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Mean Increase (mean + increase)
Selected AbstractsInstructing pelvic floor contraction facilitates transversus abdominis thickness increase during low-abdominal hollowingPHYSIOTHERAPY RESEARCH INTERNATIONAL, Issue 2 2002Duncan Critchley Abstract Background and Purpose Low abdominal hollowing in four-point kneeling is used clinically to test and rehabilitate transversus abdominis (TrA) but many people find this exercise difficult to perform. Contracting pelvic floor muscles (PF) during low abdominal hollowing may facilitate contraction of TrA. Thickness increase in the abdominal muscles during low abdominal hollowing has been measured with real-time ultrasound scanning and may indicate muscle contraction. The present study investigated the effect of instructing PF contraction on TrA thickness increase during low abdominal hollowing. Method Twelve females and eight males with no reported pelvic floor dysfunction or low back pain in the last two years were taught low abdominal hollowing in four-point kneeling. Subjects performed low abdominal hollowing with and without instruction to contract PF in random order. Transversus abdominis, obliquus internus (OI) and obliquus externus (OE) thickness were measured with ultrasound scanning at rest and during both tests. Results Mean increase in TrA thickness during low abdominal hollowing was 49.71% (SD 26.76%), during low abdominal hollowing with PF it was 65.81% (SD 23.53%). Paired Student's t -tests indicated a significant difference between tests (p=0.015). There were no significant differences between tests for OE or OI thickness increase. Conclusions Instructing healthy subjects to co-contract PF results in greater increase in TrA thickness during low abdominal hollowing in four-point kneeling. This may indicate greater contraction of TrA and thus be useful for clinicians training TrA. Further research could investigate the validity of change of thickness as a measure of abdominal muscle contraction, investigate the effect of instructing PF co-contraction on TrA in patients with low back pain and measure PF and TrA activity simultaneously. Copyright © 2002 Whurr Publishers Ltd. [source] Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of ,7 or ,6 subunit mRNA: an autoradiography and in situ hybridization study in rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Manolo Mugnaini Abstract It is well established that exposure of experimental animals to nicotine results in upregulation of the ,4,2-subtype of neuronal nicotinic acetylcholine receptors (nAChRs). The aim of this study was to determine the effect of nicotine on the levels of ,7-nAChRs in rat brain, for which only partial information is available. Rats were infused with nicotine (3 mg/kg/day) or saline for 2 weeks and their brains processed for receptor autoradiography with [3H]methyllycaconitine (MLA), a radioligand with nanomolar affinity for ,7-nAChRs. In control rats binding was high in hippocampus, intermediate in cerebral cortex and hypothalamus, and low in striatum, thalamus and cerebellum. There was high correlation between the distribution of [3H]MLA binding sites and ,7 subunit mRNA (r = 0.816). With respect to saline-treated controls, nicotine-treated rats presented higher [3H]nicotine binding in 11 out of 15 brain regions analysed (average increase 46 ± 6%). In contrast, only four regions showed greater [3H]MLA binding, among which the ventral tegmental area (VTA) and cingulate cortex (mean increase 32 ± 3%). No changes in ,7 mRNA levels were observed after nicotine treatment. Similarly, there was no variation of ,6 subunit transcript in the VTA, a region which may contain MLA-sensitive (non-,7)-,6*-nAChRs (Klink et al., 2001). In conclusion, nicotine increased [3H]MLA binding, although to a smaller extent and in a more restricted regional pattern than [3H]nicotine. The enhancement of binding was not paralleled by a significant change of ,7 and ,6 subunit transcription. Finally, the present results provide the first anatomical description of the distribution of [3H]MLA binding sites in rat brain. [source] Cost-effectiveness analysis of two strategies for mass screening for colorectal cancer in FranceHEALTH ECONOMICS, Issue 3 2004Célia Berchi Abstract The implementation of colorectal cancer mass screening is a high public health priority in France, as in most other industrialised countries. Despite evidences that screening using guaiac fecal occult blood test may reduce colorectal cancer mortality, no European country has organised widespread mass screening with this test. The low sensitivity of this test constitutes its main limitation. Immunological tests, which provide higher sensitivity than the guaiac test, may constitute a satisfactory alternative. This study was carried out to compare the costs and the effectiveness of 20 years of biennial colorectal cancer (CRC) screening with an automated reading immunological test (Magstream) with those obtained with a guaiac stool test (Haemoccult). The model used to estimate the costs and effectiveness of successive biennial CRC screening campaigns was a transitional probabilistic model. The parameters used in this model concerning costs and CRC epidemiological data were calculated from results obtained in the screening program run in Calvados or from published results of foreign studies because of the lack of French studies. The use of Magstream for 20 years of biennial screening costs 59 euros more than Haemoccult per target individual, and should lead to a mean increase in individual life expectancy of 0.0198 years (i.e. about one week), which corresponds to an incremental cost-effectiveness ratio of 2980 euros per years of life saved. Our results suggest that using an immunological test could increase the effectiveness of CRC screening at a reasonable cost for society. Copyright © 2003 John Wiley & Sons, Ltd. [source] Epoetin alfa corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapyHEMATOLOGICAL ONCOLOGY, Issue 4 2003Timothy J. Littlewood Abstract Anemia, a commonly occurring morbidity in patients with cancer, often leads to diminished quality of life (QOL). Numerous clinical trials have shown that epoetin alfa treatment improves hematologic and QOL variables in cancer patients. The clinical trial analysis reported here was performed to assess response to epoetin alfa in patients with hematologic malignancies. Cancer patients with anemia undergoing non-platinum-based chemotherapy who were enrolled in a multinational, randomized (2:1), double-blind, placebo-controlled trial were prospectively stratified by tumor type (hematologic, solid). Efficacy endpoints included proportion of patients transfused after day 28; change in hemoglobin (Hb) level from baseline to last assessment; proportion of treatment responders (increase in Hb ,2,g/dl unrelated to transfusion) and correctors (patients whose Hb levels reached ,12,g/dl during the study); and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study, and survival for the full study cohort was estimated using Kaplan,Meier techniques. Efficacy analyses of hematologic and QOL variables, as well as Kaplan,Meier estimates of survival, were