Potential application of the consistency approach for vaccine potency testing.

The Consistency Approach offers the possibility of reducing the number of animals used for a potency test. However, it is critical to assess the effect that such reduction may have on assay performance. Consistency of production, sometimes referred to as consistency of manufacture or manufacturing, is an old concept implicit in regulation, which aims to ensure the uninterrupted release of safe and effective products. Consistency of manufacture can be described in terms of process capability, or the ability of a process to produce output within specification limits. For example, the standard method for potency testing of inactivated rabies vaccines is a multiple-dilution vaccination challenge test in mice that gives a quantitative, although highly variable estimate. On the other hand, a single-dilution test that does not give a quantitative estimate, but rather shows if the vaccine meets the specification has been proposed. This simplified test can lead to a considerable reduction in the number of animals used. However, traditional indices of process capability assume that the output population (potency values) is normally distributed, which clearly is not the case for the simplified approach. Appropriate computation of capability indices for the latter case will require special statistical considerations.

Mortality of full-term infants during the first month of life in a tertiary care hospital.

OBJECTIVE: The neonatal mortality rate is disproportionately influenced by preterm infants and does not reflect the rate in full-term infants. Our objectives were to estimate the full-term neonatal mortality rate and to identify causes of death in full-term infants during the first month of life. STUDY DESIGN: A retrospective study of full-term infant deaths during a 6-year period from 2000 to 2005, in a tertiary medical center. RESULT: During the study period there were 44,703 full-term births and 31 deaths, representing a mortality rate of 0.69 per 1,000 live births. The main cause of death was congenital anomalies (64.5%), specifically cardiac anomalies. Other causes were chromosomal anomalies or syndromes (12.9%), labor complications (12.9%), infections (3.2%), congenital diseases (3.2%) and metabolic disorders (3.2%). CONCLUSION: The mortality rate of full-term infants may be lower than previous estimates. Efforts aimed at decreasing mortality among full-term infants should focus on prenatal diagnosis.

Bronchopulmonary dysplasia in very low birth weight infants is associated with prolonged hospital stay.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with prolonged hospital length of stay (LOS) and delayed discharge home. OBJECTIVES: To evaluate the association between BPD and LOS and to assess the contribution of concomitant major morbidities on LOS among infants with BPD. STUDY DESIGN: A population-based observational study of very low birth weight (VLBW) infants born from 1995 through 2003. Multivariate analyses, adjusted for perinatal variables, assessed the association between BPD and concomitant morbidities on LOS. RESULTS: Of 10 134 survivors, 1926 (19.0%) had BPD. The adjusted LOS for infants with and without BPD was 84.1 days (95% CI, 82.8, 85.6) and 58.1 days (95% CI, 57.2, 59.0), respectively. Addition of a single concomitant morbidity increased mean LOS by 4 to 13 days. CONCLUSIONS: BPD is a major cause of increased length of hospitalization among VLBW infants. Preventive or therapeutic modalities are required to reduce the significant burden of this condition.

Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation.

OBJECTIVE: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). STUDY DESIGN: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. RESULTS: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). CONCLUSIONS: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Skin barrier properties in different body areas in neonates.

OBJECTIVE: The aim of the study was to investigate skin barrier function in neonates in different anatomic sites during the first 2 days of life. DESIGN: The study population consisted of 44 healthy full-term newborn infants. Transepidermal water loss (TEWL), stratum corneum hydration (SCH), and skin surface pH were measured in different anatomic sites (forehead, flexor part of forearm, upper back, abdomen, inguinal region, palms, and soles) during the first 10 hours of life and 24 hours later. Measurements were recorded with a Tevameter, a Corneometer, and a skin pH meter with a flat glass electrode. Results were compared with those in 20 healthy adults. RESULTS: TEWL was lower in infants than in adults in the forehead, palms, soles, and higher in the forearms. It was significantly higher on day 1 than on day 2 in the soles, palms, and forearms, and in the forearm, palms, and inguinal region compared with the other anatomic sites. SCH was significantly lower in the infants on the forehead, back, and abdomen, and higher on the forearms and palms; it was significantly higher on the first day of life on the forearms and palms, and lower in the inguinal region. Skin surface pH was significantly higher in the infants in all body sites (>6.6 in most measurements). On day 2, it was significantly lower than on day 1, but still higher than in adults. SCH correlated positively with TEWL in the neonates but not in the adults. None of the variables were related to gestational age, sex, mode of delivery, or body weight. CONCLUSIONS: Changes take place in SCH, water loss, and pH in the first 2 days after birth, suggesting that the stratum corneum barrier is still in the process of adapting to extrauterine life. The significant anatomic variability in TEWL and SCH should be taken into account in evaluating the permeation of skin care products and topical medications in newborns.

