Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel–Haenszel χ2 test, Kaplan–Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (P<0.0001). Similarly, Kaplan–Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2–10.2; P<0.0001 for progression; relative risk 7.1; 95% CI 4.7–10.9; P<0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

The goal of this study is to clarify whether the expression of metallothionein (MT) could affect the prognosis and the metastatic potential of squamous cell carcinoma (SCC) of the oesophagus. In paraffin-embedded specimens resected from 57 patients, MT mRNA and protein expressions were detected by in situ hybridization and immunohistochemistry respectively. The expression of MT was evaluated in respect of clinicopathologic variables and patients' survival. MT mRNA expression was significantly associated with the proportion of lymph node metastasis (71% in MT mRNA-positive tumours vs 42% in MT mRNA-negative tumours; P = 0.0343) and that of distant metastasis (29% in MT mRNA-positive tumours vs 5% in MT mRNA-negative tumours; P = 0.0452). In respect of MT protein expression, the frequency of distant metastasis was more common in MT-positive tumours than in MT-negative tumours (30% in MT-positive tumours vs 8% in MT-negative tumours; P = 0.0446). The survival rate of the patients with MT protein-negative tumours was significantly better than that of the patients with MT protein-positive tumours (P = 0.0340). There was a positive correlation between the expression of MT protein and that of proliferating cell nuclear antigen (P = 0.0018). Therefore, we conclude that MT expression, both at the mRNA and protein levels, may be a potential marker predicting metastatic and proliferative activities of oesophageal SCC. © 1999 Cancer Research Campaig

Khat Use Is Associated with Impaired Working Memory and Cognitive Flexibility

Rationale Khat consumption has increased during the last decades in Eastern Africa and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as The Netherlands, United Kingdom, Canada, and the United States. Very little is known, however, about the relation between khat use and cognitive control functions in khat users. Objective We studied whether khat use is associated with changes in working memory (WM) and cognitive flexibility, two central cognitive control functions. Methods Khat users and khat-free controls were matched in terms of sex, ethnicity, age, alcohol and cannabis consumption, and IQ (Raven's progressive matrices). Groups were tested on cognitive flexibility, as measured by a Global-Local task, and on WM using an N-back task. Result Khat users performed significantly worse than controls on tasks tapping into cognitive flexibility as well as monitoring of information in WM. Conclusions The present findings suggest that khat use impairs both cognitive flexibility and the updating of information in WM. The inability to monitor information in WM and to adjust behavior rapidly and flexibly may have repercussions for daily life activities

The Consumption of Khat and Other Drugs in Somali Combatants: A Cross-Sectional Study

Having interviewed military personnel in Somali, Michael Odenwald and colleagues conclude that drug-related problems, mainly relating to the use of khat, have reached proportions formerly unknown to the country

Khat use as risk factor for psychotic disorders: A cross-sectional and case-control study in Somalia

BACKGROUND: Little is known about the prevalence of khat-induced psychotic disorders in East African countries, where the chewing of khat leaves is common. Its main psycho-active component cathinone produces effects similar to those of amphetamine. We aimed to explore the prevalence of psychotic disorders among the general population and the association between khat use and psychotic symptoms. METHODS: In an epidemiological household assessment in the city of Hargeisa, North-West Somalia, trained local interviewers screened 4,854 randomly selected persons from among the general population for disability due to severe mental problems. The identified cases were interviewed based on a structured interview and compared to healthy matched controls. Psychotic symptoms were assessed using the items of the WHO Composite International Diagnostic Interview and quantified with the Positive and Negative Symptoms Scale. Statistical testing included Student's t-test and ANOVA. RESULTS: Local interviewers found that rates of severe disability due to mental disorders were 8.4% among males (above the age of 12) and differed according to war experiences (no war experience: 3.2%; civilian war survivors: 8.0%; ex-combatants: 15.9%). The clinical interview verified that in 83% of positive screening cases psychotic symptoms were the most prominent manifestations of psychiatric illness. On average, cases with psychotic symptoms had started to use khat earlier in life than matched controls and had been using khat 8.6 years before positive symptoms emerged. In most cases with psychotic symptoms, a pattern of binge use (> two 'bundles' per day) preceded the onset of psychotic symptoms, in contrast to controls of the same age. We found significant correlations between variables of khat consumption and clinical scales (0.35 to 0.50; p < 0.05), and between the age of onset of khat chewing and symptom onset (0.70; p <0.001). CONCLUSION: Evidence indicates a relationship between the consumption of khat and the onset of psychotic symptoms among the male population, whereby not the khat intake per se but rather early onset and excessive khat chewing seemed to be related to psychotic symptoms. The khat problem must be addressed by means other than prohibition, given the widespread use and its role in Somali culture

Insights from computational modeling in inflammation and acute rejection in limb transplantation

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection. © 2014 Wolfram et al