Most dystrophic neurites in the common 5xFAD Alzheimer mouse model originate from axon terminals.

How dystrophic neurites form around amyloid plaques is a key aspect of understanding the early pathophysiology of Alzheimer's disease. At present, three hypotheses prevail: (1) dystrophies result from extracellular amyloid-beta (Aß) toxicity; (2) dystrophies results from accumulation of Aß into distal neurites; and (3) dystrophies represent blebbing of the somatic membrane of a neuron with high Aß load. We utilized a unique feature of the common 5xFAD AD mouse model to test these hypotheses. Cortical layer 5 pyramidal neurons show intracellular APP and Aß accumulation before amyloid plaque formation while dentate granule cells in these mice show no APP accumulation at any age. However, the dentate gyrus shows amyloid plaques by 3 months of age. By a careful confocal microscopic analysis we found no evidence of severe degeneration in amyloid laden layer 5 pyramidal neurons in contrast to hypothesis 3. Using injecting red fluorescent marker into lateral entorhinal projection neurons in 5xFAD mice with endogenous green fluorescent protein (GFP) in dentate granule cells we could demonstrate that all dystrophies is outer molecular layer originate from the axon terminal of entorhinal projection neurons. Immunostaining with vesicular glutamate transporter supported the axonal nature of the dystrophies in the acellular dentate molecular layer. We observed few small dystrophies in the GFP labeled granule cell dendrites. In general GFP labeled dendrites appear normal around the amyloid plaques. These findings favor hypothesis 2 as the most likely mechanism of dystrophic neurite formation.

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (1 mg/kg/month) (n = 13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels decreased in both treatment groups during the 12-month follow-up (P < 0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P = 0.002; LH vs iB, r = 0.72, P < 0.0001), but not with the changes in AMH (P = NS). At 12 months, AMH levels did not differ between the groups (P = NS). Serum Lz levels (range, 124-1262 nmol/L) were largely explained by the Lz dose per weight (at 3 months r = 0.62, P = 0.01; at 6 months r = 0.52, P = 0.05). Lz levels did not associate with changes in indices of hypothalamic-pituitary-gonadal axis activity or Sertoli cell markers (in all, P = NS). LIMITATIONS, REASONS FOR CAUTION: The original trial was not blinded for practical reasons and included a limited number of participants. WIDER IMPLICATIONS OF THE FINDINGS: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Lz induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Academy of Finland, the Foundation for Pediatric Research, the Emil Aaltonen Foundation, Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: NCT01797718.

Elevated age-related cortical iron, ferritin and amyloid plaques in APP(swe)/PS1(deltaE9) transgenic mouse model of Alzheimer's disease.

Iron is very important element for functioning of the brain. Its concentration changes with aging the brain or during disease. The aim of our work was the histological examination of content of ferritin and free iron (unbound) in brain cortex in association with Abeta plaques from their earliest stages of accumulation in amyloid plaque forming APP/PS1 transgenic mice. Light microscopy revealed the onset of plaques formation at 8-monthage. Detectable traces of free iron and no ferritin were found around plaques at this age, while the rate of their accumulation in and around Abeta plaques was elevated at 13 months of age. Ferritin accumulated mainly on the edge of Abeta plaques, while the smaller amount of free iron was observed in the plaque-free tissue, as well as in and around Abeta plaques. We conclude that free iron and ferritin accumulation follows the amyloid plaques formation. Quantification of cortical iron and ferritin content can be an important marker in the diagnosis of Alzheimer's disease.

Disorders of sex development: timing of diagnosis and management in a single large tertiary center.

BACKGROUND: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. METHODS: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. RESULTS: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome (14.5%, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P < 0.001). CONCLUSIONS: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.

Terpene Composition Complexity Controls Secondary Organic Aerosol Yields from Scots Pine Volatile Emissions.

