Carbamoylated Erythropoietin-Induced Cerebral Blood Perfusion and Vascular Gene Regulation.

Cerebral hypoperfusion is associated with enhanced cognitive decline and increased risk of neuropsychiatric disorders. Erythropoietin (EPO) is a neurotrophic factor known to improve cognitive function in preclinical and clinical studies of neurodegenerative and psychiatric disorders. However, the clinical application of EPO is limited due to its erythropoietic activity that can adversely elevate hematocrit in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered non-erythropoietic derivative of EPO, does not alter hematocrit and maintains neurotrophic and behavioral effects comparable to EPO. Our study aimed to investigate the role of CEPO in cerebral hemodynamics. Magnetic resonance imaging (MRI) analysis indicated increased blood perfusion in the hippocampal and striatal region without altering tight junction integrity. In vitro and in vivo analyses indicated that hippocampal neurotransmission was unaltered and increased cerebral perfusion was likely due to EDRF, CGRP, and NOS-mediated vasodilation. In vitro analysis using human umbilical vein endothelial cells (HUVEC) and hippocampal vascular gene expression analysis showed CEPO to be a non-angiogenic agent which regulates the MEOX2 gene expression. The results from our study demonstrate a novel role of CEPO in modulating cerebral vasodilation and blood perfusion.

Cerebrospinal fluid proteome evaluation in major depressive disorder by mass spectrometry.

BACKGROUND: Depression affects approximately 7.1% of the United States population every year and has an annual economic burden of over $210 billion dollars. Several recent studies have sought to investigate the pathophysiology of depression utilizing focused cerebrospinal fluid (CSF) and serum analysis. Inflammation and metabolic dysfunction have emerged as potential etiological factors from these studies. A dysregulation in the levels of inflammatory proteins such as IL-12, TNF, IL-6 and IFN-γ have been found to be significantly correlated with depression. METHODS: CSF samples were obtained from 15 patients, seven with major depressive disorder and eight age- and gender-matched non-psychiatric controls. CSF protein profiles were obtained using quantitative mass spectrometry. The data were analyzed by Progenesis QI proteomics software to identify significantly dysregulated proteins. The results were subjected to bioinformatics analysis using the Ingenuity Pathway Analysis suite to obtain unbiased mechanistic insight into biologically relevant interactions and pathways. RESULTS: Several dysregulated proteins were identified. Bioinformatics analysis indicated that the potential disorder/disease pathways include inflammatory response, metabolic disease and organismal injury. Molecular and cellular functions that were affected include cellular compromise, cell-to-cell signaling & interaction, cellular movement, protein synthesis, and cellular development. The major canonical pathway that was upregulated was acute phase response signaling. Endogenous upstream regulators that may influence dysregulation of proinflammatory molecules associated with depression are interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), oncostatin M, PR domain zinc finger protein 1 (PRDM1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). CONCLUSIONS: The proteome profiling data in this report identifies several potential biological functions that may be involved in the pathophysiology of major depressive disorder. Future research into how the differential expression of these proteins is involved in the etiology and severity of depression will be important.

Injury rate and risk factors among small-scale gold miners in Ghana.

BACKGROUND: To determine the potential risk factors for injury, estimate the annual injury rate and examine the safety perceptions, and use of personal protective equipment among small-scale gold miners in Ghana. METHODS: A cross-sectional survey was carried out with 494 small-scale gold miners from four major mining districts in Ghana. A household-based approach was used to obtain a representative sample of miners. The study was conducted from June 2015 to August 2016. A systematic sampling technique was used to select households and recruit respondents to interview. Miners were asked about any mining related injury that they had sustained in the past year. A logistics regression model was employed to examine the association between risk factors and injury. Data were analyzed with STATA version 14.0. RESULTS: The annual incidence rate of mining-related injury was 289 per 1000 workers. Injuries were mainly caused by machinery/tools 66(46.1%), followed by slip/falls 46(32.2%). The major risk factor for injury was underground work (adjusted odds ratio for injury 3.19; 95% CI = 1.42-7.20) compared with surface work. Higher education levels were protective, with adjusted odds ratios of 0.48 (95% CI = 0.24-0.99) for middle school education and 0.38 (95% CI 0.17-0.83) for secondary school compared with no schooling. Only 15(3.0%) of miners reported to have had safety training in the past year and 105(21.3%) indicated that there were safety regulations at their work place. A moderate number of workers reported using work boots 178(36.0%) and hand gloves 134(27.1%), but less than 10% of workers used other personal protective equipment. CONCLUSION: The annual injury incidence rate among small-scale gold miners is high. Potential targets for improving safety include increasing safety training, increasing use of personal protective equipment, and better understanding potential changes that can be made in the machinery and tools used in small-scale mining, which were associated with almost half of all injuries.

