Introducing the White Noise task in childhood: associations between speech illusions and psychosis vulnerability.

BACKGROUND: Auditory verbal hallucinations (AVH) are common during development and may arise due to dysregulation in top-down processing of sensory input. This study was designed to examine the frequency and correlates of speech illusions measured using the White Noise (WN) task in children from the general population. Associations between speech illusions and putative risk factors for psychotic disorder and negative affect were examined. METHOD: A total of 1486 children aged 11-12 years of the Copenhagen Child Cohort 2000 were examined with the WN task. Psychotic experiences and negative affect were determined using the Kiddie-SADS-PL. Register data described family history of mental disorders. Exaggerated Theory of Mind functioning (hyper-ToM) was measured by the ToM Storybook Frederik. RESULTS: A total of 145 (10%) children experienced speech illusions (hearing speech in the absence of speech stimuli), of which 102 (70%) experienced illusions perceived by the child as positive or negative (affectively salient). Experiencing hallucinations during the last month was associated with affectively salient speech illusions in the WN task [general cognitive ability: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.03-3.93]. Negative affect, both last month and lifetime, was also associated with affectively salient speech illusions (aOR 2.01, 95% CI 1.05-3.83 and aOR 1.79, 95% CI 1.11-2.89, respectively). Speech illusions were not associated with delusions, hyper-ToM or family history of mental disorders. CONCLUSIONS: Speech illusions were elicited in typically developing children in a WN-test paradigm, and point to an affective pathway to AVH mediated by dysregulation in top-down processing of sensory input.

Psychotic experiences and hyper-theory-of-mind in preadolescence--a birth cohort study.

BACKGROUND: Knowledge on the risk mechanisms of psychotic experiences (PE) is still limited. The aim of this population-based study was to explore developmental markers of PE with a particular focus on the specificity of hyper-theory-of-mind (HyperToM) as correlate of PE as opposed to correlate of any mental disorder. METHOD: We assessed 1630 children from the Copenhagen Child Cohort 2000 regarding PE and HyperToM at the follow-up at 11-12 years. Mental disorders were diagnosed by clinical ratings based on standardized parent-, teacher- and self-reported psychopathology. Logistic regression analyses were performed to test the correlates of PE and HyperToM, and the specificity of correlates of PE v. correlates of any Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) mental disorder. RESULTS: Univariate analyses showed the following correlates of PE: familial psychiatric liability; parental mental illness during early child development; change in family composition; low family income; regulatory problems in infancy; onset of puberty; bullying; concurrent mental disorder; and HyperToM. When estimating the adjusted effects, only low family income, concurrent mental disorder, bullying and HyperToM remained significantly associated with PE. Further analyses of the specificity of these correlates with regard to outcome revealed that HyperToM was the only variable specifically associated with PE without concurrent mental disorder. Finally, HyperToM did not share any of the investigated precursors with PE. CONCLUSIONS: HyperToM may have a specific role in the risk trajectories of PE, being specifically associated with PE in preadolescent children, independently of other family and child risk factors associated with PE and overall psychopathology at this age.

European Society of Coloproctology consensus on the surgical management of intestinal failure in adults.

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Change in cannabis use, clinical symptoms and social functioning among patients with first-episode psychosis: a 5-year follow-up study of patients in the OPUS trial.

