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Although the incidence of human monkeypox has greatly increased in Central Africa over the last decade, resources for surveillance remain extremely limited. We conducted a geospatial analysis using existing data to better inform future surveillance efforts. Using active surveillance data collected between 2005 and 2007, we identified locations in Sankuru district, Democratic Republic of Congo (DRC) where there have been one or more cases of human monkeypox. To assess what taxa constitute the main reservoirs of monkeypox, we tested whether human cases were associated with (i) rope squirrels (Funisciurus sp.), which were implicated in monkeypox outbreaks elsewhere in the DRC in the 1980s, or (ii) terrestrial rodents in the genera Cricetomys and Graphiurus, which are believed to be monkeypox reservoirs in West Africa. Results suggest that the best predictors of human monkeypox cases are proximity to dense forests and associated habitat preferred by rope squirrels. The risk of contracting monkeypox is significantly greater near sites predicted to be habitable for squirrels (OR = 1.32; 95% CI 1.08-1.63). We recommend that semi-deciduous rainforests with oil-palm, the rope squirrel's main food source, be prioritized for monitoring.

Background: In many malaria-endemic countries, increasing resistance may soon compromise the efficacy of sulphadoxine-pyrimethamine (SP) for intermittent preventative treatment (IPT) of malaria in pregnancy. Artemisinin-based IPT regimens represent a promising potential alternative to SP. Pharmacokinetic and safety data supporting the use of artemisinin derivatives in pregnancy are urgently needed., Methods: Subjects included pregnant women with asymptomatic falciparum parasitaemia between 22-26 weeks (n = 13) or 32-36 weeks gestation (n = 13), the same women at three months postpartum, and 25 non-pregnant parasitaemic controls. All subjects received 200 mg orally administered AS. Plasma total and free levels of AS and its active metabolite DHA were determined using a validated LC-MS method. Non-compartmental pharmacokinetic analysis was performed using standard methods., Results: All pregnant women delivered live babies. The median birth weight was 3025 grams [range 2130, 3620]; 2 of 26 babies had birth weights less than 2500 grams. Rates of parasite clearance by 12 hours post-dose were high and comparable among the groups. Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy:postpartum ratio of geometric means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for the pregnancy:control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63-0.95) not fully contained within the 0.66 - 1.50 interval. All subjects cleared parasites rapidly, and there was no difference in the percentage of women who were parasitaemic 12 hours after dosing., Conclusions: A single dose of orally administered AS was found to be both effective and without adverse effects in this study of second and third trimester pregnant women in the DRC. Although DHA AUC during pregnancy and postpartum were similar, the AUC for the pregnant group was less than the non-pregnant controls. The findings of this study suggest that additional studies on the pharmacokinetics of AS in pregnant women are needed., Trial Registration: ClinicalTrials.gov: NCT00538382.

Background: Inadequate and inappropriate complementary feeding are major factors contributing to excess morbidity and mortality in young children in low resource settings. Animal source foods in particular are cited as essential to achieve micronutrient requirements. The efficacy of the recommendation for regular meat consumption, however, has not been systematically evaluated., Methods/design: A cluster randomized efficacy trial was designed to test the hypothesis that 12 months of daily intake of beef added as a complementary food would result in greater linear growth velocity than a micronutrient fortified equi-caloric rice-soy cereal supplement. The study is being conducted in 4 sites of the Global Network for Women's and Children's Health Research located in Guatemala, Pakistan, Democratic Republic of the Congo (DRC) and Zambia in communities with toddler stunting rates of at least 20%. Five clusters per country were randomized to each of the food arms, with 30 infants in each cluster. The daily meat or cereal supplement was delivered to the home by community coordinators, starting when the infants were 6 months of age and continuing through 18 months. All participating mothers received nutrition education messages to enhance complementary feeding practices delivered by study coordinators and through posters at the local health center. Outcome measures, obtained at 6, 9, 12, and 18 months by a separate assessment team, included anthropometry; dietary variety and diversity scores; biomarkers of iron, zinc and Vitamin B12 status (18 months); neurocognitive development (12 and 18 months); and incidence of infectious morbidity throughout the trial. The trial was supervised by a trial steering committee, and an independent data monitoring committee provided oversight for the safety and conduct of the trial., Discussion: Findings from this trial will test the efficacy of daily intake of meat commencing at age 6 months and, if beneficial, will provide a strong rationale for global efforts to enhance local supplies of meat as a complementary food for young children., Trial Registration: NCT01084109.

Objective: To determine the comparability between cause of death (COD) by a single physician coder and a two-physician panel, using verbal autopsy., Methods: The study was conducted between May 2007 and June 2008. Within a week of a perinatal death in 38 rural remote communities in Guatemala, the Democratic Republic of Congo, Zambia and Pakistan, VA questionnaires were completed. Two independent physicians, unaware of the others decisions, assigned an underlying COD, in accordance with the causes listed in the chapter headings of the International classification diseases and related health problems, 10th revision (ICD-10). Cohen's kappa statistic was used to assess level of agreement between physician coders., Results: There were 9461 births during the study period; 252 deaths met study enrolment criteria and underwent verbal autopsy. Physicians assigned the same COD for 75% of stillbirths (SB) (K = 0.69; 95% confidence interval: 0.61-0.78) and 82% early neonatal deaths (END) (K = 0.75; 95% confidence interval: 0.65-0.84). The patterns and proportion of SBs and ENDs determined by the physician coders were very similar compared to causes individually assigned by each physician. Similarly, rank order of the top five causes of SB and END was identical for each physician., Conclusion: This study raises important questions about the utility of a system of multiple coders that is currently widely accepted and speculates that a single physician coder may be an effective and economical alternative to VA programmes that use traditional two-physician panels to assign COD., (© 2010 Blackwell Publishing Ltd.)

HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Maternal and newborn mortality rates remain unacceptably high, especially where the majority of births occur in home settings or in facilities with inadequate resources. The introduction of emergency obstetric and newborn care services has been proposed by several organizations in order to improve pregnancy outcomes. However, the effectiveness of emergency obstetric and neonatal care services has never been proven. Also unproven is the effectiveness of community mobilization and community birth attendant training to improve pregnancy outcomes., Methods/design: We have developed a cluster-randomized controlled trial to evaluate the impact of a comprehensive intervention of community mobilization, birth attendant training and improvement of quality of care in health facilities on perinatal mortality in low and middle-income countries where the majority of births take place in homes or first level care facilities. This trial will take place in 106 clusters (300-500 deliveries per year each) across 7 sites of the Global Network for Women's and Children's Health Research in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. The trial intervention has three key elements, community mobilization, home-based life saving skills for communities and birth attendants, and training of providers at obstetric facilities to improve quality of care. The primary outcome of the trial is perinatal mortality. Secondary outcomes include rates of stillbirth, 7-day neonatal mortality, maternal death or severe morbidity (including obstetric fistula, eclampsia and obstetrical sepsis) and 28-day neonatal mortality., Discussion: In this trial, we are evaluating a combination of interventions including community mobilization and facility training in an attempt to improve pregnancy outcomes. If successful, the results of this trial will provide important information for policy makers and clinicians as they attempt to improve delivery services for pregnant women and newborns in low-income countries., Trial Registration: ClinicalTrials.gov NCT01073488.

Objective: to determine the prevalence of suicidal thoughts and attempts and to identify demographic variables and mental health correlates such as anxiety/depression and domestic violence among pregnant women in an urban community in Pakistan., Design: cross-sectional data from a prospective cohort study are presented., Setting: women enrolled in an antenatal care clinic and followed to delivery in an urban area of Pakistan., Population: cohort of pregnant women in Pakistan., Methods: a total of 1,369 pregnant women were enrolled and interviewed regarding various maternal characteristics and pregnancy outcomes, and were asked specific questions about suicidal thoughts and attempts and administered the Aga Khan University Anxiety Depression Scale at 20-26 weeks of gestation., Main Outcome Measures: suicidal thoughts and attempts, verbal, sexual or physical abuse., Results: overall, 148 of the 1,369 (11%) women studied had considered suicide. Of these, 148 women, 67 (45%) had attempted suicide. In all, 18% of the women were classified as having depression/anxiety, almost half (48%) reported experiencing verbal abuse and 20% reported physical/sexual abuse. Women who had anxiety/depression or had experienced verbal or physical/sexual abuse were significantly more likely to have had suicidal thoughts and attempts., Conclusions: women at the greatest risk for having suicidal thoughts or a suicide attempt were those who were depressed/anxious and had experienced some form of domestic abuse. With the high prevalence of these conditions, attention should be given to the establishment of effective mental health treatment programs for pregnant women.

Objective: This study was designed to test the hypothesis that 2 training programs would reduce incrementally 7-day neonatal mortality rates for low-risk institutional deliveries., Methods: Using a train-the-trainer model, certified research midwives sequentially trained the midwives who performed deliveries in low-risk, first-level, urban, community health clinics in 2 cities in Zambia in the protocol and data collection, in the World Health Organization Essential Newborn Care (ENC) course (universal precautions and cleanliness, routine neonatal care, resuscitation, thermoregulation, breastfeeding, kangaroo care, care of small infants, and common illnesses), and in the American Academy of Pediatrics Neonatal Resuscitation Program (in-depth basic resuscitation). Data were collected during 3 periods, after implementation of each training course., Results: A total of 71 689 neonates were enrolled in the 3 study periods. All-cause, 7-day neonatal mortality rates decreased from 11.5 deaths per 1000 live births to 6.8 deaths per 1000 live births after ENC training (relative risk: 0.59 [95% confidence interval: 0.48-0.77]; P < .001), because of decreases in rates of deaths attributable to birth asphyxia and infection. Perinatal mortality rates but not stillbirth rates decreased. The 7-day neonatal mortality rate was decreased further after Neonatal Resuscitation Program training, after correction for loss to follow-up monitoring., Conclusions: ENC training for midwives reduced 7-day neonatal mortality rates in low-risk clinics. Additional in-depth basic training in neonatal resuscitation may reduce mortality rates further.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Studies on the burden of human monkeypox in the Democratic Republic of the Congo (DRC) were last conducted from 1981 to 1986. Since then, the population that is immunologically naïve to orthopoxviruses has increased significantly due to cessation of mass smallpox vaccination campaigns. To assess the current risk of infection, we analyzed human monkeypox incidence trends in a monkeypox-enzootic region. Active, population-based surveillance was conducted in nine health zones in central DRC. Epidemiologic data and biological samples were obtained from suspected cases. Cumulative incidence (per 10,000 population) and major determinants of infection were compared with data from active surveillance in similar regions from 1981 to 1986. Between November 2005 and November 2007, 760 laboratory-confirmed human monkeypox cases were identified in participating health zones. The average annual cumulative incidence across zones was 5.53 per 10,000 (2.18-14.42). Factors associated with increased risk of infection included: living in forested areas, male gender, age < 15, and no prior smallpox vaccination. Vaccinated persons had a 5.2-fold lower risk of monkeypox than unvaccinated persons (0.78 vs. 4.05 per 10,000). Comparison of active surveillance data in the same health zone from the 1980s (0.72 per 10,000) and 2006-07 (14.42 per 10,000) suggests a 20-fold increase in human monkeypox incidence. Thirty years after mass smallpox vaccination campaigns ceased, human monkeypox incidence has dramatically increased in rural DRC. Improved surveillance and epidemiological analysis is needed to better assess the public health burden and develop strategies for reducing the risk of wider spread of infection.

