Effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics.

OBJECTIVE: this analysis was to investigate the effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics. DESIGN, SETTING AND PARTICIPANTS: the study was a double-blind, randomised, placebo-controlled trial of 99 women (mean 76.6 +/- 6.0 year) with the low DHEA-S level and frailty. INTERVENTION: participants received 50 mg/day DHEA or placebo for 6 months; all received calcium (1,000-1,200 mg/day diet) and supplement (combined) and cholecalciferol (1,000 IU/day). Women participated in 90-min twice weekly exercise regimens, either chair aerobics or yoga. MAIN OUTCOME MEASURES: assessment of outcome variables included hormone levels (DHEA-S, oestradiol, oestrone, testosterone and sex hormone-binding globulin (SHBG)), lipid profiles (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides), body composition measured by dual energy absorptiometry, glucose levels and blood pressure (BP). RESULTS: eighty-seven women (88%) completed 6 months of study; 88% were pre-frail demonstrating 1-2 frailty characteristics and 12% were frail with > or =3 characteristics. There were significant changes in all hormone levels including DHEA-S, oestradiol, oestrone and testosterone and a decline in SHBG levels in those taking DHEA supplements. In spite of changes in hormone levels, there were no significant changes in cardiovascular risk factors including lipid profiles, body or abdominal fat, fasting glucose or BP. CONCLUSION: research to date has not shown consistent effects of DHEA on cardiovascular risk, and this study adds to the literature that short-term therapy with DHEA is safe for older women in relation to cardiovascular risk factors. This study is novel in that we recruited women with evidence of physical frailty.

Femoral bone mineral density in patients with heart failure.

INTRODUCTION: Heart failure and osteoporosis are common conditions in older, frail individuals. It is important to investigate interactions of the common problems in the aging population to devise relevant interventions. METHODS: Sixty individuals (43 men, mean age 77+/-9 years, and 17 women, mean age 78+/-12 years) with heart failure (HF) and 23 age- and gender-matched non-HF controls (15 men, eight women; mean age 77+/-9 years) underwent hip and bone mineral density (BMD) assessments; frailty assessment; physical performance assessment including 6-min walk, grip strength, and self-reported physical activity; and biochemical assessment including calcium, parathyroid hormone (PTH), 25-hydroxy vitamin D (25-OHD), estradiol, creatinine (Cr), and blood urea nitrogen levels (BUN). RESULTS: Significant differences between HF and control groups were found for BMD Z-scores of the femoral neck, total femur, and trochanteric region at the femur (p<.05). Further differences between groups included frailty score (p=.02), 6-min walking distance (p<.001), and self-reported physical activity (p=.001). In addition, several differences between groups were present for calcium (p=.054), PTH (p<.001), 25-OHD (p=.01), Cr (p=.04), and BUN (p=.01). In regression analysis, HF (defined as case, by ejection fraction, or by New York Heart Association class), frailty status, and vitamin D were significant predictors of lower bone mass at the femur. CONCLUSIONS: Individuals with HF have lower BMD, in part related to lower vitamin D status and higher frailty rates. Interventions to optimize vitamin D and physical activity should be explored to prevent bone loss in individuals with heart failure.

The effect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer.

OBJECTIVE: To evaluate body composition changes, specifically skeletal muscle mass, in men receiving androgen deprivation with luteinizing-hormone releasing hormone-agonist (LHRH-A) for prostate cancer (PCa) in comparison with healthy controls. DESIGN: Retrospective analysis of body composition changes in men with prostate cancer receiving LHRH-A therapy from 2 clinical trials compared to men without prostate cancer serving as a placebo-control in another clinical trial. SETTING: Clinical Research Center in Connecticut. PARTICIPANTS: Thirty men (> 60 years) receiving 6 months of LHRH-A therapy for PCa were compared to a healthy group of 25 men without PCa. MEASUREMENTS: Appendicular skeletal muscle/height2 (ASM/ht2), lean and fat mass were assessed by dual energy x-ray absorptiometry. Total testosterone levels were assessed by enzyme immunoassay. RESULTS: At baseline, 12/30 (40%) of the treatment group and 7/25 (28%) of the control group (p = 0.11) met criteria for sarcopenia. There were no differences between control groups in ASM/ht2 or lean mass. The LHRH-A group had a higher percent body fat than the control group, 29.8 +/- 6.3 versus 26.3 +/- 4.6 (p = 0.02). ASM/ht2 and lean mass decreased in the LHRH-A group from 7.5 +/- 0.9 kg to 7.3 +/- 0.9 kg (-2.3% +/- 0.03; p < or = 0.001) and 53.5 +/- 5.4 kg to 52.3 +/- 5.3 kg (-2.1% +/- 0.03; p < or = 0.001), respectively. There was no muscle loss in the control group. At 6 months, the LHRH-A group had increased percent body fat from 29.8 +/- 6.4 to 32.2 +/- 5.8 (9.5% +/- 0.13; p < or = 0.001), whereas the control group had decreased in percent body fat from 26.6 +/- 4.6 to 25.3 +/- 5.0 (-3.8% +/- 0.08; p = 0.02). CONCLUSIONS: Men undergoing LHRH-A treatment for PCa decreased appendicular skeletal muscle and lean tissue and increased body fat within 6 months of initiation of therapy. Lifestyle changes or medical interventions to minimize the effects of androgen deprivation therapy for PCa deserve investigation.

