Effect of ß-casein A1 or A2 milk on body composition, milk intake, and growth in Holstein, Simmental, and crossbred dairy calves of both sexes.

The aim of this study was to compare the effects of feeding homozygous ß-CN A1 or A2 milk on the body composition, milk intake, and growth of German Holstein (GH), German Simmental (GS), and crossbred (CR) dairy calves of both sexes during the first 2 wk of life. A total of 104 calves (n = 54 female, f; and n = 50 male, m) from the breed groups GH (n = 23), GS (n = 61), and crossbred GH × GS (n = 20) were evaluated. Calves were weighed after birth and received colostrum ad libitum. On the second day, calves were alternately housed in pairs in double-igloo systems according to their random birth order and received either A1 milk (n = 52; 27 female and 25 male) or A2 milk (n = 52; 27 female and 25 male). They were offered 7.5 L/d, and the individual actual total milk intake was recorded. Daily energy-corrected milk intake was also calculated based on the milk composition (fat and protein). Fecal scores were recorded daily. On d 15, visceral adipose tissue (VAT) volume was assessed by open magnetic resonance imaging and dual-energy X-ray absorptiometry (DXA). In addition, fat and lean mass (g), as well as bone mineral content (g) and bone mineral density (g/cm2), were determined by DXA. The body composition, milk intake, and growth were similar between the 2 types of milk in the first 2 wk of life. Female calves had more VAT and fat mass, but less lean mass than male calves. GH and CR calves had more VAT and less lean mass than GS calves. Male calves were heavier than female calves after birth and on d 15. The average days with diarrhea and diarrhea occurrence were similar between calves fed A1 and A2 milk and between both sex groups. GS calves presented slightly more days with diarrhea and increased odds of having diarrhea compared with GH calves, not differing from CR.

Neurodegeneration, oxidative stress and lipid metabolism plasma biomarkers to differentiate Parkinson's disease from atypical parkinsonian syndromes.

INTRODUCTION: The identification of blood biomarkers appears to be a means of improving diagnosis accuracy in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS). We, therefore, evaluate the performance of neurodegeneration, oxidative stress and lipid metabolism plasma biomarkers to distinguish PD from APS. METHODS: This was a monocentric study with a cross-sectional design. Plasma levels and discriminating power of neurofilament light chain (NFL), malondialdehyde (MDA) and 24S-Hydroxycholesterol (24S-HC) were assessed in patients with clinical diagnoses of PD or APS. RESULTS: In total, 32 PD cases and 15 APS cases were included. Mean disease durations were 4.75 years in PD group and 4.2 years in APS group. Plasma levels of NFL, MDA and 24S-HC differed significantly between the APS and PD groups (P=0.003; P=0.009; P=0.032, respectively). NFL, MDA and 24S-HC discriminated between PD and APS (AUC=0.76688; AUC=0.7375; AUC=0.6958, respectively). APS diagnosis significantly increased with MDA level≥23.628nmol/mL (OR: 8.67, P=0.001), NFL level≥47.2pg/mL (OR: 11.92, P<0.001) or 24S-HC level≤33.4pmol/mL (OR: 6.17, P=0.008). APS diagnosis considerably increased with the combination of NFL and MDA levels beyond cutoff values (OR: 30.67, P<0.001). Finally, the combination of NFL and 24S-HC levels, or MDA and 24S-HC levels, or all three biomarkers' levels beyond cutoff values systematically classified patients in the APS group. CONCLUSION: Our results suggest that 24S-HC and especially MDA and NFL could be helpful for differentiating PD from APS. Further studies will be needed to reproduce our findings on larger, prospective cohorts of patients with parkinsonism evolving for less than 3 years.

Gene transfer of two entry inhibitors protects CD4⁺ T cell from HIV-1 infection in humanized mice.

Targeting viral entry is the most likely gene therapy strategy to succeed in protecting the immune system from pathogenic HIV-1 infection. Here, we evaluated the efficacy of a gene transfer lentiviral vector expressing a combination of viral entry inhibitors, the C46 peptide (an inhibitor of viral fusion) and the P2-CCL5 intrakine (a modulator of CCR5 expression), to prevent CD4⁺ T-cell infection in vivo. For this, we used two different models of HIV-1-infected mice, one in which ex vivo genetically modified human T cells were grafted into immunodeficient NOD.SCID.γc⁻/⁻mice before infection and one in which genetically modified T cells were derived from CD34⁺ hematopoietic progenitors grafted few days after birth. Expression of the transgenes conferred a major selective advantage to genetically modified CD4⁺ T cells, the frequency of which could increase from 10 to 90% in the blood following HIV-1 infection. Moreover, these cells resisted HIV-1-induced depletion, contrary to non-modified cells that were depleted in the same mice. Finally, we report lower normalized viral loads in mice having received genetically modified progenitors. Altogether, our study documents that targeting viral entry in vivo is a promising avenue for the future of HIV-1 gene therapy in humans.