performed post hoc for the hematologic tumor stratum. Among patients with hematologic malignancies, the mean increase in Hb levels was greater with epoetin alfa than with placebo treatment (2.2 vs. 0.3,g/dl). Transfusion requirements were lower in patients who received epoetin alfa versus placebo (25.2 vs. 43.1%), and the proportion of responders and correctors was higher with epoetin alfa than with placebo (75.2 vs. 16.7% and 72.6 vs. 14.8%, respectively). Patients who received epoetin alfa had improved QOL while patients who received placebo had decreased QOL. These results are similar to those seen in the full study cohort, where differences between epoetin alfa and placebo were significant (P<0.05) for all five primary cancer- and anemia-specific QOL domains evaluated. Although the study was not powered for survival, Kaplan,Meier estimates showed a trend in overall survival favoring epoetin alfa in both the full study cohort and the hematologic subgroup. Epoetin alfa treatment was well tolerated. Epoetin alfa therapy increased Hb levels, reduced transfusion requirements, and improved QOL in patients with anemia undergoing non-platinum chemotherapy for hematologic malignancies. Copyright © 2004 John Wiley & Sons, Ltd. [source] Effect of halothane on type 2 immobility-related hippocampal theta field activity and theta-on/theta-off cell dischargesHIPPOCAMPUS, Issue 1 2003Brian H. Bland Abstract Rats were studied in acute and chronic (freely moving) recording conditions during exposure to different levels of the volatile anesthetic halothane, in order to assess effects on hippocampal theta field activity in the chronic condition and on theta-related cellular discharges in the acute condition. Previous work has shown that the generation of hippocampal type 2 theta depends on the coactivation of cholinergic and GABAergic inputs from the medial septum. Based on these data and recent findings that halothane acts on interneuron GABAA receptors, we predicted that exposure of rats to subanesthetic levels would result in the induction of type 2 theta field activity. In the chronic condition, exposure to subanesthetic levels of halothane (0.5,1.0 vol %) was found to induce theta field activity during periods of immobility (type 2 theta) with a mean increase of 39% in amplitude (mV) compared to control levels during movement. The total percentage of signal power (V2) associated with peak theta frequencies (80% compared to control levels of 47%) was also increased by halothane. Over the whole range of administered halothane concentrations, theta field frequency progressively declined from a mean peak frequency of 6.5 ± 0.8 Hz at 0.5 vol % halothane to a mean peak frequency of 4.0 ± 1.8 Hz at 2.0 vol % halothane. Subsequent administration of a muscarinic cholinergic antagonist, atropine sulfate, selectively abolished all type 2 immobility-related theta field activity, while type 1 movement-related theta was still intact. At anesthetic levels (1.5,2.0 vol %) in acute experiments, hippocampal field activity spontaneously cycled between theta and large-amplitude irregular activity. Analysis of depth profiles in four experiments revealed they were identical to those previously described for rats under urethane anesthesia conditions. In addition, the discharge properties of 31 theta-related cells, classified as tonic and phasic theta-on and tonic and phasic theta-off cells, did not differ significantly from those described previously in rats anesthetized with urethane. These data provide further support for an involvement of GABAA receptors in the generation of hippocampal theta. Hippocampus 2003;13:38,47. © 2003 Wiley-Liss, Inc. [source] Efficacy and safety of quetiapine for depressive symptoms in patients with schizophreniaHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 6 2009Kyoung-Uk Lee Abstract Objective To investigate the efficacy and safety of quetiapine for depressive symptoms in patients with schizophrenia. Method Thirty-nine patients fulfilling DSM-IV-TR diagnostic criteria for schizophrenia and had depressive symptoms were studied in a prospective 6-week open-label design using quetiapine monotherapy. The brief psychiatric rating scale (BPRS), 17-item Hamilton depression rating scale (HAMD-17), Simpson,Angus rating scale, and the Barnes Akathisia rating scale (BARS) were used to assess patients at baseline, week 1, 2, 4, and 6. Results Thirty patients (76.9%) completed this study. The dose of quetiapine at endpoint was 583 (±235 SD),mg/day. Treatment with Quetiapine was associated with significantly reduced depressive symptoms (HAMD-17 total score and BPRS depression/anxiety subscale) from the first week of treatment. Changes of mean score from baseline to endpoint were 7.8,±,6.2 for HAMD-17 total score and 3.4,±,3.6 for BPRS depression/anxiety subscale (LOCF, n,=,39, p,<,0.001). Quetiapine was well tolerated, with minimal extrapyramidal symptoms and non-significant increase in body weight (mean increase of 0.8,kg). Conclusions While the interpretation of findings from the open-label design of this study warrants appropriate caution, the results suggest that quetiapine may be an effective and tolerable treatment for depression in patients with schizophrenia. Copyright © 2009 John Wiley & Sons, Ltd. [source] Lower weight gain with the orally disintegrating olanzapine than with standard tablets in first-episode never treated psychotic patientsHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2007B. Arranz Abstract Objective A post-hoc analysis of the data from a randomised clinical trial involving prescription of antipsychotic treatment to never treated first-onset psychotic patients was used to compare the weight change after 6-week olanzapine treatment (standard tablets vs. orally disintegrating formulation). Method In the subgroup of 38 patients randomised to olanzapine, standard olanzapine tablets were non-randomly and consecutively prescribed to the first 19 patients, with the orally disintegrating formulation being prescribed to the following 19 patients. Results After 6-week treatment with olanzapine, a significant higher increase in weight was noted in those patients on standard tablets (mean weight increase 6.3,±,1.9,Kg) as compared to those on orally disintegrating olanzapine (mean weight increase 3.3,±,3.2,Kg) (F,=,7.7; p,=,0.009). BMI increase was also significantly higher in the olanzapine tablet group (mean increase of 2.1,Kg/m2 as compared with 1.1,Kg/m2 in the orally disintegrating group) (F,=,4.7; p,=,0.036). Substantial weight gain (SWG) (,7% increase from baseline weight) was noted in 84.2% (n,=,16) of the olanzapine tablet patients and in 31.6% (n,=,6) of the orally disintegrating olanzapine patients, with the olanzapine tablet group showing a significant increase in the mean percentage of weight gain (F,=,4.0; p,=,0.014). Conclusions Partial sublingual absorption occurring with orally disintegrating olanzapine may bypass gastrointestinal metabolisation and hence lead to differences in metabolite versus parent compound ratios. However, the need arises to replicate the present study with a longer follow-up. Copyright © 2007 John Wiley & Sons, Ltd. [source] Runoff and peak flow responses to timber