A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels.

We investigated five methylation markers recently linked to body mass index, for their role in the neuropathology of obesity. In neuroimaging experiments, our analysis involving 23 participants showed that methylation levels for the cg07814318 site, which lies within the KLF13 gene, correlated with brain activity in the claustrum, putamen, cingulate gyrus and frontal gyri, some of which have been previously associated to food signaling, obesity or reward. Methylation levels at cg07814318 also positively correlated with ghrelin levels. Moreover, expression of KLF13 was augmented in the brains of obese and starved mice. Our results suggest the cg07814318 site could be involved in orexigenic processes, and also implicate KLF13 in obesity. Our findings are the first to associate methylation levels in blood with brain activity in obesity-related regions, and further support previous findings between ghrelin, brain activity and genetic differences.

Higher resting-state activity in reward-related brain circuits in obese versus normal-weight females independent of food intake.

BACKGROUND: In response to food cues, obese vs normal-weight individuals show greater activation in brain regions involved in the regulation of food intake under both fasted and sated conditions. Putative effects of obesity on task-independent low-frequency blood-oxygenation-level-dependent signals-that is, resting-state brain activity-in the context of food intake are, however, less well studied. OBJECTIVE: To compare eyes closed, whole-brain low-frequency BOLD signals between severely obese and normal-weight females, as assessed by functional magnetic resonance imaging (fMRI). METHODS: Fractional amplitude of low-frequency fluctuations were measured in the morning following an overnight fast in 17 obese (age: 39±11 years, body mass index (BMI): 42.3±4.8 kg m-2) and 12 normal-weight females (age: 36±12 years, BMI: 22.7±1.8 kg m-2), both before and 30 min after consumption of a standardized meal (~260 kcal). RESULTS: Compared with normal-weight controls, obese females had increased low-frequency activity in clusters located in the putamen, claustrum and insula (P<0.05). This group difference was not altered by food intake. Self-reported hunger dropped and plasma glucose concentrations increased after food intake (P<0.05); however, these changes did not differ between the BMI groups. CONCLUSION: Reward-related brain regions are more active under resting-state conditions in obese than in normal-weight females. This difference was independent of food intake under the experimental settings applied in the current study. Future studies involving males and females, as well as utilizing repeated post-prandial resting-state fMRI scans and various types of meals are needed to further investigate how food intake alters resting-state brain activity in obese humans.

A local outbreak of quinolone-resistant gonorrhoea in Norway, January 2008.

Since 1994, the incidence of gonorrhoea in Østfold county, Norway, has remained within the range of 1-8 cases per year, with 40% of cases being imported from abroad. On 20 January 2008, a general practitioner in the county diagnosed two seemingly unrelated domestic cases of gonorrhoea in three days and started contact tracing. A case was defined as a person with clinical symptoms of gonorrhoea who was a part of the sexual network. Available isolates from the samples taken were tested for resistance. Among 13 contacts identified in the sexual network, eight were classified as cases on the basis of symptoms, four of whom had laboratory-confirmed gonorrhoea. The index case acquired the infection abroad. The three isolated strains were resistant to ciprofloxacin, but sensitive to ceftriaxone which was used for treatment. In the outbreak described, most cases were diagnosed only after contact tracing although they had had symptoms. A quinolone-resistant strain was imported from abroad and introduced into the population. The Norwegian national treatment guidelines, which still recommend quinolones for empirical treatment, should be updated.

Alpha2-adrenoceptors inhibit antidiuretic hormone-stimulated Na+ absorption across tight epithelia (Rana esculenta).

