Ligand specificity and conformational dependence of the hepatic nuclear factor-4alpha (HNF-4alpha ).
Hepatic nuclear factor-4alpha (HNF-4alpha) controls the expression of genes encoding proteins involved in lipid and carbohydrate metabolism. Fatty acyl-CoA thioesters have recently been proposed to be naturally occurring ligands of HNF-4alpha and to regulate its transcriptional activity as function of their chain length and degree of unsaturation (Hertz, R., Magenheim, J., Berman, I., and Bar-Tana, J. (1998) Nature 392, 512-516). However, the apparent low affinities (microm K(d) values) obtained with a radiolabeled fatty acyl-CoA ligand binding assay raised questions regarding the physiological significance of this finding. Furthermore, it is not known whether interaction with fatty acyl-CoA alters the structure of HNF-4alpha. These issues were examined using rat recombinant HNF-4alpha ligand-binding domain (HNF-4alphaLBD) in conjunction with photon counting fluorescence and circular dichroism. First, fluorescence resonance energy transfer between HNF-4alphaLBD tryptophan (Trp) and cis-parinaroyl-CoA yielded an intermolecular distance of <or=42 A, thus pointing to direct molecular interaction rather than nonspecific coaggregation. Second, quenching of HNF-4alphaLBD intrinsic Trp fluorescence by fatty acyl-CoAs (e.g. pamitoyl-, stearoyl-, linoleoyl-, and arachidonoyl-CoAs) yielded a single binding site with K(d) values of 1.6-4.0 nm. These affinities were 2-3 orders of magnitude higher than those previously derived by radiolabeled fatty acyl-CoA ligand binding assay. Third, binding of fatty acyl-CoAs was specific as the binding affinities of the respective free fatty acids or free CoA (K(d) values of 421-742 nm) were significantly lower. Fourth, circular dichroism demonstrated that the HNF-4alphaLBD secondary structure was significantly and differentially altered by fatty acyl-CoA binding. The opposite effects of saturated versus polyunsaturated fatty acyl-CoAs on HNF-4alpha LBD secondary structure correlated with their opposite regulatory effects on HNF-4alpha function. Fifth, the CoA thioesters of some hypolipidemic peroxisome proliferators bind with high affinity (K(d) values as low as 2.6 nm) to HNF-4alpha LBD, thus indicating that HNF-4alpha may serve as target for these drugs. In summary, these data demonstrate for the first time high affinity binding to HNF-4alpha of fatty and xenobiotic acyl-CoAs in the physiological range, resulting in significantly altered HNF-4alpha conformation.


Benzo [b]-promazines, chlorpromazine free radical and analino-N, N-dimethylpropylamine analogs influence rat striatal DA-adenylate cyclase and calmodulin-phosphodiesterase.
A series of Benzo [b]-promazines and analino-N, N-dimethylpropylamine analogs and the free radical of chlorpromazine were compared to chlorpromazine and promazine in the rat striatum for their ability to inhibit either dopamine activated adenylate cyclase or calmodulin stimulation of a partially purified high Km cyclic AMP phosphodiesterase. Chlorpromazine and the corresponding free radical were generally the most potent inhibitors of the two enzyme preparations, however, Piperazino-Benzo [b]-promazine, 1-Oxo-Benzo [b]-promazine, N-38-76-3A and Benzo [b]-promazine were relatively effective inhibitors. To a lesser extent, tyrosine, N-57-77, Piperidino-Benzo [b]-promazine, Diethyl-Benzo [b]-promazine, promazine and 1-Oxo-Diethyl-Benzo [b]-promazine exerted varying degrees of antagonism of the two enzymes. In all instances the compounds inhibited dopamine-sensitive adenylate cyclase to a greater extent than the calmodulin activated phosphodiesterase.


'The research compass': an introduction to research in medical education: AMEE Guide no. 56.
This AMEE Guide offers an introduction to research in medical education. It is intended for those who are contemplating conducting research in medical education but are new to the field. The Guide is structured around the process of transforming ideas and problems into researchable questions, choosing a research approach that is appropriate to the purpose of the study and considering the individual researcher's preferences and the contextual possibilities and constraints. The first section of the Guide addresses the rationale for research in medical education and some of the challenges posed by the complexity of the field. Next is a section on how to move from an idea or problem to a research question by placing a concrete idea or problem within a conceptual, theoretical framework. The following sections are structured around an overview model of approaches to medical education research, 'The research compass'. Core to the model is the conceptual, theoretical framework that is the key to any direction. The compass depicts four main categories of research approaches that can be applied when studying medical education phenomena, 'Explorative studies'; 'Experimental studies'; 'Observational studies'; and 'Translational studies'. Future AMEE Guides in the research series will address these approaches in more detail.


With whom are you dealing? Using social network analysis as a tool to strengthen service delivery structures for low socioeconomic status populations.
Background: Health disparities between populations with different socioeconomic status (SES) are increasing. Although a wide variety of support service organizations and arrangements are in place, no general overview of this social network, its reach, and harmonization of services surrounding low-SES populations are available. The present participatory health research study examined the current network structure and the utility of using social network analysis (SNA) as a tool to improve service delivery structures. Design and methods: We applied a mixed-methods study design. An online-questionnaire was used to examine the relationships among organizations assumed to support low-SES individuals in the municipality of Vaals, the Netherlands. In addition, semi-structured interviews and a networking session were used to examine the current network structure and to explore opportunities for improvement. Results: The SNA revealed a weak network structure, and all interviewed professionals mentioned that the current structure should be improved. Participants indicated that a first step would be to install a central information system. Conclusions: SNA can be a useful tool to gain more in-depth insights into the relations within a service delivery network. The professionals were assisted in discovering new organizations that could help them reach low SES populations and in harmonizing and improving their service delivery.


Newborn infants perceive abstract numbers.
Although infants and animals respond to the approximate number of elements in visual, auditory, and tactile arrays, only human children and adults have been shown to possess abstract numerical representations that apply to entities of all kinds (e.g., 7 samurai, seas, or sins). Do abstract numerical concepts depend on language or culture, or do they form a part of humans' innate, core knowledge? Here we show that newborn infants spontaneously associate stationary, visual-spatial arrays of 4-18 objects with auditory sequences of events on the basis of number. Their performance provides evidence for abstract numerical representations at the start of postnatal experience.


Isoflurane suppresses cortical spreading depolarizations compared to propofol--implications for sedation of neurocritical care patients.
Sedatives in the neurointensive care unit can strongly influence patients' risks of developing secondary brain damage. In particular, isoflurane, a volatile anesthetic, has been recently re-introduced to the neurointensive care unit, and first clinical studies suggest beneficial effects due to elevation of cerebral blood flow and reduction of metabolism. In contrast, propofol is a commonly used intravenous sedative that reduces cerebral blood flow and intra-cranial pressure. We have here studied the influence of these two sedatives on the occurrence of cortical spreading depolarizations (CSDs), which have emerged over the last decade as a major mechanism of delayed brain injury in stroke and brain trauma, constituting a substantial vascular and metabolic threat to peri-infarct tissue and being associated with poor patient outcome. Two experimental models were tested in Wistar rats anesthetized either with isoflurane or with propofol: KCl-evoked CSDs (n=10) and spontaneous CSDs after occlusion of the middle cerebral artery (n=14). Spatiotemporal patterns of CSD waves were observed by real-time laser speckle imaging of regional cerebral blood flow changes associated with the CSDs. During 30 min of cortical KCl application, 5.2±0.7 CSDs were induced under isoflurane compared to 10.2±1.8 CSDs under propofol (p<0.001). After focal ischemia, 2.43±1.0 CSDs/h emerged spontaneously under isoflurane versus 6.83±2.5 CSDs/h under propofol (p<0.001). Furthermore, baseline blood flow and glycemia were much higher under isoflurane compared to propofol, which may set the tissue in better metabolic conditions to recover from the occurrence of CSD waves. We conclude that isoflurane, in comparison to propofol, decreases the occurrence of CSDs and may improve recovery from these metabolically demanding waves. To reduce CSD induced secondary tissue damage, we suggest isoflurane to be favored over propofol to sedate acute stroke and trauma patients in the neurointensive care unit.


Long-term impact of pediatric endoscopic endonasal skull base surgery on midface growth.
Cranial base development plays a large role in anterior and vertical maxillary growth through 7 years of age, and the effect of early endonasal cranial base surgery on midface growth is unknown. The authors present their experience with pediatric endoscopic endonasal surgery (EES) and long-term midface growth. This is a retrospective review of cases where EES was performed from 2000 to 2016. Patients who underwent their first EES of the skull base before age 7 (prior to cranial suture fusion) and had a complete set of pre- and postoperative imaging studies (CT or MRI) with at least 1 year of follow-up were included. A radiologist performed measurements (sella-nasion [S-N] distance and angles between the sella, nasion, and the most concave points of the anterior maxilla [A point] or anterior mandibular synthesis [B point], the SNA, SNB, and ANB angles), which were compared to age- and sex-matched Bolton standards. A Z-score test was used; significance was set at p < 0.05. The early surgery group had 11 patients, with an average follow-up of 5 years; the late surgery group had 33 patients. Most tumors were benign; 1 patient with a panclival arteriovenous malformation was a significant outlier for all measurements. Comparing the measurements obtained in the early surgery group to Bolton standard norms, the authors found no significant difference in postoperative SNA (p = 0.10), SNB (p = 0.14), or ANB (0.67) angles. The S-N distance was reduced both pre- and postoperatively (SD 1.5, p = 0.01 and p = 0.009). Sex had no significant effect. Compared to patients who had surgery after the age of 7 years, the early surgery group demonstrated no significant difference in pre- to postoperative changes with regard to S-N distance (p = 0.87), SNA angle (p = 0.89), or ANB angle (p = 0.14). Lesion type (craniopharyngioma, angiofibroma, and other types) had no significant effect in either age group. Though our cohort of patients with skull base lesions demonstrated some abnormal measurements in the maxillary-mandibular relationship before their operation, their postoperative cephalometrics fell within the normal range and showed no significant difference from those of patients who underwent operations at an older age. Therefore, there appears to be no evidence of impact of endoscopic endonasal skull base surgery on craniofacial development within the growth period studied.


