Randomized trial of a dual-hormone artificial pancreas with dosing adjustment during exercise compared with no adjustment and sensor-augmented pump therapy.

AIMS: To test whether adjusting insulin and glucagon in response to exercise within a dual-hormone artificial pancreas (AP) reduces exercise-related hypoglycaemia. MATERIALS AND METHODS: In random order, 21 adults with type 1 diabetes (T1D) underwent three 22-hour experimental sessions: AP with exercise dosing adjustment (APX); AP with no exercise dosing adjustment (APN); and sensor-augmented pump (SAP) therapy. After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate, with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP therapy, subjects could adjust dosing before exercise. The two primary outcomes were percentage of time spent in hypoglycaemia (<3.9 mmol/L) and percentage of time spent in euglycaemia (3.9-10 mmol/L) from the start of exercise to the end of the study. RESULTS: The mean (95% confidence interval) times spent in hypoglycaemia (<3.9 mmol/L) after the start of exercise were 0.3% (-0.1, 0.7) for APX, 3.1% (0.8, 5.3) for APN, and 0.8% (0.1, 1.4) for SAP therapy. There was an absolute difference of 2.8% less time spent in hypoglycaemia for APX versus APN (p = .001) and 0.5% less time spent in hypoglycaemia for APX versus SAP therapy (p = .16). Mean time spent in euglycaemia was similar across the different sessions. CONCLUSIONS: Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycaemia compared with no adjustment and performs similarly to SAP therapy when insulin is adjusted before exercise.

Economic benefit of the PHLAME wellness programme on firefighter injury.

BACKGROUND: Work-related injuries and illness are prevalent and costly. Firefighting is especially hazardous and many firefighters sustain work-related injuries. Workplace health promotion programmes have shown positive return on investment (ROI). Little is known about how similar programmes would impact injury and cost among firefighters. AIMS: To evaluate the impact of a workplace health promotion intervention on workers' compensation (WC) claims and medical costs among Oregon fire departments participating in the PHLAME (Promoting Healthy Lifestyles: Alternative Models' Effects) health promotion programme compared with Oregon fire departments not participating in PHLAME. METHODS: Data from firefighters from four large urban fire departments in Oregon were evaluated using a retrospective quasi-experimental study design. Outcomes were (i) total annual firefighter WC claims, (ii) total annual incurred medical costs prior to and after implementation of the PHLAME firefighter worksite health promotion programme (iii) and an ROI analysis. RESULTS: Data were obtained from 1369 firefighters (mean age of 42 years, 91% white, 93% male). WC claims (P < 0.001) and medical costs (P < 0.01) were significantly lower among PHLAME fire departments compared with Oregon fire departments not participating in the programme. Fire departments participating in the PHLAME TEAM programme demonstrated a positive ROI of 4.61-1.00 (TEAM is used to indicate the 12-session peer-led health promotion programme). CONCLUSIONS: Fire department WC claims and medical costs were reduced after implementation of the PHLAME workplace health promotion programme. This is a low cost, team-based, peer-led, wellness programme that may provide a feasible, cost-effective means to reduce firefighter injury and illness rates.

Analgesic efficacy and safety of the diclofenac epolamine topical patch 1.3% (DETP) in minor soft tissue injury.