Objective: To compare the accuracy of the reported date of the last menstrual period (LMP) with that of symphysis-fundal height (SFH) in the estimation of gestational age (GA), using an ultrasound (US) scan as reference., Methods: Gestational age was concurrently assessed by the 3 methods in this prospective, population-based, pregnancy-outcome study conducted in Hyderabad, Pakistan, from June 18, 2003, through August 31, 2005, with 1128 women between 20 and 26 weeks of a singleton pregnancy., Results: The mean GA was less by ultrasound than by SFH measurement or the reported LMP, and the mean differences with the US result were statistically significant (P<0.001 for both). At delivery, about 75% of the GA values estimated by SFH measurement were within 7 days and almost 91% were within 14 days of the estimation by ultrasound, compared with 65% and 82% for the GA estimated by the reported LMP. Moreover, using the US as reference, the SFH correctly classified 84% of the term, 68% of the preterm, and 86% of the post-term deliveries (weighted kappa=0.58) compared with the corresponding 79%, 61%, and 55% predicted by the reported LMP (weighted kappa=0.44)., Conclusion: The SFH measurement was found to be more accurate than the reported LMP as a tool to estimate GA and therefore date of delivery, but neither were as accurate as a US scan., (Copyright 2010 International Federation of Gynecology and Obstetrics. All rights reserved.)

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described., (Copyright 2010 Elsevier Ltd. All rights reserved.)

After age 6 mo, the combination of breast-feeding and unfortified plant-based complementary feeding provides inadequate zinc (Zn). Additionally, high phytate intakes compromise the bioavailability of zinc. Our principal objective in this randomized controlled, doubly masked trial was to determine the effect of substituting low-phytate maize, a daily 5-mg zinc supplement, or both, in infants between ages 6-12 mo on impaired linear growth velocity, a common feature of zinc deficiency. In the Western Highlands of Guatemala, 412 infants were randomized to receive low-phytate or control maize. Within each maize group, infants were further randomized to receive a zinc supplement or placebo. Length, weight, and head circumference were measured at 6, 9, and 12 mo of age. There were no significant differences between the 2 maize groups or between the Zn supplement and placebo groups and no treatment interaction was observed for length-for-age (LAZ), weight-for-length (WLZ) or head circumference Z-scores. Overall mean (+/- SD) Z-scores at 6 mo for combined treatment groups were: LAZ, -2.1 +/- 1.1; WLZ, 0.7 +/- 1.0; and head circumference Z-score, -0.7.0 +/- 1.0. At 12 mo, these had declined further to: LAZ, -2.5 +/- 1.1; WLZ, -0.0 +/- 0.9; and head circumference Z-score, -0.9 +/- 1.1; 83.3% were stunted and 2% were wasted. Low linear growth in older Guatemalan infants was not improved with either low-phytate maize or a daily 5-mg zinc supplement. Low contribution of maize to the complementary food of the infants negated any potential advantage of feeding low-phytate maize.

Background: Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year, 98% occur in developing countries. An evaluation of community-based interventions designed to reduce the number of these deaths is needed., Methods: With the use of a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (which focuses on routine neonatal care, resuscitation, thermoregulation, breast-feeding, "kangaroo" [skin-to-skin] care, care of the small baby, and common illnesses) and (except in Argentina) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (which teaches basic resuscitation in depth). The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before-and-after design. The Neonatal Resuscitation Program intervention was assessed as a cluster-randomized, controlled trial involving 62,366 infants. The primary outcome was neonatal death in the first 7 days after birth., Results: The 7-day follow-up rate was 99.2%. After birth attendants were trained in the Essential Newborn Care course, there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth (relative risk with training, 0.99; 95% confidence interval [CI], 0.81 to 1.22) or in the rate of perinatal death; there was a significant reduction in the rate of stillbirth (relative risk with training, 0.69; 95% CI, 0.54 to 0.88; P=0.003). In clusters of births in which attendants had been randomly assigned to receive training in the Neonatal Resuscitation Program, as compared with control clusters, there was no reduction in the rates of neonatal death in the 7 days after birth, stillbirth, or perinatal death., Conclusions: The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. (ClinicalTrials.gov number, NCT00136708.), (2010 Massachusetts Medical Society)

A 5' Taq nuclease assay utilizing Minor Groove Binder technology and targeting the thymidine kinase gene of gallid herpesvirus 1 (GaHV-1) was designed and optimized for use in diagnosing avian infectious laryngotracheitis. The assay was specific for GaHV-1 in that it did not react with other avian viral or bacterial pathogens. The detection limit was 1.0x10(-2) median tissue culture infectious dose per reaction or 90 target copies per reaction. Fifteen out of 41 diagnostic samples from sick birds reacted in the assay, five of which produced a typical alphaherpesvirus cytopathic effect (CPE) on chicken kidney (CK) cells. Sequencing, using amplicons generated by a polymerase chain reaction with primers flanking the 5' Taq nuclease amplicon, confirmed the presence of GaHV-1 in six samples (two producing alphaherpesvirus CPE on CK cells, three not producing alphaherpesvirus CPE, and one that was not inoculated onto CK cells). Tracheal swabs taken from 18 healthy broilers did not react in the assay. The ability of the assay to determine viral load in samples was demonstrated. Overall the assay is suitable for the rapid diagnosis of infectious laryngotracheitis.

Lamina I of the rat spinal cord contains neurons that project to various brain areas including thalamus, periaqueductal grey matter (PAG), lateral parabrachial area (LPb), caudal ventrolateral medulla and a region in dorsal medulla that includes the nucleus tractus solitarius and dorsal reticular nucleus. We have shown that spinothalamic lamina I neurons are infrequent in rat lumbar enlargement, where they constitute approximately 5% of the estimated 400 projection neurons on each side of the L4 segment (Al-Khater and Todd, 2009). They are more numerous in cervical enlargement, but the total number of lamina I projection neurons in this region was not known. Here we have used paired injections of retrograde tracers into the brainstem to estimate the number of lamina I projection cells in the C7 segment. Our results suggest that there are approximately 215 lamina I projection cells per side, and that spinothalamic cells therefore make up approximately 42% of this population. The proportion of lamina I projection neurons labelled from PAG is higher in cervical than lumbar enlargement, while the proportion labelled from dorsal medulla is similar in the two regions. We also found that lamina I cells in L4 that project to the dorsal medulla are included in the population retrogradely labelled from LPb, thus confirming the estimate that there are around 400 lamina I projection cells in this segment.

