Neuropeptide levels in Dercum's disease (adiposis dolorosa).
Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), β-endorphin-like immunoreactivity (β-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.


Diagnosing alpha 1-antitrypsin deficiency.
Alpha 1-antitrypsin deficiency is a genetically transmitted disorder associated with an increased risk of emphysema and liver disease. The highest incidence occurs in whites of Northern European descent; the disorder affects between 70,000 and 100,000 individuals in the United States. Most persons with alpha 1-antitrypsin deficiency are misdiagnosed or undiagnosed. The laboratory tests used to screen for and diagnose the disorder are simple, inexpensive, and provide an opportunity to prevent the development of clinical disease through education about cofactor avoidance. This article provides a review of the epidemiology, genetics, and clinical presentation of this disorder.


99Tc(m)-ECD SPET perfusion changes by internal pallidum stimulation in Parkinson's disease.
High-frequency stimulation of the internal pallidum is an effective surgical approach for patients with advanced Parkinson's disease suffering from motor fluctuations and L-dopa induced dyskinesia. To study the acute effects of internal pallidum stimulation, changes in cerebral blood flow were measured by means of a single-day split-dose protocol using 99Tc(m)-ECD SPET. Nine patients with advanced Parkinson's disease and with a clinical picture predominated by tremor and drug-induced dyskinesia, were imaged before and immediately after electrostimulation. Brain perfusion data were mirrored to the same electrode side (five left and four right implants), co-registered and analysed statistically on a voxel-by-voxel basis (Statistical Parametric Mapping) and by an automated volume-of-interest approach. Acute stimulation of the internal pallidum induced a significantly decreased perfusion in the ipsilateral thalamus and striatum, as well as in the right parietal cortex. For the subgroup of seven patients with effective motor score improvements, a significant correlation between thalamic and striatal perfusion changes and UPDRS III motor score was present (P = 0.04). These results suggest that effective stimulation of the internal globus pallidus may produce symptom relief through decreased activity in pallido-thalamo-cortical circuits.


Long-term river invertebrate community responses to groundwater and surface water management operations.
River flow regimes have been transformed by groundwater and surface water management operations globally, prompting widespread ecological responses. Yet, empirical evidence quantifying the simultaneous effects of groundwater and surface water management operations on freshwater ecosystems remains limited. This study combines a multi-decadal freshwater invertebrate dataset (1995-2016) with groundwater model outputs simulating the effects of different anthropogenic flow alterations (e.g. groundwater abstraction, effluent water returns) and river discharges. A suite of flow alteration- and flow-ecology relationships were modelled that tested different invertebrate community responses (taxonomic, functional, flow response guilds, individual taxa). Most flow alteration-ecology relationships were not statistically significant, highlighting the absence of consistent, detectable ecological responses to long-term water management operations. A small number of significant statistical models provided insights into how flow alterations transformed specific ecological assets; including Ephemeroptera, Plecoptera and Trichoptera taxa which are rheophilic in nature being positively associated with groundwater abstraction effects reducing river discharges by 0-15%. This represents a key finding from a water resource management operation perspective given that such flow alteration conditions were observed on average in over two-thirds of the study sites examined. In a small number of instances, specific invertebrate responses displayed relative declines associated with the most severe groundwater abstraction effects and artificial hydrological inputs (predominantly effluent water returns). The strongest flow-ecology relationships were recorded during spring months, when invertebrate communities were most responsive to antecedent minimum and maximum discharges, and average flow conditions in the preceding summer months. Results from this study provide new evidence indicating how groundwater and surface water resources can be managed to conserve riverine ecological assets. Moreover, the ensemble of flow alteration- and flow-ecology relationships established in this study could be used to guide environmental flow strategies. Such findings are of global importance given that future climatic change and rising societal water demands are likely to further transform river flow regimes and threaten freshwater ecosystems.


Mapping, Infrastructure, and Data Analysis for the Brazilian Network of Rare Diseases: Protocol for the RARASnet Observational Cohort Study.
A rare disease is a medical condition with low prevalence in the general population, but these can collectively affect up to 10% of the population. Thus, rare diseases have a significant impact on the health care system, and health professionals must be familiar with their diagnosis, management, and treatment. This paper aims to provide health indicators regarding the rare diseases in Brazil and to create a network of reference centers with health professionals from different regions of the country. RARASnet proposes to map, analyze, and communicate all the data regarding the infrastructure of the centers and the patients' progress or needs. The focus of the proposed study is to provide all the technical infrastructure and analysis, following the World Health Organization and the Brazilian Ministry of Health guidelines. To build this digitized system, we will provide a security framework to assure the privacy and protection of each patient when collecting data. Systems development life cycle methodologies will also be applied to align software development, infrastructure operation, and quality assurance. After data collection of all information designed by the specialists, the computational analysis, modeling, and results will be communicated in scientific research papers and a digital health observatory. The project has several activities, and it is in an initial stage. Initially, a survey was given to all health care centers to understand the technical aspects of each network member, such as the existence of computers, technical support staff, and digitized systems. In this survey, we detected that 59% (23/39) of participating health units have electronic medical records, while 41% (16/39) have paper records. Therefore, we will have different strategies to access the data from each center in the data collection phase. Later, we will standardize and analyze the clinical and epidemiological data and use these data to develop a national network for monitoring rare diseases and a digital health observatory to make the information available. The project had its financing approved in December 2019. Retrospective data collection started in October 2020, and we expect to finish in January 2021. During the third quarter of 2020, we enrolled 40 health institutions from all regions of Brazil. The nature of rare disease diagnosis is complex and diverse, and many problems will be faced in the evolution of the project. However, decisions based on data analysis are the best option for the improvement of the rare disease network in Brazil. The creation of RARASnet, along with all the digitized infrastructure, can improve the accessibility of information and standardization of rare diseases in the country. DERR1-10.2196/24826.


Muscle fatigability measured with Pneumatic and Hydraulic handgrip systems are not interchangeable.
Fatigue resistance (FR) was here defined as the time during which grip strength (GS) drops to 50% of its maximum during sustained contraction. Since different GS systems exist, we compared FR obtained with Pneumatic (Pneu) and Hydraulic (Hydr) handgrip systems. Hand pain induced by both systems was also investigated since this might influence FR-outcomes. 618 young controls (Y: reference group), 426 middle-aged (MA) and 234 old community-dwelling adults (OLD), and 50 hospitalized patients (HOSP) participated. FR was recorded with Pneu and Hydr. Grip work corrected for body weight (area under the strength-time curve; GWBW = 0.75 ∗ maximal GS ∗ FR / body weight) was calculated. We corrected for body weight since heavier or more obese participants will have to engage more strength and sustain the effort over time. Thereafter GWBW was expressed as T-scores representing the deviation from the mean score of the sex-specific reference group. Experienced pain, its intensity and whether pain hindered participants to sustain the contraction were questioned. Overall, although significant correlation between FR measured with both systems was found (r = 0.418, p < 0.001), FR measured by Pneu (55.7 ± 35.0 s) was higher compared to Hydr (34.2 ± 18.4 s). There was a proportional difference in FR measured with both systems (R2 = 0.36, p < 0.001), highlighting the longer participants could sustain FR test, the higher the difference in FR measured with both systems. Overall, there was no difference in pain variables between both systems. Independent of sex and system, GWBW deviated less from reference group in MA compared to OLD and HOSP. In OLD, GWBW deviated less from reference group than HOSP, independent of sex and system. Participants were unable to sustain the contraction with Hydr as long as with Pneu. Hydr seems less able to identify subjects with higher levels of muscle endurance. Based on the GWBM-scores we can conclude that either system can be used for assessing muscle fatigability, but Pneu may be more sensitive as differences can be detected more easily.


Parents' depressive symptoms and reflective functioning predict parents' proficiency in relational savoring and children's physiological regulation.
This study examined parental depression and parental reflective functioning (PRF) as predictors of parental proficiency in relational savoring (RS), the association between RS proficiency and a marker of children's physiological self-regulation, respiratory sinus arrhythmia (RSA), during a stressor, and indirect effects of parental depression and PRF on children's RSA via parents' RS. At Time 1 (T1), parents of 8- to 12-year-old children (N = 139) reported on their depressive symptoms and completed a parenting interview, coded for PRF. After 1.5 years (Time 2; T2), parents savored a positive relational memory that involved their children, which was coded for savoring proficiency. Children's RSA was measured during a stressful task (a series of impossible puzzles). Depressive symptoms (inversely) and PRF (positively) were associated with RS proficiency. Higher parental RS proficiency was associated with children's higher mean levels of RSA during the stressor. Indirect effects models supported that T2 RS proficiency mediated the negative association between parental T1 depressive symptoms and children's T2 RSA, and between T1 PRF and children's T2 RSA. We discuss these findings in terms of implications for parents' emotion regulation, children's emotion regulation, children's mental health, and intervention.


The bioactivity of saponins: triterpenoid and steroidal glycosides.
Triterpenoid and steroidal glycosides, referred to collectively as saponins, are bioactive compounds present naturally in many plants. They have considerable potential as pharmaceutical and/or nutraceutical agents in natural or synthetic form. Saponins, from a variety of sources, have been shown to have hypocholesterolemic, anti-coagulant, anticarcinogenic, hepatoprotective, hypoglycemic, immunomodulatory, neuroprotective, anti-inflammatory and anti-oxidant activity. This paper reviews saponin research of the last decade, focussing on developments in understanding their mechanism of action and structure-activity relationships. Virtually all of this work has used animal and in vitro models. To date there are very few human data.


Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders.
Individuals with attention-deficit/hyperactivity disorder (AD/HD) and autism spectrum disorders (ASD) often display symptoms from other diagnostic categories. Exclusion criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Statistical Classification of Diseases and Related Health Problems (ICD-10) impede the use of categorical diagnoses to describe the particular problem constellation in a patient. In this study, we describe the prevalence and patterns of comorbid bipolar and psychotic disorders in 241 consecutively referred adult patients with AD/HD and/or ASD. Thirty per cent of patients with AD/HD had comorbid ASD and 38% of patients with ASD had comorbid AD/HD. Of the subjects with ASD, 7% had bipolar disorder with psychotic features, and 7.8% had schizophrenia or another psychotic disorder. The corresponding figures for the patients with AD/HD were 5.0% and 5.0%, respectively. Current diagnostic criteria have to be revised to acknowledge the comorbidity of bipolar and/or psychotic disorders in AD/HD and ASD.


Generation of human bronchial epithelial cell lines expressing inactive mutants of GALNT3.
As a tool to understand the role of mucins in the infection of respiratory viruses, we established cell lines stably expressing inactive mutants of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which initiates O-glycosylation of mucins. We introduced single amino acid mutations into the regions essential for the enzyme activity of GALNT3 using the expression plasmid of human GALNT3 and transfected the mutant constructs into a human bronchial epithelial cell line, BEAS-2B. We showed that although the mutants of GALNT3 exhibit an authentic localization at the Golgi apparatus, the glycosylation pattern of the expressing cell lines appeared to be different from that of the cells expressing wild-type GALNT3. These results suggested that the established cell lines express inactive forms of GALNT3 and might be useful in investigation of the significance of O-glycosylation of mucins in respiratory virus infections.


Is MMTV associated with human breast cancer? Maybe, but probably not.
Conflicting results regarding the association of MMTV with human breast cancer have been reported. Published sequence data have indicated unique MMTV strains in some human samples. However, concerns regarding contamination as a cause of false positive results have persisted. We performed PCR assays for MMTV on human breast cancer cell lines and fresh frozen and formalin fixed normal and malignant human breast epithelial samples. Assays were also performed on peripheral blood mononuclear cells from volunteer blood donors and subjects at risk for human retroviral infections. In addition, assays were performed on DNA samples from wild and laboratory mice. Sequencing of MMTV positive samples from both humans and mice were performed and phylogenetically compared. Using PCR under rigorous conditions to prevent and detect "carryover" contamination, we did detect MMTV DNA in human samples, including breast cancer. However, the results were not consistent and seemed to be an artifact. Further, experiments indicated that the probable source of false positives was murine DNA, containing endogenous MMTV, present in our building. However, comparison of published and, herein, newly described MMTV sequences with published data, indicates that there are some very unique human MMTV sequences in the literature. While we could not confirm the true presence of MMTV in our human breast cancer subjects, the data indicate that further, perhaps more traditional, retroviral studies are warranted to ascertain whether MMTV might rarely be the cause of human breast cancer.


Agrobacterium-mediated transformation of tomato with the ICE1 transcription factor gene.
ICE1 genes play a very important role in plants in cold conditions. To improve the cold resistance of tomato, the ICE1 gene of Arabidopsis thaliana was used to construct the plant expression vector p3301-ICE1, and was overexpressed in tomato through Agrobacterium-mediated transformation. Five strains of resistant plants were obtained. PCR and half-quantitative results showed that the ICE1 gene was transferred to tomato; three strains tested positive. After low-temperature stress treatment, praline content and peroxide and catalase activities in the transgenic tomato plants were higher compared with non-transgenic controls, while malondialdehyde content was clearly lower.


Use of indwelling pleural catheters for chronic pleural infection.
Recurrent, chronic pleural infection creates difficult management issues. Surgical drainage is currently recommended for patients who have failed initial "medical treatment" (ie, tube thoracostomy and antibiotic therapy), but the options for patients not fit for surgery are limited. Prolonged closed tube drainage may be an option in this group, although concerns exist regarding the efficacy and risk of catheter blockage. Long-term indwelling pleural catheters are increasingly used for the treatment of recurrent malignant pleural effusion. Pleural infection is recognized as a complication and is cited as a contraindication to insertion of an indwelling pleural drain within the product literature. We report two patients with empyema in a fixed pleural space in whom the insertion of an ambulatory catheter produced successful drainage. Long-term indwelling pleural catheters may have a role in maintaining the drainage of a chronically infected pleural space that is not readily treated in other ways.


Genetically modified adenovirus vector containing an RGD peptide in the HI loop of the fiber knob improves gene transfer to nonhuman primate isolated pancreatic islets.
The ability to transfer immunoregulatory, cytoprotective, or antiapoptotic genes into pancreatic islets (PIs) may allow enhanced post-transplantation survival. The available gene transfer vectors differ greatly in their ability to infect and express genes in different cell types. One limitation associated with the use of viral vectors is related to the virus reliance on the presence of its primary binding site. Tropism of the viral vectors can be altered using retargeting strategies. Results on phage biopanning proved that the RGD motif has in vivo targeting capabilities. This motif interacts especially with cellular integrins of the alphavbeta3 and alphavbeta5 types, highly expressed on pancreatic islets. In this report, we have explored the utility of a retargeted adenovirus vector (Ad) containing an RGD motif in the HI loop of the fiber knob in order to improve the infection efficiency to intact isolated nonhuman primate PIs and reduce toxicity after the genetic modification. Nonhuman primate Pis were isolated by a semi-automated technique. Steptozotocin-induced diabetic mice with severe combined immunodeficiency disease (SCID) were used as recipients. A recombinant Ad containing a heterologous RGD peptide and expressing luciferase (AdRGDLuc) or green fluorescent protein (AdRGDGFP) were generated in our laboratory. Similar Ads without the RGD peptide were used as a control (AdLuc and AdGFP). Higher transfection efficiency was demonstrated using AdRGDGFP compared with AdGFP (>80% of the islet cells were infected at 10 particle-forming units (pfu)/cell using AdRGDGFP vs. 7% after infection with AdGFP).More than 90% of the infected cells were insulin-producing cells. Significantly higher transgene expression was demonstrated after infection with AdRGDLuc compared with AdLuc at different titers. Analysis of the glucose-stimulated insulin response demonstrated better performance of PI transfected with AdRGDLuc at low titers (10 pfu/cell in order to achieve > 80% transfection efficiency) compared with AdLuc at high titers. Finally, long-term euglycemia (>250d) was observed in 89% of the animals that received PI infected with AdRGDLuc compared with none of the animals that received PI infected with AdLuc. The present study provides new information about the possibility of tropism modification of Ad vectors to increase the transfection efficiency and transgene expression to isolated PI. Incorporation of the RGD sequence in the HI loop of the fiber knob allows highly efficient transfection efficiency to nonhuman primate insulin-producing cells and adequate long-term function of the p-cell after transplantation.


[The social-political-environmental and health reality of families belonging to a vulnerable community].
The scope of this paper is to ascertain the perception of community leadership, health professionals and users regarding citizenship status and the enhancement of the healthcare conditions of families belonging to a vulnerable community. This is an exploratory study of a qualitative nature, guided by theory based on data. Data were collected between July and December 2009, by means of interviews with four community health leaders, a team of eight family health team professionals and twelve health users. The codification of the data resulted in the following categories: Understanding the social conditions, the political conditions, the environmental conditions and the health conditions of families in a vulnerable community. The conclusions reached were, that if on the one hand the social security and health policies made it possible to reduce poverty and local inequalities, on the other hand they do not ensure the requisite enhancement of citizenship or even the improvement of health conditions.


Non-pharmacological strategies on pain relief during labor: pre-testing of an instrument.
This descriptive study aimed to evaluate the effectiveness of Non-Pharmacological Strategies (NFS) on pain relief of parturients as part of a research instrument to be utilized in a Doctoral Dissertation. In order to evaluate the NFS, the Analogous Visual Scale (AVS) was used on 30 parturients attended at the Humanized Labor Unit of a school-maternity hospital in Natal, RN, Brazil. Of the six NFS (respiratory exercises, muscular relaxation, lumbossacral massage, shower washing, deambulation and pelvic swing), two were excluded post-test (deambulation and pelvic swing) for not being accepted by the parturients. The remaining NFS (respiratory exercises, muscular relaxation, lumbossacral massage, and shower washing) which reached satisfactory acceptation and applicability rates, were found to be effective in relieving pain of these parturients, and thus deemed adequate for use in the Doctoral Dissertation data collection process.


Glutaminase 1 is essential for the differentiation, proliferation, and survival of human neural progenitor cells.
Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Previous studies have revealed that mice lacking glutaminase 1 (GLS1), the dominant isoform in the brain and kidney, died shortly after birth due to disrupted glutamatergic transmission, suggesting the critical role of GLS1 in the physiological functions of synaptic network. However, whether GLS1 regulates neurogenesis, a process by which neurons are generated from neural progenitor cells (NPCs), is unknown. Using a human NPC model, we found that both GLS1 isotypes, kidney-type glutaminase and glutaminase C, were upregulated during neuronal differentiation, which were correlated with the expression of neuronal marker microtubule-associated protein 2 (MAP-2). To study the functional impact of GLS1 on neurogenesis, we used small interference RNA targeting GLS1 and determined the expressions of neuronal genes by western blot, real-time polymerase chain reaction, and immunocytochemistry. siRNA silencing of GLS1 significantly reduced the expression of MAP-2, indicating that GLS1 is essential for neurogenesis. To unravel the specific process(es) of neurogenesis being affected, we further studied the proliferation and survival of NPCs in vitro. siRNA silencing of GLS1 significantly reduced the Ki67(+) and increased the TUNEL(+) cells, suggesting critical roles of GLS1 for the proliferation and survival of NPCs. Together, these data suggest that GLS1 is critical for proper functions of NPCs, including neuronal differentiation, proliferation, and survival.


