Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease.

BACKGROUND: Addition of glutamine to parenteral nutrition in surgical infants remains controversial. The aim of this trial was to determine whether glutamine supplementation of parenteral nutrition in infants requiring surgery would reduce the time to full enteral feeding and/or decrease the incidence of sepsis and septicaemia. METHODS: A prospective double-blind multicentre randomized clinical trial was performed in surgical infants less than 3 months old who required parenteral nutrition. Patients were allocated to treatment or control groups by means of minimization. Infants received either 0·6 g per kg per day alanyl-glutamine (treatment group) or isonitrogenous isocaloric parenteral nutrition (control group) until full enteral feeding was achieved. Primary outcomes were time to full enteral feeding and incidence of sepsis. Cox regression analysis was used to compare time to full enteral feeding, and to calculate risk of sepsis/septicaemia. RESULTS: A total of 174 patients were randomized, of whom 164 completed the trial and were analysed (82 in each group). There was no difference in time to full enteral feeding or time to first enteral feeding between groups, and supplementation with glutamine had no effect on the overall incidence of sepsis or septicaemia. However, during total parenteral nutrition (before the first enteral feed), glutamine administration was associated with a significantly decreased risk of developing sepsis (hazard ratio 0·33, 95 per cent confidence interval 0·15 to 0·72; P = 0·005). CONCLUSION: Glutamine supplementation during parenteral nutrition did not reduce the incidence of sepsis in surgical infants with gastrointestinal disease. REGISTRATION NUMBER: ISRCTN83168963 (http://www.controlled-trials.com).

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment.

Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children. Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ET(A) and ET(B), respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n=7), following extended combined bosentan and epoprostenol therapy (n=5) and from normal subjects (n=5). Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ET(A) was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ET(A), ET(B) and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ET(A) and ET(B) were normal and eNOS increased. In smooth muscle, ET(A) expression was reduced in treated cases but ET(B) expression increased in all arteries of both treated and untreated cases. In summary, ET(A) is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Rat embryo development on human sera is related to numbers of previous spontaneous abortions and nutritional factors.

OBJECTIVES: The objectives were to determine (1) if sera from women with histories of spontaneous abortions were teratogenic to cultured embryos more often than were sera of nonaborters, (2) if the teratogenicity could be corrected by adding nutrients to the sera, and (3) if these findings were relevant to reproductive outcomes. STUDY DESIGN: Rat embryos were cultured for 48 hours on sera from 102 subjects who had experienced spontaneous abortions. Samples from 48 were retested with nutrients added and 10 took dietary supplements, were again tested with embryo cultures, and reported on their pregnancy outcomes. RESULTS: The frequencies of teratogenic sera increased with numbers of spontaneous abortions (0 to > or = 5) in a manner that did not deviate from linearity (27% to 89%) (chi 2 p > 0.957). Nutrient supplements were added to 48 samples, and 40 were corrected and 10 subjects were given dietary supplement. Sera from six showed improved embryo cultures, and these women completed their pregnancies. CONCLUSIONS: Rat embryo cultures may provide unique insights into the causes and treatment of spontaneous abortions.

Methionine decreases the embryotoxicity of sodium valproate in the rat: in vivo and in vitro observations.

Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approximately twice the level of serum-free methionine and consumed only one-half the volume of water of controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from neural tube defects, nor did the addition of methionine to a medium of serum obtained from rats previously dosed with sodium valproate. However, protection from the teratogenic effects of sodium valproate was afforded by methionine when the culture medium was sera from rats consuming methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine. These observations along with those of others indicated the importance of dietary and culture media methionine levels in evaluating experimental and regulatory teratology studies and suggested the possibility that methionine may play an important role in human teratology where multifactorial causes have been implicated in problems such as neural tube closure defects.

Whole rat embryos require methionine for neural tube closure when cultured on cow serum.

