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.

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.

Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine study.

BACKGROUND: Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adults. METHODS AND RESULTS: A sample of 182 men and 136 women aged 33 to 42 years living in Muscatine, Iowa, underwent B-mode carotid ultrasound to determine the mean of 12 measurements of maximal carotid IMT. CAC was defined as calcification in the proximal coronary arteries in >/=3 contiguous pixels with a density of >/=130 HU. The mean IMT was 0.788 mm (SD 0.127) for men and 0.720 mm (SD 0.105) for women. CAC was present in 27% of men and 14% of women and was significantly associated with IMT in men (P<0.025) and women (P<0.005). With multivariate analysis, after adjustment for age, significant risk factors for carotid IMT were LDL cholesterol (P<0.001) and pack-years of smoking (P<0.05) in men and LDL cholesterol (P<0.001) and systolic blood pressure (P<0.01) in women. These risk factors remained significant after CAC was included in the multivariate model. CONCLUSIONS: There is an association between increased carotid IMT and CAC and between cardiovascular risk factors and increased IMT in young adults. Carotid IMT may provide information in addition to CAC that can be used to identify young adults with premature atherosclerosis.

Is prophylactic cranial irradiation indicated in small-cell lung cancer?

Although prophylactic cranial irradiation (PCI) is frequently used in the treatment of patients with limited-extent small-cell lung cancer (SCLC), its role remains controversial. One hundred fourteen SCLC patients with limited disease treated at Indiana University were retrospectively reviewed. Fifty-eight of 114 (51%) patients achieved a complete remission (CR) and were analyzed. Thirty-eight of these 58 CR patients received PCI (+PCI) and 20 of 58 CR patients did not receive PCI (-PCI). Twenty-six of 38 patients who received PCI subsequently relapsed. No patient initially relapsed in the CNS, although one patient had a brain metastasis following recurrence in the chest. Eleven of 38 patients who were treated with PCI survived for longer than 30 months and were considered long-term survivors. Seven of these 11 patients (63%) developed clinically significant neurological toxicity. Sixteen of 20 patients who did not receive PCI relapsed, but there was only one initial relapse in the CNS. Three additional patients who relapsed in the chest subsequently developed CNS metastasis. All responded to palliative radiation with improvement in their symptoms. The high incidence of CNS toxicity in the long-term survivors and the relatively infrequent incidence of isolated CNS recurrent in patients not subjected to PCI raise serious questions concerning the role, if any, of PCI in limited SCLC.

The newborn transitional circulation: a two-dimensional Doppler echocardiographic study.

To characterize changes in circulation after birth, 11 normal full-term infants were examined with two-dimensional and pulsed Doppler echocardiography. The initial examination was performed within 10 hours after delivery and serially for 3 days. Retrograde diastolic pulmonary artery velocities, which are evidence for a patent ductus arteriosus, were detected in 10 infants (91%) on day 1, in 2 (18%) on day 2 and in none on day 3. Retrograde systolic descending aortic velocities, which are evidence of flow from the aorta into the ductus arteriosus, were observed in 10 infants (91%) on day 1, 9 (81%) on day 2 and 7 (64%) on day 3. Persistence of the retrograde systolic velocity in the descending aorta in the absence of retrograde diastolic velocity in the pulmonary artery is consistent with physiologic ductal closure beginning near the pulmonary artery end of the ductus arteriosus. Localized turbulent retrograde systolic flow, proximal to the septal leaflet of the tricuspid valve and consistent with tricuspid insufficiency, was detected in six patients (55%) on day 1, in eight (73%) on day 2 and in seven (64%) on day 3. Thus, tricuspid insufficiency appears to be a frequent observation in healthy newborns. Normal Doppler velocities in the great arteries and across the tricuspid and mitral valves of newborns up to 3 days of age are presented. These normal measures of intracardiac flow velocities may be used for comparison to identify abnormal flow profiles in newborns with congenital heart defects.

Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study.

OBJECTIVES: This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life. BACKGROUND: Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults. METHODS: Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination. RESULTS: The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol. CONCLUSIONS: Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Factors related to tracking of blood pressure in children. U.S. National Center for Health Statistics Health Examination Surveys Cycles II and III.

