Developing priorities for quality improvement in acute medicine using a modified Delphi method A consensus process hosted by the Society for Acute Medicine Quality Improvement Committee (SAM-QI).

INTRODUCTION: The SAM Quality Improvement Committee (SAM-QI), set up in 2016, has worked over the last year to determine the priority Acute Medicine QI topics. They have also discussed and put forward proposals to improve QI training for Acute Medicine professionals. METHODS: A modified Delphi process was completed over four rounds to determine priority QI topics. Online meetings were also used to develop proposals for QI training. RESULTS: Same Day Emergency Care (SDEC) was chosen as the priority topic for QI work within Acute Medicine. CONCLUSION: The SAM-QI group settled on SDEC being the priority topic for Acute Medicine QI development. Throughout the Delphi process SAM-QI has also developed proposals for QI training that will help Acute Medicine professionals deliver coordinated meaningful improvements in care.

Why do women attend antenatal care but give birth at home? a qualitative study in a rural Ghanaian District.

BACKGROUND: The Sustainable Development Goal Three has prioritised reducing maternal, under-5 and neonatal mortalities as core global health policy objectives. The place, where expectant mothers choose to deliver their babies has a direct effect on maternal health outcomes. In sub-Saharan Africa, existing literature has shown that some women attend antenatal care during pregnancy but choose to deliver their babies at home. Using the Andersen and Newman Behavioural Model, this study explored the institutional and socio-cultural factors motivating women to deliver at home after attending antenatal care. METHODS: A qualitative, exploratory, cross-sectional design was deployed. Data were collected from a purposive sample of 23 women, who attended antenatal care during pregnancy but delivered their babies at home, 10 health workers and 17 other community-level stakeholders. The data were collected through semi-structured interviews, which were audio-recorded, transcribed and thematically analysed. RESULTS: In line with the Andersen and Newman Model, the study discovered that traditional and religious belief systems about marital fidelity and the role of the gods in childbirth, myths about consequences of facility-based delivery, illiteracy, and weak women's autonomy in healthcare decision-making, predisposed women to home delivery. Home delivery was also enabled by inadequate midwives at health facilities, the unfriendly attitude of health workers, hidden charges for facility-based delivery, and long distances to healthcare facilities. The fear of caesarean section, also created the need for women who attended antenatal care to deliver at home. CONCLUSION: The study has established that socio-cultural and institutional level factors influenced women's decisions to deliver at home. We recommend a general improvement in the service delivery capacity of health facilities, and the implementation of collaborative educational and women empowerment programmes by stakeholders, to strengthen women's autonomy and reshape existing traditional and religious beliefs facilitating home delivery.

Implementation of midwifery continuity of care models for Indigenous women in Australia: Perspectives and reflections for the United Kingdom.

Maternity models that provide midwifery continuity of care have been established to increase access to appropriate services for Indigenous Australian women. Understanding the development and implementation of continuity models for Indigenous women in Australia provides useful insights for the development and implementation of similar models in other contexts such as those for vulnerable and socially disadvantaged women living in the United Kingdom. To ensure better health outcomes for mothers and babies, it is crucial to promote culturally competent and safe public health models in which midwives work collaboratively with the multidisciplinary team.

Functional dyspepsia: the economic impact to patients.