c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations.

Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.

Usefulness of triiodothyronine (T3) treatment after surgery for complex congenital heart disease in infants and children.

This is a study of the use of T3 infusion in the postoperative period in 6 pediatric patients who underwent complex cardiac surgical procedures under cardiopulmonary bypass. Normalization of serum T3 levels was reflected in a marked decrease in requirement of inotropic support, conversion to normal sinus rhythm, and progressively improving clinical course.

Differential responses of brain, liver, and muscle glycogen to opiates and surgical stress.

We examined the effects of intracerebroventricular (ICV) cannula implantation followed by the administration of morphine sulfate (MOR) and its metabolite, morphine-6-glucuronide (M6G), on the glycogen content of the brain, liver, and muscle. ICV cannulation resulted in nearly a 30% reduction in brain glycogen, and ICV MOR resulted in a 36% reduction in liver glycogen content compared to time-matched controls, but it had no additional effect on either the brain or muscle glycogen content. ICV M6G showed a more significant reduction, to 50% of liver glycogen, but it had no effect on either brain or muscle glycogen. Neither IV MOR nor M6G produced any significant alteration in tissue glycogen content. These results indicate that the stress response associated with neurosurgery, especially the placement of the ICV cannula, is associated with a decrement in brain glycogen. The activation of opioid receptors in the brain results in enhanced hepatic glycogenolysis but has no additional effect on the brain glycogen content.

Subclavian artery pseudoaneurysm in type IV Ehlers-Danlos syndrome.

We report case of a subclavian artery pseudoaneurysm in a patient with type IV Ehlers-Danlos Syndrome. A 16-year-old boy underwent successful repair of a subclavian artery pseudoaneurysm that occurred after a cervical hyperextension injury. Subsequent workup included skin biopsy and fibroblast culture, which were consistent with a diagnosis of type IV Ehlers-Danlos Syndrome. This condition is a dominantly inherited connective tissue disorder, which in this patient was found to be caused by a spontaneous point mutation in the COL3A1 gene that encodes the chains of type III procollagen. The clinical, genetic, and molecular characteristics of type IV Ehlers-Danlos Syndrome are briefly reviewed.

An avian sodium-hydrogen exchanger.

Intestinal sodium transporters, such as the Na+/H+ exchanger (NHE) are important for Na+ conservation in land birds. In mammals, at least five isoforms of the exchanger, NHEs 1-5, have been cloned, with NHE-1 occurring in epithelial basolateral and nonepithelial cell membranes and NHE-3 being restricted to epithelial apical/brush border membranes. We had demonstrated earlier that chicken intestinal brush border membranes possess NHE activity that functionally resembles mammalian NHE-3. In this study, we used mammalian NHE-1 and NHE-3 probes to examine if chicken enterocytes possess these transporters. Antisera against rat NHE-3 recognized a 97 kDa protein in chicken intestinal brush border membrane, while a NHE-3 cDNA probe failed to recognize any transcript. A NHE-1 antibody failed to recognize any protein in brush border or basolateral membrane, while a NHE-1 cDNA probe recognized a 3.9 kb transcript. Thus, there is more than one NHE isoform in chicken intestine, and our results suggest a novel avian NHE family.

Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans.