Necessity of subcutaneous suction drains in ileostomy reversal (DRASTAR)-a randomized, controlled bi-centered trial.

PURPOSE: Data regarding length of hospital stay of patients undergoing ileostomy reversal are very heterogeneous. There are many factors that may have an influence on the length of postoperative hospital stay, such as postoperative wound infections. One potential strategy to reduce their incidence and to decrease hospital stay is to insert subcutaneous suction drains. The purpose of this study was to examine the influence of the insertion of subcutaneous suction drains on hospital stay and postoperative wound infections in ileostomy reversal. Risk factors for postoperative wound infection were determined. METHODS: This is a randomized controlled two-center non-inferiority trial with two parallel groups. The total length of hospital stay as primary endpoint and the occurrence of a surgical site infection, the colonization of the abdominal wall with bacteria, and the occurrence of hematomas/seromas as secondary endpoints were monitored. RESULTS: One hundred eighteen patients with elective ileostomy reversal were included. Fifty-nine patients were randomly assigned to insertion of a subcutaneous suction drain, and 59 patients were randomly assigned to receive no drain. After 3 months of follow-up, 50 patients in the group with drain and 53 patients in the group without drain could be analyzed. Median total length of hospital stay was 8 days in the SD group and 9 days in the group without SD (p = 0.17). Fourteen percent of patients with SD and 17 % without SD developed SSI, p = 0.68. Multivariate analysis revealed anemia (p < 0.01), intraoperative bowel perforation (p = 0.02) and resident (p = 0.04) or fellow (p = 0.048) performing the operation as risk factors for SSI. CONCLUSIONS: This trial shows that the omission of subcutaneous suction drains is not inferior to the use of subcutaneous suction drains after ileostomy reversal in terms of length of hospital stay, surgical site infections, and hematomas/seromas.

Maternal and neonatal outcomes in pregnant women with PCOS: comparison of different diagnostic definitions.

STUDY QUESTION: Does the prevalence of adverse maternal and neonatal outcomes vary in women diagnosed with polycystic ovary syndrome (PCOS) according to different definitions? SUMMARY ANSWER: A comparison of different criteria revealed that there is a substantial risk for perinatal complications in PCOS women, regardless of the used definition. WHAT IS KNOWN ALREADY: Pregnant women with PCOS are susceptible to perinatal complications. At present, there are three main definitions for PCOS. So far, we are aware of only one study, which found that the elevated risk for complications varied widely depending on the different phenotypes and features but only considered a relatively small sample size for some of the phenotypes. STUDY DESIGN, SIZE, DURATION: Retrospective matched cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data of primiparous women with PCOS according to ESHRE/ASRM 2003 criteria and healthy controls giving birth to neonates ≥500 g were included. A total of 885 women were analysed: out of 177 women with PCOS, 85 (48.0%) met the National Institutes of Health (NIH) 1990 criteria, another 14 (7.9%) featured the additional phenotypes defined by The Androgen Excess and PCOS Society (AE-PCOS) 2006 criteria, 78 (44.1%) were classified as PCOS exclusively by the ESHRE/ASRM 2003 definition, and 708 represented the control group. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of adverse maternal (49.4 versus 64.3 versus 60.3%, P = 0.313) and neonatal (27.1 versus 35.7 versus 23.1%, P = 0.615) outcomes did not differ within the three PCOS groups (ESHRE/ASRM, NIH, AE-PCOS, respectively). Compared with healthy controls, the risk for maternal complications was increased in PCOS patients [odds ratio (OR) 2.57; 95% confidence interval (CI) 1.82-3.64; P < 0.001] while there was no difference in neonatal complications (OR 0.83; 95% CI 0.56-1.21; P = 0.343). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its retrospective design and the relatively small sample size, particularly in the AE-PCOS subgroup. WIDER IMPLICATIONS OF THE FINDINGS: Since women with PCOS have, regardless of the used definition, a high risk of maternal and neonatal complications they should be informed and advised to follow regular checks in units where problems can be detected early to allow specialized care. STUDY FUNDING/COMPETING INTERESTS: Marietta Blau Grant (Austrian Agency for International Cooperation in Education and Research; OeAD-GmbH) and mobility scholarship (Medical University of Graz).

