Adipokine expression in brown and white adipocytes in response to hypoxia.

BACKGROUND: Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. METHODS: Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. RESULTS: Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. CONCLUSIONS: WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT.

Sympatho-adrenergic activity and the renin-angiotensin system are considered critical regulators of obesity and hypertension. The novel angiotensin II type 1 receptor-associated protein (ATRAP) has been demonstrated to modulate angiotensin II signalling in smooth muscle cells and cardiomyocytes. Adipose tissue expresses important renin angiotensin system components and contributes to cardiometabolic disease. However, ATRAP expression and regulation in adipocytes are unknown. We investigated expression of this novel modulator of angiotensin signalling and its regulation by beta-adrenergic receptors. We found ATRAP to be expressed in differentiated brown and white adipocytes. Stimulation of beta-adrenoceptors strongly suppressed ATRAP expression. We hypothesised a role for JAK/STAT signalling elements. Indeed, beta3-adrenergic stimulation robustly stimulated both STAT1 and STAT3 phosphorylation in a time- and dose-dependent manner. This effect was abrogated by inhibition of PKA and JAK2 signalling. Moreover, inhibition of JAK/STAT and PKA signalling reversed the beta3-adrenergic suppression of ATRAP expression. This study provides the first evidence for expression and adrenergic regulation of the angiotensin II signalling modulator ATRAP in adipocytes. Further, it indicates a novel regulatory link between beta-adrenergic and JAK/STAT signalling.

Screening for colorectal lesions with high-resolution video colonoscopes in a German male average-risk population at 40 to 59 years of age.

BACKGROUND: Prevalence data for colorectal neoplastic lesions obtained from screening colonoscopies have recently been reported for a U. S. American and a Polish average-risk population. However, prevalence data for a German average-risk population have not been published. METHODS: From 1998 until 2003 a screening colonoscopy was offered to all male participants of a health assessment program. In a total of 618 volunteers with an average risk for colorectal cancer, polypoid lesions were identified and removed using high-resolution video colonoscopes. The histological features of the lesions were categorised according to those of the most advanced one. An advanced lesion was defined as an adenoma of at least 1 cm in diameter, a polyp with villous histological features or high-grade intraepithelial neoplasms or a cancer. Data were analysed in two groups: age 40 - 49 years (group A) and age 50 - 59 years (group B). RESULTS: In group A (age 40 - 49 years, n = 285), 133 subjects (47 %) had polypoid lesions. Histological findings revealed that 57 subjects (20 %) had non-neoplastic and 76 subjects (27 %) had neoplastic lesions. In nine cases (3.2 %) polyps were classified as advanced lesions with a maximal diameter of 35 mm. In group B (age 50 - 59, n = 333), 183 subjects (55 %) had polypoid lesions. Histological findings revealed that 64 subjects (19 %) had non-neoplastic and 119 subjects (36 %) had neoplastic lesions. Among those, 34 (10.2 %) had advanced lesions with a maximal diameter of 55 mm. In neither group was an invasive cancer detected. The difference in the prevalence of neoplastic lesions between the two age groups was statistically significant (chi (2) = 5.85). An exceptionally high rate of 27 % neoplastic lesions was detected in subjects at 40 to 49 years of age. The rate of detected lesions in the group of older subjects was 36 %. CONCLUSION: By using high-resolution endoscopes we found an unexpectedly large number of neoplastic lesions in the colon even in a relatively young average-risk population. The question whether screening colonoscopy should therefore not only aim at detecting early colorectal cancer but also at identifying and removing precursor adenomas at younger ages clearly deserves further attention.

Detection of aquatic colloids in drinking water during its distribution via a water pipeline network.