[Hemoglobin-oxygen affinity in acute respiratory and circulatory disorders in patients following open heart surgery].
Hemodynamic parameters, lung gas exchange, hemoglobin, acid-base balance, gases, blood lactate and pO2 have been studied in 105 patients with acute cardiorespiratory disturbances (CRD) after open heart surgery. The actual P50 was determined by the venous point, using the Severinghaus blood gas analyser. The method of multidimensional regression analysis was used to study the contribution of some factors determining oxyhemoglobin dissociation curve (ODC) shift. It has been shown that CRD are characterized not only by Bohr's effect and temperature impact but also by ODC shifts, which cannot be accounted for by changes in erythrocyte 2,3-diphosphoglycerate concentration. As hypoxia is universal for any CRD the index of mixed venous blood saturation with O2 (Sv-O2) was considered as a factor determining hypoxic ODC shift and a numerical contribution of hypoxia to P50 changes has been determined. The coefficient in delta Sv-O2 was 0.0025-0.0030 15% Sv-O2 changes were in Bohr's effect equivalent to ODC shift, with pH changing by 0.1. The role of hypoxia in the changes of Hb-O2 affinity in CRD is discussed.


Effects of antisense oligodeoxynucleotides on peptide release from hypothalamoneurohypophysial explants.
Rapid effects of antisense oligodeoxynucleotides (AODNs) on the function of the neurohypophysial system have been reported previously. The present studies were designed to determine the effects of vasopressin (VP) and oxytocin (OT) AODNs on osmotically or potassium-stimulated VP and OT release from perifused hypothalamoneurohypophysial (HNS) explants. The AODNs were 18-mer phosphorothioate forms targeted toward the translation initiation sites of either VP or OT mRNA, or a mixed base sequence (4 microM). The explants were exposed to a ramp increase in NaCl (either 20 or 30 mosmol/6 h) or to 25 mM KCl. VP and OT release was measured by radioimmunoassay in sequential 20-min fractions of the perifusate. There was a peptide-specific inhibition by the AODNs of osmotically stimulated VP and OT release. VP AODN inhibited VP, but not OT release, and vice vorsa. However, the AODNs had no effect on potassium-stimulated peptide release, demonstrating that depolarization-secretion coupling was still intact. Furthermore, there were no significant differences in VP and OT mRNA and peptide content after antisense treatment. Thus these observations indicate that acute exposure to peptide AODNs interrupts osmotically stimulated VP and OT release in a peptide-specific manner.


Gastroenterology Procedures Generate Aerosols: An Air Quality Turnover Solution to Mitigate COVID-19's Propagation Risk.
The growing fear of virus transmission during the 2019 coronavirus disease (COVID-19) pandemic has called for many scientists to look into the various vehicles of infection, including the potential to travel through aerosols. Few have looked into the issue that gastrointestinal (GI) procedures may produce an abundance of aerosols. The current process of risk management for clinics is to follow a clinic-specific HVAC formula, which is typically calculated once a year and assumes perfect mixing of the air within the space, to determine how many minutes each procedural room refreshes 99% of its air between procedures when doors are closed. This formula is not designed to fit the complex dynamic of small airborne particle transport and deposition that can potentially carry the virus in clinical conditions. It results in reduced procedure throughput as well as an excess of idle time in clinics that process a large number of short procedures such as outpatient GI centers. We present and tested a new cyber-physical system that continuously monitors airborne particle counts in procedural rooms and also at the same time automatically monitors the procedural rooms' state and flexible endoscope status without interfering with the clinic's workflow. We use our data gathered from over 1500 GI cases in one clinical suite to understand the correlation between air quality and standard procedure types as well as identify the risks involved with any HVAC system in a clinical suite environment. Thanks to this system, we demonstrate that standard GI procedures generate large quantities of aerosols, which can potentially promote viral airborne transmission among patients and healthcare staff. We provide a solution for the clinic to improve procedure turnover times and throughput, as well as to mitigate the risk of airborne transmission of the virus.


Context-dependent smooth eye movements evoked by stationary visual stimuli in trained monkeys.
The appearance of a stationary but irrelevant cue triggers a smooth eye movement away from the position of the cue in monkeys that have been trained extensively to smoothly track the motion of moving targets while not making saccades to the stationary cue. We have analyzed the parameters that regulate the size of the cue-evoked smooth eye movement and examined whether presentation of the cue changes the initiation of pursuit for subsequent steps of target velocity. Cues evoked smooth eye movements in blocks of target motions that required smooth pursuit to moving targets, but evoked much smaller smooth eye movements in blocks that required saccades to stationary targets. The direction of the cue-evoked eye movement was always opposite to the position of the cue and did not depend on whether subsequent target motion was toward or away from the position of fixation. The latency of the cue-evoked smooth eye movement was near 100 ms and was slightly longer than the latency of pursuit for target motion away from the position of fixation. The size of the cue-evoked smooth eye movement was as large as 10 degrees /s and decreased as functions of the eccentricity of the cue and the illumination of the experimental room. To study the initiation of pursuit in the wake of the cues, we used bilateral cues at equal eccentricities to the right and left of the position of fixation. These evoked smaller eye velocities that were consistent with vector averaging of the responses to each cue. In the wake of bilateral cues, the initiation of pursuit was enhanced for target motion away from the position of fixation, but not for target motion toward the position of fixation. We suggest that the cue-evoked smooth eye movement is related to a previously postulated on-line gain control for pursuit, and that it is a side-effect of sudden activation of the gain-controlling element.


The microscopic structure of mono-disperse granular heaps and sediments of particles on inclined surfaces.
Granular heaps of particles created by deposition of mono-disperse particles raining from an extended source of finite size are characterized by a non-homogeneous field of density. It was speculated that this inhomogeneity is due to the transient shape of the sediment during the process of construction of the heap, thus reflecting the history of the creation of the heap. By comparison of structural characteristics of the heap with sediments created on top of inclined planes exploiting the method of Minkowski tensors, we provide further evidence to support this hypothesis. Moreover, for the case of sediments generated by homogeneous rain on surfaces, we provide relationships between the inclination of the surface and the Minkowski measures characterizing the isotropy of local particle environments.


Surgical management of complex proximal humerus fractures-a systematic review of 92 studies including 4500 patients.
To compare the outcomes of open reduction and internal fixation (ORIF), closed reduction and percutaneous pinning, hemiarthroplasty (HA), and reverse shoulder arthroplasty (RSA) for proximal humerus fractures. The search was performed on September 9, 2012 using an explicit search algorithm in the following databases: Medline, SportDiscus, CINAHL, and Cochrane Central Register of Controlled Trials. Inclusion criteria were English language studies reporting clinical outcomes after surgical treatment of 3- or 4-part proximal humerus fractures with a minimum of 1-year follow-up. English language studies reporting clinical outcomes after surgical treatment of 3- or 4-part proximal humerus fractures with a minimum of 1-year follow-up. Levels 1-4 studies were eligible for inclusion. Study methodological quality and bias was evaluated using the Modified Coleman Methodology Score. Two-proportion Z test and multivariate linear regression analyses were used for group comparisons. Significantly better clinical outcomes were observed for ORIF over HA and RSA (American Shoulder and Elbow Score, Disabilities of Arm, Shoulder, and Hand, Constant) (P < 0.05). However, ORIF had a significantly higher reoperation rate versus HA and RSA (P < 0.001 for both). Comparing HA with RSA, there was no difference in any outcome measure. The rate of tuberosity nonunion was 15.4% in the HA group. There were more complications following closed reduction and percutaneous pinning versus ORIF, HA, and RSA (P < 0.05). ORIF for proximal humerus fractures demonstrates better clinical outcome scores but with a significantly higher reoperation rate. HA and RSA are effective as well, but tuberosity nonunion remains a concern with HA.


Cervical spinal cord injury following cephalic presentation and delivery by Caesarean section.
We describe a term infant with an acute spinal cord injury following emergency Caesarean section. Foetal movements were normal on the day that the mother was admitted for postterm induction of labour. Caesarean section was performed because of foetal distress and failure to progress during labour. The initial clinical picture suggested acute birth asphyxia. The presence of a high cervical spine injury became more obvious as the clinical picture evolved over the next 7 days. A discontinuity of the cervical spinal cord at C4-5 was confirmed on MRI. Spontaneous respiration failed to develop and intensive care was withdrawn on day 15. No evidence of trauma, or a vascular, neurological, or congenital anomaly of the cervical spinal cord was found at post mortem. The absence of a similar case following cephalic presentation and Caesarean section made bereavement counselling of the parents especially difficult.


Exploration of high-pressure structural transition and electronic properties of BaFe2S3.
The iron-based compound BaFe2S3 has received considerable attention in recent years due to its unique electronic properties with important applications. But, there has been relatively little attention devoted to the structure evolution of BaFe2S3 under high pressure. Here, we report a detailed theoretical study of the structural, electronic and sound velocity properties of BaFe2S3 under high pressure by CALYPSO structure search method in combination with the first-principles calculations. We have uncovered three novel structures of BaFe2S3 under high pressure with space group P2221, Imm2, and C2/m symmetries. Theoretical calculations reveal that the structures of BaFe2S3 under high pressure satisfy the phase transition sequence of Cmcm → P2221 → Imm2 → C2/m, and the corresponding transition pressures are 31.6, 47.4 and 57.0 GPa, respectively. Our results enrich the high pressure phases of BaFe2S3 and will stimulate future experiments to synthesize these new phases.


