Impact of high-volume, intermediate-volume and low-volume bowel preparation on colonoscopy quality and patient satisfaction: An observational study.

Background: Although optimal bowel preparation is essential for high-quality screening colonoscopy, documentation of preparation quality, patient satisfaction and adherence is scarce. Aim: The aim of this article is to compare low-volume (LV, 300 ml sodium picosulfate), intermediate-volume (IV, 2 l polyethylene glycol, PEG + ascorbic acid and sodium ascorbate), and high-volume (HV, 4 l PEG) purgatives. Results: A total of 5000 individuals (50.5% women) were enrolled between March 2015 and July 2017 (LV:IV:HV = 3.61:1.54:1). Overall sex- and age-adjusted adenoma detection rate was 25.4% (LV 23.8%, IV 25.4%, HV 29.8%), median age was 59.6 years, and cleansing was successful in 96.8%. Success rates of bowel cleansing were highest with HV (97.6%), followed by LV (97.2%) and IV (95.3%) with OR 2.04 (CI 95% 1.20-3.45, p = 0.008) and OR 1.79 (CI 95% 1.27-2.50, p = 0.001), respectively, compared to IV. A total of 93.5% of the LV group would use the same purgative in the future, 73.2% of IV and 69.4% of HV. A total of 84.4% would prefer overnight preparation, 12.1% same-day preparation. Conclusion: All purgatives investigated showed good bowel cleansing quality results, patient satisfaction and compliance. Improvement in patient information might lead to even higher participation rates in screening colonoscopy since one in five patients stated that bowel preparation worried him or her most prior to colonoscopy.

The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study.

Essentials Long-term recurrence risk of venous thromboembolism (VTE) is uncertain. We performed a prospective cohort study of 839 patients with first unprovoked VTE. VTE recurrence risk is high, particularly in men with proximal thrombosis or pulmonary embolism. Sex and VTE site determine the recurrence risk and should be considered for patient counseling. SUMMARY: Background The long-term recurrence risk (ltRR) of venous thromboembolism (VTE) is uncertain. Objective To assess the ltRR of patients with first unprovoked VTE. Patients/methods Patients were classified into three categories: distal deep vein thrombosis (DVT), proximal DVT or pulmonary embolism (PE), that is, PE associated with DVT or isolated PE. Patients with major thrombophilia or antithrombotic therapy were excluded. The endpoint was recurrent symptomatic VTE. Results A total of 839 patients were followed for a median of 7.7 years. VTE recurred in 263 patients (31%). After 10 and 20 years, the cumulative ltRR was 32% (95% confidence interval [CI], 29-36) and 44% (95% CI, 38-49) with 3.9 (95% CI, 3.3-4.6) and 3.3 (95% CI, 2.7-4.0) events per 100 patient-years, respectively. The adjusted hazard ratio was 2.1 (95% CI, 1.4-3.2) and 2.1 (95% CI, 1.4-3.2) for patients with proximal DVT or PE compared with patients with distal DVT and was 2.1 (95% CI, 1.6-2.9) for men compared with women. At 10 years, 4.7 (95% CI, 3.8-5.8) events per 100 patient-years occurred in men with proximal DVT or PE, 2.4 (95% CI, 1.2-4.4) in men with distal DVT, 1.9 (95% CI, 1.2-2.8) in women with proximal DVT or PE and 0.9 (95% CI, 0.2-1.9) in women with distal DVT. Conclusion The ltRR of patients with first unprovoked VTE is high and dependent upon sex and VTE site.

Prognostic role of pretreatment plasma fibrinogen in patients with solid tumors: A systematic review and meta-analysis.

