Transitions Study of predictors of illness progression in young people with mental ill health: study methodology.

AIM: An estimated 75% of mental disorders begin before the age of 24 and approximately 25% of 13-24-year-olds are affected by mental disorders at any one time. To better understand and ideally prevent the onset of post-pubertal mental disorders, a clinical staging model has been proposed that provides a longitudinal perspective of illness development. This heuristic model takes account of the differential effects of both genetic and environmental risk factors, as well as markers relevant to the stage of illness, course or prognosis. The aim of the Transitions Study is to test empirically the assumptions that underpin the clinical staging model. Additionally, it will permit investigation of a range of psychological, social and genetic markers in terms of their capacity to define current clinical stage or predict transition from less severe or enduring to more severe and persistent stages of mental disorder. METHOD: This paper describes the study methodology, which involves a longitudinal cohort design implemented within four headspace youth mental health services in Australia. Participants are young people aged 12-25 years who have sought help at headspace and consented to complete a comprehensive assessment of clinical state and psychosocial risk factors. A total of 802 young people (66% female) completed baseline assessments. Annual follow-up assessments have commenced. CONCLUSIONS: The results of this study may have implications for the way mental disorders are diagnosed and treated, and progress our understanding of the pathophysiologies of complex mental disorders by identifying genetic or psychosocial markers of illness stage or progression.

Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma.

BACKGROUND: Protease-activated receptors (PARs), which are G protein-coupled receptors that are activated after proteolytic cleavage of the amino terminus of the receptor, are likely to play a major role in airway inflammation. PARs are activated by endogenous proteases, including thrombin (PAR-1, -3, and -4) and tryptase (PAR-2 and -4), both of which are present in inflamed airways. OBJECTIVE: The purpose of this study was to compare the expression and distribution of PARs in biopsy specimens obtained from asthmatic and normal subjects and to examine the effect of inhaled corticosteroids on PAR expression. METHODS: Biopsy specimens were obtained from 10 normal and 20 asthmatic patients, and sections were stained for PAR-1, -2, -3, and -4 through use of specific antibodies. Staining was scored semiquantitatively for both intensity and distribution. RESULTS: Staining for all PARs was seen on the epithelium and smooth muscle in biopsy specimens from both normal and asthmatic subjects. In the epithelium, PAR-1 and -3 staining appeared to be apically concentrated, whereas PAR-2 and -4 staining was more diffuse. In normal subjects, epithelial staining intensity of PAR-1 and -3 was significantly greater than for PAR-4 (P < .05). Staining for PAR-1, -3, and -4 in biopsy specimens from asthmatic subjects was similar to that in specimens from normal subjects, irrespective of whether the former were using inhaled corticosteroids. However, PAR-2 staining in asthmatic epithelium was significantly increased in comparison with normal epithelium. Expression of PARs in airway smooth muscle did not differ between groups. CONCLUSION: Asthma per se is associated with increased PAR-2 expression in bronchial epithelium. Importantly, staining was not influenced by inhaled corticosteroids. These results suggest that PAR-2 might be involved in airway inflammation.

Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins.

Myofibroblasts, characterised by high expression of alpha-smooth muscle actin (alpha-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via alpha v and beta 1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in alpha-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins alpha v, beta 1, alpha v beta 3 and alpha v beta 5 induced the expression of alpha-SMA and its organization into stress fibers. Expression of alpha-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of alpha-SMA. The expression and organization of alpha-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of alpha-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of alpha-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.

Myotube formation is delayed but not prevented in MyoD-deficient skeletal muscle: studies in regenerating whole muscle grafts of adult mice.

We compared the time course of myogenic events in vivo in regenerating whole muscle grafts in MyoD(-/-) and control BALB/c adult mice using immunohistochemistry and electron microscopy. Immunohistochemistry with antibodies to desmin and myosin revealed a striking delay by about 3 days in the formation of myotubes in MyoD(-/-) autografts compared with BALB/c mice. However, myotube formation was not prevented, and autografts in both strains appeared similar by 8 days. Electron microscopy confirmed myotube formation in 8- but not 5-day MyoD(-/-) grafts. This pattern was not influenced by cross-transplantation experiments between strains examined at 5 days. Antibodies to proliferating cell nuclear antigen demonstrated an elevated level of replication by MyoD(-/-) myoblasts in autografts, and replication was sustained for about 3 days compared with controls. These data indicate that the delay in the onset of differentiation and hence fusion is related to extended proliferation of the MyoD(-/-) myoblasts. Overall, although muscle regeneration was delayed it was not impaired in MyoD(-/-) mice in this model.

No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia.