BACKGROUND: Several studies indicate that cannabis use among patients with psychotic disorders is associated with worse outcome, but only a few studies have controlled for baseline condition and medication. METHOD: At 5-year follow-up, interviews were carried out with 314 first-episode psychosis patients included in the OPUS trial. The patients included were in the age range of 18 to 45 years old and 59% were male. Cannabis use was extracted from the Schedule for Clinical Assessment in Neuropsychiatry. At follow-up, the patients were divided into different groups according to the variable cannabis use: abstainers, stoppers, starters and continuers. Psychotic, negative and disorganized dimensions (ranging from zero to five) were calculated for each of the four groups based on the Schedule for the Assessment of Positive and Negative Symptoms in Schizophrenia. RESULTS: Cannabis users were younger (24.6 years v. 27.4 years, p < 0.001) and had a lower level of education. At the 5-year follow-up, users of cannabis had higher scores on the psychotic dimension [difference 0.97, 95% confidence interval (CI) 0.41-1.53, p = 0.001] and lower levels of the Global Assessment of Functioning (difference 8.26, 95% CI 2.13-14.39, p = 0.01). Those who stopped using cannabis between entry and 5-year follow-up had a significantly lower level of psychotic symptoms at 5-year follow-up even after controlling for baseline level of psychotic symptoms and for insufficient antipsychotic medication (adjusted difference in psychotic dimension -1.04, 95% CI -1.77 to -0.31, p = 0.006). CONCLUSIONS: Continuous cannabis use was associated with higher levels of psychotic symptoms after 5 years, and this association was only partly explained by insufficient antipsychotic medication.

Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells.

AIMS: Caffeic acid, naringenin and quercetin are naturally occurring phenolic compounds (PCs) present in many plants as secondary metabolites. The aim of this study was to investigate their effect on glucose-stimulated insulin secretion (GSIS) in INS-1E cells and to explore their effect on expression of genes involved in ß-cell survival and function under normoglycaemic and glucotoxic conditions. METHODS: For acute studies, INS-1E cells were grown in 11 mM glucose (72 h) and then incubated with the PCs (1 h) with 3.3/16.7 mM glucose; whereas, for chronic studies, the cells were grown in 11 mM glucose (72 h) with/without the PCs, and then incubated with 3.3/16.7 mM glucose (1 h); thereafter, GSIS was measured. For GSIS and gene expression studies (GES) under glucotoxic conditions, two sets of cells were grown in 11/25 mM glucose with/without the PCs (72 h): one was used for GES, using real time RT-PCR, and the other was exposed to 3.3/16.7 mM glucose, followed by measurement of GSIS. RESULTS: The study demonstrated that the PCs can enhance GSIS under hyperglycaemic and glucotoxic conditions in INS-1E cells. Moreover, these compounds can differentially, yet distinctly change the expression profile of genes [Glut2 (glucose transporter 2), Gck (glucokinase), Ins1 (insulin 1), Ins2, Beta2 (neurogenic differentiation protein 1), Pdx1 (pancreatic and duodenal homeobox protein 1), Akt1 (RAC-α serine/threonine-protein kinase encoding gene), Akt2 (RAC-ß serine/threonine-protein kinase encoding gene), Irs1 (insulin receptor substrate 1), Acc1 (acetyl CoA carboxylase 1), Bcl2 (ß-cell lymphoma 2 protein), Bax (Bcl-2 associated X protein), Casp3 (Caspase 3), Hsp70 (heat shock protein 70), and Hsp90] involved in ß-cell stress, survival and function. CONCLUSION: The results indicate that the PCs tested enhance GSIS and glucose sensitivity in INS-1E cells. They also modulate gene expression profiles to improve ß-cell survival and function during glucotoxicity.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Impact of glucagon-like peptide-1 (7-36) amide, isosteviol and 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside on leucine-mediated α-cell dysfunction.