harvest and forest age in southern ChileHYDROLOGICAL PROCESSES, Issue 1 2006Professor Andrés Iroumé Abstract Runoff and peak flows in three experimental catchments with different forest conditions were analysed in a rainy temperate climate in southern Chile. The hydrological effects of clearcutting a Pinus radiata plantation covering 79·4% of the La Reina catchment were studied by analysing runoff and peak flows in the pre- and post-harvesting periods. Mean annual runoff increased 110% after timber harvesting. Clearcutting generated a 32% mean increase in peak flows. Peak flow and runoff were examined in two adjacent catchments with different forest conditions. The older plantation in Los Ulmos 1 increasingly consumed more water than the younger plantation established at Los Ulmos 2, whereas differences in peak flows between these two catchments were not significant. Runoff and peak flows comparisons not only reflected changes in forest cover, but also the effect of rainfall characteristics during the study periods and the basins' morphologies. Comparisons between pre- and post-harvesting peak discharges must be undertaken with caution, because a previous analysis at La Reina using a partial set of data overestimated changes in peak flows after timber harvesting. Copyright © 2005 John Wiley & Sons, Ltd. [source] Modulation of angiogenesis is effective in a model of rheumatoid arthritisJOURNAL OF ANATOMY, Issue 5 2002A. O. Afuwape A feature of rheumatoid arthritis (RA) is prominent hyperplasia of the synovium, which results in an increased distance between the invasive pannus and the existing synovial vasculature. Concomitantly the hyperplastic tissue imposes an augmented metabolic demand on the pre-existing vasculature. As a consequence the synovium in RA becomes hypoxic, resulting in an increased rate of formation of new blood vessels, to supply nutrients and oxygen. Targeting the vasculature in RA is a potential therapeutic approach in RA. VEGF, a key vascular permeability and angiogenic factor, is expressed in RA. In this study we utilised adenovirus expressing the secreted form of the extracellular domain of the Flt-1 VEGF receptor (sFlt-1) to inhibit VEGF in the collagen-induced arthritis (CIA) model, to determine whether blocking the effects of vegf might be an effective treatment for RA. AdvsFlt-1, administered intravenously on the first day of arthritis, significantly suppressed CIA. For example, on d 6 of arthritis the mean increase in paw thickness, which reflects oedema, for untreated and null adenovirus-treated animals was 0.23 ± 0.05 mm and 0.38 ± 0.08, respectively, compared to 0.07 ± 0.05 for AdvsFlt-1-treated mice (P < 0.001 vs. Adv0-treated and untreated mice by 2-way anova). Western blot analyses revealed the presence of a 100-kDa band, corresponding to human sFlt-1, in liver extracts from arthritic mice infected with AdvsFlt-1 at 24 h but not 72 h after infection. This band was absent in liver extracts from Adv0-infected mice and all synovial extracts. Measurement of protein levels by ELISA demonstrated the presence of sFlt-1 in liver, synovium and serum, although levels declined by 72 h post infection. These data suggest efficient but transient expression of sFlt-1. Sera from adenovirus infected mice were found to contain antiviral antibodies and additionally, sera from AdvsFlt-1-infected but not Adv0-infected mice recognised human recombinant sFlt-1. These observations demonstrate that adenoviral mediated delivery of human sFlt-1 leads to transient gene expression and suppression of CIA. This effect is reduced later in the course of disease due to the expression of antiadenovirus as well as antisFlt-1 antibodies. Future studies will assess the effect of combination treatment, using AdvsFlt-1 together with anti-TNF(antibody, to prolong the beneficial effects of VEGF blockade. These results suggest that blocking the pro-angiogenic and permeability action of VEGF may be beneficial for treatment of RA. [source] Left Ventricular Reconstruction for Ischemic CardiomyopathyJOURNAL OF CARDIAC SURGERY, Issue 3 2002Vincent Dor M.D. The technique is conducted under a totally arrested heart; coronary revascularization is accomplished first. The mitral valve is checked by TEE and repaired if necessary. Endocardectomy and cryotherapy are used in case of ventricular tachycardia. At the limit between scarred and normal tissue, a continuous suture is tied on a balloon inflated at the theoretical diastolic volume of the patient, and a patch is fixed inside the ventricle. Autologous tissue can be also used. The experience of the author is more than 1000 cases since 1984. The global hospital mortality of the whole series is 7.3%, and 13% in patients with very poor ejection fraction (<30%). In the series of the last 3 years, these mortality rates are 4.8% and 7.9%, respectively. Both geometry and performances of the LV are improved, and the mean increase of ejection fraction is between 10 and 15 points. Three causes can explain delayed impairment; continuum in remodeling, lack in diastolic capacity, or absence of mitral repair. After an infarct, with or without successful coronary recanalization, that leaves a large asynergic scarred ventricle (50% of LV circumference), LVR is recommended to avoid or prevent permanent congestive heart failure with global dilatation. In end-stage ischemic cardiomyopathy with congestive heart failure, and poor response to full medical therapy, LVR, with acceptable risk, could slow down the remodeling and avoid or delay heart transplantation. [source] Interleukin-1 gene polymorphisms and experimental gingivitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 2 2003Søren Jepsen Abstract Background: Recently, an association between the severity of periodontitis and specific variations in the interleukin-1 (IL1) , and , genes has been demonstrated. Aim: The purpose of this study was to evaluate the relationship of the IL1 genotype to the development of experimental gingivitis. Materials and Methods: Twenty young adult subjects presenting with healthy gingival conditions participated after giving their informed consent. The group included 10 risk genotype positive (P+) and 10 risk genotype negative (P,) individuals. The IL1 genotypes were determined on DNA samples from peripheral blood using PCR-RFLP analyses for the IL1, and IL1, polymorphisms. Experimental gingivitis was allowed to develop in two posterior sextants per subject. Bleeding on probing (BOP%) and gingival crevicular fluid volume (GCF) were assessed at baseline and days 2, 7, 9, 14, 16 and 21. The day 21 results for BOP and GCF as well as the rate of increase of these parameters , mean area under the curve (AUC) and mean increase per day (slope) , were evaluated using risk analyses for IL1 genotype, smoking status and gender. Results: Experimental gingivitis developed with a gradual increase in BOP scores and GCF values (expressed as Periotron units=PU) from baseline to day 21 (BOP, P+: 0.5 to 26.0%; P,: 1.0 to 28.1%; GCF, P+: 36.8 to 138.5 PU, P,: 43.1 to 143.4 PU). No significant risk was associated with P+ and P, for day 21 results, AUC or slope. Conclusion: The results of this study failed to provide evidence that the