Secondary organic aerosol (SOA) impact climate by scattering and absorbing radiation and contributing to cloud formation. SOA models are based on studies of simplified chemical systems that do not account for the chemical complexity in the atmosphere. This study investigated SOA formation from a mixture of real Scots pine (Pinus sylvestris) emissions including a variety of monoterpenes and sesquiterpenes. SOA generation was characterized from different combinations of volatile compounds as the plant emissions were altered with an herbivore stress treatment. During active herbivore feeding, monoterpene and sesquiterpene emissions increased, but SOA mass yields decreased after accounting for absorption effects. SOA mass yields were controlled by sesquiterpene emissions in healthy plants. In contrast, SOA mass yields from stressed plant emissions were controlled by the specific blend of monoterpene emissions. Conservative estimates using a box model approach showed a 1.5- to 2.3-fold aerosol enhancement when the terpene complexity was taken into account. This enhancement was relative to the commonly used model monoterpene, "α-pinene". These results suggest that simplifying terpene complexity in SOA models could lead to underpredictions in aerosol mass loading.

Opposing effects of APP/PS1 and TrkB.T1 genotypes on midbrain dopamine neurons and stimulated dopamine release in vivo.

Brain derived neurotrophic factor (BDNF) signaling disturbances in Alzheimer׳s disease (AD) have been demonstrated. BDNF levels fall in AD, but the ratio between truncated and full-length BDNF receptors TrkB.T1 and TrkB.TK, respectively, increases in brains of AD patients and APPswe/PS1dE9 (APP/PS1) AD model mice. Dopaminergic (DAergic) system disturbances in AD and detrimental effects of BDNF signaling deficits on DAergic system functions have also been indicated. Against this, we investigated changes in nigrostriatal dopamine (DA) system in mice carrying APP/PS1 and/or TrkB.T1 transgenes, the latter line modeling the TrkB.T1/TK ratio change in AD. Employing in vivo voltammetry, we found normal short-term DA release in caudate-putamen of mice carrying APP/PS1 or TrkB.T1 transgenes but impaired capacity to recruit more DA upon prolonged stimulation. However, mice carrying both transgenes did not differ from wild-type controls. Immunohistochemistry revealed normal density of tyrosine hydroxylase positive axon terminals in caudate-putamen in all genotypes and intact presynaptic machinery for DA release and reuptake, as shown by unchanged levels of SNAP-25, α-synuclein and DA transporter. However, we observed increased DAergic neurons in substantia nigra of TrkB.T1 mice resulting in decreased tyrosine hydroxylase per neuron in TrkB.T1 mice. The finding of unchanged nigral DAergic neurons in APP/PS1 mice largely confirms earlier reports, but the unexpected increase in midbrain DA neurons in TrkB.T1 mice is a novel finding. We suggest that both APP/PS1 and TrkB.T1 genotypes disrupt DAergic signaling, but via separate mechanisms.

Behavioral and neuropathological consequences of transient global ischemia in APP/PS1 Alzheimer model mice.

Alzheimer's disease (AD) typically manifests in elderly people with several co-morbidities, especially cardiovascular, whereas transgenic mouse models of this disease usually employ middle-aged animals that have a good general health status. To assess the combined effect of compromised cerebral blood circulation and brain amyloid pathology we induced transient (17min) global ischemia (TGI) to young adult APPswe/PS1dE9 (APdE9) mice modeling AD amyloid pathology, and assessed the outcome on behavior two weeks and on histopathology five weeks after the ischemic insult. Ischemic injury resulted in reduced motor coordination and impaired spatial learning and memory. Neuropathological examination revealed circumscribed sites of neuronal loss in ischemic mice, including hippocampal CA2, lateral CA3 and medial CA1 pyramidal cell layer, and superficial layers of cortical patches. Notably, Fluoro-Jade staining revealed dying neurons as late as five weeks after the initial insult, and staining for active microglia and astrocytes confirmed the presence of inflammatory reaction. The extent of neuronal loss in CA2 and CA1 correlated significantly with impairment in spatial memory. There was no genotype difference in either behavioral or neuropathological consequences of TGI. However, the post-operative survival of transgenic animals was greatly reduced compared to wild type animals. APdE9 mice at a pre-plaque age appear to be more sensitive than wild-type mice to TGI in terms of post-operative recovery but the surviving APdE9 mice do not display more severe neurological deficits than wild-type mice.

