Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes

It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT(1) as well MT(2)), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3',5'-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP(3) pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and beta1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin-insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained.     

Pharmacokinetics of the main alkamides after administration of three different Echinacea purpurea preparations in humans

Establishing the pharmacological basis for efficacy of herbal medicinal products (HMPs) is a continuous challenge. In this context, also the question of bioavailability, the elucidation of metabolic pathways and their pharmacokinetics is of major interest. These data are relevant to link results from pharmacological IN VITRO assays and clinical studies. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimes. The preparations used in the present pharmacokinetic single-dose study are different ECHINACEA PURPUREA formulations (Echinaforce) with various excipients. The concentrations of the active compounds (alkamides) in the administered products have been in the low mg range per dose. Due to the expected necessary detection of ng ranges, a sensitive and selective LC-ESI-MS-based method that is capable of monitoring plasma levels of traces of active constituents in humans was developed and validated. The resulting maximum concentrations (mean +/- standard deviation) of dodeca-2 E,4 E,8 Z, 10 E/ Z-tetraenoic acid isobutylamides in plasma were 0.22 +/- 0.07 ng/mL after administration of Echinaforce tablets, 0.22 +/- 0.15 ng/mL after taking Echinaforce Junior tablets and 0.23 +/- 0.16 ng/mL after administration of an Echinacea sore throat spray. The areas under the curve were 0.22 ng/mL x h, 0.20 ng/mL x h and 0.23 ng/mL x h, respectively.     

Whole body vibration added to treatment as usual is effective in adolescents with depression: a partly randomized,three-armed clinical trial in inpatients

There is growing evidence for the effectiveness of exercise in the treatment of adult major depression. With regard to adolescents, clinical trials are scarce. Due to the inherent symptoms of depression (lack of energy, low motivation to exercise), endurance training forms could be too demanding especially in the first weeks of treatment. We hypothesized that an easy-to-perform passive muscular training on a whole body vibration (WBV) device has equal anti-depressive effects compared to a cardiovascular training, both administered as add-ons to treatment as usual (TAU). Secondly, we presumed that both exercise interventions would be superior in their response, compared to TAU. In 2 years 64 medication-naïve depressed inpatients aged 13–18, were included. Both exercise groups fulfilled a supervised vigorous training for 6 weeks. Depressive symptoms were assessed by self-report (“Depressions Inventar für Kinder und Jugendliche”—DIKJ) before intervention and after weeks 6, 14 and 26. Compared to TAU, both groups responded earlier and more strongly measured by DIKJ scores, showing a trend for the WBV group after week 6 (p = 0.082). The decrease became statistically significant for both intervention groups after week 26 (p = 0.037 for ergometer and p = 0.042 for WBV). Remission rates amounted to 39.7% after week 6 and 66% after week 26, compared to 25% after week 26 in TAU. These results provide qualified support for the effectiveness of exercise as add-on treatment for medication-naïve depressed adolescents. The present results are limited by the not randomized control group.     

Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology

The epidermal growth factor receptor (EGFR) network, including its seven ligands and four related receptors, represents one of the most complex signaling systems in biology. In many tissues, including the skin and its appendages (notoriously the hair follicles), its correct function is necessary for proper development and tissue homeostasis, and its deregulation rapidly results in defects in cellular proliferation and differentiation. The consequences are impaired wound healing, development of psoriasis-like lesions, structural and functional defects of the hair follicles, and tumorigenesis. In addition to in vitro experiments and data from clinical studies, several genetically modified mouse models displaying alterations in the interfollicular skin and hair follicles attributable to mutations in components of the EGFR system have been reported. These animals, in many cases representing bona fide models of known human diseases, have been seminal in the study of the role of EGFR and its ligands in the skin and its appendages. In this review, we take the multiple phenotypes of these animal models as a basis to summarize and discuss the effects elicited by members of the EGFR system in diverse aspects of skin biology and pathology, including cellular proliferation and differentiation, wound healing, hair follicle morphogenesis, and tumorigenesis.     

Primary CNS lymphoma and HLA class I and II alleles in a German cohort of immunocompetent patients

Human leukocyte antigens (HLA) are involved in the regulation of immune response to infection and in malignant transformation. Several HLA alleles are associated with immunological or malignant diseases. The aim of the present study was to evaluate a potential association of HLA class I and II alleles with primary central nervous system lymphoma (PCNSL) in immunocompetent patients. We therefore analyzed particular HLA-A, HLA-B and HLA-DRB1 alleles in 82 PCNSL patients and compared the data to those in 327 population controls. No significant difference between these two groups was found using Pearson's chi(2) test. These data do not support the hypothesis that HLA alleles play a major role in the pathogenesis of PCNSL.     