Examining school-based hygiene facilities: a quantitative assessment in a Ghanaian municipality.

BACKGROUND: The crucial role of adequate water, sanitation and hygiene (WASH) facilities in influencing children's handwashing behaviour is widely reported. Report from UNICEF indicates a dearth of adequate data on WASH facilities in schools, especially in the developing world. This study sought to contribute to building the evidence-base on school hygiene facilities in Ghana. The study further explored for possible associations and differences between key variables within the context of school water, sanitation and hygiene. METHODS: Data was collected from 37 junior high schools using an observational checklist. Methods of data analysis included a Scalogram model, Fisher's exact test, and a Student's t-test. RESULTS: Results of the study showed a facility deficiency in many schools: 33% of schools had students washing their hands in a shared receptacle (bowl), 24% had students using a single cotton towel to dry hands after handwashing, and only 16% of schools had a functional water facility. Furthermore, results of a proportion test indicated that 83% of schools which had functional water facilities also had functional handwashing stations. On the other hand, only 3% of schools which had functional water facilities also had a functional handwashing stations. A test of difference in the proportions of the two sets of schools showed a statistically significant difference (p < 0.001). In addition, 40% of schools which had financial provisions for water supply also had functional handwashing stations. On the other hand, only 7% of schools which had financial provisions for water supply also had functional handwashing stations. There was a statistically significant difference in the proportions of the two sets of schools (p = 0.02). CONCLUSION: We conclude that it is essential to have a financial provision for water supply in schools as this can potentially influence the existence of a handwashing station in a school. An intervention by government, educational authorities and civil society organisations towards enabling schools in low resource areas to have a sustainable budgetary allocation for WASH facilities would be timely.

Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice.

The inbred mouse strains, C57BL/6 and BALB/c have been used widely in preclinical psychiatric research. The differences in stress susceptibility of available strains has provided a useful platform to test pharmacological agents and behavioral responses. Previous brain gene profiling efforts have indicated that the inflammation and immune response gene pathway is the predominant gene network in the differential stress response of BALB/c and C57BL/6 mice. The implication is that a composite stress paradigm that includes a sequence of extended, varied and unpredictable stressors induces inflammation-related genes in the hippocampus. We hypothesized that the regulation of inflammation genes in the brain could constitute a primary stress response and tested this by employing a simple stress protocol, repeated exposure to the same stressor for 10 days, 2 h of restraint per day. We examined stress-induced regulation of 13 proinflammatory cytokine genes in male BALB/c and C57BL/6 mice using quantitative PCR. Elevated cytokine genes included tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), interleukin 10 (IL10), tumor necrosis factor (TNF) super family members and interleukin 1 receptor 1 (IL1R1). In addition, we examined restraint stress-induced regulation of 12 glutamate receptor genes in both strains. Our results show that restraint stress is sufficient to elevate the expression of inflammation-related genes in the hippocampus of both BABLB/c and C57BL/6 mice, but they differ in the genes that are induced and the magnitude of change. Cell types that are involved in this response include endothelial cells and astrocytes. Lay summary Repeated exposure to a simple restraint stress altered the activities of genes involved in inflammation and the functions of the excitatory neurotransmitter, glutamate. These changes in the hippocampus of the mouse brain showed differences that were dependent on the strain of mice and the length of the stress exposure. The effects of stress on activity of these genes may lead to alterations in behavior.

Vascular growth factors in neuropsychiatry.

Recent advances in understanding the cellular and molecular basis of psychiatric illnesses have shed light on the important role played by trophic factors in modulating functional parameters associated with disease causality and drug action. Disease mechanisms are now thought to involve multiple cell types, including neurons and endothelial cells. These functionally distinct but interactively coupled cell types engage in cellular cross talk via shared and common signaling molecules. Dysregulation in their cellular signaling pathways influences brain function and alters behavioral performance. Multifunctional trophic factors such as VEGF and EPO that possess both neurotrophic and angiogenic actions are of particular interest due to their ability to rescue structural and plasticity deficits in neurons and vasculature. Obtaining insight into the behavioral, cellular and molecular actions of multi-functional trophic factors has the potential to open new and transformative therapeutic approaches.