Long-term outcome of patients with acute non-specific abdominal pain compared to acute appendicitis: prospective symptom audit after two decades.

BACKGROUND: Non-specific abdominal pain (NSAP) and acute appendicitis (AA) are the two most frequent diagnoses of acute abdomen in the emergency wards. The long-term morbidity, mortality and quality of life of the patients with NSAP compared to AA are unknown. METHODS: The study group consisted of 186 patients with acute NSAP compared to 147 patients with AA initially treated during 1985-1986. Medical history, social background, quality of life and abdominal symptoms were assessed with standardized questionnaires in both groups during 2006-2009. The patients who continued to have abdominal symptoms were invited to a check-up visit. RESULTS: During 1985-6, the NSAP group had more previous abdominal symptoms and operations than the AA group. Some 29% of patients with NSAP and 11% of patients with AA had still abdominal symptoms at long-term check-up (p < 0.0001). Chronic abdominal pain (38 vs 17) and peptic ulcer disease (18 vs 2) occurred more often in the NSAP group than in the controls, respectively (p = 0.001). After five years of follow-up, 11 patients in the NSAP group and 6 patients in the AA group had died (ns). During the twenty years of follow-up, mortality was higher (46/22, 25/15%) in the patients with NSAP than in controls (p = 0.013). Ischaemic heart disease was the leading cause of death in both groups (18 NSAP vs 5 AA, p = 0.017). The quality of life scores were comparable in both study groups. CONCLUSION: Over 70% of NSAP- and almost 90% of AA-patients were free of symptoms after 20 years of follow-up. Mortality was higher and various alimentary track diseases were more frequent in patients with NSAP than in AA.

Transduced wild-type but not P301S mutated human tau shows hyperphosphorylation in transgenic mice overexpressing A30P mutated human alpha-synuclein.

Neuropathological and cell culture studies suggest that tau and α-synuclein pathologies may promote each other. To study the relevance and functional implications of these findings in vivo, we transduced hippocampal neurons of wild-type or human A30P α-synuclein transgenic mice with wild-type or P301S mutated human tau using an adeno-associated virus vector. Green fluorescent protein transduction was used as a control. We assessed spontaneous exploratory activity, anxiety and spatial learning and memory 11 weeks after the transduction and perfused the mice for histology. The transduced tau was mainly found in axon terminals and largely restricted within the hippocampi. In addition, neurons around the injection site showed cytoplasmic staining for human tau in both wild-type and A30P mice. Of these tau-positive neurons, 44% in A30P mice but only 3% in wild-type mice receiving human wild-type tau transduction formed paired helical filament-1 (PHF-1)-positive cytoplasmic densities. In contrast, only 1% of tau-positive neurons were also PHF-1 positive after transduction with P301S tau in mice of either genotype. Transduction of P301S tau reduced swimming speed but otherwise tau transduction had no significant behavioral consequences. Cytoplasmic PHF-1 densities were associated with poor spatial memory in wild-type mice but slightly improved memory in A30P mice, indicating that also tau hyperphosphorylation does not necessarily compromise neural functions. These data demonstrate that α-synuclein promotes tau hyperphosphorylation depending on the amino acids on the 301 site.

Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland.

