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PubMed2000

Estimates of genetic parameters for hip and elbow dysplasia in Finnish Rottweilers.

Data from 2,764 Rottweiler dogs born from 1987 to 1996 were analyzed with a Restricted Maximum Likelihood procedure using a mixed linear animal model to obtain variance component estimates for hip and elbow dysplasia. The data included 2,764 hip dysplasia and 2,278 elbow dysplasia records. Hip joints were scored as normal (0), borderline (1), slight (2), moderate (3), and severe (4, 4.5, and 5) hip dysplasia. Elbow joints were graded normal or borderline (0), slight (1), moderate (2), and severe (3) elbow dysplasia. The mean for the hip scores was 1.07 and for the elbow scores .60. Environmental effects influencing hip dysplasia were age, birth year, birth year x season interaction, and experience of the veterinarian responsible for x-raying the dog. For elbow dysplasia, statistically significant effects were age, birth year, sex of the dog, and panelist responsible for each screening. Estimates of heritability for hip and elbow dysplasia were .58 +/- .04 and .31 +/- .04, respectively, with a genetic correlation of .37 +/- .08 between the traits. Genetic improvement of almost one genetic standard deviation was observed in both traits during the 10 yr covered by the data.

Age Factors↗
PubMed2006

Factors associated with ELISA scores for paratuberculosis in an Angus-Brahman multibreed herd of beef cattle.

Cow and calf genetic and environmental factors were evaluated for their association with ELISA scores for paratuberculosis in a multibreed population of beef cattle. The ELISA scores are a measure of the presence or absence of antibodies against Mycobacterium avium subsp. paratuberculosis in bovine serum. The linear mixed-model analysis used 352 ELISA scores from 238 cows: 51 Angus (A); 34 Brahman (B); 41 (3/4 A 1/4 B); 45 (1/2 A 1/2 B); 34 (1/4 A 3/4 B); and 33 Brangus (5/8 A 3/8 B). Cows were assumed to be unrelated. Year affected (P < 0.001) ELISA scores, but age of cow did not, which was expected to be significant because of the chronic progressive nature of this disease. Important regressions on fixed effects associated with cows were 1) a positive estimate of cow B breed effect (0.59 +/- 0.24; P < 0.017), indicating an upward trend of ELISA scores toward 100% B cows; 2) a negative estimate for weight change from before calving (late November) to the date of the blood sample in May (-0.0062 +/- 0.0019 score/kg; P < 0.002), indicating that poorer maintenance of cow weights was associated with higher ELISA scores; and 3) a positive estimate for days in lactation of cow on the date of the blood sample (0.0086 +/- 0.0034 score/d; P < 0.021), indicating the production of larger amounts of antibodies against Mycobacterium avium subsp. paratuberculosis as lactation progressed. Relevant regressions on fixed effects associated with calves were 1) calf birth weight (-0.022 +/- 0.010 score/kg; P < 0.035), and 2) calf gain from birth to the date of the cow blood sample (-0.0092 +/- 0.0027 score/kg; P < 0.001). These estimates indicate that cows that produced lighter calves at birth and/or calves with slower preweaning growth tended to have greater ELISA scores. Although the sensitivity (percentage of infected animals detected) of ELISA was only 50%, these results suggest that subclinical paratuberculosis may be negatively affecting cows and their offspring. Factors identified as associated with ELISA scores could help producers with culling decisions related to paratuberculosis control and eradication in beef cattle.

Animals↗
PubMed2006

Genetic variation of farrowing kinetics traits and their relationships with litter size and perinatal mortality in French Large White sows.

