Association between cerebral glutamate and human behaviour: the sensation seeking personality trait

INTRODUCTION: Brain imaging studies have linked the anterior cingulate cortex (ACC) to motivation, drive, and personality traits like novelty and sensation seeking. Animal studies have shown glutamatergic neurotransmission to be important in ACC function as well as motivated behaviour. However, the role of glutamate in related personality traits like sensation seeking has not been investigated in humans. METHODS: The associations between sensation seeking personality scores and absolute glutamate concentrations in the ACC and the hippocampal region measured by 3-Tesla proton magnetic resonance spectroscopy (1H-MRS) were investigated. RESULTS: ACC glutamate concentration was negatively correlated with the sensation seeking sum score and the experience seeking subscore. A weak negative correlation was also observed between the hippocampal glutamate and the sensation seeking sum score. The reexamination of the glutamate concentration after 4 weeks revealed a similar relationship with sensation seeking. DISCUSSION: Although preliminary, the results are in line with the key role of the ACC for motivation and executive control and with the impact of glutamate on novelty related behaviour observed in animal experiments. The role of the hippocampus for novelty processing is discussed. Glutamate measurement with 1H-MRS may facilitate the understanding of biological underpinnings of personality traits and psychiatric diseases associated with dysfunctions in motivation and drive.     

LDL oxidation is associated with increased blood hemoglobin A1c levels in diabetic patients

AIM: To investigate whether levels of blood HbA1c in diabetic patients are associated with susceptibility of LDL to oxidation. METHODS: LDL was separated from blood of 40 diabetic patients with known blood glucose and HbA1c levels. The tendency to undergo lipid peroxidation was assessed via lag time required for initiation of LDL oxidation. HbA1c formation was measured in vitro following incubation of red blood cell (RBC) hemolysate for 3 months with increasing concentrations of glucose in the absence or presence of LDL or oxidized LDL. RESULTS: Lag time for copper-induced LDL oxidation was twice as long in normal subjects compared to diabetic patients. Correlation analyses between LDL oxidation lag time and HbA1c blood levels revealed an R value of 0.74. Incubation of RBC hemolysate with high glucose concentration (up to 400 mg/dl) resulted in increased blood HbA1c concentration by up to 107%. Addition of LDL to this hemolysate over a period of 3 months resulted in LDL oxidation and an increase in HbA1c levels by up to 168%. Similarly, addition of oxidized LDL to the hemolysate increased HbA1c by up to 240%. CONCLUSIONS: Increased tendency of LDL to undergo lipid peroxidation in diabetic patients contributes to increased levels of blood HbA1c, mainly in those with HbA1c<7.3.     

Effects of root extracts of Fagara zanthoxyloides on the in vitro growth and stage distribution of Plasmodium falciparum

The development of resistance by Plasmodium falciparum to conventional drugs poses a threat to malaria control. There is therefore a need to find new, effective, and affordable remedies for malaria, including those derived from plants. This study demonstrates that crude, reverse-phase high-pressure liquid chromatography (RP-HPLC)-semipurified, and RP-HPLC-purified root extracts of Fagara zanthoxyloides inhibit the growth of P. falciparum in vitro, with 50% inhibitory concentrations (IC(50)s) of 4.90, 1.00, and 0.13 microg/ml, respectively. Roots of F. zanthoxyloides, known as chewing sticks, are widely used for tooth cleaning in West Africa. Microscopic examination of Giemsa-stained slides showed a virtual absence of schizonts in ring-stage synchronized cultures treated with crude extracts at concentrations of 30 to 60 microg/ml during 36 to 48 h of incubation. These observations suggest that the active constituent in the extract may be cytotoxic for P. falciparum trophozoites, thereby inhibiting their development to the schizont stage. A pure bioreactive fraction was subsequently obtained from the chromatographic separations. When this fraction was mixed with pure fagaronine, the mixture coeluted as a single peak on the analytical RP-HPLC column, suggesting that fagaronine may be the active antimalarial constituent of Fagara root extracts. Additional experiments showed that fagaronine also inhibited P. falciparum growth, with an IC(50) of 0.018 microg/ml. The results of this study suggest that the antimalarial activity of fagaronine deserves further investigation.     

Orlistat Reverse Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.     

Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

Somatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2(+/-) mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.     

Are chronic hepatitis C viral infections more benign in patients with hemophilia?

BACKGROUND AND AIMS: Cirrhosis is associated with thromboses of the intrahepatic vasculature. This raises the possibility that HCV infections in hemophiliacs may differ from those in non-hemophiliacs METHODS: Liver biopsy findings from 12 hemophiliacs and 20 age- and gender-matched, non-hemophiliac controls with chronic hepatitis C viral (HCV) infections were compared for inflammatory activity and fibrosis. RESULTS: The mean ages of hemophiliacs and controls were 35.0 +/- 3.0 yr and 39.6 +/- 5.6 yr, respectively (P= 0.2). Serum aspartate aminotransferase (AST) levels were lower (44 +/- 13 vs 70 +/- 43 U/L) and the duration of the partial thromboplastin (PTT) time longer (49.2 +/- 16.9 vs 31.2 +/- 1.2 s.) in hemophiliacs than in controls (P < 0.02 and <0.001, respectively). Six of the seven hemophiliac patients (86%) and 8/17 controls (46%) were infected with genotypes 1a or 1b with the remainder being infected with 2b, 3a, or 3b. Histological activity and fibrosis scores were significantly lower in hemophiliacs than in controls (1.9 +/- 0.6 vs 3.6 +/- 2.7 and 0.3 +/- 0.2 vs 1.5 +/- 1.5, P < 0.05 and P < 0.01, respectively). None of the hemophiliacs had histological evidence of advanced disease (bridging fibrosis and/or cirrhosis) as compared to 7/20 (30%) controls (P < 0.05). CONCLUSION: HCV infections in hemophiliacs may be less severe than in HCV infected patients without hemophilia.     

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.     

Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT)

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic myeloid metaplasia (AMM), myelofibrosis with myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) "leukemic" transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).     

Genetic diversity on the Comoros Islands shows early seafaring as major determinant of human biocultural evolution in the Western Indian Ocean

The Comoros Islands are situated off the coast of East Africa, at the northern entrance of the channel of Mozambique. Contemporary Comoros society displays linguistic, cultural and religious features that are indicators of interactions between African, Middle Eastern and Southeast Asian (SEA) populations. Influences came from the north, brought by the Arab and Persian traders whose maritime routes extended to Madagascar by 700–900 AD. Influences also came from the Far East, with the long-distance colonisation by Austronesian seafarers that reached Madagascar 1500 years ago. Indeed, strong genetic evidence for a SEA, but not a Middle Eastern, contribution has been found on Madagascar, but no genetic trace of either migration has been shown to exist in mainland Africa. Studying genetic diversity on the Comoros Islands could therefore provide new insights into human movement in the Indian Ocean. Here, we describe Y chromosomal and mitochondrial genetic variation in 577 Comorian islanders. We have defined 28 Y chromosomal and 9 mitochondrial lineages. We show the Comoros population to be a genetic mosaic, the result of tripartite gene flow from Africa, the Middle East and Southeast Asia. A distinctive profile of African haplogroups, shared with Madagascar, may be characteristic of coastal sub-Saharan East Africa. Finally, the absence of any maternal contribution from Western Eurasia strongly implicates male-dominated trade and religion as the drivers of gene flow from the North. The Comoros provides a first view of the genetic makeup of coastal East Africa.