Evidence that luteinising hormone receptor polymorphisms may contribute to male undermasculinisation.
The luteinising hormone receptor (LHR) is necessary for the stimulation of androgen production and male genital development. It contains three protein polymorphisms: a leucine and glutamine insertion between codons 8 and 9 (LQ+) and two amino acid substitutions (N291S, N312S). To determine whether these LHR polymorphisms are associated with male genital undermasculinisation or the androgen receptor polyglutamine repeat polymorphism (AR(Q)n), which contributes in some cases to the cause of genital undermasculinisation. The LHR polymorphisms were assessed by PCR amplification of genomic DNA, followed by restriction enzyme analysis. The frequency of the LHR polymorphisms were compared between an undermasculinised male group (n=75) and a control group (n=55). LQ+ was not independently associated with the undermasculinised group (P=0.09), but it was associated with increased AR(Q)n within the undermasculinised group (P=0.02), particularly for AR(Q)n lengths >or=26 (P=0.002). In the undermasculinised group, homozygosity for N291 (872A/A) was more frequent (P=0.05), whereas homozygosity for N312 (935A/A) was less frequent (P=0.05). The combination of the presence of 872A/A and the absence of 935A/A showed a stronger association with the undermasculinised group than either polymorphism independently (P=0.006). The odds ratio of this genotype compared with any other, between the undermasculinised and control groups was 3.28 (95% confidence interval (CI) 1.33 to 8.08). LHR polymorphisms may contribute to genital undermasculinisation.


Complications of surgical management of upper tract calculi in spina bifida patients: analysis of nationwide data.
The management of upper urinary tract stones in patients with spina bifida is challenging but poorly described in the literature. We compared urolithiasis interventions and related complications in patients with spina bifida to those in other stone formers using a national database. We retrospectively reviewed the NIS to identify hospital admissions for renal and ureteral stones from 1998 to 2011. We used ICD-9-CM codes to identify urological interventions, including shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy and ureteral stent placement. NSQIP data were used to identify postoperative complications. We identified 4,287,529 weighted stone hospital admissions, including 12,315 (0.3%) of patients with spina bifida. Compared to those without spina bifida the patients with spina bifida who had urolithiasis were significantly younger (mean age 34 vs 53 years), more likely to have public insurance (72% vs 44%) and renal vs ureteral calculi (81% vs 58%), and undergo percutaneous nephrolithotomy (27% vs 8%). After adjusting for age, insurance, comorbidity, treatment year, surgery type, stone location and hospital factors patients with spina bifida were more likely to have urinary tract infections (OR 2.5), urinary complications (OR 3.1), acute renal failure (OR 1.9), respiratory complications (OR 2.0), pneumonia (OR 1.5), respiratory insufficiency (OR 3.2), prolonged mechanical ventilation (OR 3.2), sepsis (OR 2.7), pulmonary embolism (OR 3.0), cardiac complications (OR 2.4) and bleeding (OR 1.6). Compared to those without spina bifida the patients with spina bifida who were hospitalized for urolithiasis were younger, and more likely to have renal stones and undergo percutaneous nephrolithotomy. Urolithiasis procedures in patients with spina bifida were associated with a significantly higher risk of in-hospital postoperative complications.


Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection.
An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection. The molecular mechanisms regulating the fate of the initial immune response to infection, either as a protective response or as detrimental immunopathology, are not well understood. The purinergic receptor P2X7 is an ionotropic nucleotide-gated ion channel receptor expressed on immune cells that has been implicated in induction and maintenance of excessive inflammation. Here, we analyze the role of this receptor in a mouse model of influenza virus infection using a receptor knockout (KO) mouse strain. Our results demonstrate that the absence of the P2X7 receptor results in a better outcome to influenza virus infection characterized by reduced weight loss and increased survival upon experimental influenza challenge compared to wild-type mice. This effect was not virus strain specific. Overall lung pathology and apoptosis were reduced in virus-infected KO mice. Production of proinflammatory cytokines and chemokines such as interleukin-10 (IL-10), gamma interferon (IFN-γ), and CC chemokine ligand 2 (CCL2) was also reduced in the lungs of the infected KO mice. Infiltration of neutrophils and depletion of CD11b+ macrophages, characteristic of severe influenza virus infection in mice, were lower in the KO animals. Together, these results demonstrate that activation of the P2X7 receptor is involved in the exacerbated immune response observed during influenza virus infection.IMPORTANCE A hallmark of influenza virus infection is the development of lung pathology induced by an exacerbated immune response. The mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood. Purinergic receptors, and in particular the purinergic receptor P2X7 (P2X7r), are involved in activation of the immune response. We used mice lacking the P2X7r (P2X7r KO mice) to better understand the mechanisms that lead to development of lung pathology during influenza virus infection. In our studies, we observed that P2X7r KO mice developed less lung immunopathology and had better survival than the wild-type mice. These results implicate P2X7r in the induction of an exacerbated local immune response to influenza virus and help us to better understand the mechanisms leading to the lung immunopathology observed during severe viral infections.


Atresia of the left atrioventricular orifice associated with a Holmes heart.
The first well-documented case of Holmes heart associated with an atretic left atrioventricular orifice is reported. The Holmes heart may be considered as a single ventricle in which the main chamber has the morphologic characteristics of a left ventricle, the infundibular chamber is not inverted, and the great arteries are normally arranged. The importance of this report is greater than its simple description since it definitely establishes the coexistence of a true single ventricle and atresia of the atrioventricular orifice is possible.


Peer assisted learning: a planning and implementation framework: AMEE Guide no. 30.
Much has been written about the benefits and applications of Peer Assisted Learning (PAL) in the literature. Curriculum developers increasingly consider PAL as a vehicle to help undergraduate healthcare students learn to teach; an outcome which has received more attention in the UK since the General Medical Council stated in Tomorrow's Doctors that medical graduates must 'Be able to demonstrate appropriate teaching skills'. This guide is primarily designed to assist curriculum developers, course organisers and educational researchers develop and implement their own PAL initiatives. It is structured around a PAL planning framework consisting of 24 questions. The questions are grouped in threes, around eight themes. Each question is discussed with reference to the PAL literature and other related subjects, and is exemplified by responses from a recent PAL project developed at The University of Edinburgh. Working through the 24 questions, particularly with discussion in a small planning group, will enable readers to efficiently develop their ideas for PAL into comprehensive and practical project plans cognisant of current educational theory, existing PAL literature and the local context. The framework is particularly suitable for those who want to develop healthcare undergraduate PAL initiatives yet have little or no experience of PAL, as it provides an introduction to the relevant literature field and a step-by-step process for the design and implementation of such projects. It will also be of interest to those with experience of PAL and those seeking a structured framework for planning non-PAL curriculum developments in undergraduate healthcare curricula.


Skeletal imaging in metastatic disease.
Radionuclide bone scanning is a well-established technique for the investigation of suspected metastatic disease to bone. Most commonly, primary cancers of breast, prostate, and lung tend to metastasize to the skeleton. Current topics on the role of bone scanning in patients with these conditions are reviewed. Despite the now known sensitivity of MR imaging for the detection of bone marrow involvement, bone scanning continues to be the methodology of choice in view of its simplicity, low cost, and ability to screen the whole body. Tumor markers such as prostate-specific antigens have a new role in the investigation of metastasis arising from prostate carcinoma; this area is also reviewed. Although bone-seeking radionuclide tracers have, on the whole, remained unchanged from a diagnostic point of view, new bone-seeking tracers have been developed for the treatment of unremitting pain in patients with multiple secondary tumors to the skeleton. This new area appears particularly promising and will widen the scope of the radionuclide tracer method as a therapeutic modality. Single-photon emission CT is helpful in improving the more exact localization of areas of increased tracer uptake in the skeleton and is therefore more often used as an imaging methodology.


The implication of AMPA receptor in synaptic plasticity impairment and intellectual disability in fragile X syndrome.
Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.


Artificial Intelligence and COVID-19: A Systematic umbrella review and roads ahead.
Artificial Intelligence (AI) has played a substantial role in the response to the challenges posed by the current pandemic. The growing interest in using AI to handle Covid-19 issues has accelerated the pace of AI research and resulted in an exponential increase in articles and review studies within a very short period of time. Hence, it is becoming challenging to explore the large corpus of academic publications dedicated to the global health crisis. Even with the presence of systematic review studies, given their number and diversity, identifying trends and research avenues beyond the pandemic should be an arduous task. We conclude therefore that after the one-year mark of the declaration of Covid-19 as a pandemic, the accumulated scientific contribution lacks two fundamental aspects: Knowledge synthesis and Future projections. In contribution to fill this void, this paper is a (i) synthesis study and (ii) foresight exercise. The synthesis study aims to provide the scholars a consolidation of findings and a knowledge synthesis through a systematic review of the reviews (umbrella review) studying AI applications against Covid-19. Following the PRISMA guidelines, we systematically searched PubMed, Scopus, and other preprint sources from 1st December 2019 to 1st June 2021 for eligible reviews. The literature search and screening process resulted in 45 included reviews. Our findings reveal patterns, relationships, and trends in the AI research community response to the pandemic. We found that in the space of few months, the research objectives of the literature have developed rapidly from identifying potential AI applications to evaluating current uses of intelligent systems. Only few reviews have adopted the meta-analysis as a study design. Moreover, a clear dominance of the medical theme and the DNN methods has been observed in the reported AI applications. Based on its constructive systematic umbrella review, this work conducts a foresight exercise that tries to envision the post-Covid-19 research landscape of the AI field. We see seven key themes of research that may be an outcome of the present crisis and which advocate a more sustainable and responsible form of intelligent systems. We set accordingly a post-pandemic research agenda articulated around these seven drivers. The results of this study can be useful for the AI research community to obtain a holistic view of the current literature and to help prioritize research needs as we are heading toward the new normal.


Corynebacterium spp. in dogs and cats with otitis externa and/or media: a retrospective study.
The role of Corynebacterium spp. in the pathogenesis of canine and feline otitis externa/media and their appropriate antimicrobial therapy are unclear. The objectives of this study were to (1) better establish the pathogenicity of Corynebacterium spp. in otitis utilizing reported criteria and by assessing clinical response to antibiotic therapy and (2) to determine the antimicrobial susceptibility patterns of Corynebacterium spp. associated with otitis. The study was retrospective, targeting cultures positive for Corynebacterium spp. Corynebacterium spp. were part of mixed microbial populations in 79/81 cultures. Corynebacterium spp. pathogenicity was highly questionable because of their almost invariable presence with other microbes and the observation that Corynebacterium spp. usually disappear from the ear with resolution of other infections, even when the Corynebacterium spp. are resistant to the prescribed antibiotic(s). However, 2/81 cultures came from two canine ears wherein Corynebacterium spp. may have been pathogenic. Antimicrobial sensitivities for Corynebacterium spp. were available for 54 isolates. Most isolates were susceptible to chloramphenicol (53/54), amikacin (50/54), tetracycline (50/54), gentamicin (46/54), and enrofloxacin (32/54). Among those antibiotics available in otic products, gentamicin and enrofloxacin would be rational choices for the empirical, topical therapy of Corynebacterium spp.


