Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

BACKGROUND: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. OBJECTIVE: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. METHODS: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. RESULTS: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related. CONCLUSIONS: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.

[Midwife-led birth centres: an alternative to hospital childbirth?]. / Geburtshäuser: Versorgungsalternative zur Klinikentbindung?

After midwife-led birth centres had been included into the Social Security Statute Book (§134a SGB V) and thus become covered by German Public Health Insurance since April 1st, 2007 contract negotiations on flat rate costs have followed. Meanwhile the 2nd edition of this -agreement has come into effect. The present contribution describes how this non-hospital obstetric care has developed in the last 3 years. The medical care situation is explained based on legal conditions. Special attention is paid to regulations concerning quality management as well as the certification or auditing required to remain listed in the national register of midwife-led units at the Social Health Insurance. Results are shown from data collected by the Associa-tion for Quality Assurance on Out-of-hospital births (QUAG) and from a pilot project which also contains comparisons with clinical findings. The discussion refers to data taken from German as well as international publications. The conclusion points out some aspects in need of further development.

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6-8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0-21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.

Iron supplementation for preterm infants receiving restrictive red blood cell transfusions: reassessment of practice safety.

OBJECTIVE: To reassess iron supplementation practice safety in very low birth weight (VLBW) preterm infants receiving restrictive red blood cell transfusions during initial hospitalization. STUDY DESIGN: Iron status, including hemoglobin (Hb), serum iron, ferritin, and soluble transferrin receptor (sTfR) levels and reticulocyte count of transfused (n=236) and non-transfused (n=166) preterm infants at ≤24 h and 2, 4 and 8 weeks were recorded. As per protocol, a restrictive blood transfusion policy and supplementation of 5 mg kg(-1) per day of iron polymaltose complex from 4 weeks and 25 mg(-1) per day of vitamin E from 2 weeks were imposed for all infants. Normative reference cord-blood ferritin value of preterm infants was used for comparison. Vitamin E levels and incidence of morbidities associated with prematurity were recorded. RESULT: At ≤24 h, the characteristics and iron status of both groups were similar. At 2, 4 and 8 weeks, the transfused group had significantly higher Hb, iron and ferritin levels; sTfR levels were lower at 4 and 8 weeks (all indices, P<0.05). At 8 weeks, the median ferritin levels of our transfused group were lower than that of normative reference cord-blood value (115 (50th percentile) vs 79 (43 to 107) µg l(-1), respectively). Vitamin E levels and the incidence of morbidities associated with prematurity of the transfused and non-transfused groups were not different (both indices, P>0.18). CONCLUSION: Adding iron supplementation to preterm infants receiving restrictive blood transfusions has shown to be a judicious and safe practice in terms of iron status for VLBW preterm infants.

Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans.

The low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions. This study tested the hypothesis that Tibetans resident at 4,200 m offset physiological hypoxia and achieve normal oxygen delivery by means of higher blood flow enabled by higher levels of bioactive forms of NO, the main endothelial factor regulating blood flow and vascular resistance. The natural experimental study design compared Tibetans at 4,200 m and U.S. residents at 206 m. Eighty-eight Tibetan and 50 U.S. resident volunteers (18-56 years of age, healthy, nonsmoking, nonhypertensive, not pregnant, with normal pulmonary function) participated. Forearm blood flow, an indicator of systemic blood flow, was measured noninvasively by using plethysmography at rest, after breathing supplemental oxygen, and after exercise. The Tibetans had more than double the forearm blood flow of low-altitude residents, resulting in greater than sea level oxygen delivery to tissues. In comparison to sea level controls, Tibetans had >10-fold-higher circulating concentrations of bioactive NO products, including plasma and red blood cell nitrate and nitroso proteins and plasma nitrite, but lower concentrations of iron nitrosyl complexes (HbFeIINO) in red blood cells. This suggests that NO production is increased and that metabolic pathways controlling formation of NO products are regulated differently among Tibetans. These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia.

Apigenin--strong cytostatic and anti-angiogenic action in vitro contrasted by lack of efficacy in vivo.

The cancer chemopreventive agent apigenin also has strong cytostatic and anti-angiogenic effects in vitro. We now investigated its efficacy against experimental Lewis lung carcinomas (LLC), C-6 gliomas and DHDK 12 colonic cancers in vivo. Tumour bearing mice received 50 mg/kg/day apigenin in three different galenical formulations during 12 days in 8-hourly intervals. Only weak effects of apigenin on the size and the number of new tumour blood vessels of both established and newly transplanted tumours were recorded although the intratumoural necrosis was elevated (45 +/- 15% vs. 20 +/- 7% (control), p < 0.05%). These results contrast sharply with the high in vitro sensitivity of LLC, C-6, DHDK 12 and endothelial cells to apigenin where complete growth suppression occurs at concentrations beyond 30 g/ml. Possible causes are discussed.

Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy.

PURPOSE: We evaluated whether dose-intensive or high-dose chemotherapy can eliminate micrometastases in high-risk breast cancer patients. EXPERIMENTAL DESIGN: We monitored cytokeratin (CK)/17-1A positive cells in the bone marrow (BM) and peripheral blood stem cells (PBSC) and studied Her-2/neu serum levels of patients with locally advanced (n = 13; group 1) and metastatic breast cancer (n = 30; group 2) using immunomagnetic separation, immunocytochemistry, and ELISA. RESULTS: CK+ cells were found in the BM of 3 of 13 (23%) group 1 patients before but not after chemotherapy, resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2 of 9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18 of 30 patients) before and 40% (4 of 10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7 of 24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS, whereas tumor cell-free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all of CK+ PBSC, and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. CONCLUSION: Micrometastatic cells are present in PBSC grafts and can survive even high-dose chemotherapy. The presence of immunotherapeutic target antigens supports the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.

Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum).

OBJECTIVE: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin. METHODS: The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). RESULTS: There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. CONCLUSION: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter.

Oxybutynin chloride inhibits proliferation and suppresses gene expression in bladder smooth muscle cells.

PURPOSE: We test the hypothesis that oxybutynin chloride inhibits bladder smooth muscle cell proliferation. MATERIALS AND METHODS: Cultured rat bladder smooth muscle cells were grown in Medium 199 supplemented with 10% fetal bovine serum in the presence of 0, 1, 10 and 100 microM. oxybutynin. Cell proliferation was assessed by counting cell numbers 48 and 96 hours after plating. To investigate the role of oxybutynin in bladder smooth muscle cell proliferation after mechanical stretch, cells were grown on silicone elastomer bottomed culture plates and subjected to cyclical stretch-relaxation for 48 hours in the presence of 10 microM. oxybutynin. Deoxyribonucleic acid synthesis was assessed by tritiated thymidine incorporation assay. To examine the effect of oxybutynin on stretch activated gene expression, bladder smooth muscle cells were subjected to stretch-relaxation for 2 hours with and without 10 microM. oxybutynin, and relative c-jun messenger (m) ribonucleic acid (RNA) levels were assessed by semiquantitative reverse transcriptase-polymerase chain reaction with normalization to glyceraldehyde-3-phosphate dehydrogenase mRNA levels. RESULTS: The serum stimulated increase in bladder smooth muscle cell growth was inhibited by oxybutynin in a dose dependent manner. In bladder smooth muscle cells there was a 4.7-fold increase in deoxyribonucleic acid synthesis after mechanical stretch, which decreased by 40% (p <0.01) when cells were stretched in the presence of oxybutynin. Stretch stimulated significant increase in c-jun mNRA levels, which was significantly decreased by oxybutynin. CONCLUSIONS: Oxybutynin chloride inhibits bladder smooth muscle cell proliferation induced by serum and mechanical stretch. A potential mechanism by which oxybutynin inhibits proliferation may be the down regulation of growth promoting genes, such as c-jun. We speculate that oxybutynin may be useful for preventing permanent hypertrophic bladder changes in addition to decreasing intravesical pressure.

Iron metabolism and human ferritin heavy chain cDNA from adult brain with an elongated untranslated region: new findings and insights.