Genetic parameters of litter traits and their relationships with farrowing kinetics traits were estimated in a Large White population to examine the impact of selection for litter size on perinatal mortality and one of its main determinants, farrowing kinetics. Data were collected on 2,947 farrowings from 1,267 sows between 1996 and 2004. Litter traits included the number born in total (NBT), number born alive (NBA), and the number (NSB) and proportion (PSB) of stillborn piglets. Four farrowing kinetics traits were considered: farrowing duration (FD), birth interval (BI = FD/NBT), heterogeneity of birth intervals (SDNB = SD of the number of piglets born each one-half hour), and birth assistance (BA) during the farrowing process. Genetic parameters were estimated using restricted maximum likelihood methodology. All traits were analyzed using a mixed linear animal model including year x month and parity as fixed effects; the additive genetic value of each animal and the sow permanent environment were treated as random effects. To normalize their distribution, kinetics traits were Box-Cox-transformed. Low heritability estimates were obtained for litter size and mortality traits, which was in agreement with literature results (i.e., 0.10 +/- 0.02, 0.08 +/- 0.02, 0.19 +/- 0.02, and 0.14 +/- 0.02 for NBT, NBA, NSB, and PSB, respectively). Heritability values were also low for kinetics traits: 0.10 +/- 0.02, 0.08 +/- 0.02, 0.01 +/- 0.01, and 0.05 +/- 0.03 for FD, BI, SDNB, and BA, respectively. The genetic correlation between NBT and NBA was strongly positive (ra = 0.90). On both phenotypic and genetic scales, NBT was positively associated with stillbirth (ra = 0.45 +/- 0.11, rp = 0.38 for NSB; ra = 0.46 +/- 0.13, rp = 0.17 for PSB). Conversely, NBA had low correlations with SB and PSB. Number born in total was moderately correlated to FD (ra = 0.34 +/- 0.15) and BI (ra = -0.37 +/- 0.15). A stronger relationship was found between NBA and BI (ra = -0.49 +/- 0.13), whereas the relationship with FD was lower (ra = 0.16 +/- 0.17). Moreover, FD was strongly correlated with stillbirth (ra = 0.42 +/- 0.12 with NSB), whereas BI was nearly independent of stillbirth. Contrary to selection on NBT, selection on NBA appears to be a good way to limit the negative side effects on stillbirth. Moreover, selection on NBA would lead to a small increase in FD and a faster and more regular birth process than would be obtained by selecting on NBT.

Animals↗
PubMed2003

Heifer fertility in Norwegian dairy cattle: variance components and genetic change.

Variance components and genetic change were estimated for 56-d nonreturn rate in virgin heifers using first insemination records of a total of 1,632,961 Norwegian Dairy Cattle daughters of 2945 sires. Six univariate mixed linear sire models were compared. The heritabilities varied from 1.2% to 1.4%. All models gave favorable, although different, estimates of genetic change of 56-d nonreturn rate. The method used to validate the genetic trend did not detect bias in any of the models. Goodness-of-fit and predictive ability were used to further validate the models. Three models included service sire, but this effect had little influence on the results. Models treating the herd-year effects as random showed smaller prediction error and higher correlation between observed and predicted values than the models treating herd-year effect as fixed. To avoid confounding of environmental and genetic effects, the model including fixed effect of month-year was preferred over a model with only month of first insemination to estimate the genetic change. Female fertility has been successfully included in the total merit index of Norwegian Dairy Cattle for 20 yr. This has resulted in genetic improvement and the chosen model showed annual genetic change of 0.04% for 56-d nonreturn rate in heifers between 1979 and 2000.

Animals↗
PubMed2004

Genetic parameters for clinical mastitis, somatic cell score, and production in the first three lactations of Swedish holstein cows.

Using a mixed linear animal model, genetic parameters were estimated for clinical mastitis (MAST), lactation average somatic cell score (LSCS), and milk production traits in the first 3 lactations of more than 200,000 Swedish Holstein cows with first calving from 1995 to 2000. Heritability estimates for MAST (0.01 to 0.03) were distinctly lower than those for LSCS (0.10 to 0.14) and production traits (0.23 to 0.36). The genetic correlation between MAST and LSCS was high for all lactations (mean 0.70), implying that selection for low LSCS will reduce the incidence of mastitis. Undesirable genetic relationships with production were found for both MAST and LSCS with genetic correlations ranging from 0.01 to 0.45. This emphasizes the need for including udder health traits in the breeding goal. Genetic correlations across lactations for the same trait were positive and high for both MAST (>0.7), LSCS (>0.8), and production traits (>0.9), with the strongest correlations between second and third parity for all traits (>0.9 for udder health traits and close to unity for production traits).