Laser-induced Breakdown Detection (LIBD) is a highly sensitive method for the direct detection of nano-particles (colloids). During the detection process plasmas are generated on single particles by a focused laser beam, the resulting plasma light emissions are detected optically. The method is based on the difference in breakdown thresholds of liquid and solid matter, it is lower for solid material. The laser pulse energy is adjusted precisely so that in the pure liquid no breakdown events occur, and only in the presence of colloids is the breakdown threshold in the focal volume exceeded. The spatial distribution of several thousand recorded plasma flashes within the focal volume reveals the mean particle diameter. The evaluation of the number of breakdown events per number of laser pulses results in a breakdown probability, together with the particle size the concentration is calculated using specially-designed computer software. Compared to conventional laser light scattering methods the LIBD is approximately 6 orders of magnitude more sensitive for particles smaller than ca. 0.05 pm. Together with laser light obscuration the LIBD technique has been used successfully for the quantification of aquatic nano-particles during drinking water processing and its distribution via a pipeline network of nearly 1,700 km total length. In addition, the particulate content of several brands of mineral water has been investigated.

Erythropoiesis and performance after two weeks of living high and training low in well trained triathletes.

The purpose of our study was to evaluate hematologic acclimatization during 2 weeks of intensive normoxic training with regeneration at moderate altitude (living high-training low, LHTL) and its effects on sea-level performance in well trained athletes compared to another group of equally trained athletes under control conditions (living low - training low, CONTROL). Twenty-one triathletes were ascribed either to LHTL (n = 11; age: 23.0 +/- 4.3 yrs; VO 2 max: 62.5 +/- 9.7 [ml x min -1 x kg -1]) living at 1956 m of altitude or to CONTROL (n = 10; age: 18.7 +/- 5.6 yrs; VO 2 max: 60.5 +/- 6.7 ml x min -1 x kg -1) living at 800 m. Both groups performed an equal training schedule at 800 m. VO 2 max, endurance performance, erythropoietin in serum, hemoglobin mass (Hb tot, CO-rebreathing method) and hematological quantities were measured. A tendency to improved performance in LHTL after the camp was not significant (p < 0.07). Erythropoietin concentration increased temporarily in LHTL (Delta 14.3 +/- 8.7 mU x ml -1; p < 0.012). Hb tot remained unchanged in LHTL whereas was slightly decreased from 12.5 +/- 1.3 to 11.9 +/- 1.3g x kg -1 in CONTROL (p < 0.01). As the reticulocyte number tended to higher values in LHTL than in CONTROL, it seems that a moderate stimulation of erythropoiesis during regeneration at altitude served as a compensation for an exercise-induced destruction of red cells.

Xenin--a novel suppressor of food intake in rats.

Peptides related to the amphibian octapeptide xenopsin are present in various locations in mammalians, such as the gastrointestinal mucosa or brain tissue. In the gastrointestinal tract, xenopsin-related peptides induce partially neurogenic contractions of the colon in humans. In brain, however, their function is not known. Structural similarities of xenopsin-related peptides with neurotensin, a known modulator of ingestive behavior, suggest a possible role in feeding regulation. Therefore, we examined the effect of xenin, a recently identified xenopsin-related pentacosa peptide, on feeding behavior of fasted rats. Male Wistar rats (n=12) were intracerebroventricularly (i.c.v.) injected with either saline (10 microl) or xenin at 0.5, 1.5, 5 or 15 microg dissolved in an identical volume of 10 microl, respectively. In further experiments, xenin 15 microg/0.5 microl or 0.5 microl saline were injected into the lateral hypothalamus (LH). After injections, food intake (g), percentage of time spent with feeding (%) and prandial water intake (ml) were subsequently recorded for 2 h. After i.c.v. injection of 15 microg of xenin 1-h food intake was significantly reduced by 42% and 2-h food intake was diminished by 25%, respectively, compared to saline injection (p<0.01). This reduction of food intake was paralleled by a significant decrease of time spent with feeding by 41% (after 1 h) or 23% (after 2 h). The xenin-induced suppression of feeding behavior was dose-dependent. Thus, the minimal effective dose of xenin was 1.5 microg, while the dose of 0.5 microg was ineffective. Prandial water intake was significantly reduced only by the highest dose of xenin. Following injection of 15 microg of xenin into the lateral hypothalamus food intake was not different from control experiments. These data demonstrate a potent feeding suppressive action of xenin following intracerebroventricularly injection but not injection into the lateral hypothalamus suggesting a possible role of xenin in the central control of feeding termination and satiety.