BACKGROUND: Although highly prevalent, little is known about the economic impact of functional dyspepsia (FD). AIMS: To quantify FD patients' health care utilisation patterns and to estimate direct and indirect costs of FD to patients. METHODS: ICD-9 codes identified adult patients with dyspepsia. A validated questionnaire was mailed to patients who met Rome III criteria for FD. RESULTS: Three hundred and fifty-five patients met all inclusion criteria. The response rate was 63%. The respondents' mean age was 50 (14) years; 75% were women; 52% of respondents rated their FD as moderate. Patients reported 3 visits (mean) to their PCP over 12 months; 75% reported having blood work, 92% an EGD, 59% an ultrasound and 40% a CT scan. The direct cost of testing using Medicare reimbursement rates per patient was $582. To treat FD symptoms, 89% tried dietary changes, 89% over-the-counter medications, 87% prescription medications and 25% alternative therapies. Mean patient expenditure over the last year was $246 for OTC medications (range $0-12,000), $290 for co-payments (range $0-9,000) and $110 for alternative treatments (range $0-3,741). Total mean direct cost yearly to patients was $699. In the 7 days prior to completing the questionnaire, respondents reported a mean of 1.4 h absence from work. Extrapolating the results to the US population, we conservatively calculate the costs of FD were $18.4 billion in 2009. CONCLUSIONS: Functional dyspepsia patients incur significant direct and indirect costs and work productivity is impaired by dyspeptic symptoms.

Comparison of on-line detectors for field flow fractionation analysis of nanomaterials.

Characterization of nanomaterials must include analysis of both size and chemical composition. Many analytical techniques, such as dynamic light scattering (DLS), are capable of measuring the size of suspended nanometer-sized particles, yet provide no information on the composition of the particle. While field flow fractionation (FFF) is a powerful nanoparticle sizing technique, common detectors used in conjunction with the size separation, including UV, light-scattering, and fluorescence spectroscopy, do not provide the needed particle compositional information. Further, these detectors do not respond directly to the mass concentration of nanoparticles. The present work describes the advantages achieved when interfacing sensitive and elemental specific detectors, such as inductively coupled plasma atomic emission spectroscopy and mass spectrometry, to FFF separation analysis to provide high resolution nanoparticle sizing and compositional analysis at the µg/L concentration level, a detection at least 10-100-fold lower than DLS or FFF-UV techniques. The full benefits are only achieved by utilization of all detector capabilities, such as dynamic reaction cell (DRC) ICP-MS. Such low-level detection and characterization capability is critical to nanomaterial investigations at biologically and environmentally relevant concentrations. The techniques have been modified and applied to characterization of all four elemental constituents of cadmium selenide-zinc sulfide core-shell quantum dots, and silver nanoparticles with gold seed cores. Additionally, sulfide coatings on silver nanoparticles can be detected as a potential means to determine environmental aging of nanoparticles.

Antioxidant dietary supplementation in mice exposed to proton radiation attenuates expression of programmed cell death-associated genes.

Dietary antioxidants have radioprotective effects after ionizing radiation exposure that limit hematopoietic cell depletion. We sought to determine the mechanism of proton-induced hematopoietic cell death in animals receiving a moderate dose of whole-body proton radiation. In addition, animals were maintained on diets supplemented with or without dietary antioxidants. In the presence of the dietary antioxidants, total bone marrow mRNA and protein expression of apoptosis-related genes were decreased compared to the expression profiles in the irradiated mice not receiving the antioxidant formulation. These data confirm high-energy proton-induced gene expression of classical apoptosis markers including BAX, caspase-3 and PARP-1. Antioxidant supplementation resulted in decreased expression of these genes in addition to increased protein expression of the anti-apoptosis markers Bcl2 and Bcl-xL. In conclusion, oral supplementation with antioxidants appears to be an effective approach for radioprotection against hematopoietic cell death.

Polyphenol-rich grape powder extract (GPE) attenuates inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media.