The diclofenac epolamine topical patch 1.3% was designed to deliver analgesic concentrations of diclofenac to an underlying soft tissue injury site, while limiting systemic exposure to diclofenac. This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of the diclofenac epolamine topical patch for the treatment of acute pain due to minor soft tissue injury. Patients (18-65 years, inclusive) with clinically significant minor soft tissue injuries (mild or moderate sprain, strain, or contusion) incurred within 7 days of study entry and having pain scores ≥ 5 on a Visual Analog Scale of 0-10 were enrolled. Patients were randomized to receive the diclofenac epolamine topical patch (n=207) or placebo patch (n=211) application twice daily for 14 days or until pain resolution. Patients recorded pain scores every 12 h at the time of patch removal using the Visual Analog Scale. Investigator-assessed global response to therapy was also evaluated. Safety data were collected throughout the study. Twice-daily treatment with diclofenac epolamine topical patch produced a statistically significant reduction in mean pain score relative to baseline by an additional 18.2% in the diclofenac epolamine topical patch group (0.435 ± 0.268) compared with the placebo group (0.532 ± 0.293) (p=0.002; overall) beginning after application of the second patch. Consistent with this treatment effect, median time to pain resolution was shortened by 2 days in the diclofenac epolamine topical patch group relative to the placebo group (p=0.007). These results were reinforced independently by investigators who reported treatment as good or excellent for 58% of diclofenac epolamine topical patch-treated patients compared with 49% in the placebo patch group (p=0.008). The most common adverse events were treatment site related (n=16, 7.9% diclofenac epolamine topical patch; n=12, 5.8% placebo patch). Most (80%) patients reported tolerability as excellent or good. In conclusion, the diclofenac epolamine topical patch provides effective, rapid pain relief for the treatment of acute pain from minor soft tissue injury and appears generally safe and well tolerated.

A cluster of hypoplastic left heart malformation in Baltimore, Maryland.

Congenital cardiovascular malformations (CCVMs) of the left side of the heart show familial recurrence of various forms of obstructive malformations, including hypoplastic left heart (HLH), interrupted aortic arch, coarctation of the aorta, and aortic stenosis. In a previous population-based study in the Baltimore-Washington region, these malformations were associated with parental reports of occupational or leisure solvent exposure, overt diabetes, and family history of CCVM in first-degree relatives. Spatial analysis in this well-characterized study population may augment self-reported data by revealing additional associations with potential environmental risk factors. We used spatial analysis to identify clusters of HLH as a group. The study population included all live-born cases of hypoplastic left heart syndrome diagnosed in the first year of life between 1981 and 1989 and a random sample of unaffected infant controls matched by year and hospital of birth. The nested case-control cohort in this spatial analysis included 77 HLH cases and 1894 controls in Maryland and the District of Columbia. Nonparametric and regression analyses included personal variables from the interview data set as well as spatial variables. A region of Baltimore was identified that contained HLH at twice the expected frequency based on the distribution of population younger than 5 years of age. The region included 30 of 77 geocoded cases of HLH in the cohort and is significant by spatial scanning at p = 0.056. Within this region, male cases of HLH were disproportionately present compared to females. This cluster is in a region of Baltimore with industrial release of solvents, dioxin, and polychlorinated biphenyls in air. Outside the cluster, HLH is associated with family history of CCVM in a first-degree relative, maternal exposure to miscellaneous solvents, paternal anesthesia, maternal art painting, aspirin ingestion, and maternal diabetes. Inside the cluster, father's painting and exposure to sympathomimetic drugs were associated risk factors. Spatial analysis of HLH cases delineated an urban region with increased prevalence of this left heart malformation. Within this region, excess male cases of HLH occurred, and industrial release to air of solvents, dioxin, and polychlorinated biphenyl compounds was documented. We propose that both genetic and environmental factors contribute to the phenotype of HLH.

Insurance and education determine survival in infantile coarctation of the aorta.

Health outcomes are determined by case severity, physician decisions, and patient variables. In a population-based study between 1981 and 1989, 103 cases of infant coarctation of the aorta were diagnosed before one year of age. The goal of this study was to determine whether patient race, gender, income, and insurance status had effects on outcome of coarctation of the aorta that were distinct from the effect of case severity. Survival of infants with coarctation of the aorta, a common congenital cardiovascular malformation, is associated with greater maternal education and with having any health insurance but not with measures of severity. Infants without health insurance are 12.8 times more likely to die than infants with any health insurance. Fifty-five percent of all deaths in infant coarctation occur prior to surgical treatment. One-third of deaths occur without diagnosis. Outcome measures require knowledge of the entire population and of insurance status to inform policy.

Failure to diagnose congenital heart disease in infancy.