IL1 risk genotype was associated with higher GCF volume and percentage BOP during the development of experimental gingivitis. Zusammenfassung Hintergrund: Kürzlich ist eine Beziehung zwischen dem Schweregrad von Parodontitis und speziellen Varianten der Interleukin-1 (IL1),- und -,-Gene gezeigt worden. Zielsetzung: Untersuchung des Zusammenhanges zwischen dem ILl-Genotyp und der Entwicklung einer experimentellen Gingivitis. Material und Methoden: 20 junge Erwachsene mit gesunden parodontalen Verhältnissen, von denen 10 für den Risikogenotyp positiv (P+) und 10 negativ (P-) waren, nahmen an der Studie teil, nachdem sie ihr Einverständnis dazu gegeben hatten. Die IL1 -Genotypen wurden aus DNS-Proben aus peripherem Blut mittels PCR-RFLP-Analyse auf ILl,- und IL1/,-Polymorphismen untersucht. In 2 Seitenzahnsextanten ließ jeder Proband eine experimentelle Gingivitis entwickeln. Bluten auf Sondieren (BOP%) und Sulkiksfiüssigkeitsvolumen (SFV) wurden zu Beginn der Studie und nach 2, 7, 9, 14, 16 und 21 Tagen bestimmt. Sowohl die Ergebnisse für BOP und SFV an Tag 21 als auch die Zunahme dieser Werte , mittlere Fläche unter der Kurve (AUC) und mittlere Zunahme pro Tag (Steigung) , wurden mittels Risikoanalyse fur IL1 -Genotyp, Rauchen und Gescnlecht bestimmt. Ergebnisse: Die experimentelle Gingivitis entwickelte sich mit einem stetigen Anstieg der BOP- und SFV-Werte (ausgedrückt als Periotroneinheiten=PU) vom Beginn der Studie bis zum 21. Tag (BOP, P+: 0,5% to 26,0%, P-: 1,0% to 28,1%; GCF, P+: 36,8 to 138,5 PU, P-: 43,1 to 143,4 PU). Mit P+und P- war kein signifikantes Risiko für die Werte am 21. Tag, die AUC oder die Steigung verbunden. Schlussfolgerung: Die Ergebnisse dieser Studie konnten keine Beziehung zwischen dem IL1 -Risikogenotype und erhöhtem SFV bzw. Anteil von Stellen mit BOP in % während der Entwicklung einer experimentellen Gingivitis zeigen. Résumé Contexte: Récemment, une association entre la sévérité de la parodontite et des variations spéifiques des gènes codant pour l'interleukin-1 (IL1) , et , a été démontrée. But: Cette étude se propose d'évaluer la relation entre le génotype IL1 dans le developpment de la gingivite expérimentale. Méthods: 20 jeunes sujets adultes présentant une bonne santé gingivale ont participé cette étude après consentement éclairé. Dans ce groupe, il y avait 10 individus à risque positif (P+) et 10 individus à génotype de risque négatif (P,). génotypes lL1 furent déterminés sur des échantillons d'ADN prélevés du sang périphérique par analyse en PCR-RFLP pour les polymorphismes d' IL1, et IL1,. On a laissé se développer une gingivite expérimentale sur 2 sextants postérieurs chez chaque sujet. Le saignement au sondage (BOP%) et le volume de fluide gingival (GCF) furent notes au départ et aux jours 2, 7, 9, 14, 16, et 21. Au vingt et unième jour, les résultats pour BOP et GCF ainsi que le taux d'augmentation de ces paramètres- La surface moyenne sous la courbe (AUC) et l'augmentation moyenne par jour (pente) - furent évalués par analyses du risque pour les génotypes IL1, le tabagisme et le sexe. Résultats: gingivite expérimentale se développa avec une augmentation graduelle des et scores de BOP et des valeurs de GCF (exprimées en unités Periotron=PU) du début de l'étude jusqu'au jour 21 (BOP, P+: 0.5%à 26.0%, P-: 1.0%à 28.1%; GCF, P+: 36.8 à 43.1 à 143.4 PU). Aucun risque significatif ne fut associe avec P+et P-ats à 21 jours, AUC ou la pente. Conclusion: -es résultats de cette étude n'ont pas pu donner de preuves d'associations entre le génotype de risque IL1 et un volume accru de GCF et le % BOP lors du t d'une gingivite expérimentale. [source] Raloxifene, conjugated oestrogen and endothelial function in postmenopausal womenJOURNAL OF INTERNAL MEDICINE, Issue 1 2003E. J. J. Duschek Abstract., Duschek EJJ, Stehouwer CDA, de Valk-de Roo GW, Schalkwijk CG, Lambert J, Netelenbos C (VU University Medical Center, Amsterdam; Sophia Hospital, Zwolle; The Netherlands). Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women. J Intern Med 2003; 254: 85,94. Objectives., To study the long-term effects of raloxifene, a potential designer oestrogen, and oestrogen monotherapy on endothelial function in healthy postmenopausal women. Design., A 2-year double-blind, randomized and placebo-controlled study in an Academic Medical Center. Fifty-six hysterectomized but otherwise healthy postmenopausal women randomly received raloxifene hydrochloride 60 mg day,1 (n = 15) or 150 mg day,1 (n = 13), conjugated equine oestrogen (CEE) 0.625 mg day,1 (n = 15), or placebo (n = 13). Main outcome measures., Endothelial function as estimated from brachial artery flow-mediated, endothelium-dependent vasodilation and nitroglycerine-induced endothelium-independent vasodilation, and plasma levels of the endothelium-derived regulatory proteins, von Willebrand factor (vWF) and endothelin (ET). Results., Raloxifene 60 mg did not significantly affect endothelial function. As compared with placebo, at 6 months of therapy, raloxifene 150 mg and CEE were associated with a mean increase in vWF of 25.5% point (95% CI 3.6,47.3) and 26.6% point (95% CI 6.9,46.3), respectively. At 24 months of therapy, raloxifene 150 mg was associated with a mean decrease in ET of 0.96 pg mL,1 (95% CI ,1.57 to ,0.36). Raloxifene nor CEE significantly affected endothelium-dependent and/or -independent vasodilation. Conclusions., Our results suggest that long-term therapy with raloxifene or oral CEE does not affect endothelium-dependent vasodilation in healthy postmenopausal women. Raloxifene 150 mg day,1 might have both positive and negative effects on endothelium. The clinical significance of these findings remains to be investigated. [source] Kinematics of the ACL-deficient canine knee during gait: Serial changes over two yearsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2004Scott Tashman Abstract The ACL-deficient dog is a model for investigating the development and progression of mechanically driven osteoarthrosis of the knee. ACL loss creates dynamic instability in the ACL-deficient knee which presumably leads to progressive joint degeneration, but the nature of this instability over the time course of disease development is not well understood. The goal of this study was to characterize three-dimensional motion of the canine knee during gait, before and serially for two years after ACL transection. Canine tibial-femoral kinematics were assessed during treadmill gait before and serially for two years after ACL transection (ACL-D group; 18 dogs) or sham transection (ACL-I group; five dogs). Kinematic data was collected at 250 frames/s using a biplane video-radiographic system. Six degree-of-freedom motions of the tibia relative to the femur were calculated, and values immediately prior to pawstrike as well as the maximum, minimum, midpoint and range of motion during early/mid stance were extracted. Between-group differences relative to baseline (pre-transection) values, as well as changes over time post-transection, were determined with a repeated-measures ANCOVA. In the ACL-D group, peak anterior tibial translation (ATT) increased by 10 mm (p < 0.001), and did not change over time (p = 0.76). Pre-pawstrike ATT was similar to ACL-intact