Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Antenatal and early postnatal antecedents of parent-reported attention problems at 2 years of age.

OBJECTIVES: To assess antenatal and early postnatal antecedents of attention problems identified by the Child Behavior Checklist in extremely preterm children. STUDY DESIGN: In a cohort of 826 children born between 23 and 27 weeks' gestation, we collected demographic, birth, and postnatal information. We then identified behavior problems by using parent ratings from the Child Behavior Checklist at 2 years' adjusted age. We created time-oriented logistic regression risk models to identify significant risk factors for attention problems and Diagnostic and Statistical Manual of Mental Disorders-compatible attention deficit/hyperactivity problems (ADHP(DSM)). RESULTS: Children were at increased risk of both attention problems if they were born to a woman who had no formal education beyond high school and/or a woman who was exposed to secondhand smoke. Recovery of a single organism from the placenta was associated with increased risk of an attention problem, and fetal stem vessel thrombosis and recovery of Mycoplasma species were associated with increased risk of ADHP(DSM). Infants of multifetal gestations were at reduced risk of both attention problems. The only postnatal risk factor for an attention problem was recovery of bacteria from a tracheal aspirate. CONCLUSION: Among extremely preterm infants, several potentially modifiable antenatal and perinatal antecedents are associated with increased risk for attention problems and ADHP(DSM) at 2 years adjusted age.

A multicenter matched-cohort analysis of gastroschisis outcomes in infants born before 32 weeks gestation.

OBJECTIVE: To examine neonatal outcomes of infants with gastroschisis born <32 weeks' gestation compared to matched infants without gastroschisis. STUDY DESIGN: Retrospective matched-cohort analysis of infants with gastroschisis born <32 weeks' gestation at Children's Hospitals Neonatal Consortium (CHNC) NICUs from 2010 to 2022 compared to gestational age-matched controls. RESULTS: The study included 119 infants with gastroschisis and 357 matched infants; 60% of infants born 29-32 weeks, 23% born 26-28 weeks, and 16% born < 25 weeks. Mortality was not significantly different between groups (11% vs. 9%, p = 0.59). Preterm co-morbidities such as IVH, BPD, ROP, and PVL were similar, as were rates of surgical NEC. Infants with gastroschisis had longer hospital stays (92 vs. 67 days), higher CLABSI and UTIs, and were more likely to need feeding support at discharge. CONCLUSION: Compared to infants without gastroschisis, infants <32 weeks' gestation with gastroschisis had similar risks for inpatient mortality, NEC, and other preterm co-morbidities.

Patient-clinician communication about end-of-life care for Dutch and US patients with COPD.

Improving patient-clinician communication about end-of-life care is important in order to enhance quality of care for patients with chronic obstructive pulmonary disease (COPD). Our objective was to compare quality of patient-clinician communication about end-of-life care, and endorsement of barriers and facilitators to this communication in the Netherlands and the USA. The present study was an analysis of survey data from 122 Dutch and 391 US outpatients with COPD. We compared quality of patient-clinician communication about end-of-life care (Quality of Communication questionnaire) and barriers and facilitators to communication about end-of-life care (Barriers and Facilitators Questionnaire) between the Netherlands and the USA, controlling for patients' demographic and illness characteristics. Although Dutch patients in this study had worse lung function and disease-specific health status than US patients, Dutch patients reported lower quality of communication about end-of-life care (median score 0.0 (interquartile range 0.0-2.0) versus 1.4 (0.0-3.6); adjusted p<0.005). Clinicians in both countries rarely discussed life-sustaining treatment preferences, prognoses, dying processes or spiritual issues. Quality of communication about end-of-life care needs to improve in the Netherlands and the USA. Future studies to improve this communication should be designed to take into account international differences and patient-specific barriers and facilitators to communication about end-of-life care.

Animal Health Ireland: providing national leadership and coordination of non-regulatory animal health issues in Ireland.

Livestock production plays an important role in the Irish economy. Regulatory animal health issues are the responsibility of government, but until recently there has been no national coordination of non-regulatory animal health issues. This gap has recently been filled with the establishment of Animal Health Ireland (AHI), a not-for-profit, partnership-based organisation providing national leadership and coordination of non-regulatory animal health issues in Ireland. Animal Health Ireland provides benefits to livestock producers and processors by providing the knowledge, education and coordination required to establish effective control strategies, both on-farm and nationally. This paper presents a brief overview of the context for AHI, and of its establishment and initial activities. Non-regulatory animal health issues have been prioritised. A series of work programmes (each focusing on a high-priority issue) have been established. Partnership is critical to success, both for AHI as an organisation and for effective farm-level transfer of knowledge. This model for national leadership and coordination of non-regulatory animal health issues may be of relevance elsewhere.

