Hospital-based cluster randomised controlled trial to assess effects of a multi-faceted programme on influenza vaccine coverage among hospital healthcare workers and nosocomial influenza in the Netherlands, 2009 to 2011.

Nosocomial influenza is a large burden in hospitals. Despite recommendations from the World Health Organization to vaccinate healthcare workers against influenza, vaccine uptake remains low in most European countries. We performed a pragmatic cluster randomised controlled trial in order to assess the effects of implementing a multi-faceted influenza immunisation programme on vaccine coverage in hospital healthcare workers (HCWs) and on in-patient morbidity. We included hospital HCWs of three intervention and three control University Medical Centers (UMCs), and 3,367 patients. An implementation programme was offered to the intervention UMCs to assess the effects on both vaccine uptake among hospital staff and patient morbidity. In 2009/10, the coverage of seasonal, the first and second dose of pandemic influenza vaccine as well as seasonal vaccine in 2010/11 was higher in intervention UMCs than control UMCs (all p<0.05). At the internal medicine departments of the intervention group with higher vaccine coverage compared to the control group, nosocomial influenza and/or pneumonia was recorded in 3.9% and 9.7% of patients of intervention and control UMCs, respectively (p=0.015). Though potential bias could not be completely ruled out, an increase in vaccine coverage was associated with decreased patient in-hospital morbidity from influenza and/or pneumonia.

Influenza vaccination in healthcare workers; comparison of side effects and preferred route of administration of intradermal versus intramuscular administration.

OBJECTIVE: To explore the nature and severity of side effects and future preference of intradermal versus intramuscular influenza vaccination in healthcare workers. DESIGN: Prospective cohort study. SETTING: Two University Medical Centers in The Netherlands. PARTICIPANTS: Healthcare workers receiving an influenza vaccination. METHODS: Healthcare workers that were vaccinated during the influenza vaccination season of 2012-2013 were approached for participation in a questionnaire study. The questionnaire was divided into two parts. The first part had to be answered directly after vaccination and the second part two weeks after vaccination. The motivation for vaccine uptake, whether or not the HCWs had direct contact with patients and the prevalence and severity of local and systemic side effects of influenza vaccination were explored. In addition, it was assessed how participants experienced the vaccination and which type of administration they preferred for future vaccination. RESULTS: Side effects of vaccination were more prevalent in the intradermal group versus the intramuscular group (56% versus 26%, p<0.001). Local side effects were perceived as more severe in healthcare workers receiving the intradermal vaccine. Directly after vaccination, healthcare workers preferred the intradermal vaccination. Two weeks after vaccination both types of vaccine were equally appreciated. CONCLUSIONS: This study shows that there are significant differences in the nature and severity of side effects upon intramuscular and intradermal influenza vaccination. This difference did not result in a preference among the vaccinated subjects for one type of vaccine.

Genotype distribution amongst hepatitis C patients in The Netherlands.

BACKGROUND: The prevalence of the genotypes of the hepatitis C virus (HCV) differs according to geographical location. In the United States and in European countries, the majority of patients are infected with genotype 1, 2 or 3. There is a lack of data on the distribution of HCV genotypes in The Netherlands. METHODS: The current survey determined the distribution of HCV genotypes amongst recently genotyped patients seen by physicians treating hepatitis C in The Netherlands. RESULTS: Almost half of the 351 patients (49.3%) were infected with genotype 1. Genotype 3 was the second most dominant genotype with a prevalence of 29.3%. Genotypes 2 and 4 were found in 9.7 and 10.5% of the patients, respectively. For 61.5% of the patients (n=216), the subtype was available. For genotype 1 the prevalence of subtype 1a and 1b was very similar, while for genotype 3 a large majority of patients were infected with subtype 3a. CONCLUSION: This survey gives the first estimation of the distribution of HCV genotypes amongst unselected HCV patients in The Netherlands.

Influence of interferon preparations on the proliferative capacity of human and mouse bone marrow cells in vitro.