Long-term outcomes in blunt trauma: who goes back to work?
Trauma patients continue to improve after discharge from the trauma center, but the completeness of this recovery remains uncertain. The purpose of this study was to compare the characteristics of patients who do and who do not return to work after blunt trauma. Consecutive survivors of blunt trauma discharged from a regional trauma center over a 1-year interval (July of 1994 to June of 1995) were included in the study. Patients completed the SF-36 Health Survey and some additional questions related to employment status both at discharge and again after 1 year. Our principal analysis compared patients who were employed and unemployed at 1-year follow-up. Complete data were available for 195 patients. The typical patient was a young man who had been in a motor vehicle collision and had an injury severity score of 25. At 1-year follow-up, 101 patients had returned to work and 94 remained unemployed. Employed individuals were younger (31 vs. 44 years, p < 0.0001), less severely injured (mean injury severity score 23 vs. 27, p < 0.001), and more likely to hold professional jobs (50 vs. 16%, p < 0.0001). Patterns of injury and operative procedures were similar for employed and unemployed patients. However, the average employed patient had fewer days in the intensive care unit (2 vs. 5 days, p < 0.001), a shorter total hospitalization (19 vs. 28 days, p < 0.01), and was more likely to be discharged to home (62 vs. 39%, p < 0.01). At discharge, those who went on to employment had marginally better SF-36 Health Survey scores on seven of the eight scales (all except general health). During the year after discharge, both groups improved significantly, although employed individuals to a greater extent on all scales of the SF-36 Health Survey. Almost one half of the multiple system blunt trauma patients remain unemployed 1 year after hospital discharge. Those patients who return to work are usually young professionals with a lower severity of injury. Functional status at discharge predicts future employment status, but underestimates the extent of long-term recovery.


Exploring Medical Foster Care as a Placement Option for Children With Medical Complexity.
Medical foster care (MFC) offers a family-home setting for children with medical complexity (CMC) who cannot be cared for by their parents. We explored MFC as a placement option for CMC via in-depth interviews with the individuals providing and monitoring care. In collaboration with an MFC agency, we recruited care team members for 15 CMC. Semistructured interviews were audiotaped and transcribed. Descriptive analyses were performed on care team composition and roles, the placement process, and child medical, placement, and quality of life (QoL) characteristics. Foster parents completed child QoL questionnaires. Conventional content analysis was applied to participant suggestions for MFC improvements. Fifty-eight interviews were conducted; a median of 4 care team members interviewed per child. An extensive network of individuals and systems are involved in providing care. Each child received care from multiple subspecialists (median = 5). Most children were technology dependent (87%), developmentally delayed (87%), and entered MFC from the hospital (73%) because of medical neglect (86%). Nearly half were in care for >2 years. Changes in placement and/or care team were common. QoL scoring showed impairments in multiple domains, whereas respondent interviews described positive aspects of QoL. Participants provided suggestions to improve care within MFC. MFC is a promising placement option for CMC. Because many CMC are entering MFC directly from the hospital and require ongoing care from pediatric subspecialists, pediatricians should be familiar with MFC, the placement process, and the various systems and individuals involved. Pediatricians can play important roles in ensuring that children in MFC receive coordinated and high-quality care.


Ribonuclease inhibits Ah receptor transformation in vitro.
The aryl hydrocarbon (Ah) receptor undergoes a ligand-dependent transformation to a heteromeric structure which has the ability to bind DNA sequence-specifically with high affinity. By this mechanism, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related xenobiotics modify gene expression. We observed that transformation was inhibited in vitro by the presence of ribonuclease A (RNAase) during incubation of rat hepatic cytosol with TCDD. This effect was detected as a decreased ability of the TCDD-receptor complex to bind to calf thymus DNA covalently linked to Sepharose, and to a dioxin-responsive enhancer which is upstream of the cytochrome P450IA1 structural gene. RNAase had no effect on previously transformed TCDD-receptor complexes. These observations indicated that RNAase acted during ligand binding and/or transformation of the Ah receptor. Saturation binding analyses demonstrated that RNAase decreased the receptor affinity for TCDD without changing the total number of binding sites. RNAase also inhibited transformation of the TCDD-bound, partially purified, untransformed, receptor. Thus RNAase does not interfere with ligand binding, but inhibits the subsequent transformation of the receptor monomer to the heteromeric, transcriptionally active, form.


Unbiased Metabolomic Investigation of Alzheimer's Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism.
Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.


Turning gold into 'junk': transposable elements utilize central proteins of cellular networks.
The numerous discovered cases of domesticated transposable element (TE) proteins led to the recognition that TEs are a significant source of evolutionary innovation. However, much less is known about the reverse process, whether and to what degree the evolution of TEs is influenced by the genome of their hosts. We addressed this issue by searching for cases of incorporation of host genes into the sequence of TEs and examined the systems-level properties of these genes using the Saccharomyces cerevisiae and Drosophila melanogaster genomes. We identified 51 cases where the evolutionary scenario was the incorporation of a host gene fragment into a TE consensus sequence, and we show that both the yeast and fly homologues of the incorporated protein sequences have central positions in the cellular networks. An analysis of selective pressure (Ka/Ks ratio) detected significant selection in 37% of the cases. Recent research on retrovirus-host interactions shows that virus proteins preferentially target hubs of the host interaction networks enabling them to take over the host cell using only a few proteins. We propose that TEs face a similar evolutionary pressure to evolve proteins with high interacting capacities and take some of the necessary protein domains directly from their hosts.


[Vectorial competence of Glossina tachinoides Westwood and Glossina palpalis gambiensis Vanderplank infected by Trypanosoma brucei brucei EATRO 1125].
The vectorial competence (VC) of teneral (less than 32 h) Glossina tachinoides Westwood and G. palpalis gambiensis Vanderplank, fed simultaneously on a guinea-pig infected with Trypanosoma brucei brucei EATRO 1125, was assessed. Statistical analysis of the experimental results revealed that female G. tachinoides had a significantly higher midgut infection rate than males. Such a sex-related difference was not observed in G. p. gambiensis. Male G. p. gambiensis had higher midgut infection rates than male G. tachinoides. The metacyclic index did not differ between both subspecies, although G. p. gambiensis showed relatively more metacyclic infections than G. tachinoides. A global VC of 0.0242 and 0.0483 was found for G. tachinoides and G. p. gambiensis, respectively. VC did not differ significantly either between sexes or between the two species. However, G. tachinoides more rapidly infected the feeding host than G. p. gambiensis. In all infected flies, the procyclic index value was superior to the metacylic index value, suggesting that the infection is established by an ascending origin. Both large and slender parts of the salivary glands were constantly infected. Longitudinally dividing trypomastigotes of unequal length have been observed in the alimentary canal of the flies.


Structural insights of cell wall integrity signaling during development and immunity.
A communication system between plant cells and their surrounding cell wall is required to coordinate development, immunity, and the integration of environmental cues. This communication network is facilitated by a large pool of membrane- and cell-wall-anchored proteins that can potentially interact with the matrix or its fragments, promoting cell wall patterning or eliciting cellular responses that may lead to changes in the architecture and chemistry of the wall. A mechanistic understanding of how these receptors and cell wall proteins recognize and interact with cell wall epitopes would be key to a better understanding of all plant processes that require cell wall remodeling such as expansion, morphogenesis, and defense responses. This review focuses on the latest developments in structurally and biochemically characterized receptors and protein complexes implicated in reading and regulating cell wall integrity and immunity.


Preliminary study of the effect of user intent recognition errors on volitional control of powered lower limb prostheses.
Previously developed user-intent-recognition (UIR) systems have demonstrated promising accuracy for identifying the user's locomotion mode, which is potentially useful for volitional control of powered artificial legs in ambulation. The fundamental question facing us now is whether or not the prosthesis users are safe when the UIR system is directly integrated with the intrinsic controller to operate powered artificial legs. In this preliminary study, we aimed to address this question by investigating the effect of UIR errors on the walking stability of users, wearing a UIR-controlled powered transfemoral (TF) prosthesis. First, a novel control of powered prosthesis was developed, which hierarchically connected our designed UIR system with an intrinsic controller. Three types of errors were purposely added into the UIR output at different gait phase while an able-bodied subject walked on a treadmill with the powered prosthesis. Subjective opinions were obtained to evaluate the effect of applied UIR errors on the user's walking balance. The kinematics and kinetics of the prosthetic knee were quantified while the errors occurred. The preliminary results showed that not all the UIR errors applied caused a subjective feeling of balance instability. The effects of UIR errors on the prosthesis control and user's balance depended on the gait phase when the errors happened and the amount of mechanical work applied to the knee joint caused by the errors. The results of this study could aid the future design of true bionic prostheses that enable lower limb amputees to perform various activities intuitively and safely.


Single Cell Microwave Biosensor for Monitoring Cellular Response to Electrochemotherapy.
This paper presents a 40 GHz microwave biosensor used to monitor and characterize single cells (THP-1) subjected to electrochemotherapy and obtain an electronic signature of the treatment efficiency. This biosensor proposes a non-destructive and label-free technique that first allows, with the rapid measurement of single untreated cells in their culture medium, the extraction of two frequency-dependent dielectric parameters, the capacitance (C (f)) and the conductance (G (f)). Second, this technique can powerfully reveal the effects of a chemical membrane permeabilizing treatment (Saponin). At last, it permits us to detect, and predict, the potentiation of a molecule classically used in chemotherapy (Bleomycin) when combined with the application of electric pulses (principle of electrochemotherapy). Treatment-affected cells show a decrease in the capacitive and conductive contrasts, indicating damages at the cellular levels. Along with these results, classical biological tests are conducted. Statistical analysis points out a high correlation rate (R2>0.97), which clearly reveals the reliability and efficacy of our technique and makes it an attractive technique for biology related researches and personalized medicine.