Analysis of Variance↗
PubMed2007

Genetic analysis of postpartum measures of luteal activity in dairy cows.

The objective of this study was to estimate genetic parameters for measures of luteal activity during the first 60 d postpartum. Analyses were made with different sampling intervals to investigate the possibility of combining progesterone measurement with routinely performed milk recording. Progesterone level in milk as an indicator of female fertility when selecting sires in a progeny-testing scheme was also examined. Data were collected from 1996 to 1999, and comprised 1,212 lactations from 1,080 British Holstein-Friesian cows at 8 commercial dairy farms in the United Kingdom. Milk samples for progesterone analysis were collected thrice weekly. Mixed linear animal models were used to analyze the data. Heritability for the percentage of samples with luteal activity during the first 60 d postpartum (PLA) was 0.30 and decreased with more infrequent sampling to 0.25, 0.20, and 0.14 for weekly, twice-monthly, and monthly sampling, respectively. Measures of PLA had a high negative genetic correlation with prolonged anovulation (-0.53 for monthly sampling, < -0.87 otherwise) and a moderate positive genetic correlation with persistent corpus luteum in the first estrus cycle (>0.65 if at least twice-monthly sampling). Genetic correlations with interval from calving to commencement of luteal activity were close to -1 for all PLA measurements and the selection index calculations showed that monthly progesterone sampling could be used with high accuracy (0.80 with 50 daughters per bull) to predict breeding values for commencement of luteal activity. Progesterone analysis at the time of regular milk recording could thereby be used to select for an early interval from calving to commencement of luteal activity and, at the same time, a decreased frequency of prolonged anovulation during the postpartum period.

Animals↗
PubMed1999

Effect of milk protein genotypes on milk protein composition and its genetic parameter estimates.

The effects of kappa-casein (CN) and beta-lactoglobulin (LG) genotypes on milk protein concentration and composition were estimated for the US Holstein-Friesian population using a single-trait, mixed, linear animal model on 592 individual milk samples from 233 cows. Both milk protein genotypes had no statistically significant effect on the total milk protein concentration; however, substitution of the kappa-CN A allele additively increased the proportion of kappa-CN, and substitution of the beta-LG B allele additively increased the proportion of beta-LG in total milk protein. In response, proportions of the other milk proteins, mainly alpha S1-CN, were decreased. For proportions of alpha S1-CN, kappa-CN, and beta-LG in total milk protein, kappa-CN and beta-LG genotypes explain more than 50 and 25% of the heritability and repeatability estimates, respectively. We concluded that kappa-CN and beta-LG genotypes affect the phenotypic and genetic variation of milk protein composition but do not significantly affect milk protein concentration. A possible explanation for our conclusion is that altered gene sequences in the promoter region of kappa-CN B and beta-LG A, linked closely to the respective genotypes, favor the transcription or translation of their own protein at the expense of the synthesis of other milk proteins, in particular of alpha S1-CN.