The toxicity of interferon to bone marrow was studied by the use of in vitro colony forming assays for hemopoietic cells. In the same study the relative inhibitory effects of two clinically common interferon preparations, leukocyte and fibroblast interferons, were compared with regard to their effect on both myeloid [colony-forming unit, culture (CFUc)] and erythroid [colony-forming unit, erythroid (CFUe)] progenitor cells. CFUe formation in human bone marrow cells in vitro appeared to be fairly resistant to both interferons. Only high doses of both interferons gave a marked inhibition of CFUe. However, the toxicity of leukocyte and fibroblast interferon was divergent for CFUe in human bone marrow. Leukocyte interferon appeared to be considerably more inhibitory for CFUe than was fibroblast interferon. The effects of mouse interferon, induced in L929 cells, on the growth of CFUc and CFUe in murine bone marrow cells were comparable with those of fibroblast interferon on human cells. The toxicity of human and murine interferon was species specific. Except for the toxicity of leukocyte interferon to CFUc in human bone marrow, the toxicity of interferon was marked only with concentrations on interferon far exceeding the amount necessary to produce an antiviral state in vitro.

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Light-induced phase shifts in onset and offset of running-wheel activity in the Syrian hamster.

The effects of light pulses on activity onset and offset were assessed in intergeniculate leaflet- and ventral lateral geniculate nucleus-lesioned Syrian hamsters with a precise onset and offset of circadian wheel-running activity. Light pulses applied to animals in constant darkness during the early subjective night induced phase delays in both activity onset and offset, while light pulses during the late subjective night induced phase advances in the onset and offset of activity. Despite the fact that the direction of onset and offset shifts were similar, differences were found in the magnitude of light-induced phase shifts. Steady state phase delays were larger in the activity onset, while steady state phase advances were largest in the offset of activity. We found phase delays and phase advances within one cycle after the presentation of a light pulse in both activity onset and offset. Differences in magnitude of these immediate phase shifts in activity onset and offset resulted in a compression of activity time for a number of cycles following a light pulse. Similar results were obtained in a selected group of intact animals indicating that intergeniculate leaflet- and ventral lateral geniculate nucleus-lesioned hamsters provide a good model to investigate the effects of light on circadian onset and offset of running-wheel activity.

Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report.

Two multicentre phase II trials were designed to determine if tumour responses can be achieved in progressive small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) patients treated with ISIS 5132, an inhibitor of C-raf kinase mRNA expression (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA), and to further characterise the safety of the compound. Between August 1998 and November 1999, 26 patients (18 NSCLC, 8 SCLC) were entered. Out of these, 23 were eligible, 22 (18 NSCLC, 4 SCLC) were treated with ISIS 5132 (2 mg/kg/day, 21 days continuous intravenous (i.v.) infusion every 4 weeks) and were evaluable for toxicity and 18 (15 NSCLC, 3 SCLC) were evaluable for efficacy. For the whole group haematological toxicity did not exceed grade 2. One patient experienced a grade 4 increased prothrombin time. Non-haematological toxicity was mild to moderate, with the observation of asthenia and nausea and vomiting. Progressive disease (PD) was diagnosed in 10 patients (8 NSCLC and 2 SCLC). 8 more patients (7 NSCLC, 1 SCLC) were considered as treatment failures. In conclusion, this study using ISIS 5132 with this dose and schedule of administration excludes a 20% response rate with 95% confidence intervals for NSCLC and cannot draw any conclusions for SCLC patients as only a few were involved in the study.

The effects of electrical stimulation of the optic nerves and anterior optic chiasm on the circadian activity rhythm of the Syrian hamster: involvement of excitatory amino acids.