BACKGROUND: Obesity-associated inflammation is characterized by an increased abundance of macrophages (MPhis) in white adipose tissue (WAT), leading to the production of inflammatory cytokines, chemokines and prostaglandins (PGs) that can cause insulin resistance. Grape powder extract (GPE) is rich in phenolic phytochemicals that possess anti-oxidant and anti-inflammatory properties. OBJECTIVE: We examined the ability of GPE to prevent lipopolysaccharide (LPS)-mediated inflammation in human MPhis and silence the cross-talk between human MPhis and adipocytes. DESIGN: We investigated the effect of GPE pretreatment on LPS-mediated activation of mitogen activated protein kinases (MAPKs), nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1), and induction of inflammatory genes in human MPhis (that is, differentiated U937 cells). In addition, we determined the effect of GPE pretreatment of MPhis on inflammation and insulin resistance in primary human adipocytes incubated with LPS-challenged MPhi-conditioned medium (MPhi-CM). METHODS AND RESULTS: Pretreatment of MPhis with GPE attenuated LPS-induction of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta; chemokines, such as IL-8 and interferon-gamma inducible protein-10 (IP-10); and a marker of PG production, cyclooxygenase-2 (COX-2). Grape powder extract also attenuated LPS activation of MAPKs, NF-kappaB and AP-1 (c-Jun), as evidenced by decreased (1) phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38; (2) degradation of IkappaBalpha and activation of an NF-kappaB reporter construct; and (3) phosphorylation of c-Jun and Elk-1. Using LPS-challenged MPhi-CM, GPE pretreatment attenuated MPhi-mediated inflammatory gene expression, activation of an NF-kappaB reporter and suppression of insulin-stimulated glucose uptake in human adipocytes. CONCLUSION: Collectively, these data demonstrate that GPE attenuates LPS-mediated inflammation in MPhis, possibly by decreasing the activation of MAPKs, NF-kappaB and AP-1, and that GPE decreases the capacity of LPS-stimulated MPhis to inflame adipocytes and cause insulin resistance.

COMPARATIVE ASSESSMENT OF TOTAL PHENOLIC CONTENT IN SELECTED MEDICINAL PLANTS.

This study was to compare the total phenolic (TP) content in extracts from eleven plant materials collected at different geographical locations in Kenya, Nigeria, and USA. These plants have been selected because the majority of them are highly pigmented, from yellow to purple, and would therefore have economic value in industries for producing antioxidants and surfactants. Two of them were collected from the industrial and domestic waste outlets. Each analysis was achieved using the Folin-Ciocalteau technique. The order of decreasing phenolic acid content as gallic acid concentration (mg/g dry weight) was Prunus africana (55.14) > Acacia tortilis (42.11) > Khaya grandifoliola (17.54) > Curcuma longa (17.23) > Vernonia amygdalina (14.9)> Russelia equisetiformis (14.03) > Calendula officinalis (7.96) >Phragmites australis (control) (7.09) > Rauwolfia vomitoria (6.69) > Phragmites australis (industrial) (6.21) > Cnidoscolus aconitifolius (5.6). The TP contents of Spartina alterniflora species were below the detection limit.

Effect of Cnidoscolus aconitifolius leaf extract on the blood glucose and insulin levels of inbred type 2 diabetic mice.

The effects of Cnidoscolus aconitifolius (CA) leaf extract and chlorpropamide on blood glucose and insulin levels in the inbred type 2 diabetic mice are reported. After treatment with CA, the glucose levels were measured at 0 and 2-hour intervals in experimental groups and controls. Group I received no treatment and served as control; Group II was the reference and it received chlorpropamide; Groups I-III were moderately diabetic, 100-300 mg/dL blood glucose levels while Group IV were severely diabetic (> 300 mg/dL). Groups III and IV received CA and served as test groups. There was no significant difference between the blood glucose levels at 0 and 2 hours for the control group, (P>0.23) but there were statistically significant differences for Group II (P<0.0002); Group III (P<0.002) and Group IV (P<0.0001). For moderately diabetic mice, CA and chlorpropamide decreased the glucose levels by 25.6% and 16.3% respectively while for the severely diabetic mice CA decreased the blood glucose by 43.7%. It is proposed that CA has an insulinogenic property that possibly stimulated dormant beta-cells to secrete insulin. The histopathology of several organs in the treated animals was found to differ from the expected. The islets of Langerhans for example were found to be preserved in the time frame examined. Also the liver and kidney were found to display milder pathology in the treated groups.

Protective effects of L-selenomethionine on space radiation induced changes in gene expression.