values early on (2,4 months) but then increased significantly over time, by 3.5 mm (p < 0.001). The range of ab/adduction motion nearly doubled after ACL loss (from 3.3° to 6.1°). The magnitude (midpoint) of knee adduction also increased significantly over time (mean increase 3.0°; p = 0.036). All changes occurred primarily between 6 and 12 months. There were no significant differences between groups in the transverse plane, and no significant changes over time in the ACL-I group. In summary, peak anterior tibial translation and coronal-plane instability increased immediately after ACL loss, and did not improve with time. ATT just prior to pawstrike and mean knee adduction throughout stance became progressively more abnormal with time, with the greatest changes occurring between 6 and 12 months after ACL transection. This may be due to overload failure of secondary restraints such as the medial meniscus, which has been reported to fail in a similar timeframe in the ACL-deficient dog. The relationships between these complex mechanical alterations and the rate of OA development/progression are currently under investigation. © 2004 Published by Elsevier Ltd. on behalf of Orthopaedic Research Society. [source] Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: A 1-year clinical pilot of etanercept vs. placeboJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2003Edward M. Schwarz Although total hip replacement (THR) is amongst the most successful and beneficial medical procedures to date, long-term outcomes continue to suffer from aseptic loosening secondary to peri-prosthetic osteolysis. Extensive research over the last two decades has elucidated a central mechanism for osteolysis in which wear debris generated from the implant stimulates inflammatory cells to promote osteoclastogenesis and bone resorption. The cytokine tumor necrosis factor alpha (TNF,) has been demonstrated to be central to this process and is considered to be a leading target for intervention. Unfortunately, even though FDA approved TNF antagonists are available (etanercept), currently there are no reliable outcome measures that can be used to evaluate the efficacy of a drug to prevent peri-prosthetic osteolysis. To the end of developing an effective outcome measure, we evaluated the progression of lesion size in 20 patients with established peri-acetabular osteolysis (mean = 29.99 cm3, range = 2.9,92.7 cm3) of an uncemented primary THR over 1-year, using a novel volumetric computer tomography (3D-CT) technique. We also evaluated polyethylene wear, urine N-telopeptides and functional assessments (WOMAC, SF-36 and Harris Hip Score) for comparison. At the time of entry into the study baseline CT scans were obtained and the patients were randomized to etanercept (25 mg s.q., twice/week) and placebo in a double-blinded fashion. CT scans, urine and functional assessments were also obtained at 6 and 12 months. No serious adverse drug related events were reported, but one patient had to have revision surgery before completion of the study due to aseptic loosening. No remarkable differences between the groups were observed. However, the study was not powered to see significant drug effects. 3D-CT data from the 19 patients was used to determine the mean increase in lesion size over 48 weeks, which was 3.19 cm3 (p < 0.0013). Analysis of the urine N-telopeptides and functional assessment data failed to identify a significant correlation with wear or osteolysis. In conclusion, volumetric CT was able to measure progression of osteolysis over the course of a year, thus providing a technology that could be used in therapeutic trials. Using the data from this pilot we provide a model power calculation for such a trial. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trialLIVER TRANSPLANTATION, Issue 10 2009Paolo De Simone Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262,1269, 2009. © 2009 AASLD. [source] Pneumoperitoneum versus abdominal wall lift: effects on central haemodynamics and intrathoracic pressure during laparoscopic cholecystectomyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2003L. Andersson Background:, It has been shown repeatedly that laparoscopic cholecystectomy using pneumoperitoneum (CO2 insufflation) may be associated with increased cardiac filling pressures and an increase in blood pressure and systemic vascular resistance. In the present study, the effects on the central circulation during abdominal wall lift (a gasless method of laparoscopic cholecystectomy) were compared with those during pneumoperitoneum. The study was also aimed at elucidating the relationships between the central filling pressures and the intrathoracic pressure. Methods:, Twenty patients (ASA I), scheduled for laparoscopic cholecystectomy, were randomised into two groups, pneumoperitoneum or abdominal wall lift. Measurements were made by arterial and pulmonary arterial catheterization before and during pneumoperitoneum or abdominal wall lift with the patient in the horizontal position. Measurements were repeated after head-up tilting the patients as well as after 30 min head-up tilt. The intrathoracic pressure was monitored in the horizontal position before and during intervention using an intraesophageal balloon. Results:, After pneumoperitoneum or abdominal wall lifting there were significant differences between the two groups regarding MAP, SVR, CVP, CI, and SV. Analogous to previous studies, in the pneumoperitoneum group CVP, PCWP, MPAP, and MAP as well as SVR were increased after CO2 insufflation (P < 0.01), while CI and SV were not affected. In contrast, in the abdominal wall lift group, CI and SV were significantly increased (P < 0.01), as was MAP (P < 0.01), while CVP, PCWP, MPAP, and SVR were not significantly affected. There was a significant difference in intraesophageal pressure between the two groups. In the pneumoperitoneum group, the intraesophageal pressure was increased by insufflation (P < 0.01) while, in the abdominal wall lift group, it was unaffected. In the pneumoperitoneum group the mean increases in cardiac filling pressures were of the same magnitude as the mean increase in the intraesophageal pressure. Conclusions:, In healthy patients, abdominal wall lift increased cardiac index while pneumoperitoneum did not. Cardiac filling pressures and systemic vascular resistance were increased by pneumoperitoneum but unaffected by abdominal wall lift. The recorded elevated cardiac filling pressures during pneumoperitoneum may be only a reflection of the increased intra-abdominal pressure. [source] FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease,,§AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010Min Lu On June 30, 2009, the United States Food and Drug Administration (FDA) approved ferumoxytol (FerahemeÔ injection, AMAG Pharmaceuticals), an iron-containing product for intravenous (IV) administration, for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). The safety and efficacy of ferumoxytol were assessed in three randomized, open-label, controlled clinical trials. Two trials evaluated patients with nondialysis dependent CKD and a third trial assessed patients undergoing hemodialysis. Randomization was either