BACKGROUND: Plasma fibrinogen may be involved in several stages of cancer progression. Clinical studies have demonstrated that pretreatment plasma fibrinogen is associated with poor survival in various cancers. The aim of this meta-analysis was to examine the prognostic effect of circulating fibrinogen in solid tumors. MATERIALS AND METHODS: We searched Medline, EMBASE, Cochrane Database of Systematic Reviews, and meeting proceedings to identify studies assessing the effect of pretreatment plasma fibrinogen on survival of cancer patients. Pooled multivariable-adjusted hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were estimated using random-effects models. RESULTS: Data from 52 observational studies and 15,371 patients were summarized. An elevated baseline plasma fibrinogen was significantly associated with worse OS (pooled HR = 1.69; 95% CI = 1.48­1.92). The highest negative effect of elevated plasma fibrinogen on OS was demonstrated in renal cell carcinoma (pooled HR = 2.22), followed by head and neck cancer (pooled HR = 2.02), and colorectal cancer (pooled HR = 1.89). The adverse prognostic impact of high plasma fibrinogen remained in both non-metastatic and metastatic disease and patients of different ethnicity. Patients with high baseline fibrinogen had a significantly shorter DFS (pooled HR = 1.52) and CSS (pooled HR = 2.50). CONCLUSIONS: An elevated pretreatment plasma fibrinogen significantly correlates with decreased survival in patients with solid tumors. Future clinical trials are warranted to determine whether plasma fibrinogen could be incorporated in cancer staging systems and whether fibrinogen-lowering therapies have a favorable effect on disease recurrence and mortality.

The INTERPRET-DD study of diabetes and depression: a protocol.

AIM: People with diabetes are at an increased risk of developing depression and other psychological disorders. However, little is known about the prevalence, correlates or care pathways in countries other than the UK and the USA. A new study, the International Prevalence and Treatment of Diabetes and Depression Study (INTERPRET-DD) aims to address this dearth of knowledge and identify optimal pathways to care across the globe. METHOD: INTERPRET-DD is a 2-year longitudinal study, taking place in 16 countries' diabetes outpatients' facilities, investigating the recognition and management of depressive disorders in people with Type 2 diabetes. Clinical interviews are used to diagnose depression, with clinical and other data obtained from medical records and through patient interviews. Pathways to care and the impact of treatment for previously unrecognized (undocumented) depression on clinical outcomes and emotional well-being are being investigated. RESULTS: Initial evidence indicates that a range of pathways to care exist, with few of them based on available recommendations for treatment. Pilot data indicates that the instruments we are using to measure both the symptoms and clinical diagnosis of depression are acceptable in our study population and easy to use. CONCLUSIONS: Our study will increase the understanding of the impact of comorbid diabetes and depression and identify the most appropriate (country-specific) pathways via which patients receive their care. It addresses an important public health problem and leads to recommendations for best practice relevant to the different participating centres with regard to the identification and treatment of people with comorbid diabetes and depression.

Central nervous system effects and chemical composition of two subspecies of Agastache mexicana; an ethnomedicine of Mexico.

ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana subspecies mexicana (Amm) and xolocotziana (Amx) are used in Mexican traditional medicine to relief cultural affiliation syndromes known as "susto" or "espanto", for "nervous" condition, and as a sleep aid. Despite its intensive use, neuropharmacological studies are scarce, and the chemical composition of the aqueous extracts has not been described. Aims of the study are: (1) To analyze the chemical composition of aqueous extracts from aerial parts of Amm and Amx. (2) To evaluate the anxiolytic-like, sedative, antidepressant-like effects. (3) Analyze the general toxic effects of different doses. MATERIALS AND METHODS: Anxiolytic-like and sedative effects were measured in the avoidance exploratory behavior, burying behavior and the hole-board tests. The antidepressant-like actions were studied in the forced swimming and tail suspension tests. Finally, general activity and motor coordination disturbances were evaluated in the open field, inverted screen and rota-rod tests. The acute toxicity of Amm and Amx was determined by calculating their LD50 (mean lethal dose). The chemical analyses were performed employing chromatographic, photometric and HPLC-ESI-MS techniques. RESULTS: Low doses of Amm and Amx (0.1σ1.0mg/kg) induced anxiolytic-like actions; while higher doses (over 10mg/kg) induced sedation and reduced the locomotor activity, exerting a general inhibition in the central nervous system (CNS). CONCLUSIONS: Results support the use of Amm and Amx in traditional medicine as tranquilizers and sleep inducers. Additionally, this paper contributes to the knowledge of the chemical composition of the aqueous extracts of these plants.

Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer.

BACKGROUND: Gamma-glutamyltransferase (GGT) - a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance - is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients. METHODS: In this multicenter study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. RESULTS: Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l(-1)) than in patients with BTO (20.01 (12.78) U l(-1), P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1-1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03). CONCLUSION: High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels.