Contrast-induced acute kidney injury after computed tomography prior to transcatheter aortic valve implantation.

AIM: To identify independent predictors of contrast medium-induced acute kidney injury (CI-AKI) after enhanced multidetector-row computed tomography (MDCT) prior to transcatheter aortic valve implantation (TAVI) in high-risk patients. MATERIALS AND METHODS: The present single-centre study analysed retrospectively 361 patients who were assessed using MDCT prior to TAVI. CI-AKI was defined as an increase in serum creatinine (SCr) of ≥ 25% or ≥ 0.5 mg/dl in at least one sample over baseline (24 h before MDCT) and at 24, 48, and 72 h after MDCT. RESULTS: A total of 38 patients (10.5%) experienced CI-AKI. As compared to patients without CI-AKI, they presented more frequently with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), (81.6% versus 64.4%, p = 0.045) and tended to receive higher volumes of iodinated contrast media (ICM; 55.3% versus 39%, p = 0.057). There was a significant interaction between baseline eGFR and the amount of intravenous ICM administered (pfor interaction = <0.001) identifying the amount of ICM >90 ml as independent predictive factor of CI-AKI only in patients with baseline eGFR <60 ml/min/1.73m(2) (OR 2.615; 95% CI: 1.21-5.64). CONCLUSION: One in ten elderly patients with aortic stenosis undergoing MDCT to plan a TAVI procedure experienced CI-AKI after intravenous ICM injection. Intravenous administration of <90 ml of ICM reduces this risk in patients with or without pre-existing impaired renal function. However, in the majority of patients renal function recovers before the TAVI procedure.

Adjuvant IMRT/XELOX radiochemotherapy improves long-term overall- and disease-free survival in advanced gastric cancer.

PURPOSE: In a retrospective analysis, adjuvant intensity-modulated radiation therapy (IMRT) combined with modern chemotherapy improved advanced gastric cancer survival rates compared to a combination of three-dimensional conformal radiation therapy (3D-CRT) and conventional chemotherapy. We report on the long-term outcomes of two consecutive patient cohorts that were treated with either IMRT and intensive chemotherapy, or 3D-CRT and conventional chemotherapy. PATIENTS AND METHODS: Between 2001 and 2008, 65 consecutive gastric cancer patients received either 3D-CRT (n = 27) or IMRT (n = 38) following tumor resection. Chemotherapy comprised predominantly 5-fluorouracil/folinic acid (5-FU/FA) in the earlier cohort and capecitabine plus oxaliplatin (XELOX) in the latter. The primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: Median OS times were 18 and 43 months in the 3D-CRT and IMRT groups, respectively (p = 0.0602). Actuarial 5-year OS rates were 26 and 47 %, respectively. Within the IMRT group, XELOX gave better results than 5-FU/FA in terms of OS, but this difference was not statistically significant. The primary cause of death in both groups was distant metastasis. Median DFS times were 14 and 35 months in the 3D-CRT and IMRT groups, respectively (p = 0.0693). Actuarial 5-year DFS rates were 22 and 44 %, respectively. Among patients receiving 5-FU/FA, DFS tended to be better in the IMRT group, but this was not statistically significant. A similar analysis for the XELOX group was not possible as 3D-CRT was almost never used to treat these patients. No late toxicity exceeding grade 3 or secondary tumors were observed. CONCLUSION: After a median follow-up period of over 5 years, OS and DFS were improved in the IMRT/XELOX treated patients compared to the 3D-CRT/5-FU/FA group. Long-term observation revealed no clinical indications of therapy-induced secondary tumors or renal toxicity.

[Cervical cancer screening in Germany. Current status]. / Gynäkologische Krebsvorsorge in Deutschland. Gegenwärtiger Stand.