to ferumoxytol or oral iron. Ferumoxytol was administered as two 510 mg IV injections, separated by 3,8 days. Oral iron, Ferro-Sequels®, was administered at a dose of 100 mg twice daily for 21 days. In all three clinical trials, ferumoxytol administration increased the mean blood hemoglobin (Hgb) concentrations by ,1.0 g/dL over the 35 day period, a mean increase that was greater than what was observed in patients receiving oral iron. Patients receiving ferumoxytol also had increases in blood transferrin saturation (TSAT) and ferritin values. For the proposed ferumoxytol dosing regimen, 4.9% of patients had serum ferritin ,800 ng/mL and TSAT ,50% post-treatment. The most important ferumoxytol safety concerns were hypersensitivity reactions and/or hypotension. Anaphylaxis or anaphylactoid reactions were reported in 0.2% of subjects, and other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria, or wheezing) were reported in 3.7%. Hypotension was observed in 1.9%, including three patients with serious hypotensive reactions. Ferumoxytol administration may transiently affect the diagnostic ability of magnetic resonance imaging and the drug label provides further information regarding this effect. Am. J. Hematol. 2010. Published 2010 Wiley-Liss, Inc. [source] Does stretching induce lasting increases in joint ROM?PHYSIOTHERAPY RESEARCH INTERNATIONAL, Issue 1 2002A systematic review Abstract Background and Purpose Stretching (that is, interventions that apply tension to soft tissues) induces increases in the extensibility of soft tissues, and is therefore widely administered to increase joint mobility and reverse contractures. However, it is not clear whether the effects of stretching are lasting. A systematic review was conducted to determine if stretching (either self-administered, administered manually by therapists or by some external device such as a splint) produces lasting increases in the mobility of joints not directly affected by surgery, trauma or disease processes. Method In order to determine the lasting effects of stretching, only studies that measured joint range of motion (ROM) at least one day after the cessation of stretching were included. MEDLINE (from 1966 to June 2000), EMBASE (from 1988 to June 2000), the Cochrane Controlled Trials Register and PEDro databases were searched, and citation tracking was used to identify randomized studies that met the inclusion criteria. Each study was rated by two independent assessors on the PEDro scale, which rated trials according to criteria such as concealed allocation, blinding and intention-to-treat analysis. Results Thirteen studies satisfied the inclusion criteria. All examined the effect of stretching (median number of stretch sessions = eight) on joint ROM in healthy subjects without functionally significant contractures. Four studies were of ,moderate' quality and the remaining nine were of ,poor' quality. The ,moderate' quality studies suggest that regular stretching increases joint ROM (mean increase in ROM = 8°;95% CI 6° to 9°) for more than one day after cessation of stretching and possibly that the effects of stretching are greater in muscle groups with limited extensibility. Conclusions The results of four ,moderate' quality studies show a convincing effect of stretching in people without functionally significant contracture. These findings require verification with high-quality studies. Lasting effects of intensive stretching programmes (for example, stretching applied for more than six weeks or for more than 20 minutes a day) or of stretching on people with functionally significant contracture have not yet been investigated with randomized studies. Copyright © 2002 Whurr Publishers Ltd. [source] Photosynthetic parameters of birch (Betula pendula Roth) leaves growing in normal and in CO2 - and O3 - enriched atmospheresPLANT CELL & ENVIRONMENT, Issue 4 2004H. EICHELMANN ABSTRACT Two silver birch (Betula pendula Roth) clones K1659 and V5952 were grown in open-top chambers over 3 years (age 7,9 years). The treatments were increased CO2 concentration (+CO2, 72 Pa), increased O3 concentration (+O3, 2 × ambient O3 with seasonal AOT40 up to 28 p.p.m. h) and in combination (+CO2 + O3). Thirty-seven photosynthetic parameters were measured in the laboratory immediately after excising leaves using a computer-operated routine of gas exchange and optical measurements. In control leaves the photosynthetic parameters were close to the values widely used in a model (Farquhar, von Caemmerer and Berry, Planta 149, 78,90, 1980). The distribution of chlorophyll between photosystem II and photosystem I, intrinsic quantum yield of electron transport, uncoupled turnover rate of Cyt b6f, Rubisco specificity and Km (CO2) were not influenced by treatments. Net photosynthetic rate responded to +CO2 with a mean increase of 17% in both clones. Dry weight of leaves increased, whereas protein, especially Rubisco content and the related photosynthetic parameters decreased. Averaged over 3 years, eight and 17 mechanistically independent parameters were significantly influenced by the elevated CO2 in clones K1659 and V5952, respectively. The elevated O3 caused a significant decrease in the average photosynthetic rate of clone V5952, but not of clone K1659. The treatment caused changes in one parameter of clone K1659 and in 11 parameters of clone V5952. Results of the combined treatment indicated that +O3 had less effect in the presence of +CO2 than alone. Interestingly, changes in the same photosynthetic parameters were observed in chamberless grown trees of clone V5952 as under +O3 treatment in chambers, but this was not observed for clone K1659. These results suggest that during chronic fumigation, at concentrations below the threshold of visible leaf injuries, ozone influenced the photosynthetic parameters as a general stress factor, in a similar manner to weather conditions that were more stressful outside the chambers. According to this hypothesis, the sensitivity of a species or a clone to ozone is expected to depend on the growth conditions: the plant is less sensitive to ozone if the conditions are close to optimal and it is more sensitive to ozone under conditions of stress. [source] Composition of alveolar surfactant changes with training in humansRESPIROLOGY, Issue 3 2000Ian R. Doyle Objective: We test the hypothesis that the changes we observed previously in the relative amounts of disaturated phospholipids (DSP), cholesterol (CHOL), and surfactant protein-A (SP-A) in human alveolar surfactant in response to acute exercise, and which were related to fitness, can be induced by training. Methodology: We examine the effect of 7 weeks' training on these major surfactant components, together with surfactant protein-B (SP-B), in bronchoalveolar lavage fluid harvested from 17 males, both at rest and after acute exercise. Fitness was assessed as workload/heart rate achieved during cycling for 30 min at 90% of theoretical maximal heart rate, and was increased in all subjects following training (mean increase 22.2 ± 3.91%; P = 0.001). Results: Training significantly increased the SP-A/DSP, SP-B/DSP, SP-A/CHOL and SP-A/SP-B ratios in whole surfactant harvested from subjects