Infant formula and neurocognitive outcomes: impact of study end-point selection.

OBJECTIVES: Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. STUDY DESIGN: We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. RESULTS: We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. CONCLUSION: The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials.

Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.

Expression of arginase isozymes in mouse brain.

The two forms of arginase (AI and AII) in man, identical in enzymatic function, are encoded in separate genes and are expressed differentially in various tissues. AI is expressed predominantly in the liver cytosol and is thought to function primarily to detoxify ammonia as part of the urea cycle. AII, in contrast, is predominantly mitochondrial, is more widely expressed, and is thought to function primarily to produce ornithine. Ornithine is a precursor in the synthesis of proline, glutamate, and polyamines. This study was undertaken to explore the cellular and regional distribution of AI and AII expression in brain using in situ hybridization and immunohistochemistry. AI and AII were detected only in neurons and not in glial cells. AI presented stronger expression than AII, but AII was generally coexpressed with AI in most cells studied. Expression was particularly high in the cerebral cortex, cerebellum, pons, medulla, and spinal cord neurons. Glutamic acid decarboxylase 65 and glutamic acid decarboxylase 67, postulated to be related to the risk of glutamate excitotoxic and/or gamma-aminobutyric acid inhibitoxic injury, were similarly ubiquitous in their expression and generally paralleled arginase expression patterns, especially in cerebral cortex, hippocampus, cerebellum, pons, medulla, and spinal cord. This study showed that AI is expressed in the mouse brain, and more strongly than AII, and sheds light on the anatomic basis for the arginine-->ornithine-->glutamate-->GABA pathway.

Trasplante renal doble: donante y receptor añoso / Double renal transplant: elderly donor and elderly receptor

Se presenta el caso clínico del trasplante de dos riñones, provenientes de un hombre mayor de 64 años hipertenso, en una misma receptora de 63 años. La evolución postoperatoria fue satisfactoria, y a un año de efectuada la intervención la paciente realiza una vida normal, con una función satisfactoria de sus injertos. Esta primera experiencia nacional, de un injerto renal de estas características permitiría plantear una nueva alternativa terapéutica e incluir dentro del grupo de donantes efectivos a individuos que tradicionalmente eran descartados como donantes potenciales desde un primer momento

Tratamiento trombolítico en infarto agudo al miocardio posteroinferior / Thromolythic treatment in posteroinferior acute micardium infarction

Antecedentes. Con el advenimiento de la trombólisis (TBL), numerosas publicaciones han observado su utilidad en el infarto al miocardio (IAM). Objetivo. Conocer los beneficios de la trombólisis en el IAM posteroinferior y describir el efecto de este tratamiento sobre la estancia y la mortalidad hospitalaria. Material y métodos. Estudio retrospectivo, transversal, observacional, para comparar la trombólisis y el tratamiento conservador en 39 y 25 pacientes, respectivamente, del Hospital Angeles del Pedregal de 1989 a 1995, en relación con los días de estancia intrahospitalaria, complicaciones y mortalidad. Resultados. No se encontraron diferencias estadísticas significativas, pero sí en el porcentual. Conclusión. La significancia clínica de la trombólisis en infarto agudo al miocardio posteroinferior en nuestra población, necesita probarse en un estudio de mayor número de pacientes

Streptococcus pneumoniae resistant to penicillin: incidence and potential therapeutic options.

Streptococcus pneumoniae was recovered from 12 (50%) samples of middle ear fluid of 24 consecutive patients with AOME and in mixed culture of middle ear pathogens from one (4%) additional specimen. Two (15.3%) isolates had intermediate resistance to penicillin (minimal inhibitory concentration (MIC) 0.125 and 1.0 micrograms/mL). The antimicrobial susceptibility to various antimicrobials of 30 S pneumoniae strains recovered from patients seen in the last 12 months was also determined. One of the patients with AOME developed bacteremia that resolved uneventfully, whereas the other developed meningitis. MIC90 was determined from penicillin (2 micrograms/mL), erythromycin (> 32 micrograms/mL), cefaclor (32 micrograms/mL), loracarbef (> or = 64 micrograms/mL), cefixime (16 micrograms/mL), ceftibuten (> 64 micrograms/mL), chloramphenicol (16 micrograms/mL), cefpodoxime (4 micrograms/mL), ciprofloxacin (2 micrograms/mL), cephalexin (> or = micrograms/mL), augmentin (2 micrograms/mL), cefprozil (8 micrograms/mL), clindamycin (64 micrograms/mL), TMP-SXT (> 64 micrograms/mL), clarithromycin (32 micrograms/mL), rifampin (0.06 micrograms/mL), cefuroxime (2 micrograms/mL), cefotaxime (0.25 micrograms/mL), vancomycin (0.25 micrograms/mL), and imipenem (0.5 micrograms/mL). Cefprozil, vancomycin, and rifampin inhibited all strains, whereas cefpodoxime, cefuroxime, clindamycin, and clarithromycin exhibited very good activity.

Cefaclor in the treatment of susceptible infections in infants and children.

Cefaclor is a new oral cephalosporin with in vitro activity against a wide variety of organisms including S. aureus, S. pneumoniae, S. pyogenes and H. influenzae (including ampicillin-resistant strains). Seventy-nine patients ranging in age from 2 months to 14 years with soft tissue infections (17 cases), otitis media (17), and streptococcal pharyngitis (45) were studied. They received cefaclor orally at a dose of 40 mg/kg per day in three or four divided doses for a minimum of five days. Results were generally good with favourable clinical and bacteriological responses obtained in 90% of cases. Most patients became afebrile within 48 hours after starting cefaclor. Two patients with H. influenzae cellulitis and bacteraemia defervesced within 24 hours and their blood cultures became negative promptly. Hepatic, renal and haematopoietic studies showed no adverse reactions except for an occasional increase in the eosinophil count with no clinical counterpart of hypersensitivity. Pharmacokinetic studies revealed that following a 10 mg/kg oral dose, peak serum levels of 8 micrograms/ml were observed at one hour, followed by a rather rapid tapering off so that at the end of four hours, virtually no cefaclor was detectable in serum.

Epidemiology of human rotavirus Types 1 and 2 as studied by enzyme-linked immunosorbent assay.

To determine the relative importance of two known serotypes of human rotavirus, we developed an enzyme-linked immunosorbent assay to differentiate serotype-specific rotavirus antigen and antibody. Using this technic, we studied the epidemiology of the two serotypes in acute gastroenteritis. Seventy-seven per cent of 414 rotavirus isolates were Type 2, and the remainder were Type 1. The serotype distribution was similar in specimens from children in Washington, D.C., and other parts of the world. Sero-epidemiologic studies revealed that most children living in the Washington, D.C., area acquired antibody to both types by the age of two years. An analysis of children who were reinfected indicated that sequential infections usually involved different serotypes and that illness caused by one serotype did not provide resistance to illness caused by the other serotype. These results suggest that, to be completely effective, a vaccine must provide resistance to both serotypes.