Normal pulmonary function in a monoamniotic twin discordant for bilateral renal agenesis: report and review.

Renal agenesis and obstructive urinary tract anomalies causing oligohydramnios usually result in pulmonary hypoplasia. We report on the first female monoamniotic twin born with a combination of bilateral renal agenesis, agenesis of the urinary collecting system, absent external genitalia, anal atresia and single umbilical artery, compatible with VATER association but with normal pulmonary function. The infant had none of the manifestations of Potter sequence, in particular the facial changes and pulmonary hypoplasia typically associated with bilateral renal a/dysgenesis. The monoamniotic cotwin had normal renal function, such that sufficient amniotic fluid volume was maintained. This patient emphasizes the importance of adequate amniotic fluid volume for normal pulmonary development. The possible underestimation of genital malformations in the VATER association should be considered. Also noteworthy is the rare absence of external genitalia.

Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome.

We report on 8 patients from two families with Alpers syndrome. The onset in one family was prenatal and in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity were found. The second family presented with an early infantile form. All the affected offspring had micrognathia and one had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all the patients died before age 20 months. Results of comprehensive biochemical and metabolic studies in both families were normal and the diagnosis was supported by demonstration of extensive progressive brain atrophy on CT and typical histological findings. Patients without a detectable defect in energy metabolism and normal liver histology comprise a distinct subset of Alpers syndrome. Until the metabolic defect(s) is defined, we suggest naming the acute neonatal form of this subset of Alpers syndrome "type 1."

MODED: microcephaly-oculo-digito-esophageal-duodenal syndrome.

We report on 4 families with microcephaly, type A brachydactyly, variable learning disabilities, short stature, duodenal atresia, patent ductus arteriosus (PDA), hallux valgus, restricted elbow and finger movements, and amesophalangy and syndactyly of toes. Three previous families manifested all signs of the syndrome, and in another four reports the phenotype was incomplete. These cases are reviewed. Penetrance of digital and toe anomalies is almost complete and microcephaly is present in 78% of known cases. Short stature was present in 70% of our cases, but this is probably an overestimation. Esophageal and duodenal atresias were present in 25% of known cases. Correction for ascertainment bias gave a lower estimate of 16.6%. Learning disabilities were present in 31% of all patients. Longitudinal follow-up suggested that hypoplasia or absence of the diaphyseal ossification centers is the primary cause of the phalangeal changes. Observations in a 9-year-old girl, followed since age 3.3, suggest that the eventual absence of the middle phalanges of the toes may be caused by fusion.

Syndrome of alopecia totalis and 17b-hydroxysteroid dehydrogenase deficiency.

A distinct and previously undescribed syndrome of alopecia totalis, ichthyosis, and male pseudohermaphroditism due to steroid 17b-hydroxysteroid dehydrogenase deficiency was observed in an Israeli-Arab newborn infant.

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample.

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.

Liver enzyme abnormalities in gram-negative bacteremia of premature infants.

BACKGROUND: Hyperbilirubinemia and liver enzyme abnormalities are commonly observed in sepsis. However, the frequency in premature neonates and the specific relation to gram-negative bacteria are not known. PATIENTS AND METHODS: Charts of all preterm infants who had positive blood cultures for either gram-negative bacteria or coagulase-negative staphylococci were reviewed. Neonates with gram-negative bacteremia (n = 54) were compared with neonates with coagulase-negative staphylococcal bacteremia (n = 31). In addition infants with gram-negative bacteremia and elevated liver enzymes (n = 25) were compared with infants with gram-negative bacteremia and normal liver enzymes (n = 29). RESULTS: Liver enzyme abnormalities accompanied 46.3% (25 of 54) of gram-negative bacteremia and 12.9% (4 of 31) of episodes of coagulase-negative staphylococcal bacteremia (P = 0.002). Serum concentrations of liver enzymes were significantly higher in infants with gram-negative bacteremia than in those with coagulase-negative staphylococcal bacteremia (P < 0.0001), but no difference in alkaline phosphatase serum values was observed. Infants with gram-negative bacteremia and elevated liver enzymes were not fed for a longer period than infants with gram-negative bacteremia and normal liver enzymes (7.3 +/- 6.3 days vs. 4.0 +/- 4.3 days, P = 0.03), and this was accompanied by significant conjugated hyperbilirubinemia (P < 0.0001). Ventilation, total parenteral nutrition and medications were not responsible for the observed differences. Klebsiella pneumoniae bacteremia was commonly associated with elevated liver enzymes (12 of 18), whereas none of the infants with Pseudomonas aeruginosa bacteremia had elevated liver enzymes. CONCLUSIONS: Gram-negative bacteremia is commonly associated with cholestasis in premature neonates. Liver enzyme abnormalities are more common than elevated conjugated bilirubin, not all gram-negative bacteria have the same effect and the lack of enteral feeding seems to play a more significant role than the administration of parenteral nutrition.