both at rest and immediately following exercise. Training also increased the SP-B/CHOL ratio at rest. Changes were particularly marked at rest in the SP-A/DSP, SP-A/CHOL, and SP-B/CHOL ratios in the tubular myelin-rich fraction, and after exercise in the SP-A/DSP, SP-A/CHOL, and SP-A/SP-B ratios in the tubular myelin-poor fraction. Conclusion: We conclude that training markedly alters the composition of alveolar surfactant both at rest and with exercise; the physiological significance of these changes remains to be determined. [source] National Health Service Corps Staffing and the Growth of the Local Rural Non-NHSC Primary Care Physician WorkforceTHE JOURNAL OF RURAL HEALTH, Issue 4 2006Donald E. Pathman MD ABSTRACT:,Context: Beyond providing temporary staffing, National Health Service Corps (NHSC) clinicians are believed by some observers to contribute to the long-term growth of the non-NHSC physician workforce of the communities where they serve; others worry that NHSC clinicians compete with and impede the supply of other local physicians. Purpose: To assess long-term changes in the non-NHSC primary care physician workforce of rural underserved counties that have received NHSC staffing support relative to workforce changes in underserved counties without NHSC support. Methods: Using data from the American Medical Association and NHSC, we compared changes from 1981 to 2001 in non-NHSC primary care physician to population ratios in 2 subsets of rural whole-county health professional shortage areas: (1) 141 counties staffed by NHSC physicians, nurse practitioners, and/or physician assistants during the early 1980s and for many of the years since and (2) all 142 rural health professional shortage area counties that had no NHSC clinicians from 1979 through 2001. Findings: From 1981 to 2001, counties staffed by NHSC clinicians experienced a mean increase of 1.4 non-NHSC primary care physicians per 10,000 population, compared to a smaller, 0.57 mean increase in counties without NHSC clinicians. The finding of greater non-NHSC primary care physician to population mean ratio increase in NHSC-supported counties remained significant after adjusting for baseline county demographics and health care resources (P < .001). The estimated number of "extra" non-NHSC physicians in NHSC-supported counties in 2001 attributable to the NHSC was 294 additional physicians for the 141 supported counties, or 2 extra physicians, on average, for each NHSC-supported county. Over the 20 years, more NHSC-supported counties saw their non-NHSC primary care workforces grow to more than 1 physician per 3,500 persons, but no more NHSC-supported than nonsupported counties lost their health professional shortage area designations.Conclusions: These data suggest that the NHSC contributed positively to the non-NHSC primary care physician workforce in the rural underserved counties where its clinicians worked during the 1980s and 1990s. [source] Intraoperative Assessment of an Implantable Electrode Array for Cavernous Nerve StimulationTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2008Arthur L. Burnett ABSTRACT Introduction., Erectile dysfunction remains a major functional complication of radical prostatectomy in the modern era despite surgical techniques to preserve the penile autonomic nerve supply. Aim., To develop and evaluate a neurostimulation system for cavernous nerve electrical stimulation for future use as a chronic implantation device that neurotrophically promotes erectile function recovery following radical prostatectomy. Method., After radical retropubic prostatectomy, the neurovascular bundle was stimulated using a temporarily placed electrode array of an implantable neurostimulation system (20 Hz frequency, 260 µ seconds pulse width, 5 mA,60 mA amplitude up to 10 minutes), and penile circumference increases were measured. Main Outcome Measure., Increase in penile circumference. Results., Among 12 men (mean age 60.3 years) enrolled in this study, 6 (50%) demonstrated measurable increases in penile circumference in response to cavernous nerve stimulation. Among these six men, the mean increase was 5.0 mm (range 1.6 mm to 7.0 mm). Temporary surgical placement of the device was done with relative ease, and there was no evidence of injury to the neurovascular bundle. Conclusions., A chronic implantable nerve stimulation system for cavernous nerve stimulation having possible neuromodulatory effects on the recovery of penile erections after radical prostatectomy is feasible. Burnett AL, Teloken PE, Briganti A, Whitehurst T, and Montorsi F. Intraoperative assessment of an implantable electrode array for cavernous nerve stimulation. J Sex Med 2008;5:1949,1954. [source] Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and PharmacokineticsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2008E. Van Gurp CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19+ B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4+ or CD8+ T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration. [source] Post-Traumatic Stress Disorder Symptomology Associated with Witnessing Unsuccessful Out-of-hospital Cardiopulmonary ResuscitationACADEMIC EMERGENCY MEDICINE, Issue 3 2009Scott Compton PhD Abstract Objectives:, The objective was to assess symptoms of post-traumatic stress disorder (PTSD) associated with witnessing unsuccessful out-of-hospital cardiopulmonary resuscitation (CPR) on a family member. Methods:, Adult family members of deceased, adult, nontraumatic out-of-hospital cardiac arrest victims who were transported to a large, Midwestern hospital were contacted by telephone beginning 1 month after the event. Subjects were dichotomized as to whether or not they were physically present during the patient's resuscitation. A structured interview obtained the patient's prearrest functioning, whether the family member witnessed or performed CPR, patient and family demographic data, key cardiac arrest events, and a measure of subject PTSD symptoms (PTSD Symptom Scale-Interview [PSS-I]). Results:, There were 34 witnesses and 20 nonwitnesses. Each group was similar in race, religion, age, gender, and relationship to the patient. Patients in each group were similar in prearrest functioning. Witnesses' total PTSD symptom scores were nearly two times higher than nonwitnesses (14.47 vs. 7.60, respectively; mean difference = 6.87, 95% confidence interval [CI] = 0.57 to 13.17). Two PSS-I subscales were higher for witnesses than nonwitnesses: Avoidance (5.41 vs. 2.25; mean difference = 3.16, 95% CI = 0.74 to 5.58) and Increased Arousal (4.26 vs. 2.20; mean difference = 2.06, 95% CI = 0.08 to 4.05), while Reexperiencing was not (4.79 vs. 3.15; mean difference = 1.64, 95% CI = ,0.62 to 3.91). Linear regression analysis indicated that witnessing CPR of a loved one was associated with a mean increase of nearly 12 points on the PSS-I after controlling for the possibility of other potentially influential events and characteristics. Results were similar when CPR providers (n = 6) were removed from the witness group. Conclusions:, Witnessing a failed CPR attempt of a loved one in an out-of-hospital location may be associated with displaying symptoms of PTSD in the