Oculo-auriculo-vertebral spectrum with craniosynostosis and osteo-cartilagineous multiple defects: a diffuse chondro-membranous-osteo-dysplasia.
We report on a female with oculo-auriculo-vertebral spectrum, low height, and on X-ray lambdoid suture synostosis, cerebral cyst/mild holoprosencephalia and cholesteatoma, and multiple abnormalities of bones of chondral origin. On the right side, maxillary, mandibular bones, external auditory canal, middle ear were hypoplastic as well as semicircular canal, cranial base, bones vestibule. On the left side, coclea, timpanic cavity, mastoid antrum were hypoplastic, while stapes was misshapen. Limbs bones were slender with thin metaphyses and some carpal bones were absent. Hand second phalanx was hypoplastic and fifth finger presented clynodactily. Lambdoid synostosis expressed membranous ossification abnormality. We hypothesize that during the blastogenesis a mutation of a factor responsible for abnormal generalized endochondral and connectival ossification (possibly fibroblast growth factor receptor) occurs.


Detection of rare Leydig cell hypoplasia in somatic cell cloned male piglets.
In this investigation, 22 cloned male piglets were obtained by male fetal fibroblast-cell-derived nuclear transfer. Eighteen of the cloned animals died. The two cell lines did not differ significantly with regard to efficiency of live piglet production. The gross anatomy of the testes of male piglets that died was normal. However, one piglet displayed Leydig cell hypoplasia (LCH). No anatomical defects were detected in the testes of other cloned male piglets. TUNEL analysis of the testis with LCH revealed significant apoptosis in the Leydig cells, while apoptosis was rarely detected in Sertoli cells and spermatogonia. In contrast, testes from the remaining 17 piglets that died appeared normal in size, and their Sertoli and Leydig cell numbers were comparable to those in control piglet testes. Although cloned piglets were derived from fibroblasts obtained from the same fetus, phenotypic instability between cells used for the production of somatic cell cloned piglets suggests that abnormalities in male cloned piglets are caused not by technical problems and/or reprogramming effects, but rather by epigenetically and/or genetically damaged cell-specific effects.


A decline in the incidence of invasive non-typhoidal Salmonella infection in The Gambia temporally associated with a decline in malaria infection.
Malaria is a risk factor for invasive non-typhoidal Salmonella (NTS) infection in children. In the last 10 years, indices of malaria infection in The Gambia have fallen substantially. We compared temporal trends of childhood malaria and NTS infection in two Gambian locations. In Fajara, on the coast, the incidence of NTS infection at three time points between 1979 and 2005 was compared to the percentage of malaria positive outpatient thick blood films and the percentage of admissions associated with malaria over time. In Basse, in the eastern part of the country, the incidence of NTS infection at three time points between 1989 and 2008 was compared to the prevalence of malaria parasitaemia at four time points between 1992 and 2008. The estimated incidence of NTS infection in Fajara fell from 60 (1979-1984) to 10 (2003-05) cases per 100,000 person years. The proportion of outpatients in Fajara with suspected malaria who were parasitaemic fell from 33% (1999) to 6% (2007) while the proportion of admissions associated with malaria fell from 14.5% (1999) to 5% (2007). In Basse, the estimated incidence of NTS infection fell from 105 (1989-1991) to 29 (2008) cases per 100,000 person years while the prevalence of malaria parasitaemia fell from 45% (1992) to 10% (2008). The incidence of pneumococcal bacteraemia in Fajara and Basse did not fall over the study period. These data support an association between malaria and NTS infection. Reductions in malaria infection may be associated with reduced rates of invasive childhood NTS infection.


Impact of Tranexamic Acid in Total Knee and Total Hip Replacement.
To evaluate the net clinical benefit of tranexamic acid use in patients undergoing total knee or total hip replacement. This is a retrospective study of patients undergoing total knee or total hip replacement. The primary outcome was the net clinical benefit of tranexamic acid use. Secondary outcomes included length of stay, incidence of venous thromboembolism, change in hemoglobin, and number of units of blood transfused. Four hundred and six patients were screened for inclusion and 327 patients met inclusion criteria; 174 patients received tranexamic acid versus 153 patients who received usual care. Tranexamic acid demonstrated a positive net clinical benefit versus usual care (40.8% vs 13.7%, P < .01) but did not affect length of stay (3.39 vs 3.37 days, respectively, P = .76). Venous thromboembolism was comparable between groups (2.3% vs 0.7%, P = .38). Average change in hemoglobin and need for transfusion were lower in the treatment group versus the usual care group, respectively (3.46 vs 4.26 mg/dL, P < .01). Tranexamic acid demonstrated a significant benefit in decreasing change in hemoglobin as well as the need for blood transfusion with no increase in the risk of venous thromboembolism in patients undergoing total knee or total hip replacement.


The Importance of the Structural Similarity of Drugs Used for Depression and Inflammation, Two Comorbid Diseases.
Growing evidence links inflammation to depression and the combination of antiinflammatory drugs with an antidepressant to treat depressive symptoms is currently suggested. There are only few studies concerning the molecular mechanism underlying this comorbidity, and many of them point out the importance of the tryptophan pathway. There is yet no data that analyzes the structural similarity of the molecules used for the treatment of these comorbid diseases. This review aimed first to classify current antidepressant drugs and Non-steroidal Anti-inflammatory Drugs (NSAIDs) according to their structure. Molecules with two aromatic rings linked with a heteroatom or a carbonyl group (vortioxetine, ketoprofen, diclofenac), or presenting a naphtyl moiety in their structure (duloxetine, agomelatine, naproxen, nabumetone) were found to be structurally related. The antidepressant activity of these NSAIDs and the anti-inflammatory activity of these antidepressants were investigated. The literature search interestingly revealed reports indicating a serotonin-related antidepressant activity of the NSAIDs for structures found to be structurally similar to some antidepressants. Similarly, the antiinflammatory activity of the corresponding antidepressants was found to be correlated to the tryptophan metabolism pathway. These findings suggest a common molecular mechanism involved in both of the diseases and exhibit the importance of the molecular structure for a drug to be a potent antidepressant and/or anti-inflammatory agent.


Turbo Spin-echo Diffusion-weighted Imaging Compared with Single-shot Echo-planar Diffusion-weighted Imaging: Image Quality and Diagnostic Performance When Differentiating between Ductal Carcinoma in situ and Invasive Ductal Carcinoma.
To compare the image quality between turbo spin-echo (TSE)-diffusion weighted imaging (DWI) and single-shot echo-planar imaging (EPI)-DWI, and to verify the diagnostic performance of the apparent diffusion coefficient (ADC) parameters of the two techniques by using histogram analysis in terms of differentiation between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) lesions. Ninety-four women with 94 lesions diagnosed as breast cancer by surgery underwent IRB-approved preoperative magnetic resonance imaging, including TSE and EPI-DWI with b-values of 50 and 850 s/mm2. Twenty lesions were identified as DCIS and 74 as IDC. Image quality [signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and geometric distortion] was evaluated quantitatively and compared between the TSE and EPI-DWI. A histogram analysis of the entire tumor voxel-based ADC data was performed, and the 10th, 25th, 50th, 75th, and 90th percentile values of each technique were compared between DCIS and IDC lesions. The SNR and CNR of TSE-DWI were significantly higher than those of EPI-DWI (P < 0.0001 and < 0.0001). The geometric distortion of TSE-DWI was significantly lower than that of EPI-DWI (P < 0.0001). In TSE-DWI, the 10th, 25th, 50th, and 75th percentile values were significantly different between the DCIS and IDC lesions (P = 0.0010, 0.0004, 0.0008, and 0.0044, respectively). In EPI-DWI, the 50th and 75th percentile values were significantly different between the two groups (P = 0.0009 and 0.0093). There was no significant difference in the area under the curve of the receiver operating characteristic analysis of the 10th, 25th, 50th, and 75th percentile values of TSE-DWI, and the 50th and 75th percentile values of EPI-DWI (P = 0.29). The image quality of TSE-DWI was better than that of EPI-DWI. DCIS lesions were distinguished from IDC lesions with a wider range of percentile values in TSE-DWI than in EPI-DWI, although diagnostic performance was not significantly different between the techniques.


Onset of postoperative jaundice related to anaesthetic history.
A review of 182 cases from the U.S. National Halothane Study showed the interval to the onset of jaundice after one exposure to halothane (91 cases) to be slightly shorter than the interval for those having had multiple exposures to the agent. These findings are in sharp contrast to other recently published results. Thirty-three cases of jaundice after the use of other anaesthetic agents are also reported.


Lekking birds in a tropical forest forego sex for migration.
Facultative, partially migratory animals provide a contemporary window into the evolution of migration, offering rare opportunities to examine the life-history trade-offs associated with migration. For the first time, to our knowledge, we describe the nature of these trade-offs, using a lek-breeding tropical bird, the white-ruffed manakin (Corapipo altera). Previous evidence indicated that weather drives post-breeding migration to lower elevations bringing condition-related benefits. Using elevation-sensitive stable isotope measurements and more than 1200 h of behavioural observations, we show that male manakins which migrate incur costs of diminished social status and matings with females the following breeding season. Because migratory tendency depends on inter-annual variation in weather, physical costs of displays and breeding prospects the following year, migratory decisions are subject to both natural and sexual selection, with the outcome of such decisions linked to changing climatic regimes.