Nomogram prediction for overall survival of patients diagnosed with cervical cancer.

BACKGROUND: Nomograms are predictive tools that are widely used for estimating cancer prognosis. The aim of this study was to develop a nomogram for the prediction of overall survival (OS) in patients diagnosed with cervical cancer. METHODS: Cervical cancer databases of two large institutions were analysed. Overall survival was defined as the clinical endpoint and OS probabilities were estimated using the Kaplan-Meier method. Based on the results of survival analyses and previous studies, relevant covariates were identified, a nomogram was constructed and validated using bootstrap cross-validation. Discrimination of the nomogram was quantified with the concordance probability. RESULTS: In total, 528 consecutive patients with invasive cervical cancer, who had all nomogram variables available, were identified. Mean 5-year OS rates for patients with International Federation of Gynecologists and Obstetricians (FIGO) stage IA, IB, II, III, and IV were 99.0%, 88.6%, 65.8%, 58.7%, and 41.5%, respectively. Seventy-six cancer-related deaths were observed during the follow-up period. FIGO stage, tumour size, age, histologic subtype, lymph node ratio, and parametrial involvement were selected as nomogram covariates. The prognostic performance of the model exceeded that of FIGO stage alone and the model's estimated optimism-corrected concordance probability was 0.723, indicating accurate prediction of OS. We present the prediction model as nomogram and provide a web-based risk calculator (http://www.ccc.ac.at/gcu). CONCLUSION: Based on six easily available parameters, a novel statistical model to predict OS of patients diagnosed with cervical cancer was constructed and validated. The model was implemented in a nomogram and provides accurate prediction of individual patients' prognosis useful for patient counselling and deciding on follow-up strategies.

pHH3 and survivin are co-expressed in high-risk endometrial cancer and are prognostic relevant.

BACKGROUND: Phosphohistone-H3 (pHH3) is a promising reliable mitotic count biomarker. Our purpose was to study the relationship between the novel proliferation marker pHH3 and the established anti-apoptotic marker survivin and consider their prognostic relevance in endometrial cancer. METHODS: A total of 106 patients with endometrial cancer (type I/endometrioid, n=81; type II carcinomas, n=18) and simple hyperplasia without atypia (n=7) were investigated. pHH3 and survivin expression were assessed using immunohistochemistry from paraffin-embedded tissue blocks. RESULTS: A strong positive correlation was observed between pHH3 and survivin expression (P<0.0001). Patients with high-grade tumours and patients with type II carcinomas expressed significantly more pHH3 and survivin than low grade and endometrioid tumours (P<0.0001, P<0.0001, P<0.0001, and P<0.0001, respectively). In univariate survival analysis, overexpression of pHH3 and survivin were associated with increased recurrence and mortality (P<0.0001, P<0.0001, P<0.0001, and P<0.0001, respectively), in the multivariable Cox regression analyses both pHH3 and survivin could be identified as independent parameters for overall survival (P=0.004, and P=0.023, respectively). CONCLUSION: In endometrial cancer, pHH3 and survivin were strongly positive correlated and were both associated with type II and high-grade tumours. Increasing expression levels of pHH3 and survivin were associated with adverse prognostic factors.

Neuropharmacological study of Dracocephalum moldavica L. (Lamiaceae) in mice: sedative effect and chemical analysis of an aqueous extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Dracocephalum moldavica is used as a tranquilizer and as remedy for nervous conditions relief in the Mexican traditional medicine. Despite its intensive use no literature reported neuropharmacological studies on Dracocephalum moldavica as yet. AIM OF THE STUDY: The sedative, anxiolytic-like and antidepressant-like effects of the aqueous extract of aerial parts of Dracocephalum moldavica (Lamiaceae) (DM) were evaluated in behavioral models in mice. The general toxic effects of DM were evaluated as well as their chemical analysis was performed. MATERIALS AND METHODS: DM effects were evaluated on pentobarbital-induced sleeping time (SPT), the hole-board (HBT), and the avoidance exploratory behavior (AEBT) tests and on the forced swimming test (FST). General activity and motor coordination were evaluated in the open field (OFT) and Rota-rod tests, respectively. The acute toxicity of DM was determinate by its LD(50) dose. The chemical analyses DM were performed by chromatographic and HPLC-ESI-MS techniques. RESULTS: DM prolonged the pentobarbital-induced sleeping time, induced sedation in the HBT, decreased spontaneous activity and produced motor coordination impairment in mice. However, DM did not show anxiolytic effects in the AEBT or HBT and it was not effective in FST. The DM-treatment produced mortalities with LD(50)=470 mg/kg body weight. The HPLC-ESI-MS analysis of DM revealed that (acacetin, apigenin and luteolin)-7-O-ß-D-(6″-O-malonyl)-glucoside derivates are the main compounds of DM. CONCLUSIONS: DM induced sedative actions and a general inhibition of CNS activity observed by the decrease of animals' general activity, motor coordination and exploration.