Effect of the iChoose Kidney decision aid in improving knowledge about treatment options among transplant candidates: A randomized controlled trial.
We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays individualized risk estimates of survival and mortality, for the treatment modalities of dialysis versus kidney transplantation. We examined the effect of iChoose Kidney on change in transplant knowledge and access to transplant in a randomized controlled trial among patients presenting for evaluation in three transplant centers. A total of 470 patients were randomized to standard transplantation education (control) or standard education plus iChoose Kidney (intervention). Change in transplant knowledge (primary outcome) among intervention versus control patients was assessed using nine items in pre- and postevaluation surveys. Access to transplant (secondary outcome) was defined as a composite of waitlisting, living donor inquiries, or transplantation. Among 443 patients (n = 226 intervention; n = 216 control), the mean knowledge scores were 5.1 ± 2.1 pre- and 5.8 ± 1.9 postevaluation. Change in knowledge was greater among intervention (1.1 ± 2.0) versus control (0.4 ± 1.8) patients (P < .0001). Access to transplantation was similar among intervention (n = 168; 74.3%) versus control patients (n = 153; 70.5%; P = .37). The iChoose Kidney decision aid improved patient knowledge at evaluation, but did not impact transplant access. Future studies should examine whether combining iChoose Kidney with other interventions can increase transplantation. (Clinicaltrials.gov NCT02235571).


Isolex 300i CD34-selected cells to support multiple cycles of high-dose therapy.
We have previously reported that repeated cycles of high-dose therapy (HDT), can be supported by unmanipulated autologous PBPC. Here we investigate whether purified CD34+ cells, obtained by immunomagnetic separation using the Isolex 300i device, can support such therapy. Twenty-nine consecutive patients with metastatic breast cancer had PBPC mobilized and harvested following chemotherapy and G-CSF (10 microg/kg per day). Patients with > 4.0 x 10(6)/kg CD34+ cells in the apheresis product underwent CD34-selection using the Isolex 300i (v2.0) device. All cells collected were equally divided into three aliquots and cryopreserved. Patients who did not achieve this threshold had unmanipulated cells collected and stored. Patients subsequently received three cycles of HDT with paclitaxel (175 mg/m2), thiotepa (300 mg/m2) and either ifosfamide (10 g/m2) or cyclophosphamide (4 g/m2). It was intended for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e 1/3 for each cycle) and to compare hemopoietic recovery between patients receiving CD34-selected cells or unmanipulated cells. Thirteen of the 29 patients (45%) did not mobilize sufficient CD34+ cells to undergo CD34-selection. The remaining 16 patients underwent CD34-selection with a median purity of 84.3% (range: 16.3-96.1%) and yield of 34% (range: 1-60%). Fifteen of these patients proceeded to HDT and 42 of the planned 45 cycles were administered. Nine patients had all three HDT cycles supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (range: 0.04-3.01). Three of the 15 patients required infusion of 'back-up' unmanipulated cells because of delayed neutrophil recovery. Of the 13 patients whose PBPCs did not undergo CD34+ cell selection, 11 proceeded to HDT with a median of 3.2 x 10(6)/kg (range: 2.0-4.4) unselected cells infused per cycle and 31 of 33 planned cycles were delivered. When hemopoietic recovery was compared between cycles of HDT supported by CD34-selected (n = 34) and unmanipulated cells (n = 31), there was a modest slowing in the patients receiving CD34-selected cells; time to ANC > 1.0 x 10(9)/L = 11 days versus 10 days (P = 0.0122) and platelets > 20 x 10(9)/L = 14 days versus 13 days (P = 0.0009). No difference in recovery to 50 x 10(9)/L was observed (P = 0.54). We have demonstrated that Isolex 300i CD34-selected cells are capable of supporting multiple cycles of HDT. However, we were unable to acquire sufficient CD34+ cells to perform this processing in 45% (13/29) of patients and further improvements in yield are required to overcome the modest delay in neutrophil and platelet recovery.


Microtubule reorganization is related to rate of heart myocyte hypertrophy in rat.
Since stimulation of heart hypertrophy by pressure overload was previously shown to be accompanied by a densification of microtubule network in rat heart myocytes, we verified that similar process occurred during postnatal growth in euthyroid rats and in hypothyroid rats whose growth was stimulated by 4 micrograms/day L-thyroxine (T4). For this purpose, tubulin, the constituent protein of microtubules, was immunolabeled in myocytes isolated at various times after birth. Myocyte hypertrophy was evaluated by myocyte size, the number of nuclei per cell and isomyosin expression. In hypothyroid rats, the microtubule network, which was underdeveloped, was most dense around the nucleus. During the phase of fast myocyte hypertrophy observed in euthyroid rats during late postnatal development and in hypothyroid rats after T4 administration, transient microtubule densification occurred in a myocyte subpopulation in which size was mainly determined by the rate of myocyte hypertrophy. The densification process and its kinetics resembled those observed when heart hypertrophy was induced by pressure overload. It is concluded that in rat heart myocytes undergoing hypertrophy, microtubule densification might be related to fast sarcomerogenesis, whether the stimulus is mechanical (e.g., pressure overload) or hormonal (e.g., T4).


The effect of age on outcome following traumatic brain injury in rats.
Age of the patient is one of the most important predictors of outcome following human traumatic brain injury. This study employs the fluid-percussion model to investigate the effects of aging on outcome following traumatic brain injury in rats. The results revealed that there was an age-associated increase in mortality rate following both low (1.7 to 1.8 atm) and moderate (2.00 to 2.25 atm) levels of traumatic brain injury. Age-related changes in systemic physiological, neurological, and histopathological indexes of brain injury were also examined following a low level of traumatic brain injury. Traumatic brain injury produced equivalent acute hypertension and increased plasma glucose levels in both young adult and aging rats. Injury produced an acute increase in heart rate in the young adult rat group, while the heart rate decreased in the aged rats. At low levels of brain injury, no significant gross histopathological alterations were produced in either age group. Neurological outcome was assessed by measuring the duration of suppression of a number of nonpostural and postural reflexes and more complex somatomotor functions (righting, escape, head support). Except for head support, there was a significant age-related increase in the duration of the suppression of these reflexes following brain injury. These data demonstrate that aging is associated with an increased mortality rate and greater acute neurological deficits following traumatic brain injury. These data also demonstrate the usefulness of the fluid-percussion model for studying the mechanisms responsible for the age-related increase in vulnerability to brain injury.


Tampon absorbency, composition and oxygen content and risk of toxic shock syndrome.
Tampon use has been identified as a major risk factor for toxic shock syndrome, although the etiologic role of tampons is not clearly understood. Two epidemiologic studies conducted to date have reported an association between tampon absorbency and risk of toxic shock syndrome. This finding is not corroborated by laboratory studies, however, which have suggested that absorbency may be a marker for other characteristics that create an environment conductive to the elaboration of toxic shock syndrome toxin 1. We used data from the previously reported Tri-state study to estimate simultaneously the effects of tampon oxygen content, absorbency and chemical composition. Although the data are sparse, oxygen content was more strongly associated with risk of toxic shock syndrome than either absorbency or chemical composition. The results suggest that it may be possible to develop a highly absorbent tampon that is not associated with a high risk of toxic shock syndrome.


Long-Term Testosterone Therapy Improves Urinary and Sexual Function, and Quality of Life in Men with Hypogonadism: Results from a Propensity Matched Subgroup of a Controlled Registry Study.
We investigated the effects of long-term testosterone therapy on urinary and sexual function, and quality of life in hypogonadal men. We performed an observational, prospective, cumulative registry study in 656 men with a mean ± SD age of 60.7 ± 7.2 years who had total testosterone 12.1 nmol/l or less and symptoms of hypogonadism. In the testosterone treated group 360 men received parenteral testosterone undecanoate 1,000 mg/12 weeks for up to 10 years. The 296 men who elected against testosterone therapy served as controls. From each group 82 patients were propensity matched by age, waist circumference and body mass index, resulting in 82 matched pairs of 164 men. Data were analyzed and estimated differences between the groups were adjusted for components of metabolic syndrome and quality of life. We found significant decreases in I-PSS (International Prostate Symptom Score) and post-void bladder volume (each p <0.0001) in patients receiving testosterone therapy but not in the untreated group. We recorded a decrease in AMS (Aging Males' Symptoms Scale) in the testosterone treated group but not in the untreated group (p <0.0001). We also recorded significant improvement in the IIEF-EF (International Index of Erectile Function-Erectile Function) domain in the testosterone treated group but not in the untreated group (p <0.0001). The improvement was maintained throughout followup. Long-term testosterone therapy in hypogonadal men resulted in significant improvements in urinary and sexual function, and in quality of life. In untreated hypogonadal men voiding and erectile function deteriorated with continued followup.


