in HSC activity, indicating that these channels, but not NSCs, were comprised of at least alphaENaC protein. LPS increased NF-kappaB DNA binding activity and phosphorylation of extracellular signal-related kinase (ERK)1/2, but decreased phosphorylation of ERK5 in H441 cells. Pretreatment of monolayers with PD98059 (20 microM) inhibited ERK1/2 phosphorylation, promoted phosphorylation of ERK5, increased alphaENaC protein abundance, and reversed the effect of LPS on I (sc) and the shift in amiloride sensitivity. Inhibitors of NF-kappaB activation were without effect. Taken together, our data indicate that LPS acts via ERK signaling pathways to decrease alphaENaC transcription, reducing HSC/ENaC channel abundance, activity, and transepithelial Na(+) transport in H441 airway epithelial cells.

The circulating concentration and ratio of total and high molecular weight adiponectin in post-menopausal women with and without osteoporosis and its association with body mass index and biochemical markers of bone metabolism.

OBJECTIVES: There is increasing evidence suggesting that adiponectin plays a role in the regulation of bone metabolism. DESIGN AND METHODS: This was a cross-sectional study of 34 post-menopausal women with and 37 without osteoporosis. All subjects had body mass index (BMI), bone mineral density (BMD), total-, high molecular weight (HMW)-adiponectin and their ratio, osteoprotegerin (OPG), a marker of bone resorption (betaCTX) and formation (P1NP) measured. RESULTS: We observed a positive correlation between BMI and BMD (r=0.44, p<0.001). When normalised for BMI, total-, HMW-adiponectin concentrations and HMW/total-adiponectin ratio were significantly lower in obese compared to lean subjects but there was no difference between those with or without osteoporosis. There were significant negative correlations between HMW/total-adiponectin ratio and BMI (r=-0.27, p=0.030) and with OPG (r=-0.44, p<0.001). CONCLUSIONS: Our data suggests that there is no significant difference in the circulating concentration of fasting early morning total- or HMW-adiponectin in post-menopausal women with or without osteoporosis. The correlation between HMW/total-adiponectin ratio and OPG may indicate that adiponectin could influence bone metabolism by altering osteoblast production of OPG thereby affecting osteoclasts mediated bone resorption.

Fluorescence as a tool for advanced diagnostics.

Fluorescence is a versatile technique with applications ranging from ultra-low-cost tests that are available over the counter via point of care instruments for use in the doctor's office to state-of-the-art clinical analysers. This article describes fluorescence, draws on a number of examples to illustrate its versatility and looks at what the future has in store for this powerful technique.

Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle.

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1-(13)C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d(5)-phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB (P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser(473) and p70(S6k) Thr(389) increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser(2448), 4E-BP1 Thr(37/46), or GSK3beta Ser(9) and decreased that of eEF2 Thr(56), higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.

A longitudinal study of changes in respiratory status in young adults, 1993-2001.

SETTING: There is little information regarding the prognosis of respiratory symptoms in early adulthood or the effects of potential risk factors. OBJECTIVE: To observe changing respiratory morbidity in a group of young adults over a period of 6-8 years. DESIGN: Subjects responding to three or more consecutive postal respiratory surveys carried out between 1993 and 2001 were included in the study. In addition to asthma (defined by a validated scoring system), two symptoms were examined: wheeze and being woken by cough. Five outcomes were defined: persistent, remission, new onset, never and intermittent. RESULTS: Of 2693 subjects who responded to at least one survey, about one third were eligible for inclusion: 10.2% reported wheeze at each survey (persistent) and 3.6% had persistent asthma. Persistent wheeze was seen in almost half (46.7%) of those reporting the symptom at their first survey. The corresponding figure for asthma was 32%. New onset wheeze was found in 16.2% of subjects without wheeze at baseline (asthma 9.7%). Smoking was significantly associated with new onset wheeze (OR 1.97, 95% CI 1.30-3.00) and asthma (OR 2.14, 95% CI 1.26-3.50), but not with persistent symptoms. CONCLUSION: These findings highlight the importance of policies to reduce smoking prevalence in young adults, and will help in the planning of future health care.

Prevalence of respiratory symptoms in under 5s: 1993 to 2001.