Localization of alpha 2-adrenoceptor-mediated increase in renal Na+, K+, and water excretion.
Free-flow micropuncture and clearance studies were conducted in male Sprague-Dawley rats to investigate the effects of alpha 2-adrenoceptor stimulation on Na+, K+, and water transport along the nephron. Intravenous infusion of the selective alpha 2-adrenoceptor agonist B-HT 933 at 1 mg X kg-1 X h-1 increased urinary flow rate from 16.2 +/- 3.6 to 84.8 +/- 11.9 microliter/min, fractional excretion of Na+ from 1.36 +/- 0.31 to 3.57 +/- 0.52%, and fractional excretion of K+ from 26.9 +/- 3.0 to 42.3 +/- 2.2%, The diuresis, saluresis, and kaliuresis were not the result of increases in glomerular filtration rate or mean arterial blood pressure. Urine osmolality decreased from 1,126 +/- 177 to 325 +/- 33 mosmol/kg water and in 8 of the 11 animals studied B-HT 933 decreased urine osmolality to hyposmotic levels, suggesting a possible interaction between the alpha 2-adrenoceptor agonist and vasopressin. The alpha 2-adrenoceptor antagonist yohimbine (0.25/mg bolus, iv) inhibited the diuresis, saliuresis, and kaliuresis. In micropuncture studies, B-HT 933 was without effect on single-nephron glomerular filtration rate or on Na+, K+, and water transport along the superficial proximal tubule, loop of Henle, or distal tubule. Thus stimulation of alpha 2-adrenoceptors increases Na+, K+, and water excretion by inhibiting tubule reabsorption of these substances at nephron sites beyond the superficial distal tubule, most likely by the collecting tubule.


New opportunities in micro- and macro-attenuated total reflection infrared spectroscopic imaging: spatial resolution and sampling versatility.
New opportunities exist to obtain chemical images using attenuated total reflection infrared (ATR-IR) spectroscopy. This paper shows the feasibility of obtaining FT-IR images with a spatial resolution of at least 3-4 microm using a Ge ATR objective coupled with an infrared microscope. The improved spatial resolution compared to FT-IR images obtained by the transmission method is due to the high refractive index of the ATR crystal, which gives a high numerical aperture and hence, a higher spatial resolution. FT-IR imaging with a conventional diamond ATR accessory has been investigated. This is the first time that FT-IR imaging is reported using such a versatile accessory based on a diamond ATR crystal. These results showed that a spatial resolution up to 13 microm can be achieved without the use of infrared microscope objectives. One advantage of the diamond element is that it allows pressure to be applied and hence, good contact to be obtained over the whole field of view.


The Positive Outlook Study: A Randomised Controlled Trial Evaluating Online Self-Management for HIV Positive Gay Men.
The aim of this paper was to evaluate the effectiveness of an online self-management program in improving health outcomes and well-being for gay men living with HIV in Australia. The online Positive Outlook Program was based on self-efficacy theory and used a self-management approach to enhance HIV-positive gay men's skills, confidence and abilities to manage the psychosocial issues associated with HIV in daily life. The 7-week program was delivered in closed groups and comprised information modules, action-planning activities, moderated discussion boards, and weekly peer-facilitated 'live chats'. A randomised controlled trial was conducted to establish the effectiveness of the Positive Outlook program compared to a 'usual care' control. Participants were HIV-positive gay men 18 years or older living in Australia. Primary outcomes were evaluated at three time-points (baseline, post-intervention and 12-week's post-intervention follow-up) and included HIV-related quality of life (PROQOL-HIV), outcomes of health education (HeiQ) and HIV specific self-efficacy (Positive Outlook Self-Efficacy Scale). A total of 132 gay men with HIV in Australia were randomly allocated to the intervention (n = 68) or usual care control (n = 64) groups. Maximum likelihood marginal-linear modelling indicated significant improvement in the intervention group on the PROQOL-HIV subscales of body change (p = 0.036), social relationships (p = 0.035) and emotional distress (p = 0.031); the HeiQ subscales of health-directed activity (p = 0.048); constructive attitudes and approaches (p = 0.015); skill and technique acquisition (p = 0.046) and health service navigation (p = 0.008); and the Positive Outlook Self-Efficacy Scale on the subscales of relationships (p = 0.019); social participation (p = 0.006); and emotions (p = 0.041). Online delivery of self-management programs is feasible and has the potential to improve quality of life, self-management skills and domain specific self-efficacy for gay men with HIV.


[Study of fumonisins B1 and B2 contamination of baby food].
Fumonisins content were studied in the baby foods, grits and flour by HPLC. FB1 +FB2 were found in 95% of 129 samples of grits and flour in quantities from 30 to 4350 microg/kg (mean: 580 microg/kg). Fumonisins were found in baby food in 52% of snacks in the range from 10 to 720 microg/kg (mean: 35 microg/kg). Processed cereal-based and cereal and dairy-based food contained FB1+FB2 in 39% of cases in the amount from 10 to 9200 microg/kg (mean: 244 microg/kg). Fumonisins were not found in canned baby food on the cereal-based with meat, fish or fruit products.


Histomorphometric study of age-related changes in remodelling activity of human desmodontal bone.
To study age-related changes in human desmodontal bone remodelling, histological specimens were prepared from 42 human mandibles from individuals aged between 16 and 71 years which were obtained from autopsies. Microradiographs of horizontal ground sections and the corresponding undecalcified histological sections stained with Goldner trichrome were used for analysis. Histomorphometric measurements of static bone remodelling were performed along the desmodontal bone surface using a computer assisted semiautomatic measurement system. External influences from the individual dental occlusion and periodontal conditions were superimposed on age changes. A modest but significant age-dependent decrease in the surface extent of osteoid seams covered by 'active' osteoblasts was found. In addition, the number of osteoclasts per unit of resorptive bone surface diminished, leading to an increase in Howship's lacunae, devoid of osteoclasts. Both phenomena were interpreted as being due to a decrease in active bone forming capacity with age.


Increased breast cancer mortality only in the lower education group: age-period-cohort effect in breast cancer mortality by educational level in South Korea, 1983-2012.
A steadily increasing pattern of breast cancer mortality has been reported in South Korea since the late 1980s. This paper explored the trends of educational inequalities of female breast cancer mortality between 1983 and 2012 in Korea, and conducted age-period-cohort (APC) analysis by educational level. Age-standardized mortality rates of breast cancer per 100,000 person-years were calculated. Relative index of inequality (RII) for breast cancer mortality was used as an inequality measure. APC analyses were conducted using the Web tool for APC analysis provided by the Division of Cancer Epidemiology and Genetics at the U.S. National Cancer Institute. An increasing trend in breast cancer mortality among Korean women between 1983 and 2012 was due to the increased mortality of the lower education groups (i.e., no formal education or primary education and secondary education groups), not the highest education group. The breast cancer mortality was higher in women with a tertiary education than in women with no education or a primary education during 1983-1992, and the reverse was true in 1993-2012. Consequently, RII was changed from positive to negative associations in the early 2000s. The lower education groups had the increased breast cancer mortality and significant cohort and period effects between 1983 and 2012, whereas the highest group did not. APC analysis by socioeconomic position used in this study could provide an important clue for the causes on breast cancer mortality. The long-term monitoring of socioeconomic patterning in breast cancer risk factors is urgently needed.


Exploring the Physiological and Psychological Effects of Group Chanting in Australia: Reduced Stress, Cortisol and Enhanced Social Connection.
Chanting, an ancient ritual practiced in diverse cultures and traditions worldwide, has typically been employed for meditation, healing, self-awareness, and psychological growth. However, there is little understanding of the physiological and psychological benefits of chanting, and how vocalization might contribute to such effects. This study aimed to determine whether 12-minutes of group chanting, through vocal or silent repetition of the sound "om," would reduce stress and anxiety, while increasing feelings of social connection, and whether vocal chanting would yield stronger effects. Thirty-four participants were randomly assigned to vocal or silent group chanting conditions. Saliva samples were collected before and after chanting to assess cortisol levels, while self-report measures included the State Trait Anxiety Inventory and the Adapted Self-Report Altruism Scale (including additional items on cross-cultural altruism). Following chanting, participants also provided a written description of their experiences. Both vocal and silent chanting resulted in significant decreases in cortisol levels and self-reported anxiety. The reduction in cortisol was similar for vocal and silent chanting, but self-reported anxiety decreased more following vocal chanting. Altruism scores increased following both vocal and silent chanting. However, there was no evidence of altruistic tendencies extending toward people from a culture other than one's own. Results are discussed in relation to the phenomenology of chanting, and to current theory and evidence on the physiological and psychological effects of chanting and singing.


Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart.
Energy of the cardiac muscle largely depends on fatty acid oxidation. It is known that the atrium and ventricle have chamber-specific functions, structures, gene expressions, and pathologies. The left ventricle works as a high-pressure chamber to pump blood toward the body, and its muscle wall is thicker than those of the other chambers, suggesting that energy utilization in each of the chambers should be different. However, a chamber-specific pattern of metabolism remains incompletely understood. Recently, innovative techniques have enabled the comprehensive analysis of metabolites. Therefore, we aimed to clarify differences in metabolic patterns among the chambers. Male C57BL6 mice at 6 wk old were subject to a comprehensive measurement of metabolites in the atria and ventricles by capillary electrophoresis and mass spectrometry. We found that overall metabolic profiles, including nucleotides and amino acids, were similar between the right and left ventricles. On the other hand, the atria exhibited a distinct metabolic pattern from those of the ventricles. Importantly, the high-energy phosphate pool (the total concentration of ATP, ADP, and AMP) was higher in both ventricles. In addition, the levels of lactate, acetyl CoA, and tricarboxylic acid cycle contents were higher in the ventricles. Accordingly, the activities and/or expression levels of key enzymes were higher in the ventricles to produce more energy. The present study provides a basis for understanding the chamber-specific metabolism underlining pathophysiology in the heart.