OBJECTIVE: To identify factors that predict failure to diagnose congenital heart disease in newborns. DESIGN: All fatal cases in the Baltimore-Washington Infant Study were compiled. The Baltimore-Washington Infant Study includes 4390 cases of infants with congenital cardiovascular malformations identified in a population-based study between 1981 and 1989 in the Baltimore-Washington metropolitan area. Death occurred in 800 such infants in the first year of life. In 76 of these infants, death occurred before diagnosis of heart disease. These cases were identified by community search of autopsy records. Their characteristics are compared with those of infants who died after a cardiac diagnosis was made. RESULTS: Infant characteristics (birth weight, gestational age, intrauterine growth retardation, and chromosomal anomaly) are associated with death of infants with congenital cardiovascular malformations and with death of such infants before diagnosis. Diagnoses of coarctation of the aorta, Ebstein's anomaly, atrial septal defect, and truncus arteriosus are overrepresented in infants found by community search, particularly in those infants without associated malformations. Paternal education is associated with failure to diagnose congenital heart disease in life but other sociodemographic characteristics of the infant's family are not. CONCLUSIONS: Diagnosis of congenital cardiovascular malformations requires close observation in the neonatal period. Analysis of age at death of infants with undiagnosed congenital cardiovascular malformation suggests that such infants may be at risk if discharged within the first 2 days of life.

Precipitous exit block with epicardial steroid-eluting leads.

Between January 1990 and October 1992, we implanted 16 steroid-eluting ventricular epicardial pacing leads (Medtronic 10295A and 10295B/4965) in 12 patients. There were 8 males and 4 females ranging in age from 3 months to 49 years (mean 8.7 +/- 13.2, median 6.0 years). Structural cardiac disease was present in 11 of 12 patients. Follow-up ranged from 3-73 months postimplant (mean 35.7 +/- 22.3, median 28.5 months). Lead fracture (10295A) occurred in 1 of 12 patients. Of the remaining 11 patients, 8 of 11 have very low long-term pacing thresholds. Unexpectedly, 3 patients demonstrated precipitous threshold increases from 3 months to 3.5 years postimplant. Although no deaths resulted in these exit block patients, 1 of 3 exit block patients developed marked worsening of congestive heart failure. We reviewed and analyzed the data obtained at 4 weeks postimplant for all of the 10295A and 4965 patients in the entire Medtronic clinical study database. Using the criterion of a 4 week postimplant pacing threshold > or = 0.12 ms (5 V), we found that the long-term risk of eventual exit block was 27.3% for the 10295A lead (P = 0.005) and 7.5% for the 10295B/4965 lead (P = 0.03). We, therefore, recommend that in patients implanted with the 4965 steroid-eluting epicardial lead, ventricular pacing thresholds > or = 0.12 ms (5 V) measured at 4 weeks postimplant should prompt frequent threshold testing to detect late and potentially sudden ventricular pacing threshold increases.

Rapid postmortem invasion of cecal mucosa of macaques by nonpathogenic Entamoeba chattoni.

Although Entamoeba histolytica is the third leading parasitic cause of death in the world, most infections in humans are asymptomatic and restricted to the intestinal lumen. Entamoeba histolytica infections have also been reported in most species of captive nonhuman primates, with New World monkeys being particularly susceptible to fatal invasive amebiasis. In contrast, Old World monkeys appear to be resistant to the disease, although tissue invasion in asymptomatic monkeys has been reported. Our initial objectives were to determine the incidence, the predisposing factors, and the light microscopic and ultrastructural features of invasive amebiasis in Macaca mulatta (rhesus) and and M. fasicularis (cynomolgus) macaques. Our findings indicate that nonpathogenic E. chattoni in macaques can invade cecal mucosa rapidly (within 1 hr) after death. Therefore, the presence of invasive Entamoeba trophozoites in routinely collected necropsy materials should be interpreted with caution, particularly in cases where tissue fixation is delayed.

Nucleocapsid- and virus-like particles assemble in cells infected with recombinant baculoviruses or vaccinia viruses expressing the M and the S segments of Hantaan virus.

