Orbitofrontal structural markers of negative affect in alcohol dependence and their associations with heavy relapse-risk at 6 months post-treatment.

BACKGROUND: Alcohol relapse is often occurring to regulate negative affect during withdrawal. On the neurobiological level, alcoholism is associated with gray matter (GM) abnormalities in regions that regulate emotional experience such as the orbitofrontal cortex (OFC). However, no study to our knowledge has investigated the neurobiological unpinning of affect in alcoholism at early withdrawal and the associations of OFC volume with long-term relapse risk. METHODS: One hundred and eighty-two participants were included, 95 recently detoxified alcohol dependent patients (ADP) and 87 healthy controls (HC). We measured affective states using the positive and negative affect schedule (PANAS). We collected T1-weighted brain structural images and performed Voxel-based morphometry (VBM). RESULTS: Findings revealed GM volume decrease in alcoholics in the prefrontal cortex (including medial OFC), anterior cingulate gyrus, and insula. GM volume in the medial OFC was positively associated with NA in the ADP group. Cox regression analysis predicted that risk to heavy relapse at 6 months increases with decreased GM volume in the medial OFC. CONCLUSIONS: Negative affect during alcohol withdrawal was positively associated with OFC volume. What is more, increased GM volume in the OFC also moderated risk to heavy relapse at 6 months. Reduced GM in the OFC poses as risk to recovery from alcohol dependence and provides valuable insights into transient negative affect states during withdrawal that can trigger relapse. Implications exist for therapeutic interventions signifying the OFC as a neurobiological marker to relapse and could explain the inability of ADP to regulate internal negative affective states.

Comorbidity, family history and personality traits in pathological gamblers compared with healthy controls.

BACKGROUND: While DSM-5 classified pathological gambling as an addictive disorder, there is debate as to whether ICD-11 should follow suit. The debate hinges on scientific evidence such as neurobiological findings, family history of psychiatric disorders, psychiatric comorbidity, and personality variables. METHODS: In the "Baden-Württemberg Study of Pathological Gambling", we compared a group of 515 male pathological gamblers receiving treatment with 269 matched healthy controls. We studied differences in sociodemographic characteristics, gambling-related variables, psychiatric comorbidity (lifetime), family history of psychiatric conditions, as well as personality traits such as impulsivity (Barratt Impulsiveness Scale), sensation seeking (Zuckerman's Sensation Seeking Scale) and the NEO-FFI big five. Personality traits were validated in an age- and ethnicity-matched subsample of "pure" gamblers without any psychiatric comorbidity (including nicotine dependence). Data were analyzed using two-sample t-tests, Chi2 analyses, Fisher's exact test and Pearson correlation analysis, as appropriate. Bonferroni correction was applied to correct for multiple comparisons. RESULTS: Only 1% of the gamblers had been diagnosed with an impulse control disorder other than gambling (ICD-10). Notably, 88% of the gamblers in our sample had a comorbid diagnosis of substance dependence. The highest axis I comorbidity rate was for nicotine dependence (80%), followed by alcohol dependence (28%). Early age of first gambling experience was correlated with gambling severity. Compared to first-degree relatives of controls, first-degree relatives of pathological gamblers were more likely to suffer from alcohol dependence (27.0% vs. 7.4%), pathological gambling (8.3% vs. 0.7%) and suicide attempts (2.7% vs. 0.4%). Significant group differences were observed for the NEO-FFI factors neuroticism, agreeableness and conscientiousness. Gamblers were also more impulsive than controls, but did not differ from controls in terms of sensation seeking. CONCLUSIONS: Our findings support classifying pathological gambling as a behavioural addiction in the ICD-11. This decision will have a significant impact on the approaches available for prevention (e.g. age limits) and treatment.

Lipoprotein profile, glycemic control and physical fitness after strength and aerobic training in post-menopausal women with type 2 diabetes.