Headfold-stage rat embryos, when cultured on cow serum without supplemental methionine, failed to close their neural tubes, lacked eyes and branchial arches, were abnormally shaped and were reduced in protein content compared to methionine-supplemented embryos. Methionine was essential during the first 18 h of culture, a period in which neural tube closure was initiated in supplemented cultures. All cow serum samples tested were found to require methionine addition, and the methionine was not replaced by other amino acids or vitamins, including folate. Methionine was not toxic to cultured rat embryos at concentrations up to at least 500 micrograms/ml. Analyses of serum free amino acids revealed lower levels of free methionine in cow serum compared to rat serum, and cow serum proteins contained less methionine relative to other amino acids than did rat serum proteins. Dialysis of cow serum reduced but did not eliminate the requirement for methionine. This suggested either that the free amino acids of cow serum were imbalanced or that a dialyzable component in serum interfered with the availability/utilization of methionine. Dietary supplementation of cows with rumen-protected DL-methionine increased the serum methionine level, and serum drawn from supplemented cows supported normal rat embryo development without additional methionine.

Methionine and iron as growth factors for rat embryos cultured in canine serum.

Development of headfold-staged rat embryos cultured in canine serum containing various supplements was compared with development in rat serum to seek suitable alternatives to rat serum in rodent embryo culture and to identify nutritional factors for cultured rodent embryos that may have relevance for normal mammalian embryonic growth and development. Supplementation of canine serum with glucose, methionine, and a lipophilic iron chelate allowed growth and development of cultured rat embryos, approximating those obtained with rat serum. These findings suggest that properly supplemented canine serum can serve as a suitable rodent embryo culture medium and that glucose, iron, and methionine may be important nutrients in mammalian embryonic development.

Calcium-channel blockers for combined angina pectoris and systemic hypertension.

Calcium-channel blockers have been successfully used in the treatment of angina of effort and systemic hypertension. Many patients present with concomitant angina pectoris and hypertension. Controlled clinical trials demonstrate that the calcium-channel blockers are safe and effective as monotherapy in the treatment of these patients, and that their use compares favorably with that of propranolol. The effectiveness of these agents in hypertension appears to be primarily due to their ability to induce systemic vasodilation. Calcium-channel blockers have several therapeutic effects in angina pectoris. Beneficial actions on the major determinants of oxygen consumption, i.e. heart rate, blood pressure and contractility, are generally seen. The potent coronary vasodilating actions of these agents allow for increased coronary blood flow. Improvements in ventricular compliance, regression of left ventricular hypertrophy and cardioprotection appear to be additional effects of the calcium-channel blockers; their contribution to the drugs' overall therapeutic efficacy is presently being evaluated. Calcium-channel blockers are a welcome addition to drug regimens available for the management of patients with coexisting angina pectoris and hypertension.

Human serum teratogenicity studied by rat embryo culture: epilepsy, anticonvulsant drugs, and nutrition.

Epileptic women have a greater risk for spontaneous abortions and children with birth defects than do nonepileptics. In a unique approach to identifying causes of these problems, we have cultured whole rat embryos for 48 h on blood sera from epileptics. In the first part of the study, three embryos were cultured on each serum sample from 128 different epileptics being treated with either single anticonvulsants or no drug to compare the teratogenicity of these drugs. Sera from subjects receiving either phenobarbital or no drug had comparable frequencies of cultured embryo abnormalities, which were lower than those from subjects taking phenytoin, valproic acid, or carbamazepine. In the second phase of the study, attempts to identify causes for serum teratogenicity led to the finding that the abnormalities and reduced embryo growth produced by many serum samples could be completely overcome by adding vitamins and/or amino acids to the serum. Of 53 samples tested, 32 (60%) were corrected by supplementation (17 of 23 phenytoin, seven of nine phenobarbital, six of 12 carbamazepine, none of six valproic acid, and two of three no drug). Although the results of this study provided a general assessment of drug teratogenicity that agreed with other studies and emphasized the role of nutrition in fetal defects, the importance of individual differences in causes of teratogenicity was also noted.

Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. A placebo-controlled double-blind randomized crossover trial.