The formation of Hantaan (HTN) virus nucleocapsid-like structures (NLS) or virus-like particles (VLP) from expressed gene products was investigated in two eukaryotic systems. Baculovirus expression of the HTN virus small segment (S), which encodes the viral nucleocapsid protein, resulted in assembly of NLS inside infected insect cells. The NLS and authentic ribonucleocapsids, prepared by detergent disruption of HTN virions, had similar sedimentation characteristics and morphologies, and were recognized by HTN virus N-specific antibodies. Co-expression of S and the medium segment (M), which encodes the two viral envelope glycoproteins (G1 and G2), did not efficiently generate VLP in the baculovirus-insect cell system, but VLP were observed in lysates and supernatants of cells infected with a recombinant vaccinia virus co-expressing HTN virus M and S. The VLP sedimented in sucrose to densities consistent with HTN virions, and some of them bore a striking resemblance to Hantaan virions when examined by immunoelectron microscopy.

Effective control of hypercholesterolemia in children with dietary interventions based in pediatric practice.

BACKGROUND: Based on recent recommendations, the number of hypercholesterolemic children who would require dietary therapy could overwhelm current preventive pediatric cardiology resources. No previous studies have established the efficacy of such therapy in the pediatrician's office. The purpose of this study was to evaluate two programs of office-based therapy. METHODS: We randomly assigned 295 children with hypercholesterolemia (> 185 mg/dl) two interventions: one single or four multiple 90-min sessions of family-oriented nutritional education, based in pediatric practices. We examined total cholesterol, 3-day food records, height and weight, and in the multisession group high-density lipoprotein cholesterol and triglycerides at the beginning and at intervals of 8.5-9 and 21 to 33 weeks (single-session and multisession groups, respectively). RESULTS: Total cholesterol was lowered equally in both treatment groups over the course of the study. This was accompanied by dietary changes: a decrease in calories derived from total and saturated fats, and increased intake of fiber, protein, and carbohydrate. However, more single-session patients withdrew from the program during the study. CONCLUSIONS: The two interventions were equally effective in lowering total and low-density lipoprotein cholesterol and in reducing intake of total and saturated fat. However, the higher completion rate of the multisession group suggests that this approach may be the more effective.

Should a school honor a student's DNR order?

Physicians first present the case of a sixteen-year-old cardiac patient who has refused a heart transplant and cardiac resuscitation. Her family and physicians accept the decision. The family has asked the school system to honor her do not resuscitate order if she goes into cardiac arrest in school The school system has refused to do so. Following the case presentation, a lawyer, a physician/ethicist, and an educator consider the important issues raised by this ongoing case.

Metabolic evaluation of obese and nonobese siblings.

OBJECTIVE: To test the hypotheses that obese adolescents have a lower resting metabolic rate and less aerobic endurance than their nonobese siblings. DESIGN: Case-referent study of obese and nonobese siblings from the same kindred. SETTING: Tertiary referral center. PARTICIPANTS: Telephone screening of community volunteers resulted in a consecutive sample of 16 kindreds. Obese and nonobese siblings were similar in age, height, and pubertal status. Significantly more female subjects were in the obese group (p less than 0.01). MEASUREMENTS AND MAIN RESULTS: Body composition studies revealed that the obese siblings had higher body fat (p less than 0.001) but that fat-free mass was similar to that of the lean siblings. Resting metabolic rates determined by indirect calorimetry for the obese and nonobese pairs did not differ. Although the obese siblings appeared less fit when maximal oxygen consumption was measured in relation to total weight, maximal oxygen consumption did not differ when values were standardized for fat-free mass. CONCLUSIONS: The obese adolescents did not have a reduced resting metabolic rate. As in adults, the relationship between resting metabolic rate and fat-free mass was similar for obese and nonobese children and adolescents. Any decreased sport participation by the obese siblings was not due to inherent reductions in aerobic capacity.

Metabolic myopathies: evaluation by graded exercise testing.

