Vaccination against hepatitis B virus among people who inject drugs - A 20year experience from a Swedish needle exchange program.

BACKGROUND: People who inject drugs (PWID) are at particular risk of hepatitis B virus (HBV) acquisition, but often have poor access or adherence to HBV vaccination. Vaccination against HBV has been offered at a major Swedish needle exchange program (NEP) since 1994. The aim of this study was to evaluate vaccine completion and response rates, and the effect of sequential booster doses to non-responders to the standard vaccination schedule. METHODS: PWID enrolled in the NEP 1994-2013, without serological markers for HBV at baseline (negative for HBsAg/anti-HBc/anti-HBs), were offered a three-dose standard intramuscular vaccination schedule (Engerix®-B, GSK, 20µg/mL, intended to be received at months 0, 1 and 6). Vaccination response was defined as protective levels of anti-HBs (⩾10mIU/mL). Up to three booster doses were then offered for non-responders, each followed by anti-HBs testing. RESULTS: HBV data was available for 2352 identifiable individuals at NEP enrolment, of whom 1516 (64.5%) had no markers for previous HBV exposure or vaccination. Vaccination was initiated for 1142 (75.3%) individuals and 898 (59.2%) completed the standard vaccination schedule. Post-vaccination anti-HBs levels were available from 800 individuals, with 598 (74.8%) responding to the basic vaccination schedule. After up to three booster doses a total of 676 (84.5%) individuals achieved protective anti-HBs levels. Non-response to vaccination was associated with higher age and anti-HCV positivity (p<0.001). Eighteen incident cases of HBV infection were observed among vaccine non-responders, as well as 30 cases among those who had not completed vaccination. CONCLUSION: We demonstrate the feasibility of including HBV vaccination in the services offered by a NEP, with completion of vaccination in a majority of HBV-susceptible PWID. The response to HBV vaccination among PWID was relatively low; however, the addition of up to three booster doses improved the response rate from 74.8 to 84.5%.

Risk of recurrent laryngeal nerve palsy in patients undergoing thyroidectomy with and without intraoperative nerve monitoring.

BACKGROUND: Vocal cord palsy occurs in 3-5 per cent of patients after thyroidectomy. To reduce this complication, intraoperative nerve monitoring (IONM) has been introduced, although its use remains controversial. This study investigated the risk of postoperative vocal cord palsy with and without the use of intermittent IONM. METHODS: Patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery, 2009-2013, were included. Early palsy of the recurrent laryngeal nerve was diagnosed within 6 weeks after surgery. Permanent palsy was defined as that persisting after 6 months. Univariable and multivariable logistic regression analyses were used to examine risk factors for vocal cord palsy. RESULTS: The cohort consisted of 5252 patients undergoing thyroidectomy. IONM was used in 3277 operations (62·4 per cent); postoperative laryngoscopy was performed in 1757 patients (33·5 per cent). Early vocal cord palsy occurred in 217 patients (4·1 per cent), of which three were bilateral, all in the group without IONM. Permanent vocal cord palsy occurred in 62 patients (1·2 per cent). In the multivariable analysis of 1757 patients who had postoperative laryngoscopy, the use of IONM was not associated with a decreased risk of early vocal cord palsy (odds ratio (OR) 0·67, 95 per cent c.i. 0·44 to 1·01), but decreased the risk of permanent vocal cord palsy (OR 0·43, 0·19 to 0·93). [Correction added on 11 November 2016 after first publication: the word 'routine' has been removed from this section.] CONCLUSION: IONM reduced the risk of permanent vocal cord palsy. No bilateral recurrent laryngeal nerve injury occurred following IONM.

Neurobiological insight into hyperbaric hyperoxia.

