The effects of high molecular weight hydroxyethyl starch solutions on platelets

Physicochemical characteristics of hydroxyethyl starch (HES) molecules determine their side effects on hemostasis. Our aim in the present experiments was to test the antiplatelet effect of novel high molecular weight HES. Citrated whole blood was hemodiluted in vitro (0% and 20%) with either HES 550 (Hextend), HES 600 (6%Hetastarch-Baxter), HES 200 (Eloh?st), or the solvent of Hextend in its commercially available solution. The availability of glycoprotein IIb-IIIa was assessed on nonstimulated and on agonist-induced platelets using flow cytometry. Glycoprotein IIb-IIIa availability increased significantly after hemodilution with Hextend and its solvent by 23% and 24%, respectively, but decreased in the presence of 6% Hetastarch-Baxter and Eloh?st by 18% and 15%, respectively, with no significant difference between the latter two colloids. This study shows that Hextend does not inhibit platelet function as anticipated by its high molecular weight and degree of substitution. The unexpected platelet stimulating effect of Hextend is unique among the currently available HES preparations and may, at least in part, be induced by its solvent containing calcium chloride dihydrate (2.5 mmol/L). The platelet-inhibiting effect of 6%Hetastarch-Baxter was not significantly different from that of medium molecular weight HES 200.     

Safe and reliable sound threshold measures with direct vibration of the ossicular chain

OBJECTIVES: The aim of the study was to evaluate the safety and feasibility of piezoelectric malleus vibration audiometer (MVA), which presents micromechanical vibrations to the umbo membranae tympani. STUDY DESIGN: Phase I study performed in a tertiary referral center (University Hospital). METHODS: The coupling rod of the MVA was moved slowly through the outer ear canal toward the eardrum with a micromanipulator. Coupling was completed when the rod tip touched the umbo membranae tympani. Basic audiologic measures of sound threshold obtained with direct stimulation of the malleus are presented. We used MANOVA (multivariate repeated measures ANOVA) to investigate the repeatability of MVA thresholds from one day to the other and when decoupling and retracting the coupling rod 2 mm off the umbo. We also selected the MANOVA to test for unwanted bone-conduction threshold shifts after MVA application. We assessed normality of the data by quantile-quantile plots of the residuals. RESULTS: Twenty-eight male and 10 female subjects with normal hearing, 22.2 to 34.6 years old (median age, 27.2 yr) underwent an examination. Thirty-six subjects underwent MVA, because 2 of the 38 subjects who volunteered for the study have not undergone the procedure due to the external auditory canal anatomy preventing application of the MVA. The results show that it is possible to safely and reliably measure thresholds of direct vibration of the ossicular chain. Using pure tone audiograms, no pure tone bone- and/or air-conduction threshold shifts occurred after the procedure. None of the subjects reported any other ear-related symptoms such as vertigo, tinnitus, or dizziness. Geometric mean vibratory displacements at threshold ranged from 0.55 nm at 250 Hz to 0.03 nm at 6 kHz. MANOVA demonstrated a repeatability of MVA thresholds. CONCLUSION: Malleus vibration audiometry will not allow exact linkage of actual implantable hearing aid. But the present study demonstrates that MVA can provide an audiometric tool for assessing ossicular function and integrity prior to implantation of an electronic hearing amplifier.     

S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. [ISRCTN36233495]

Background  

S-Adenosylmethionine (SAMe) is a dietary supplement used in the management of osteoarthritis (OA) symptoms. Studies evaluating SAMe in the management of OA have been limited to Non Steroidal Anti-inflammatory Drugs (NSAIDs) for comparison. The present study compares the effectiveness of SAMe to a cyclooxygenase-2 (COX-2) inhibitor (celecoxib) for pain control, functional improvement and to decrease side effects in people with osteoarthritis of the knee.     