Antidepressant-like effects of an alkaloid extract of the aerial parts of Annona cherimolia in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Several species of Annona (Annonaceae) are used in traditional Mexican medicine by their anti-anxiety, anticonvulsant and tranquilizing properties. It has been reported that the alkaloids isolated from some species of the Annona have affinity to serotonergic 5-HT(1A) receptors and modulate dopaminergic transmission, which is involved in depressive disorders. AIM OF THE STUDY: To investigate the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice. MATERIALS AND METHODS: The antidepressant-like effect was evaluated in the forced swimming test. To elucidate a possible mechanism of action, experiments of synergism with antidepressant drugs, such as imipramine (IMI), clomipramine (CLIMI), and fluoxetine (FLX), were carried out. The neurotransmitter content (DA: dopamine, 5HT: serotonin and its metabolites, HVA: homovanillic acid and 5HIAA: 5-hydroxyindoleacetic) in the whole brain of mice were also determined by HPLC method. TA chemical composition was determined using high performance liquid chromatography-electrospray mass spectrometry. RESULTS: The results showed that repeated treatment with TA produced antidepressant-like effects in mice. This effect was not related to an increase in locomotor activity. Administration of TA facilitated the antidepressant effect of IMI and CLIMI as well as increased the turnover of DA and 5-HT. The alkaloids: 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine were the main constituents of TA. CONCLUSIONS: Results showed that TA produces an antidepressant-like action from a generalized increase in monominergic turnover, supporting the use in tradicional medicine of Annona cherimolia, and strongly suggest its therapeutic potency as an antidepressant agent.

Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice.

Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl2-enriched (1%) or control food, starting at the age of 4 months. Locomotor activity was increased by Mn without significant effect of the transgenes. Mice were sacrificed at the age of 7 or 20 months. Striatal Mn was significantly increased about three-fold in those exposed to MnCl2. The number of tyrosine hydroxylase positive substantia nigra compacta neurons was significantly reduced in 20 months old mice (-10%), but Mn or transgenes were ineffective (three-way ANOVA with the factors gene, Mn and age). In 7 months old mice, striatal homovanillic acid (HVA)/dopamine (DA) ratios and aspartate levels were significantly increased in control mice with human α-syn as compared to non-transgenic controls (+17 and +11%, respectively); after Mn exposure both parameters were significantly reduced (-16 and -13%, respectively) in human α-syn mice, but unchanged in non-transgenic animals and mice with mutated α-syn (two-way ANOVA with factors gene and Mn). None of the parameters were changed in the 20 months old mice. Single HVA/DA ratios and single aspartate levels significantly correlated across all treatment groups suggesting a causal relationship between the rate of striatal DA metabolism and aspartate release. In conclusion, under our experimental conditions, Mn and human α-syn, wild-type and doubly mutated, did not interact to induce PD-like neurodegenerative changes. However, Mn significantly and selectively interacted with human wild-type α-syn on indices of striatal DA neurotransmission, the neurotransmitter most relevant to PD.

Depressant effects of Clinopodium mexicanum Benth. Govaerts (Lamiaceae) on the central nervous system.

