Prevalence of antimicrobial-resistant bacteria in conventional vs. organic livestock farms in Egypt: a cross-sectional comparative study.

The silent pandemic of antimicrobial resistance (AR) has been on the rise for the past decades. It is essential to determine the burden of AR in animal farms that spreads leading to human exposure. A total of 100 samples including soil, litter, animal excreta, and wastewater were collected from seven conventional and one organic farm in Egypt. The prevalence of extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-producing E. coli), fluoroquinolone-resistant E. coli, fluoroquinolone-resistant Salmonella, and vancomycin-resistant enterococci (VRE) was determined in studied farms. Conventional farms had a higher prevalence of antimicrobial-resistant bacteria than the organic farm (73.81% vs. 18.75%, P < .001). In conventional farms 21.43% of samples yielded mixed isolates; however, in the organic farm, only single isolates of ESBL-producing E. coli were detected. The most prevalent ESBL-production gene was blaTEM (82.14%), followed by blaCTX-M (48.22%), and blaSHV (19.64%), either alone or in combination with another gene. The most prevalent fluoroquinolone-resistance genes were qnrS (82.69%) and qnrB (42.30%), either alone or in combination with another gene(s). A total of five VRE isolates harbored vanA gene (83.33%), none carried vanB gene, and one isolate was negative for both genes. The studied conventional livestock farms had significantly higher rates of serious AR threats than the organic farm.

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied. OBJECTIVE: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women. STUDY DESIGN: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood. RESULTS: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.

MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy.

Epilepsy is often associated with altered expression or function of ion channels. One example of such a channelopathy is the reduction of A-type potassium currents in the hippocampal CA1 region. The underlying mechanisms of reduced A-type channel function in epilepsy are unclear. Here, we show that inhibiting a single microRNA, miR-324-5p, which targets the pore-forming A-type potassium channel subunit Kv4.2, selectively increased A-type potassium currents in hippocampal CA1 pyramidal neurons in mice. Resting membrane potential, input resistance and other potassium currents were not altered. In a mouse model of acquired chronic epilepsy, inhibition of miR-324-5p reduced the frequency of spontaneous seizures and interictal epileptiform spikes supporting the physiological relevance of miR-324-5p-mediated control of A-type currents in regulating neuronal excitability. Mechanistic analyses demonstrated that microRNA-induced silencing of Kv4.2 mRNA is increased in epileptic mice leading to reduced Kv4.2 protein levels, which is mitigated by miR-324-5p inhibition. By contrast, other targets of miR-324-5p were unchanged. These results suggest a selective miR-324-5p-dependent mechanism in epilepsy regulating potassium channel function, hyperexcitability and seizures.

The fetal origins of mental illness.

The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections-or simply inflammation-may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain.

Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways.

Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents.

Placental Macrophages Demonstrate Sex-Specific Response to Intrauterine Inflammation and May Serve as a Marker of Perinatal Neuroinflammation.

Preterm birth (PTB) is considered to be one of the most frequent causes of neonatal death. Prompt and effective measures to predict adverse fetal outcome following PTB are urgently needed. Placenta macrophages are a critical immune cell population during pregnancy, phenotypically divided into M1 and M2 subsets. An established mouse model of intrauterine inflammation (IUI) was applied. Placenta (labyrinth) and corresponding fetal brain were harvested within 24 hours post injection (hpi). Flow cytometry, Western blot, real-time qPCR, and regular histology were utilized to examine the cytokines, macrophage polarization, and sex-specificity. Placental exposure to LPS led to significantly reduced labyrinth thickness compared to PBS-exposed controls as early as 3 hpi, accompanied by apoptosis and necrosis. Pro-inflammatory M1 markers, Il-1ß, and iNOS, and anti-inflammatory M2 marker Il-10 increased significantly in placentas exposed to IUI. Analysis of flow cytometry revealed that fetal macrophages (Hofbauer cell, HBCs) were mostly M1-like and that maternal inter-labyrinth macrophages (MIM) were M2-like in their features in IUI. Male fetuses displayed significantly decreased M2-like features in HBCs at 3 and 6 hpi, while female fetuses showed significant increase in M2-like features in MIM at 3 and 6 hpi. Furthermore, there was a significant correlation between the frequency of HBCs and corresponding microglial marker expression at 3 and 6 hpi. Placental macrophages demonstrated sex-specific features in response to IUI. Specifically, HBCs may be a potential biomarker for fetal brain injury at preterm birth.

Genetic Influence on Efficacy of Pharmacotherapy for Pediatric Attention-Deficit/Hyperactivity Disorder: Overview and Current Status of Research.

Multiple stimulant and non-stimulant medications are approved for the treatment of attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent childhood neurodevelopmental disorders. Choosing among the available agents and determining the most effective ADHD medication for a given child can be a time-consuming process due to the high inter-individual variability in treatment efficacy. As a result, there is growing interest in identifying predictors of ADHD medication response in children through the burgeoning field of pharmacogenomics. This article reviews childhood ADHD pharmacogenomics efficacy studies published during the last decade (2009-2019), which have largely focused on pharmacodynamic candidate gene investigations of methylphenidate and atomoxetine response, with a smaller number investigating pharmacokinetic candidate genes and genome-wide approaches. Findings from studies which have advanced the field of ADHD pharmacogenomics through investigation of meta-analytic approaches and gene-gene interactions are also overviewed. Despite recent progress, no one genetic variant or currently available pharmacogenomics test has demonstrated clinical utility in pinpointing the optimal ADHD medication for a given individual patient, highlighting the need for further investigation.