Autopsy findings in an outbreak of severe systemic illness in heroin users following injection site inflammation: an effect of Clostridium novyi exotoxin?
An epidemic of unexplained illness among injecting drug users characterized by injection site inflammation and severe systemic toxicity occurred in Ireland and the United Kingdom from April to August 2000. One hundred eight persons became ill, and 43 persons died. In Dublin, 8 of 22 patients died. Six of the 8 fatal cases were epidemiologically linked to a source of heroin. Most had experienced local injection site lesions for 7 to 14 days before developing a rapidly fatal systemic illness characterized by hypotension, thirst, pulmonary edema, pericardial and pleural effusions, and leukocytosis. To document the clinical course and autopsy findings of the fatal cases in Dublin. To study the clinical, autopsy, microbiologic, and toxicologic findings from the 8 fatal cases in Dublin. In Dublin, there were 6 men and 2 women who were fatally involved in the epidemic, with the mean age being 34 years (range, 22-51 years). The injection site inflammations involved the buttock (n = 4), leg, iliac region, arm, and a Portacath site. At autopsy, the local lesions were ulcerated, swollen, and indurated but were inconspicuous in 2 patients. All the deceased had pulmonary edema. There were pleural effusions in 7, 2 of whom had pericardial effusions. Five had prominent left ventricular subendocardial hemorrhages. Five had splenomegaly. Microscopy showed pulmonary edema and a granulocytic reaction mainly in the spleen, marrow, and myocardium. Toxicology showed a range of narcotic drugs in the toxic or fatal range. Clostridium novyi type A, a fastidious toxin-producing anaerobe, was identified in 2 cases. The clinicopathologic findings of a local inflammatory lesion followed 7 to 14 days later by a rapidly fatal systemic illness are consistent with the effect of exotoxin produced by organisms growing in the local inflammatory site. Clostridium novyi-derived exotoxin is the likely cause of such a syndrome, although the fastidious organism was isolated from only 2 of 8 cases (from none of the 14 surviving patients and from only 13 of 60 cases in Scotland). In the setting of an epidemic, the toxic and fatal range blood levels of narcotics are unlikely to explain these events, and no other candidate organism could be isolated. The heroin is likely to have come from Afghanistan, but local contamination at a putative distribution site in the United Kingdom is more likely than international terrorism to be the initiating factor.


[Methods of analysis of food and nutritional security programs: an experience in Brazil].
The development of methods that enable analysis of programs and public policies is a key point for their objectives to be attained. This study presents a Brazilian experience of analysis of two food and nutritional security programs in cities in Brazil's northeast region, namely the National Program for Vitamin A Supplementation, and monitoring health conditions of those included in the Family Allowance Program. The methodological stages included the definition of programs to be analyzed, data collection locations, the population participating in the research, collection procedures and data analysis. The methodology used made it possible to ascertain the perception of the different social actors involved in the operationalization of these programs, proving to be an important tool for the insertion of these actors, not only as objects of analysis, but also mainly as subjects of self-evaluation.


Predictors of therapeutic outcome and process.
This article presents an intensive study of the outcome and process of the psychotherapeutic treatments conducted at the Blanquerna Psychotherapy Service in Barcelona. It analyzes in detail the relation between outcome (improvement) and process (therapeutic alliance). Specifically, it discusses (a) the therapeutic process in terms of the relation between therapeutic alliance and psychotherapy outcome and (b) the effects of the temporary weakening of the therapeutic alliance and temporary symptomatic relapse on therapeutic outcome and process. Two hundred thirty-nine clients were included in the study, and the assessment instruments were the CORE Outcome Measure and the short version of the Working Alliance Inventory. In addition to good outcome of psychotherapy and maintenance of therapeutic change after treatment, the results also demonstrated the significance of different aspects of the therapeutic alliance as predictors of the therapeutic outcome and process.


Exploring the international uptake of the "F-words in childhood disability": A citation analysis.
The "F-words in childhood disability" (function, family, fitness, fun, friends, and future) were introduced in a concept paper in 2012 entitled, "The F-words in childhood disability: I swear this is how we should think!". The "F-words" are grounded in, and aim to operationalize, the World Health Organization's (World Health Organization, 2001) International Classification of Functioning, Disability and Health (ICF) framework. A citation analysis was conducted to explore the extent of research uptake of the "F-words" concepts. Three databases-Google Scholar, Wiley Online, and Web of Science-were searched from July 2012 to December 2018 for sources that cited the original F-words paper. Dates of publication and countries of first authors were extracted from all cited articles, and a taxonomy was developed to categorize the type of usage. The search yielded 157 sources from 26 countries, and the number of citations has continued to increase since the paper's publication. Sources were placed into three categories: cited/referenced (n = 109; i.e., the paper was simply cited), integrated/informed (n = 36; i.e., the F-words were stated within the text), and non-English (n = 12). Of the 36 integrated/informed sources, 34 (94.4%) applied the F-words to the ICF framework and five themes emerged with respect to the use of the F-words: (a) support of a holistic approach to childhood disability, (b) association of the F-words to physical activity and rehabilitation, (c) application and measurement of quality of life, (d) F-words research team-related papers, and (e) "other" category. This citation analysis shows that the F-words are mainly being used to operationalize the ICF, support a holistic approach to childhood disability, and inform physical activity and rehabilitation-based interventions. These perspectives will play an important role in informing the next steps with respect to moving the F-words into research and practice.


Application of Wireless Contralateral Routing of Signal Technology in Unilateral Cochlear Implant Users with Bilateral Profound Hearing Loss.
The aim of the study was to determine if contralateral routing of signal (CROS) technology results in improved hearing outcomes in unilateral cochlear implant (CI) patients and provides similar gains in speech perception in noise to traditional monaural listeners (MLs). The study is a prospective, within-subject repeated-measures experiment. Adult, English-speaking patients with bilateral severe-profound sensorineural hearing loss using an Advanced Bionics CI (n = 12) in one ear were enrolled for the study. Hearing performance in the monaural listening condition (CI only) was compared with the CROS-aided (unilateral CI + CROS) condition. Participants were tested for speech-in-noise performance using the Bamford-Kowal-Bench Speech-in-Noise™ test materials in the speech front/noise front (0 degrees/0 degrees azimuth), speech front/noise back (0 degrees/180 degrees azimuth), speech deaf ear/noise monaural ear (90 degrees/270 degrees azimuth), and speech monaural ear/noise deaf ear (90 degrees/270 degrees azimuth) configurations. Localization error was assessed using three custom stimuli consisting of 1/3 octave narrowband noises centered at 500 and 4000 Hz and a broadband speech stimulus. Localization stimuli were presented at random in the front hemifield by 19 speakers spatially separated by 10 degrees. Outcomes were compared with a previously described group of traditional MLs in the CROS-aided condition (normal hearing ear + CROS). All participants were tested acutely with no adaptation to the CROS device. Statistical analyses were performed using Wilcoxon signed rank tests for nonparametric data and paired sample. Statistical significance was set to p < 0.00625 after Bonferroni adjustment for eight tests. Significant benefit was observed from unaided to the CI + CROS-aided condition for listening in noise across most listening conditions with the greatest benefit observed in the speech deaf ear/noise monaural ear (90 degrees/270 degrees azimuth) condition (p < 0.0005). When compared with traditional MLs, no significant difference in decibel gain from the unaided to CROS-aided conditions was observed between participant groups. There was no improvement in localization ability in the CROS-aided condition for either participant group and no significant difference in performance between traditional MLs and unilateral CI listeners. These findings support that unilateral CI users are capable of achieving similar gains in speech perception to that of traditional MLs with wireless CROS. These results indicate that the use of wireless CROS stimulation in unilateral CI recipients provides increased benefit and an additional rehabilitative option for this population when bilateral implantation is not possible. The results suggest that noninvasive CROS solutions can successfully rehabilitate certain monaural listening deficits, provide improved hearing outcomes, and expand the reach of treatment in this population.


Isolation, characterization, and expression of cDNAs encoding murine alpha-mannosidase II, a Golgi enzyme that controls conversion of high mannose to complex N-glycans.
Golgi alpha-mannosidase II (GlcNAc transferase I-dependent alpha 1,3[alpha 1,6] mannosidase, EC 18.104.22.168) catalyzes the final hydrolytic step in the N-glycan maturation pathway acting as the committed step in the conversion of high mannose to complex type structures. We have isolated overlapping clones from a murine cDNA library encoding the full length alpha-mannosidase II open reading frame and most of the 5' and 3' untranslated region. The coding sequence predicts a type II transmembrane protein with a short cytoplasmic tail (five amino acids), a single transmembrane domain (21 amino acids), and a large COOH-terminal catalytic domain (1,124 amino acids). This domain organization which is shared with the Golgi glycosyl-transferases suggests that the common structural motifs may have a functional role in Golgi enzyme function or localization. Three sets of polyadenylated clones were isolated extending 3' beyond the open reading frame by as much as 2,543 bp. Northern blots suggest that these polyadenylated clones totaling 6.1 kb in length correspond to minor message species smaller than the full length message. The largest and predominant message on Northern blots (7.5 kb) presumably extends another approximately 1.4-kb downstream beyond the longest of the isolated clones. Transient expression of the alpha-mannosidase II cDNA in COS cells resulted in 8-12-fold overexpression of enzyme activity, and the appearance of cross-reactive material in a perinuclear membrane array consistent with a Golgi localization. A region within the catalytic domain of the alpha-mannosidase II open reading frame bears a strong similarity to a corresponding sequence in the rat liver endoplasmic reticulum alpha-mannosidase and the vacuolar alpha-mannosidase of Saccharomyces cerevisiae. Partial human alpha-mannosidase II cDNA clones were also isolated and the gene was localized to human chromosome 5.