Mycetoma of the renal pelvis caused by Fusarium species.

A preterm infant, with posterior urethral valves had a mycetoma of the renal pelvis caused by Fusarium species. Prolonged treatment with amphotericin B alone or with flucytosine failed. Combined surgical drainage and medical therapy resulted in full resolution.

Cord serum inhibits allogeneic mixed lymphocyte reaction and stimulates lymphokine production.

An inhibitory activity on the two-way allogeneic mixed lymphocyte reaction (MLR) was detected in maternal and cord serum at delivery. The inhibitory effect of the maternal serum was found to be more pronounced and was detected in almost all sera tested, whereas the inhibitory capacity of cord sera was observed in only 70% of the cases. In addition, a lower stimulatory activity for interleukin-2 (IL-2) production was found in the maternal serum, suggesting an additional mechanism for the suppression of the maternal immune system during pregnancy. On the other hand, a higher stimulatory activity for IL-2 production was observed in cord serum as compared with adult normal serum. The possibility that a fetal humoral factor is involved in the regulation of the immune system via the stimulation of IL-2 production is discussed.

Pleiotropy of the serotonin transporter gene for seasonality and neuroticism.

Pleiotropy refers to the ability of a single gene to influence multiple traits. A polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has previously been found to be associated both with the personality trait of neuroticism and with seasonal changes in mood and behavior, or seasonality. Hypothesizing that the contribution of the serotonin transporter gene to seasonality is specific, i.e. independent of neuroticism, we measured 5-HTTLPR genotypes and both psychological traits in 236 healthy volunteers. The results indicated that the 5-HTTLPR contributions to variation in the two traits are largely independent; approximately three-quarters of the effect of the gene on seasonality are not related to its effects on neuroticism. Moreover, the gene has a larger effect on the covariation between neuroticism and seasonality than it does on either trait alone. Sibling-pair analysis confirmed that the effects of the 5-HTTLPR are due to genetic pleiotropy rather than population stratification.

A genetic association for cigarette smoking behavior.

Dopaminergic genes are likely candidates for heritable influences on cigarette smoking. In an accompanying article, Lerman et al. (1999) report associations between allele 9 of a dopamine transporter gene polymorphism (SLC6A3-9) and lack of smoking, late initiation of smoking, and length of quitting attempts. The present investigation extended their study by examining both smoking behavior and personality traits in a diverse population of nonsmokers, current smokers, and former smokers (N = 1,107). A significant association between SLC6A3-9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3-9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. It is hypothesized that individuals carrying the SLC6A3-9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes.

Risk factors associated with candidaemia in the neonatal intensive care unit: a case-control study.

The incidence of candidaemia is steadily increasing in neonatal intensive care units (NICUs). Several neonatal risk factors for candidaemia have been identified, however, the number of cases in controlled studies is small and knowledge concerning maternal and perinatal risk factors is limited. The present study attempted to identify modifiable, independent maternal, perinatal and neonatal risk factors for candidaemia using a retrospective case-control study in the NICU of a tertiary-care paediatric medical centre. The study group consisted of 56 neonates admitted to the NICU between 1996 and 2000 who acquired candidaemia. The control group comprised the first infant admitted immediately after each study infant matched for gestational age (+/-10 days) and birthweight (+/-200 g). Potential maternal, perinatal and neonatal risk factors were compared between the groups using statistical methods and analysed by univariate and multivariate stepwise logistic regression models. The independent risk factors found to be significantly associated with increased risk of candidaemia were duration of ventilation and presence of bacteraemia before candidaemia. Maternal steroids had a significant protective effect. The positive predictive value using these three parameters was 78.38%. Maximizing in-utero steroid treatment in high-risk pregnancies, minimizing the days of mechanical ventilation and investment of efforts in prevention of bacteraemia may help to reduce the incidence of candidaemia in the NICU.

Keratometry measurements in preterm and full term newborn infants.