Alleles↗
PubMed2005

Long-term maintenance therapy with quetiapine versus haloperidol decanoate in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: To compare the long-term efficacy and tolerability of oral quetiapine with those of intramuscular haloperidol. METHOD: Patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder requiring long-term antipsychotic treatment were randomly assigned to open-label oral quetiapine or intramuscular haloperidol decanoate for 48 weeks. Clinicians were instructed to target dosing at 500 mg/day of quetiapine or 200 mg of haloperidol decanoate every 4 weeks. The Positive and Negative Syndrome Scale was used to assess efficacy; the Simpson-Angus Scale and the Barnes Akathisia Scale were used to assess safety and tolerability. For statistical analyses, a general linear mixed-model repeated-measures analysis of covariance was used, with change scores for dependent variables computed with the baseline score as covariate. Data were collected from 1998 to 2001. RESULTS: Thirty-five patients were enrolled, but 6 did not participate after being informed of their treatment assignment; 4 of the 6 withdrawals were assigned to haloperidol decanoate. Mean doses at week 48 were 493 mg/day of quetiapine (N = 16) and 170 mg/28 days of haloperidol decanoate (N = 9). Survival analysis showed no between-group differences in estimates of the number of patients remaining exacerbation-free over time. Both drugs were efficacious, but quetiapine was significantly better than haloperidol decanoate in controlling negative symptoms (p < .05). The incidence of extrapyramidal symptoms was low in both groups; patients receiving quetiapine showed significantly greater improvement in rigidity and akathisia (p < .05). CONCLUSION: Oral quetiapine was as efficacious as intramuscular haloperidol in preventing symptom exacerbation over 48 weeks in patients with schizophrenia or schizoaffective disorder, with fewer extrapyramidal symptoms, especially rigidity and akathisia. Quetiapine was more efficacious than haloperidol decanoate in treating negative symptoms.

Administration, Oral↗
PubMed2001

Effect of soymilk consumption on serum estrogen and androgen concentrations in Japanese men.

Soy consumption has been associated with a reduced risk of prostate cancer. The mechanism for this association may involve the effect of soy on the endocrine system. We conducted a randomized dietary intervention study to determine the effects of soy consumption on serum levels of steroid hormones in men. Thirty-five men were randomly assigned to either a soymilk-supplemented group or a control group. The men in the soy-supplemented group were asked to consume 400 ml of soymilk daily for 8 weeks. The men in the control group maintained their usual diet. Blood samples were obtained just before the initiation of the dietary period and thereafter every two weeks for 12 weeks. Changes in hormone concentrations were analyzed and compared between the two groups using the mixed linear regression model against weeks from the start of the dietary period. The mean (SD) soymilk intake estimated from dietary records during the dietary study period was 342.9 (SD, 74.2) ml in the soymilk-supplemented group. There was a significant difference between the two groups in terms of changes in serum estrone concentrations, which tended to decrease in the soy-supplemented group and increase in the control group over time. None of the other hormones measured (estradiol, total and free-testosterone, or sex hormone-binding globulin) showed any statistical difference between the two groups in terms of patterns of change. The results of the study indicate that soymilk consumption may modify circulating estrone concentrations in men.

Adult↗
PubMed2003

Development of hand function among children with cerebral palsy: growth curve analysis for ages 16 to 70 months.

This study documents the development of hand and upper-extremity function in young children who have cerebral palsy (CP) with upper-extremity involvement using longitudinal data. Assessments of hand function and the quality of upper-extremity movement were conducted on 29 males and 22 females (mean age 36.2 months, SD 10.6; age range 16 to 60 months at baseline) and on four other occasions over 10 months. Linear mixed effects modeling was used to estimate average developmental curves and the degree of individual differences in the patterns of development which were conditional on the body-site distribution of CP and severity of impairments. Results indicate that hand function in this clinical population develops differently from overall upper-extremity skills with declines in function in upper-extremity skills being more common and pronounced among older children. However, there is substantial interindividual variation. Distribution of CP and severity of impairments were significant predictors of development. Results are discussed in terms of their clinical implications.

Age Factors↗
PubMed2004

Effects of a 2-year randomized soy intervention on sex hormone levels in premenopausal women.