In this paper we examine the relationship of growth, obesity, and the degree of sexual and bone maturation to blood pressure in a U.S. national probability sample of 2165 children examined by the U.S. National Center for Health Statistics on two occasions, approximately 4 years apart. Subjects who maintained, increased, or decreased their peer rank order of blood pressure are described. Children who maintained their blood pressure in the upper quintile were taller, heavier, more obese, had greater bone age, greater numbers of permanent teeth, and were more sexually mature than their peers, while those maintaining their blood pressure in the lowest quintile of blood pressure were shorter, lighter, less obese, had lesser bone age, fewer permanent teeth, and were less sexually mature. Subjects whose blood pressures were initially in the lowest four quintiles and then rose to the top quintile were also taller, heavier, more obese, and had greater bone age, while those with blood pressures falling to the lowest quintile from the upper four quintiles were shorter, lighter, less obese, and had lesser bone age. Thus, the level at which blood pressure tracks during childhood is related to growth, obesity, and to the degree of maturation acquired. In addition, children whose blood pressures are rising or falling in relation to their peers have body growth and maturation characteristics similar to those who maintain their rank order high or low respectively.

Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine Study.

From echocardiography measurements of left heart dimensions, cardiac output was estimated in 264 school children whose systolic blood pressure persisted in the lowest, middle, or highest quintile of the distribution for their age and sex. Children with blood pressure in the upper quintile were taller, heavier, and more obese. Echocardiographically determined left ventricular wall mass, corrected for body size, was significantly greater in these children than those in the lower quintiles of blood pressure. These children displayed a continuum of cardiac output. Those with the highest cardiac output in the upper blood pressure quintile had the greatest left ventricular wall mass.

The cardiovascular responses to exercise in children across the blood pressure distribution. The Muscatine study.

Children with elevated systolic blood pressure have a wide range of cardiac output. To better understand the mechanisms regulating resting and exercise blood pressure, we investigated the cardiovascular responses to both dynamic and isometric exercise in 264 children who were selected from the low, middle, and upper quintile of the distribution of blood pressure of an entire school population. We sought to identify patterns of response to exercise that correlated with both resting cardiac output and resting blood pressure. During isometric exercise, systolic pressure adjusted for age and body size increased in all groups. The low group's mean pressure remained significantly lower than the high group's pressure throughout the entire exercise period. Body size adjusted group systolic and diastolic blood pressure level differences exist during dynamic exercise. The product of the systolic blood pressure times the heart rate, in the high blood pressure group, was significantly higher throughout dynamic exercise than in the other two groups. Elevated resting resistance is correlated with elevated resistance during isometric exercise and elevated diastolic blood pressure during dynamic exercise. Cardiac index had a significant negative correlation to age (r = -0.58) at all levels of blood pressure. This observation, in children, lends some support to the concept of the evolution from a hyperkinetic circulation in early childhood to a circulation with lower cardiac output and more elevated systemic vascular resistance at an older age.

Left ventricular mass and exercise responses predict future blood pressure. The Muscatine Study.

Increased blood pressure and left ventricular mass are associated with increased morbidity and mortality in adults with coronary heart disease. To define the predictors of subsequent childhood blood pressure and left ventricular mass, serial echocardiograms and blood pressure responses during exercise were studied in 274 children aged 6 to 15 years, whose systolic blood pressures were in the high, middle, or low range. Persistence of rank order for left ventricular mass and blood pressure, at rest and during exercise, was maintained over a mean follow-up period of 3.4 years, with correlations ranging from 0.33 to 0.44. Subsequent systolic blood pressure was best predicted from initial resting and maximal exercise systolic blood pressures and left ventricular mass. Subsequent left ventricular mass was best predicted from initial left ventricular mass and maximal exercise diastolic blood pressure, but resting systolic blood pressure did not add to this latter prediction. Since left ventricular mass relates best to exercise blood pressure and not to resting blood pressure, left ventricular mass may provide an integrated view of the effects of blood pressure both at rest and during stress. We speculate that increased left ventricular mass in childhood may be an important predictor of subsequent hypertension and its consequences.

Enhanced forearm blood flow during mental stress in children of hypertensive parents.

This study compared changes in forearm blood flow, forearm vascular resistance, blood pressure, and heart rate elicited by mental stress (mental arithmetic) in 12 adolescents with a hypertensive parent and 13 age-matched adolescents with normotensive parents. The two groups did not differ in resting forearm blood flow, forearm vascular resistance, heart rate, or blood pressure. During mental stress, children with a family history of hypertension had a significantly greater increase in forearm blood flow than did children of normotensive parents (+37.5 +/- 8.0 vs +12.8 +/- 7.5%; p less than 0.05) and a trend toward reduced forearm vascular resistance (p = 0.08). Mental stress significantly increased systolic blood pressure (p less than 0.0001), diastolic blood pressure (p less than 0.001), and heart rate (p less than 0.03) in both groups. The blood pressure and heart rate responses to stress were not significantly different between groups. There was no evidence of a prolonged response or a different pattern of recovery in children with a family history of hypertension. This study indicates that regional blood flow responses underlying similar blood pressure increases during mental stress may be different in adolescents with and without a family history of hypertension.

Childhood predictors of future blood pressure.

