The Effect of High Pressure on Polymorphs of a Derivative of Blatter's Radical: Identification of the Structural Signatures of Subtle Phase Transitions.

The effect of pressure on the α and ß polymorphs of a derivative of Blatter's radical, 3-phenyl-1-(pyrid-2-yl)-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl, has been investigated using single-crystal X-ray diffraction to maximum pressures of 5.76 and 7.42 GPa, respectively. The most compressible crystallographic direction in both structures lies parallel to π-stacking interactions, which semiempirical Pixel calculations indicate are also the strongest interactions present. The mechanism of compression in perpendicular directions is determined by void distributions. Discontinuities in the vibrational frequencies observed in Raman spectra measured between ambient pressure and ∼5.5 GPa show that both polymorphs undergo phase transitions, the α phase at 0.8 GPa and the ß phase at 2.1 GPa. The structural signatures of the transitions, which signal the onset of compression of initially more rigid intermolecular contacts, were identified from the trends in the occupied and unoccupied volumes of the unit cell with pressure and in the case of the ß phase by deviations from an ideal model of compression defined by Birch-Murnaghan equations of state.

Factors associated with mobile phone usage to access maternal and child healthcare among women of urban slums in Dhaka, Bangladesh: a cross-sectional study.

INTRODUCTION: With the acute shortage of human resources and infrastructure, mobile phones can be a critical tool for accessing health services and strengthening health systems in Bangladesh. Yet, there is a scarcity of evidence on the use of mobile phones in this context for accessing health services. In this study, we sought to explore the current use of mobile phones for accessing maternal and child healthcare and its determinants among recently delivered women in urban slums of Bangladesh. METHODS: The data were collected through interviewing 800 recently delivered women from eight slums of Dhaka city of Bangladesh during May and June 2018. The study followed a cross-sectional design and a two-stage cluster random sampling procedure was followed. A pretested structured questionnaire was employed to collect information. Chi square tests were performed for descriptive analyses and a multilevel binary logistic regression model was executed to explore the determinants of mobile phone usage for accessing maternal and childcare among the participants. RESULTS: Overall, 73.8% of study participants used mobile phones for accessing maternal and child healthcare. After adjusting for potential confounders, participants' age, husband's occupation, sex of household head, women's ownership of mobile phones and household wealth status were found to be significantly associated with higher odds of using mobile phones to access maternal and child healthcare. CONCLUSION: The study highlighted the possibility of implementing large-scale mobile health (mHealth) interventions in slum settlements for accessing maternal and child healthcare and is a sustainable mitigation strategy for the acute health worker crisis in Bangladesh. The findings of this study are particularly crucial for policymakers and practitioners while they revise the health policy to incorporate mHealth interventions as highlighted in the recently initiated Digital Health Strategy of Bangladesh.

Exploring Factors Associated with Women's Willingness to Provide Digital Fingerprints in Accessing Healthcare Services: A Cross-Sectional Study in Urban Slums of Bangladesh.

Digital fingerprints are increasingly used for patient care and treatment delivery, health system monitoring and evaluation, and maintaining data integrity during health research. Yet, no evidence exists about the use of fingerprinting technologies in maternal healthcare services in urban slum contexts, globally. The present study aimed to explore the recently delivered women's willingness to give digital fingerprints to community health workers to access healthcare services in the urban slums of Bangladesh and identify the associated factors. Employing a two-stage cluster random sampling procedure, we chose 458 recently delivered women from eight randomly selected urban slums of Dhaka city, Bangladesh. Chi-square tests were performed for descriptive analyses, and binary logistic regression analyses were performed to explore the factors associated with willingness to provide fingerprints. Overall, 78% of the participants reported that they were willing to provide digital fingerprints if that eased access to healthcare services. After adjusting for potential confounders, the sex of the household head, family type, and household wealth status were significantly associated with the willingness to provide fingerprints to access healthcare services. The study highlighted the potentials of using fingerprints for making healthcare services accessible. Focus is needed for female-headed households, women from poor families, and engaging husbands and in-laws in mobile health programs.

Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome.