AIM: To investigate the acute and chronic effects of l-leucine on pancreatic α-cell function in vitro. Furthermore, we wanted to explore if glucagon-like peptide-1 (GLP-1), isosteviol (ISV) and 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR) counteract changes in α-cell function induced by chronic exposure to leucine. METHODS: Isolated mice islets were incubated with 10 mM leucine for 2 or 72 h. We investigated glucagon and insulin secretion at 2 mM and 16.7 mM glucose. In addition, we cultured clonal α-TC1-6 cells with 5 mM leucine, 5 mM leucine plus GLP-1 (10(-6) M), or ISV (10(-6) M) or AICAR (10(-5) M) at high glucose for 72 h. We measured the glucagon secretion, cholesterol (CHO) and triglyceride (TG) content, cell proliferation as well as gene expression. RESULTS: Ten millimolar of leucine for 2 h significantly stimulated glucagon and insulin secretion both at 2 and 16.7 mM glucose in mice islets. After 72 h incubation with 10 mM leucine the glucagon secretion was enhanced at both 2 and 16.7 mM glucose, whereas the glucose-stimulated insulin secretion (16.7 mM glucose) was inhibited. Chronic exposure to 5 mM leucine increased glucagon secretion, CHO and TG content, cell proliferation and Pcsk2 (p < 0.001), MafB (p < 0.05), Gcg (p < 0.001), Prkaa1 (p < 0.01), Hmgcr (p < 0.001), Srebf2 (p < 0.001), Acaca (p < 0.001), Mtor (p < 0.05) mRNA expression in clonal α-TC1-6 cells. While GLP-1 was cable of reducing glucagon hypersecretion and Pcsk2 (p < 0.05) mRNA expression. ISV and AICAR had no effect on leucine-induced glucagon hypersecretion. CONCLUSIONS: Long-term exposure to leucine induces hypersecretion of glucagon secretion, that is, aminoacidotoxicity and influences some key genes of pancreatic α-cells. Interestingly, GLP-1 counteracts the leucine-induced α-cell dysfunction.

Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome.

BACKGROUND AND AIMS: Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure. METHODS: In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥ 10%. Responders were subjects who demonstrated reductions of ≥ 20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose. RESULTS: Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 ± 475 and 354 ± 334 ml/day), the trend towards higher baseline parenteral volume (1816 ± 1008 vs 1374 ± 639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo. CONCLUSIONS: Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185.

A multi-national survey of experience and attitudes towards commencing home parenteral nutrition for patients with advanced cancer.

INTRODUCTION: Advanced cancer (AC) is increasingly an indication for home parenteral nutrition (HPN) but an area with possible variation in practice between geographical locations. The aims of this study are to explore the views and experiences of international multi-disciplinary teams to determine opinions and practices. METHODS: An online questionnaire was developed with members of the Home Artificial Nutrition and Chronic Intestinal Failure interest group of the European Society for Clinical Nutrition and Metabolism (ESPEN) and distributed to colleagues involved in managing patients with AC on HPN. RESULTS: A total of 220 responses were included from 5 continents including 36 countries, with 90% of all responses from Europe. Predicted survival was a key factor influencing the decision to commence HPN for most respondents 152/220 (75%), with the majority of participants reporting that patients should have a predicted survival of ≥3 months if considered for HPN (≥3 months: n = 124, 56% vs. <3 months: n = 47, 21%, p < 0.001). However, most respondents were not confident about predicting overall survival in more than 50% of cases (confident n = 40, 23% vs not confident n = 135, 77%, p < 0.001). Barriers to utilising HPN in AC included colleagues' objections (n = 91, 46%), lack of local expertise (n = 55, 28%) and funding restrictions (n = 34, 17%). CONCLUSIONS: Significant consensus was observed regarding AC as indication for HPN, while areas of variation exist. Survival prognostication is often used as an indication for commencing HPN in people with AC, although the majority of respondents were not confident in prognosticating, suggesting better clinical prognostication tools will be of assistance. Further studies are also required to better understand the obstacles faced by clinical teams to commencing HPN that may explain variations in clinical practice between countries, as well as adressing variation in funding.

Nonlinear properties of and nonlinear processing in hydrogenated amorphous silicon waveguides.

We propose hydrogenated amorphous silicon nanowires as a platform for nonlinear optics in the telecommunication wavelength range. Extraction of the nonlinear parameter of these photonic nanowires reveals a figure of merit larger than 2. It is observed that the nonlinear optical properties of these waveguides degrade with time, but that this degradation can be reversed by annealing the samples. A four wave mixing conversion efficiency of + 12 dB is demonstrated in a 320 Gbit/s serial optical waveform data sampling experiment in a 4 mm long photonic nanowire.