Cervical cancer screening was introduced in Germany 40 years ago and the incidence of cancer of the cervix has subsequently decreased by close to 70%. The remaining incidence of 5,600 cases per year represents only 2.8% of all newly occurring cases of cancer in women and these cases occur mainly in patients who do not participate in regular screening. Thus, cervical cancer screening by cytological smears has been proven to be successful. The structure of the German cancer screening program is characterized by decentralized organization, exclusive involvement of medical specialists such as gynecologists and pathologists and strict quality assurance. The recruitment is 50% on a yearly basis and the cumulative participation over 3 years reaches 79%. Since 2008 all laboratories are required to report complete data sets to local quality control agencies.The Joint Federal Committee in charge of evaluating new technologies in Germany mandated an inquiry into the possible role of screening by human papillomavirus (HPV) testing. According to this report published by the Institute for Quality Assurance and Efficiency in Healthcare there are indications for advantages. There are, however, no data in the literature as to possible disadvantages of HPV testing. A similar study for the US Preventive Services Task Force was published in May 2011 with almost identical conclusions.

Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene.

OBJECTIVES: Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long-term viro-immunological follow-up of HIV-infected patients harbouring virus with protease insertions. METHODS: Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected. RESULTS: Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI-naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI-naïve patients were infected with an HIV-1 non-B subtype. Follow-up of these PI-naïve patients showed that the insert-containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI-experienced patients, 63% were infected with HIV-1 subtype B; one had been antiretroviral-free for 5 years and seven were heavily PI-experienced (median duration of follow-up 24 months; range 10-62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI-resistance mutations, and following long-term exposure to PIs. The insert-containing virus persisted for a median of 32 months (range 12-62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity. CONCLUSION: Our data, obtained during long-term follow-up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI-based regimens, although further work is required to confirm it.

Functional characteristics of apheresis-derived platelets treated with ultraviolet light combined with either amotosalen-HCl (S-59) or riboflavin (vitamin B2) for pathogen-reduction.

BACKGROUND: To examine if different pathogen-reduction technologies (PRTs) induce different degrees of platelet (PLT) storage lesion. DESIGN: Twenty-seven split triple-dose apheresis PLTs were PRT treated using ultraviolet light with either riboflavin (M) or psoralen (I) or remained untreated (C). Samples taken on days (d) 0 to 8 were analysed for PLT count, blood gas (pH, pO(2) and pCO(2)), metabolism (lactate, glucose, ATP content), in vitro function [swirling, hypotonic shock response (HSR) and aggregation], activation (p-selectin expression) and cellular integrity (JC-1 signal, annexin A5 release). RESULTS: Platelet counts of all study groups remained unchanged during storage indicating that PRT treatment did not induce relevant cell lysis. Although M units demonstrated the highest values for HSR until d5, PRT treatment lowered all parameters examined with significant differences to untreated controls by d7 of storage. During final storage, M was significantly superior over I for HSR, aggregation with TRAP-6 as agonist (collagen was similar), annexin A5 release and JC-1 signal. Regarding blood gas and metabolic analysis, the most evident effect of PRT was an elevated glycolytic flux combined with higher acidity due to increased lactate accumulation. Most likely due to impaired O(2) consumption, pH and ATP decreased more rapidly in I relative to C and M. CONCLUSION: Pathogen reduction technology-treated PLTs remained comparable to untreated units throughout 7 days of storage. Mitochondria-based oxidative respiration appeared up-regulated after the riboflavin-based PRT. Compared to the psoralen-based PRT, this resulted in significantly better ATP maintenance and in vitro function during the last storage period (d7, d8).

Pigment alterations in the brown mussel Perna perna.

Potential sex and/or gametogenic stage differences in the metabolism of chlorophyll-a and carotenoids in the brown mussel Perna perna of southern Brazil were studied using high performance liquid chromatography (HPLC). Carotenoids derived directly from diet (phytoplankton) were fucoxanthin plus diatoxanthin (diatoms), alloxanthin (cryptophytes) and zeaxanthin (mainly cyanobacteria). Females accumulated carotenoid-diols and epoxides (~3-4 mg/g-dry wt.) while males had much lower concentrations (~0.7 mg/g-dry wt.). An antioxidant/free radical scavenging role is proposed for carotenoids in females. Mean ratios of chlorophyll plus derivatives (Chlns-a) to carotenoids for male and female P. perna were 50:1 and 4:1, respectively. The higher ratio in males relates to both higher carotenoid contents in females plus higher total Chlns-a in males (~22 mg/g-dry wt.), relative to the females (~4 mg/g-dry wt.). Chlorophyll-a metabolism in both sexes followed two distinct pathways. First, cyclization of pyropheophorbide-a gave 13(2), 17(3)-cyclopheophorbide-a-enol (CPPaE) which was further oxidized to hydroxy-chlorophyllone. Second, chlorophyll-a derivatives retaining the 13(2)-carbomethoxy moiety were oxidized to purpurin-18 which was hydrolyzed to chlorin-p(6). In both cases, metabolism of dietary chlorophyll-a was oxidative and derivatives could either serve as antioxidants or merely be the results of non-specific digestive processes.

