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PubMed2006

Sleep in healthy seniors: a diary study of the relation between bedtime and the amount of sleep obtained.

The aim of this study was to determine whether naturally occurring inter-individual and intra-individual differences in bedtime selection in the elderly might be lawfully related to the amount of sleep that is obtained. A total of 128 seniors (63f, 65m) aged 70-92 years each provided a week of sleep diary data yielding a total of 896 subject-nights for analysis. From each subject-night the diary was used to derive measures of time in bed (TIB) and total sleep time (TST). These measures were used as dependent variables in mixed-effect linear models (nights nested within subjects) with the independent variable being bedtime for that subject-night, arbitrarily expressed as minutes since 19:00 hours. Although there were strong inter-individual and intra-individual differences, for both genders, bedtime had a statistically significant effect (P < 0.001) on both TIB and TST. We observed that later bedtimes were associated with less time in bed and less time asleep. On average between 7 and 8 min of less TIB and TST were associated with each 10-min delay in bedtime from 19:00 hours. These results are interpreted in terms of increases in sleep being derived from living in a better harmony with an earlier peaking circadian pacemaker characteristic of older age, although other possible mechanisms are also considered (e.g. age-dependent alterations in phase angle and homeostatic sleep need).

Aged↗

PubMed2005

Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana).

We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.

Administration, Oral↗

PubMed2005

Population pharmacokinetics of levocetirizine in very young children: the pediatricians' perspective.

Developmental changes during infancy and childhood can affect drug pharmacokinetics (PK), i.e., absorption, distribution, metabolism, and renal excretion. This, in turn, influences optimal dosing, efficacy, and safety. To date, of the 40 H1-antihistamines available worldwide, only 11 have been studied in children using a PK approach. Here, we provide the pediatricians' perspective on the population PK of levocetirizine, the pharmacologically active enantiomer of cetirizine, in very young children who received oral cetirizine, and describe the factors that influence levocetirizine PK in this population. In a prospective, randomized, double-blind, parallel-group, placebo-controlled study, very young children received oral cetirizine 0.25 mg/kg twice daily for 18 months. Plasma levocetirizine concentrations were measured in timed, sparse blood samples collected at steady-state (3, 12 and 18 months after commencement of treatment) for the purpose of monitoring safety, and levocetirizine population, PK parameters were derived by using non-linear mixed effects modeling. In 343 children (age 14-46 months, body weight 8.2-20.5 kg), a total of 943 blood samples were obtained. Compliance with cetirizine dosing was documented. The population PK model used predicted that with increasing body weight, levocetirizine oral clearance would increase by 0.044 l/h/kg, and levocetirizine volume of distribution would increase by 0.639 l/kg. Levocetirizine PK were not influenced by eosinophilia, sensitization to allergens, allergic disease, gastroenteritis/diarrhea, or concomitant ingestion of other medications. This population PK model predicts that in very young children, the oral clearance of levocetirizine will be rapid and will increase as body weight and age increase, therefore, levocetirizine dosing should be based on body weight and age in this population. Compared with older patients, on a mg/kg basis, relatively higher doses may be needed, and twice-daily dosing may be necessary, as previously reported for the related racemic H1-antihistamine cetirizine.

Administration, Oral↗

PubMed2003

Effects of topical administration of 1% brinzolamide on normal cat eyes.

OBJECTIVE: To evaluate the effect of short-term daily topical administration of 1% brinzolamide on the intraocular pressure (IOP) of healthy domestic cats with normotensive eyes and to assess the potential for negative side effects of drug administration. ANIMALS: Twelve privately owned adult domestic cats without physical or ocular abnormalities. PROCEDURE: Normal variation in IOP was determined on day 1. Cats were then treated on days 2-8 with a topical placebo (artificial tear solution) OU q 12 h. On days 9-15 the cats were treated q 12 h with 1% brinzolamide in one randomly selected eye and the placebo in the contralateral eye. All medications (drug and placebo) were administered twice daily at 7 a.m. and 7 p.m. On days 16-22 the cats received no topical medications. IOP, horizontal pupil size in mm and assessment of conjunctival hyperemia were noted OU on days 1, 8, 15 and 22 at 5 time points (9 a.m., 11 a.m., 1 p.m., 3 p.m. and 5 p.m.). Mixed linear regression models were used to compare the IOP of each eye at all time periods for each cat, controlling for age and weight. RESULTS: Mean IOP was not significantly altered in any eye at any time point during the treatment period compared with pretreatment, baseline, or follow-up evaluations. Conjunctival hyperemia and miosis were not detected in either eye at any time point. Conclusions and clinical relevance Short-term q 12 h administration of 1% brinzolamide did not significantly reduce IOP in this small sample population of normotensive cats under these study conditions. No clinically relevant side effects were noted with brinzolamide administration.