ETHNOPHARMACOLOGICAL RELEVANCE: The decoction of leaves of Clinopodium mexicanum Benth. Goaverts (Lamiaceae), commonly known as "Toronjil de Monte", is used in the Mexican traditional medicine to induce sleep, as well as sedative and analgesic remedy. AIM OF THE STUDY: To evaluate the putative depressant effects of an aqueous extract of the medicinal plant Clinopodium mexicanum on the central nervous system (CNS). MATERIALS AND METHODS: The effects of the extract (AECM) on mice were tested in several animal paradigms, including sodium pentobarbital-induced sleep, open field tests, and hole-board tests. The effects of AECM on pentylenetetrazole- and picrotoxin-induced convulsions in mice and on the antithermonociceptive response in the hot-plate paradigm were also tested. Additionally, the active extract (AECM) was analyzed with HPLC-ESI-MS techniques. RESULTS: Mice acutely treated with AECM at 100, 200, 500 and 1000mg/kg doses prolonged the sleeping time induced by sodium pentobarbital (42mg/kg). This extract, at 100 and 200mg/kg doses, showed a sedative effect in the hole-board paradigm and decreased spontaneous activity in mice. AECM at 10, 100 and 200mg/kg prolonged the onset of seizures induced by pentylenetetrazole (90mg/kg) and antagonized tonic convulsions induced by picrotoxin (10mg/kg). Additionally, AECM inhibited the response to a thermonociceptive stimulus. The intraperitoneal AECM treatment produced mortality with an LD(50)=2154mg/kg. Chemical analysis showed that the flavanone glycosides neoponcirin, poncirin, and isonaringenin are the main compounds of the active extract. CONCLUSIONS: This study demonstrates that an acutely administered single dose of an aqueous extract of Clinopodium mexicanum can exert depressant effects on the CNS. These findings are in agreement with the traditional use of Clinopodium mexicanum to induce sleep as well as sedative and analgesic remedy. The chemical analysis of AECM revealed the presence of the flavanone glycosides neoponcirin, poncirin, and isonaringin.

Concomitant endothelin-1 overexpression in lung transplant donors and recipients predicts primary graft dysfunction.

Primary graft dysfunction (PGD) causes significant morbidity following lung transplantation (LTX). Mortality is high in PGD and therapeutic strategies are limited. To investigate whether endothelin-1 (ET-1) that mediates increased vascular permeability and edema formation in lung grafts can predict PGD, ET-1 mRNA expression was examined in lung tissue biopsies of 105 donors and recipients obtained shortly before LTX. Serum ET-1 concentration was assessed by ELISA. PGD grade was diagnosed and scored by oxygenation and radiological characteristics according to ISHLT guidelines. PGD grade 3 developed in 11% of patients. ET-1 mRNA expression was significantly increased in both donor (p < 0.0001) and recipient (p = 0.01) developing PGD as compared to no PGD group. Pretransplant ET-1 serum concentrations were elevated in recipients with PGD as compared to no PGD group (p < 0.0001), although serum ET-1 was not different between donors whose grafts developed PGD grades 0-3. In regression analysis, concomitant elevated donor tissue ET-1 and recipient serum ET-1 predicted PGD grade 3. This study indicates that pretransplant ET-1 mRNA overexpression in donors associated with elevated pretransplant serum ET-1 in recipients contribute to PGD development and that their assessment might be beneficial to predict PGD and to identify recipients who could benefit from a targeted ET-1 blockade.

Long-term outcome after thrombectomy in acute myocardial infarction.

BACKGROUND: Current data appear in favour of thrombectomy for ST-elevation myocardial infarction (STEMI). However, information on long-term outcome after thrombectomy is limited. We performed a retrospective long-term study to assess the risk of cardiac re-hospitalizations and survival after discharge from the index hospitalization for STEMI. METHODS: Patients originally randomized to percutaneous coronary intervention (PCI) with thrombectomy vs. standard PCI were included in a retrospective long-term observational study. The primary study endpoint was the combined risk for all-cause death or cardiac re-hospitalization after index discharge under optimal medical therapy. The cumulative number of cardiac hospitalization days and ventricular remodelling assessed by echocardiography and plasma biomarkers were secondary endpoints. RESULTS: Of 94 STEMI patients who had been randomized between 11/2000 and 03/2003, 89 patients consented to long-term follow-up. A total of 43 patients had been allocated to thrombectomy and 46 to standard primary PCI. The minimum follow-up time was 1115 days. There was a significantly lower risk for death or cardiac re-hospitalization for patients of the thrombectomy group (hazard ratio = 0.69, 95% CI: 0.49-0.98, P = 0.036). The incidence of recurrent myocardial infarction was not different (P = 0.343). No differences in cardiac remodelling were detected by echocardiography, with the exception that heart-type fatty acid binding protein at 53.2 +/- 17 months was lower in the thrombectomy group (P = 0.045). CONCLUSION: Thrombectomy in STEMI may decrease the long-term risk for death or cardiac re-hospitalization.