Objective: We studied exposure to solid fuel and second-hand tobacco smoke among pregnant women in south Asia, Africa and Latin America., Design: Prospective cross-sectional survey., Setting: Antenatal clinics in Argentina, Brazil, Ecuador, Guatemala, Uruguay, Democratic Republic of Congo, Zambia, India and Pakistan., Sample: A total of 7,961 pregnant women in ten sites in nine countries were interviewed between October 2004 and September 2005., Methods: A standardized questionnaire on exposure to indoor air pollution (IAP) and second-hand smoke was administered to pregnant women during antenatal care., Main Outcome Measures: Exposure to IAP and second-hand tobacco smoke., Results: South Asian pregnant women commonly reported use of wood (49.1-89.7%), crop residue and animal dung as cooking and heating fuel. African pregnant women reported higher use of charcoal (85.4-93.5%). Latin American pregnant women had greater use of petroleum gas. Among south Asian women, solid fuel use and cooking on an open flame inside the home were common. There was a significant association between solid fuel use and allowing smoking within the home at the Asian sites and in Zambia (p < 0.05)., Conclusions: Pregnant women from low/middle income countries were commonly exposed to IAP secondary to use of solid fuels. Among these populations, exposure to second-hand tobacco smoke was also common. This combination of exposures likely increases the risk of poor pregnancy outcomes among the most vulnerable women. Our study highlights the importance of further research on the combined impact of IAP and second-hand tobacco smoke exposures on adverse maternal and perinatal outcomes.

Objectives: To develop a standardized verbal autopsy (VA) training program and evaluate whether its implementation resulted in comparable knowledge required to classify perinatal cause of death (COD) by physicians and non-physicians., Methods: Training materials, case studies, and written and mock scenarios for this VA program were developed using conventional VA and ICD-10 guidelines. This program was used to instruct physicians and non-physicians in VA methodology using a train-the-trainer model. Written tests of cognitive and applied knowledge required to classify perinatal COD were administered before and after training to evaluate the effect of the VA training program., Results: Fifty-three physicians and non-physicians (nurse-midwives/nurses and Community Health Workers [CHW]) from Pakistan, Zambia, the Democratic Republic of Congo, and Guatemala were trained. Cognitive and applied knowledge mean scores among all trainees improved significantly (12.8 and 28.8% respectively, P < 0.001). Cognitive and applied knowledge post-training test scores of nurse-midwives/nurses were comparable to those of physicians. CHW (high-school graduates with 15 months or less formal health/nursing training) had the largest improvements in post-training applied knowledge with scores comparable to those of physicians and nurse-midwives/nurses. However, CHW cognitive knowledge post-training scores were significantly lower than those of physicians and nurses., Conclusions: With appropriate training in VA, cognitive and applied knowledge required to determine perinatal COD is similar for physicians and nurses-midwives/nurses. This suggests that midwives and nurses may play a useful role in determining COD at the community level, which may be a practical way to improve the accuracy of COD data in rural, remote, geographic areas.

Background: Few studies have examined the relationship between antenatal depression, anxiety and domestic violence in pregnant women in developing countries, despite the World Health Organization's estimates that depressive disorders will be the second leading cause of the global disease burden by 2020. There is a paucity of research on mood disorders, their predictors and sequelae among pregnant women in Pakistan., Aims: To determine the prevalence of anxiety and depression and evaluate associated factors, including domestic violence, among pregnant women in an urban community in Pakistan., Methods: All pregnant women living in identified areas of Hyderabad, Pakistan were screened by government health workers for an observational study on maternal characteristics and pregnancy outcomes. Of these, 1,368 (76%) of eligible women were administered the validated Aga Khan University Anxiety Depression Scale at 20-26 weeks of gestation., Results: Eighteen per cent of the women were anxious and/or depressed. Psychological distress was associated with husband unemployment (p = 0.032), lower household wealth (p = 0.027), having 10 or more years of formal education ( p = 0.002), a first (p = 0.002) and an unwanted pregnancy ( p < 0.001). The strongest factors associated with depression/anxiety were physical/sexual and verbal abuse; 42% of women who were physically and/or sexually abused and 23% of those with verbal abuse had depression/anxiety compared to 8% of those who were not abused., Conclusions: Anxiety and depression commonly occur during pregnancy in Pakistani women; rates are highest in women experiencing sexual/physical as well as verbal abuse, but they are also increased among women with unemployed spouses and those with lower household wealth. These results suggest that developing a screening and treatment programme for domestic violence and depression/anxiety during pregnancy may improve the mental health status of pregnant Pakistani women.

Objective: To develop a prospective perinatal registry that characterizes all deliveries, differentiates between stillbirths and early neonatal deaths (ENDs), and determines the ratio of fresh to macerated stillbirths in the northwest Democratic Republic of Congo., Method: Birth outcomes were obtained from 4 rural health districts., Results: A total of 8230 women consented, END rate was 32 deaths per 1000 live births, and stillbirth rate was 33 deaths per 1000 deliveries. The majority (75%) of ENDs and stillbirths occurred in neonates weighing 1500 g or more. Odds of stillbirth and END increased in mothers who were single or who did not receive prenatal care, and among premature, low birth weight, or male infants. The ratio of fresh to macerated stillbirths was 4:1., Conclusion: Neonates weighing 1500 g or more at birth represent a group with a high likelihood of survival in remote areas, making them potentially amenable to targeted intervention packages. The ratio of fresh to macerated stillbirths was approximately 10-fold higher than expected, suggesting a more prominent role for improved intrapartum obstetric interventions.