The A(-1438)G promoter polymorphism of the 5-hydroxytryptamine 2a receptor (5-HT2AR) gene and its influence on the cortical density of 5-HT2AR was studied using brain tissue donated at autopsy from 58 schizophrenic and 64 non-schizophrenic subjects. A linkage between genotypes for the A(-1438)G and a T102C polymorphic site identified in a previous study was observed. Our data suggest no association of the A(-1438)G polymorphism with schizophrenia and no effect of the promoter genotype upon 5-HT2AR densities in either the schizophrenic or non-schizophrenic groups.

[The evaluation of the time of gastric radio-isotopic emptying in subjects with non-insulin dependent diabetes mellitus]. / Valutazione dei tempi di svuotamento gastrico radio-isotopico in soggetti con NIDDM in terapia con cisapride.

Abnormal gastro-intestinal motility is a well-recognized complication of autonomic neuropathy in diabetics; delayed gastric emptying is frequently documented. Various pharmacologic agents have been used to treat this complication such as cisapride. We have evaluated the effects of cisapride on gastric emptying in nine diabetic patients with autonomic neuropathy through radio-scintigraphic method. Gastric emptying diabetic patients was significantly prolonged compared control subjects (p < 0.01). In our study cisapride increased gastric emptying, but this did not reach statistical significance. We concluded that cisapride may be considered as a good alternative in cases where limited efficacy or side effects preclude the use of metoclopramide.

[The motility of the biliary tract studied with 99mTc-Br-IDA in patients with type-2 diabetes mellitus]. / Studio sulla motilità delle vie biliari con 99mTc-Br-IDA in pazienti con diabete mellito di tipo II.

Autonomic neuropathy in diabetes mellitus can cause alterations of the motor function of various segments of the gastroenteric apparatus. With hepatocholangio-cholecystiscintigraphy-HIDA we have studied the motility of the biliary system in patients with diabetes mellitus type II. The research has been carried out in 29 patients with diabetic autonomic neuropathy; 12 healthy volunteers have been studied to compare the results obtained. The results showed a delay in the appearance of radionucleotide in the small intestine of diabetic subjects compared to controls with statistical significance. Moreover the diabetic subjects with a serious neuropathic injury showed increased intestinal transit time. These results match those obtained by other authors that have studied the cholecystic emptying in diabetic subjects with other methods. Consequently the biliary system is also affected by the diabetic autonomic neuropathy that can be in its turn the cause of other pathologies such as biliary lithiasis.

[Effects of fenoverine on biliary kinetics evaluated by hepatobiliary scintigraphy with 99mTc-Br-IDA]. / Effetti della fenoverina sulla cinetica biliare valutata con scintigrafia epatobiliare con 99mTc-Br-IDA.

Hepatobiliary scintigraphy was used to evaluate the action of fenoverine in 16 patients suffering from dyskinesia of the biliary tract; the drug was administered in doses of 300 mg per day per os for 20 days, the patients being subjected to hepatobiliary scintigraphy before and after treatment. The following parameters--accurate indicators of the motor coordination of the biliary tract--were evaluated: tracer appearance time in the gallbladder (Tc) and in the intestine (Ti). After treatment there was a normalization of these two parameters which initially were extended. Statistical analysis showed a highly significant reduction in these times. Stress is laid on the importance of hepatobiliary scintigraphy in the diagnosis of biliary dyskinesia and on the effectiveness of fenoverine in the treatment of this conditions.

[Gastric emptying after duodenogastric resection]. / Lo svuotamento gastrico dopo resezione duodeno-gastrica.

The gastric emptying has been studied with 99Tc labelled in 35 patients followed for 2-8 years after duodenogastric resection. All patients had been undergone a gastric resection of 2/3 of stomach. In 18 had been performed a Billroth II (BII) and in 17 a gastrojejunostomy with a Roux-en-Y anastomosis. The jejunal loop had been carried out about 25-35 cm from the Treitz, the mesenteric margin isolated for 2-3 cm and the jejunojejunostomy performed about 50 cm from the gastrojejunostomy. Nobody complained symptoms from altered gastric emptying. In all patients with Roux-en-Y anastomosis there was an intense radioactivity in the new stoma till the 150th minute, and peristaltic activity was valid and coordinated. In patients with BII there was no radioactivity in the new stoma before the 150th minute, and peristaltic activity was always convulsive and uncoordinated.

[Study of esophageal transit with radioisotopes in the diagnosis of achalasia]. / Lo studio del transito esofageo con radioisotopi nella diagnostica della acalasia.