Optical switching and detection of 640 Gbits/s optical time-division multiplexed data packets transmitted over 50 km of fiber.

We demonstrate 1×4 optical-packet switching with error-free transmission of 640 Gbits/s single-wavelength optical time-division multiplexed data packets including clock distribution and short pulse generation for optical time demultiplexing based on a cavityless pulse source.

Modern treatment of adult short bowel syndrome patients.

By definition, intestinal failure prevails when oral compensation is no longer feasible and parenteral support is necessary to maintain nutritional equilibrium. In the past, conventional treatment has mainly focused on "making the most of what the short bowel syndrome patient still had" by optimizing remnant intestinal function through dietary interventions, antidiarrheals and antisecretory agents. However, modern treatment options are in the near horizon, and the increased understanding of the mediators for intestinal adaptation will lead to the expansion of the limited treatment armamentarium in short bowel syndrome patients with intestinal failure. The clinical meaningfulness and implications of the observed effects of growth hormone, glutamine, glucagon-like peptide 2 (GLP-2) and the dipeptidyl peptidase-4 degradation resistant analog, teduglutide, is presented in this review and balanced against treatment related adverse events and possible unfavourable effects of long-term, possibly lifelong, treatments.

Effects of elevated fatty acid and glucose concentrations on pancreatic islet function in vitro.

AIMS/HYPOTHESIS: The aims of this study were to elucidate long-term effects of increased fatty acids and glucose concentrations on islet hormone secretion, triglyceride (TG) accumulation and fuel metabolism, and to determine the role of insulin on glucagon secretion. METHODS: Isolated normal mouse islets were exposed to palmitate (0.6 mM) in the presence of high glucose (16.7 mM). After 48 h culture, glucagon secretion and content, insulin secretion and content, TG content and glucose oxidation were measured. The impact of etomoxir, an inhibitor of carnitine palmitoyl transferase-1, as well as of insulin, and alterations in gene expression were also investigated. RESULTS: In the presence of palmitate, (i) high glucose caused no statistically significant suppression of glucagon while this was seen in the absence of palmitate; (ii) the insulin response to high glucose was impaired and (iii) an accumulation of TG and a decline in glucose oxidation were detected, whereas the glucagon content remained unchanged. However, etomoxir was capable of reducing glucagon secretion. Addition of exogenous insulin (10(-10)-10(-6) M) failed to restore alpha cell response to normal. Furthermore, 0.6 mM palmitate reduced the mRNA levels of acetyl-CoA carboxylase-1 and sterol regulatory element-binding protein-1c. CONCLUSIONS/INTERPRETATION: In summary, high concentrations of palmitate and glucose cause a relative increase in glucagon secretion, a decline in insulin secretion, a loss of alpha cell sensitivity to glucose and an accumulation of TG. The inability of insulin to suppress glucagon may be because of insulin resistance of alpha cells.

Isosteviol increases insulin sensitivity and changes gene expression of key insulin regulatory genes and transcription factors in islets of the diabetic KKAy mouse.

AIMS: Isosteviol (ISV), a diterpene molecule, is an isomer of the backbone structure of a group of substances with recently proven antidiabetic capabilities in both man and rodents. The aim of this study was to investigate if ISV possesses beneficial effects on the metabolism in the diabetic KKAy mouse and to establish the long-term in vivo effects of ISV on the gene expression profile of key insulin regulatory genes in islets. METHODS: Twenty KKAy mice, aged 5 weeks, were divided into two groups and treated for 9 weeks with either (i) standard chow diet (control) or (ii) chow + 20 mg/kg body weight of ISV. Blood samples were collected before and after intervention and were subsequently analysed. As a non-diabetic control group, 10 normal C57BL mice were fed with standard chow diet. Gene expression was determined in islets by quantitative real-time RT-PCR and Affymetrix microarray. RESULTS: We demonstrated that long-term treatment with ISV improves glucose homeostasis, increases insulin sensitivity, lowers plasma triglycerides and lowers weight in the diabetic KKAy mice. Furthermore, ISV markedly changes the gene expression profile of key insulin regulatory genes GLUT2, Ins1, Ins2, Pdx1/Ipf1, Beta2/Neurod1, Pax6 and 11-beta-HSD-1 and beta-cell transcription factors Nkx2-2, Nkx6-1, C/EBPalpha and FoxA2 in isolated islets of the KKAy mice. CONCLUSIONS: The results indicate that ISV improves glucose and insulin sensitivity as well as improving the lipid profile and upregulates the gene expression of key beta-cell genes, including insulin regulatory transcription factors.

Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels.

Recently, we showed that rebaudioside A potently stimulates the insulin secretion from isolated mouse islets in a dose-, glucose- and Ca(2+)-dependent manner. Little is known about the mechanisms underlying the insulinotropic action of rebaudioside A. The aim of this study was to define the signalling system by which, rebaudioside A acts. Isolated mouse islets were used in the cAMP[(125)I] scintillation proximity assay to measure total cAMP level, and in a luminometric method to measure intracellular ATP and ADP concentrations. Conventional and permeabilized whole-cell configuration of the patch-clamp technique was used to verify the effect of rebaudioside A on ATP-sensitive K(+)-channels from dispersed single beta cells from isolated mouse islets. Insulin was measured by radioimmunoassay from insulinoma MIN6 cells. In the presence of 16.7 mM glucose, the addition of the maximally effective concentration of rebaudioside A (10(-9) M) increased the ATP/ADP ratio significantly, while it did not change the intracellular cAMP level. Rebaudioside A (10(-9) M) and stevioside (10(-6) M) reduced the ATP-sensitive potassium channel (K(ATP)) conductance in a glucose-dependent manner. Moreover, rebaudioside A stimulated the insulin secretion from MIN6 cells in a dose- and glucose-dependent manner. In conclusion, the insulinotropic effect of rebaudioside A is mediated via inhibition of ATP-sensitive K(+)-channels and requires the presence of high glucose. The inhibition of ATP-sensitive K(+)-channels is probably induced by changes in the ATP/ADP ratio. The results indicate that rebaudioside A may offer a distinct therapeutic advantage over sulphonylureas because of less risk of causing hypoglycaemia.

Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

Active repression of methylated genes by the chromosomal protein MBD1.

MBD1 belongs to a family of mammalian proteins that share a methyl-CpG binding domain. Previous work has shown that MBD1 binds to methylated sites in vivo and in vitro and can repress transcription from methylated templates in transcription extracts and in cultured cells. In the present study we established by several experimental criteria that, contrary to a previous report, MBD1 is not a component of the MeCP1 repressor complex. We identified a powerful transcriptional repression domain (TRD) at the C terminus of MBD1 that can actively repress transcription at a distance. Methylation-dependent repression in vivo depends on the presence of both the TRD and the methyl-CpG binding domain. The mechanism is likely to involve deacetylation, since the deacetylase inhibitor trichostatin A can overcome MBD1-mediated repression. Accordingly, we found that endogenous MBD1 is particularly concentrated at sites of centromeric heterochromatin, where acetylated histone H4 is deficient. Unlike MBD2 and MeCP2, MBD1 is not depleted by antibodies to the histone deacetylase HDAC1. Thus, the deacetylase-dependent pathway by which MBD1 actively silences methylated genes is likely to be different from that utilized by the methylation-dependent repressors MeCP1 and MeCP2.

Crosstalk between cardiomyocyte-rich perivascular tissue and coronary arteries is reduced in the Zucker Diabetic Fatty rat model of type 2 diabetes mellitus.