[Occlusion of an esophagobronchial fistula by implantation of a Montgomery esophageal and a dynamic tracheal stent after failure of conventional endoprosthesis]. / Verschluss einer ösophagobronchialen Fistel durch Implantation eines ösophagealen Montgomery- und eines trachealen Dynamic-Stents nach Versagen konventioneller Endoprothetik.

Esophagorespiratory fistulas were frequently caused by malignant tumors, bougienage, laser therapy or radiochemotherapy. We here report the case of a patient with inoperable bronchial cancer, who developed a symptomatic esophagorespiratory fistula during combined radiochemotherapy with Cisplatin. A sufficient occlusion of the fistula could not be achieved with conventional plastic tubes or novel self-expanding silicone-coated Gianturco Song stents. After extraction of two Gianturco Song stents we inserted a Montgomery Salivary Bypass Stent into the esophagus and Dynamic stent into the trachea. This resulted in a total occlusion of the fistula. This present case suggests that the Montgomery stent may have little tendency to migrate due to its characteristic configuration and fixation and further demonstrates that the novel self-expanding silicone-coated Gianturco Song stents can be removed, if necessary.

Role of vagal fibers and bombesin/gastrin-releasing peptide-neurons in distention-induced gastrin release in rats.

In the rat the exact role of vagal fibers and the interaction between the extrinsic and intrinsic neural system in distention-induced gastrin release are still a matter of debate. Accordingly, the aim of the present study was to examine the contribution of afferent and efferent vagal fibers as well as intrinsic neurons on gastrin response to gastric distention. In anesthetized rats graded gastric distention by 5, 10 and 15 ml saline for 20 min caused a significant volume-dependent increase of plasma gastrin levels by 12+/-6 pg/ml (5 ml saline, n = 8, P =0.05), 26+/-7 pg/ml (10 ml saline, n = 10, P < 0.05) and 37+/-7 pg/ml (15 ml saline, n = 8, P < 0.01 ), respectively. To examine the role of the extrinsic vagal innervation, gastrin response to distention was studied in anesthetized rats after bilateral truncal vagotomy (n = 9) or selective afferent vagotomy following pretreatment with capsaicin (n = 6). Stimulation of gastrin release by 10 ml distention in sham-operated control rats was reversed to an inhibition after truncal vagotomy (26+/-7 vs. -11+/-4 pg/ml; P<0.05) and capsaicin-treatment (37+/-18 vs. -34+/-11 pg/ml; P<0.05). A contribution of cholinergic mechanisms to this vagovagal-mediated stimulation of distention-induced gastrin release was excluded, since atropine (100 microg/kg/h; n = 8) further augmented distention-stimulated gastrin release. Since bombesin/gastrin-releasing peptide (GRP)-neurons contribute to vagally stimulated gastrin secretion, we have examined gastrin response to distention in the presence of the specific bombesin-receptor antagonist D-Phe6-BN(6-13)OMe (400 microg/kg/h: n = 10). This bombesin-antagonist completely reduced distention-stimulated gastrin release in vivo. In contrast, distention of the isolated, extrinsically denervated stomach significantly decreased gastrin release by 13+/-5 pg/min (5 ml saline, n = 8, P < 0.05), 28+/-8 pg/min (10 ml saline, n = 11, P < 0.05) and 35+/-10 pg/min (15 ml saline, n = 8, P < 0.01), respectively, without changing the activity of bombesin/GRP-neurons. Distention-induced decrease of gastrin release was attenuated to 50 percent by atropine (10(-7) M: n = 10) or tetrodotoxin (TTX) (10(-6) M; n = 10), respectively. These data demonstrate, that in anesthetized rats distention-stimulated gastrin secretion depends on the activation of a vagovagal reflex and intrinsic bombesin/GRP-neurons. In contrast distention of the isolated rat stomach inhibits gastrin release in part via intrinsic cholinergic pathways and other as yet unknown mechanisms.