Administration, Topical↗

PubMed2004

Factors associated with urea reduction ratio in acute renal failure.

Prescription and delivery of hemodialysis (HD) in acute renal failure (ARF) may be affected by patient-related factors such as hemodynamic instability, catabolism, variable extracellular fluid volume, and coagulation disturbances. This study was undertaken in a cohort of patients with ARF requiring HD, to quantify patient- and dialysis-related variables that influence dialysis delivery. The urea reduction ratio (URR) was calculated for each HD session. Patient-related variables included age, gender, weight, mean arterial pressure, and Acute Physiological and Chronic Health Evaluation (APACHE) II and Multiple Organ Failure (MOF) scores. Dialysis-related variables were dialyzer characteristics (membrane type, surface area, KoA, and K(UF)), blood flow rate (Qb), session length, anticoagulant use, vascular access, and ultrafiltration volume. The analysis of factors associated with URR was performed using mixed linear statistical models. The cohort consisted of 81 adult patients with ARF who underwent 419 consecutive dialysis sessions. Mean (+/- SD) age was 60 +/- 18 years; 57% were male. At dialysis initiation, APACHE II score was 23 +/- 8 and MOF score 2 +/- 1. The number of HD treatments averaged 5.5 +/- 6.1/patient and 0.8 +/- 0.2/patient/day, mean URR was 54 +/- 15%, and session length 3.2 +/- 1.1 h; 58% used a femoral venous catheter, and 92% polysulfone dialyzers. Among patient-related variables, the only independent predictor of delivered dose of dialysis, as measured by URR was the predialysis weight (P < 0.01). Among the dialysis-related variables, treatment time (P < 0.01), dialyzer surface area (P < 0.01), dialyzer K(UF) (P = 0.04), blood flow rate (P < 0.01), and the use of a femoral venous catheter (P < 0.01) were also independently associated with URR. An interaction between vascular access site and blood flow rate was also found to be significant (P < 0.01). This study underscores the importance of the dialysis prescription parameters and vascular access site in influencing the dialysis dose in critically ill patients, and argues against the importance of patient-related characteristics such as disease severity.

APACHE↗

PubMedDate not supplied

Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse.

OBJECTIVE: To determine radiocarpal (RC) joint synovial fluid and plasma ceftiofur concentrations after regional intravenous perfusion (RIP) and systemic intravenous (IV) administration. STUDY DESIGN: Experimental cross-over study. ANIMALS: Five normal adult horses. METHODS: One RC joint was randomly selected for RIP and the contralateral RC joint was sampled to determine intrasynovial ceftiofur concentrations after IV administration. Wash-out between IV and RIP was > or = 14 days. After surgical introduction of an intraarticular catheter, ceftiofur (2 g) was administered under general anesthesia either IV or by RIP after tourniquet application. Plasma and synovial fluid were collected over 24 hours. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection and the results were statistically analyzed using a linear mixed effect model. RESULTS: Mean synovial fluid ceftiofur concentrations were consistently higher after RIP than after IV administration and were > 1 mug/mL (minimal inhibitory concentration [MIC] for common pathogens) for >24 hours. Mean synovial fluid peak concentration of ceftiofur after RIP and IV administration was 392.7+/-103.29 microg/mL at 0.5 hours postinjection (HPI) and 2.72+/-0.31 mug/mL at 1 HPI, respectively. Large variations in synovial fluid and plasma ceftiofur concentrations were observed between horses regardless of administration technique. RIP did not cause adverse effects. CONCLUSIONS: Under the present experimental conditions RIP with ceftiofur (2 g) induced significantly higher intraarticular antibiotic concentrations in the RC joint in comparison with IV administration. Moreover, after RIP, synovial fluid ceftiofur concentrations remain above the MIC for common pathogens (1 microg/mL) for > 24 hours. No adverse effects from the technique or the antibiotic were observed. CLINICAL RELEVANCE: RIP with high doses of ceftiofur may be a beneficial adjunctive therapy when treating equine synovial infections which are caused by cephalosporin susceptible microorganisms.