AIM: We tested the hypothesis that crosstalk between cardiomyocyte-rich perivascular tissue (PVT) and coronary arteries is altered in diabetes. METHODS: We studied the vasoactive effects of PVT in arteries from the Zucker Diabetic Fatty (ZDF) rat model of type 2 diabetes, streptozotocin (STZ)-treated Wistar rats with type 1 diabetes, and corresponding - heterozygous Zucker Lean (ZL) or vehicle-treated Wistar - control rats. Vasocontractile and vasorelaxant functions of coronary septal arteries with and without PVT were investigated using wire myography. RESULTS: After careful removal of PVT, vasoconstriction in response to serotonin and thromboxane analogue U46619 was similar in arteries from ZDF and ZL rats, whereas depolarization-induced vasoconstriction - caused by elevating extracellular [K+ ] - was reduced in arteries from ZDF compared to ZL rats. PVT inhibited serotonin-, U46619- and depolarization-induced vasoconstriction in arteries from ZL rats, but this anticontractile influence of PVT was attenuated in arteries from ZDF rats. Methacholine-induced vasorelaxation was smaller in arteries from ZDF than ZL rats both with and without PVT, and the antirelaxant influence of PVT was comparable between arteries from ZDF and ZL rats. We observed no differences in vasoconstriction, vasorelaxation or PVT-dependent vasoactive effects between arteries from STZ- and vehicle-treated Wistar rats. CONCLUSION: Anticontractile influences of PVT are attenuated in coronary arteries from ZDF rats but unaffected in arteries from STZ-treated rats. Signs of endothelial dysfunction are evident in coronary septal arteries - with and without PVT - from ZDF rats but not STZ-treated rats. We propose that altered signalling between cardiomyocyte-rich PVT and coronary arteries can contribute to cardiovascular complications in type 2 diabetes mellitus.

Impaired retinal autoregulation in small retinal arterioles before and after focal laser treatment for diabetic maculopathy.

AIMS: To study the effect of an acute increase in the arterial blood pressure on the diameter response of retinal arterioles supplying areas with focal diabetic macular oedema before and after laser photocoagulation, and control arterioles supplying areas without oedema. METHODS: In 17 diabetic patients the diameter response of arterioles after an increase in the arterial blood pressure induced by isometric exercise was studied using the retinal vessel analyser (RVA). In each patient a study arteriole supplying a focal area of macular oedema as well as a control arteriole supplying a retinal area without retinopathy lesions was selected, and the diameter response of these vessels was performed immediately before, and 1 hour and 3 months after focal laser photocoagulation of the focal oedema area. RESULTS: The diameter response was impaired in both study arterioles and control arterioles before focal laser photocoagulation. The treatment induced regression of the focal retinal oedema, but did not affect the diameter response in the arteriole supplying this area (p = 0.85). CONCLUSION: Impairment of the diameter response in small arterioles from diabetic patients does not parallel the regional distribution of retinopathy lesions. Other factors than disturbed autoregulation are probably involved in generating flow disturbances and oedema in diabetic maculopathy.

Integrated treatment ameliorates negative symptoms in first episode psychosis--results from the Danish OPUS trial.

PURPOSE: To investigate the effect of integrated treatment on negative, psychotic and disorganised symptoms in patients with first episode psychosis. METHOD: A RCT comparing integrated treatment (IT) with standard treatment (ST) was conducted, including 547 patients, aged 18-45, diagnosed with schizophrenia spectrum disorders. All patients were assessed with SCAN, SAPS and SANS at entry and after 1 and 2 years. The IT consisted of assertive community treatment, multifamily groups, psycho-education and social skills training, and the caseload was 1:10 compared with 1:25 in ST. Since attrition was considerable, a mixed model analysis with repeated measurements was used to examine the possible effects of IT statistically. RESULTS: IT reduced both negative and positive symptoms significantly better than ST. Most marked were the results from the negative dimension, where all five global scores from SANS had a significantly better reduction in IT. Sub-analyses did not single out any one element in the integrated treatment that could explain this result. CONCLUSION: Integrated treatment significantly reduced both negative and psychotic symptoms, assumably due to the different psychosocial treatment elements that were provided in the IT. The results indicate that the integrated approach is crucial, since, most likely, many aspects of the integrated treatment have contributed to the reduction of symptoms.