Identification and partial characterization of a domain in CFTR that may bind cyclic nucleotides directly.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is activated by cAMP-dependent phosphorylation. CFTR channel activity is also stimulated by cGMP-dependent protein kinase and protein kinase C. RESULTS: Here, we show that CFTR channel activation by cGMP may also occur directly. In oocytes from one-third of Xenopus donors, the activation of CFTR by cGMP averaged 87% of the level achieved by cAMP. The currents activated by either cyclic nucleotide displayed similar current-voltage relationships, kinetics, pharmacology and halide selectivity. Sequential stimulation by cAMP and cGMP was not additive, suggesting that both cyclic nucleotides activate the same channel; cGMP was one order of magnitude more potent than cAMP, and its action was insensitive to protein kinase inhibitors. Analysis of the amino-acid sequence of CFTR revealed a domain in the amino-terminal portion of the third cytoplasmic loop that resembles a class of cyclic-nucleotide-binding domains related to that of the catabolite-gene activator protein, CAP. Two CFTR residues in this domain--Val397 and Lys420--were identified which, when changed to alanine, altered the response to cGMP independently of the response to cAMP. CONCLUSIONS: We conclude that direct cyclic nucleotide binding may play a role in channel gating of CFTR. The cGMP-binding domain may provide a useful target for pharmacologic intervention in cystic fibrosis.

Brain regions where cholecystokinin exerts its effect on satiety.

The neuropeptide cholecystokinin (CCK), which is localized within the hypothalamus in integrative centers of feeding regulation, can suppress feeding behavior when exogenously applied into the lateral hypothalamus. Moreover, the endogenous peptide can be released from the same brain locus by stimuli that physiologically are associated with satiety (i.e., gastric meal loads). This endogenously released CCK contributes to the inhibition of feeding behavior during meal intake. These data strongly suggest that hypothalamic CCK may play a physiological role in the termination of feeding behavior. The presence of additional sites sensitive to CCK in extrahypothalamic regions (e.g., medial pons and lateral medulla) argue that the CCK receptor systems may functionally (1) have several links in a linear chain or (2) exist as several parallel systems. The relevance of these extrahypothalamic loci for feeding regulation will require further studies which need to be directed towards the physiological role of the endogenously released CCK in these particular areas, by use of selective CCK antagonists.

Cutaneous lymphosarcoma and leukemia in a cat.

A cat with cutaneous lymphosarcoma and leukemia, similar to Sézary syndrome in human beings, had initial clinical signs that included pruritus and exfoliative dermatosis, associated with weight loss and lymphadenopathy. Dermatopathologic findings and ultrastructural morphologic features of the circulating cells and cellular infiltrate were consistent with Sézary cells. Cutaneous lymphosarcoma and leukemia should be considered in cats with chronic pruritic exfoliative dermatoses.

Use of metyrapone to treat pituitary-dependent hyperadrenocorticism in a cat with large cutaneous wounds.

Metyrapone, a drug that inhibits cortisol production, was used to lower plasma cortisol concentration and alleviate skin lesions caused by pituitary-dependent hyper-adrenocorticism in a cat. Plasma cortisol concentration was documented by ACTH stimulation test results. During metyrapone treatment, alopecia, thin skin, and large cutaneous wounds resolved. Metyrapone was administered orally at a dosage of 65 mg/kg of body weight, every 12 hours. Metyrapone may be used in conjunction with surgery in the management of pituitary-dependent hyperadrenocorticism in cats.

Effect of galanin on food intake in rats: involvement of lateral and ventromedial hypothalamic sites.

Galanin has previously been reported to elicit feeding in satiated animals when injected into the hypothalamic paraventricular nucleus. It is not known, however, 1) whether this action is due to activation of feeding signals or suppression of satiety signals or both or 2) whether other hypothalamic regions such as the lateral hypothalamus (LH) or the ventromedial hypothalamus (VMH) are involved in this action. The effects of galanin on food intake were therefore examined in satiated and in fasted rats both after intracerebroventricular injection (0.1, 1, and 10 micrograms/10 microliters) and after microinjection (1 and 5 micrograms/0.5 microliters) into the LH and VMH. Twenty minutes after intracerebroventricular injection, galanin significantly and dose dependently augmented food intake by up to sevenfold in freely feeding rats and by up to 79% in fasted animals. The galanin-induced augmentation of cumulative food intake up to 2 h after injection was due to the initial increase in food consumption during the 0 to 20-min interval. This suggests that galanin acts by activation of feeding behavior and not by suppression of satiety signals in these fasted animals, in which satiety signals are presumably not initially operative. Twenty minutes after intrahypothalamic injections into both the LH and VMH, galanin (5 micrograms) significantly increased food consumption, fivefold in freely feeding rats and 30-35% in fasted rats. Thus stimulation of feeding by centrally injected galanin also involves loci within the LH and VMH.