Ionizing radiation can produce adverse biological effects in astronauts during space travel. Of particular concern are the types of radiation from highly energetic, heavy, charged particles known as HZE particles. The aims of our studies are to characterize HZE particle radiation induced biological effects and evaluate the effects of L-selenomethionine (SeM) on these adverse biological effects. In this study, microarray technology was used to measure HZE radiation induced changes in gene expression, as well as to evaluate modulation of these changes by SeM. Human thyroid epithelial cells (HTori-3) were irradiated (1 GeV/n iron ions) in the presence or in the absence of 5 microM SeM. At 6 h post-irradiation, all cells were harvested for RNA isolation. Gene Chip U133Av2 from Affymetrix was used for the analysis of gene expression, and ANOVA and EASE were used for a determination of the genes and biological processes whose differential expression is statistically significant. Results of this microarray study indicate that exposure to small doses of radiation from HZE particles, 10 and 20 cGy from iron ions, induces statistically significant differential expression of 196 and 610 genes, respectively. In the presence of SeM, differential expression of 77 out of 196 genes (exposure to 10 cGy) and 336 out of 610 genes (exposure to 20 cGy) is abolished. In the presence or in the absence of SeM, radiation from HZE particles induces differential expression of genes whose products have roles in the induction of G1/S arrest during the mitotic cell cycle, as well as heat shock proteins. Some of the genes, whose expressions were affected by radiation from HZE particles and were unchanged in irradiated cells treated with SeM, have been shown to have altered expression levels in cancer cells. The conclusions of this report are that radiation from HZE particles can induce differential expression of many genes, some of which are known to play roles in the same processes that have been shown to be activated in cells exposed to radiation from photons (like cell cycle arrest in G1/S), and that supplementation with SeM abolishes HZE particle-induced differential expression of many genes. Understanding the roles that these genes play in the radiation-induced transformation of cells may help to decipher the origins of radiation-induced cancer.

Evidence for a stimulatory action of melanin-concentrating hormone on luteinising hormone release involving MCH1 and melanocortin-5 receptors.

The present series of studies aimed to further our understanding of the role of melanin-concentrating hormone (MCH) neurones in the central regulation of luteinising hormone (LH) release in the female rat. LH release was stimulated when MCH was injected bilaterally into the rostral preoptic area (rPOA) or medial preoptic area (mPOA), but not when injected into the zona incerta (ZI), of oestrogen-primed ovariectomised rats. In rats that were steroid-primed to generate a surge-like release of LH, MCH administration into the ZI blocked this rise in LH release: no such effect occurred when MCH was injected into the rPOA or mPOA. In vitro, MCH stimulated gonadotrophin-releasing hormone (GnRH) release from hypothalamic explants. Double-label immunohistochemistry showed GnRH-immunoreactive neurones in the vicinity of and intermingled with immunoreactive MCH processes. MCH is the endogenous ligand of the MCH type 1 receptor (MCH1-R). Previously, we have shown a role for melanocortin-5 receptors (MC5-R) in the stimulatory action of MCH, so we next investigated the involvement of both MCH1-R and/or MC5-R in mediating the actions of MCH on GnRH and hence LH release. The stimulatory action of MCH in the rPOA was inhibited by administration of antagonists for either MCH1-R or MC5-R. However, in the mPOA, the action of MCH was blocked only by the MC5-R antagonist. LH release was stimulated by an agonist for MC5-R injected into the rPOA or mPOA; this was blocked by the MC5-R antagonist but not the MCH1-R antagonist. These results indicate that both MCH1-R and MC5-R are involved in the central control of LH release by MCH.

Mucosal bacteria in ulcerative colitis.