AIM: Hyperbaric hyperoxia (HBO) is known to modulate aerobic metabolism, vasoreactivity and blood flow in the brain. Nevertheless, mechanisms underlying its therapeutic effects, especially in traumatic brain injury (TBI) and stroke patients, are debated. The present study aimed at investigating regional cerebral blood flow (rCBF) distribution during acute HBO exposure. METHODS: Regional cerebral blood flow response was investigated in seven healthy subjects exposed to either normobaric normoxia or HBO with ambient pressure/inspired oxygen pressure of 101/21 and 250/250 kPa respectively. After 40 min at the desired pressure, they were injected a perfusion tracer and subsequently underwent brain single photon emission computed tomography. rCBF distribution changes in the whole brain were assessed by Statistical Parametric Mapping. RESULTS: During HBO, an increased relative rCBF distribution was found in sensory-motor, premotor, visual and posterior cingulate cortices as well as in superior frontal gyrus, middle/inferior temporal and angular gyrus and cerebellum, mainly in the dominant hemisphere. During normobaric normoxia, a higher (99m) Tc-HMPAO distribution in the right insula and subcortical structures as well as in bilateral hippocampi and anterior cingulated cortex was found. CONCLUSIONS: The present study firstly confirmed the rCBF distribution increase during HBO in sensory-motor and visual cortices, and it showed for the first time a higher perfusion tracer distribution in areas encompassed in dorsal attention system and in default mode network. These findings unfold both the externally directed cognition performance improvement related to the HBO and the internally directed cognition states during resting-state conditions, suggesting possible beneficial effects in TBI and stroke patients.

Epigenetic screen identifies genotype-specific promoter DNA methylation and oncogenic potential of CHRNB4.

Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P<0.001), which resulted in overexpression of the transcript in tumors (P<0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P<0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (PA549<0.05;PH1299<0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential.

Gray matter volume alterations related to trait dissociation in PTSD and traumatized controls.

OBJECTIVE: This study used voxel-based morphometry (VBM) to investigate brain structural alterations related to trait dissociation and its relationship with post-traumatic stress disorder (PTSD). METHOD: Thirty-two subjects either developing (N = 15) or non-developing (N = 17) PTSD underwent MRI scanning and were assessed with the Dissociative Experience Scale (DES), subscales for pathological (DES-T) and non-pathological trait (DES-A) dissociation, and other clinical measures. Gray matter volume (GMV) was analyzed using VBM as implemented in SPM. PTSD and non-PTSD subjects were compared to assess brain alterations related to PTSD pathology, whereas correlation analyses between dissociation measures and GMV were performed on the whole sample (N = 32), irrespective of PTSD diagnosis, to identify alterations related to trait dissociation. RESULTS: As compared to traumatized controls, PTSD subjects showed reduced GMV in the prefrontal cortex, hippocampus and lingual gyrus. Correlations with dissociation measures (DES, DES-T, and DES-A) consistently showed increased GMV in the medial and lateral prefrontal, orbitofrontal, parahippocampal, temporal polar, and inferior parietal cortices. CONCLUSION: PTSD and dissociation seem to be associated with opposite volumetric patterns in the prefrontal cortex. Trait dissociation appears to involve increased GMV in prefrontal, paralimbic, and parietal cortices, with negligible differences between pathological and non-pathological dissociation.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy.

BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Self-rating scales assessing subjective well-being and distress correlate with rCBF in PTSD-sensitive regions.

BACKGROUND: The aim of this study was to investigate the distribution of the regional cerebral blood flow (rCBF) in occupational-related post-traumatic stress disorder (PTSD) subjects and to seek possible correlations between brain perfusion and self-rating scales (SRS) in order to cross-check their diagnostic value and to look for their neural correlates. METHOD: A total of 13 traumatized underground and long-distance train drivers developing (S) and 17 not developing (NS) PTSD who had experienced a 'person under train' accident or who had been assaulted at work underwent clinical assessment and 99mTc-HMPAO SPECT imaging during autobiographical trauma scripts. Statistical parametric mapping was applied to analyse rCBF changes in S as compared with NS and to search for correlations between rCBF and the administered SRS scores, modelling age, months to SPECT and the ratio 'grey matter/intra-cranial volume' as nuisance variables. RESULTS: Significantly higher activity was observed during trauma script in left posterior and anterior insula, posterior cingulate, inferior parietal lobule, precuneus, caudate and putamen in PTSD subjects as compared with the trauma-exposed control group. Impact of Event Scale and World Health Organisation (10) Well-Being Index scores highly correlated with tracer uptake to a great extent in the same regions in which rCBF differences between S and NS were found. CONCLUSIONS: These findings support the involvement of insular, cingulate and parietal cortices (as well as the basal ganglia) in the pathogenesis of PTSD and in the processing of related subjective well-being and distress.