Nosocomial outbreak of VIM-2 metallo-ß-lactamase-producing Pseudomonas aeruginosa associated with retrograde urography.

Pseudomonas aeruginosa is well adapted to the hospital setting and can cause a wide array of nosocomial infections that occasionally culminate in recalcitrant outbreaks. In the present study, we describe the first nosocomial outbreak of infection caused by bla(VIM-2)-positive P. aeruginosa in Germany. In November and December 2007, highly resistant P. aeruginosa isolates were recovered from the urine of 11 patients in the Department of Urology of a University Hospital. Bacterial isolates were typed by multilocus sequence typing and screened for known metallo-ß-lactamase (MBL) genes by PCR. Environmental sources of transmission were tested for bacterial contamination using surveillance cultures. Furthermore, a matched case-control study was performed in search of medical procedures significantly associated with case status. Typing of recovered isolates confirmed VIM-2 MBL-producing P. aeruginosa of sequence type 175 in all cases. Surveillance cultures did not lead to the identification of an environmental source of the outbreak strain. Case-control analysis revealed retrograde urography as the only exposure significantly associated with case status. The analyses suggest the transmission of a single clone of VIM-2 MBL-producing P. aeruginosa leading to the infection of 11 patients within 47 days. Events in temporal proximity to retrograde urographies appear to have facilitated infection in the majority of cases. Department-specific infection control measures, including reinforced hygiene procedures during retrograde urography, quickly terminated the outbreak.

Gene expression signature of chronic lymphocytic leukaemia with Trisomy 12.

BACKGROUND: The prognosis of chronic lymphocytic leukaemia (CLL) patients is largely determined by the karyotype of the malignant clone. We have investigated the gene expression profile associated with trisomy 12 (+12). DESIGN: Initially, unselected peripheral blood mononuclear cells of four patients with +12 were compared with 16 CLL controls using microarray analysis. RESULTS: were validated by quantitative real-time PCR with RNA from 61 patients (29 with +12, 32 CLL controls). Results Seven genes showing the strongest correlation with +12 in microarray analysis were selected for real-time PCR: HIP1R, MYF6, SLC2A6, CD9 (overexpressed); CD200, P2RY14, RASGRP3 (underexpressed). Four genes were significantly associated with +12: HIP1R (P<0.0001), MYF6 (P=0.007), P2RY14 (P=0.014), CD200 (P=0.028). Receiver Operating Characteristic curve analysis revealed that HIP1R expression was a highly sensitive and specific marker for +12 in CLL patients. MYF6 was exclusively expressed in normal or malignant B cells in peripheral blood but was poorly predictive for +12. As expected, a number of overexpressed genes are located on chromosome 12 (HIP1R, MYF6). Interestingly, both significantly underexpressed genes (P2RY14, CD200) reside on the long arm of chromosome 3 pointing to trans-repression in this region. CONCLUSIONS: Analysis of the molecular signature of trisomy 12 in CLL resulted in: (i) identification of a surrogate marker for PCR (HIP1R); (ii) observation of a gene dosage effect; and (iii) detection of specific underexpression of genes located on chromosome 3. These results should help to improve diagnosis and treatment decisions for patients with CLL and trisomy 12.

Anxiolytic-like actions of the hexane extract from leaves of Annona cherimolia in two anxiety paradigms: possible involvement of the GABA/benzodiazepine receptor complex.