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain.

Fetuses exposed to an inflammatory environment are predisposed to long-term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well-established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba-1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67-positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS-induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.

Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model.

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110ß. FMRP deficiency increases p110ß protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110ß-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110ß-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110ß inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

Vancomycin resistance among Staphylococcus aureus isolates in a rural setting, Egypt.

INTRODUCTION: With the increased occurrence of methicillin resistant S. aureus (MRSA), the consumption of vancomycin, the drug of choice, has also increased. As a consequence, strains of S. aureus resistant to vancomycin have started to emerge. This study aimed to evaluate the level of vancomycin resistance among clinical and nasal S. aureus isolates in a rural town in Egypt. METHODS: This cross-sectional study was held in the general hospital at the rural town of Kafr Eldawar in Egypt, during the period from January 2013 to January 2014. S. aureus isolates were collected from clinical samples and from nasal swabs. RESULTS: Two hundred S. aureus isolates were collected, 80 (40%) from clinical samples and 120 (60%) from nasal carriage samples. Vancomycin resistant S. aureus (VRSA) was only detected in clinical samples, all collected from the outpatient clinic. Eleven VRSA isolates (13.8% of total S. aureus clinical isolates) and one strain of vancomycin-intermediate S. aureus (from nasal carriage) were detected. VRSA isolates were most resistant to ciprofloxacin (90.9%) and erythromycin (81.8%). Five isolates were resistant to all tested antibiotics: ciprofloxacin, clindamycin, erythromycin, linezolid, oxacillin, penicillin and trimethoprim-sulfamethoxazole. MRSA was found to constitute 43.8% of clinical S. aureus isolates. The MRSA colonization rate among community individuals was 43.6%, 42.9% among healthcare workers and 51.4% among patients. CONCLUSION: The prevalence of VRSA was high in clinical samples suggesting that there is a high level of VRSA strains in Egypt that goes undetected since most laboratories only use disk diffusion for detection of vancomycin resistance.

Design and analysis of siloxanes removal by adsorption from landfill gas for waste-to-energy processes.

Separation of volatile methyl siloxanes from landfill gas using fixed adsorption beds was modeled with the objective of identifying appropriate technology and the economics associated with this purification step. A general adsorption model assuming plug flow and radial symmetry was developed and used to conduct a parametric sweep of 162 unique cases. The varied parameters were adsorbent type (activated carbon and silica gel), bed height (3.05-9.15 m/10-30 ft), inlet siloxane concentration (5-15 mg/m3), moisture content (0-100% relative humidity at STP or RH), and siloxane tolerance limit (0.094-9.4 mg/m3) that correlated to three distinct energy conversion technologies (electricity production using engines or fuels cells or catalytic conversion to liquid hydrocarbon fuels). Due to the detrimental effect of RH on siloxane absorption, the maximum allowable moisture content of LFG before purification is 50% RH and moisture removal processes are also required. The design calculations using a selected case study show that the adsorption bed height required needed for 6 months minimum breakthrough time for catalytic fuel production is twice that for engine applications. Fuel cell applications require 3 times the bed height compared to engine applications. However, the purification costs amounted to 94%, 16% and 52% of recovered product value for engine, liquefaction, and fuel cell applications, respectively indicating the need for a high value product to justify purification costs. The approaches and conclusions can be extended to specific process conditions for landfill gas purification and to other processes that use biogas produced from waste as a feedstock.

Using ADHD Medications to Treat Coexisting ADHD and Reading Disorders: A Systematic Review.

Attention-deficit/hyperactivity disorder (ADHD), the most common pediatric neurobehavioral disorder, frequently presents with coexisting reading disorders (RDs). Despite this, it is unclear whether medication improves symptoms and function in children with comorbid ADHD and RD. We present a systematic review of studies investigating the effects of ADHD medications on ADHD symptoms, academic outcomes, and neuropsychological measures in this important group.

Requirements, techniques, and costs for contaminant removal from landfill gas.

Waste-to-energy projects are an increasingly prominent component of future energy portfolios. Landfill gas (LFG)-to-energy (LFGTE) projects are particularly important as they address greenhouse gas emissions. Contaminants in LFG may hamper these projects both from environmental and economic standpoints. The purpose of this review is to highlight key aspects (LFG composition ranges, LFG flowrates, and allowable tolerances for LFGTE technologies, performance and costs for contaminant removal by adsorption). Removal of key contaminants, H2S and siloxanes, by adsorption are surveyed in terms of adsorption capacities and regeneration abilities. Based on the open literature, costing analyses are tabulated and discussed. The findings indicate economics of contaminant removal depend heavily on the feed concentrations of contaminants, allowable tolerances for the LFGTE technology, and the current market for the product. Key trends, identification of challenges, and general purification guidelines for purifying LFG for energy projects are also discussed.