Animals↗

PubMed2006

Associations between canine juvenile weight gain and coxofemoral joint laxity at 16 weeks of age.

OBJECTIVE: Evaluation of the relationship between canine weight gain from 6 to 15 weeks of age and passive coxofemoral joint (CFJ) laxity at 16 weeks of age. STUDY DESIGN: Longitudinal cohort study. ANIMALS: Full- or half-sibling hounds (n = 56). METHODS: Hounds were weighed weekly from 6 to 15 weeks of age. Individual average daily gain (ADG) was calculated for each week (weekly) and for the study (overall). PennHIP distraction index (DI) was determined for each CFJ at 16 weeks. Mixed effects linear models were evaluated for associations of DI (highest and mean) with 15-week weight and ADGs (actual or normalized). Left and right DIs were compared with a Student's paired t-test. Significance was set at P<.05. Trends were considered at P<.10. RESULTS: Mean (+/-SD) 16-week DI score and 15-week weight was 0.67 +/- 0.16 and 12.5 +/- 1.8 kg, respectively. Within animal left and right DIs were not significantly different. There were no significant associations between DI and any of the weight gains evaluated. There was a trend for a negative relationship between normalized 14-week ADG and DI in one statistical model. CONCLUSIONS: Weight gain from 6 to 15 weeks of age was unrelated to 16-week PennHIP DI in a homogenous canine population with moderate-to-severe CFJ joint laxity. CLINICAL RELEVANCE: Based on our results, ad libitum feeding between 6 and 15 weeks of age does not appear to have an adverse impact on joint laxity at 16 weeks of age as measured by the PennHIP DI.

Animal Feed↗

PubMed2005

Assessing the effectiveness of whole blood-derived platelets stored as a pool: a randomized block noninferiority trial.

BACKGROUND: Prestorage pooling of whole blood-derived platelets (PLTs) would simplify bacterial detection. This study evaluated the in vivo effect of the prestorage pooling of PLTs stored for up to 5 days, by assessing the corrected count increment (CCI) 18 to 24 hours after transfusion of the product. STUDY DESIGN AND METHODS: A randomized block noninferiority design was used. Eligible patients had chemotherapy-induced thrombocytopenia and were considered likely to need at least six PLT transfusions. For every block of two transfusion events, one consisted of PLTs stored individually and then pooled before transfusion, and the other was a product pooled before storage. The primary outcome was categorized as a successful (>4.5) or unsuccessful (<or=4.5) 18- to 24-hour posttransfusion CCI analyzed with a matched pair score test. A mixed-effect linear model estimated the mean difference in CCI between the two types of storage. RESULTS: Twenty-three eligible patients received a total of 189 PLT transfusions. The median number of PLT transfusions was 7 (range, 0-27). Eighty-five complete transfusion pairs were used in the primary analysis. The proportions of transfusions leading to a CCI of greater than 4.5 was identical for both routine and PLTs pooled before storage (45/85=52.9%; relative risk, 1.00; lower limit of the one-sided 95% confidence interval [CI], 0.83). The estimate of the mean difference in CCI between pooled and routine storage (pooled-routine) was -0.45 (95% CI, -2.23 to 1.33; p=0.63). CONCLUSION: These results provide evidence that storage of PLTs as a pool for up to 5 days results in posttransfusion CCIs that are not inferior to PLTs stored individually.

Adult↗

PubMed1999

Effect of inhaled beta 2 adrenoceptor agonist, albuterol sulphate, on performance of horses.