OBJECTIVE: Several epidemiologic studies have described protective effects of soy consumption against breast cancer. The goal of this trial among premenopausal women was to examine the effect of soy foods on menstrual cycle length and circulating sex hormone levels. METHODS: This 2-year dietary intervention randomized 220 healthy premenopausal women. The intervention group consumed two daily servings of soy foods containing approximately 50 mg of isoflavones; the control group maintained their regular diet. Five blood samples (obtained in months 0, 3, 6, 12, and 24) were taken 5 days after ovulation as determined by an ovulation kit. The serum samples were analyzed for estrone, estradiol, sex hormone binding globulin, androstenedione, and progesterone by immunoassay. RESULTS: At baseline, both groups had similar demographic, anthropometric, and nutritional characteristics. The dropout rates of 15.6% (17 of 109) in the intervention group and 12.6% (14 of 111) in the control group did not differ significantly. According to soy intake logs, 24-hour recalls, and urinary isoflavone excretion, the women closely adhered to the study regimen. Menstrual cycles became slightly shorter in both groups but did not differ by group. Mixed general linear models indicated no significant intervention effect on any of the serum hormones. However, androstenedione and progesterone decreased significantly over time in both groups. CONCLUSIONS: The results of this study suggest that the preventive effects of soy on breast cancer risk in premenopausal women may not be mediated by circulating sex hormone levels. Different mechanisms of actions or effects of exposure earlier in life are alternate hypotheses that require further investigation.

Adult↗
PubMed2005

Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study.

OBJECTIVE: The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz. METHODS: Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated. RESULTS: Clearance of nevirapine in the induction phase (<14 days) and at steady state (>28 days) were 2.02 I/h and 2.81 I/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h(-1), respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 4181 and 0.287 h(-1), respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population. CONCLUSIONS: The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz.

Adult↗
PubMed2005

Meta-analysis: a unifying meta-likelihood approach framing unobserved heterogeneity, study covariates, publication bias, and study quality.

OBJECTIVES: This contribution provides a unifying concept for meta-analysis integrating the handling of unobserved heterogeneity, study covariates, publication bias and study quality. It is important to consider these issues simultaneously to avoid the occurrence of artifacts, and a method for doing so is suggested here. METHODS: The approach is based upon the meta-likelihood in combination with a general linear nonparametric mixed model, which lays the ground for all inferential conclusions suggested here. RESULTS: The concept is illustrated at hand of a meta-analysis investigating the relationship of hormone replacement therapy and breast cancer. The phenomenon of interest has been investigated in many studies for a considerable time and different results were reported. In 1992 a meta-analysis by Sillero-Arenas et al. concluded a small, but significant overall effect of 1.06 on the relative risk scale. Using the meta-likelihood approach it is demonstrated here that this meta-analysis is due to considerable unobserved heterogeneity. Furthermore, it is shown that new methods are available to model this heterogeneity successfully. It is argued further to include available study covariates to explain this heterogeneity in the meta-analysis at hand. CONCLUSIONS: The topic of HRT and breast cancer has again very recently become an issue of public debate, when results of a large trial investigating the health effects of hormone replacement therapy were published indicating an increased risk for breast cancer (risk ratio of 1.26). Using an adequate regression model in the previously published meta-analysis an adjusted estimate of effect of 1.14 can be given which is considerably higher than the one published in the meta-analysis of Sillero-Arenas et al. In summary, it is hoped that the method suggested here contributes further to a good meta-analytic practice in public health and clinical disciplines.

Confidence Intervals↗
PubMedDate not supplied

Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography.

BACKGROUND: To study the longitudinal variations of plasma B-type natriuretic peptide (BNP) with reference to left ventricular ejection fraction (LVEF) during and after chemotherapy with cardiotoxic drugs. PATIENTS AND METHODS: We prospectively measured plasma BNP using an immunoradiometric assay in 12 anthracycline-treated breast cancer patients monitored for a mean time of 880+/-293 days (pilot group). Prior to each cycle and throughout the following year, LVEF and cardiac output were measured by radionuclide ventriculography. Anthracycline pharmacokinetics was studied during the first cycle. Relationships between serial observations were analysed with the general linear mixed effects model. Identical methods were subsequently applied to a test group of 67 anthracycline or trastuzumab-treated patients. RESULTS: Five out of 70 (6.33%) patients developed anthracycline-induced heart failure. BNP concentrations were found to be positively correlated to anthracycline cumulative dose and negatively to LVEF values. Variables entering the mixed models were cumulative anthracycline dose, time and cardiac output. CONCLUSION: An infra-clinical cardiotoxicity of anthracyclines as defined by BNP elevation is frequent but reversible. Patients who developed heart failure showed a continuous BNP increase and concentrations over 100 ng/ml.