We studied the effects on blood lipids and physical fitness after a training program that combined strength and aerobic exercise in postmenopausal women with type 2 diabetes. Ten patients (55.0 +/- 5.2 years) followed four exercise sessions per week, two strength and two aerobic, and ten (59.4 +/- 3.2 years) served as a control group. Lipid profile, glycated hemoglobin (HbA(1c)), HOMA2 index, exercise stress and muscular testing were assessed at the beginning and after 16 weeks of training program. Exercise training increased significantly HDL-C (17.2%; P < 0.001) and decreased triglycerides (18.9%), HbA(1c) (15.0%), fasting plasma glucose (5.4%), insulin resistance (HOMA2 25.2%) and resting blood pressure (P < 0.01). After 16 weeks of training, exercise time (17.8%) and muscular strength increased significantly (P < 0.001). The results indicated that a combined strength and aerobic training program could induce positive adaptations on lipid profile, glycemic control, insulin resistance, cardiovascular function, and physical fitness in post-menopausal women with type 2 diabetes.

Bipolar electrocoagulation vs conventional monopolar hot biopsy forceps in the endoscopic treatment of diminutive rectal adenomas.

OBJECTIVE: To assess whether a cold biopsy from a diminutive rectal adenoma followed by destruction with bipolar (gold probe) electrocoagulation using large probes and high power setting would be a safe and efficient alternative to conventional monopolar hot biopsy forceps (MHBF). PATIENTS AND METHODS: Eligible patients were those undergoing colonoscopy, fulfilling the criteria of additional clearing colonoscopy and having at least one suspected rectal adenoma < or = 5 mm. At the time of endoscopy patients were randomized to receive treatment for their diminutive rectal adenomas either with cold biopsy followed by repeated gold probe electrocoagulation (Group A) using a 10 Fr catheter with setting 8 (40 W) for 1 second or with MHBF (Group B). These patients were followed up with a colonoscopy at 2-4 months. RESULTS: A total number of 24 (15 males, 9 females; mean age 56 years) patients were included in group A and 26 (14 males, 12 females; mean age 58 years) in group B. A total number of 38 and 37 diminutive rectal adenomas was detected in patients of Group A and Group B, respectively. At follow up colonoscopy residual adenoma tissue was found in 2 (5.2%) adenomas of 38 in Group A and in 4 (10.8%) of 37 in Group B (P > 0.3). No complications related to colonoscopy or endoscopic treatments in both groups occurred. CONCLUSIONS: Our data suggest that the use of cold biopsy followed by bipolar electrocoagulation using large probes and high power setting for destroying diminutive rectal adenoma seems to be equally effective and safe as MHBF.

Prevalence of polyps and diverticulosis of the large bowel in the Cretan population. An autopsy study.

While a number of studies have been performed in the United States, northern Europe, and some other countries on the epidemiology of large bowel polyps and diverticulosis, information from southern Europe and especially Greece is very limited. Our autopsy study sought to determine the prevalence of large bowel polyps and diverticulosis in the population on Crete. Specimens of colon and rectum were obtained during forensic postmortem autopsies and examined for the presence of polypoid lesions and diverticulosis. Data were collected from a total of 502 autopsies (320 men, 182 women; median age 65 years (range 16-93). Polyps were found in 106 cases (21.1%). These were adenomas in 73 cases (14.5%), hyperplastic polyps in 25 (4.9%), and mucosal tags in 8 (1.5%). Diverticulosis of the large bowel was found in 115 (22.9%). The prevalence of adenomas and diverticulosis increased with advanced age. The prevalence of colonic diverticulosis in Crete is slightly lower than that which has been reported in most other studies in economically developed countries. The prevalence of colorectal adenomas in Crete is one of the lowest rates reported in Europe and is compatible to the known low incidence of colorectal cancer in Crete.

The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor" in rheumatoid arthritis and osteoarthritis.