Ferritin is a ubiquitous protein which plays a major role in iron sequestration, detoxification and storage. In this paper we highlight the role of ferritin in iron homeostasis and describe factors and diseases that affect its expression. We also describe new studies which further characterize the structure and expression of a novel form of ferritin heavy (H) chain mRNA that was identified in brain and discuss possible implications of these findings. Human fetal and adult brain cDNA libraries previously were screened with cDNA for well-characterized liver ferritin H. In addition to 'liver-like' brain ferritin H cDNA, novel ferritin H cDNAs with an additional 279 nucleotide sequence at the 3'untranslated region (UTR) were identified in both libraries (see refs. 1 and 2; Dhar, M., Chauthaiwale, V., and Joshi, J. G., Gene, 1993, 126, 275 and Dhar, M., and Joshi, J. G., J. Neurochem., 1993, 61, 2140). However, relative to liver ferritin H cDNA, these novel cDNAs were incomplete at their 5'ends [see ref. 3; Joshi, J. G., Fleming, J. T., Dhar, M. S., and Chauthaiwale, V., J. Neurol Sci., 1995, 134, (Suppl.), 52]. In the present paper, by sequencing of cDNAs using reverse transcriptase polymerase chain reaction, we show that the 279 nt 3'UTR sequence, a coding sequence identical to that in human liver ferritin H, and a full-length 5'UTR that includes one mRNA regulatory iron-response element sequence, co-exist in at least one species of ferritin H transcript in six normal human adult and six late-onset, sporadic Alzheimer disease (AD) brains. This sequence is the same in the normal and AD brains. Dot-blot analysis of poly A+ RNAs from different human tissues indicates that relative to the coding sequence of ferritin H, expression of the 279 nt 3'UTR sequence varies among different tissues, is highest in the adult brain, and is very low in fetal brain. In normal adult hippocampus, ferritin H RNA with the novel 279 nt sequence localizes strongly to small non-neuronal cells, capillary endothelial cells, and to selected populations of neurons (granule cells of the dentate gyrus). Significant homology was observed between a region in the 279 nt 3'UTR segment of ferritin H RNA and the 3'UTR of cyclooxygenase-2 mRNA (an inducible iron-containing enzyme involved in prostaglandin synthesis). Possible functions for ferritin H protein derived from the novel message and for the elongated 3'UTR and 5'UTR are discussed.

Bladder stimulation therapy improves bladder compliance: results from a multi-institutional trial.

PURPOSE: We examined data from multiple institutions to determine whether intravesical bladder stimulation therapy is effective in improving bladder compliance by increasing bladder capacity and lowering bladder storage pressures. MATERIALS AND METHODS: The charts of 568 patients from 11 institutions were evaluated. Of the 568 patients 335 had adequate and accurate pretreatment and posttreatment urodynamic studies, and were included in this study. A total of 155 patients was from Children's Memorial Hospital, while the remaining 180 were from 10 other institutions. Bladder capacity and bladder capacity pressure were determined for each patient before and after therapy. RESULTS: Overall, 53% of patients had increased bladder capacity of 20% or greater after treatment (average increase 105 cc), which represents a 63% increase from pretreatment values. This increase occurred in an average of 1.9 years. Further analysis of this subset of patients revealed that in 90% intravesical storage pressures were decreased or maintained within a safe range (less than 40 cm. water). Evaluation of patients who did not respond to bladder stimulation with a 20% or greater increase in bladder capacity revealed that they had nearly normal bladder capacity before therapy. When the data on bladder capacity and bladder capacity pressure from Children's Memorial Hospital were compared to results from the 10 other institutions, there were no appreciable differences. CONCLUSIONS: Bladder stimulation is effective in increasing bladder capacity without significantly elevating storage pressure in a majority of patients. We conclude that this technique is safe and effective in improving bladder compliance, and that it is reproducible elsewhere.

[Eradication of metronidazole-resistant Helicobacter pylori: is omeprazole/amoxicillin a therapeutic alternative?]. / Eradikation Metronidazol-resistenter Helicobacter pylori: Ist Omeprazol/Amoxicillin eine therapeutische Alternative?

Recommended therapies with the highest eradication rates for Helicobacter pylori (HP) are triple therapies comprising bismuth salts, nitroimidazole and amoxicillin or tetracycline. Primary and secondary resistance of HP to nitroimidazole, however, represents a major problem of this treatment since it is the main cause of eradication failure. In these cases therapeutic regimes without nitroimidazole could prove more successful. High dose omeprazole/amoxicillin has been suggested as a simple and effective therapy with few side effects. The effectiveness of this combination in eradicating metronidazole resistant HP has not been established so far. The aim of this study was to evaluate high dose omeprazole/amoxicillin in eradicating metronidazole resistant HP in our population. 33 patients (6 women, 27 men, mean age 39 [range 21-68]) with recurrent duodenal ulcer and gastric colonization by metronidazole resistant HP were examined. Smokers were defined as patients currently smoking > 10 cigarettes/day. Exclusion criteria were: gastric surgery or intake of antibiotics, omeprazole bismuth salts and NSAIDs within four weeks before study entry endoscopy. Biopsy specimens were obtained in a standardized manner: 5 from the gastric antrum (1 CLO, 1 culture, 3 histology: H & E, Giemsa) and 2 from the gastric body (histology). Resistance testing for penicillin, amoxicillin and metronidazole was performed using a disk diffusion test (E-test, AB Biodisk, Sweden). Metronidazole resistance was defined as a minimal inhibitory concentration (MIC) of metronidazole of > 8 micrograms/ml. Eradication therapy consisted of oral omeprazole (40 mg bid) and amoxicillin solute (750 mg tid) for 10 days. Subsequently, for ulcer treatment, patients were given omeprazole (20 mg per day) for 20 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychoneuroimmunology and cancer: an integrated review.