High absolute coronary disease risk among Turks: involvement of risk factors additional to conventional ones.
To confirm previous findings on excess absolute coronary heart disease (CHD) risk among Turks. The observed incident CHD risk of a representative population sample was compared with that anticipated by Framingham risk scores (FRS). At 7.4 years of follow-up of 3,027 participants free of CHD at baseline, risk estimation was contrasted in the 398 cases of newly developed fatal and nonfatal CHD. CHD developed at a rate 2.2 times higher than the anticipated risk. In sex-specific quintiles of FRS, the 10-year incidence of CHD events in males in the 2 highest quintiles was 2 times the anticipated levels. In women, the 3 highest quintiles displayed an incidence 2.7 times the anticipated risk. Such individuals typically had abdominal obesity and evidence of dysfunctional apolipoprotein (apo) A-I. Men had high levels of non-high-density lipoprotein (HDL) cholesterol, total apoC-III, apoB and triglycerides. In Cox proportional hazard regression analyses, the 10-year probability of remaining free of CHD was low (81.1% in men, 84.2% in women). Women exhibited C-reactive protein as an independent predictor of CHD, lack of protection by HDL cholesterol and no conferred risk from current smoking. The observed excess CHD risk was primarily attributed to central obesity and related dysfunction of HDL, apoC-III and apoA-I. Dysfunction of protective serum proteins associated with metabolic syndrome impacts on CHD events, in addition to conventional risk factors.


Neuropathological correlates of memory dysfunction in the Wernicke-Korsakoff syndrome.
The Wernicke-Korsakoff syndrome is a neuropathological term which encompasses two clinical syndromes in thiamine-deficient alcoholics, Wernicke's encephalopathy and Korsakoff's psychosis. Wernicke's encephalopathy is characterised by eye and gait disorders and mental confusion, and can lead to the profound and permanent amnesia known as Korsakoff's psychosis. Despite this specific difference, both conditions appear to have identical neuropathology with haemorrhages and other lesions around the ventricular system. The memory deficit has been attributed to a number of brain lesions, including a recent suggestion that brain pathways utilising particular neurotransmitters are specifically damaged. To examine this, the number of chemically identified neurons in particular brain regions was quantified in patients with Wernicke's encephalopathy alone or in combination with Korsakoff's psychosis and compared with age- and sex-matched controls. Noradrenaline, a neurotransmitter thought to be involved in the process of selective attention, is localised in pathways projecting to the cortex. Our patients with either Wernicke's encephalopathy or additional Korsakoff's psychosis do not differ from controls in the distribution and number of these cells. Serotonin is another neurotransmitter that has been linked with alcohol dependency. Both patient groups have a profound loss of serotonin-containing neurons compared with controls. The loss of forebrain neurons containing acetylcholine in patients with Alzheimer's disease has implicated this neurotransmitter in the maintenance of memory functions. There was a large variation in the number of these forebrain neurons in thiamine-deficient alcoholics compared with controls. Cholinergic cell loss reflected the severity of cognitive dysfunction, but was not exclusive to patients with amnesia. Two thalamic nuclei are involved in relaying memories for storage and retrieval, the anterior and mediodorsal thalamic nuclei. While patients with Wernicke's encephalopathy often had neuronal loss in the mediodorsal nucleus, only patients with Korsakoff's psychosis had cell loss in both medial thalamic nuclei. The results suggest that cumulative lesions contribute to the amnesia seen in thiamine-deficient alcoholics, including deficits in serotonergic, cholinergic and medial thalamic pathways.


Light and electron microscopic localization of beta I-, beta II-, and gamma-subspecies of protein kinase C in rat cerebral neocortex.
We have localized the beta I-, beta II-, and gamma-subspecies of protein kinase C in cerebral neocortex with light and electron microscopic immunocytochemistry using a monoclonal antibody against gamma-PKC and polyclonal antisera to beta I- or beta II-PKC-specific oligopeptides. The gamma-PKC-immunopositive cell bodies were seen mostly in layers II, V, and VI, and the vast majority of them were pyramidal cells. The beta II-PKC immunoreactive cell bodies were observed in layers II, III, V, and VI, and most of them seemed to be pyramidal cells. Both gamma- and beta II-PKC were colocalized in some pyramidal cells in layers II, V, and VI. The small number of beta I-PKC immunoreactive cell bodies were observed in the neocortex, and many of them were nonpyramidal cells. About 80% of the beta I-PKC-immunoreactive cells were shown to be GABAergic neurons. The gamma-PKC-immunopositive neuropils were observed in layers I, II, V, and VI, while beta II-PKC-immunoreactive neuropils were seen in layers I-III, V, and VI. The distribution of each subspecies is much the same throughout all regions of the neocortex, although with different intensities of immunoreactivity. electron microscopic studies revealed that, in the perikarya, gamma-PKC was distributed throughout the cytoplasm, beta I-PKC was just adjacent to the plasma membrane, and beta II-PKC was located around the Golgi complex. The immunoreactivity of these 3 subspecies was also seen in dendrites and axons, but no immunoreactivity of these subspecies was found in the presynaptic terminals in the present study. The discrete cellular and intracellular distributions of protein kinase C subspecies imply that each subspecies has a specific role in neuronal activity in the cerebral neocortex.


Comparative actions of phenytoin and other anticonvulsant drugs on potassium- and veratridine-stimulated calcium uptake in synaptosomes.
The actions of phenytoin and several anticonvulsants drugs on veratridine-stimulated (Na-dependent) and K-stimulated (Na-independent) Ca uptake were studied in isolated nerve terminals (synaptosomes) from rat cerebral cortex. Phenytoin inhibits both veratridine- and K-induced Ca uptake but is more potent against veratridine. Inhibition of veratridine-stimulated Ca uptake by phenytoin appears to be a competitive relationship, whereas the interaction between K and phenytoin is noncompetitive. Hydroxyphenyl-phenylhydantoin, mephenytoin and ethylphenylhydantoin have actions similar to phenytoin but all are substantially less potent. Carbamazepine, phenobarbital, diazepam and lidocaine also inhibit veratridine- and K-stimulated Ca uptake, but ethosuximide and valproic acid are ineffective. Only carbamazepine and lidocaine have a relatively selective action against veratridine which is similar to phenytoin, and only these three drugs are active at concentrations which approximate their clinically effective anticonvulsant blood levels. The results of this study, in conjunction with reported data, suggest that phenytoin inhibits Na and Ca conductances in nervous tissue by separate and probably independent mechanisms. The present data also lead to the hypothesis that inhibition of Na uptake (perhaps associated with inhibition of Ca uptake) in nervous tissues is a mechanism of action responsible for some of the selective antiepileptic effects and/or analgesic effects of phenytoin, carbamazepine and lidocaine.


Accurate transcriptome-wide prediction of microRNA targets and small interfering RNA off-targets with MIRZA-G.
Small interfering RNA (siRNA)-mediated knock-down is a widely used experimental approach to characterizing gene function. Although siRNAs are designed to guide the cleavage of perfectly complementary mRNA targets, acting similarly to microRNAs (miRNAs), siRNAs down-regulate the expression of hundreds of genes to which they have only partial complementarity. Prediction of these siRNA 'off-targets' remains difficult, due to the incomplete understanding of siRNA/miRNA-target interactions. Combining a biophysical model of miRNA-target interaction with structure and sequence features of putative target sites we developed a suite of algorithms, MIRZA-G, for the prediction of miRNA targets and siRNA off-targets on a genome-wide scale. The MIRZA-G variant that uses evolutionary conservation performs better than currently available methods in predicting canonical miRNA target sites and in addition, it predicts non-canonical miRNA target sites with similarly high accuracy. Furthermore, MIRZA-G variants predict siRNA off-target sites with an accuracy unmatched by currently available programs. Thus, MIRZA-G may prove instrumental in the analysis of data resulting from large-scale siRNA screens.


PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.
Traumatic brain injury (TBI) is a chronic, life threatening injury for which few effective interventions are available. Evidence in animal models suggests un-checked immune activation may contribute to the pathophysiology. Changes in regional density of active brain microglia can be quantified in vivo with positron emission topography (PET) with the relatively selective radiotracer, peripheral benzodiazepine receptor 28 (11 C-PBR28). Phenotypic assessment (activated vs resting) can subsequently be assessed (ex vivo) using morphological techniques. To elucidate the mechanistic contribution of immune cells in due to TBI, we employed a hybrid approach involving both in vivo (11 C-PBR28 PET) and ex vivo (morphology) to elucidate the role of immune cells in a controlled cortical impact (CCI), a rodent model for TBI. Density of activated brain microglia/macrophages was quantified 120 hours after injury using the standardized uptake value (SUV) approach. Ex vivo morphological analysis from specific brain regions using IBA-1 antibodies differentiated ramified (resting) from amoeboid (activated) immune cells. Additional immunostaining of PBRs facilitated co-localization of PBRs with IBA-1 staining to further validate PET data. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated density of amoeboid microglia/macrophages in the ipsilateral dentate gyrus, corpus callosum, thalami and injury penumbra of injured animals compared to sham animals. PBR co-stained with amoeboid microglia/macrophages in the injury penumbra and not with astrocytes. These data suggest the technologies evaluated may serve as bio-signatures of neuroinflammation following severe brain injury in small animals, potentially enabling in vivo tracking of neuroinflammation following TBI and cellular-based therapies.