Human cytomegalovirus (HCMV) is a major cause of viral disease in the young and the immune-suppressed. At sites of infection, HCMV recruits the neutrophil, a cell with a key role in orchestrating the initial immune response. Herein, we report a profound survival response in human neutrophils exposed to the clinical HCMV isolate Merlin, but not evident with the attenuated strain AD169, through suppression of apoptosis. The initial survival event, which is independent of viral gene expression and involves activation of the ERK/MAPK and NF-κB pathways, is augmented by HCMV-stimulated release of a secretory cytokine profile that further prolongs neutrophil lifespan. As aberrant neutrophil survival contributes to tissue damage, we predict that this may be relevant to the immune pathology of HCMV, and the presence of this effect in clinical HCMV strains and its absence in attenuated strains implies a beneficial effect to the virus in pathogenesis and/or dissemination. In addition, we show that HCMV-exposed neutrophils release factors that enhance monocyte recruitment and drive monocyte differentiation to a HCMV-permissive phenotype in an IL-6-dependent manner, thus providing an ideal vehicle for viral dissemination. This study increases understanding of HCMV-neutrophil interactions, highlighting the potential role of neutrophil recruitment as a virulence mechanism to promote HCMV pathology in the host and influence the dissemination of HCMV infection. Targeting these mechanisms may lead to new antiviral strategies aimed at limiting host damage and inhibiting viral spread.

The anterior insula bidirectionally modulates cost-benefit decision-making on a rodent gambling task.

Deficits in cost-benefit decision-making, as assessed in the Iowa Gambling Task (IGT), are commonly observed in neuropsychiatric disorders such as addiction. There is considerable variation in the maximization of rewards on such tasks, both in the general population and in rodent models, suggesting individual differences in decision-making may represent a key endophenotype for vulnerability to neuropsychiatric disorders. Increasing evidence suggests that the insular cortex, which is involved in interoception and emotional processes in humans, may be a key neural locus in the control of decision-making processes. However, the extent to which the insula contributes to individual differences in cost-benefit decision-making remains unknown. Using male Sprague Dawley rats, we first assessed individual differences in the performance over the course of a single session on a rodent analogue of the IGT (rGT). Rats were matched for their ability to maximize reward and received bilateral excitotoxic or sham lesions of the anterior insula cortex (AIC). Animals were subsequently challenged on a second rGT session with altered contingencies. Finally, animals were also assessed for instrumental conditioning and reversal learning. AIC lesions produced bidirectional alterations on rGT performance; rats that had performed optimally prior to surgery subsequently showed impairments, and animals that had performed poorly showed improvements in comparison with sham-operated controls. These bidirectional effects were not attributable to alterations in behavioural flexibility or in motivation. These data suggest that the recruitment of the AIC during decision-making may be state-dependent and help guide response selection towards subjectively favourable options.

Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus.

Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (ΦSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.

Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens.

The release of neutrophil extracellular traps (NETs) is a major immune mechanism intended to capture pathogens. These histone- and protease-coated DNA structures are released by neutrophils in response to a variety of stimuli, including respiratory pathogens, and have been identified in the airways of patients with respiratory infection, cystic fibrosis, acute lung injury, primary graft dysfunction, and chronic obstructive pulmonary disease. NET production has been demonstrated in the lungs of mice infected with Staphylococcus aureus, Klebsiella pneumoniae, and Aspergillus fumigatus. Since the discovery of NETs over a decade ago, evidence that "NET evasion" might act as an immune protection strategy among respiratory pathogens, including group A Streptococcus, Bordetella pertussis, and Haemophilus influenzae, has been growing, with the majority of these studies being published in the past 2 years. Evasion strategies fall into three main categories: inhibition of NET release by down-regulating host inflammatory responses; degradation of NETs using pathogen-derived DNases; and resistance to the microbicidal components of NETs, which involves a variety of mechanisms, including encapsulation. Hence, the evasion of NETs appears to be a widespread strategy to allow pathogen proliferation and dissemination, and is currently a topic of intense research interest. This article outlines the evidence supporting the three main strategies of NET evasion-inhibition, degradation, and resistance-with particular reference to common respiratory pathogens.

Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition.

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.

From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior.

Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal.