Building Capacity for Evidence-Informed Priority Setting in the Indian Health System: An International Collaborative Experience.

India's rapid economic growth has been accompanied by slower improvements in population health. Given the need to reconcile the ambitious goal of achieving Universal Coverage with limited resources, a robust priority-setting mechanism is required to ensure that the right trade-offs are made and the impact on health is maximised. Health Technology Assessment (HTA) is endorsed by the World Health Assembly as the gold standard approach to synthesizing evidence systematically for evidence-informed priority setting (EIPS). India is formally committed to institutionalising HTA as an integral component of the EIPS process. The effective conduct and uptake of HTA depends on a well-functioning ecosystem of stakeholders adept at commissioning and generating policy-relevant HTA research, developing and utilising rigorous technical, transparent, and inclusive methods and processes, and a strong multisectoral and transnational appetite for the use of evidence to inform policy. These all require myriad complex and complementary capacities to be built at each level of the health system . In this paper we describe how a framework for targeted and locally-tailored capacity building for EIPS, and specifically HTA, was collaboratively developed and implemented by an international network of priority-setting expertise, and the Government of India.

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. Objectives: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. Design, Setting, and Participants: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. Interventions: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. Main Outcomes and Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. Results: A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). Conclusions and Relevance: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

An examination of the effects of the antioxidant Pycnogenol on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population.

The study examines the effects of the antioxidant flavonoid Pycnogenol on a range of cognitive and biochemical measures in healthy elderly individuals. The study used a double-blind, placebo-controlled, matched-pair design, with 101 elderly participants (60-85 years) consuming a daily dose of 150 mg of Pycnogenol for a three-month treatment period. Participants were assessed at baseline, then at 1, 2, and 3 months of the treatment. The control (placebo) and Pycnogenol groups were matched by age, sex, body mass index, micronutrient intake, and intelligence. The cognitive tasks comprised measures of attention, working memory, episodic memory, and psychomotor performance. The biological measures comprised levels of clinical hepatic enzymes, serum lipid profile, human growth hormone, and lipid peroxidation products. Statistically significant interactions were found for memory-based cognitive variables and lipid peroxidation products, with the Pycnogenol group displaying improved working memory and decreased concentrations of F2-isoprostanes relative to the control group.

Association of in utero magnesium exposure and spontaneous intestinal perforations in extremely low birth weight infants.

OBJECTIVE: The objective of this study is to determine whether antenatal exposure to magnesium is associated with spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants (⩽1000 g). STUDY DESIGN: We identified all ELBW infants admitted to 1 of 323 neonatal intensive care units from 2007 to 2013. We used multivariable conditional logistic regression to compare outcomes in the first 21 days after birth between infants exposed and unexposed to magnesium in utero. RESULTS: Of the 28 035 infants, 11 789 (42%) were exposed to antenatal magnesium (AM). There was no difference in the risk of SIP, odds ratio=1.08 (95% confidence interval; 0.91 to 1.29), between infants exposed and unexposed to AM. Mortality in the first 21 days after birth was lower in the magnesium-exposed infants, odds ratio=0.76 (0.70 to 0.83). CONCLUSION: AM exposure in ELBW infants was not associated with increased risk of SIP.

Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5.

BACKGROUND/AIMS: Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. METHODS: All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). RESULTS: The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. CONCLUSION: Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation.

Driving impairment due to propofol at effect-site concentrations relevant after short propofol-only sedation.