The circadian pacemaker of the suprachiasmatic nuclei (SCN) is entrained to the environmental light-dark cycle via the retinohypothalamic tract (RHT). It is unknown whether light activates or suppresses firing of the retinal ganglion cells which mediate photic entrainment. We therefore electrically stimulated the optic nerves and the anterior optic chiasm of hamsters with free-running activity rhythms in continuous darkness. These electrical stimulations are thought to induce a release of neurotransmitter at the RHT terminals. Electrical stimulation mimicked the phase dependent shifts induced by light pulses. The phase shifts were significantly larger than the shifts induced by sham stimulation in the same animals or by electrical stimulation in animals with an electrode outside the optic nerves and chiasm. Our results indicate that the retinal ganglion cells which project to the SCN are activated by light. Intraperitoneal administration of MK-801, a non-competitive antagonist of the NMDA-receptor, attenuated the phase delays induced by electrical stimulation in the early subjective night. This suggests that an excitatory amino acid mediates the effects of light upon the circadian pacemaker.

Glutamate immunoreactivity in terminals of the retinohypothalamic tract of the brown Norwegian rat.

The mammalian circadian pacemaker of the suprachiasmatic nucleus (SCN) is entrained to the environmental light-dark cycle via a retinal projection, the retinohypothalamic tract (RHT). Several studies suggest that an excitatory amino acid, possibly glutamate, is involved in photic entrainment. However, it has not yet been established whether glutamate is a transmitter of the RHT itself. We have now identified terminals of the RHT in the SCN of brown Norwegian rats by intravitreous injections of horse radish peroxidase conjugated to cholera toxin. To detect glutamate immunoreactivity (IR), post-embedding immunocytochemistry was performed with polyclonal antibodies which were visualized for electron microscopy with colloidal gold particles. Retinal terminals had a significantly 82% higher glutamate-IR than their post-synaptic dendrites and a significantly 76% higher glutamate-IR than non-retinal terminals. These observations provide ultrastructural evidence that glutamate is a transmitter of the RHT.

Prognostic factors in patients continuing in vitro fertilization or intracytoplasmic sperm injection treatment and dropouts.

OBJECTIVE: To investigate whether cumulative pregnancy rates using life table analysis but without considering dropouts are representative of the whole population of patients entering an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) program. DESIGN: Retrospective study. SETTING: University hospital-based infertility center. PATIENT(S): One thousand one hundred sixty-nine patients entering our IVF/ICSI program from January 1993 to December 1996. INTERVENTION(S): Comparison of prognostic factors between pregnant and nonpregnant patients, and between patients continuing IVF/ICSI treatment and dropouts. MAIN OUTCOME MEASURE(S): Prognostic factors, such as patient age, cancellation of oocyte retrieval because of poor response to ovarian stimulation, number of oocytes retrieved, fertilization rate, number and quality of embryos transferred. RESULT(S): No statistical differences in prognostic factors were found between patients continuing IVF/ICSI treatment and dropouts. CONCLUSION(S): Cumulative pregnancy rates using life table analysis can be considered representative of the whole population of patients for at least the first three treatment cycles.

Aspartate injections into the suprachiasmatic region of the Syrian hamster do not mimic the effects of light on the circadian activity rhythm.

The excitatory amino acids glutamate and aspartate are thought to be involved in the photic entrainment of the circadian pacemaker of the suprachiasmatic nuclei (SCN). When applied to the SCN region glutamate imitates the effects of dark pulses on the circadian activity rhythm rather than those of light. We have now injected aspartate into the SCN region of Syrian hamsters. These injections mimicked the effects of dark pulses as well, in so far as slight advances of the activity rhythm were obtained during the subjective day. However, the mean phase shift was not significantly different from the shift obtained with control injections. It is concluded that (1) aspartate has little or no effect on the phase of the circadian activity rhythm and (2) none of the putative transmitters of the photic afferents of the SCN produces the effects of light upon injection.

Long-term trends in sperm counts of dairy bulls.