Impact of acute hypobaric hypoxia on blood flow distribution in brain.

AIM: Acute hypobaric hypoxia is well known to alter brain circulation and to cause neuropsychological impairment. However, very few studies have examined the regional changes occurring in the brain during acute exposure to extreme hypoxic conditions. METHODS: Regional cerebral blood flow (rCBF) response to hypoxia was investigated in six healthy subjects exposed to either normobaric normoxia or hypobaric hypoxia with ambient pressure/inspired oxygen pressure of 101/21 kPa and 50/11 kPa respectively. After 40 min at the desired pressure they were injected (99m)Tc-HMPAO and subsequently underwent single photon emission computed tomography. Regional cerebral blood flow distribution changes in the whole brain were assessed by Statistical Parametric Mapping, a well established voxel-based analysis method. RESULTS: Hypobaric hypoxia increased rCBF distribution in sensorymotor and prefrontal cortices and in central structures. PCO(2) correlated positively and SatO(2) negatively with rCBF in several temporal, parahippocampal, parietal and central structures. CONCLUSIONS: These findings underscore the specific sensitivity of the frontal lobe to acute hypobaric hypoxia and of limbic and central structures to blood gas changes emphasizing the involvement of these brain areas in acute hypoxia.

Minimal transmission of HIV despite persistently high transmission of hepatitis C virus in a Swedish needle exchange program.

The aim of this study was to examine the prevalence and incidence of HIV and hepatitis B and C (HBV and HCV) among injecting drug users in a Swedish needle exchange programme (NEP) and to identify risk factors for blood-borne transmission. A series of serum samples from NEP participants enrolled from 1997 to 2005 were tested for markers of HIV, HBV and HCV (including retrospective testing for HCV RNA in the last anti-HCV-negative sample from each anti-HCV seroconverter). Prevalence and incidence were correlated with self-reported baseline characteristics. Among 831 participants available for follow-up, one was HIV positive at baseline and two seroconverted to anti-HIV during the follow-up of 2433 HIV-negative person-years [incidence 0.08 per 100 person-years at risk (pyr); compared to 0.0 in a previous assessment of the same NEP covering 1990-1993]. The corresponding values for HBV were 3.4/100 pyr (1990-1993: 11.7) and for HCV 38.3/100 pyr (1990-1993: 27.3). HCV seroconversions occurred mostly during the first year after NEP enrolment. Of the 332 cases testing anti-HCV negative at enrolment, 37 were positive for HCV RNA in the same baseline sample (adjusted HCV incidence 31.5/100 pyr). HCV seroconversion during follow-up was significantly associated with mixed injection use of amphetamine and heroin, and a history of incarceration at baseline. In this NEP setting, HIV prevalence and incidence remained low and HBV incidence declined because of vaccination, but transmission of HCV was persistently high. HCV RNA testing in anti-HCV-negative NEP participants led to more accurate identification of timepoints for transmission.

Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis.

BACKGROUND: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans. METHODS: Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg(-1) min(-1), n = 8), GLP-1 (0.75 pmol kg(-1) min(-1), n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin. KEY RESULTS: Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg(-1) min(-1) decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg(-1) min(-1) decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg(-1) min(-1) increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05-0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06). CONCLUSION & INFERENCES: The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.

Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man.

Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg(-1) min(-1)) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1+/-5.2 (saline) to 87.0+/-11.5 min (PYY3-36), whereas retention at 120 min was 2.5+/-1.4% for saline, 10.7+/-4.4 for PYY1-36 and 15.8+/-4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5+/-22.6 mm) and decreased prospective consumption (VAS change 39.5+/-7.7 mm). In conclusion, PYY3-36's reducing effect upon food intake might be mediated by a decreased gastric emptying rate.

Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer.

BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.

The role of adrenal scintigraphy in the preoperative management of primary aldosteronism.

BACKGROUND AND AIMS: Differentiation between the two major subgroups of primary aldosteronism, bilateral hyperplasia and aldosterone producing adenoma is essential since therapy in the former is medical and in the latter surgical. The aim of the present study was to evaluate the clinical utility of adrenocortical scintigraphy in the management of primary aldosteronism. MATERIAL AND METHODS: [131I] norcholesterol (NP-59) scintigraphy with dexamethasone suppression for subclassification and lateralization of primary aldosteronism was evaluated in 49 patients with long-term follow-up after diagnosis and treatment. RESULTS: Thirty-three patients with the diagnosis of aldosterone producing adenoma were operated with adrenalectomy. Preoperative scintigraphy showed lateralized isotope uptake in 27/33 patients while 6 showed no uptake. Twenty-two were cured and three significantly improved. Thus, in 25/33 (76%), scintigraphy showed the correct side as the patients benefited of surgery. Two patients did not improve. Fourteen patients with a probable diagnosis of bilateral hyperplasia had normal scintigraphies. CONCLUSIONS: In the present retrospective study we found limited sensitivity of NP-59 scintigraphy. However, when a lateralized scintigraphic uptake is achieved it has a high accuracy. Scintigraphy may be used as an adjunct in cases where adrenal venous sampling is inconclusive.

Recreational values of the natural environment in relation to neighbourhood satisfaction, physical activity, obesity and wellbeing.

OBJECTIVES: The aim of this population-based study was to investigate associations between recreational values of the close natural environment and neighbourhood satisfaction, physical activity, obesity and wellbeing. METHODS: Data from a large public health survey distributed as a mailed questionnaire in suburban and rural areas of southern Sweden were used (N = 24,819; 59% participation rate). Geocoded residential addresses and the geographical information system technique were used to assess objectively five recreational values of the close natural environment: serene, wild, lush, spacious and culture. RESULTS: On average, a citizen of the Scania region, inner city areas excluded, only had access to 0.67 recreational values within 300 metres distance from their residence. The number of recreational values near the residence was strongly associated with neighbourhood satisfaction and physical activity. The effect on satisfaction was especially marked among tenants and the presence of recreational values was associated with low or normal body mass index in this group. A less marked positive association with vitality among women was observed. No evident effect on self-rated health was detectable. CONCLUSIONS: Immediate access to natural environments with high recreational values was rare in the study population and was distributed in an inequitable manner. Moreover, such access was associated with a positive assessment of neighbourhood satisfaction and time spent on physical activity, which can be expected to reduce obesity and increase vitality by having a buffering effect on stress.

Operation for primary hyperparathyroidism: the new versus the old order. A randomised controlled trial of preoperative localisation.

BACKGROUND AND AIMS: In patients with primary hyperparathyroidism (PHPT), parathyroid imaging is nowadays routinely used for the purpose to perform a focused unilateral minimally invasive operation. The outcome of this new strategy has, however, not been established in randomised trials. MATERIAL AND METHODS: Patients were randomised to either preoperative localisation with sestamibi scintigraphy and ultrasonography (group I) or no preoperative localisation (group II). In group I, a minimally invasive parathyroidectomy was performed in patients in whom both localisation studies were consistent with a single pathological gland, whereas a conventional bilateral neck exploration was performed in cases with negative localisation findings. In group II all patients underwent conventional bilateral neck exploration. Primary outcome measure was normocalcaemia at 6 months postoperatively. RESULTS: In the preoperative localisation group (group I) 23/50 (46%) of the patients could be operated on with the focused operation whereas 26/50 (52%) were operated on by bilateral neck exploration. All patients in the no localisation group (group II; n = 50) were operated on with the intended bilateral neck operation. Normocalcaemia was obtained in 96% and 94% in group I and II, respectively. Total (localisation and operative) costs were 21% higher in group I. CONCLUSIONS: Routine preoperative localisation, with the intention to perform minimally invasive parathyroidectomy, is not cost effective if concordant results of scintigraphy and ultrasonography are a prerequisite for the focused operation. Less than half of the patients were successfully managed with this strategy, at a higher cost and without obtaining a more favourable clinical outcome.