AIM: To describe changes in the prevalence of respiratory symptoms in 1-4 year olds in two general practice populations observed on four occasions over an eight year period. METHODS: In 1993, 1995, 1999, and 2001, questionnaires were posted to the parents of patients aged 15 years or younger and registered with either of two general practices. Only children aged 1-4 years at time of questionnaire completion were included in this study. For each survey, the prevalence of five key variables was determined. RESULTS: The response rates for all children in the four surveys were 72.8%, 70.6%, 65.0%, and 60.7% respectively. When respondents aged 1-4 years old were stratified into one-year age bands, there was a decrease in the prevalence of symptoms over the study period. This was statistically significant for wheeze and night cough in 2 year olds and for night cough in 4 year olds. Repeated antibiotic prescriptions decreased significantly for 2 and 3 year olds. There were no changes in the prevalence of hay fever or eczema and family history of asthma. CONCLUSIONS: The downward trend in symptom prevalence might represent a real decrease in symptoms or improvements in treatment. In the absence of changes in the prevalence of hay fever and family history of asthma, the downward trend in symptom prevalence may suggest changes in the prevalence of conditions other than asthma.

Trends in smoking habits: a longitudinal population study.

BACKGROUND: In 1998, the UK government published a White Paper in which it set long-term targets for reducing smoking in the population. This longitudinal study aimed to examine whether progress has been made in achieving these in two adult general practice populations over an 8-year period. METHODS: Postal respiratory questionnaires, based on the European Community Respiratory Health Questionnaire, were sent to all patients registered with two practices in North West England on four occasions between 1993 and 2001. Two analyses were carried out. The first (smaller cohort) included only those subjects answering the question concerning current smoking on all four occasions, the second (larger cohort) those answering at least twice. RESULTS: The smaller cohort included 2403 subjects (19.6% of all respondents). Almost one-quarter reported in all four surveys that they smoked, the highest proportion being in those aged 35-44 years. The proportion of smokers decreased from 34.2% (1993) to 30.3% (2001) (P < 0.001 for trend) and the prevalence of heavy smokers fell from 15.9 to 13.3% (P < 0.001 for trend) over the same period. There were, however, no reductions in those aged <45 years in 1993. These changes were confirmed in the larger cohort which included 7274 subjects (59.3% of respondents). CONCLUSIONS: If smoking-related disease is to be reduced, it is important that adults are targeted for smoking prevention and cessation before they reach middle age. Only when such initiatives show success will smoking prevention among their children become a practical proposition.

Cimetidine and chlorpheniramine in the treatment of chronic idiopathic urticaria: a multi-centre randomized double-blind study.

One hundred and twenty patients with chronic idiopathic urticaria, who entered a study at five centres (Sheffield, London, Bristol, Cardiff and Leeds) were treated with therapeutic doses of the H1 antagonist chlorpheniramine for 6 weeks. Histamine H1 non-responders (40 patients) were entered into a double-blind study and received chlorpheniramine plus cimetidine 400 mg q.d.s. (21 patients) or chlorpheniramine plus placebo (19 patients) for a further 8 weeks. The most important response measure was the change from baseline of the total symptom score: an assessment of the number and duration of new weals and degree of itching. There was a statistically significant difference between the average response in the two treatment groups in favour of chlorpheniramine plus cimetidine after 4 and 8 weeks' treatment (P less than 0.05 and P less than 0.01, respectively). No significant side-effects related to treatment were noted.

Clinical, histologic, and cell kinetic discriminants between lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma.

Patients described as having lamellar ichthyosis (LI) may not all have the same disorder. We studied nine patients, four of whom had erythroderma and generalized fine scaling, while the remainder had more marked scaling and hyperkeratosis without erythema. The former group is referred to as having nonbullous congenital ichthyosiform erythroderma (CIE), and the other is said to have LI. The clinical differences were paralleled by cell kinetic and histologic differences. The mean tritiated thymidine autoradiographic labeling indices were 9.36 +/- 4.05 and 19.70 +/- 5.84 for the LI and CIE groups, respectively. The histologic differences were delineated using 10-cm analogue scales and showed statistically significant differences for hyperkeratosis and parakeratosis. These data support the hypothesis that LI and CIE are separate disorders.

Follicular ichthyosis.

We describe four patients with congenital follicular hyperkeratosis, of whom three also had pseudoacanthosis nigricans and two had facial abnormalities. Skin specimens were studied by light microscopy, autoradiography, histochemistry and scanning electron microscopy, and the results were compared with those from patients with keratosis pilaris. The condition appears to constitute a distinctive form of ichthyosis in which the abnormal epidermal differentiation occurs mainly within the hair follicles.