Regulation of trophic factors in the choroid plexus of aged mice.

Background: The choroid plexus (CP) is an understudied tissue in the central nervous system (CNS), primarily implicated in cerebrospinal fluid (CSF) production. Additionally, CP produces numerous neurotrophic factors (NTF), which circulate to different regions of the brain. Regulation of NTF in the CP during natural aging has yet to be discovered. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and water channel protein Aquaporin (AQP1). Methods: We used male and female mice for our study. We analyzed neurotrophic factor gene expression patterns using quantitative and digital droplet PCR at three different time points: mature adult, middle-aged, and aged. Additionally, we used immunohistochemical analysis (IHC) to evaluate in vivo protein expression. We further investigated the cellular phenotype of these NTFS, TJP and water channel proteins in the mouse CP by co-labeling them with the classical vascular marker, Isolectin B4, and epithelial cell marker, plectin. Results: Aging significantly altered the NTF's gene expression in the CP Brain-derived neurotrophic factor (BDNF), Midkine, VGF, Insulin-like growth factor (IGF1), IGF2, klotho, Erythropoietin, and its receptor were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression is unchanged in the aged CP while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJP's JAM, CLAUDIN1, CLAUDIN2, and CLAUDIN5 were reduced in aged mice. Conclusions: Our study highlights transcriptional level changes in the CP during aging. The age-related transcriptional changes exhibit similarities as well as gene-specific differences in the CP of males and females. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.

Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress.

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.

Effect on postpartum hemorrhage of prophylactic oxytocin (10 IU) by injection by community health officers in Ghana: a community-based, cluster-randomized trial.

BACKGROUND: Oxytocin (10 IU) is the drug of choice for prevention of postpartum hemorrhage (PPH). Its use has generally been restricted to medically trained staff in health facilities. We assessed the effectiveness, safety, and feasibility of PPH prevention using oxytocin injected by peripheral health care providers without midwifery skills at home births. METHODS AND FINDINGS: This community-based, cluster-randomized trial was conducted in four rural districts in Ghana. We randomly allocated 54 community health officers (stratified on district and catchment area distance to a health facility: ≥10 km versus <10 km) to intervention (one injection of oxytocin [10 IU] one minute after birth) and control (no provision of prophylactic oxytocin) arms. Births attended by a community health officer constituted a cluster. Our primary outcome was PPH, using multiple definitions; (PPH-1) blood loss ≥500 mL; (PPH-2) PPH-1 plus women who received early treatment for PPH; and (PPH-3) PPH-2 plus any other women referred to hospital for postpartum bleeding. Unsafe practice is defined as oxytocin use before delivery of the baby. We enrolled 689 and 897 women, respectively, into oxytocin and control arms of the trial from April 2011 to November 2012. In oxytocin and control arms, respectively, PPH-1 rates were 2.6% versus 5.5% (RR: 0.49; 95% CI: 0.27-0.88); PPH-2 rates were 3.8% versus 10.8% (RR: 0.35; 95% CI: 0.18-0.63), and PPH-3 rates were similar to those of PPH-2. Compared to women in control clusters, those in the intervention clusters lost 45.1 mL (17.7-72.6) less blood. There were no cases of oxytocin use before delivery of the baby and no major adverse events requiring notification of the institutional review boards. Limitations include an unblinded trial and imbalanced numbers of participants, favoring controls. CONCLUSION: Maternal health care planners can consider adapting this model to extend the use of oxytocin into peripheral settings including, in some contexts, home births. TRIAL REGISTRATION: ClinicalTrials.gov NCT01108289 Please see later in the article for the Editors' Summary.

Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.

Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.

Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial.

