Causes of Exocrine Pancreatic Insufficiency Other Than Chronic Pancreatitis.
Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malnutrition, results from primary pancreatic disease or is secondary to impaired exocrine pancreatic function. Although chronic pancreatitis is the most common cause of EPI, several additional causes exist. These include pancreatic tumors, pancreatic resection procedures, and cystic fibrosis. Other diseases and conditions, such as diabetes mellitus, celiac disease, inflammatory bowel disease, and advanced patient age, have also been shown to be associated with EPI, but the exact etiology of EPI has not been clearly elucidated in these cases. The causes of EPI can be divided into loss of pancreatic parenchyma, inhibition or inactivation of pancreatic secretion, and postcibal pancreatic asynchrony. Pancreatic enzyme replacement therapy (PERT) is indicated for the conditions described above presenting with clinically clear steatorrhea, weight loss, or symptoms related to maldigestion and malabsorption. This review summarizes the current literature concerning those etiologies of EPI less common than chronic pancreatitis, the pathophysiology of the mechanisms of EPI associated with each diagnosis, and treatment recommendations.


Prostate Cancer Germline Variations and Implications for Screening and Treatment.
Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1, BRCA2, MMR, HOXB13, CHEK2, and NBS1 as conferring moderate risks, with some leading to a more aggressive disease behavior. Considering this knowledge, several research strategies have been developed to determine whether targeted prostate screening using genetic information can overcome the limitations of population-based prostate-specific antigen (PSA) screening. Germline DNA-repair mutations are more frequent in men with metastatic disease than previously thought, and these patients have a more favorable response to therapy with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Genomic information is a practical tool that has the potential to enable the concept of precision medicine to become a reality in all steps of PCa patient care.


Nutritional care; do process and structure indicators influence malnutrition prevalence over time?
To date, no information is available about the effect of structural and process factors of nutritional care on the prevalence of malnutrition over time in the long-term care sector. This study analyzes the trend of malnutrition prevalence rates between 2007 and 2011 in the long-term care sector, and the related effects of(1) process indicators such as nutritional screening and treatment and 2) structural indicators (guideline, protocol or nutritional screening policy). From 2007 to 2011, the Dutch National Prevalence Measurement of Care Problems (LPZ) was performed in Dutch long-term care organizations using a standardized questionnaire involving measurements at institutional, ward and resident level. The data were analyzed by mixed-linear regression for longitudinal data. Presence of malnutrition was assessed by BMI, undesired weight loss and nutritional intake. Seventy-four care homes were included (26,101 residents). The malnutrition prevalence trend significantly decreased (P < 0.001) from 26% to 18% from 2007 to 2011. In the final model of the mixed effects analysis only the interacted process indicators nutritional screening and oral nutritional supplementation (ONS) were significant in influencing malnutrition prevalence rates over time. Structural indicators had no impact on the malnutrition prevalence over time. In conclusion, over time a lower prevalence of malnutrition is associated with a higher degree of nutritional screening. As might be expected, a higher prevalence of malnutrition is associated with higher use of ONS. Structural nutritional screening is an important intervention to tackle the problem of malnutrition in the long term care sector.


[Technical means of the new generation used for autonomous supply of the mobile medical formations of RF Armed Forces medical service with oxygen].
According to the tasks and initiative of RF MD Main Military Medical Headquarters the series of research and experimental designers' work was performed. It allowed determining the main principles of anew conception of supplying the mobile medical formations with oxygen and creating the necessary technical means for its realization, i.e. for autonomous supply of medical service troop link with oxygen. The most optimal schemes of new technical mean application to obtain the oxygen at the stages of medical evacuation were worked out. The oxygen supply system based on the use of created technical means of its production is easily adapted to dynamically changing problems of medical service. The state trials have confirmed the prospects of the conception proposed.


Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases.
Human Dickkopf-1 (Dkk-1) upregulates a noncanonical Wnt/JNK pathway, resulting in osteoclast stimulation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) of cancer cells. Ace-1-Dkk-1, a canine prostate cancer (PCa) cell line overexpressing Dkk-1, was used to investigate Wnt signaling pathways in PCa tumor growth. SP600125, a JNK inhibitor, was used to examine whether it would decrease tumor growth and bone tumor phenotype in canine PCa cells in vitro and in vivo. Ace-1-VectorYFP-Luc and Ace-1-Dkk-1YFP-Luc cells were transplanted subcutaneously, while Ace-1-Dkk-1YFP-Luc was transplanted intratibially into nude mice. The effects of Dkk-1 and SP600125 on cell proliferation, in vivo tumor growth, and bone tumor phenotype were investigated. The mRNA expression levels of Wnt/JNK-related genes were measured using RT-qPCR. Dkk-1 significantly increased the mRNA expression of Wnt/JNK-signaling-related genes. SP600125 significantly upregulated the mRNA expression of osteoblast differentiation genes and downregulated osteoclastic-bone-lysis-related genes in vitro. SP600125 significantly decreased tumor volume and induced spindle-shaped tumor cells in vivo. Mice bearing intratibial tumors had increased radiographic density of the intramedullary new bone, large foci of osteolysis, and increased cortical lysis with abundant periosteal new bone formation. Finally, SP600125 has the potential to serve as an alternative adjuvant therapy in some early-stage PCa patients, especially those with high Dkk-1 expression.


Imitation of body postures and hand movements in children with specific language impairment.
Within the domain-general theory of language impairment, this study examined body posture and hand movement imitation in children with specific language impairment (SLI) and in their age-matched peers. Participants included 40 children with SLI (5 years 3 months to 6 years 10 months of age) and 40 children with typical language development (5 years 3 months to 6 years 7 months of age). Five tests were used to examine imitation and its underlying cognitive and motor skills such as kinesthesia, working memory, and gross motor coordination. It was hypothesized that children with SLI show a weakness in imitation of body postures and that this deficit is not equally influenced by the underlying cognitive and motor skills. There was a group effect in each cognitive and motor task, but only gross motor coordination proved to be a strong predictor of imitation in children with SLI. In contrast, hand movement imitation was strongly predicted by performance in the Kinesthesia task in typically developing children. Thus, the findings show not only that children with SLI performed more poorly on the imitation tasks than their typically developing peers but also that the groups' performances showed qualitative differences. The results of the current study provide additional support to the view that the weaknesses in children with SLI are not limited to the verbal domain.


[Effect of Kegel exercise to prevent urinary and fecal incontinence in antenatal and postnatal women: systematic review].
The aim of this study was to review the literature to determine whether intensive pelvic floor muscle training during pregnancy and after delivery could prevent urinary and fecal incontinence. Randomized controlled trials (RCT) of low-risk obstetric populations who had done Kegel exercise during pregnancy and after delivery met the inclusion criteria. Articles published between 1966 and 2012 from periodicals indexed in Ovid Medline, Embase, Scopus, KoreaMed, NDSL and other databases were selected, using the following keywords: 'Kegel, pelvic floor exercise'. The Cochrane's Risk of Bias was applied to assess the internal validity of the RCT. Fourteen selected studies were analyzed by meta-analysis using RevMan 5.1. Fourteen RCTs with high methodological quality, involving 6,454 women were included. They indicated that Kegel exercise significantly reduced the development of urinary and fecal incontinence from pregnancy to postpartum. Also, there was low clinical heterogeneity. There is some evidence that for antenatal and postnatal women, Kegel exercise can prevent urinary and fecal incontinence. Therefore, a priority task is to develop standardized Kegel exercise programs for Korean pregnant and postpartum women and make efficient use of these programs.