Objectives: To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers >or=4 0 years to the corresponding rates among infants of younger mothers., Study Design: Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome., Results: The sample consisted of 14 671 live ELBW births divided into maternal age groups: <20, 20 to 29, 30 to 39, and >or= 40 years. Of infants born to mothers >or= 40 years, 20% were multiples. Mothers >or= 40 years had high rates of obstetric interventions and medical morbidities compared with mothers <40 years. ELBW live births of mothers >or= 40 years were 22% more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared with mothers <20. Multiple birth, however, was associated with a 10% greater risk of neurodevelopmental impairment or death., Conclusion: Although mothers >or= 40 years had high pregnancy-related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.

Objective: To evaluate the effectiveness of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP) in improving knowledge, skills, and self-efficacy of nurse midwives in low-risk delivery clinics in a developing country., Study Design: We used the content specifications of the NRP material applicable to college-educated nurse midwives working in low-risk clinics in Zambia to develop performance and self-efficacy evaluations focused on principles of resuscitation, initial steps, ventilation, and chest compressions. These evaluations were administered to 127 nurse midwives before and after NRP training and 6-months later., Results: After training, written scores (knowledge evaluation) improved from 57%+/-14% to 80%+/-12% (mean+/-SD; P< .0001); performance scores (skills evaluation) improved the most from 43%+/-21% to 88%+/-9% (P< .0001); self-efficacy scores improved from 74%+/-14% to 90%+/-10% (P< .0001). Written and performance scores decreased significantly 6 months after training, but self-efficacy scores remained high., Conclusions: As conducted, the NRP training improved educational outcomes in college-educated practicing nurse midwives. Pre-training knowledge and skills scores were relatively low despite the advanced formal education and experience of the participants, whereas the self-efficacy scores were high. NRP training has the potential to substantially improve knowledge and skills of neonatal resuscitation.

Objective: Determine the baseline incidence of birth asphyxia in neonatal intensive care unit (NICU) survivors in a developing country and the early neurodevelopmental outcomes of such infants., Study Design: This cross-sectional, prospective study collected diagnostic and examination findings on all infants seen in the University of Zambia NICU follow-up clinic over a 4-week period., Result: Of the 182 infants, 42 (23%) had a clinical diagnosis of birth asphyxia. Of 42 infants with birth asphyxia, 13 (31%) had an abnormal neurologic examination during the clinic visit; in contrast, 13 of 141 infants without birth asphyxia (9%) had an abnormal examination (odds ratio 4.4, 95% confidence interval: 1.8, 10.4)., Conclusion: Birth asphyxia survivors account for almost a quarter of NICU survivors in a developing country and half of those with an abnormal neurologic examination. Studies are necessary to determine the percent of birth asphyxia survivors who have permanent motor and cognitive disabilities.

Cluster randomized trials have become the design of choice for evaluating the effect of selected interventions on well-known health indicators such as neonatal mortality rate, episiotomy rate, and postpartum hemorrhage rate in a community setting. Determining the sample size of a cluster randomized trial requires a reliable estimate of cluster size and the intracluster correlation (ICC), because sample size can be substantially impacted by these parameters. During the design phase of a trial, the investigators may have estimates of the valid range of the health indicator which is the primary outcome variable. Furthermore, investigators often have an estimate of the average cluster size or range of cluster sizes that exist among the proposed samples they are planning to include in the trial. We present in this article a simulation technique to estimate the ICC value and its distribution for known binary outcome variables and a varying number of clusters and cluster sizes. We applied this technique to estimate ICC values and confidence intervals for a multi-country trial assessing the effect of neonatal resuscitation to decrease seven-day neonatal mortality, where communities within a country were clusters. This simulation technique can be used to estimate the possible ranges of the ICC values and to help to design an appropriately powered trial.

Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.

Background: Ninety-nine percent of the 4 million neonatal deaths per year occur in developing countries. The World Health Organization (WHO) Essential Newborn Care (ENC) course sets the minimum accepted standard for training midwives on aspects of infant care (neonatal resuscitation, breastfeeding, kangaroo care, small baby care, and thermoregulation), many of which are provided by the mother., Objective: The aim of this study was to determine the association of ENC with all-cause 7-day (early) neonatal mortality among infants of less educated mothers compared with those of mothers with more education., Methods: Protocol- and ENC-certified research nurses trained all 123 college-educated midwives from 18 low-risk, first-level urban community health centers (Zambia) in data collection (1 week) and ENC (1 week) as part of a controlled study to test the clinical impact of ENC implementation. The mothers were categorized into 2 groups, those who had completed 7 years of school education (primary education) and those with 8 or more years of education., Results: ENC training is associated with decreases in early neonatal mortality; rates decreased from 11.2 per 1000 live births pre-ENC to 6.2 per 1000 following ENC implementation (P < .001). Prenatal care, birth weight, race, and gender did not differ between the groups. Mortality for infants of mothers with 7 years of education decreased from 12.4 to 6.0 per 1000 (P < .0001) but did not change significantly for those with 8 or more years of education (8.7 to 6.3 per 1000, P = .14)., Conclusions: ENC training decreases early neonatal mortality, and the impact is larger in infants of mothers without secondary education. The impact of ENC may be optimized by training health care workers who treat women with less formal education.

Objective: Periodontal disease may increase the risk of adverse birth outcomes; however, results have been mixed. Few studies have examined periodontal disease in developing countries. We describe the relationship between periodontal disease and birth outcomes in a community setting in Pakistan., Study Design: This was a prospective cohort study. Enrollment occurred at 20-26 weeks of gestation. A study dentist performed the periodontal examination to assess probing depth, clinical attachment level, gingival index, and plaque index. Outcomes included stillbirth, neonatal death, perinatal death, < 32 weeks preterm birth, 32-36 weeks preterm birth, and low birthweight and are presented for increasing periodontal disease severity by quartiles., Results: Dental examinations and outcome data were completed for 1152 women: 81% of the women were multiparous, with a mean age of 27 years; 33% of the women had no education. Forty-seven percent of the women had dental caries; 27% of the women had missing teeth, and 91% of the women had had no dental care in the last year. Periodontal disease was common: 76% of the women had > or = 3 teeth with a probing depth of > or = 3 mm; 87% of the women had > or = 4 teeth with a clinical attachment level of > or = 3 mm; 56% of the women had > or = 4 teeth with a plaque index of 3; and 60% of the women had > or = 4 teeth with a gingival index of 3. As the measures of periodontal disease increased from the 1st to 4th quartile, stillbirth and neonatal and perinatal death also increased, with relative risks of approximately 1.3. Early preterm birth increased, but the results were not significant. Late preterm birth and low birthweight were not related to measures of periodontal disease., Conclusion: Pregnant Pakistani women have high levels of moderate-to-severe dental disease. Stillbirth and neonatal and perinatal deaths increased with the severity of periodontal disease.