Active angiogenesis, together with an up-regulation of angiogenic factors, is evident in the synovium of both rheumatoid arthritis (RA) and osteoarthritis (OA). The present study assessed, by immunohistochemistry, the microvessel density in the synovium of these arthritides and in normal controls, in relation to the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) and the apoptosis-related proteins bcl-2 and p53. More importantly, using the novel 11B5 MAb, the activated "VEGF/flk-1(KDR)-receptor" microvessel density was assessed. VEGF expression in fibroblasts was diffuse in both RA and OA. Diffuse PD-ECGF expression of fibroblasts was noted in all cases of RA, while fibroblast reactivity was focal in the OA material. The standard microvessel density (sMVD), as assessed with the anti-CD31 monoclonal antibody (MAb), was higher in RA (64+/-12) and in OA (65+/-16) than in normal tissues (52+/-8; p=0.008 and 0.0004, respectively). The activated microvessel density (aMVD), assessed with the 11B5 MAb, was significantly higher in RA (29+/-10) than in OA (17+/-4; p<0.0001) and than in normal tissues (14+/-2; p<0.0001). The "activation ratio" (aMVD/sMVD) was statistically higher in RA (0.46+/-0.17) than in OA and normal synovial tissues, the latter two having a similar ratio (0.28+/-0.08 and 0.26+/-0.03, respectively). Cytoplasmic bcl-2 expression was frequent in the synovial cells of OA, but rare in RA. Nuclear p53 protein accumulation was never observed. It is suggested that the angiogenic pathway VEGF/flk-1(KDR) may play an important role in the pathogenesis of RA and OA. Thus, failure of VEGF/flk-1(KDR) activation, in the presence of increased VEGF expression, may indicate a synovium with an impaired capacity to establish a viable vasculature, consistent with the degenerative nature of OA. On the other hand, the activated angiogenesis in RA shows a functional, still pathologically up-regulated VEGF/flk-1(KDR) pathway. Whether restoration of an impaired VEGF/flk-1(KDR) pathway in OA, or inhibition of this in RA, would prove of therapeutic importance requires further investigation.

P21/waf1 protein expression in nasopharyngeal carcinoma. Comparative study with PCNA, p53 and MDM-2 protein expression.

We investigated the immunohistochemical expression of p21/waf1 protein in 59 cases of nasopharyngeal carcinomas (NPC) and compared p21 expression with PCNA, p53 and mdm2 protein expression. We found p21, PCNA, p53 and mdm2 in 59/59, 59/59, 18/59 and 12/59 nasopharyngeal carcinomas, respectively. We observed a tendency to a relationship between high expression of PCNA (> 25% positivity in tumour cells) and low expression of p21 protein. Parallel p53/p21 protein expression was found in 18 cases. Twelve were also mdm2 positive. This pattern may represent NPC with wild type (wt) p53 since mdm2 and p21 proteins are inducible by wt p53 gene. In these cases p53 protein expression may be due to stabilisation to mdm2 protein. This could be important in the pathogenesis of these cases since mdm2 may deregulate the p53-dependent growth suppressive pathway. Discordant p53-/p21+ protein expression was found in 41 cases. All were also mdm2 negative. This pattern suggests immunohistochemically undetectable wt p53 gene which is able to induce p21 protein expression.

p53 protein expression in breast carcinomas. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1.