Australian guidelines state "Following brief surgery or procedures with short acting anaesthetic drugs, the patient may be fit to drive after a normal night's sleep. After long surgery or procedures requiring longer lasting anaesthesia, it may not be safe to drive for 24 hours or more". The increasing use of the short-acting anaesthetic drug propofol as a solitary sedative medication for simple endoscopy procedures suggests a need to review this blanket policy. Thirty patients presenting for elective day surgery were recruited as volunteers for a pre-procedure driving simulation study and randomised to propofol or placebo arms. Driving ability was assessed at baseline and then, in the propofol group, at three effect-site concentrations. Driving impairment at these concentrations of propofol was compared to that of a third group of volunteers with a blood alcohol concentration of 0.05% (g/100 ml). Driving impairment at 0.2 µg/ml propofol effect-site concentration was not statistically different to placebo. Impairment increased with propofol effect-site concentration (P=0.002) and at 0.4 µg/ml it was similar to that found with a blood alcohol concentration of 50 mg/100 ml (0.05%). Plasma propofol concentrations of 0.2 µg/ml, as might be found approximately an hour after short (<1 hour duration) propofol-only sedation for endoscopy, were not associated with driving impairment in our young cohort of volunteers.

The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction.

PURPOSE: To develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication. METHODS: A panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability. RESULTS: This classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables. CONCLUSIONS: We present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies.

The UK Neovascular AMD Database Report 3: inter-centre variation in visual acuity outcomes and establishing real-world measures of care.

PurposeInternational variations in visual acuity (VA) outcomes of eyes treated for neovascular age-related macular degeneration (nAMD) are well-documented, but intra-country inter-centre regional variations are not known. These data are important for national quality outcome indicators. We aimed to determine intra-country and inter-centre regional variations in outcomes for treatment of nAMD.Patients and methodsProspective multicentre national database study of 13 UK centres that treated patients according to a set protocol (three loading doses, followed by Pro-Re-Nata retreatment). A total of 5811 treatment naive eyes of 5205 patients received a total of 36 206 ranibizumab injections over 12 months.ResultsMean starting VA between centres varied from 48.9 to 59.9 ETDRS letters. Mean inter-centre VA change from baseline to 12 months varied from +6.9 letters to -0.6 letters (mean of +2.5 letters). The proportion of eyes achieving VA of 70 letters or more varied between 21.9 and 48.7% at 12 months. Median number of injections (visits) at each centre varied from 5 to 8 (9 to 12), with an overall median of 6 (11). Age, starting VA, number of injections, and visits, but not gender were significantly associated with variation in these VA outcomes (P<0.01). Significant variation between centres persisted even after adjusting for these factors.ConclusionThere are modest differences in VA outcomes between centres in the UK. These differences are influenced, but not completely explained, by factors such as patient age, starting VA, number of injections, and visits. These data provide an indication of the VA outcomes that are achievable in real-world settings.

Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree.

BACKGROUND/AIMS: Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. The aim of this study was to perform linkage analysis in a large family affected with FEVR to determine whether the mutation involved was in one of the three known autosomal dominant FEVR loci or in another as yet unidentified gene. METHODS: Genomic DNA samples from family members were polymerase chain reaction (PCR) amplified with fluorescently tagged microsatellite markers spanning the EVR1/EVR4 locus (11q13-14) and the EVR3 locus (11p12-13). The resulting PCR products were resolved using an automated DNA sequencer and the alleles sized. These data were used to construct haplotypes across each locus and linkage analysis was performed to prove or exclude linkage. RESULTS: The clinical evaluation in this family suggested features typical of FEVR, with deficient peripheral retinal vascularisation being the common phenotype in all affected individuals. However, linkage analysis proved that this family has a form of FEVR genetically distinct from the EVR1, EVR3 and EVR4 loci. CONCLUSION: The exclusion of linkage in this family to any of the known FEVR loci proves the existence of a fourth locus for autosomal dominant FEVR and shows that this rare disorder is far more heterogeneous than previously thought.

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.

The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects.

RATIONALE: Extracts of Bacopa monniera have been reported to exert cognitive enhancing effects in animals. However, the effects on human cognition are inconclusive. OBJECTIVE: The current study examined the chronic effects of an extract of B. monniera (Keenmind) on cognitive function in healthy human subjects. METHODS: The study was a double-blind placebo-controlled independent-group design in which subjects were randomly allocated to one of two treatment conditions, B. monniera (300 mg) or placebo. Neuropsychological testing was conducted pre-(baseline) and at 5 and 12 weeks post drug administration. RESULTS: B. monniera significantly improved speed of visual information processing measured by the IT task, learning rate and memory consolidation measured by the AVLT (P<0.05), and state anxiety (P<0.001) compared to placebo, with maximal effects evident after 12 weeks. CONCLUSIONS: These findings suggest that B. monniera may improve higher order cognitive processes that are critically dependent on the input of information from our environment such as learning and memory.

Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause.

OBJECTIVE: To compare an oral estrogen-androgen combination with estrogens alone on bone, menopausal symptoms, and lipoprotein profiles in postmenopausal women. METHODS: Surgically menopausal women received oral esterified estrogens (1.25 mg), or esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) daily, for 2 years. Bone mineral density of the lumbar spine and hip, menopausal symptoms, lipoprotein profiles, and biochemical and hematologic indices were evaluated. RESULTS: Sixty-six patients were enrolled in the study. Both treatment regimens prevented bone loss at the spine and hip; combined estrogen-androgen therapy was associated with a significant increase in spinal bone mineral density compared with baseline (n = 24; mean score +/- standard error 3.4 +/- 1.2%, P < .01). In the estrogen group, high-density lipoprotein (HDL) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly. Cholesterol, HDL cholesterol, and triglycerides decreased significantly in the estrogen-androgen group. Menopausal symptoms of somatic origin (hot flashes, vaginal dryness, and insomnia) were improved significantly by both treatments. Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group. CONCLUSION: Oral estrogen-androgen increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms. Safety indices, including lipoprotein levels, indicated that the combination was well tolerated over the 2 years of treatment.

Exposure to low concentrations of nicotine during cranial nerve development inhibits apoptosis and causes cellular hypertrophy in the ventral oculomotor nuclei of the chick embryo.

Maternal cigarette use during pregnancy is associated with increased incidence of neural impairments in offspring, but nicotine's unique contribution to any neuropathology remains unclear, and nicotine's neurodevelopmental effects assessed in animal models vary with concentration. During ontogenesis, the chick oculomotor complex (OMN) is regulated by central nervous system (CNS) afferent-derived and target-derived trophic factors, allowing assessment of nicotine's potential interference in receptor-mediated CNS trophic phenomena, unconfounded by myriad other compounds in cigarette smoke. In the current study, 100 ng nicotine applied daily in ovo to yolk during embryonic days (E) 1-7 mimicked maternal plasma nicotine concentrations during fetal cranial nerve development. Nicotine-treated embryos exhibited a 15% decrease in whole body weight and 7% decrease in brain weight at E16. However, at E16, nicotine-treated embryos had 37% and 15% increases in the combined ventromedial+lateral (v) OMN motoneuron density and soma area, respectively, effects not observed in the optic tectum, in which nicotine cholinergic receptor expression is delayed until E8-12. Incorporation of tritiated thymidine into whole brain DNA demonstrated that the nicotine treatment did not cause increased rates of whole brain mitosis, suggesting that the dosage regimen did not elicit a cytotoxic, wound-healing, response of differentiating cells. As determined by DNA fragment-labeling assay during the normal period of cell death, vOMN apoptosis occurs maximally on E11 during a normal period of declining cell density, and a dose-response study demonstrated 78% E11 vOMN apoptotic suppression at approximately 0.30 microM cumulative yolk nicotine with an inhibition threshold between 0.10 and 0.20 microM. These results suggest that plasma nicotine concentrations resulting from tobacco use or nicotine replacement therapy (NRT) are sufficient to inhibit motoneuron apoptosis and enhance neuronal growth.

A double-blind crossover study comparing betahistine and cinnarizine in the treatment of recurrent vertigo in patients in general practice.

A double-blind crossover study was carried out in general practice in 88 patients with peripheral vertigo of unknown origin to compare the efficacy and tolerance of 12 mg betahistine dihydrochloride and 15 mg cinnarizine. Patients were allocated at random to receive 2 tablets 3-times daily of one or other drug for 3 consecutive months before being crossed over to the alternative medication for a further 3 months. Severity of symptoms was assessed at 4-week intervals using the Clinical Global Impression scale and patients kept a record in a daily diary of the frequency and duration of attacks. Details were also recorded of any side-effects reported. The results were analyzed for 46 patients who completed the 6-month study period. Both drugs were shown to be equally effective in reducing the duration and severity of symptoms. Significantly fewer attacks of vertigo, however, occurred during betahistine therapy. Side-effects were the most common reason for dropping out whilst on cinnarizine (9 patients) and were complained of by 38 patients during the study (16 only when on betahistine, 19 only on cinnarizine, 3 whilst on both drugs). The most frequently reported were drowsiness or lethargy affecting 16 patients on cinnarizine and 7 on betahistine.