The new field of psychoneuroimmunology (PNI) studies the measurable interaction between psychological and physiological processes. Specifically, PNI is the study of the intricate interaction of consciousness (psycho), central nervous system (neuro), and the body's defense against external infection and aberrant cell division (immunology). Over the last 30 years, the body of knowledge in PNI has emerged and in the last 10 years has flourished. PNI has many implications for clinical nursing practice. This study provides supportive empirical evidence to systems theories, which have played a major role in nursing's attempt to comprehend the interaction between the mind and the body. Nurses are ideal candidates to take a lead in this new field because it reinforces the holistic perspective which is the essence and uniqueness of our discipline. Although a variety of clinical populations have been used in PNI research, the scope of this integrated review will be limited to PNI and cancer. Research studies addressing psychosocial variables' effect on aetiology, response to treatment, immunocompetence and overall survival in the oncology population will be examined.

[Music therapy single case process research--development and organization of a research field]. / Musiktherapeutische Einzelfall-Prozessforschung--Entwicklung und Aufbau eines Forschungsfeldes.

Music therapy yet to be discovered as a target of psychotherapy research. A first step consists in creating adequate samples of significant musical dialogues. Video-recording is an essential requirement for establishing such data. To test the clinical view that the emotional content of the musical dialogue in music therapy reflects the basic relationship issues of a patient was the objective of this study. By using ratings of significant musical dialogue sequences with the instrument of semantic differential comparing groups with varying clinical expertise (music therapists, psychoanalyts, lay persons) the results demonstrate that there is considerable stability of the judgments; however, systematic differences exists among the three groups of raters.

Growth of Aureobasidium pullulans on waste water hemicelluloses.

Strain Aureobasidium pullulans capable of utilizing hemicelluloses and xylan was cultivated on processed waste dialysis liquor from the production of viscose fibres, containing about 1.5% hemocelluloses. Basic conditions of biomass production were tested on a laboratory scale. The dialysis waste liquor adjusted with mineral acids to pH 4--5 and supplemented with 0.05% yeast autolyzate and 0.2% ammonium sulphate affords protein yields of about 0.8 g/l, corresponding to 4.0--4.5 g dry biomass. Biomass is isolated together with residual water-insoluble hemicelluloses which are not utilized by the microorganism. The total utilization of hemicelluloses attains about 70%.

Pilot scale exponential growth of Escherichia coli W to high cell concentration with temperature variation.

An efficient method to grow Escherichia coli W to high cell concentrations on the pilot scale is described and discussed. The method involves growth linked introduction of glucose and ammonia to the culture, sparging with oxygen, and maintenance of aerobic conditions by gradually decreasing the temperature in the culture in order to keep the oxygen demand within the limits of the capacity of supply. Under these conditions the linear rate of cell mass production is actually the result of exponential growth with a gradually decreasing growth-rate constant. About 10 kg packed cells were produced in a 50 liter working-volume fermentor in one run of 13 hr. The concentration of the cells at the end of the growth was about 47 g dry cells/liter. The expenditure for nutrients was minimal and the controls were of simple automatic nature. From the determined yield constants for glucose, nitrogen, phosphorus, and oxygen it may be inferred that the cells grown by this method are similar to those grown exponentially at constant temperature.

Effect of 2-deoxyglucose on cell wall formation in Saccharomyces cerevisiae and its relation to cell growth inhibition.

The growth inhibition and the lysis of Saccharomyces cerevisiae caused by 2-deoxy-d-glucose (2-DG) were shown to be a consequence of unbalanced cellular growth and division. The lysis, but not the repression of growth and osmotic fragility of cells, could be suppressed by the addition of mannitol as an osmotic stabilizer. This result, as well as the morphological changes observed in the cells and changes in the chemical composition of the cell walls, showed that S. cerevisiae grown in the presence of 2-DG formed weakened cell walls responsible for the osmotic fragility. Evidence is presented for the first time demonstrating the incorporation of 2-DG into yeast cell wall material. Other data suggest that the inhibition of yeast growth by 2-DG results from an interference of phosphorylated metabolites of 2-DG with metabolic processes of glucose and mannose involved in the synthesis of structural cell wall polysaccharides.