Objective: Our goal was to determine stillbirth rates in a multisite population-based study in community settings in the developing world., Study Design: Outcomes of all community deliveries in 5 resource-poor countries (Democratic Republic of Congo, Guatemala, India, Zambia, and Pakistan) and in 1 mid-level country (Argentina) were evaluated prospectively over an 18-month period. Births of > 1000 g with no signs of life were defined as stillbirth., Results: Outcomes of 60,324 deliveries were included. Stillbirth rates ranged from 34 per 1000 in Pakistan to 9 per 1000 births in Argentina. Increased stillbirth rates were associated significantly with lower skilled providers, out-of-hospital births, and low cesarean section rates. Maceration was present in 17.2% of stillbirths., Conclusion: The stillbirth rates among births of > or = 1000 g in these developing countries were substantially higher than reported stillbirth rates in developed countries (3-5/1000 births). Because most developed countries define stillbirth as > or = 20 weeks of gestation or > or = 500 g and because almost one-half of all stillbirths are < 1000 g, the developing/developed country difference is actually larger than apparent from this study. Maceration was uncommon, which indicates that most of the deaths probably occurred during labor. The low rates of physician attendance, hospital delivery, and cesarean section deliveries suggest that stillbirth rates could be reduced by access to higher quality institutional deliveries.

Introduction: To determine the outcomes of vaginal deliveries in three study hospitals in Lhasa, Tibet Autonomous Region (TAR), People's Republic of China (PRC), at high altitude (3650 m)., Methods: Prospective observational study of 1121 vaginal deliveries., Results: Pre-eclampsia/gestational hypertension (PE/GH) was the most common maternal complication 18.9% (n=212), followed by postpartum hemorrhage (blood loss > or = 500 ml) 13.4%. There were no maternal deaths. Neonatal complications included: low birth weight (10.2%), small for gestational age (13.7%), pre-term delivery (4.1%) and low Apgar (3.7%). There were 11 stillbirths (9.8/1000 live births) and 19 early neonatal deaths (17/1000 live births)., Conclusion: This is the largest study of maternal and newborn outcomes in Tibet. It provides information on the outcomes of institutional vaginal births among women delivering infants at high altitude. There was a higher incidence of PE/GH and low birth weight; rates of PPH were not increased compared to those at lower altitudes.

Aims: To investigate the occurrence and levels of Arcobacter spp. in pig effluent ponds and effluent-treated soil., Methods and Results: A Most Probable Number (MPN) method was developed to assess the levels of Arcobacter spp. in seven pig effluent ponds and six effluent-treated soils, immediately after effluent irrigation. Arcobacter spp. levels in the effluent ponds varied from 6.5 x 10(5) to 1.1 x 10(8) MPN 100 ml(-1) and in freshly irrigated soils from 9.5 x 10(2) to 2.8 x 10(4) MPN g(-1) in all piggery environments tested. Eighty-three Arcobacter isolates were subjected to an abbreviated phenotypic test scheme and examined using a multiplex polymerase chain reaction (PCR). The PCR identified 35% of these isolates as Arcobacter butzleri, 49% as Arcobacter cryaerophilus while 16% gave no band. All 13 nonreactive isolates were subjected to partial 16S rDNA sequencing and showed a high similarity (>99%) to Arcobacter cibarius., Conclusions: A. butzleri, A. cryaerophilus and A. cibarius were isolated from both piggery effluent and effluent-irrigated soil, at levels suggestive of good survival in the effluent pond., Significance and Impact of the Study: This is the first study to provide quantitative information on Arcobacter spp. levels in piggery effluent and to associate A. cibarius with pigs and piggery effluent environments.

Objectives: To evaluate the effectiveness of the World Health Organization (WHO) Essential Newborn Care (ENC) course in improving knowledge and skills of nurse midwives in low-risk delivery clinics in a developing country., Methods: The investigators identified the content specifications of the training material, developed both written and performance evaluations and administered the evaluations both before and after training clinical nurse midwives in Zambia., Findings: Based on these evaluations, both the knowledge and skills of the nurse midwives improved significantly following the course (from a mean of 65% correct pretraining to 84% correct post-training and from 65% to 77% correct on the performance and written evaluations, respectively). The ENC course written evaluation was validated and both tools allowed evaluation of the ENC course training., Conclusions: We found significant improvements in trainees' knowledge and skills in essential newborn care following the WHO ENC course; however, lack of basic resources may have limited the application of the ENC guidelines. Implementation of the ENC course should be undertaken in consideration with the local conditions available for newborn care.