ChIPXpress: using publicly available gene expression data to improve ChIP-seq and ChIP-chip target gene ranking.
ChIPx (i.e., ChIP-seq and ChIP-chip) is increasingly used to map genome-wide transcription factor (TF) binding sites. A single ChIPx experiment can identify thousands of TF bound genes, but typically only a fraction of these genes are functional targets that respond transcriptionally to perturbations of TF expression. To identify promising functional target genes for follow-up studies, researchers usually collect gene expression data from TF perturbation experiments to determine which of the TF targets respond transcriptionally to binding. Unfortunately, approximately 40% of ChIPx studies do not have accompanying gene expression data from TF perturbation experiments. For these studies, genes are often prioritized solely based on the binding strengths of ChIPx signals in order to choose follow-up candidates. ChIPXpress is a novel method that improves upon this ChIPx-only ranking approach by integrating ChIPx data with large amounts of Publicly available gene Expression Data (PED). We demonstrate that PED does contain useful information to identify functional TF target genes despite its inherent heterogeneity. A truncated absolute correlation measure is developed to better capture the regulatory relationships between TFs and their target genes in PED. By integrating the information from ChIPx and PED, ChIPXpress can significantly increase the chance of finding functional target genes responsive to TF perturbation among the top ranked genes. ChIPXpress is implemented as an easy-to-use R/Bioconductor package. We evaluate ChIPXpress using 10 different ChIPx datasets in mouse and human and find that ChIPXpress rankings are more accurate than rankings based solely on ChIPx data and may result in substantial improvement in prediction accuracy, irrespective of which peak calling algorithm is used to analyze the ChIPx data. ChIPXpress provides a new tool to better prioritize TF bound genes from ChIPx experiments for follow-up studies when investigators do not have their own gene expression data. It demonstrates that the regulatory information from PED can be used to boost ChIPx data analyses. It also represents an important step towards more fully utilizing the valuable, but highly heterogeneous data contained in public gene expression databases.


Implication of UGT2B15 Genotype Polymorphism on Postoperative Anxiety Levels in Patients Receiving Lorazepam Premedication.
Lorazepam is used as premedication for its anxiolytic properties. The UGT2B15 genotype is of importance for the metabolism of lorazepam. The clinical effect of genetic polymorphisms in UGT2B15 genotype on the treatment of anxiety levels in same-day surgery patients receiving lorazepam, however, is unknown. Three hundred ninety-eight same-day surgery patients of mixed sex (from a previous double-blinded randomized controlled trial who were assigned to either lorazepam [n = 198] or placebo [n = 200]) were assessed for the UGT2B15*2 variant allele. Anxiety was measured preoperatively and postoperatively by the State part of the State-Trait Anxiety Inventory. The difference between these 2 measurements served as outcome of the study. Analysis of variance was used to assess the State part of the State-Trait Anxiety Inventory difference for interactions among the following factors: UGT2B15 genotype status, treatment condition (lorazepam or placebo), patient sex, and preoperative anxiety score. The anxiety difference was complex in that the interaction of lorazepam and UGT2B15 genotype status also was dependent on the joint effect of patient sex and preoperative anxiety score (F = 7.15, P = .008). Further exploration showed clinical relevant results in patients with high preoperative anxiety scores. Striking was that females with high preoperative anxiety scores and genetically reduced lorazepam glucuronidation (UGT2B15*2 homozygotes) showed more postoperative anxiety reduction than males with the same genotype. UGT2B15 genotype contributes to postoperative anxiety reduction after lorazepam premedication. Future research that focuses on patients with high preoperative anxiety scores could help to gain a deeper understanding in the clinical relevance of the interaction between lorazepam and UGT2B15 genotype on postoperative anxiety levels.


Increasing community capacity to prevent childhood obesity: challenges, lessons learned and results from the Romp & Chomp intervention.
Obesity is a major public health issue; however, only limited evidence is available about effective ways to prevent obesity, particularly in early childhood. Romp & Chomp was a community-wide obesity prevention intervention conducted in Geelong Australia with a target group of 12,000 children aged 0-5 years. The intervention had an environmental and capacity building focus and we have recently demonstrated that the prevalence of overweight/obesity was lower in intervention children, post-intervention. Capacity building is defined as the development of knowledge, skills, commitment, structures, systems and leadership to enable effective health promotion and the aim of this study was to determine if the capacity of the Geelong community, represented by key stakeholder organisations, to support healthy eating and physical activity for young children was increased after Romp & Chomp. A mixed methods evaluation with three data sources was utilised. 1) Document analysis comprised assessment of the documented formative and intervention activities against a capacity building framework (five domains: Partnerships, Leadership, Resource Allocation, Workforce Development, and Organisational Development); 2) Thematic analysis of key informant interviews (n = 16); and 3) the quantitative Community Capacity Index Survey. Document analysis showed that the majority of the capacity building activities addressed the Partnerships, Resource Allocation and Organisational Development domains of capacity building, with a lack of activity in the Leadership and Workforce Development domains. The thematic analysis revealed the establishment of sustainable partnerships, use of specialist advice, and integration of activities into ongoing formal training for early childhood workers. Complex issues also emerged from the key informant interviews regarding the challenges of limited funding, high staff turnover, changing governance structures, lack of high level leadership and unclear communication strategies. The Community Capacity Index provided further evidence that the project implementation network achieved a moderate level of capacity. Romp & Chomp increased the capacity of organisations, settings and services in the Geelong community to support healthy eating and physical activity for young children. Despite this success there are important learnings from this mixed methods evaluation that should inform current and future community-based public health and health promotion initiatives. ANZCTRN12607000374460.


Measuring outcome after arterial ischemic stroke in childhood with two different instruments.
Assessment of outcome after childhood stroke is important both for clinical practice and for research purposes. The objective of this study was to compare two frequently used outcome measures. In 40 children with arterial ischemic stroke (AIS), dichotomized outcome obtained from the Pediatric Stroke Outcome Measure (PSOM) was compared with a dichotomized modified Rankin Scale (mRS) combined with information on type of school attendance. In addition, we compared dichotomized outcome, obtained from the PSOM and the mRS combined with school attendance, with the results of pediatric quality of life (PedsQL) questionnaires and the impressions of the child's general functioning on a visual analogue scale (VAS) that was filled out by parents and investigators. In 35 children (88%), outcome classification was concordant between the two outcome measures. Five children had a poor outcome according to the PSOM and good outcome with the mRS including school performance. In these patients, mRS outcome classification agreed better with the impression of the investigators, as reflected by VAS scores ≥7.5. For both the PSOM and mRS in combination with school performance, patients with a good outcome had significantly higher PedsQL and VAS scores than those with a poor outcome (p values <0.01 for all comparisons). VAS scores of investigators and parents correlated significantly with PedsQL. In children with AIS, both PSOM and mRS combined with school type correlated significantly with quality of life and VAS scores of general functioning. The mRS combined with school type is easier to obtain than the PSOM, reflects function rather than deficits, includes an important measure of cognitive outcome, and corresponds better with the doctor's impression of outcome.


Enhanced reactive oxygen species metabolism of air space cells in hypersensitivity pneumonitis.
Reactive oxygen species (ROS) are produced by phagocytic cells as part of host defense mechanisms, but these same products released by air space cells have been shown to contribute to pulmonary inflammation in interstitial lung diseases and likely represent a general mechanism of lung injury. However, the possible contribution of these compounds to lung inflammation in hypersensitivity pneumonitis (HP) has yet to be reported. We performed 11 bronchoalveolar lavage (BAL) studies in six patients with HP and compared the results with results from studies in 21 healthy normal volunteers. In patients with HP, spontaneous and stimulated measures of ROS metabolism by air space cells were significantly higher than those seen in normal volunteers. When alveolar macrophages were purified by depleting neutrophils and eosinophils on density gradients of Percoll (specific gravity 1.075 gm/ml), ROS metabolism remained elevated when compared with that in cells obtained from healthy controls, confirming that alveolar macrophage ROS metabolism is enhanced in patients with HP. Further, we found significant elevations in BAL total protein, lymphocytes, eosinophils, and neutrophils in patients with HP when they were compared with normal volunteers, with an increased proportion of BAL T lymphocytes expressing CD8 and natural killer surface antigens, consistent with previous work. Lavage samples from patients with HP with clinically active disease had higher proportions of BAL eosinophils and concentrations of total protein, lower forced expiratory volume in 1 second, lower forced vital capacity, and lower arterial oxygen tensions, and higher indices of ROS metabolism than samples from patients with HP with inactive disease. HP is associated with evidence of air space inflammation, to which alveolar macrophage-derived ROS may contribute.


Magnesium and the heart.
Magnesium is a most important cation in the body mostly distributed in the skeleton, muscles and liver. The most important causes of magnesium deficiency in the body include wide range of gastrointestinal disorders, diuretic therapy, endocrine disorders, renal diseases, alcoholism, etc. The demonstration of hypomagnesemia in patients of digitalis toxicity is of great clinical significance since magnesium can be replaced among these patients and toxicity and mortality due to this drug can be minimised. In patients with low serum magnesium, the cellular content of this ion may be normal. Therefore, it is of great interest to study the myocardial level of this ion in cardiovascular diseases. The clinical features of magnesium deficit are related to neuromuscular disorders. However, ST and T waves changes are quite commonly seen in the electrocardiogram and cardiac arrhythmias rarely have also been described. Magnesium administration on the other hand causes hypotention, bradycardia, and conduction defects. Magnesium depresses central nervous system, neuromuscular transmission and conductivity of the heart. Magnesium therapy is indicated when clinical features of magnesium deficiency are present in association with low serum or tissue levels.


Nutrition Support Protocols: Enhancing Delivery of Enteral Nutrition.
In critical care, malnutrition has a significant, negative impact on a patient's ability to respond to medical treatment. Enteral nutrition is known to counteract the metabolic changes associated with critical illness that increase the risk for serious complications and poor clinical outcomes. Inadequate delivery of nutrition support and underfeeding persist in intensive care units despite the availability of guidelines and current research for best practice. Recent studies have shown that nutrition support protocols are effective in promoting nutritional goals in a wide variety of intensive care patients. It is essential to find approaches that enhance early delivery of enteral nutrition that meets requirements and supports improved outcomes. Nurses are in a unique position to take an active role in promoting the best nutritional outcomes for their patients by using and evaluating nutrition support protocols.


Live Imaging of 3D Hanging Drop Arrays through Manipulation of Light-Responsive Pyroelectric Slippery Surface and Chip Adhesion.
Three-dimensional (3D) hanging drop cell culture is widely used in organoid culture because of its lack of selection pressure and rapid cell aggregation. However, current hanging drop technology has limitations, such as a dependence on complex microfluidic transport channels or specific capillary force templates for drop formation, which leads to unchangeable drop features. These methods also hinder live imaging because of space and complexity constraints. Here, we have developed a hanging drop construction method and created a flexible 3D hanging drop construction platform composed of a manipulation module and an adhesion module. Their harmonious operation allows for the easy construction of hanging drops of varying sizes, types, and patterns. Our platform produces a cell hanging drop chip with small sizes and clear fields of view, thereby making it compatible with live imaging. This platform has great potential for personalized medicine, cancer and drug discovery, tissue engineering, and stem cell research.