A possible decline in sperm counts in men and its potential relation to exposure to environmental contaminants are subjects of a broad discussion. Whereas data for human research in this area are limited, records over prolonged periods on sperm counts in dairy bulls are amply available and provide useful information. Therefore, 75,238 ejaculates collected between 1977 and 1996 from 2,314 bulls at Noordwest, a center for artificial insemination (AI) in the Netherlands, were used to evaluate long-term trends in sperm output. Data were adjusted for known effects, of which age was the most important, followed by interval between semen collections, breed and season of collection. Mean sperm output per year of collection from 1978 through 1996 varied between 6.2 x 10(9) and 9.5 x 10(9) without any long-term decline. Mean sperm output per year of birth from 1970 through 1995 showed less variation, between 6.7 x 10(9) and 9.0 x 10(9), also without any long-term decline. Earlier published data of 22,120 ejaculates of 3,030 bulls of the same region, tested between 1962 and 1977, showed a corresponding sperm output, confirming the absence of any decline. The unaffected sperm output in bulls in the Netherlands during the last decades in spite of exposure to pesticides and other polychlorinated organic compounds, the type of environmental contaminants under discussion, is a positive signal, although a complete extrapolation to the human situation remains difficult.

Retrograde labeling of retinal ganglion cells and brain neuronal subsets by [3H]-D-aspartate injection in the Syrian hamster hypothalamus.

The circadian pacemaker in the suprachiasmatic nuclei (SCN) is entrained to the environmental light-dark cycle via a direct retinal projection to the hypothalamus. This projection is thought to use glutamate or aspartate as neurotransmitter. [3H]-D-Aspartate was microinjected in the SCN and adjacent hypothalamic nuclei of Syrian hamsters. This neuronal tracer is selectively taken up by terminals of neurons that use glutamate or aspartate as neurotransmitter and retrogradely transported to their perikarya. With autoradiography labeled cells were visualized in the retinal ganglion cell layer. Labeled cells were also found in a subset of brain nuclei known to project to the injection area. Labeled cells were detected in the bed nucleus of the stria terminalis, paraventricular nucleus of the thalamus, lateral septal nucleus, and medial amygdaloid nucleus. No labeled cells were observed in the medial septal nucleus, intergeniculate leaflet, and ventral lateral geniculate nucleus, which are also known to project to the SCN. Our results indicate that glutamatergic/aspartatergic retinal ganglion cells project to the SCN and adjacent medial hypothalamic nuclei. Moreover, the SCN may receive glutamatergic/aspartatergic input from the brain neuronal subsets that were retrogradely labeled with [3H]-D-aspartate.

The immunological and psychological effects of bereavement: does grief counseling really make a difference? A pilot study.

This study evaluates psychological and immunological functioning after bereavement and the influence of group counseling. Eighteen widows (bereaved within 3 months of enrolment) and a reference group of 10 married control subjects were asked to fill in self-report scales and to donate a blood sample (T1). After T1, half of the widows (the experimental group) were randomly assigned to grief counseling (13 sessions over 4 months), while the other subjects (the control group) received no treatment. Seven months after bereavement (T2) or, in the case of the experimental group, immediately after the intervention, a follow-up was conducted in the widowed subsample using the same measures. Blood samples were analyzed to determine the total number of white blood cells, number of lymphocyte subsets, natural killer cell activity (NKCA) and lymphocyte proliferative response to phytohemagglutinin (PHA), anti-CD3 and pokeweed mitogen (PWM). At T1, we found significant differences between widows and non-widows regarding both psychological and immunological measures. Widows felt more anxious, depressed, hostile and agoraphobic. At T1, widows had a lower number of the CD19+CD5+ B cell subpopulation. The cell function tests for T and B cells showed higher responses in widows (lymphocyte proliferation response to PHA, anti-CD3 and PWM). No significant difference in NKCA was found between widows and non-widows. At T2, there appeared to be no significant difference between widows and non-widows on the psychological measures. With respect to the immunological measures, widows and non-widows showed no significant differences for the total number of white blood cells, number of lymphocyte subsets and NKCA. Consistent with our findings at T1, the lymphocyte proliferation response to PHA, anti-CD3 and PWM at T2 appeared to be higher in widows than in non-widows. Comparing the experimental group (widows) and the control group (widows) with respect to psychological measures at T1, widows in the experimental group felt more insufficient and had more sleep disturbances. With respect to the immunological measures, no differences were found between those two groups. When the same two groups were again compared at T2, no differences were found in any of the psychological or immunological measures (lymphocyte sub-populations, proliferation tests and the NKCA).

Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study.

OBJECTIVE: To determine whether the risk of pregnancy-induced hypertensive disorders (PIHD) is higher in patients with the polycystic ovary syndrome (PCOS) than in non-PCOS controls, matched for age and parity. STUDY DESIGN: Retrospective analysis of eighty-one patients with PCOS, consecutively becoming pregnant during a seven-year period. Each PCOS-patient was matched for age and parity with one control patient. Chi-squared, Mann-Whitney or Fisher's exact-tests were used for statistical analysis. RESULTS: Overall incidence of PIHD was similar in both study groups. However, incidence of preeclampsia was significantly higher in patients with PCOS than in controls (P = 0.02). This higher incidence can not be explained by body mass index, endocrine profile before pregnancy, induction of ovulation or treatment regimens. CONCLUSIONS: PCOS-patients are at a significantly higher risk for preeclampsia than non-PCOS controls.

Short-term results and long-term patients' appraisal of abdominal colposacropexy for treatment of genital and vaginal vault prolapse.

OBJECTIVE: To evaluate short-term results and long-term patients' satisfaction of abdominal colposacropexy performed for massive genital prolapse in our institute during a 14-year period. STUDY DESIGN: A retrospective analysis was performed of 101 consecutive women who underwent abdominal colposacropexy. The procedure consisted of retroperitoneal interposition of a Mersilene mesh between a prolapsed vaginal vault or uterus and the anterior surface of the sacrum. A questionnaire was used to evaluate patients' satisfaction after surgery. RESULTS: In the short-term there was an acceptable rate of complications of surgery, comparable with that reported in the literature. Prolapse-related complaints evaluated by questionnaire were markedly diminished after surgery. Pain and functional complaints were only partly improved in a subgroup of patients. Only 32% of the patients responded that they were fully cured after operation. CONCLUSIONS: Abdominal colposacropexy shows a particularly favorable result on prolapse-related complaints. Functional complaints and pain are not substantially relieved by this procedure. The complication rate of surgery is acceptable.

Use of AI technician scores for body condition, uterine tone and uterine discharge in a model with disease and milk production parameters to predict pregnancy risk at first AI in Holstein dairy cows.

Technicians recorded body condition score (BCS) and several parameters related to estrus and/or metritis for 1694 first insemination cows on 23 farms. Additional variables for modeling the adjusted odds ratios (OR) for pregnancy were data on disease prior to or within 21 days of AI and test day milk yields. Significant predictors for pregnancy were farm, year and season, BCS, uterine tone, contaminated insemination gun after AI, fat-protein corrected kilograms milk (FPCM), days in milk (DIM), and diseases. Vaginal mucus, ease of cervical passage, and lameness were not significant predictors for pregnancy. Pregnancy risk at AI increased with increasing DIM, reaching a near optimum after 82 days. Lack of uterine tone was associated with a lowered pregnancy risk (OR = 0.69) as was contaminated insemination gun (OR = 0.67), first-parity lactation, FPCM >33 kg (OR = 0.71), BCS 2.5 at AI (OR = 0.65), clinical mastitis (OR = 0.53), cystic ovarian disease (OR = 0.53), and metritis (OR = 0.74). It was concluded that data on BCS and uterine findings, as collected by AI technicians, are significant predictors of AI outcome. Dairy producers and veterinarians should jointly examine the potential costs and value of such AI technician-based data to improve herd fertility.

[Economic contribution of mofetil mycofenolate as preventive immunosuppressive treatment after renal transplantation from cadaver]. / Apport économique du mycophénolate mofétil comme traitement immunosuppresseur prophylactique après transplantation rénale de cadavre.

OBJECTIVES: The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system. METHODS: The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared. RESULTS: The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results. CONCLUSION: Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.