Anthracyclines↗
PubMed2006

Promoting repeat tobacco dependence treatment: are relapsed smokers interested?

BACKGROUND: Promotion of repeat tobacco dependence treatment among relapsed smokers interested in "recycling" (repeat quit attempt) may be a promising approach to increase quit rates. OBJECTIVE: To report relapsed smokers' interest in recycling and their treatment preferences. STUDY DESIGN: Descriptive analysis of a population of relapsed smokers who were randomized to receive a recycling intervention strategy to increase tobacco dependence treatment rates, as part of a randomized controlled trial at 5 Veterans Affairs medical centers. METHODS: Individuals prescribed a tobacco dependence medication in 2002 were eligible and were identified from the Department of Veterans Affairs Pharmacy Benefits Management database. Intervention group participants (n = 951) were contacted for a standardized telephone interview approximately 6 months after the prescription fill date to assess smoking status, interest in recycling, and treatment preferences. Bivariate analyses and generalized linear mixed-model regressions were used to describe outcomes. RESULTS: The response rate to the intervention telephone call was 62% (586/951), at which 61% (357/586) of respondents had relapsed. Almost two thirds of relapsed smokers were interested in recycling within 30 days. Of these, 91% wanted behavioral or pharmacologic smoking cessation treatment, and 64% wanted behavioral and pharmacologic treatment. In multivariate analyses, independent predictors of interest in recycling within 30 days included black race, lower smoking level, and greater number of smoking-related medical conditions. CONCLUSION: Most smokers who attempt to quit but relapse want to quit again right away, and most are interested in receiving behavioral and pharmacologic treatment.

Adult↗
PubMed2006

Percutaneous vertebroplasty in patients with intractable pain from osteoporotic or metastatic fractures: A prospective study using quality-of-life assessment.

PURPOSE: Percutaneous vertebroplasty (PVP) is a minimally invasive outpatient procedure whereby vertebral compression fractures are stabilized by the injection of bone cement, or polymethyl methacrylate (PMMA). Rapid partial or complete pain relief can usually be achieved through this procedure. We prospectively evaluate the efficacy of PVP in the relief of pain and improvement in quality of life of patients with intractable pain from osteoporotic and metastatic fractures. MATERIALS AND METHODS: Patients with intractable pain from vertebral metastases (many resistant to palliative radiation therapy) and patients with intractable painful osteoporotic fractures were treated with parapedicular or transpedicular injection of PMMA. Plane X-rays, computed tomography (CT) scan, and magnetic resonance imaging (MRI) scan were performed on all patients. With a reflex hammer, percussion pain was correlated to the imaging abnormalities. The preplanning CT scan was used to calculate the exact entry point and angle of the bone-biopsy needle. All patients were assessed before and after the procedure for quality of life and amount of pain. The following measures were used: 1) the Edmonton Symptom Assessment System (ESAS), for global pain, nausea, tiredness, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath; 2) a site-specific pain score (SSPS); 3) the amount of analgesic intake in morphine equivalents in the last 24 hours; and 4) the Townsend Functional Assessment Scale (TFAS), ascertaining mobility. A postprocedural CT scan was performed the same day on all patients. Follow-up assessment consisted of a phone call at Days 1, 2, and 4 and Weeks 1, 2, 4, 8, and 12. Patients with recurrent back pain or complications were followed in the bone metastases clinic. RESULTS: Thirty patients (19 women, 11 men) were evaluated. Their median age was 68 years (range 31 to 87 years). Thirty procedures (n = 30) at 45 vertebral levels were performed; 13 were for pathologic fractures, and 17 were for osteoporotic fractures. SSPS showed a decrease of 2 or more levels in 88.5% of patients at 12-week follow-up. The mean SSPS with movement was 8.7 preprocedure and 1.8 postprocedure (P < 0.0001). Also, there was significant improvement in all 9 ESAS domains (P < 0.0004). The ingestion of analgesics in morphine equivalents showed a trend toward reduction post-PVP (P < 0.0599). When the patients with pathologic fractures were separated out, the reduction in ingestion of analgesics was significant (P < 0.0008). The TFAS demonstrated significant improvement in patient mobility and function. Extravertebral extravasation of cement was noted in 55.6% of the levels. We used a general linear mixed-model repeated-measures analysis of variance to analyze the data. CONCLUSIONS: PVP in osteoporotic and metastatic fractures significantly improved many patients' global quality-of-life scores and function by markedly decreasing their back pain and reducing their intake of pain medications. The procedure is safe, with no serious complications noted in our study.