Blood pressure in infants and children is much lower than that in adults. It is suspected that children whose blood pressures are greatest for their age or body size may be destined for future hypertension. However, it is apparent that some children with lower blood pressures are also destined for hypertension as adults. Children with a family history of hypertension demonstrate greater blood pressure and heart rate responses to mental challenge. These responses are enhanced when a high salt diet is consumed. Increased maximal exercise systolic blood pressure and increased left ventricular wall mass in childhood add significantly to the prediction of future high blood pressure. In addition, the acquisition of excess weight for height from childhood to young adult life adds to the prediction of future blood pressure elevations. Both children and adults who are obese have significantly higher blood pressures than those who are lean. Approximately 34% of the variability in body mass index is explained by genotype differences at a single recessive locus, 41% by genotype differences at polygenic loci, and 25% by nongenetic factors. Thus, the genetic influence of obesity may be an important factor responsible for elevated blood pressure in both children and adults.

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,

Working memory in young children: evidence for modality-specificity and implications for cerebral reorganization in early childhood.

Digit span (DS) and visual-spatial memory span (VMS) tasks have been considered indices of auditory and visual spatial processing, respectively, often classified as "primary memory" or "attention". There has been limited evidence for their modality specificity, however. We present two children who showed visual spatial processing deficiencies (including VMS) and non-dominant manual inefficiency with normal visual-spatial perception, auditory-verbal processing and dominant fine manual skills. These children support a distinction between auditory and visual-spatial memory span. These findings are discussed with regard to a hypothesis that the unique expression of VMS is time-limited, that visual-spatial processing becomes more verbalized as children learn to read and that these behavioral changes produce a lateral shift in cortical processing of visual spatial information.

Management of the myelodysplastic syndromes.

It is important to make the correct diagnosis of MDS and to exclude very carefully all other disorders that may induce dysplastic features in the bone marrow. In patients without excess of bone marrow blasts, cytogenetics and in vitro bone marrow cultures may aid in making the correct diagnosis. MDS patients without excess of bone marrow blasts or symptomatic cytopenia or cytogenetic abnormalities associated with poor prognosis should be followed on a regular basis with sequential examinations of blood counts and bone marrow specimens. In the absence of obvious disease progression, ie, increasing cytopenia or increasing percentage of marrow blasts, patients should only receive supportive care. An increase in RBC requirements alone is insufficient reason to start cytotoxic therapy. Once progression of the disease has been well documented, cytotoxic treatment is indicated. There is no reason to delay treatment until these patients have progressed to overt AML. In patients over the age of 50, the best available therapy is low-dose cytarabine with a 30% probability of a good response; this therapy requires careful supervision and the availability of intensive supportive care. In patients under 50 years with progressive disease, or with clear evidence of a poor prognosis, allogeneic BMT is the therapy of choice if a HLA-identical sibling can be identified. In those patients who lack a HLA-identical sibling, intensive combination therapy is the treatment of choice and should preferably include high-dose cytarabine. Intensive consolidation therapy will be necessary for a durable remission. Trials with inducers of differentiation remain experimental. Results to date have been disappointing.

Childhood risk factors for high adult blood pressure: the Muscatine Study.

In adult populations, elevated blood pressure is related to the development of occlusive atherosclerosis, stroke, and renal disease. The significance of blood pressure levels in childhood, unless extremely elevated, has not been related to disease outcomes. In this study, the risk of high blood pressure in young adult life is evaluated based on the observations of blood pressure and other factors made during the school-aged years. Subjects, 2445 in number, were first observed at ages 7 through 18 years and again between 20 and 30 years. During childhood, measurements of blood pressure, height, and weight were made in alternate years. At adult ages, the same measurements were again made and a health questionnaire was administered. According to the data, adult blood pressure is correlated with childhood blood pressure, body size, and change in ponderosity from childhood to adult life. Adult ponderosity is related to childhood ponderosity, and those who are most obese as adults show the greatest increase in weight for height from their childhood years. These observations suggest that strategies to prevent the acquisition of excess ponderosity during adolescence may be useful in preventing adult hypertension.

Factors affecting the relationship between childhood and adult cholesterol levels: the Muscatine Study.

A group of 2,446 subjects initially examined at 8 to 18 years of age were reexamined as young adults of 20 to 25 or 26 to 30 years of age. Measurements of cholesterol, height, weight, and triceps skinfold thickness were obtained during childhood. Lipids, lipoprotein fractions, and family history, as well as medication, alcohol, and tobacco use, were determined during the adult examination. Elevated levels of cholesterol during childhood were associated with elevation in adult life. Obesity acquired in adolescence and the young adult years, oral contraceptive use, and cigarette smoking had deleterious effects on adult cholesterol levels and lipoprotein fractions.