early term of the bereavement period. While preliminary, these data suggest that the relationship exists even after controlling for other potential factors that may also affect the propensity for displaying such symptoms, such as the suddenness and location of the patient's cardiac arrest. [source] Folinic acid protects against suppression of growth by Methotrexate in miceBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2001M. Perwaiz Iqbal Abstract The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean±SD body weight 9.64±0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8±0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid. Copyright © 2001 John Wiley & Sons, Ltd. [source] Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Ruth Dixon WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes. , Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder. , Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients. WHAT THIS STUDY ADDS , This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines. , The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia's and Bazett's). , The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man. AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic,pharmacodynamic (PK,PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo ,7.48 ms, 90% CI ,10.49, ,4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK,PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50,200 mg b.d.) were not associated with QT prolongation in healthy subjects. [source] The effects of ziprasidone on steady-state lithium levels and renal clearance of lithiumBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2000G. Apseloff Aims, To assess the potential of ziprasidone to alter the renal clearance and steady-state serum levels of lithium. Methods, Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day,,1, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day,,1, given as two divided daily doses, on days 9,11 followed by 80 mg day,,1, given as two divided daily doses on days 12,15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium. Results, Ziprasidone administration was associated with a 0.07 mmol l,,1 (13%) mean increase in steady-state serum lithium levels compared with a mean increase of 0.06 mmol l,,1 (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h,,1 (5%) in the ziprasidone group and by 0.14 l h,,1 (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant. Conclusions, Ziprasidone does not alter steady-state serum lithium concentrations or renal clearance of lithium. [source] Valproic acid and phenobarbital blood levels during the first month of treatment with the ketogenic dietACTA NEUROLOGICA SCANDINAVICA, Issue 4 2010G. Coppola Coppola G, Verrotti A, D'Aniello A, Arcieri S, Operto FF, Della Corte R, Ammendola E, Pascotto A. Valproic acid and phenobarbital blood levels during the first month of treatment with the ketogenic diet. Acta Neurol Scand: 2010: 122: 303,307. © 2010 John Wiley & Sons A/S. Objective,,, The aim of this study was to assess how the ketogenic diet influences the blood levels of antiepileptic drugs in the first month of treatment in a pediatric population with drug-resistant epilepsy. Methods,,, The plasma concentrations of antiepileptic drugs were investigated in an open study on 36 consecutive children and adolescents (20 males), aged between 6 months and 16 years (mean age 4.7 years), who were put on the ketogenic diet because of medically refractory epilepsy. The plasma levels of antiepileptic drugs were determined 30 days and immediately before the diet and on days 8, 15, 22 and 29 after the start of the diet. The daily dose of each drug was not changed during the first month of treatment, while the daily dose of benzodiazepines was reduced by up to 30% if excessive sedation or drowsiness occurred. Results,,, While plasma concentrations of phenobarbital did not change in the first month on the ketogenic diet (mean increase of 2.3 mg/l ± 1.0), valproic acid showed a slight but not significant decrease (mean decresase of 6.7 mg/l ± 3.2), 2 weeks after the start of the diet. Conclusions,,, Adjustments in the daily dose of either drug before the start of the diet do not however appear to be justified. [source] Glossopharyngeal pistoning for lung insufflation in children with spinal muscular atrophy type IIACTA PAEDIATRICA, Issue 8 2009Malin Nygren-Bonnier Abstract Aim:, To evaluate whether children with spinal muscular atrophy (SMA) type II were able to learn glossopharyngeal pistoning for lung insufflation (GI), and to evaluate the effects of GI on pulmonary function and chest expansion. Methods:, Eleven children with SMA type II were recruited. They performed 10 cycles of GI, four times per week, for 8 weeks. Lung function and chest expansion were measured before and after the 8-week period. Results:, Five of the 11 children learned the technique. The median GI volume was 0.28 (range 0.15,0.98) L. Four of the children who completed the study showed a mean increase in inspiratory vital capacity (IVC) of 0.13 L (95% confidence interval (CI) 0.03,0.23) and peak expiratory flow (PEF) of 116 L/min (95% CI 60,173). They also had an increased chest expansion with GI at the level of the xiphoid process of 1.50 cm (95% CI 0.16,2.84) and at the level of the fourth costa of 1.79 cm (95% CI 0.85,2.73). The children reported temporary symptoms of dizziness and tension in the chest. Conclusion:, Five of the 11 children were able to learn the technique of GI and for the four who fulfilled the training, it had positive effects on IVC, PEF and chest expansion. GI did not cause major discomfort. [source] ,2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and childrenCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2004S. W. Turner Summary Background We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function. Objective The current study aimed to determine whether the Arg16Gly polymorphism of the ,2 adrenoceptor (,2AR) gene was important to this relationship. Methods A cohort that initially numbered 253 individuals underwent assessments of AR and lung function aged 1 month, 6 and 11 years; genotyping for polymorphisms of the ,2AR was performed. Results At 1 month of age, the genotype homozygous Arg16 (n=24) was associated with a mean increase in log dose,response slope (AR) of 0.27 [95% confidence interval (CI) 0.07, 0.49] compared with the genotype homozygous Gly16 (n=58), P=0.01. At 11 years of age, the genotype homozygous Arg16 (n=35) was associated with a mean reduction in the percentage of forced expiratory volume in 1 s of 5.3% [95% CI 0.3, 10.2] compared with the genotype homozygous Gly16 (n=65), P=0.03. There was no association between the Arg16Gly polymorphism and atopy or diagnosed asthma. However, nine of 69 individuals with the genotype homozygous Gly16 were admitted to hospital with asthma compared with five out of 111 individuals with the remaining genotypes (P<0.05). Conclusion The Arg16Gly polymorphism may be important to the association between increased AR in infancy and reduced lung function in childhood and may also be a determinant of asthma severity in children but not asthma per se. [source] | |||||||||||||||||||||||||||||||