White matter integrity deficits in prefrontal-amygdala pathways in Williams syndrome.
Williams syndrome is a neurodevelopmental disorder associated with significant non-social fears. Consistent with this elevated non-social fear, individuals with Williams syndrome have an abnormally elevated amygdala response when viewing threatening non-social stimuli. In typically-developing individuals, amygdala activity is inhibited through dense, reciprocal white matter connections with the prefrontal cortex. Neuroimaging studies suggest a functional uncoupling of normal prefrontal-amygdala inhibition in individuals with Williams syndrome, which might underlie both the extreme amygdala activity and non-social fears. This functional uncoupling might be caused by structural deficits in underlying white matter pathways; however, prefrontal-amygdala white matter deficits have yet to be explored in Williams syndrome. We used diffusion tensor imaging to investigate prefrontal-amygdala white matter integrity differences in individuals with Williams syndrome and typically-developing controls with high levels of non-social fear. White matter pathways between the amygdala and several prefrontal regions were isolated using probabilistic tractography. Within each pathway, we tested for between-group differences in three measures of white matter integrity: fractional anisotropy (FA), radial diffusivity (RD), and parallel diffusivity (λ(1)). Individuals with Williams syndrome had lower FA, compared to controls, in several of the prefrontal-amygdala pathways investigated, indicating a reduction in white matter integrity. Lower FA in Williams syndrome was explained by significantly higher RD, with no differences in λ(1), suggestive of lower fiber density or axon myelination in prefrontal-amygdala pathways. These results suggest that deficits in the structural integrity of prefrontal-amygdala white matter pathways might underlie the increased amygdala activity and extreme non-social fears observed in Williams syndrome.


miR394 and LCR are involved in Arabidopsis salt and drought stress responses in an abscisic acid-dependent manner.
MicroRNAs (miRNAs) are a class of short, endogenous non-coding small RNAs that have ability to base pair with their target mRNAs to induce their degradation in plants. miR394a/b are conserved small RNAs and its target gene LCR (LEAF CURLING RESPONSIVENESS) encodes an F-box protein (SKP1-Cullin/CDC53-F-box) but whether miR394a/b and its target gene LCR are involved in regulation of plant response to abscisic acid (ABA) and abiotic stresses is unknown. Mature miR394 and precursor miR394a/b are shown to be slightly induced by ABA. By contrast, LCR expression is depressed by ABA. Analysis of LCR and its promoter (pLCR::GUS) revealed that LCR is expressed at all development stages. MIR394a/b over-expression (35S::MIR394a/b) and lcr (LCR loss of function) mutant plants are hypersensitive to salt stress, but LCR over-expressing (35S::m5LCR) plants display the salt-tolerant phenotype. Both 35S::MIR394a/b and lcr plants are highly tolerant to severe drought stress compared with wild-type, but 35S::m5LCR plants are susceptible to water deficiency. Over-expression of MIR394a/b led to ABA hypersensitivity and ABA-associated phenotypes, whereas 35S::m5LCR plants show ABA resistance phenotypes. Moreover, 35S::MIR394a/b plants accumulated higher levels of ABA-induced hydrogen peroxide and superoxide anion radicals than wild-type and 35S::m5LCR plants. Expressions of ABA- and stress-responsive genes, ABI3, ABI4, ABI5, ABF3, and ABF4 are up-regulated in MIR394a/b over-expressing plants but down-regulated in 35S::m5LCR plants. Over-expression of MIR394a in abi4-1 or abi5-1 background resulted in loss of ABA-sensitivity in 35S::MIR394a plants. The silencing of LCR mRNA by miR394 is essential to maintain a certain phenotype favorable for the adaptive response to abiotic stresses. The contrasting phenotypes of salt and drought responses may be mediated by a functional balance between miR394 and LCR. If the balance is perturbed in case of the abiotic stress, an identical phenotype related to the stress response occurs, resulting in either ABA sensitive or insensitive response. Thus, miR394-regulated LCR abundance may allow plants to fine-tune their responses to ABA and abiotic stress.


Prevalence and treatment pattern of Parkinson's disease dementia in Korea.
The aim of the present study was to investigate the point prevalence of dementia and mild cognitive impairment (MCI) in patients with Parkinson's disease (PD). A total of 1200 patients with PD from 12 hospitals were included in the study. All patients were grouped into normal cognition, MCI and dementia subgroups. General cognitive status and dementia severity were assessed by the Korean version of the Mini-Mental State Examination, Clinical Dementia Rating and Global Deterioration Scale, and parkinsonian motor status was assessed by the Hoehn and Yahr staging score. Associated sleep behaviors and other medical conditions were checked. Prescribing patterns of antidementia medications were analyzed. Cognitive impairment was frequent in patients with PD; MCI was found in 38.9% of patients, whereas dementia was in 38.3% of patients. The prevalence of cognitive impairment increased with increasing age and longer disease duration, and the symptoms of postural instability and symptoms mimicking rapid eye movement sleep behavior disorder were associated with cognitive impairment. Many dementia patients (95.2%) and 23.6% of MCI patients were treated with antidementia drugs, with rivastigmine the most frequently used. The point prevalence of cognitive impairment in patients with PD was 77.2%. Cognitive impairment was associated with age, disease duration and specific parkinsonian motor/non-motor symptoms. Over 90% of the patients with dementia were treated with antidementia medication, and rivastigmine was the most frequently used for the management of dementia.


Factors Affecting the Independence Level of 4-6-Year-Old Children with Cerebral Palsy in Activities of Daily Living.
Enhancing the independence of children with cerebral palsy in their daily activities can significantly alleviate caregiver stress and challenges, thereby improving the quality of life for caregivers.. This study aimed to identify the influential factors in the independence level of children with CP in Activities of Daily Living (ADL) (self-care) and Instrumental Activities of Daily Living (IADL) (home participation). In this cross-sectional study, 116 children with different types of CP (61 boys and 55 girls) in the 4-6 age range and their parents were non-randomly selected through convenience sampling. The Iranian-Children Participation Questionnaire was used to measure the children's independence level in self-care activities and home participation. Several instruments, along with a demographic questionnaire, were used to assess personal factors, such as the Gross Motor Function Classification System, Manual Ability Classification System, Communication Function Classification System, SPARCLE (for determining children's cognitive level), and Eating and Drinking Ability Classification System. Eventually, the collected data were analyzed using stepwise linear regression.. The results showed that the level of Gross Motor Function Classification System (GMFCS) and Communication Function Classification System (CFCS) and the child's age had the most correlation with the independence level in self-care activities. Moreover, GMFCS, Manual Ability Classification System (MACS), cognitive level, and child's age were most associated with home participation. Personal factors are more effective than environmental factors in determining the independence of children with CP.


Biomarkers in autism spectrum disorder: the old and the new.
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with onset during early childhood and typically a life-long course. The majority of ASD cases stems from complex, 'multiple-hit', oligogenic/polygenic underpinnings involving several loci and possibly gene-environment interactions. These multiple layers of complexity spur interest into the identification of biomarkers able to define biologically homogeneous subgroups, predict autism risk prior to the onset of behavioural abnormalities, aid early diagnoses, predict the developmental trajectory of ASD children, predict response to treatment and identify children at risk for severe adverse reactions to psychoactive drugs. The present paper reviews (a) similarities and differences between the concepts of 'biomarker' and 'endophenotype', (b) established biomarkers and endophenotypes in autism research (biochemical, morphological, hormonal, immunological, neurophysiological and neuroanatomical, neuropsychological, behavioural), (c) -omics approaches towards the discovery of novel biomarker panels for ASD, (d) bioresource infrastructures and (e) data management for biomarker research in autism. Known biomarkers, such as abnormal blood levels of serotonin, oxytocin, melatonin, immune cytokines and lymphocyte subtypes, multiple neuropsychological, electrophysiological and brain imaging parameters, will eventually merge with novel biomarkers identified using unbiased genomic, epigenomic, transcriptomic, proteomic and metabolomic methods, to generate multimarker panels. Bioresource infrastructures, data management and data analysis using artificial intelligence networks will be instrumental in supporting efforts to identify these biomarker panels. Biomarker research has great heuristic potential in targeting autism diagnosis and treatment.


[A case-control study of the impact of tuberculosis on the quality of life of patients].
A prospective study was conducted on 72 patients of pulmonary tuberculosis (TB) and 201 healthy controls in a third level hospital. The HRQoL questionnaire (12-Item Short Form Health Survey, SF-12) was used to assess the QoL at the onset of treatment DOTS. Patients with TB had significantly lower mean scores than controls for overall QoL (51.1 +/- SD 22.6) versus 75.9 (+/- SD 17.6), p < 0.0001. The most affected domains were physical and psychological. Active TB patients shown difficulties in activities of daily living and alterations of the psychological state.


Impedance investigation of the highly efficient polymer solar cells with composite CuBr2/MoO3 hole transport layer.
Developing an air-stable, low-cost, non-toxic, and high-transparency charge buffer layer is a critical strategy to achieve the high photoelectric conversion efficiency of polymer photovoltaic cells. This paper reports the remarkable improvement of device performance by employing a combination of copper bromide (CuBr2) and molybdenum trioxide (MoO3) (CuBr2/MoO3) as the hole transport layer (HTL) of inverted-type polymer solar cells (PSCs). The bulk transport processes and resistive capacitance elements in the operating PTB7:PC71BM bulk heterojunction PSCs were characterized using impedance spectroscopy. The impedance response was modeled using two equivalent circuital models, which are the general transmission line circuit (GTLC) model and the electrochemical polarization model. The effective carrier lifetime, conductivity, and mobility for both devices were extracted from the models. The improved hole transport at the anode and the efficient electron transport blocking decreased interface recombination and contact resistance, resulting in improved power conversion efficiency (PCE) values ranging from 7.30% to 9.56%. These results suggest that quantitative interpretation and modeling of the impedance spectroscopy results provide an effective way to unravel the operating mechanism of photovoltaic devices.