The investigations employed in the diagnosis of oesophageal achalasia have been assessed critically. Although electromanometry contributes most to diagnosis and pinpoints with absolute precision the physiopathological elements that characterise the disease, radioisotopic study of oesophageal transit is an important diagnostic aid. More readily than any other, this technique permits morphofunctional evaluation in selected patients; it also represents the most physiological investigation and the best tolerated and, second only to manometry, the most reliable. Oesophagography with baritate meal and oesophagoscopy also play a diagnostic role in oesophageal achalasia. The former makes it possible to document the cardial stop and the presence or otherwise of mega-oesophagus, the second excludes the presence of organic dysphagias and also has a therapeutic use because cycles of dilatation of the oesophago-cardial junction can be carried out.

[Protirelin in the treatment of cerebrovascular disorders]. / La protirelina nel trattamento degli accidenti cerebro-vascolari.

Effects of protirelin tartrate, administered for 14 days (2 mg/day, i.m.) to 15 patients with acute cerebrovascular disease have been investigated. The evaluation was performed by means of SPECT, at enrollment and at the end of treatment. This evaluation was aimed at the early detection of ischemic damage and assessment of the size of the hypoperfusion area. Treatment with protirelin tartrate was well tolerated and led to definite improvement of the scintigraphic findings in about 74% of the patients.

[Effect of clebopride on gastric emptying studied using a physiologic meal marked with Tc 99m colloid in subjects with non-ulcer dyspepsia]. / Effetti della clebopride sullo svuotamento gastrico studiato con pasto fisiologico marcato con Tc99m coll. in soggetti con dispepsia non ulcerosa.

The authors studied the action of clebopride on gastric emptying in subjects with non-ulcer dyspepsia by using radioactive isotopes. Eighteen subjects complaining of dyspeptic symptoms were studied in whom the tests undertaken had not shown organic lesions of the digestive tract. Tests with radioactive isotopes were performed before and after administration of clebopride (0.5 mg, three times daily for 15 days). In all patients gastric emptying time was normalized and gastric peristalsis became regular. In addition, in 85% of the patients, symptoms disappeared or were markedly reduced. Side effects requiring withdrawal of the drug were not observed. The above study, therefore, showed clebopride to be a useful drug for the treatment of non-ulcer dyspepsia, thus confirming data found in the literature.

Effectiveness of pinaverium bromide in the treatment of primitive biliary dyskinesia: 99mTc-P-IDA scintigraphic evaluation.

The 99mTc-P-IDA (technetium-p-iminodiacetic acid) hepatocholangiocholecystoscintigraphy is a diagnostic technique which allows information on the liver biligenetic and excretory capabilities to be obtained. It is, moreover, a test that mirrors closely the anatomic and functional conditions of the cholecyst and choledochus. In this study the authors wanted to verify whether pinaverium bromide, a drug with a documented musculotropic-spasmolytic activity, was able to induce changes in some abnormal instrumental parameters observed in 24 subjects with primitive biliary dyskinesia. The results revealed that the ti values, characteristically longer in those subjects, were significantly reduced in the group of patients treated with pinaverium bromide. On the contrary, in the group of patients treated with placebo, there was no change with respect to this parameter.

[Effect of polyunsaturated phosphatidylcholine and vitamin B complex on the metabolism of selenium homotaurocholic acid in patients with chronic liver disease]. / Azione della fosfatidilcolina polinsatura (EPL) + complesso vitaminico B sul metabolismo del SeHCAT in pazienti con epatopatia cronica.

SeHCAT, a synthetic homologue of thaurocolic acid, may be used to examine the dynamics of enterohepatic circulation. A greater retention of SeHCAT may be attributed to a defective hepatic clearance and to a partial redistribution of the biliary acid pool outside the enterohepatic circle. This method has been applied to 20 patients affected with chronic hepatic disorders. The percentage of retention of SeHCAT in normal subjects was 19-20 on average. The hepatopathic patient has an average SeHCAT retention of 54%. After treatment with polyunsaturated phosphatidylcholine (EPL) plus vitamin B complex i.v., the percentage of SeHCAT retention was significantly less than 31% (P less than 0.001). It can be hypothesized that the drug determines an improvement of the enterohepatic circle (acting on the hepatic clearance) in patients with chronic hepatic disorders as shown by the reduction of the percentage of SeHCAT retention noticed.

[Behavior of the somatotroph in prepubertal subjects with underdeveloped gonads]. / Comportamento del somatotropo in soggetti in fase prepubere con ipoevolutismo gonadale.

After a rapid review of the reciprocal effects of hGH and testosterone in somatic development during puberty, the behaviour of the growth hormone after appropriate stimulation was examined in prepuberal subjects with underdeveloped gonads. These subjects revealed defective secretion of the hormone which may be explained by a reduction in the efficiency of the diencephalohypophyseal factors controlling puberty and sexual function.