IMPORTANCE: In sub-Saharan Africa, malaria is a leading cause of childhood morbidity and iron deficiency is among the most prevalent nutritional deficiencies. In 2006, the World Health Organization and the United Nations Children's Fund released a joint statement that recommended limiting use of iron supplements (tablets or liquids) among children in malaria-endemic areas because of concern about increased malaria risk. As a result, anemia control programs were either not initiated or stopped in these areas. OBJECTIVE: To determine the effect of providing a micronutrient powder (MNP) with or without iron on the incidence of malaria among children living in a high malaria-burden area. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, cluster randomized trial of children aged 6 to 35 months (n = 1958 living in 1552 clusters) conducted over 6 months in 2010 in a rural community setting in central Ghana, West Africa. A cluster was defined as a compound including 1 or more households. Children were excluded if iron supplement use occurred within the past 6 months, they had severe anemia (hemoglobin level <7 g/dL), or severe wasting (weight-for-length z score <-3). INTERVENTIONS: Children were randomized by cluster to receive a MNP with iron (iron group; 12.5 mg/d of iron) or without iron (no iron group). The MNP with and without iron were added to semiliquid home-prepared foods daily for 5 months followed by 1-month of further monitoring. Insecticide-treated bed nets were provided at enrollment, as well as malaria treatment when indicated. MAIN OUTCOMES AND MEASURES: Malaria episodes in the iron group compared with the no iron group during the 5-month intervention period. RESULTS: In intention-to-treat analyses, malaria incidence overall was significantly lower in the iron group compared with the no iron group (76.1 and 86.1 episodes/100 child-years, respectively; risk ratio (RR), 0.87 [95% CI, 0.79-0.97]), and during the intervention period (79.4 and 90.7 episodes/100 child-years, respectively; RR, 0.87 [95% CI, 0.78-0.96]). In secondary analyses, these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status overall (adjusted RR, 0.87; 95% CI, 0.75-1.01) and during the intervention period (adjusted RR, 0.86; 95% CI, 0.74-1.00). CONCLUSION AND RELEVANCE: In a malaria-endemic setting in which insecticide-treated bed nets were provided and appropriate malaria treatment was available, daily use of a MNP with iron did not result in an increased incidence of malaria among young children. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01001871.

Synergism of Carbamoylated Erythropoietin and Insulin-like Growth Factor-1 in Immediate Early Gene Expression.

Trophic factors are secreted proteins that can modulate neuronal integrity, structure, and function. Previous preclinical studies have shown synergistic effects on decreasing apoptosis and improving behavioral performance after stroke when combining two such trophic factors, erythropoietin (EPO) and insulin-like growth factor-1 (IGF-1). However, EPO can elevate the hematocrit level, which can be life-threatening for non-anemic individuals. A chemically engineered derivative of EPO, carbamoylated EPO (CEPO), does not impact hematological parameters but retains neurotrophic effects similar to EPO. To obtain insight into CEPO and IGF-1 combination signaling, we examined immediate early gene (IEG) expression after treatment with CEPO, IGF-1, or CEPO + IGF-1 in rat pheochromocytoma (PC-12) cells and found that combining CEPO and IGF-1 produced a synergistic increase in IEG expression. An in vivo increase in the protein expression of Npas4 and Nptx2 was also observed in the rat hippocampus. We also examined which kinase signaling pathways might be mediating these effects and found that while AKT inhibition did not alter the pattern of IEG expression, both ERK and JAK2 inhibition significantly decreased IEG expression. These results begin to define the molecular effects of combining CEPO and IGF-1 and indicate the potential for these trophic factors to produce positive, synergistic effects.

Diminished activity-dependent BDNF signaling differentially causes autism-like behavioral deficits in male and female mice.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. Recent human genetic studies have identified multiple high-risk genes for ASD, which produce similar phenotypes, indicating that diverse genetic factors converge to common molecular pathways. We and others have hypothesized that activity-dependent neural signaling is a convergent molecular pathway dysregulated in ASD. However, the causal link between diminished activity-dependent neural signaling and ASD remains unclear. Brain-derived neurotrophic factor (BDNF) is a key molecule mediating activity-dependent neural signaling. We therefore hypothesize that diminished activity-dependent BDNF signaling could confer autism-like behavioral deficits. Here, we investigated the effect of diminished activity-dependent BDNF signaling on autism-like behavioral deficits by using mice with genetic knock-in of a human BDNF methionine (Met) allele, which has decreased activity-dependent BDNF release without altering basal BDNF level. Compared with wild-type (WT) controls, diminished activity-dependent BDNF signaling similarly induced anxiety-like behaviors in male and female mice. Notably, diminished activity-dependent BDNF signaling differentially resulted in autism-like social deficits and increased self-grooming in male and female mice, and male mice were more severe than female mice. Again, sexually dimorphic spatial memory deficits were observed in female BDNF+/Met mice, but not in male BDNF+/Met mice. Our study not only reveals a causal link between diminished activity-dependent BDNF signaling and ASD-like behavioral deficits, but also identifies previously underappreciated sex-specific effect of diminished activity-dependent BDNF signaling in ASD. These mice with genetic knock-in of the human BDNF Met variant provide a distinct mouse model for studying the cellular and molecular mechanisms underlying diminished activity-dependent neural signaling, the common molecular pathway dysregulated in ASD.

Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depression.

The noradrenergic locus coeruleus (LC) is the principal source of brain norepinephrine, a neurotransmitter thought to play a major role in the pathology of major depressive disorder (MDD) and in the therapeutic action of many antidepressant drugs. The goal of this study was to identify potential mediators of brain noradrenergic dysfunction in MDD. Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-ß superfamily, is a critical mediator of noradrenergic neuron differentiation during development and has neurotrophic and neuroprotective effects on mature catecholaminergic neurons. Real-time PCR of reversed transcribed RNA isolated from homogenates of LC tissue from 12 matched pairs of MDD subjects and psychiatrically normal control subjects revealed low levels of BMP7 gene expression in MDD. No differences in gene expression levels of other members of the BMP family were observed in the LC, and BMP7 gene expression was normal in the prefrontal cortex and amygdala in MDD subjects. Laser capture microdissection of noradrenergic neurons, astrocytes, and oligodendrocytes from the LC revealed that BMP7 gene expression was highest in LC astrocytes relative to the other cell types, and that the MDD-associated reduction in BMP7 gene expression was limited to astrocytes. Rats exposed to chronic social defeat exhibited a similar reduction in BMP7 gene expression in the LC. BMP7 has unique developmental and trophic actions on catecholamine neurons and these findings suggest that reduced astrocyte support for pontine LC neurons may contribute to pathology of brain noradrenergic neurons in MDD.

Impact on postpartum hemorrhage of prophylactic administration of oxytocin 10 IU via Uniject™ by peripheral health care providers at home births: design of a community-based cluster-randomized trial.

BACKGROUND: Hemorrhage is the leading direct cause of maternal death globally. While oxytocin is the drug of choice for postpartum hemorrhage prevention, its use has generally been limited to health facilities. This trial assesses the effectiveness, safety, and feasibility of expanding the use of prophylactic intramuscular oxytocin to peripheral health care providers at home births in four predominantly rural districts in central Ghana. METHODS: This study is designed as a community-based cluster-randomized trial in which Community Health Officers are randomized to provide (or not provide) an injection of oxytocin 10 IU via the Uniject™ injection system within one minute of delivery of the baby to women who request their presence at home at the onset of labor. The primary aim is to determine if administration of prophylactic oxytocin via Uniject™ by this cadre will reduce the risk of postpartum hemorrhage by 50 % relative to deliveries which do not receive the prophylactic intervention. Postpartum hemorrhage is examined under three sequential definitions: 1) blood loss ≥500 ml (BL); 2) treatment for bleeding (TX) and/or BL; 3) hospital referral for bleeding and/or TX and/or BL. Secondary outcomes address safety and feasibility of the intervention and include adverse maternal and fetal outcomes and logistical concerns regarding assistance at home births and the storage and handling of oxytocin, respectively. DISCUSSION: Results from this trial will build evidence for the effectiveness of expanding the delivery of this established prophylactic intervention to peripheral settings. Complementary data on safety and logistical issues related to this intervention will assist policymakers in low-income countries in selecting both the best uterotonic and service delivery strategy for postpartum hemorrhage prevention. Results of this trial are expected in mid-2013. The trial is registered at ClinicalTrials.gov: NCT01108289.

Antidepressant-like effects of trophic factor receptor signaling.

A significant body of research has demonstrated that antidepressants regulate neurotrophic factors and that neurotrophins themselves are capable of independently producing antidepressant-like effects. While brain derived neurotrophic factor (BDNF) remains the best studied molecule in this context, there are several structurally diverse trophic factors that have shown comparable behavioral effects, including basic fibroblast growth factor (FGF-2), insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF). In this review we discuss the structural and biochemical signaling aspects of these neurotrophic factors with antidepressant activity. We also include a discussion on a cytokine molecule erythropoietin (EPO), widely known and prescribed as a hormone to treat anemia but has recently been shown to function as a neurotrophic factor in the central nervous system (CNS).