Radial Nerve Palsy Associated with Humeral Shaft Fractures in Children.
This is the first systematic review of the relationship between humeral shaft fractures and radial nerve palsy in children. The present comprehensive review is aimed at identifying important clinical findings between humeral diaphysis fractures and radial nerve injuries and assessing the effects of treatment. We searched electronic bibliographic databases, including PubMed, the Cochrane Library, Scopus, and Web of Knowledge, until March 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the patients, interventions, comparisons, outcomes guidelines. We identified 23 original papers, of which 10 were eligible for further analysis. Cases of 32 young patients with radial nerve palsy were identified and analyzed. The prevalence of radial nerve palsy was 4.34% (eight cases out of 184 patients with humeral shaft fractures). The radial nerve was most often associated with a simple transverse fracture (12A3, 17 cases (65.4%)). Radial nerve injury in humeral shaft fractures in children is rare, with a frequency of 4.34%. We highly recommend early surgical nerve exploration with transverse fractures in the distal third segment combined with primary radial palsy. Furthermore, we recommend making thoughtful decisions regarding early nerve exploration in the Holstein-Lewis fractures. In addition, consideration of early surgical nerve exploration in fractures resulting from high-energy trauma and open fractures despite their morphology is recommended.


A novel syntaxin 6-interacting protein, SHIP164, regulates syntaxin 6-dependent sorting from early endosomes.
Membrane fusion is dependent on the function of SNAREs and their alpha-helical SNARE motifs that form SNARE complexes. The Habc domains at the N-termini of some SNAREs can interact with their associated SNARE motif, Sec1/Munc18 (SM) proteins, tethering proteins or adaptor proteins, suggesting that they play an important regulatory function. We screened for proteins that interact with the Habc domain of Syntaxin 6, and isolated an uncharacterized 164-kDa protein that we named SHIP164. SHIP164 is part of a large (approximately 700 kDa) complex, and interacts with components of the Golgi-associated retrograde protein (GARP) tethering complex. Depletion of GARP subunits or overexpression of Syntaxin 6 results in a redistribution of soluble SHIP164 to endosomal structures. Co-overexpression of Syntaxin 6 and SHIP164 produced excessive tubulation of endosomes, and perturbed the transport of cation-independent mannose-6-phosphate receptor (CI-MPR) and transferrin receptor. Thus,we propose that SHIP164 functions in trafficking through the early/recycling endosomal system.


Prenatal detection of trisomy 21 and 18 from amniotic fluid by quantitative fluorescent polymerase chain reaction.
Prenatal diagnosis of fetal trisomies is usually performed by cytogenetic analysis on amniotic fluid. This requires lengthy laboratory procedures and high costs, and is unsuitable for large scale screening of pregnant women. An alternative method, which is both rapid and inexpensive and suitable for diagnosing trisomies even from single fetal cells, is the fluorescent polymerase chain reaction using polymorphic small tandem repeats (STRs). In this paper we present the preliminary results of a larger study comparing parallel prenatal diagnoses of trisomies 21 and 18 using cytogenetics with quantitative fluorescent polymerase chain reaction using STR markers. The results obtained by the two techniques were concordant in all cases. This is the first study reporting significant numbers of prenatal diagnoses using the quantitative fluorescent polymerase chain reaction. We believe that further studies on greater numbers of samples will determine the absolute reliability of this technique. These results also provide a model for diagnosis of trisomy from single fetal cells isolated from maternal blood.


Parent-Child Communication and Adjustment Among Children With Advanced and Non-Advanced Cancer in the First Year Following Diagnosis or Relapse.
To examine parent-child communication (i.e., openness, problems) and child adjustment among youth with advanced or non-advanced cancer and comparison children. Families (n = 125) were recruited after a child's diagnosis/relapse and stratified by advanced (n = 55) or non-advanced (n = 70) disease. Comparison children (n = 60) were recruited from local schools. Children (ages 10-17) reported on communication (Parent-Adolescent Communication Scale) with both parents, while mothers reported on child adjustment (Child Behavior Checklist) at enrollment (T1) and one year (T2). Openness/problems in communication did not differ across groups at T1, but problems with fathers were higher among children with non-advanced cancer versus comparisons at T2. Openness declined for all fathers, while changes in problems varied by group for both parents. T1 communication predicted later adjustment only for children with advanced cancer. Communication plays an important role, particularly for children with advanced cancer. Additional research with families affected by life-limiting conditions is needed.


Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis.
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new therapies is a highly necessary clinical need. Angiogenesis is a promising target for this tumor type, however clinical trials with the use of anti-angiogenic drugs have so far not met expectations. Therefore, it is important to better characterize the expression of molecules whose expression levels may impact on the efficacy of the treatments. In this study the characteristics of the gastric tumor associated blood vessels were first assessed by endomicroscopy. Next, we analyzed the expression of Multimerin-2, EMILIN-2 and EMILIN-1, three molecules of the EMI Domain ENdowed (EDEN) protein family. These molecules play important functions in the tumor microenvironment, affecting cancer progression both directly and indirectly impinging on angiogenesis and lymphangiogenesis. All the molecules were highly expressed in the normal mucosa whereas in a number of patients their expression was altered. We consider that better characterizing the gastric tumor microenvironment and the quality of the vasculature may achieve effective patient tailored therapies.


Social Network Analysis for Implementation of the Sendai Framework for Disaster Risk Reduction in Iran.
Stakeholders are responsible for managing the risks of disasters. Hence, appropriate, collaborative, timely interactions of involved organizations, and having a collective view of these interactions, have an important influence on the operation of the whole system. This study was aimed at social network analysis (SNA) for the implementation of the Sendai framework for disaster risk reduction in Iran. SNA was used in this study. A review of literature on disaster risk management (DRM) plus snowball sampling technique identified a list of 85 stakeholders. Delphi method among purposefully selected experts was used to score the relationship between the stakeholders. Louvain method, along with the modularity optimization method, was applied to identify groups of stakeholders with greater interactions. Centrality measurements were used to define organizations with key-roles in the network. The density of this network was 0.75, which showed that not all the stakeholders were connected. The National Disaster Management Organization and Civil Defense Organization showed higher influences considering their responsibilities. A total of 3 clusters of stakeholders with specific duties that mostly interact with each other and have some interaction with other groups were recognized. Understanding the pre-disaster interaction of the network and the strengths and weaknesses of the interactions among stakeholders could help improve DRM.


Using measurements of unmet need to inform program investments for health service integration.
Demographic and Health Survey (DHS) data could potentially inform optimal strategies to reach women having unmet need with contraceptive services through integrated service delivery. Using 2010-11 DHS data from Nepal, Senegal, and Uganda, we estimate the proportion of married or cohabitating women of reproductive age (MWRA) having unmet need for family planning (FP) who have accessed selected health services and therefore could be offered FP services through integrated service delivery. We find substantial missed opportunities to reach MWRA having unmet need for family planning (FP) in the three countries examined. We also find considerable variation within and between countries in the potential for integrated services to reach women having unmet need. Between 4 percent and 57 percent of MWRA having unmet need in these countries could be reached through integration of FP into any single-service delivery platform we explored. This analysis has the potential to provide program managers with an evidence-based road map indicating which service-delivery platforms offer the greatest potential to reach the largest number of women having unmet need for contraception.


[ANTIMICROBIAL ALLERGY ASSESSMENT DURING PREGNANCY FOR APPROPRIATE ANTIMICROBIAL USE AT DELIVERY].
Avoidance of suspect drugs based solely on a history of drug allergy is detrimental to disease outcomes. Many antimicrobial allergy labels are not usually true allergy. Some studies have demonstrated that antimicrobial allergy assessments can be safely performed on pregnant women. The purpose of this study was to examine the usefulness of antibiotic allergy assessment during pregnancy in Japan. We reviewed pregnant women who reported antimicrobial allergies and were referred to the allergy center. Allergists conducted an interview and skin test and selected antibiotics that could be used at delivery. Twenty-four pregnant women were referred to as having antimicrobial allergies. Most of the suspected antimicrobials were cephalosporin (13 cases, 52%) and penicillin (9 cases, 36%). Five women were ruled out only by our interviews. Of the remaining 20 cases, 10 were immediate type, 6 were non-immediate type, and 4 were unknown. All 21 pregnant women who needed antimicrobials were able to use the first-line drugs (β-lactam antimicrobials) at the time of delivery. No surgical site infections or allergic reactions were observed. Pregnant women with antimicrobial allergy labels could be evaluated by antimicrobial allergy assessment during pregnancy, and first-line antimicrobials were safely and properly used at delivery.


Confidence intervals and statistical testing for ratio measures of percent change.
In public health and medical research, ratio measures of percent change relative to baseline are often used to express a change in disease incidence. Estimating variance becomes more complex when the comparison is to an expectation based on previous data (E), rather than to an observed value (O). In 2009, the decline in reported tuberculosis (TB) cases was the largest single-year decrease since national TB surveillance began in 1953. To investigate the 2009 TB decline compared with expected counts, we analyzed TB cases reported to the Center for Disease Control and Prevention's National Tuberculosis Surveillance System. We log-transformed case counts for 2000-2008, and performed linear regression stratified by patient and clinical characteristics. We calculated relative declines from expectation as (O - E) ∕ E for patient subgroups, and constructed 95% confidence intervals for TB declines. We then formulated a Z-score test statistic comparing declines across patient subgroups under the null hypothesis that the difference of the two ratio measures was zero. We illustrate our methods by comparing 2009 declines from expectation for US-born versus foreign-born patients. Predicted values and confidence intervals assessed the magnitude of unexpected TB declines within patient groups, while statistical tests comparing ratio measures evaluated relative TB declines across groups. Published 2012. This article is a US Government work and is in the public domain in the USA.