Chlorogenic acid ameliorates memory loss and hippocampal cell death after transient global ischemia.
Chlorogenic acid (CGA) is known to have antioxidant potentials, yet the effect of CGA on brain ischemia has not been sufficiently understood. Brain ischemia such as transient global ischemia disrupts many areas of the brain of rats, including the hippocampus. Male Wistar rats were randomly assigned into five groups, that is, sham-operated (SO), bilateral common carotid occlusion (BCCO), and BCCO+ 15, 30, and 60 mg/kg bw CGA groups (CGA15, CGA30, and CGA60, respectively). Brain ischemia was induced in Wistar rats with BCCO for 20 min followed by intraperitoneal injection of CGA. The rats were examined for the spatial memory in a Morris water maze test on the 3rd day and were euthanized on the 10th day after BCCO. The total number of pyramidal cells was estimated, and the mRNA expressions of Bcl2, Bax, caspase-3, SOD2, SOD1, GPx, ET-1, eNOS, CD31, and VEGF-A were measured. The BCCO group spent less time and distance in the target quadrant than any other group in the spatial memory retention test. The CA1 pyramidal cell numbers in the BCCO and CGA15 groups were lower than in the CGA30 and CGA60 groups. The mRNA expressions of Bcl2, SOD2, and CD31 in the BCCO group were lower than in the CGA15, CGA30, and CGA60 groups. The ET-1 expression was higher in the BCCO and CGA15 groups than in the SO, CGA30, and CGA60 groups. CGA improves the spatial memory and prevents the CA1 pyramidal cell death after BCCO by increasing Bcl2, SOD2, and CD31 expressions and decreasing ET-1 expression.


Backstepping and sliding mode control hybridized for a prosthetic hand.
Open loop and force controllers are compared experimentally with three robust parallel force-velocity controllers that are developed for a prosthetic hand. Robust sliding mode, backstepping, and hybrid sliding mode-backstepping (HSMBS) parallel force-velocity controllers are tested by ten able-bodied subjects. Results obtained with a myoelectrically controlled prosthesis indicate that all three robust controllers offer a statistically significant improvement over linear hand prosthesis control schemes. The robust controllers enable the human operators to more easily manipulate a delicate object. Bench top experiments combined with quantitative and qualitative evaluations from ten test subjects reveal the HSMBS controller to be the best choice to improve control of powered prosthetic hands.


Interactions between Naegleria fowleri and Legionella pneumophila.
Using electron microscopy we documented some of the intracellular events that occur in Naegleria fowleri suspended in Page amoeba saline after ingestion of Legionella pneumophila. Photomicrographs showed intracellular vacuoles containing bacteria in the process of binary fission that was accompanied by alignment of mitochondria and ribosome-like structures along the vacuole membrane. Although these intracellular events are remarkably similar to that seen in Legionella replication within human monocytes, we could not demonstrate an increase in the number of bacteria by CFU or dark-field microscopy. However, when the Naegleria cells were allowed to ingest Legionella cells while suspended in amoeba culture medium, the number of bacteria increased, and this was contingent upon the presence of viable amoebae.


Small molecule angiotensin II type 2 receptor (AT₂R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats.
Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT₂R) for the relief of neuropathic pain. Adult male Sprague-Dawley (SD) rats received single intravenous (1-10 mg/kg) or oral (5-10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve. After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1 L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400 > EMA300 > EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats. The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.


Bone formation with discs or particles of natural coral skeleton plus polyglactin 910 mesh: histologic evaluation in rat calvaria.
Several procedures have been used to regenerate localized bone defects around dental implants or to increase bone volume at an implant site, including bone grafting, placement of barrier membranes, and use of bone graft substitutes. This study sought to determine whether the bone graft substitute natural coral skeleton (NCS), with or without a protective polymer mesh, enhances bone formation in rat critical size craniotomy defects. The control group (1) had unfilled defects, while the defects in the four experimental groups (six rats each) were treated with: (2) an NCS disc of the size of the defect; (3) NCS granules; (4) NCS granules covered by a polyglactin 910 mesh; and (5) polyglactin 910 mesh alone. Undecalcified histologic sections were assessed by histomorphometric measurements 28 days later. The three NCS groups showed improved bone formation, which was statistically significant in groups (2) (NCS disc) and (4) (NCS granules covered by polyglactin 910 mesh). Group 4 had more bone formation than all the other groups. Polyglactin 910 mesh alone (group 5) produced no greater bone formation than the unfilled control. It is concluded that the bone formation obtained with NCS granules is enhanced when the particles are retained at the site of the defect with a protective mesh.


A Screening Tool to Identify Spasticity in Need of Treatment.
To develop a clinically useful patient-reported screening tool for health care providers to identify patients with spasticity in need of treatment regardless of etiology. Eleven spasticity experts participated in a modified Delphi panel and reviewed and revised 2 iterations of a screening tool designed to identify spasticity symptoms and impact on daily function and sleep. Spasticity expert panelists evaluated items pooled from existing questionnaires to gain consensus on the screening tool content. The study also included cognitive interviews of 20 patients with varying spasticity etiologies to determine if the draft screening tool was understandable and relevant to patients with spasticity. The Delphi panel reached an initial consensus on 21 of 47 items for the screening tool and determined that the tool should have no more than 11 to 15 items and a 1-month recall period for symptom and impact items. After 2 rounds of review, 13 items were selected and modified by the expert panelists. Most patients (n = 16 [80%]) completed the cognitive interview and interpreted the items as intended. Through the use of a Delphi panel and patient interviews, a 13-item spasticity screening tool was developed that will be practical and easy to use in routine clinical practice.


Beyond the Peak - Tactile Temporal Discrimination Does Not Correlate with Individual Peak Frequencies in Somatosensory Cortex.
The human sensory systems constantly receive input from different stimuli. Whether these stimuli are integrated into a coherent percept or segregated and perceived as separate events, is critically determined by the temporal distance of the stimuli. This temporal distance has prompted the concept of temporal integration windows or perceptual cycles. Although this concept has gained considerable support, the neuronal correlates are still discussed. Studies suggested that neuronal oscillations might provide a neuronal basis for such perceptual cycles, i.e., the cycle lengths of alpha oscillations in visual cortex and beta oscillations in somatosensory cortex might determine the length of perceptual cycles. Specifically, recent studies reported that the peak frequency (the frequency with the highest spectral power) of alpha oscillations in visual cortex correlates with subjects' ability to discriminate two visual stimuli. In the present study, we investigated whether peak frequencies in somatosensory cortex might serve as the correlate of perceptual cycles in tactile discrimination. Despite several different approaches, we were unable to find a significant correlation between individual peak frequencies in the alpha- and beta-band and individual discrimination abilities. In addition, analysis of Bayes factor provided evidence that peak frequencies and discrimination thresholds are unrelated. The results suggest that perceptual cycles in the somatosensory domain are not necessarily to be found in the peak frequency, but in other frequencies. We argue that studies based solely on analysis of peak frequencies might thus miss relevant information.


Lung and chest wall mechanics in patients with acquired immunodeficiency syndrome and severe Pneumocystis carinii pneumonia.
The aim of this study was to assess the mechanical characteristics of the respiratory system in patients with acquired immune deficiency syndrome (AIDS) and acute respiratory distress syndrome (ARDS) caused by Pneumocystis carinii pneumonia (PCP). In 12 mechanically ventilated patients, total respiratory system mechanics was assessed using the technique of rapid airway occlusion during constant flow inflation, and was partitioned into lung and chest wall components using the oesophageal balloon technique. We measured interrupter resistance (Rint), which mainly reflects airway resistance, additional resistance (deltaR) due to viscoelastic behaviour and time constant inequalities, and static elastance (Est). In addition, the static inflation volume-pressure (V-P) curve was assessed. In eight patients, computed tomography scans were performed within 2 days of the assessment of respiratory mechanics. Compared to values reported in the literature for normal subjects, Est and deltaR were markedly increased in AIDS patients with PCP, whilst Rint exhibited a relatively smaller increase. These changes, which involved only the lung and airways, were mainly due to the reduction of ventilated lung units, but additional factors were involved to cause independent modifications of lung stiffness, airway calibre, and viscoelastic properties. The changes in Rint, deltaR, and Est were similar to those observed in other studies on patients with ARDS of different aetiologies. At variance with common observations in the latter patients, none of the AIDS patients with PCP exhibited an inflection point on the static inflation V-P curve, suggesting little or no alveolar recruitment during lung inflation. This finding could be related to the distinctive histopathology of Pneumocystis carinii pneumonia. Indeed, computed tomography revealed homogeneous diffuse interstitial and alveolar infiltration rather than the dense, dependent opacities observed in other studies on acute respiratory distress syndrome of different aetiologies.


PAF binding to a single receptor in corneal epithelium plasma membrane.
To study the binding characteristics and the expression of platelet-activating factor receptors (PAF-R) in corneal epithelium to elucidate the site of action of PAF. Binding of [3H]PAF was investigated in subcellular fractions of the epithelia of bovine corneas and in membranes from cultured rabbit corneal epithelial cells. Dose-response inhibition curves of [3H]PAF-specific binding were generated using increasing concentrations of several PAF-R antagonists. RNA from rabbit corneal epithelial cells was probed for PAF-R expression by reverse transcription-polymerase chain reaction (RT-PCR) with specifically designed degenerated primers. Scatchard analysis showed a high-affinity binding site in bovine and rabbit corneal epithelium. The dissociation constant (Kd) and the maximum binding sites (Bmax) in a bovine membrane preparation and similar rabbit fraction were 0.77+/-0.03 nM and 180+/-21 femtomoles/mg protein and 4.3 nM and 1.3 picomoles/mg protein, respectively. Specific PAF-binding sites were found in bovine preparations enriched in plasma membranes with a Kd = 69.6 pM and Bmax = 80 femtomoles/mg protein; no specific binding was found in nuclei or microsomal fractions. RT-PCR of rabbit corneal epithelium generated a single product of the predicted size (478 bp). The deduced amino acid sequence of the purified PCR product was 87% homologous to human PAF-R. The hetrazepines BN 50727 and BN 50730 and the PAF structural analogues CV 3988 and CV 6209 competitively inhibited [3H]PAF binding to corneal epithelium with similar potency. WEB 2086 BS was two orders of magnitude less active in antagonizing PAF binding. Corneal epithelium contains a single population of receptors localized in the plasma membrane. PAF antagonists exert their actions by blocking this PAF-R. The partial sequence deduced in rabbit corneal PAF-R show a higher homology to the human PAF-R.