OBJECTIVE: We compared the prevalence and characteristics of diabetes between Somali and Finnish children in the City of Helsinki. SUBJECTS AND METHODS: Ten Somali and 310 non-Somali children <16 yr of age were treated for diabetes in Helsinki at the end of 2007. We analyzed autoantibodies, HLA alleles, and serum 25-hydroxy-vitamin D [S25(OH)D] concentrations. RESULTS: The prevalence of diabetes was 40/10,000 (95% CI 19-73/10,000) for the Somali children and 37/10,000 (95% CI 33-41/10,000) for the background population. At least one autoantibody was detected in all seven Somali patients sampled within 18 months after the diagnosis. Most Somalis (75%) carried HLA-conferred susceptibility to type 1 diabetes (T1D), DR3-DQ2 being the dominating HLA haplotype. Low S25(OH)D levels (<40 nmol/L) were seen in 83% of the Somali patients and in 60% of their siblings. CONCLUSIONS: These data show that (i) Somali children have autoimmune diabetes, (ii) the prevalence of T1D is similar among Somali and Finnish children, and (iii) both affected and unaffected Somali children have low concentrations of S25(OH)D.

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation.

AIMS/HYPOTHESIS: Epidermal growth factor receptor (EGFR) signalling is essential for the proper fetal development of pancreatic islets and in the postnatal formation of an adequate beta cell mass. In this study we investigated the role of EGFR signalling in the physiological states of beta cell mass expansion in adults during metabolic syndrome and pregnancy, as well as in regeneration after pancreatic duct ligation. METHODS: Heterozygous Pdx1-EGFR-dominant-negative (E1-DN) mice, which have a kinase-negative EGFR under the Pdx1 promoter, and wild-type mice were both subjected to a high-fat diet, pregnancy and pancreatic duct ligation. RESULTS: The beta cell mass of wild-type mice fed the high-fat diet increased by 70% and the mice remained normoglycaemic; the E1-DN mice became diabetic and failed to show any compensatory beta cell mass expansion. Similarly, pregnant wild-type mice had four times more proliferating beta cells and a 75% increase in beta cell mass at mid-gestation, in contrast to the pregnant E1-DN mice, which did not show any significant beta cell compensation and were hyperglycaemic in an intraperitoneal glucose tolerance test. However, after pancreatic duct ligation, both the wild-type and E1-DN mice showed similar expression of Ngn3 (also known as Neurog3) and beta cell proliferation increased to a similar level in the ligated part of pancreas. CONCLUSIONS/INTERPRETATIONS: EGFR signalling is essential in beta cell mass expansion during a high-fat diet and pregnancy where replication is the primary mechanism for compensatory beta cell mass expansion. In contrast, EGFR signalling appears not to be crucial to increased beta cell proliferation after pancreatic duct ligation.

ERBB receptors in developing, dysplastic and malignant oral epithelia.

Some oral squamous cell carcinomas (OSCCs) overexpress epidermal growth factor receptor (EGFR) but little is known about the receptor system overall during oral carcinogenesis. We studied all four ERBB receptors (EGFR, ERBB2-4) in developing (n=2), normal (n=7), dysplastic (n=23) and malignant (n=26) oral epithelia by means of immunohistochemistry. The investigations were supplemented by conducting reverse transcription-polymerase chain reactions in relation to 13 OSCC samples. All four ERBB receptors were detected in developing oral epithelium and, to a lesser degree, in mature oral epithelium. An increase in EGFR immunoreactivity was seen in 61% and 54% of dysplasias and OSCCs, respectively. The corresponding percentages for ERBB2 were 48 and 12, for ERBB3 48 and 43. ERBB4 nuclear staining was increased in 30% of dysplasias and 26% of OSCCs. Changes in ERBB receptor mRNA levels were not statistically significant. The results show that ERBB receptor profiles are specific to each tumour. Increased nuclear translocation of ERBB4 in some OSCCs may alter transcription of target genes and be associated with cancer progression. This information may be useful for clinicians as EGFR inhibitors are becoming treatment options in modern oncology.

Seven-year follow-up of a randomized clinical trial comparing proton-pump inhibition with surgical therapy for reflux oesophagitis.