Primary central nervous system lymphoma: monocenter, long-term, intent-to-treat analysis

BACKGROUND: This retrospective, single-center study assessed the feasibility, outcome, and late side effects of the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL) at the authors' institution. METHODS: All 72 consecutive patients diagnosed with PCNSL between January 1994 and February 2005 were scheduled to receive high-dose methotrexate (HDMTX)-based chemotherapy. RESULTS: The median age of the patients was 62 years and the median Karnofsky performance score (KPS) was 70. Twelve patients did not receive HDMTX-based chemotherapy because of poor physical condition or renal insufficiency. Of the 60 patients treated with HDMTX-based chemotherapy, the treatment of 9 was followed with whole-brain irradiation. Of 54 patients who were evaluable for response, 35 (65%) responded (52% with a complete response and 13% with a partial response), and 19 patients (35%) did not. At a median follow-up of 58.7 months, the median progression-free survival was 9 months and the median overall survival (OAS) was 41.4 months. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognosis score, patients could be divided into 3 groups with significantly different OAS: 52.9 months for patients aged <50 years, 42.4 months for patients aged >or= 50 years and with a KPS >70, and 5.2 months for patients aged >or= 50 years and with a KPS <70 (P= .009, log-rank test). CONCLUSIONS: Promising long-term results could be achieved with HDMTX-based chemotherapy in patients with PCNSL in this monocenter study. The MSKCC score proved useful for predicting survival.     

Overcoming Asymmetric Contact Resistances in Al-Contacted Mg2(Si,Sn) Thermoelectric Legs

Thermoelectric generators are a reliable and environmentally friendly source of electrical energy. A crucial step for their development is the maximization of their efficiency. The efficiency of a TEG is inversely related to its electrical contact resistance, which it is therefore essential to minimize. In this paper, we investigate the contacting of an Al electrode on Mg₂(Si,Sn) thermoelectric material and find that samples can show highly asymmetric electrical contact resistivities on both sides of a leg (e.g., 10 µΩ·cm² and 200 µΩ·cm²). Differential contacting experiments allow one to identify the oxide layer on the Al foil as well as the dicing of the pellets into legs are identified as the main origins of this behavior. In order to avoid any oxidation of the foil, a thin layer of Zn is sputtered after etching the Al surface; this method proves itself effective in keeping the contact resistivities of both interfaces equally low (<10 µΩ·cm²) after dicing. A slight gradient is observed in the n-type leg’s Seebeck coefficient after the contacting with the Zn-coated electrode and the role of Zn in this change is confirmed by comparing the experimental results to hybrid-density functional calculations of Zn point defects.     

Variable Expression of Long QT Syndrome Among Gene Carriers from Families with Five Different HERG Mutations

Objectives: This study assessed the phenotypic variability of LQTS in carriers with the same and with different mutations in the LQT2 gene. Background: Mutations of ion‐channel genes are known to cause the long QT syndrome (LQTS), a disorder associated with distinctive genotypic‐specific electrocardiographic patterns and variable clinical expression. Methods: Clinical and electrocardiographic characteristics were assessed in five large LQTS families, each with a different mutation of the HERG gene (LQT2; n = 469, 69% genotyped, 102 carriers). One mutation was located on the N‐terminus and the other four on the C‐terminus of the HERG channel protein. Results: The QTc duration and the frequency of cardiac events (syncope and LQTS‐related cardiac arrest/deatht were similar among carriers with the five HERG mutations. QTc was as variable in carriers of the same mutation as it was among carriers with different HERG mutations (P = 0.19). Qualitative assessment of the electrocardiograms revealed extensive intra‐and interfamilial variability in T‐vvave morphology. Among carriers with multiple electrocardiograms extending over 2 to 7 years, variation in QTc over time was minimal. A strong association was found between QTc and the occurrence of cardiac events in carriers of all five mutations. Conclusions: The clinical expression of LQTS was equally variable in carriers from families with the same or different HERG mutations. These findings highlight the complexity of the clinical phenotype in this Mendelian dominant disorder and suggest that one or more modifier genes contribute to the variable expression of this syndrome. A.N.E. 2002;7(1):40–46     

Osteopontin expression in primary sarcomas of the pulmonary artery

Primary tumors of the great vessels (aorta, pulmonal artery, and inferior vena cava) are rare and represent in most cases vascular leiomyosarcomas. Furthermore, there also exists a group of sarcomas arising from the intima, known as intimal sarcomas, associated with early metastasis and a very poor prognosis. Osteopontin (OPN) is an extracellular matrix protein that binds to alphav integrins, thereby promoting cell attachment, chemotaxis, and signal transduction. The reported association of OPN with malignancy and metastasis prompted us to examine the expression of this protein in seven sarcomas of the pulmonary artery. Strong OPN-specific staining could be detected in tumor cells and the adjacent extracellular matrix. Using a double labeling procedure, proliferating cells showed a strong positive reaction with antibodies against OPN. In addition, this protein could be demonstrated in the cytoplasm of macrophages. CD44, a putative receptor of OPN, was expressed on the cellular surface of tumor-associated lymphocytes. The expression of OPN in macrophages and tumor cells indicates that this molecule could possibly mediate cellular adhesion of both cell types in pulmonary sarcomas. The detection in the extracellular matrix shows that OPN is actively secreted and may interact with the corresponding receptor, CD44, on the surface of lymphocytes. Although the function of OPN is not yet fully understood, our data indicate that strong expression of this molecule in poorly differentiated sarcomas could play a role in the progression of malignancy and metastasis as described previously for carcinomas.