Restaging of patients with lymphoma. Comparison of low dose CT (20 mAs) with contrast enhanced diagnostic CT in combined [18F]-FDG PET/CT.

AIM: Assessment of the clinical benefit of i.v. contrast enhanced diagnostic CT (CE-CT) compared to low dose CT with 20 mAs (LD-CT) without contrast medium in combined [(18)F]-FDG PET/CT examinations in restaging of patients with lymphoma. PATIENTS, METHODS: 45 patients with non-Hodgkin lymphoma (n=35) and Hodgkin's disease (n=10) were included into this study. PET, LD-CT and CE-CT were analyzed separately as well as side-by-side. Lymphoma involvement was evaluated separately for seven regions. Indeterminate diagnoses were accepted whenever there was a discrepancy between PET and CT findings. Results for combined reading were calculated by rating indeterminate diagnoses according the suggestions of either CT or PET. Each patient had a clinical follow-up evaluation for >6 months. RESULTS: Region-based evaluation suggested a sensitivity/specificity of 66/93% for LD-CT, 87%/91% for CE-CT, 95%/96% for PET, 94%/99% for PET/LD-CT and 96%/99% for PET/CE-CT. The data for PET/CT were obtained by rating indeterminate results according to the suggestions of PET, which turned out to be superior to CT. Lymphoma staging was changed in two patients using PET/CE-CT as compared to PET/LD-CT. CONCLUSION: Overall, there was no significant difference between PET/LD-CT and PET/CE-CT. However, PET/CE-CT yielded a more precise lesion delineation than PET/LD-CT. This was due to the improved image quality of CE-CT and might lead to a more accurate investigation of lymphoma.

Inducible disruption of the c-myb gene allows allogeneic bone marrow transplantation without irradiation.

Allogeneic bone marrow (BM) transplantation enables the in vivo functional assessment of hematopoietic cells. As pre-conditioning, ionizing radiation is commonly applied to induce BM depletion, however, it exerts adverse effects on the animal and can limit experimental outcome. Here, we provide an alternative method that harnesses conditional gene deletion to ablate c-myb and thereby deplete BM cells, hence allowing BM substitution without other pre-conditioning. The protocol results in a high level of blood chimerism after allogeneic BM transplantation, whereas immune cells in peripheral tissues such as resident macrophages are not replaced. Further, mice featuring a low chimerism after initial transplantation can undergo a second induction cycle for efficient deletion of residual BM cells without the necessity to re-apply donor cells. In summary, we present an effective c-myb-dependent genetic technique to generate BM chimeras in the absence of irradiation or other methods for pre-conditioning.

Spatially distinct head and heart inducers within the Xenopus organizer region.

BACKGROUND: The mouse anterior visceral endoderm, an extraembryonic tissue, expresses several genes essential for normal development of structures rostral to the anterior limit of the notochord and has been termed the head organizer. This tissue also has heart-inducing activity and expresses mCer1 which, like its Xenopus homolog cerberus, can induce markers of cardiac specification and anterior neural tissue when ectopically expressed. We investigated the relationship between head and heart induction in Xenopus embryos, which lack extraembryonic tissues. RESULTS: We found three regions of gene expression in the Xenopus organizer: deep endoderm, which expressed cerberus; prechordal mesoderm, which showed overlapping but non-identical expression of genes characteristic of the murine head organizer, such as XHex and XANF-1; and leading-edge dorsoanterior endoderm, which expressed both cerberus and a subset of the genes expressed by the prechordal mesoderm. Microsurgical ablation of the cerberus-expressing endoderm decreased the incidence of heart, but not head, formation. Removal of prechordal mesoderm, in contrast, caused deficits of anterior head structures. Finally, although misexpression of cerberus induced ectopic heads, it was unable to induce genes thought to participate in head induction. CONCLUSIONS: In Xenopus, the cerberus-expressing endoderm is required for heart, but not head, inducing activity. Therefore, this tissue is not the topological equivalent of the murine anterior visceral endoderm. We propose that, in Xenopus, cerberus is redundant to other bone morphogenetic protein (BMP) and Wnt antagonists located in prechordal mesoderm for head induction, but may be necessary for heart induction.

Effects of alternations of plasma free fatty acid levels on pancreatic glucagon secretion in man.