In the present study we examined the effect of alpha-adrenergic regulation of active transepithelial Na+ absorption across the isolated frog skin epithelium. alpha-Adrenergic stimulation was achieved by addition of the adrenergic agonist noradrenaline in the presence of the beta-adrenergic blocker propranolol. alpha-Adrenergic stimulation inhibited basal as well as antidiuretic hormone (ADH)-stimulated Na+ transport. The ADH-induced increase in Na+ transport was accompanied by a membrane depolarisation due to an increase in the apical Na+ permeability. The subsequent application of noradrenaline inhibited the Na+ transport and repolarised the membrane potential, suggesting that alpha-adrenergic stimulation had reduced the apical Na+ permeability. The inhibition was abolished by the alpha2-adrenergic antagonist yohimbine whereas it was insensitive to the alpha1-adrenergic antagonist prazosin. alpha-Adrenergic stimulation had no effect on the cytosolic free [Ca2+] ([Ca2+]i). Incubation of the epithelium in the presence of ADH increased the cellular adenosine 3',5'-cyclic monophosphate (cAMP) content, an increase which was abolished by alpha-adrenergic activation. The effect of alpha-adrenergic stimulation on cAMP production was abolished by the alpha2-adrenergic antagonist yohimbine. We conclude that the noradrenaline-induced inhibition of the ADH-stimulated Na+ absorption and cAMP content is mediated by activation of alpha2-adrenoceptors. The data further indicate that the principal cells of the epithelium do not express alpha1-adrenoceptors. The noradrenaline-induced inhibition of the ADH-stimulated Na+ transport was concentration dependent, with 0.24+/-0.03 microM eliciting a half-maximal response. This alpha2-adrenergic-mediated down-regulation of Na+ absorption is achieved at a concentration of noradrenaline which begins to activate the NaCl secretion via the skin glands. The alpha2-adrenoceptors therefore appear to have considerable physiological importance.

Acute admissions to medical departments. A comparison between an urban and a rural district.

To compare hospitalization into medical departments, acute admissions into a city hospital and into a district hospital were compared prospectively over a two-week period. Patients referred to the city hospital were on average older, were more frequently living alone and they had a greater amount of social care attendance in their homes. On the other hand, distribution of referral diagnoses, overall patient activity, occupational status and contact with relatives were similar in the two areas. Sub-acute or acute illness was considered the main cause of admission in both areas; the amount of admissions for social reasons was 13 percent to the city hospital versus 3 percent to the district hospital. Relevant alternatives to hospitalization seemed to exist in 50 percent of the admissions to the city hospital versus only 3 percent to the district hospital. Since patients admitted for social reasons block hospital beds for a longer time period than those admitted for other reasons, these differences may to some extent explain why length of hospital stay is longer in city hospitals than in rural ones.

[Productivity and patient satisfaction. An evaluation of a urological short-term unit]. / Produktivitet og patienttilfredshed. Evaluering af et urologisk korttidsafsnit.

A study of a short term unit was performed in the Urological Department of the University Hospital of Copenhagen at Hvidovre. The study reflects the productivity of the unit by measuring patient flow, average admission time, utilization of the bed capacity and examination and treatment activities. Patient satisfaction was also evaluated. The results showed a total rise in productivity of 6%, a fall of one day in the average length of hospital stay and a high degree of patient satisfaction. Surgical short term units can be recommended, provided that admission criteria are precise, the nursing staff and medical staff of the unit are highly qualified and a continuity of the patients' stay at the hospital is secured.

Management of occupational risk to reproduction in a Danish county.

In Denmark pregnant women are entitled to receive maintenance allowances if the working conditions are suspected to be harmful to the fetus. The aim of the study was to evaluate these preventive measures taken to reduce occupational hazards to reproduction in Denmark. In 1985 1,247 pregnancies were identified in Ribe county during a 6-month period. Three hundred and forty-five women employed at the beginning of the pregnancy in manufacturing industries, construction work, health services, or agriculture were interviewed by telephone concerning their working conditions and the measures taken to reduce possible occupational risks. The response rate was 85%. On the basis of the interviews the risks and the preventive measures were assessed. Out of 200 women who had no changes in the working conditions during pregnancy, 46 (23%) had a working situation which was considered potentially harmful. For 57 the working situation was changed during the first months of pregnancy because of an assumed risk. The remaining 37 were out of work or received maintenance allowances because of occupational hazards. In this study a greater awareness than expected about possible occupational risks was found, but in some instances occupational risks were overlooked or neglected.

The role of exogenous calcium for gonadotropin-stimulated progesterone production by human granulosa-luteal cells.