Adult↗
PubMed1995

Pharmacokinetic development of quinolone antibiotics.

A prerequisite for the pharmacokinetic development of quinolone antibiotics is a sensitive and accurate method for the quantification of the drug in biological fluids. Both, a drug specific (e.g. HPLC) and a drug non-specific but effect related assay (e.g. bioassay) should be used during early clinical development to detect major active metabolites. The basic pharmacokinetic behavior of the drug is investigated as part of the early phase I program, where single and multiple ascending dose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studies are performed to describe the absolute bioavailability, dose proportionality, pharmacokinetics in young and elderly, male and female volunteers. The suitability of the clinical dosage from must be evaluated in comparison to an oral solution and by quantification of the effect of food on bioavailability. The characterization of the absorption in different parts of the gastrointestinal tract may be valuable for dosage form optimization. In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine, theophylline and warfarin has to be evaluated. This can be done by in vitro and in vivo preclinical experiments, before formal clinical-pharmacology studies are performed. Further pharmacokinetic characterization (e.g. studies in special subpopulation, extended interaction studies, total recovery using 14C-labelled compound, blister fluid penetration) will be done parallel to the phase II/III development program. During these efficacy and safety trials blood samples should be obtained and PK-parameters can be calculated using sparse data analysis methods like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.

4-Quinolones↗
PubMed1997

[Longitudinal study of cognitive aging in non-demented elderly subjects].

BACKGROUND: The aim of this study is to describe and compare the course of the score of two psychometric tests during a five-year period in a cohort of non-demented elderly subjects. We studied a timed test of simple logical reasoning (the Digit Symbol Substitution Test of Wechsler) and a test of short-term visual memory (the Benton Visual Retention Test). Then we compared the course of these two tests with the course of the Mini-Mental State Examination (MMSE) which evaluates the general cognitive functioning and which has been studied previously. METHODS: The sample consisted of 2792 subjects aged 65 years and older living at home at the beginning of the study (the Paquid cohort in Gironde). Subjects were interviewed at home by a psychologist at the baseline visit and one year, 3 years and 5 years after the baseline visit. All subjects who were diagnosed as demented at any of the four examinations were excluded from this study (218 subjects). The statistical analysis was performed using a mixed effects linear model and an additional analysis was performed to study sensitivity of the results to hypotheses regarding missing data mechanism. RESULTS: Among the three tests studied, only the score of the Digit Symbol Substitution Test declined over the five years (by -1.15 points for subjects aged 65 years to -3.4 points for subjects aged 85 years). We observed an improvement of the score between the first two visits which is sharper for the test of Benton and the MMSE than for the Digit Symbol Substitution Test and which reflects a stress effect at the baseline visit or a learning effect at the second visit. The difference between the cross-sectional measure of age effect and the longitudinal measure of time effect suggests either a cohort effect or a practice effect which would persist during the five years. CONCLUSIONS: The cognitive change in a non-demented elderly population is different according to the psychometric test used. Among the three tests studied, only the score of the Digit Symbol Substitution Test which has a a speed component declined over the five years.

Age Factors↗