Hypocretin/orexin has a well-established role in wakefulness and in the maintenance of arousal. Because stress is associated with arousal, it has been proposed that hypocretin is also involved in stress. However, it is not clear if this is true for all forms of stress. To clarify this issue, we compared four conditions combining high arousal with no or low stress (wakefulness and exploration) or high stress (contextual fear and restraint) in the rat. We looked at Fos expression in hypocretin neurons, hypocretin-1 levels in cerebrospinal fluid and cardiovascular and behavioural changes after pharmacological blockade with the dual hypocretin receptor antagonist, almorexant. Fos expression in hypocretin neurons was highest with wakefulness and exploration, also high with fear but not significant with restraint. Hypocretin-1 levels were consistent with this pattern, although the differences were not as marked. Hypocretin receptor blockade with almorexant reduced the pressor, tachycardic and locomotor responses of wakefulness and exploration as well as the pressor and sympathetic component of the tachycardic response of fear. In contrast, almorexant did not reduce the pressor and tachycardic responses of restraint and nor did it reduce the pressor, tachycardic and locomotor responses of another stressor, i.e. cold exposure. Thus, hypocretin is not involved in all forms of stress. Comparison of the different conditions suggests that, regardless of stress, hypocretin involvement occurs when the arousal associated with the response includes increased attention to environmental cues. When it does, hypocretin will at least contribute to the cardiovascular response. The findings are of clinical relevance to some forms of psychological stress.

Inhibition of the cardiovascular response to stress by systemic 5-HT1A activation: sympathoinhibition or anxiolysis?

5-HT(1A) agonists given systemically are known to produce anxiolytic effects. In addition, a growing body of research is showing that those compounds also have central sympathoinhibitory properties. Since emotional arousal gives rise to sympathetic activation, it is not clear whether systemic treatment with a 5-HT(1A) agonist reduces the sympathetic response to emotional stress primarily by a direct action on sympathetic-related sites in the brain or indirectly through reducing anxiety. To test this, we compared the effect of intraperitoneal injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.05 and 0.25 mg/kg), a preferential 5-HT(1A) agonist, or vehicle on the cardiovascular responses to four stressors known to produce sympathetic activation, three being emotional stressors, and one physiological. In conscious rats, 30-min exposure to either a neutral context, a fear-conditioned context, or to restraint stress led to increases in heart rate and blood pressure, which were attenuated by 8-OH-DPAT. In contrast, the same treatment did not reduce the cardiovascular response to 30-min cold exposure (4 degrees C). The results suggest that 8-OH-DPAT acts preferentially on limbic, rather than central, autonomic sites. Hence, doses of 5-HT(1A) agonists, which are just sufficient to produce anxiolysis, are not enough to cause true sympathoinhibition.

Nonshivering thermogenesis without interscapular brown adipose tissue involvement during conditioned fear in the rat.

As with other forms of psychological stress, conditioned fear causes an increase in body temperature. The mechanisms underlying this stress-induced hyperthermia are not well understood, but previous research suggests that nonshivering thermogenesis might contribute, as it does during cold exposure. The major source of nonshivering thermogenesis in the rat is brown adipose tissue (BAT), and the largest BAT deposit in that species is in the interscapular area just below the skin. BAT is also under sympathetic control via beta-adrenoceptors. If BAT contributes to fear-induced hyperthermia, then the interscapular skin should warm up faster than other skin areas, and this response should be suppressed by the beta-adrenoceptor antagonist, propranolol. We tested this noninvasively by infrared thermography. In conscious rats, 30 min of contextual fear caused hyperthermia (as indicated by a +1.5 degrees C increase in lumbar back skin temperature) and increased the difference in temperature between interscapular and lumbar back skin (TiScap - TBack) by +1 degrees C. Propranolol (10 mg/kg ip) completely abolished this hyperthermia; however, the TiScap-TBack increase was not reduced. In contrast, exposure to cold air (4 degrees C) induced a +2.7 degrees C increase in TiScap-TBack, which was reduced to +1 degrees C after propranolol. The results show that conditioned fear-induced hyperthermia is of nonshivering origin and mediated by beta-adrenoceptors, but interscapular BAT does not contribute to it and does not appear to be activated, either.

Outcomes of twin-twin transfusion syndrome managed by a specialised twin clinic.