Ghrelin stimulates gastric emptying and hunger in normal-weight humans.

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control.

CONTEXT: Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide. OBJECTIVE: The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water. DESIGN: This was a single-blind study. SETTING: The study was performed at a university hospital. PARTICIPANTS: Fourteen healthy adult subjects were studied. INTERVENTIONS: Infusion of saline or PP at 0.75 or 2.25 pmol/kg.min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg.min was given to six subjects (gastric emptying of water). MAIN OUTCOME MEASURES: The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy). RESULTS: PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water. CONCLUSIONS: PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.

Inhibitory effect of exogenous orexin a on gastric emptying, plasma leptin, and the distribution of orexin and orexin receptors in the gut and pancreas in man.

Orexin A (OXA) is a novel peptide that appears to play a role in the regulation of food intake, arousal, and energy balance. The aim of this study was to study the effect of iv infusion of OXA on gastric emptying, appetite, leptin, ghrelin, and glucose metabolism in man (six normal men) and the localization of OXA and orexin receptors (OXRs) 1 and 2 in the human gut. Gastric emptying was studied scintigraphically after ingestion of a 99mTc-labeled omelet and iv infusion of OXA (10 pmol/kg.min). Appetite ratings and blood samples were obtained at regular intervals. The immunohistochemical distribution of OXA and OXRs was examined using antibodies recognizing OXA, OX1R, and OX2R in human gastrointestinal tissue. OXA had no effect on lag phase or gastric half-emptying time. However, the gastric emptying rate was significantly slower without affecting appetite ratings. Plasma concentrations of insulin were increased by OXA, whereas plasma leptin decreased and ghrelin was unchanged. OXA immunoreactivity was observed in a subset of neurons and varicose nerve fibers in the mucosa, ganglia, and circular muscle layer and mucosal endocrine cells in the stomach and small intestine. OXA-immunoreactive cells in the islets of Langerhans contained insulin with a subset expressing OX2R. In conclusion, peripheral OXA seems to slightly affect the regulation of gastric emptying in humans without affecting appetite ratings. OXA decreased plasma levels of leptin, suggesting a possible interaction between leptin and OXA in the regulation of energy homeostasis.

Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy.

PURPOSE: To examine the effects on bone mineral density of 2 years of treatment with a luteinizing hormone-releasing hormone (LHRH) agonist alone or in combination with tamoxifen or tamoxifen alone in premenopausal breast cancer. PATIENTS AND METHODS: We recruited 89 women from two centers in Stockholm participating in a randomized multicenter trial of three different endocrine approaches in the adjuvant setting (Zoladex in Premenopausal Patients Trial). The women were assigned to receive the LHRH agonist goserelin with or without tamoxifen, tamoxifen alone, or no endocrine therapy. The treatment was given for 2 years. We measured total-body bone density before start of treatment and at 12, 24, and 36 months. RESULTS: After 2 years of treatment, there was a significant loss of bone mineral density (mean change, -5%; P <.001) in the women receiving goserelin alone. The combined goserelin and tamoxifen treatment, as well as tamoxifen alone, resulted in a lesser but statistically significant decline in bone mineral density (mean change, -1.4%; P =.02; and -1.5%; P <.001). One year after cessation of treatment, the goserelin group alone showed a partial recovery from bone loss (mean change, 1.5%; P =.02). CONCLUSION: Two years of ovarian ablation from goserelin treatment caused a significant reduction in bone mineral density but there was a partial recovery from the bone loss 1 year after cessation of treatment. The addition of tamoxifen seems to partially counteract the demineralizing effects of goserelin.

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety.

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.