Effect of intraduodenal or intragastric nutrient infusion on food intake in man.

In man, only little is known about the site of origin of satiety signals within the gastrointestinal tract. Therefore, it was the aim of this study to examine the role of the stomach and the small intestine as a source of satiety signals. 8 overnight fasted healthy volunteers received intraduodenal (100 or 200 ml/h) or intragastric (100 ml/h) infusions of a mixed liquid diet (Biosorb) or iso-osmolar saline, respectively. 20 minutes after start of the infusion, standardized mini-sandwiches and water were presented and food intake was recorded for the ensuing 90 minutes. During both rates of intraduodenal nutrient infusion, cumulative food intake was identical to that during saline infusion. However, during intragastric nutrient infusion, cumulative food intake was significantly reduced compared to saline infusion (30 +/- 1 vs. 36 +/- 2 sandwiches; p less than 0.05). These data indicate that food consumption in man is reduced, if initiation of eating is preceded by nutrient administration into the stomach, but not into the duodenum. This effect does not appear to be mediated by gastrin, since plasma gastrin levels were not different during gastric and duodenal nutrient administration. In conclusion, the results of this study suggest that the generation of satiety signals in man is dependent on the presence of food in the stomach. Food only in the duodenum has no effect, although synergistic gastric and intestinal mechanisms can as yet not be excluded.

Diabetes mellitus induced in a dog after administration of corticosteroids and methylprednisolone pulse therapy.

An 8-year-old ovariohysterectomized Chow Chow was referred because of dermatologic lesions diagnosed as pemphigus foliaceus. Intolerance to orally administered corticosteroids necessitated the use of methylprednisolone pulse therapy. One week after treatment, diabetes mellitus was diagnosed on the basis of blood and urine test results. For 3 years after treatment, the dog has remained a well-regulated diabetic. Complete remission of pemphigus foliaceus is maintained by alternate-day, orally administered prednisone (0.5 mg/kg of body weight).

Neuropeptide Y and food intake in fasted rats: effect of naloxone and site of action.

Central administration of neuropeptide Y (NPY) induces food intake in freely feeding animals and this effect is mediated by hypothalamic sites. Little is known, however, about the effect of NPY on food intake and site of action in food-deprived animals. To examine this further, 24-h fasted rats received injections of saline or NPY into the lateral cerebral ventricle (10 micrograms/10 microliters; n = 8) or into the lateral (LH) or ventromedial hypothalamus (VMH) (1 microgram/0.5 microliters; n = 44). In addition, intracerebroventricular (i.c.v.) injections of NPY were carried out with or without i.c.v. naloxone (25 micrograms), a specific opioid receptor antagonist. During the first 40 min food intake was not different with or without NPY. After 60 and 120 min, food intake was 5.9 +/- 0.4 g and 8.3 +/- 0.6 g with i.c.v. saline which was significantly augmented by i.c.v. NPY to 8.7 +/- 0.9 g and 14.4 +/- 1.5 g, respectively (P less than 0.05). This increase in food consumption was due to a prolongation of feeding time. The opioid receptor antagonist naloxone significantly augmented latency to feed, both in the absence and presence of NPY (8.0 vs 1.7 min or 14.7 vs 2.8 min, respectively) and abolished the NPY-induced increase in food intake. Following intrahypothalamic injection of NPY, an increase in food intake (greater than 20%) was observed in 50% of the histologically identified LH and VMH sites, but only in 15% of the injection sites outside the LH/VMH.(ABSTRACT TRUNCATED AT 250 WORDS)