This study was designed to test the hypothesis that a specific beta 2 adrenergic receptor agonist, albuterol sulphate, when delivered by metered-dose inhaler (MDI) would affect the performance of Thoroughbred horses during incremental exercise testing. Six conditioned Thoroughbred horses were randomly assigned to one of 2 treatment groups: Group 1 horses received placebo and Group 2 received albuterol. Each horse received both treatments in a crossover design with a 3 week interval between trials. Horses inspired albuterol (900 micrograms) or placebo over a 5 min period followed by an incremental, peak oxygen consumption (VO2peak) exercise test. Facial arterial blood gases (PaO2, PaCO2), pHa, temperature, haemoximetry (O2Hb, COHb, MetHb, RHb) and electrolytes (Na+, K+, iCa2+, Cl-) were measured. Heart rate (HR), VO2peak, CO2 production (VCO2), plasma lactate, speed at failure, exercise duration, and urine levels of albuterol and metabolites (Alburine) were monitored. The Paratrend7 intravascular sensor provided continuous arterial blood gas data. Mixed effects linear modelling using generalised least-squares estimation was used to assess treatment and speed main effects interaction. Significant differences (P < 0.01) were found between placebo and albuterol-treated horses for total run time (mean +/- s.e. 405.8 +/- 8.8 vs. 430.5 +/- 6.7 s) and run time from completion of 8 m/s until fatigue (169.3 +/- 8.6 vs. 187.3 +/- 6.7 s), as well as VO2peak (121.7 +/- 3.7 vs. 130.3 +/- 3.8 ml/kg/min), respectively. In conclusion, inhaled albuterol sulphate has a small but significant effect on the performance of fit Thoroughbred horses during incremental, VO2peak exercise testing.

Administration, Inhalation↗

PubMed1997

Performance over time of adult patients using the Ineraid or nucleus cochlear implant.

This study examined the average and individual performance over time of 49 adult cochlear implant subjects. Subjects were randomly assigned to receive either the Ineraid cochlear implant, with analog processing, or the Nucleus cochlear implant, with feature-extraction processing. All subjects had postlingual profound bilateral sensorineural hearing loss and received no significant benefit from hearing aids before implantation. Group data were examined in two ways. First, only subjects who had complete data over the test period were examined. Second, an analysis of all available data was carried out by mixed linear-model analysis. In this analysis, to account for missed follow-ups at the planned intervals, data consisting of the observations closest in time to the planned test times were modeled by natural splines with knots at the planned follow-up times. Contrasts between all pairs of planned follow-up times for each device were tested, as were contrasts between devices at each planned follow-up time. Results indicated little difference between the performance of the Ineraid and Nucleus subjects in their level of performance or their rate of learning. Postimplantation performance was typically superior to preimplantation performance within 9 months, and continued to improve up to 18-30 months depending on the speech perception measure. In some subjects, improvements in speech perception measures were observed up to four or five years postimplantation. There was also evidence that three subjects had a decrement in overall speech perception performance, although their postimplantation scores were always higher than their preimplantation scores. In at least one subjects this was likely a result of age-related cognition decrements.

Adult↗

PubMed1992

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia).

AIMS: To delineate the pattern of growth in prepubertal children with congenital disorder of glycosylation type Ia (CDG-Ia) in order to identify critical period(s) and possible cause(s) of growth failure. METHODS: Longitudinal measurements of weight, length/height, and head circumference from birth to 10 years of age in 25 CDG-Ia patients with the R141H/F119L PMM2 genotype were analysed. The data and derived body mass indices (BMI) were compared with standards and expressed as standard deviation scores (SDS). A linear mixed effects model was fitted to each set of data, and mean curves were estimated. RESULTS: The mean weight SDS decreased from -0.3 at birth to -3.0 at 7 months of age and remained low or increased slightly. The mean length SDS decreased from zero at birth to -2.4 at 7 months of age followed by a slight increase to a maximum of -1.8 SDS at the end of the second year of life. After age 2 the mean length/height SDS decreased again. The mean BMI SDS at birth was -0.7 and declined to a minimum of -2.8 at the end of the second year of life followed by a gradual increase. The mean head circumference SDS declined gradually from 0 at 3 months of age to -1.9 at age 5. CONCLUSION: CDG-Ia patients with the R141H/F119L genotype have normal fetal growth and an immediate postnatal onset of severe growth failure. A notable decline in weight end length SDS takes place during the first seven months of life with no prepubertal catch up.

Adolescent↗

PubMed2004

Impact of musculoskeletal disorders on quality of life: an inception cohort study.