Evaluation of a protein-to-creatinine dipstick diagnostic test for proteinuria screening in selected antenatal care clinics in three Districts in the Bono-East Region of Ghana.

BACKGROUND: Preeclampsia and eclampsia contribute significantly to maternal and newborn deaths worldwide. Early and accurate identification of pregnant women at risk can avert these deaths, but the necessary diagnostics are not widely available. A protein and creatinine ratio, rather than a measurement of protein alone, may provide better identification of proteinuria. The objective of this study was to assess the operational and performance characteristics of the LifeAssay Diagnostics (LAD) Test-it™ protein-to-creatinine ratio (PrCr) urinalysis dipstick test in a representative antenatal care setting (ANC). METHODS: Mixed methods were used to assess the operational and performance characteristics of the PrCr test, including a usability study with 25 participants, a prospective cross-sectional diagnostic accuracy study (N = 1483), and a targeted reassessment of discordant frozen samples (N = 200). Several other commonly used proteinuria tests were included for comparison. RESULTS: The test demonstrated improved clinical performance for detection of proteinuria over the current standard-of-care tests widely used in Ghana. The LAD PrCr test showed a sensitivity of 50.7% and specificity of 69.2% when run at the point of care. In contrast, the standard-of-care Accu-Tell® protein dipstick test was found to have a sensitivity of 32.4% and a specificity of 82.2%. The LAD test shows minor improvement over the tests currently used in Ghana to detect proteinuria. CONCLUSIONS: The PrCr test offers the potential for improved detection of proteinuria over the standard-of-care tests used in ANC. However, this test and the others evaluated for this study demonstrate limited performance, particularly among samples with a low level of proteinuria. Additional exploration in other clinical use cases, such as triage among high-risk populations, is warranted. The LAD test can also be considered a transition product, as health systems consider adopting next-generation biomarker tests when more readily available.

Characterization of electroconvulsive seizure-induced TIMP-1 and MMP-9 in hippocampal vasculature.

Degradation of the vascular basement membrane stimulates angiogenesis and is tightly controlled by balancing the actions of metalloproteases and their inhibitors. Previous work demonstrated that electroconvulsive seizure (ECS) elevates angiogenic factors and endothelial proliferation in the hippocampus. The robust induction of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) in the stratum lacunosum moleculare (SLM) corresponds to sites of increased vascular density. This led us to examine the spatial and cellular expression of TIMP-1 and its substrate, matrix metalloprotease 9 (MMP-9). Chronic ECS increased TIMP-1 by 12-fold and MMP-9 by 3-fold in discrete SLM cells. We then characterized the expression of TIMP-1 mRNA in relation to vasculature in the SLM and glial-limiting membrane (GLM). Employing laser microdissection we identified the cell types associated with SLM vasculature and also phenotyped the cells expressing TIMP-1 and MMP-9. We concluded that TIMP-1 is produced by perivascular cells positive for alpha smooth actin and that MMP-9 is expressed by GFAP-positive astrocytes. These studies suggest that ECS-induced remodelling occurs at the vascular basement membrane and facilitates neovascularization.

Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection.

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

Erythropoietin and Non-Erythropoietic Derivatives in Cognition.

Cognitive deficits are widespread in psychiatric disorders, including major depression and schizophrenia. These deficits are known to contribute significantly to the accompanying functional impairment. Progress in the development of targeted treatments of cognitive deficits has been limited and there exists a major unmet need to develop more efficacious treatments. Erythropoietin (Epo) has shown promising procognitive effects in psychiatric disorders, providing support for a neurotrophic drug development approach. Several preclinical studies with non-erythropoietic derivatives have demonstrated that the modulation of behavior is independent of erythropoiesis. In this review, we examine the molecular, cellular and cognitive actions of Epo and non-erythropoietic molecular derivatives by focusing on their neurotrophic, synaptic, myelin plasticity, anti-inflammatory and neurogenic mechanisms in the brain. We also discuss the role of receptor signaling in Epo and non-erythropoietic EPO-mimetic molecules in their procognitive effects.