INTRODUCTION: To determine the perinatal outcomes of monochorionic (MC) pregnancies complicated by the twin-twin transfusion syndrome (TTTS) that were managed in a specialised twin clinic at the KK Women's and Children's Hospital. METHODS: This was a 21-month retrospective study carried out from January 2002 to September 2003. MC pregnancies were followed up every two to three weeks with regular ultrasonographical and Doppler studies from the time monochorionicity was diagnosed. Standard criteria used for the diagnosis of TTTS are the presence of oligohydramnios/polyhydramnios sequence on ultrasonography. The severity of TTTS was staged according to Quintero's system. RESULTS: There were 77 sets of MC pregnancies in our database. 11 sets were diagnosed with TTTS, hence the incidence was 14.3 percent. The median gestation at diagnosis of TTTS was 17.4 (16.4 to 26) weeks. At first presentation, five were stage I, two were stage II, three were stage III and one was stage IV. Three pregnancies were terminated in the second trimester and one was lost to follow-up. Of the other seven, two were treated expectantly or delivered, four with amnioreduction/ septostomy and one with cord occlusion. The median gestation at delivery is 30.8 (26.7 to 36.9) weeks. Four (57 percent) were delivered before 32 weeks and these same four pairs required neonatal intensive care. The overall perinatal survival was 78 percent (11/14) and the median diagnosis to delivery interval was 10.7 (3.1 to 17.5) weeks. CONCLUSION: TTTS occurs in a significant proportion of MC pregnancies. The perinatal survival outcome of this group of patients managed in this clinic is comparable to that of other good centres.

Expression of cardiovascular and behavioural components of conditioned fear to context in T4 spinally transected rats.

A spinal cord transection at the fourth thoracic level (T4) results in paraplegia. It also removes supraspinal control of sympathetic outflow to most viscera and their blood vessels but spares the heart. We studied the effects of such a transection on the expression of the conditioned fear response to context, which includes freezing, 22 kHz ultrasonic vocalisations, a marked pressor response and a slowly rising tachycardia. Rats implanted with radiotelemetric probes were fear conditioned, tested, then transected at T4 and finally re-tested 4 weeks after transection. Baseline blood pressure in transected animals was the same as in intact animals but baseline heart rate was 127 bpm higher. There were clear signs of fear in the transected animals: although freezing occurred in the upper part of the body only, there was a 3 fold increase in the number of ultrasonic vocalisations, most probably due to paralysis of abdominal muscles that made expirations shorter and therefore more frequent. The pressor response of fear was initially the same as in intact animals but controls revealed that this was due to handling during transfer to the aversive context. The rest of the pressor response was markedly reduced (70%) confirming that it depends in large part on a sympathetically mediated increase in vascular resistance in the lower part of the body. The cardiac response was characterized by an initial bradycardia followed by a marked tachycardia, which is consistent with a baroreceptor-mediated reflex response to the altered pressor changes. Finally, none of these changes was observed when the same experiment was repeated in sham transected animals. Thus, the pressor response of fear is in large part mediated by the thoracic cord below T4 and the baroreflex is not inhibited but maintained during conditioned fear.

Changes in cutaneous and body temperature during and after conditioned fear to context in the rat.

Infrared thermography was used to image changes in cutaneous temperature during a conditioned fear response to context. Changes in heart rate, arterial pressure, activity and body (i.p.) temperature were recorded at the same time by radio-telemetry, in addition to freezing immobility. A marked drop in tail and paws temperature (-5.3 and -7.5 degrees C, respectively, down to room temperature), which lasted for the entire duration of the response (30 min), was observed in fear-conditioned rats. In sham-conditioned rats, the drop was on average half the magnitude and duration. In contrast, temperature of the eye, head and back increased (between + 0.8 and + 1.5 degrees C), with no difference between the two groups of rats. There was a similar increase in body temperature although it was slightly higher and delayed in the fear-conditioned animals. Finally, ending of the fear response was associated with a gradual decrease in body temperature and a rebound increase in the temperature of the tail (+ 3.3 degrees C above baseline). This study shows that fear, and to some extent arousal, evokes a strong cutaneous vasoconstriction that is restricted to the tail and paws. This regionally specific reduction in blood flow may be part of a preparatory response to a possible fight and flight to reduce blood loss in the most exposed parts of the rat's body in case of injury. The data also show that the tail is the main part of the body used for dissipating internal heat accumulated during fear once the animal has returned to a safe environment.

Students in compensatory education programs: analysis of scores on performance assessments for the Iowa Test of Basic Skills.

Analysis of Mathematics and Language Arts scores for 11,438 fourth- and 8,972 seventh-grade students in compensatory education programs on the performance assessments for the Iowa Test of Basic Skills indicated the students performed poorly, particularly in mathematics.