Correlation of hMLH1 and HPP1 hypermethylation in gastric, but not in esophageal and cardiac adenocarcinoma

Using methylation-specific real-time PCR, we determined the prevalence of aberrant methylation in the mismatch repair gene hMLH1 and in the recently described HPP1 gene among 50 esophageal, 50 cardiac and 50 gastric ADCs. Additionally, expression of hMLH1 protein was detected immunohistochemically and correlated with DNA MSI. Hypermethylation of hMLH1 was found in 14% of esophageal, 28% of cardiac and 32% of gastric ADCs, whereas HPP1 hypermethylation was found more frequently in the 3 tumor types (64% vs. 38% vs. 54%). In gastric ADC, HPP1 hypermethylation was found more frequently in tumors with concomitant hMLH1 hypermethylation (81%) than in those without hMLH1 hypermethylation (41%, p = 0.008). Complete loss of hMLH1 protein expression, which was present in 10 carcinomas (5 cardiac and 5 gastric), was invariably correlated with hMLH1 hypermethylation and MSI. In conclusion, our data indicate that MSI and loss of the mismatch repair protein hMLH1, which is mainly caused by hMLH1 gene hypermethylation, are more prevalent in stomach and cardia carcinogenesis than in that of the esophagus. Moreover, in gastric cancer, hMLH1 hypermethylation is correlated with hypermethylation of the HPP1 gene.     

Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection

OBJECTIVE: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection. METHODS: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated. RESULTS: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml. CONCLUSIONS: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.     

EGF-R and Her2/neu overexpressing tumors: independent collectives for treatment of breast cancer by specific monoclonal antibody-therapy

PURPOSE: In our recent studies, we demonstrated that breast cancer treatment by anti-EGF-R antibody resulted in a significant therapeutic effect in vivo. Furthermore, we were able to elucidate histopathologic parameters with an impact on therapy success. The aim of this study was the evaluation of EGF-R and Her2/neu protein expression on a large series of primary breast cancer, to elucidate if anti-EGF-R antibody therapy is a new therapeutic option for patients who are Her2/neu negative and where, therefore, anti-Her2/neu antibody treatment is not applicable. METHODS: We analyzed EGF-R and Her2/neu protein expression of 149 consecutive primary breast cancer specimens by fully quantitative enzyme-linked immunosorbent assay. For evaluation of stochastic independence, we used chi(2)-test as goodness-of-fit test. RESULTS: We found EGF-R and Her2/neu expression as stochastically independent in primary breast cancer. CONCLUSIONS: Anti-EGF-R antibody treatment is a potential therapeutic option for patients with Her2/neu negative breast cancer.     

Stomakomplikationen – Korrekturverfahren

Background: Despite the progress of surgical technique, cumulative rates of complications after stoma construction up to 70% have been reported. It is therefore apparent that correcting procedures are a focus of surgeons interest. A well functioning stoma will preserve independence and complete socialisation of the patient. Preoperatively, the patient should be informed in details by an especially trained stomatherapist. The stoma should be positioned in distance to the umbilicus, iliac spine, costal arch, or operation wounds.The stoma site brings out the bowel through the rectus muscle without any tension, while the diameter amounts to two fingers.Constitutional faults or stoma construction at itself as a locus minoris resistentiae may further stoma complications. Besides stomal prolapse, stenosis and retraction, the peristomal herniation is the most common complication after stoma construction. Surgical repair contains local procedures, which leave the stoma where it is, stoma relocation and augmentation of the abdominal wall by alloplastic meshes.Own Data: From 1997 to 2002 631 stomata were created, while 23 stomata had to be corrected.There are satisfactory results with low complication rate.Conclusion: There are different procedures to correct stoma complications, while the risk of complications increases with each new intervention. Great care should be taken when a stoma is created in order to guarantee a high functionality combined with a minimized rate of complication.     

Introducing a new recruitment approach to sample collection for genetic association studies in opioid dependence.

OBJECTIVE: In a modified case-control association study we tested the assumption that two polymorphisms (A(118)G in exon 1 and IVS2+31 in intron 2) of the human mu-opioid receptor gene (OPRM1) confer susceptibility to opioid dependence. METHODS: In contrast to classical case-control studies both groups, opioid dependent cases and non-opioid dependent controls were recruited from individuals who have had access to drugs including opioids and who had been sentenced for violation of the "Dangerous Drugs Act" in Germany. RESULTS: For the two allelic variants of OPRM1 under study we did not find evidence for association with opioid dependence. CONCLUSIONS ;Despite absence of association we think that this recruitment approach introduced here, is useful since it putatively offers a more adequate matching for case-control association studies of opioid dependent individuals.     

Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia

BACKGROUND: Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79]. METHODS: Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT). RESULTS: Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001. CONCLUSION: Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.