BACKGROUND: This randomized clinical trial compared long-term outcome after antireflux surgery with acid inhibition therapy in the treatment of chronic gastro-oesophageal reflux disease (GORD). METHODS: Patients with chronic GORD and oesophagitis verified at endoscopy were allocated to treatment with omeprazole (154 patients) or antireflux surgery (144). After 7 years of follow-up, 119 patients in the omeprazole arm and 99 who had antireflux surgery were available for evaluation. The primary outcome variable was the cumulative proportion of patients in whom treatment failed. Secondary objectives were evaluation of the treatment failure rate after dose adjustment of omeprazole, safety, and the frequency and severity of post-fundoplication complaints. RESULTS: The proportion of patients in whom treatment did not fail during the 7 years was significantly higher in the surgical than in the medical group (66.7 versus 46.7 per cent respectively; P=0.002). A smaller difference remained after dose adjustment in the omeprazole group (P=0.045). More patients in the surgical group complained of symptoms such as dysphagia, inability to belch or vomit, and rectal flatulence. These complaints were fairly stable throughout the study interval. The mean daily dose of omeprazole was 22.8, 24.1, 24.3 and 24.3 mg at 1, 3, 5 and 7 years respectively. CONCLUSION: Chronic GORD can be treated effectively by either antireflux surgery or omeprazole therapy. After 7 years, surgery was more effective in controlling overall disease symptoms, but specific post-fundoplication complaints remained a problem. There appeared to be no dose escalation of omeprazole with time.

Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial.

BACKGROUND: The impact of long-term acid suppression on the gastric mucosa remains controversial. AIM: To report further observations on an established cohort of patients with gastro-oesophageal reflux disease, after 7 years of follow-up. METHODS: Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. RESULTS: Fifty-three antireflux surgery and 39 omeprazole-treated patients had Helicobacter pylori infection at randomization. Eighty-three omeprazole-treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7-year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. CONCLUSIONS: Long-term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori-negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori-positive patients there are changes in mucosal inflammation and atrophy.

Minilaparotomy cholecystectomy versus laparoscopic cholecystectomy: a randomized study with special reference to obesity.

BACKGROUND: Minilaparotomy cholecystectomy (MC) has recently challenged the role of the laparoscopic approach (LC) for cholecystectomies. However, the situation is far from clear when operating times and recovery are evaluated. METHODS: Altogether 157 patients with uncomplicated symptomatic gallstones were randomized into MC (n = 85) and LC (n = 72) groups. Both groups were similar in terms of age, body mass index, American Society of Anesthesiology (ASA) physical fitness classification, and operating surgeon. RESULTS: The mean operating time was 55 +/- 19.5 min in the MC group and 79 +/- 27.0 min in the LC group (p < 0.0001). The postoperative hospital stay and length of sick leave did not differ between the two groups. There were no significant differences in postoperative pain, analgesic consumption, or postoperative pulmonary function between the groups. The body mass index did not influence operating time or patient recovery in either group. No major complications occurred in either groups. CONCLUSION: The MC procedure seems to be a faster technique than the LC approach for noncomplicated gallstone disease, with no difference in recovery times. The MC procedure also seems to be suitable for the obese patient.

Effect of total colectomy and PYY infusion on food intake and body weight in rats.

PYY (3-36) is postulated to act as a satiety factor in the gut-hypothalamic pathway to inhibit food intake and body weight gain in humans and rodent models. We determined the effect of 14-day continuous intravenous infusion of PYY (3-36) (175 microg/kg/day) on food intake and body weight gain in colectomized male Wistar rats. Colectomy caused an increase in plasma PYY levels at 7 days which was reduced at 14 days but still significantly elevated compared to basal preoperative values. Animals treated with continuous PYY (3-36) infusion had significantly elevated PYY levels compared to the control group throughout the whole experiment, but showed a similar pattern of food intake and body weight gain. In conclusion, although continuous intravenous infusion is the most physiologically relevant method to mimic high postprandial PYY levels, we did not observe any significant effect on food intake and body weight gain in non-food deprived colectomized animals. This suggests that PYY has, if at all, only a minor role in food intake in rats.

Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding.