The present investigation was undertaken to ascertain whether alterations in plasma free fatty acids (FFA) affect pancreatic glucagon secretion in man since FFA have been reported to influence pancreatic alpha cell function in other species. Elevation of plasma FFA from a mean (+/-SE) basal level of 0.478+/-0.036 mM to 0.712+/-0.055 mM after heparin administration caused plasma glucagon levels to fall approximately 50%, from a basal value of 122+/-15 pg/ml to 59+/-14 pg/ml (P < 0.001). Lowering of plasma FFA from a basal level of 0.520+/-0.046 mM to 0.252+/-0.041 mM after nicotinic acid administration raised plasma glucagon from a basal level of 113+/-18 pg/ml to 168+/-12 pg/ml (P < 0.005). Infusion of glucose elevated plasma glucose levels to the same degree that heparin raised plasma FFA levels. This resulted in suppression of plasma glucagon despite the fact that plasma FFA levels also were suppressed. Glucagon responses to arginine were diminished after elevation of plasma FFA (P < 0.01) and during infusion of glucose (P < 0.01). Diminution of plasma FFA by nicotinic acid did not augment glucagon responses to arginine. These results thus demonstrate that rather small alterations in plasma FFA within the physiologic range have a significant effect on glucagon secretion in man. Although the effects of glucose appear to predominate over those of FFA, alterations in plasma FFA may nevertheless exert an important physiologic influence over human pancreatic alpha cell function, especially in the postabsorptive state.

Adrenergic modulation of pancreatic glucagon secretion in man.

In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 mug/min), a beta adrenergic agonist, plasma glucagon rose from a mean (+/-SE) basal level of 104+/-10 to 171+/-15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 mug/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122+/-15 to 75+/-17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118+/-16 to 175+/-21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function.

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.

Light-induced Conductance Switching in Photomechanically Active Carbon Nanotube-Polymer Composites.

Novel, optically responsive devices with a host of potential applications have been demonstrated by coupling carbon nanomaterials with photochromic molecules. For light-induced conductance switching in particular, we have recently shown that carbon nanotube-polymer nanocomposites containing azobenzene are very attractive and provide stable and non-degradable changes in conductivity over time at standard laboratory conditions. In these composites, the photoswitching mechanisms are based on light-induced changes in electronic properties and related to the Pool-Frenkel conduction mechanism. However, no link between conductivity switching and the molecular motion of azobenzene chromophores could be found due to application of high elastic modulus polymer matrices. Here we report on single wall carbon nanotube-polymer nanocomposites with a soft polycaprolactone polymer host. Such a system clearly shows the transfer of light-induced, nano-sized molecular motion to macroscopic thickness changes of the composite matrix. We demonstrate that these photomechanical effects can indeed overshadow the electronic effects in conductivity switching behavior and lead to a reversion of the conductivity switching direction near the percolation threshold.

Effects of antiglaucoma drugs GLC756, a novel dopamine D2 agonist and D1 antagonist, and timolol on endotoxin-induced TNF-alpha release in serum of rats.

PURPOSE: Anti-inflammatory activity of an antiglaucoma drug may be an advantage for long-term treatment of glaucoma since it may reduce the risk of treatment-related inflammatory processes in outer compartments of the eye and probably also prevent or delay progression of glaucomatous retinal neurodegeneration. In this study, the effect of GLC756, a novel mixed dopamine D 2 receptor agonist and dopamine D 1 receptor antagonist, and timolol on endo-toxin-induced cytokine tumor necrosis factor-alpha (TNF-alpha) release in serum was examined. METHODS: For endotoxin-induced TNF-alpha release, 8-week-old Lewis rats were intravenously injected with 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone were either systemically (1 mg/kg SC for 5 days) or topically (0.4%, 0.5%, and 0.1%, respectively, 20 microL eye drops given 16 times over 48 hours in left and right eye) administered. TNF-alpha was measured in serum 2 and 48 hours after LPS induction. RESULTS: A marked TNF-alpha increase in serum was found 2 hours after LPS induction. Administration of GLC756 and betamethasone, systemically and topically, decreased TNF-alpha release. However, due to large scattering of mean values only the effect of systemically administered GLC756 was statistically significant. In contrast, timolol increased TNF-alpha values stronger than LPS alone. CONCLUSIONS: The significant suppression of LPS-induced TNF-alpha increase by GLC756 suggests an additional anti-inflammatory potential of the dopaminergic compound in the treatment of glaucoma.