A hexane extract of leaves of Annona cherimolia produced anxiolytic-like actions when administered to mice and tested in two animal models of anxiety: the mouse avoidance exploratory behavior and the burying behavior tests. In order to discard unspecific drug-actions on general activity, all treatments studied in the anxiety paradigms were also analyzed in the open field test. Results showed that A. cherimolia induced anxiolytic-like actions at the doses of 6.25, 12.5, 25.0 and 50.0 mg/kg. Picrotoxin (0.25 mg/kg), a GABA-gated chloride ion channel blocker, antagonized the anxiolytic-like actions of A. cherimolia, while a sub-effective dose of muscimol (0.5 mg/kg), a selective GABA(A) receptor agonist, facilitated the effects of a sub-optimal dose of A. cherimolia (3.12 mg/kg). Thus, the involvement of the GABA(A) receptor complex in the anxiolytic-like actions of A. cherimolia hexane extract is suggested. In addition the extract was also able to enhance the duration of sodium pentobarbital induced sleeping time. Taken together, results indicate that the hexane extract of A. cherimolia has depressant activity on the Central Nervous System and could interact with the GABA(A) receptor complex. On the other hand, the chromatographic separation of this extract led to the isolation of palmitone, and beta-sitosterol as major constituents. In addition a GC-MS study of some fractions revealed the presence of several compounds such beta-cariophyllene, beta-selinene, alpha-cubebene, and linalool that have been reported to show effects on behavior that could explain some of the extract effects.

Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma?

CONTEXT: Single-nucleotide polymorphisms (SNPs) of the RET protooncogene (RET) could modify disease susceptibility and clinical phenotype in patients with sporadic or familial medullary thyroid carcinoma (FMTC). OBJECTIVE/DESIGN OF THE STUDY: Because frequencies of RET SNPs have not yet been evaluated in patients with elevated serum concentrations of calcitonin (hCt), a biochemical marker for medullary thyroid carcinoma (MTC), we studied RET SNPs in patients with FMTC (n = 22), patients with sporadic MTC (n = 45), and 71 subjects presenting with moderately elevated hCt concentrations (basal, >10 pg/ml; pentagastrin stimulated, > 50 < 100 pg/ml) in comparison with an age- and gender-matched control group (n = 79) with basal hCt concentrations in the normal range (<5 pg/ml). METHODS: After DNA extraction from citrated whole blood, RET exons 10, 11, 13, 14, 15, and 16 and exon/intron boundaries were analyzed by PCR-based cycle sequencing for RET germ line mutations, exonic (G691S, L769L, S836S, S904S) and intronic (IVS13+158; NCBI rs2472737 = IVS14-24) SNPs. RESULTS: In FMTC patients, the F791Y mutation was found to be associated (P = 0.001) with the L769L SNP. The exonic SNPs (G691S, L769L, S836S, and S904S) were not different among the four groups. The intron 14 SNP (IVS14-24), however, was more frequent in individuals with elevated hCt serum concentrations (P = 0.016) and patients with sporadic MTC (P < 0.001) when compared with the control group. CONCLUSIONS: These data suggest that the exon 13 (L769L) and the intron 14 (IVS14-24) SNPs could act as genetic modifiers in the development of some forms of hereditary and sporadic MTC, respectively.

Impact of high field (3.0 T) magnetic resonance imaging on diagnosis of osteochondral defects in the ankle joint.

OBJECTIVE: To evaluate high field magnetic resonance (MR) imaging for imaging of osteochondral defects. MATERIALS AND METHODS: Nine osteochondral defects were simulated in three cadaveric talus specimens using a diamond drill. All specimens were examined on a 1.0 T MR unit and a 3.0 T MR unit. A T2-weighted turbo spin-echo (TSE) sequence with a 2 mm slice thickness and a 256 x 256 matrix size was used on both scanners. The visibility of the osteochondral separation and the presence of susceptibility artifacts at the drilling bores were scored on all images. RESULTS: Compared to the 1.0 T MR unit, the protocol on the 3.0 T MR unit allowed a better delineation of the disruption of the articular cartilage and a better demarcation of the subchondral defect. Differences regarding the visualization of the subchondral defect were found to be statistically significant (P<0.05). Differences with regard to susceptibility artifacts at the drilling bores were not statistically significant (P>0.05). The average SNR was higher using 3.0 T MRI (SNR=12), compared to 1.0 T MRI (SNR=7). CONCLUSION: High field MRI enables the acquisition of images with sufficient resolution and higher SNR and has therefore the potential to improve the staging of osteochondral defects.