The relative efficacies of oral verapamil, a calcium-entry blocking drug, and propranolol, a beta-adrenergic blocking drug, were compared in 12 patients who had both stable angina pectoris and mild to moderate systemic hypertension, using a placebo-controlled, double-blind, randomized crossover protocol. Compared with placebo, both propranolol and verapamil decreased the frequency of anginal attacks and the number of nitroglycerin tablets consumed, and increased exercise duration and total work; there were no significant differences in the antianginal effect of the two drugs. Both verapamil and propranolol reduced the supine and standing systolic and diastolic blood pressure measured at rest; compared with propranolol, however, verapamil had greater effects on standing diastolic blood pressure (p less than 0.002). Resting heart rate was reduced from placebo baseline with large doses of both drugs; compared with verapamil, however, propranolol exerted greater effects on resting heart rate and rate-pressure product. Plasma renin activity was increased from placebo baseline with verapamil (p less than 0.05), but was reduced with propranolol (p less than 0.05); no significant change in plasma aldosterone was seen with either drug. Verapamil appears to be a safe and effective treatment alternative to propranolol for relieving anginal symptoms, improving exercise tolerance, and reducing elevated systemic blood pressure in patients with both angina pectoris and mild to moderate systemic hypertension.

Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension.

The effects of sublingual nifedipine, a calcium antagonist vasodilator, were assessed in 43 patients with moderate to severe hypertension in an emergency room setting. Following a no-response placebo treatment period, the patients with supine diastolic blood pressure of less than 110 mm Hg (group A, n equals 17) received 10 mg of sublingual nifedipine, and the patients with supine diastolic blood pressure of much greater than or equal to 110 mm Hg (group B, n equals 26) received a 20-mg sublingual dose. In group A, systolic blood pressure decreased from 172.4 plus or minus 18.6 mm Hg to 140.0 plus or minus 14.6 mm Hg; diastolic pressure from 108.8 plus or minus 3.3 mm Hg to 87.6 plus or minus 9.9 mm Hg (P less than 0.001)., In group B, systolic blood pressure decreased from 203.8 plus or minus 22.1 mm Hg to 160.0 plus or minus 23.6 mm Hg; diastolic pressure from 127.7 plus or minus 11.3 mm Hg to 96.7 plus or minus 14.1 mm Hg (P less than 0.001). Heart rate increased significantly only in the 20-mg dose group, from 76 plus or minus 2 to 89 plus or minus 6 beats/min (P less than 0.005). Th effects of sublingual nifedipine were seen in one to five minutes, and the maximal effect in 20 to 30 minutes, with return to placebo baseline in four to five hours. Adverse reactions were minimal in both treatment groups. Nifedipine is an effective and safe hypotensive drug in the rapid management of moderate to severe hypertension and seems to be an effective nonparenteral agent for treatment of hypertensive emergencies.

Successful culture of rat embryos on human serum: use in the detection of teratogens.

Growth of head-fold-stage rat embryos cultured with human serum for 48 hours was enhanced by supplementation with glucose. Embryo growth (protein and DNA contents) varied with the source of the serum. Serum from 16 of 19 untreated subjects produced normal embryos. Serum from five subjects undergoing cancer chemotherapy and six subjects receiving anticonvulsants was either lethal or teratogenic.

Isolation and characterization of a glycerol auxotroph of Rhodopseudomonas capsulata: effect of lipid synthesis on the synthesis of photosynthetic pigments.

A glycerol auxotroph was isolated from Rhodopseudomonas capsulata for use as a system for studying membrane synthesis and function. When the mutant was deprived of glycerol, net phospholipid synthesis ceased immediately and a small amount of free fatty acids accumulated. A turnover of lipid occurred in both deprived and supplemented cultures. Deoxyribonucleic acid and protein synthesis continued for one doubling of cell massand then slowed down in deprived cells. Net ribonucleic acid synthesis slowed down more dramatically. Oxidative phosphorylation activity of membrane preparations from aerobically and semi-anaerobically grown cells appeared unaffected by glycerol deprivation, indicating that simultaneous lipid synthesis is not a requirement for new oxidative phosphorylating activity. In the absence of net phospholipid synthesis, bacteriochlorophyll and carotenoid syntheses were reduced to 30% of the activity of supplemented cultures. Delta-Aminolevulinic acid synthase, the first enzyme on the bacteriochlorophyll pathway that is subject to regulatory control, increased in activity in deprived cultures. Lascelles and Szilagyi (1965) showed an association between phospholipid synthesis and pigment production. They found an increased lipid content associated with pigmented cells. The present results indicate that not only is there an association between lipid and pigment synthesis, but also there is actually a dependence of bacteriochlorophyll synthesis on phospholipid synthesis.