Outcomes of a structured inter-professional ultrasound guided vascular access workshop: a program evaluation report analyzing structure, participation and satisfaction.
This article was migrated. The article was marked as recommended. Ultrasound-guided vascular access procedures are increasingly performed, particularly in the hospital setting, by a variety of health care professionals. Adequate teaching of the skills required for these procedures is important for all clinicians conducting these procedures. We created an inter-disciplinary workshop to teach these skills to anyone interested at our institution. This was a half-day workshop that combined pre-workshop teaching materials with didactic lectures and simulation based learning, which was followed by deliberate practice. Enrollment was on a first come first serve basis. We retrospectively reviewed the enrollment and performance of this workshop at our institution over 18 months. The workshop proved equally attractive to trainees and staff. Participants spanned a variety of healthcare disciplines, with the most common being intensive care (27%) and diagnostic imaging (23%). Participants indicated high satisfaction with the workshop, with a mean score of 4.7 on a 5-point Likert scale given to measure overall satisfaction. A long-term impact survey indicated regular use of skills learned in the workshop and a perceived improvement in clinical practice. This study helps demonstrate the efficacy of this inter-professional workshop structure in helping multidisciplinary healthcare professionals acquire unique skillsets for everyday clinical practice.


Wavelet based multiresolution expectation maximization image reconstruction algorithm for positron emission tomography.
Maximum Likelihood (ML) estimation based Expectation Maximization (EM) [IEEE Trans Med Imag, MI-1 (2) (1982) 113] reconstruction algorithm has shown to provide good quality reconstruction for positron emission tomography (PET). Our previous work [IEEE Trans Med Imag, 7(4) (1988) 273; Proc IEEE EMBS Conf, 20(2/6) (1998) 759] introduced the multigrid (MG) and multiresolution (MR) concept for PET image reconstruction using EM. This work transforms the MGEM and MREM algorithm to a Wavelet based Multiresolution EM (WMREM) algorithm by extending the concept of switching resolutions in both image and data spaces. The MR data space is generated by performing a 2D-wavelet transform on the acquired tube data that is used to reconstruct images at different spatial resolutions. Wavelet transform is used for MR reconstruction as well as adapted in the criterion for switching resolution levels. The advantage of the wavelet transform is that it provides very good frequency and spatial (time) localization and allows the use of these coarse resolution data spaces in the EM estimation process. The MR algorithm recovers low-frequency components of the reconstructed image at coarser resolutions in fewer iterations, reducing the number of iterations required at finer resolution to recover high-frequency components. This paper also presents the design of customized biorthogonal wavelet filters using the lifting method that are used for data decomposition and image reconstruction and compares them to other commonly known wavelets.


Altered myosin light-chain phosphorylation in resting platelets from premenopausal women with diabetes.
Gender-related differences in the rate of coronary heart disease (CHD) between premenopausal women and men are greatly diminished in women with diabetes mellitus (DM). This may be related, in part, to altered platelet function in premenopausal diabetic women. Hyperglycemia may contribute to increase platelet aggregation through enhancement of oxidative stress, increased nitric oxide (NO) destruction, and increased myosin light-chain (MLC) phosphorylation (MLC-P). Accordingly, we investigated functional and biochemical parameters of platelet function in 32 women (14 premenopausal and postmenopausal controls and 18 age-matched patients with DM); platelet MLC-P and cyclic guanosine monophosphate ([cGMP] reflecting NO) were assessed. Other parameters including age, body mass index (BMI), waist to hip ratio, total cholesterol, and platelet count were not different in the control and diabetic groups. In the premenopausal women, baseline MLC-P was lower in women with DM versus the control group (P = .02). GMP levels were similar in the two groups at baseline (22.7 +/- 3 fmol/mL in controls v 23.1 +/- 3 fmol/mL in diabetic subjects) and 3 minutes after insulin exposure. The platelet content of ascorbic acid (AA), an endogenous antioxidant compound, was elevated in premenopausal women with DM (P = .02) compared with the controls. Despite similar estradiol (beta,E2) levels, platelets of premenopausal women with DM exhibited reduced MLC-P. This paradoxic difference may be accounted for by an increase in platelet AA, as this suggests decreased platelet oxidative stress in this patient population. These observations indicate that an altered redox state and associated MLC-P of platelets does not contribute to enhanced platelet aggregation and CHD in premenopausal women with DM.


Update: Noncongenital Zika Virus Disease Cases - 50 U.S. States and the District of Columbia, 2016.
Zika virus is a flavivirus primarily transmitted to humans by Aedes aegypti mosquitoes (1). Zika virus infections also have been documented through intrauterine transmission resulting in congenital infection; intrapartum transmission from a viremic mother to her newborn; sexual transmission; blood transfusion; and laboratory exposure (1-3). Most Zika virus infections are asymptomatic or result in mild clinical illness, characterized by acute onset of fever, maculopapular rash, arthralgia, or nonpurulent conjunctivitis; Guillain-Barré syndrome, meningoencephalitis, and severe thrombocytopenia rarely have been associated with Zika virus infection (1). However, congenital Zika virus infection can result in fetal loss, microcephaly, and other birth defects (1,2). In 2016, a total of 5,168 noncongenital Zika virus disease cases were reported from U.S. states and the District of Columbia. Most cases (4,897, 95%) were in travelers returning from Zika virus-affected areas. A total of 224 (4%) cases were acquired through presumed local mosquitoborne transmission, and 47 (1%) were acquired by other routes. It is important that providers in the United States continue to test symptomatic patients who live in or recently traveled to areas with ongoing Zika virus transmission or had unprotected sex with someone who lives in or traveled to those areas. All pregnant women and their partners should take measures to prevent Zika virus infection during pregnancy. A list of affected areas and specific recommendations on how to prevent Zika virus infection during pregnancy are available at https://www.cdc.gov/pregnancy/zika/protect-yourself.html.


Value of the stroke 1-2-0 prehospital stroke education system: the experience of a general practitioner team.
Stroke is one of the leading causes of death worldwide, especially in developing countries. In China, there is an urgent need to educate people about stroke awareness and the importance of using emergency medical services (EMS) quickly after a stroke has occurred. We sought to explore the effects of the Stroke 1-2-0 Prehospital Stroke Education System based on the experience of a general practitioner team. We prospectively enrolled 119 community general practitioners to be trained in the procedures advocated by the Stroke 1-2-0 Prehospital Stroke Education System. The training content included early detection of ischemic stroke, first aid for stroke, and intravenous thrombolysis; The effects of the training were later evaluated via a before-and-after comparison. The 119 enrolled physicians formed a Stroke 1-2-0 lecturer group and taught stroke knowledge to community residents. The group remained active for 6 months, during which the medical treatment data of stroke patients (i.e., stroke onset time, prehospital delay, whether an ambulance was called, and whether thrombolytic therapy was performed) in each of 5 jurisdictions were recorded for the month before (January 2021) and that after (August 2021) the 6-month community education program. Finally, the effects of the community education program were evaluated. The participants' understanding of intravenous thrombolysis in the treatment of acute ischemic stroke improved significantly after the training as compared with their earlier understanding (96% vs. 78.99%; P < .001), and their understanding of the time window for intravenous thrombolysis increased from 26.05% before to 72% (P < .001) after the training. Most of the participants (90% vs. 67.23%; P < .001) said that they would immediately call the 120 emergency number of China's emergency phone system if they encountered individuals who appeared to be victims of acute stroke. A total of 82 stroke patients were seen before and 67 after the community education program. As for the use of the emergency call system, more patients with stroke activated that system after the program versus before (21.95% vs. 37.31%; P = .04). The 3-hour arrival rate after the program was nearly three times higher than that before the program (62.69% vs. 19.51%; P < .001). Also, regarding receiving thrombolysis after the occurrence of a stroke, the program triggered a substantial increase compared with the total earlier (19.4% vs. 6.1%; P = .013). We found that the Stroke 1-2-0 Prehospital Stroke Education System significantly improved community residents' knowledge regarding stroke.


Coordination of wing and whole-body development at developmental milestones ensures robustness against environmental and physiological perturbations.
Development produces correctly patterned tissues under a wide range of conditions that alter the rate of development in the whole body. We propose two hypotheses through which tissue patterning could be coordinated with whole-body development to generate this robustness. Our first hypothesis states that tissue patterning is tightly coordinated with whole-body development over time. The second hypothesis is that tissue patterning aligns at developmental milestones. To distinguish between our two hypotheses, we developed a staging scheme for the wing imaginal discs of Drosophila larvae using the expression of canonical patterning genes, linking our scheme to three whole-body developmental events: moulting, larval wandering and pupariation. We used our scheme to explore how the progression of pattern changes when developmental time is altered either by changing temperature or by altering the timing of hormone synthesis that drives developmental progression. We found the expression pattern in the wing disc always aligned at moulting and pupariation, indicating that these key developmental events represent milestones. Between these milestones, the progression of pattern showed greater variability in response to changes in temperature and alterations in physiology. Furthermore, our data showed that discs from wandering larvae showed greater variability in patterning stage. Thus for wing disc patterning, wandering does not appear to be a developmental milestone. Our findings reveal that tissue patterning remains robust against environmental and physiological perturbations by aligning at developmental milestones. Furthermore, our work provides an important glimpse into how the development of individual tissues is coordinated with the body as a whole.