A multiplex real-time PCR was designed to detect and differentiate equid herpesvirus 1 (EHV-1) and equid herpesvirus 4 (EHV-4). The PCR targets the glycoprotein B gene of EHV-1 and EHV-4. Primers and probes were specific to each equine herpesvirus type and can be used in monoplex or multiplex PCRs, allowing the differentiation of these two closely related members of the Alphaherpesvirinae. The two probes were minor-groove binding probes (MGB) labelled with 6-carboxy-fluorescein (FAM) and VIC for detection of EHV-1 and EHV-4, respectively. Ten EHV-1 isolates, six EHV-1 positive clinical samples, one EHV-1 reference strain (EHV-1.438/77), three EHV-4 positive clinical samples, two EHV-4 isolates and one EHV-4 reference strain (EHV-4 405/76) were included in this study. EHV-1 isolates, clinical samples and the reference strain reacted in the EHV-1 real-time PCR but not in the EHV-4 real-time PCR and similarly EHV-4 clinical samples, isolates and the reference strain were positive in the EHV-4 real-time PCR but not in the EHV-1 real-time PCR. Other herpesviruses, such as EHV-2, EHV-3 and EHV-5 were all negative when tested using the multiplex real-time PCR. When bacterial pathogens and opportunistic pathogens were tested in the multiplex real-time PCR they did not react with either system. The multiplex PCR was shown to be sensitive and specific and is a useful tool for detection and differentiation of EHV-1 and EHV-4 in a single reaction. A comprehensive equine herpesvirus disease investigation procedure used in our laboratory is also outlined. This procedure describes the combination of alphaherpesvirus multiplex real-time PCR along with existing gel-based PCRs described by other authors.

Objective: To examine the association between weight loss during the first 10 days of life and the incidence of death or bronchopulmonary dysplasia (BPD) in small for gestational age (SGA) and appropriate for gestational age (AGA) extremely low-birth-weight infants., Design/methods: This is a retrospective analysis of a cohort of ELBW (birth weight <1000 g) infants from the NICHD Neonatal Research Network's database. The cohort consisted of 9461 ELBW infants with gestational age of 24-29 weeks, admitted to Network's participating centers during calendar years 1994-2002 and surviving at least 72 h after birth. The cohort was divided into two groups, 1248 SGA (with birth weight below 10th percentile for gestational age) and 8213 AGA (with birth weight between 10th and 90th percentile) infants. We identified infants with or without weight loss during the first 10 days of life, which we termed as 'early postnatal weight loss' (EPWL). Univariate analyses were used to predict whether EPWL was related to the primary outcome, death or BPD, within each birth weight/gestation category (SGA or AGA). BPD and death were also analyzed separately in relation to EPWL. Logistic regression analysis was done to evaluate the risk of death or BPD in SGA and AGA groups, controlling for maternal and neonatal demographic and clinical factors found to be significant by univariate analysis., Results: SGA ELBW infants had a lower prevalence of EPWL as compared with AGA ELBW infants (81.2 vs 93.7%, respectively, P<0.001). In AGA infants, univariate analysis showed that death or BPD rate was lower in the group of infants with EPWL compared with infants without EPWL (53.4 vs 74.3%, respectively, P<0.001). The BPD (47.2 vs 64%, P<0.001) and death (13.8 vs 32.9%, P<0.001) rate were similarly lower in the EPWL group. The risk-adjusted odds ratios (ORs) showed that EPWL was associated with lower rate of death or BPD (OR 0.47, 95% CI: 0.37-0.60). In SGA infants, on univariate analysis, a similar association between EPWL and outcomes was seen as shown in AGA infants: death or BPD (55.9 vs 75.2%, P<0.001), BPD rate (48.3 vs 62.1%, P=0.002) and rate death (19 vs 40.8%, P<0.001) for those with or without EPWL, respectively. Multiple logistic regression showed that as in AGA ELBW infants, EPWL was associated with lower risk for death or BPD (OR 0.60, 95% CI: 0.41-0.89) among SGA infants., Conclusions: SGA infants experienced less EPWL when compared with their AGA counterparts. EPWL was associated with a lower risk of death or BPD in both ELBW AGA and SGA infants. These data suggest that clinicians who consider the association between EPWL and risk of death or BPD should do so independent of gestation/birth weight status.

By analyzing vesicle fluids and crusted scabs from 136 persons with suspected monkeypox, we identified 51 cases of monkeypox by PCR, sequenced the hemagglutinin gene, and confirmed 94% of cases by virus culture. PCR demonstrated chickenpox in 61 patients. Coinfection with both viruses was found in 1 additional patient.

A 5' Taq nuclease assay utilising minor groove binder technology and targeting the 16S rRNA gene was designed to detect Pasteurella multocida (the causative agent of fowl cholera) in swabs collected from poultry. The assay was first evaluated using pure cultures. The assay correctly identified four P. multocida taxonomic type strains, 18 P. multocida serovar reference strains and 40 Australian field isolates (17 from poultry, 11 from pigs and 12 from cattle). Representatives of nine other Pasteurella species, 26 other bacterial species (18 being members of the family Pasteurellaceae) and four poultry virus isolates did not react in the assay. The assay detected a minimum of approximately 10 cfu of P. multocida per reaction. Of 79 poultry swabs submitted to the laboratory for routine bacteriological culture, 17 were positive in the 5' Taq nuclease assay, but only 10 were positive by culture. The other 62 swabs were negative for P. multocida by both 5' Taq nuclease assay and culture. The assay is suitable for use in diagnosing fowl cholera, is more rapid than bacteriological culture, and may also have application in diagnosing P. multocida infections in cattle and pigs.

Of the 4 million neonatal deaths and 500,000 maternal deaths that occur annually worldwide, almost 99% are in developing countries and one-third are associated with infections. Implementation of proven interventions and targeted research on a select number of promising high-impact preventative and curative interventions are essential to achieve Millennium Development Goals for reduction of child and maternal mortality. Feasible, simple, low-cost interventions have the potential to significantly reduce the mortality and severe morbidity associated with infection in these settings. Studies of chlorhexidine in developing countries have focused on three primary uses: 1) intrapartum vaginal and neonatal wiping, 2) neonatal wiping alone, and 3) umbilical cord cleansing. A study of vaginal wiping and neonatal skin cleansing with chlorhexidine, conducted in Malawi in the 1990s suggested that chlorhexidine has potential to reduce neonatal infectious morbidity and mortality. A recent trial of cord cleansing conducted in Nepal also demonstrated benefit. Although studies have shown promise, widespread acceptance and implementation of chlorhexidine use has not yet occurred. This paper is derived in part from data presented at a conference on the use of chlorhexidine in developing countries and reviews the available evidence related to chlorhexidine use to reduce mortality and severe morbidity due to infections in mothers and neonates in low-resource settings. It also summarizes issues related to programmatic implementation.