UNLABELLED: Maintenance of human energy homeostasis is regulated by a complex network. Peptides secreted from the gastrointestinal tract (GI) are signaling to the brain and other organs initiating or terminating food intake and energy expenditure. In the present study we investigated basal plasma levels of apelin, orexin-A, and leptin in morbid obese patients. In addition, we measured in a subgroup of these patients in the same individual orexin-A and leptin plasma levels one year after gastric banding surgery. METHODS: Basal plasma values were determined in obese patients (BMI=48+/-1 kg/m2n=32) after an overnight fast and compared to healthy, normal weighted (BMI=22+/-2 kg/m2n=12) controls. In addition, blood samples were collected in a subgroup of patients (BMI=48+/-1 kg/m2n=8) the day before surgery and 1 year after the operation. Apelin, orexin-A, and leptin levels were analysed using ELISAs. RESULTS: One year after the operation obese patients significantly lost weight (from 48+/-2 kg/m2 to 39+/-2 kg/m2; p<0,001). Apelin, orexin-A and leptin levels in obese patients were significantly higher compared to control individuals (736+/-50 pg/ml vs. 174+/-14 pg/ml, p<0.0001; 75.3+/-24.1 pg/ml vs. 0.8+/-0.4 pg/ml, p<0.0001; 79.0+/-2.4 ng/ml vs. 5.8+/-0.8 ng/ml, p<0.0001, respectively). Apelin and leptin plasma concentrations also correlated significantly with BMI (r=0.769, p<0.0001; r=0.778; p<0.0001, respectively), while orexin-A correlation was rather weak (r=0.335, p<0.03). No difference between pre- and post-operative orexin-A levels was observed, while leptin plasma levels significantly decreased from 45.1+/-5.4 ng/ml to 27.3+/-6.0 ng/ml (p=0.015). CONCLUSIONS: Apelin, orexin-A, and leptin plasma levels correlated positively with the BMI. One year after gastric banding with significant loss in BMI basal plasma levels of leptin decreased, while orexin-A remained unchanged.

Novel splice site CACNA1A mutation causing episodic ataxia type 2.

Episodic ataxia type 2 (EA-2) is an autosomal dominant neurological disorder, characterized by episodes of ataxia, vertigo, nausea, nystagmus, and fatigue, associated with acetazolamide responsiveness. The disease is caused by mutations in the P/Q-type calcium channel Ca(v)2.1 subunit gene, CACNA1A, located on chromosome 19p13.2. We analyzed a family with 13 affected individuals for linkage to this locus and reached a two-point maximum LOD score of 4.48. A novel CACNA1A mutation, IVS36-2A>G, at the 3' acceptor splice site of intron 36 was identified by sequencing. It is the first described CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.

Effect of short-term treatment with regular or high doses of omeprazole on the detection of Helicobacter pylori in bleeding peptic ulcer patients.

BACKGROUND: It is unknown whether short-term regular or high-dose omeprazole has any influence on the colonization of Helicobacter pylori in the stomach. We therefore studied the effect of 3-day treatment of 2 different doses of omeprazole. METHODS: H. pylori-positive patients with peptic ulcer bleeding (n = 101) were randomized to receive either a regular dose (20 mg/day for 3 days) (n = 51) or a high dose of omeprazole (80 mg bolus + 8 mg/h infusion/day for 3 days) (n = 50). H. pylori status was assessed by histology and urease testing of gastric biopsies pre-entry and after 3-day therapy. RESULTS: With the high dose of omeprazole, tests for the diagnosis of H. pylori became negative significantly more often than with the regular dose (60% versus 27.5%, P=0.001 (any test), 67.6% versus 31.7%, P=0.003 (histology) and 82.2% versus 43.6%, P=0.001 (urease test)). CONCLUSION: Conversion of the H. pylori tests negative after 3-day treatment of omeprazole is dose-dependent. The diagnosis of H. pylori infection depends on the timing of biopsies in relation to the beginning of proton-pump inhibitor treatment. If samples to find H. pylori are not taken before the treatment, the presence of the bacteria may be overlooked.