Previous studies of cells from various species have indicated that exogenous calcium is necessary for gonadotropic stimulation of steroidogenesis. To determine whether this requirement for exogenous calcium is a universal attribute of steroidogenic cells, we studied baseline and stimulated progesterone (P) production by cultured human granulosaluteal cells obtained at the time of oocyte retrieval for in vitro fertilization (IVF). During 4 hours in culture, both cholera toxin (1.25 micrograms/mL) and human chorionic gonadotropin (hCG, 1 IU/mL) stimulated a significant (P less than 0.05) 2- to 4-times increase in P production. Both baseline and stimulated (cholera toxin or hCG) increases in P were unaffected when cellular uptake of exogenous calcium was inhibited by the calcium channel blocker nitrendipine (10 microM), or by culturing the cells in calcium-free medium or in calcium-free medium with [ethylenebis(oxyethylenenitrilo)]-tetra-acetic acid (EGTA, to chelate any possible free extracellular calcium). At later time points (24 and 48 hours), lack of available exogenous calcium began to have an inhibitory effect on P production, and the hCG effect was more sensitive to the lack of exogenous calcium than was the cholera toxin effect. We speculate that this apparent independence from exogenous calcium over a short culture period is due to the prior stimulation of these cells by exogenous gonadotropins employed in IVF cycles.

Rat granulosa cell apolipoprotein E secretion. Regulation by cell cholesterol.

We have demonstrated previously that cultured rat ovarian granulosa cells synthesize and secrete apoE, and this production of apoE is increased by agents that stimulate protein kinase A (cyclic AMP-dependent enzyme) (for example, cholera toxin) and protein kinase C (Ca2+/phospholipid-dependent enzyme) (for example, 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester). In the studies presented in this report, we have examined the effect of changes in cell cholesterol synthesis on the production of apoE by rat ovarian granulosa cells. Mevinolin, an inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of squalene cyclization, both attenuate the cholera toxin or 12-O-tetradecanoylphorbol-13-acetate stimulation of granulosa cell apoE secretion and apoE mRNA content in a dose-responsive manner. The inhibitory effect of mevinolin is reversed by the concomitant administration of mevalolactone, which provides the cells with the product of the reaction catalyzed by HMG-CoA reductase. Steroidogenesis per se has no effect on apoE production. Aminoglutethimide, which blocks the rate-limiting step in steroidogenesis, has no effect on apoE or apoE mRNA. The data indicate that products of HMG-CoA reductase (isoprenes, cholesterol and/or cholesterol metabolites) are required along with stimulators of protein kinases A and C, to regulate ovarian granulosa cell apoE production.

Regulation of apolipoprotein E biosynthesis by cAMP and phorbol ester in rat ovarian granulosa cells.

Apolipoprotein E (apoE) is synthesized by the liver and many peripheral cells. Rat ovarian granulosa cells synthesize and secrete apoE, and this apoE production is increased by agents that increase cellular cAMP. In these studies of granulosa cell apoE synthesis we have examined the effect of agents that stimulate various cell kinases, including protein kinases A, G, and C. The cell content of apoE mRNA was measured simultaneously. Cholera toxin (1.25 micrograms/ml), dibutyryl-cAMP (5 mg/ml), and forskolin (10(-4) M), all of which increase cellular cAMP, stimulate apoE accumulation in the medium 7-10-fold. On the other hand, dibutyryl-cGMP (20 mg/ml) has no effect on apoE synthesis or secretion. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (100 ng/ml), a protein kinase C stimulator, increases apoE accumulation in the medium 8-10-fold, while 4 alpha-phorbol 12,13-didecanoate, the inactive phorbol congener, has no such effect. The cAMP effect on apoE synthesis by granulosa cells is maximal at 48 h, while the phorbol ester effect is maximal at 72-96 h in culture. The data indicate that agents whose effects are mediated by activation of protein kinases A and C, but not G, stimulate granulosa cell apoE production. These effects on the amount of secreted apoE are temporally preceded by increases in the granulosa cell content of apoE messenger RNA. Together, these data suggest that the regulation of apoE production in the rat ovarian granulosa cell could involve transcriptional and post-transcriptional mechanisms.