Ulcerative colitis (UC) is an acute and chronic inflammatory bowel disease of unknown aetiology, although bacterial species belonging to the normal colonic microbiota are known to be involved in its initiation and maintenance. Several organisms have been linked to the disease; however, mucosa-associated bacteria are more likely to be involved than their luminal counterparts, due to their close proximity to the host epithelium. Comparative bacteriological analyses were done on rectal biopsies to investigate differences in mucosal bacteria in patients with UC and healthy controls. Complex bacterial communities were found in both groups, with significant reductions in bifidobacterial numbers in UC, which suggested that they might have a protective role in the disease. Accordingly, a therapy for treating UC was designed, with the aim of modifying the mucosal microbiota to increase bifidobacterial colonisation and reduce inflammation. Ranges of mucosal and faecal bifidobacteria were tested for their substrate preferences and their abilities to survive under a variety of environmental conditions. A synbiotic comprising a probiotic (Bifidobacterium longum) isolated from healthy rectal mucosa combined with a prebiotic (oligofructose-enriched inulin - Synergy 1) was developed. The treatment was used in a randomised controlled trial involving eighteen patients with active UC, for a period of 1 month. Rectal biopsies were collected at the beginning and end of the study. Bacteriological analysis and transcription levels of epithelium-related immune markers were assessed. Results demonstrated that short-term synbiotic treatment resulted in increased bifidobacterial colonisation of the rectal mucosa and induced significant reductions in the expression of molecules that control inflammation in active UC.

Chemical alteration of the rhizosphere of the mycorrhizal-colonized wheat root.

Plexiglass pot growth chamber experiments were conducted to evaluate the chemical alterations in the rhizosphere of mycorrhizal wheat roots after inoculation with Glomus intraradices [arbuscular mycorrhizal fungus (AMF)]. Exchange resins were used as sinks for nutrients to determine whether the inoculated plant can increase the solubility and the uptake of P and micronutrients. Treatments included: (1) soil (bulk soil); (2) AMF inoculation no P addition (I-P); (3) no inoculation with no P addition (NI-P); (4) AMF inoculation with addition of 50 mg P (kg soil)(-1) (I+P), and (5) no inoculation with addition of 50 mg P (kg soil)(-1) (NI+P). The AMF inoculum was added at a rate of four spores of G. intraradices (g soil)(-1). The exchange resin membranes were inserted vertically 5 cm apart in the middle of Plexiglass pots. Spring wheat (Triticum aestivum cv. Len) was planted in each Plexiglass pot and grown for 2 weeks in a growth chamber where water was maintained at field capacity. Rhizosphere pH and redox potential (Eh), nutrient bioavailability indices and mycorrhizal colonization were determined. Mycorrhizal inoculation increased the colonization more when P was not added, but did not increase the shoot dry weight at either P level. The rhizosphere pH was lower in the inoculated plants compared to the noninoculated plants in the absence of added P, while the Eh did not change. The decrease in pH in the rhizosphere of inoculated plants could be responsible for the increased P and Zn uptake observed with inoculation. In contrast, Mn uptake was decreased by inoculation. The resin-adsorbed P was increased by inoculation, which, along with the bioavailability index data, may indicate that mycorrhizal roots were able to increase the solubility of soil P.

Hypothalamic actions of neuromedin U.

The central nervous system and gut peptide neuromedin U (NMU) inhibits feeding after intracerebroventricular injection. This study explored the hypothalamic actions of NMU on feeding and the hypothalamo-pituitary-adrenal axis. Intraparaventricular nucleus (intra-PVN) NMU dose-dependently inhibited food intake, with a minimum effective dose of 0.1 nmol and a robust effect at 0.3 nmol. Feeding inhibition was mapped by NMU injection into eight hypothalamic areas. NMU (0.3 nmol) inhibited food intake in the PVN (0-1 h, 59 +/- 6.9% of the control value; P < 0.001) and arcuate nucleus (0-1 h, 76 +/- 10.4% of the control value; P < 0.05). Intra-PVN NMU markedly increased grooming and locomotor behavior and dose-dependently increased plasma ACTH (0.3 nmol NMU, 24.8 +/- 1.9 pg/ml; saline, 11.4 +/- 1.0; P < 0.001) and corticosterone (0.3 nmol NMU, 275.4 +/- 40.5 ng/ml; saline, 129.4 +/- 25.0; P < 0.01). Using hypothalamic explants in vitro, NMU stimulated CRH (100 nM NMU, 5.9 +/- 0.95 pmol/explant; basal, 3.8 +/- 0.39; P < 0.01) and arginine vasopressin release (100 nM NMU, 124.5 +/- 21.8 fmol/explant; basal, 74.5 +/- 7.6; P < 0.01). Leptin stimulated NMU release (141.9 +/- 20.4 fmol/explant; basal, 92.9 +/- 9.4; P < 0.01). Thus, we describe a novel role for NMU in the PVN to stimulate the hypothalamo-pituitary-adrenal axis and locomotor and grooming behavior and to inhibit feeding.

The actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes.

Tuberoinfundibular peptide is a recently discovered agonist for the PTH receptor-2; the latter has a wide distribution including the external zone of the median eminence of the hypothalamus, suggesting a role in neuroendocrine function. We have investigated the effects of tuberoinfundibular peptide on the hypothalamo-pituitary axes in vitro and in vivo. Tuberoinfundibular peptide had effects on the hypothalamo-pituitary-adrenal axis with increased release of ACTH-releasing factor (tuberoinfundibular peptide 100 nM 4.4 +/- 0.6 pmol/explant vs. control 2.9 +/- 0.4 pmol/explant, P < 0.001) and increased release of arginine vasopressin (tuberoinfundibular peptide 100 nM 563.5 +/- 55.5 fmol/explant vs. control 73.4 +/- 9.6 fmol/explant, P < 0.01) from in vitro hypothalamic explants. Intracerebroventricular administration of tuberoinfundibular peptide and PTH((1-34)) resulted in elevated plasma ACTH at 10 min post injection (saline 13.5 +/- 2.1 pg/ml, tuberoinfundibular peptide 3 nmol 32.3 +/- 4.0 pg/ml; P < 0.01 to saline: PTH((1-34)) 10 nmol 28.9 +/- 3.2 pg/ml: P < 0.05 to saline). Tuberoinfundibular peptide also had both in vitro and in vivo effects on the hypothalamo-pituitary-gonadal axis with increased release of LH-releasing hormone (tuberoinfundibular peptide 100 nM 28.5 +/- 5.1 fmol/explant vs. control 19.3 +/- 2.5 fmol/explant, P < 0.05) from in vitro hypothalamic explants. Both intracerebroventricular and peripheral administration of tuberoinfundibular peptide had effects on the hypothalamo-pituitary-gonadal axis. Intracerebroventricular injection of tuberoinfundibular peptide increased plasma LH (tuberoinfundibular peptide 10 nmol 0.70 +/- 0.09 ng/ml vs. saline 0.42 +/- 0.04 ng/ml at 10 min, P < 0.05). Intraperitoneal administration of tuberoinfundibular peptide also increased plasma LH (tuberoinfundibular peptide 30 nmol 0.53 +/- 0.09 ng/ml vs. saline 0.21 +/- 0.04 ng/ml at 10 min, P < 0.05). In addition to these actions on the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes, an increased release of GH-releasing factor (GRF) from hypothalamic explants (tuberoinfundibular peptide 100 nM 770.9 +/- 90.7 pg/explant vs. control 657.8 +/- 77.7 pg/explant, P < 0.01) was observed. Overall, these data show the actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes and suggest that it may play a role in the control of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes.

Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei.

