Lactic acid oligomers (OLAs) as prodrug moieties.

In this paper we propose the use of lactic acid oligomers (OLAs) as prodrug moieties. Two synthetic approaches are presented, on the one hand a non selective oligomerisation of lactic acid and on the other hand a block synthesis to tetramers of lactic acid. Dimers of lactic acid were investigated with respect to their plasma stability and their adsorption to albumine. Ibuprofen was chosen as the first drug for OLAylation. The ester 19 of LA(1)-ibuprofen was evaluated with respect to the degradation to human plasma and the adsorption to albumine. All results indicate that lactic acid oligomers are promising prodrug moieties.

Anaesthetic management of the child with co-existing pulmonary disease.

Children with co-existing pulmonary disease have a wide range of clinical manifestations with significant implications for anaesthetists. Although there are a number of pulmonary diseases in children, this review focuses on two of the most common pulmonary disorders, asthma and bronchopulmonary dysplasia (BPD). These diseases share the physiology of bronchoconstriction and variably decreased flow in the airways, but also have unique physiological consequences. The anaesthetist can make a difference in outcomes with proper preoperative evaluation and appropriate preparation for surgery in the context of a team approach to perioperative care with implementation of a stepwise approach to disease management. An understanding of the importance of minimizing the risk for bronchoconstriction and having the tools at hand to treat it when necessary is paramount in the care of these patients. Unique challenges exist in the management of pulmonary hypertension in BPD patients. This review covers medical treatment, intraoperative management, and postoperative care for both patient populations.

Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.

In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of antihistaminc drugs and to distinguish between first and second generation antihistamines.

Effects of cycling and/or electrical stimulation on bone mineral density in children with spinal cord injury.

STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To determine the effect of cycling and/or electrical stimulation on hip and knee bone mineral density (BMD) in children with spinal cord injury (SCI). SETTING: Children's hospital specializing in pediatric SCI. METHODS: A total of 30 children, aged 5-13 years, with chronic SCI were randomized to one of three interventions: functional electrical stimulation cycling (FESC), passive cycling (PC), and non-cycling, electrically stimulated exercise (ES). Each group exercised for 1 h, three times per week for 6 months at home. The hip, distal femur and proximal tibia BMD were examined via dual-energy X-ray absorptiometry (DXA) pre- and post-intervention. RESULTS: In all, 28 children completed data collection. The FESC group exhibited increases in hip, distal femur and proximal tibia BMD of 32.4, 6.62 and 10.3%, respectively. The PC group exhibited increases at the hip (29.2%), but no change at the distal femur (1.5%) or proximal tibia (-1.0%). The ES group had no change at the hip (-0.24%) and distal femur (3.3%), but a loss at the proximal tibia (-7.06%). There were no differences between groups or within groups over time. Significant negative correlations were found between baseline BMD and the amount of BMD change. CONCLUSION: Although not achieving statistical significance, hip BMD changes observed were greater than the reported 0.9-10% gains after exercise for children with and without disability. Thus, cycling with and without electrical stimulation may be beneficial for skeletal health in pediatric SCI, but further research is needed with a larger sample size.

Cycling for children with neuromuscular impairments using electrical stimulation--development of tricycle-based systems.

AIM: Cycling using functional electrical stimulation (FES-cycling) is a well defined exercise method for adults with spinal cord injury (SCI). Although little studied thus far, FES-cycling also has the potential to offer a means of exercise to pediatric populations, such as SCI or cerebral palsy (CP), that presently have few alternative options. The primary aim of this study was to develop FES-cycling equipment and methods which can meet the differing needs of children with SCI and CP. METHODS: Design criteria were determined based on key considerations for pediatric FES-cycling. Two separate prototype systems for training/recreation and laboratory-based research were built to meet these specifications. To experimentally verify the equipment, FES-cycling tests involving one child with motor complete SCI and one child with diplegic spastic CP were performed using the laboratory system. RESULTS: Experimental verification indicated that FES-cycling experiments involving children with SCI and CP are feasible provided that accurate measurement of both propulsive and resistive torque is achieved. Specific seating and orthotic needs for each subject population were met by both systems. CONCLUSION: The FES-cycling systems described here may assist in future investigations of pediatric FES-cycling performance and novel exercise regimes designed specifically for children.

Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.

BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.

Usefulness of the Framingham risk score and body mass index to predict early coronary artery calcium in young adults (Muscatine Study).

The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population.

Coping with grim news from genetic tests.

Clinicians need to recognize and respond to stress response syndromes that may occur after patients have received genetic testing for inherited susceptibility to serious diseases. For patients whose test results convey high risk, increased attention to prevention, surveillance, and early medical treatment may be possible, but the grim news may also lead to a formation of symptoms ranging from extreme denial to unwelcomed intrusive ideas and feelings. Genetic counseling alone may be insufficient for some people, and evaluation and psychotherapy for stress response syndromes may be indicated for them.

Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Automated analysis of Doppler ultrasound velocity flow diagrams.

A highly automated method for the identification and quantization of maximum blood velocity curves from Doppler ultrasound flow diagrams is presented. The method uses an image processing scheme to analyze video-recorded image sequences of flow diagrams. The sequences are acquired, a sequence of images relating to chronological cardiac cycles is extracted, and a maximum blood velocity envelope is determined and quantified. The results are verified against hand-traced reference curves. Excellent correlation of r = 0.99 is achieved.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

Applications of cortical signals to neuroprosthetic control: a critical review.

Cortical signals might provide a potential means of interfacing with a neuroprosthesis. Guidelines regarding the necessary control features in terms of both performance characteristics and user requirements are presented, and their implications for the design of a first generation cortical control interface for a neuroprosthesis are discussed.