Objective: To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension., Study Design: Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months., Results: The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4)., Conclusions: Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.

Objective: To document the mortality and morbidity of infants weighing 501-1500 g at birth according to gestational age, birthweight, and sex., Study Design: Prospective collection of perinatal events and neonatal course to 120 days of life, discharge, or death from January 1990 through December 2002 for infants born at 16 participating centers of the National Institute of Child Health & Human Development Neonatal Research Network., Results: Compared with 1995-1996, for 1997-2002 the survival of infants with birthweight of 501-1500 g increased by 1 percentage point (from 84% to 85%). Survival without major neonatal morbidity remained static, at 70%; this includes bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Survival increased for multiple births (26%, up from 22%), antenatal corticosteroid use (79%, up from 71%), and maternal antibiotics (70%, up from 62%) (P < .05). From 1997 to 2002, birthweight-specific survival was 55% for infants weighing 501-750 g, 88% for 751-1000 g, 94% for 1001-1250 g, and 96% for 1251-1500 g. More females survived. The incidence of NEC (7%), severe IVH (12%), and late-onset septicemia (22%) remained essentially unchanged, but BPD decreased slightly, from 23% to 22%. The use of postnatal corticosteroids declined from 20% in 1997-2000 to 12% in 2001-2002. Growth failure (weight <10th percentile) at 36 weeks' postmenstrual age decreased from 97% in 1995-1996 to 91% in 1997-2002., Conclusion: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002. We speculate that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.

Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.

We have developed efficient synthesis of morpholinone-based cyclic mimetics of the P1/P2 portion of the HIV-1 protease inhibitor Amprenavir. This effort led to discovery of allyl- and spiro-cyclopropyl-P2-substituted inhibitors 17 and 31, both 500 times more potent than the parent inhibitor 1. These results support morpholinones as novel mimetics of the P1/P2 portion of Amprenavir and potentially of other HIV-protease inhibitors, and thus provide a novel medicinal chemistry template for optimization toward more potent and drug-like inhibitors.

Objectives: The objectives of this study were to assess whether (1) in-hospital growth velocity is predictive of neurodevelopmental and growth outcomes at 18 to 22 months' corrected age among extremely low birth weight (ELBW) infants and (2) in-hospital growth velocity contributes to these outcomes after controlling for confounding demographic and clinical variables., Methods: Infants 501 to 1000 g birth weight from a multicenter cohort study were divided into quartiles of in-hospital growth velocity rates. Variables considered for the logistic-regression models included gender, race, gestational age, small for gestational age, mother's education, severe intraventricular hemorrhage, periventricular leukomalacia, age at regaining birth weight, necrotizing enterocolitis, late-onset infection, bronchopulmonary dysplasia, postnatal steroid therapy for pulmonary disease, and center., Results: Of the 600 discharged infants, 495 (83%) were evaluated at 18 to 22 months' corrected age. As the rate of weight gain increased between quartile 1 and quartile 4, from 12.0 to 21.2 g/kg per day, the incidence of cerebral palsy, Bayley II Mental Developmental Index (MDI) <70 and Psychomotor Developmental Index (PDI) <70, abnormal neurologic examination, neurodevelopmental impairment, and need for rehospitalization fell significantly. Similar findings were observed as the rate of head circumference growth increased. The in-hospital rate of growth was associated with the likelihood of anthropometric measurements at 18 months' corrected age below the 10th percentile values of the Centers for Disease Control and Prevention 2000 growth curve. Logistic-regression analyses, controlling for potential demographic or clinical cofounders, and adjusted for center, identified a significant relationship between growth velocity and the likelihood of cerebral palsy, MDI and PDI scores of <70, and neurodevelopmental impairment., Conclusions: These analyses suggest that growth velocity during an ELBW infant's NICU hospitalization exerts a significant, and possibly independent, effect on neurodevelopmental and growth outcomes at 18 to 22 months' corrected age.

Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.

Objective: This study describes medical students' perceptions of the field of psychiatry and identifies the impact of those perceptions on their career choices in order to explore the questions: Are we as a field doing all that we can to enhance the educational experience of all medical students, regardless of their career preferences? What are the most appropriate ways to encourage interested medical students that would allow for more targeted recruitment efforts toward the most receptive students?, Methods: Third-year (n=131) and fourth-year medical students (n=117) at a northeastern, urban, private university medical school completed anonymous self-report questionnaires. Students rated the impact of intellectual interest, status, earning potential, healthcare reform, quality of life, satisfaction, and stress of working with psychiatric patients on their consideration of a psychiatric career. Respondents were then systematically divided into two groups: 1) those who considered psychiatry as a possible career choice and 2) those who did not., Results: When compared to students who had been coded as "not seriously considering" a career in psychiatry, students coded as "seriously considering" gave significantly higher positive ratings to the field's intellectual content and quality of life. There were also significant differences between the groups regarding the satisfaction involved in working with psychiatric patients. Students from both groups were equally concerned about stress levels in the field., Conclusions: Acknowledging, discussing, and providing a context for stressful experiences during the psychiatry clerkship are likely to bring about productive approaches to improve recruitment into the field as well as to improve all students' psychiatric education.

Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.

Rho Kinase I (ROCK I) is a serine/threonine kinase that is involved in diverse cellular signaling. To further understand the physiological role of ROCK I and to identify and develop potent and selective inhibitors of ROCK I, we have overexpressed and purified a constitutively active dimeric human ROCK I (3-543) kinase domain using the Sf9-baculovirus expression system. In addition, using a limited proteolysis technique, we have identified a minimal functional subdomain of ROCK I that can be used in crystallization studies. The availability of multimilligram amounts of purified and well characterized functional human ROCK I kinase domains will be useful in screening and structural studies.