AIM: To evaluate the relation between postconceptional age and birth weight with keratometric values in preterm and full term infants. METHODS: A prospective cross sectional study was performed. The cohort included 99 infants (198 eyes) admitted to the Neonatal and Neonatal Intensive Care Units at Schneider Children's Medical Center of Israel from February to September 2002. Keratometry in the horizontal and vertical meridians was performed in both eyes of each infant by two ophthalmologists using an autokeratometer. The results were evaluated according to: postconceptual age (<32 weeks, 32-36 weeks, >36 weeks) and birth weight (<1500 g, 1501-2500 g, >2501 g). RESULTS: Corneal curvature measurements decreased progressively with both postconceptual age and birth weight. At <32 weeks, mean (standard deviation) readings were 63.3 (3.2) diopters (D) for the horizontal meridian and 57.3 (2.6) D for the vertical meridian; corresponding values at >36 weeks were 54.0 (3.0) D and 50.7 (2.4) D. In the <1500 g group, mean (SD) readings were 61.3 (3.9) D for the horizontal meridian and 56.0 (2.9) D for the vertical meridian; corresponding values in the >2501 g group were 51.3 (2.1) D and 48.6 (1.8) D. CONCLUSIONS: There is an inverse relation of horizontal and vertical keratometric values with both postconceptional age and birth weight. Highest readings were noted in the babies with the lowest birth weight and youngest postconceptional age. The decrease in corneal dioptric power to normal values is linear and is apparently part of the normal ocular maturation.

Diode laser treatment of posterior retinopathy of prematurity.

AIMS: To study the efficacy of infrared diode laser for the treatment of posterior retinopathy of prematurity (ROP). METHODS: 48 eyes of 25 premature babies (mean birth weight 779 (SD 127.7) g; mean gestational age 25.5 (SD 1.47) weeks) with threshold ROP in zone I and posterior zone II were treated by the indirect infrared (810 nm) diode laser. Confluent burns were applied to the avascular retina. In 18 eyes, an additional row of laser burns was added posterior to the ridge. RESULTS: Favourable anatomical results were noted in 41 eyes (85.4%). ROP stage 5 developed in two eyes, ROP stage 4A developed in four eyes, and ROP stage 4B in one eye. Three of the eyes with stage 4A eyes were successfully buckled; the fourth was not operated on and remained demarcated by laser scars. No complications were noted. CONCLUSION: In this series, the diode laser was found to be a safe and effective treatment for posterior ROP.

Biochemistry for dietetic students: course content and format.

This article presents the results of a survey of the 251 undergraduate dietetic programs for course content and level of the biochemistry course most frequently used to satisfy competencies in biochemistry under Plan IV of the ADA in 1979-80. It showed that a common core of information was stressed by all biochemistry instructors, but there was great variability in content and level of material covered and the textbook chosen, depending on whether the biochemistry course was offered to dietetic majors only, in classes with other nonchemistry majors, or in classes with chemistry majors. Variability was also seen in the time allotted for biochemistry--39 to 280 hours (total lecture and required laboratory hours); laboratory requirements--only 71%; and departmental affiliation of the instructor--17 different departments, primarily of chemistry (80%), biology (8%), and home economics (4%). Topics given greatest emphasis were descriptive ones, such as definitions, simple structures, and reactions of intermediary metabolism in general terms. Topics given least emphasis were those involving mechanistic and quantitative biochemistry, such as respiratory quotient (RQ), enzyme kinetics, calculations of energy from fat and carbohydrates, and specific structures of vitamins, ketones, and metabolic intermediates. The lack of communication between biochemistry and nutrition instructors and the great differences in the preparation of dietetic majors in biochemistry are sources of concern.

Effect of cefotaxime on cytokine production in newborns and adults in vitro.

The in vitro effect of cefotaxime on the production of interleukin (IL)-1beta, IL-2, IL-6 and tumor necrosis factor alpha (TNFalpha) was studied in term neonates and was compared with that of adults. The addition of cefotaxime caused a significant enhancement of IL-2 production by cells of both adults and neonates, and increased the secretion of TNFalpha by peripheral blood mononuclear cells (PBMC) of adults, whereas the synthesis of this cytokine by cord blood mononuclear cells (CBMC) of the newborns was not affected. In contrast with the described stimulatory effects of cefotaxime, this drug induced dose-dependent inhibition of the spontaneous and lipopolysaccharide (LPS)-induced IL-1beta production by cells of the two groups, but had no effect on the in vitro production of IL-6. These data suggest that cefotaxime, apart from its known antimicrobial activity, may modify the host immune response of both newborns and adults, via the alteration of cytokine production.