OBJECTIVE: To investigate whether an infusion of recombinant tissue plasminogen activator would dissolve microvascular thromboses and improve organ perfusion in a patient with fulminant meningococcemia. DESIGN: Descriptive case report. SETTING: Fifteen-bed pediatric intensive care unit (ICU) in a university hospital. PATIENT: A 4-month-old male with fulminant meningococcemia, refractory shock, and multiple organ failure. INTERVENTIONS: In addition to standard aggressive ICU care, the patient received a recombinant tissue plasminogen activator infusion at a total dose of 1.25 mg/kg over 4 hrs. MEASUREMENTS AND MAIN RESULTS: Heart rate, arterial blood pressure, urine output, and base deficit (as a reflection of severity of metabolic acidosis) were recorded immediately before the recombinant tissue plasminogen activator infusion and 4 hrs later, after completion of the recombinant tissue plasminogen activator infusion. The amount of exogenous vasopressor and inotropic support required to maintain the patient's hemodynamic status before and after recombinant tissue plasminogen activator infusion were also compared. Subjective observations regarding the patient's peripheral perfusion status were also noted. The patient showed a dramatic improvement in hemodynamics, urine output, and metabolic acidosis, as well as a perceived increase in skin perfusion after recombinant tissue plasminogen activator infusion. CONCLUSIONS: In this patient, recombinant tissue plasminogen activator infusion resulted in improved organ perfusion and cardiac performance. Selective use of recombinant tissue plasminogen activator in the treatment of fulminant meningococcemia merits further investigation.

Four sibs with arterial tortuosity: description and review of the literature.

We described four offspring of a consanguineous couple with arterial tortuosity "syndrome" (ATS). The affected children had extensive arterial involvement although the clinical presentations were quite variable. Clinical manifestations included cutis laxa or soft/thin skin, joint laxity or contractures, and arachnodactyly. Aortic tortuosity and pulmonary artery aneurysms with or without peripheral stenoses were demonstrated in all four sibs. All three males had inguinal hernias. Inconsistent facial anomalies were downslanting palpebral tissues, beaked nose, micrognathia, and high-arched palate. Results of collagen type I and type III biosynthesis studies were normal on skin fibroblasts. Histologic findings on autopsy of one affected child showed arterial changes with disruption of elastic fibers of the media and fragmentation of the internal elastic membrane as well as mucosal and transmural necrosis of the stomach, small bowel, colon, and extensive necrosis of the liver. Coronary artery involvement was also seen in this child as well as biventricular hypertrophy. We conclude that ATS is an autosomal recessive connective tissue condition associated with diffuse arterial changes and involvement of the skin, joints, and other organs.

Complications of care in a pediatric intensive care unit: a prospective study.

OBJECTIVES: (a) To examine the frequency, type, and severity of complications occurring in a pediatric intensive care unit; (b) to identify populations at risk; and (c) to study the impact of complications on morbidity and mortality. DESIGN: Prospective survey. SETTING: Pediatric intensive care unit (PICU) of a university-affiliated hospital. PATIENTS: 1035 consecutive admissions over an 18-month period. RESULTS: 115 complications occurred during 83 (8.0%) admissions, for 2.7 complications per 100 PICU-days; 48 (42%) complications were major, 45 (39%) moderate, and 22 (19%) minor. Sixty complications (52%) were ventilator-related, 14 were drug-related, 13 procedure-related, 24 infectious, and 22 involved invasive devices (18 vascular catheters). Human error was involved in 41 (36%) cases, 21 of which were major (18%). Treatments included reintubation < 24 h (28), intravenous antimicrobials (24), and invasive bedside procedures (14). Cardiopulmonary resuscitation was required in 6 patients. Thirteen patients with complications died (15.7%); 2 deaths were directly due to complications. Patients with complications were younger, had longer lengths of stay, and had a higher mortality. Length of stay was a positive risk factor for complication risk (odds ratio = 1.09, 95% confidence interval: 1.05 to 1.13; p = 0.0001); other patient characteristics had no predictive effect. Kaplan-Meier estimates showed that the most severe complications occurred early in the PICU stay. The best indicators of patient mortality were number of complications (odds ratio = 2.96, 95% confidence interval 1.72 to 5.08; p = 0.0001), and mortality risk derived from the Pediatric Risk of Mortality Score (odds ratio = 1.08, 95% confidence interval 1.06 to 1.10; p = 0.0001). Mortality was correlated with increasing severity of complications. CONCLUSION: Complications have a significant impact on patient care. Patients may be at increased risk earlier in their PICU course, when the number of interventions may be greatest. Complications may increase patient mortality and predict patient death better than other patient variables.

Modulation of endogenous opiate production: effect of fasting.