OBJECTIVE: To assess longitudinally the impact of new onset musculoskeletal (MSK) disorders on quality of life (QoL). METHODS: An inception cohort of 1202 subjects in France aged 45-60 years was determined to be free of MSK problems at baseline. Over 28 months of follow up between 1996 and 1998, 310 were diagnosed with MSK disorders and matched for age and sex with 620 healthy controls. The impact of the MSK disorder onset on QoL was assessed by the change in SF-36 dimension scores over time, using a linear mixed ANOVA model to compare the groups. RESULTS: The incidence of MSK disorder was 13.6% per person-year in the spine, 4.2% per person-year in a joint, and 4.6% per person-year at an extra-articular site. The greatest change in QoL was a 10 point drop in the 100 point SF-36 bodily pain dimension scale in the MSK group. Compared with controls, subjects with an MSK disorder had significantly greater reductions in the following dimensions: bodily pain (a -7.4 point difference in change), vitality (-2.7), general health (-1.8), and physical functioning (-1.3). Within the MSK group, chronic disorders had a greater impact than acute ones on the physical functioning (-2.1), role emotional (-8.4), and social functioning (-5.9) dimensions. CONCLUSION: New onset MSK disorders have a marked deleterious effect on QoL in the physical domain, with lesser effects on social and mental functioning. This evidence of an early significant impact on their QoL reinforces recent recommendations for early treatment and primary prevention.

Arthritis↗

PubMed2026

Long-acting reversible contraception, condom use and sexually transmitted infections in developing countries: a multi-country serial cross-sectional analysis using demographic and health surveys.

INTRODUCTION: Unintended pregnancy and sexually transmitted infections (STIs) are major public health issues in developing countries. While long-acting reversible contraception (LARC) effectively prevents unintended pregnancy, there is limited evidence from large multinational studies on its association with condom use and STI-related outcomes. This study aimed to investigate the association between LARC use, condom use and STIs among women in developing countries. METHODS: This serial cross-sectional study extracted data from Demographic and Health Surveys (DHS), a series of nationally representative household surveys conducted in developing countries. The analysis included women aged 15 to 49 years, with data on contraceptive methods and demographics. Generalised linear mixed effect models (GLMMs) were used to estimate adjusted prevalence ratios (aPRs) for condom use and self-reported STI-related outcomes, comparing LARC users with both non-LARC users and oral contraceptive users. Subgroup analyses were conducted at the individual level and at the country level. RESULTS: Data from 2 171 884 women across 31 countries were analysed. Overall, the prevalence of self-reported STI-related outcomes was 7.4%, 3.9% of participants used LARC, and 7.5% of participants reported consistent condom use. LARC users were significantly less likely to use condoms compared with non-LARC users (aPR=0.40, 95% CI 0.30 to 0.53) and compared with oral contraceptive users (aPR=0.61, 95% CI 0.48 to 0.78). LARC use was associated with a higher prevalence of STI-related outcomes compared with non-LARC users (aPR=1.19, 95% CI 1.10 to 1.28) and compared with oral contraceptives users (aPR=1.14, 95% CI 1.05 to 1.24). Associations were stronger in low-Human Development Index (HDI) countries, especially among younger women (15-19 years), but were not significant in high-HDI countries. Country-level heterogeneity was observed. CONCLUSIONS: LARC use is associated with reduced condom use and higher self-reported STI prevalence, particularly among younger women and in lower HDI developing countries. These findings support integrating STI prevention into LARC services and promoting dual-method use to prevent both unintended pregnancies and STIs.

Humans↗

PubMed1999

Pharmacokinetics and dose requirements of vancomycin in neonates.

AIMS: To design and evaluate dosing guidelines for vancomycin based on data collected during routine use of the drug. METHODS: Following the observation that 66% of neonatal vancomycin trough concentrations were outside the target range, new dose guidelines were developed using a population pharmacokinetic approach. NONMEM (non-linear mixed effects model) was used to analyse dose histories and 347 concentration measurements collected during routine therapeutic drug monitoring in 59 neonates. RESULTS: Postconceptual ages in the patient group ranged from 26-45 weeks, weights from 0. 57-4.23 kg, and creatinine concentrations from 18-172 micromol/l. The population estimate of vancomycin clearance (l/h/kg) was 3. 56/creatinine concentration (micromol/l) with an interpatient coefficient of variation (CV) of 22% and volume of distribution 0.67 l/kg with a CV of 18%. Residual error was 4.5 mg/l. When the new recommendations on dosing were used prospectively in a separate group of neonates the proportion of acceptable troughs increased from 33% to 72%. CONCLUSIONS: The pharmacokinetics of vancomycin in neonates and young infants depend on weight and serum creatinine. Preliminary results from the new guidelines indicate an improvement on previous practice, but also an ongoing need to monitor concentrations.