Cocaine- and amphetamine-regulated transcript is expressed in hypothalamic regions involved in the central control of food intake. Previous data have implicated cocaine- and amphetamine-regulated transcript as an anorectic peptide. We studied the effect of the active fragment of cocaine- and amphetamine-regulated transcript, cocaine- and amphetamine-regulated transcript-(55-102), on feeding when injected into discrete nuclei of the hypothalamus. Cocaine- and amphetamine-regulated transcript-(55-102) (0.04 nmol) elicited a delayed, but significant, increase in feeding in 24-h fasted rats after injection into the ventromedial nucleus (1-2 h, 261 +/- 60% of control; P < 0.05) and arcuate nucleus (1-2 h, 225 +/- 38% of control; P < 0.05) of the hypothalamus. Administration of a higher dose of cocaine- and amphetamine-regulated transcript-(55-102) (0.2 nmol) elicited a significant increase in feeding after injection into the ventromedial nucleus (1-2 h, 1253 +/- 179% of control; P < 0.001), arcuate nucleus (1-2 h, 265 +/- 43% of control; P < 0.05), paraventricular nucleus (2-4 h food intake, 186 +/- 29% of control; P < 0.05), lateral hypothalamic area (2-4 h, 280 +/- 34% of control; P < 0.001), anterior hypothalamic area (2-4 h, 252 +/- 42% of control; P < 0.01), dorsomedial nucleus (2-4 h, 368 +/- 29% of control;P < 0.001) and supraoptic nucleus (2-4 h, 212 +/- 34% of control; P < 0.05) of the hypothalamus. Administration of cocaine- and amphetamine-regulated transcript-(55-102) into the third ventricle of the hypothalamus resulted in an inhibition in feeding [0-4 h (0.4 nmol), 33 +/- 13% control; P < 0.001], but was associated with marked abnormalities in behavior, which may have interfered with feeding. These behavioral abnormalities were not observed after the administration of cocaine- and amphetamine-regulated transcript-(55-102) directly into the arcuate nucleus. These data suggest that cocaine- and amphetamine-regulated transcript may play an orexigenic role in the hypothalamic feeding circuitry.

Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vivo and in vitro, via the hypothalamus and the pituitary.

Melanin-concentrating hormone (MCH) is an orexigenic peptide encoded in the pre-pro MCH gene. Targeted deletion of MCH causes a phenotype of hypophagia and leanness with an inappropriately high metabolic rate, suggesting a role for MCH in the control of energy balance. In order to further elucidate the mechanism by which MCH controls, energy expenditure, we have investigated the effects of MCH on the hypothalamic pituitary thyroid (HPT) axis. The thyroid axis is important in energy homeostasis and starvation leads to profound suppression of the HPT axis. MCH significantly reduces plasma TSH in vivo at 10 min (0.5 +/- 0.07 ng/ml, p < 0.05, n = 8) and 60 min (0.33 +/- 0.04 ng/ml, p < 0.01, n = 10) compared to saline (0.7 +/- 0.07 ng/ml and 0.69 +/- 0.07 ng/ml respectively) when administered intracerebroventricularly. Release of TRH form hypothalamic explants was significantly reduced in the presence of MCH production (7.1 +/- 0.99 fmol/explant to 2.3 +/- 0.4 fmol/explant p < 0.01, n = 18) and Neuropeptide EI (NEI) (8.47 +/- 1.28 fmol/explant to 4.6 +/- 1.13 p < 0.05, n = 16), a peptide, also encoded in the pre-pro-MCH gene. MCH was also shown to significantly reduce TRH stimulated TSH release from dispersed pituitary cell cultures (basal = 0.5 +/- 0.06 ng/ml, 100 nM TRH = 0.9 +/- 0.2 ng/ml, p < 0.05 0.1 nM MCH = 0.5 +/- 0.1 ng/ml, p < 0.05, 1 nM MCH = 0.3 +/- 0.03 ng/ml, p < 0.01, 10 nM MCH = 0.4 +/- 0.02 ng/ml, p < 0.01, 1000 nM MCH = 0.4 +/- 0.05 ng/ml, P < 0.01, n = 4), although basal release of TSH from these cultures was unaffected. These data suggest a possible role for MCH in the control of energy homeostasis via inhibition of the thyroid axis.

Survival of colorectal cancer cell lines treated with paclitaxel, radiation, and 5-FU: effect of TP53 or hMLH1 deficiency.

Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before IR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, BNIP3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably BNIP3. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 175-185 (2000).