The endogenous opiate alkaloid content in tissues from fed, 24 h and 48 h fasted rats was determined. Plasma morphine and codeine concentrations did not change in response to fasting. Morphine levels in the spleen increased 3-fold after 24 h of fasting and were lower than fed rats by 48 h of fasting; no change was detected in spleen codeine levels. Brain morphine levels were elevated 5-fold after 24 h of fasting and were two-fold higher than those of fed rats after 48 h of fasting. Brain codeine levels did not change with fasting. These results indicate that opiate alkaloids are endogenously produced in rodent tissues, particularly in the spleen, liver, and adrenals. The synthesis of morphine, in the spleen and brain, is maximally stimulated after 24 h of fasting, without alterations in tissue codeine synthesis. These suggest differential regulation of the endogenous synthetic pathways of morphine and codeine in response to the stress of fasting.

Cardiac tamponade in an adolescent female: an unusual manifestation of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) affects approximately 0.6 children per 100,000. The disease is extremely rare in children under 5 years of age and is diagnosed predominantly in adolescent females. Children tend to present with more severe multisystem involvement than adults. Pericarditis occurs in approximately 25% of patients with SLE in all age groups. Progression to tamponade is extremely uncommon in the pediatric population. In the current report, an adolescent girl is diagnosed with SLE after presenting with signs and symptoms consistent with cardiac tamponade. A review of other pediatric patients with a similar presentation is also included.

Correlation between clinical diagnoses and autopsy findings in critically ill children.

STUDY OBJECTIVE: To examine the correlation between clinical diagnoses and autopsy findings in children who die in the pediatric intensive care unit (PICU). DESIGN: Retrospective chart review. SETTING: PICU of a university-affiliated hospital. PATIENTS: A consecutive sample of patients who died in the PICU and had autopsies performed. MEASUREMENTS AND MAIN RESULTS: Of 193 patients who died during the 7 1/2-year study period, 50 (26%) had autopsies performed. The mean age was 34.7 months (range 15 hours to 17 years), and the mean length of stay in the PICU was 12.2 days (range 2 hours to 60 days). Major admitting diagnoses included postoperative cardiac surgery (19), nonoperative cardiac disease (7), hematologic/malignant disorder (5), and acquired immunodeficiency syndrome (5). There were 5 cases (10%) where autopsy revealed a major finding that, if known prior to death, would have altered clinical management and might have resulted in cure or prolonged survival. In another 9 patients (18%) the autopsy revealed major findings that, if known prior to death, would not have altered management. Eight of these findings related to the cause of death and 2 of them involved the basic disease. There was no correlation between new findings and either patient age or length of stay in the PICU. CONCLUSIONS: Despite modern diagnostic techniques, the autopsy continues to reveal valuable and unsuspected information.

Life-threatening organophosphate-induced delayed polyneuropathy in a child after accidental chlorpyrifos ingestion.

Life-threatening organophosphate-induced delayed polyneuropathy with transient bilateral vocal cord paralysis occurred in a 3-year-old child. Recovery was slow after prolonged ventilatory support. Patients who recover from serious organophosphate intoxications should be closely monitored for the development of organophosphate-induced delayed polyneuropathy.

Bronchial hyperreactivity in children with Marfan syndrome.

Marfan syndrome is known to have pulmonary manifestations such as pneumothorax. There have been few previous studies of pulmonary function tests and none of bronchial hyperreactivity. Therefore, pulmonary function tests were performed in 11 children with Marfan syndrome and 11 normal children. Bronchial responsiveness was tested in ten of the Marfan patients by methacholine challenge test and response to bronchodilator. Because of disproportionate length of legs in Marfan patients, an "ideal" standing height was calculated from sitting height. Pulmonary function tests, as absolute values or as percent predicted based on "ideal" height, were not different in Marfan patients and normals, although a few individual patients had abnormal function (mostly airway obstruction and hyperinflation). Response to methacholine challenge was positive on forced expiratory volume in 1 second (FEV1), forced expiratory flow between 25 and 75% VC (FEF25-75%), and FEF50%, in 37.5%, 60%, and 70% of tests respectively. A significant response to bronchodilators was obtained in 40% of patients as measured by FEV1, in 90% by FEF25-75% and in 100% by FEF50%. Pulmonary function tests after bronchodilator were significantly higher when compared with values before the bronchodilator as well as with the baseline before methacholine. Therefore, most if not all patients with Marfan syndrome had hyperreactive airways in this relatively small group of patients. Even though only one patient had a diagnosis of asthma, six more had subtle symptoms. It is concluded that tests for bronchial hyperreactivity could be part of the routine investigation in Marfan syndrome. Further studies on larger numbers of patients are still needed.