The aim was to investigate the pattern of expression of p53 protein and two wild-type (wt) p53-induced proteins (mdm2 and p21/waf1), as an indirect way of assessing p53 gene status in breast carcinomas. Formalin-fixed paraffin embedded tissue from 102 cases of breast carcinomas comprising mostly ductal carcinomas (88 cases) was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins. We found p53, mdm2 and waf1/p21 protein expression in 33/102, 20/102 and 38/102 breast carcinomas, respectively. Parallel p53/mdm2 protein expression was found in 9 cases. Five were also p21/waf1 positive. Discordant p53+/ mdm2-protein expression was found in 24 cases. Nine were p21/waf1 positive and the remaining fifteen were p21/waf1 negative. The patterns mdm2+/p53-/p21- and p21+/p53-(+)/mdm2- were found in 6 and 20 cases, respectively. Parallel p53/mdm2/p21 protein expression may represent breast carcinomas with wt p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. In these cases p53 protein expression may be due to stabilisation to mdm2 protein. This could be important in the pathogenesis of these cases since mdm2 may deregulate the p53-dependent growth suppressive pathway. Discordant p53+/mdm2-/p21- protein expression may represent breast carcinomas with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Breast carcinomas with p53+/mdm2/p21+ protein expression may have either wt p53 with deregulated mdm2 gene expression or mutated p53 gene with p53-independent p21 expression. Cases with only mdm2 expression may represent tumours with mdm2 gene amplification or overexpression and cases with only p21 expression may reflect p53-independent regulation of p21 protein.

MIB1 (Ki-67) expression in non-Hodgkin's lymphomas.

The MIB1 monoclonal antibody which is used as a marker of cell proliferation was studied by immunohistochemistry on formalin-fixed and paraffin embedded biopsy specimens of lymph nodes in 40 high- and 46 lowgrade cases of non-Hodgkin's lymphomas (NHL) classified according to the Kiel classification. All cases were found to display nuclear MIB1 staining. A statistically significant difference (P < 0.005) was found between high- and low grade NHLs and this indicates that the high- grade NHL display a higher proliferation rate than low grade. In addition, remarkable variations in MIB1 expression were found among individual cases of the same histological group. These data may suggest that MIB1 index can help in the individual approach of the proliferation rate of each tumour and this may be an important parameter in association with clinical and other laboratory parameters for predicting the biological behaviour of non-Hodgkin's lymphomas.

p53 protein expression in non-Hodgkin's lymphoma. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1.

Aims-To investigate the pattern of expression of p53 protein and two wild type p53 induced proteins (mdm2 and p21/waf1) as an indirect way of assessing p53 gene status in non-Hodgkin's lymphoma.Methods-Formalin fixed, paraffin wax embedded tissue from 87 cases of nodal non-Hodgkin's lymphoma, comprising 52 high grade and 35 low grade tumours, was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins.Results-p53, mdm2 and waf1/p21 proteins were expressed in 36/52, 21/52 and 31/52 high grade and 3/35, 21/35 and 3/35 low grade non-Hodgkin's lymphomas, respectively. Parallel p53/mdm2 protein expression was found in 23 cases (21 high grade and two low grade). These 23 cases were also positive for p21/waf1 protein expression. Discordant p53 positive/mdm2 negative protein expression was found in 16 cases (15 high grade and one low grade). Eleven (10 high grade and one low grade) of these 16 cases were p21/waf1 positive and the remaining five high grade non-Hodgkin's lymphomas were p21/waf1 negative. Mdm2 and p21/waf1 proteins were not expressed in the absence of p53 protein expression.Conclusions-p53, mdm2 and waf1/p21 protein expression is more frequently associated with aggressive histotypes of non-Hodgkin's lymphoma. Parallel expression of p53, mdm2 and p21 proteins may represent non-Hodgkin's lymphomas with a wild type p53 gene as mdm2 and p21 proteins can be induced by the wild type gene. In these cases p53 protein expression may result from stabilisation via complex formation with the mdm2 protein. This could be important in the pathogenesis of these cases as mdm2 may deregulate the p53 dependent growth suppressive pathway. Discordant p53 positive/mdm2 negative/p21 negative protein expression may represent non-Hodgkin's lymphoma with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Non-Hodgkin's lymphoma with p53 positive/mdm2 negative/p21 positive protein expression may have either wild type p53 with deregulated mdm2 gene expression or mutated p53 gene with p53 independent p21 expression.