Anti-Bacterial Agents↗

PubMed2006

Long-term effect of pulmonary valve replacement on QRS duration in patients with corrected tetralogy of Fallot.

OBJECTIVE: To analyse the long-term course of QRS duration after pulmonary valve replacement in patients with a previous correction for tetralogy of Fallot. SETTING: Tertiary referral centres. METHODS: In a retrospective study, 99 adult patients with tetralogy of Fallot, who had undergone a first pulmonary valve replacement late after initial total correction, were identified from the CONCOR (CONgenital CORvitia) registry. Computer-generated QRS durations were obtained from 12-lead electrocardiogram ECG reports in the medical records. A mixed linear regression model was used to analyse the course of QRS duration over time and to identify risk factors for increase in QRS duration over time. Composite end point was created from sudden cardiac death, ventricular tachycardia or implantable cardioverter-defibrillator discharge. RESULTS: In total, 99 patients (57% men, mean (SD) age at pulmonary valve replacement 29 (11) years) with a median follow-up of 4.9 (0.1-16) years were analysed. In patients with preoperative QRS <120 ms, surgery caused no significant change in QRS duration (increase 1.3 (7.9) ms; p = 0.65), and after surgery, QRS duration remained stable over time (increase 0.0064 (0.059) ms/year; p = 0.98). By contrast, in patients with a preoperative QRS of 150-180 ms or QRS > or =180 ms, surgery resulted in QRS shortening (mean decrease 9.9 (SE 4.3) ms, p = 0.021, and 12.2 (SE 2) ms; p<0.001, respectively). During follow-up, a QRS widening 1.1(1.3) ms/year (p<0.001) in both groups was observed. In patients with a preoperative QRS > or =180 ms, no significant difference was observed in the number of patients reaching the composite end point compared with patients with a preoperative QRS of 150-180 ms (25% vs 7%; p = 0.08). However, the former more often reached QRS > or =180 ms again after surgery compared with the latter (53% vs 13%; p = 0.02, respectively). None of the patients with a preoperative QRS > or =180 ms died during follow-up. CONCLUSION: In our study, we observed a decrease in QRS duration directly after surgery, followed by a steady increase, in patients with a preoperative QRS >150 ms. The beneficial effect of pulmonary valve replacement on QRS duration was transient. The risk of developing ventricular arrhythmias after surgery was substantial when preoperative QRS was > or =180 ms, but mortality remained low.

Death, Sudden, Cardiac↗

PubMed2004

Octapeptide repeat insertions in the prion protein gene and early onset dementia.

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.

Age of Onset↗

PubMed2004

Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children.

AIMS: To investigate the association between climate and atopic diseases using worldwide data from 146 centres of the International Study of Asthma and Allergies in Childhood (ISAAC). METHODS: Between 1992 and 1996, each centre studied random samples of children aged 13-14 and 6-7 years (approx. 3000 per age group and centre) using standardised written and video questionnaires on symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema during the past 12 months. Data on long term climatic conditions in the centres were abstracted from one standardised source, and mixed linear regression models calculated to take the clustering of centres within countries into account. RESULTS: In Western Europe (57 centres in 12 countries), the prevalence of asthma symptoms, assessed by written questionnaire, increased by 2.7% (95% CI 1.0% to 4.5%) with an increase in the estimated annual mean of indoor relative humidity of 10%. Similar associations were seen for the video questionnaire and the younger age group. Altitude and the annual variation of temperature and relative humidity outdoors were negatively associated with asthma symptoms. The prevalence of eczema symptoms correlated with latitude (positively) and mean annual outdoor temperature (negatively). CONCLUSIONS: Results suggest that climate may affect the prevalence of asthma and atopic eczema in children.

Adolescent↗