Exertional muscle pain and fatigue are common complaints; some patients with these symptoms have a metabolic myopathy. We have performed graded exercise testing with analysis of expired ventilation on 13 individuals with various kinds of metabolic myopathies. Their results differed from normal and reflected the underlying biochemical abnormality. Patients with disorders of the mitochondrial electron transport chain demonstrated marked limitations in aerobic metabolism and a greatly reduced maximum oxygen consumption. During intense exertion, normal individuals increase carbon dioxide generation due to buffering of lactic acid. This did not occur in patients with McArdle disease, in whom the respiratory exchange ratio (carbon dioxide production/oxygen consumption) did not rise above 1.0 at maximum exercise. These results indicated a deficit in anaerobic metabolism. Pyruvate dehydrogenase complex allows pyruvate produced from carbohydrate metabolism to enter the citric acid cycle. Patients with this enzyme deficiency showed an initially normal pattern followed by an abrupt cessation in carbohydrate dependent aerobic metabolism at higher work loads. During high-intensity exercise, progressive anaerobic metabolism was not accompanied by additional oxygen consumption. Finally, results from a patient with carnitine palmitoyl transferase deficiency revealed an early dependence on carbohydrate metabolism. The ventilatory threshold occurred at a low percentage of maximal oxygen consumption, reflecting the limited availability of lipid substrates for aerobic metabolism. Detection of some muscle metabolic abnormalities can be made on small biopsy specimens. However, definitive diagnosis of the defect nearly always requires studies on fresh or frozen muscle tissue obtained by an open biopsy. The decision on how the tissue should be processed and which metabolic studies should be performed frequently needs to be made before the biopsy is obtained. Thus, a noninvasive method to initially characterize patients with potential metabolic disorders is useful. Exercise testing with expired gas analysis can indicate the presence of a metabolic myopathy and results can then be used to direct the appropriate biochemical evaluations.

Sustained depression of the resting metabolic rate after massive weight loss.

To assess potential long-term effects of weight loss on resting metabolic rate (RMR), the RMRs of seven obese women were measured by indirect calorimetry before weight loss, during a protein-sparing modified fast, and for 2 mo while at a stable reduced weight. Body composition was also determined at each interval. RMR significantly decreased 22% (p less than 0.01) with initiation of the modified fast. RMR values during the modified fast and during the maintenance diet at stable reduced weight were not different and all were significantly lower than the prediet RMR. Loss of lean tissue could not account for the decrease because changes in RMR per fat-free mass paralleled the total RMR reduction. A sustained decrement in RMR accompanied weight loss and persisted for greater than or equal to 8 wk despite increased caloric consumption and body weight stabilization.

Effects of acute administration of naltrexone on cardiovascular function, body temperature, body weight and serum concentrations of liver enzymes in autistic children.

The effects of acute, orally administered naltrexone (0.5, 1.0, 1.5 and 2.0 mg/kg), a potent opiate receptor antagonist, on auscultated heart rate, systolic blood pressure and axillary body temperature were investigated before and about 1 h postdrug in 5 autistic children (4-12 years of age). In addition, an electrocardiogram was recorded on each child before and about 3 h after placebo or 2.0 mg/kg of naltrexone. Finally, the serum concentrations of the liver enzymes glutamic-oxaloacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) were measured 24 h following placebo or naltrexone administration. Naltrexone had no statistically significant effects on any of these measures in comparison with baseline or placebo levels. Thus, these data provide preliminary evidence for the safety of acute administration of naltrexone in children.

Does aerobic conditioning cause a sustained increase in the metabolic rate?

We measured the metabolic rate by indirect calorimetry for 90 minutes following exercise in six healthy individuals. Ten and 30 minutes of cycling at 80% of maximal intensity produced comparable increases in the resting metabolic rate, (37% and 32%, respectively) immediately after exercise. However, by 30 minutes following exertion, the metabolic rate was not different from control values. The total additional caloric use during the 90 minutes of recovery was similar for the two exercise durations, and the mean increment in recovery energy expenditure was 11.4 +/- 7.1 kcals. The majority of caloric use with exercise is during the activity. Recovery energy expenditure following usual aerobic training results in only a minor contribution to total energy use.