The hexamer structure of Rift Valley fever virus nucleoprotein suggests a mechanism for its assembly into ribonucleoprotein complexes.
Rift Valley fever virus (RVFV), a Phlebovirus with a genome consisting of three single-stranded RNA segments, is spread by infected mosquitoes and causes large viral outbreaks in Africa. RVFV encodes a nucleoprotein (N) that encapsidates the viral RNA. The N protein is the major component of the ribonucleoprotein complex and is also required for genomic RNA replication and transcription by the viral polymerase. Here we present the 1.6 Å crystal structure of the RVFV N protein in hexameric form. The ring-shaped hexamers form a functional RNA binding site, as assessed by mutagenesis experiments. Electron microscopy (EM) demonstrates that N in complex with RNA also forms rings in solution, and a single-particle EM reconstruction of a hexameric N-RNA complex is consistent with the crystallographic N hexamers. The ring-like organization of the hexamers in the crystal is stabilized by circular interactions of the N terminus of RVFV N, which forms an extended arm that binds to a hydrophobic pocket in the core domain of an adjacent subunit. The conformation of the N-terminal arm differs from that seen in a previous crystal structure of RVFV, in which it was bound to the hydrophobic pocket in its own core domain. The switch from an intra- to an inter-molecular interaction mode of the N-terminal arm may be a general principle that underlies multimerization and RNA encapsidation by N proteins from Bunyaviridae. Furthermore, slight structural adjustments of the N-terminal arm would allow RVFV N to form smaller or larger ring-shaped oligomers and potentially even a multimer with a super-helical subunit arrangement. Thus, the interaction mode between subunits seen in the crystal structure would allow the formation of filamentous ribonucleocapsids in vivo. Both the RNA binding cleft and the multimerization site of the N protein are promising targets for the development of antiviral drugs.


Limitations of Rapid Diagnostic Testing in Patients with Suspected Malaria: A Diagnostic Accuracy Evaluation from Swaziland, a Low-Endemicity Country Aiming for Malaria Elimination.
The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized. Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards. To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors. From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing. Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively. After exclusion of samples with parasite densities <100/μL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%. Deletions of pfhrp2 were not detected. False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation. In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects. The PPV was also low, requiring further investigation. A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.


[Clinical analysis for oral mucosal disease in 21 972 cases].
To analyze the incidence and distribution of oral mucosal diseases in Hunan Province and provide reference for prevention and treatment. Methods: The clinical data for all patients, who were treated in Xiangya Hospital of Central South University from April 2013 to March 2017, were collected. After screening, weighing and classifying, sex and age distribution for the disease was analyzed. Results: The female with the age between 40 to 49 were in the majority among 21 972 patients. The ratio between men to women was 1:1.05. According to the classification of diseases, the most common diseases were as follows: recurrent aphthous ulcer (27.17%), burning mouth syndrome (15.72%), oral submucous fibrosis (14.75%), oral lichen planus (10.38%), oral leukoplakia (4.21%), traumatic ulceration (4.14%), chronic cheilitis (3.47%), oral fungal infection (3.26%), and atrophic glossitis (2.74%). Recurrent oral ulcer (28.65%), burning mouth syndrome (23.70%) and oral lichen planus (13.31%) were the most common 3 kinds of oral mucosal diseases during females in Hunan. Oral submucous fibrosis was the most common oral mucosal disease among males in Hunan (28.56%). Conclusion: Recurrent oral ulcer, burning mouth syndrome and oral lichen planus are very popular in women in Hunan Province, and oral submucous fibrosis is the most common disease in male in this region. It shows a high trend of incidence in the surrounding provinces.


Ambulatory care for traumatic brain injuries in the US, 1995-1997.
The burden of mild traumatic brain injury (TBI) is not well understood at the national level, but hospitalization rates show a decline over time. This paper describes ambulatory care for TBI patients at physician offices, hospital outpatient departments, and emergency departments (EDs) in comparison with non-TBI visits for the US during 1995-1997. An estimated 1.4 million visits for TBI were made each year for an average annual rate of 5.4/1,000 population. A decline in annual visit rate was noted during 1995-1997. Visit rates were higher for those aged 0 -14 and 75 and older. Falls (44%) and motor vehicles (28%) were the primary injury causes. Rural-urban differences were found, also in comparison with non-TBI. In 23% of visits to EDs, a CT scan was ordered or performed and in 33%, a mental status exam was conducted. Further investigations are warranted to describe ambulatory care for TBI in more detail, particularly in light of a decline in hospitalization rates.


Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat.
The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with "physiological" QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes.


Protective effects of chronic resveratrol treatment on vascular inflammatory injury in steptozotocin-induced type 2 diabetic rats: role of NF-kappa B signaling.
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of macrovascular disease. Epidemiological studies suggest that plant polyphenol resveratrol (REV) is associated with reduced risk of cardiovascular diseases. Since chronic inflammatory and endotheliar cell activation play a critical role in vascular aging and atherogenesis, we evaluated whether REV can inhibit inflammatory-induced vascular injury in T2DM. We found that REV (50 mg/kg/d) can regulate glucose and lipid metabolism, improve insulin resistance and vascular permeability, and protect against the foam cells and cholesterol crystals formation in arterial vessel walls of T2DM rats. The protective effects of REV were consistent with the decrease in nuclear translocation of nuclear factor kappa B (NF-kappa B) and there down-regulation of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levers in blood and tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) expressions in vascular wall. In addition, REV (10 and 100 nmol/L) treatment protected cultured endothelial cells against increases in the expression of TNF-α, ICAM-1, and MCP-1 mRNA and protein induced by high glucose via inhibiting nuclear translocation of NF-kappa B p65. The specific NF-kappa B inhibitor pyrrolidine dithiocarbamate- (PDTC-) or small interfering RNA directed against NF-kappa B p65-mediated downregulation of NF-kappa B p65 was further enhanced by REV (100 nmol/L) in the human endothelial cell line EZ.hy926. In conclusion, these observations suggest that chronic treatment of T2DM rats with REV attenuates the inflammatory injury of the vascular wall and the effects are associated with down-regulation of the NF-kappa B signal pathway.


Shikonin Inhibits Cholangiocarcinoma Cell Line QBC939 by Regulating Apoptosis, Proliferation, and Invasion.
This study was designed to clarify whether Shikonin causes proliferation, apoptosis, and invasion in cholangiocarcinoma cells and to investigate the mechanism of action. QBC939 cells were cultured with different doses of Shikonin, and then 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium assay was used to detect cell viability. Apoptosis of cells was detected using flow cytometry with Annexin V/propidium iodide (PI) assay after being stained with Hoechst 33242. The role of Shikonin on the invasive and metastasis ability was detected using Transwell invasion assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression of caspase-3, caspase-8, epidermal growth factor receptor (EGFR), and matrix metalloproteinase (MMP)-9. Shikonin inhibited proliferation and invasive ability of QBC939 cells in a dose-dependent manner; at the same time, apoptosis of cells was also observed in a concentration-dependent fashion. Moreover, Annexin V/PI assay and Transwell invasion assay results indicated that Shikonin induced apoptosis and invasion inhibitory probably due to upregulation of caspase-3 and caspase-8 expression and downregulation of MMP-9 and EGFR expression in a concentration-dependent fashion. Shikonin could enhance apoptosis and inhibit proliferation and invasion of QBC939 cells; such biological behaviors mainly occurred via upregulating the expression of caspase-3 and caspase-8 and downregulating the expression of MMP-9 and EGFR.


ICOHR: intelligent computer based oral health record.
The majority of work on computer use in the dental field has focused on non-clinical practice management information needs. Very few computer-based dental information systems provide management support of the clinical care process, particularly with respect to quality management. Traditional quality assurance methods rely on the paper record and provide only retrospective analysis. Today, proactive quality management initiatives are on the rise. Computer-based dental information systems are being integrated into the care environment, actively providing decision support as patient care is being delivered. These new systems emphasize assessment and improvement of patient care at the time of treatment, thus building internal quality management into the caregiving process. The integration of real time quality management and patient care will be expedited by the introduction of an information system architecture that emulates the gathering and storage of clinical care data currently provided by the paper record. As a proposed solution to the problems associated with existing dental record systems, the computer-based patient record has emerged as a possible alternative to the paper dental record. The Institute of Medicine (IOM) recently conducted a study on improving the efficiency and accuracy of patient record keeping. As a result of this study, the IOM advocates the development and implementation of computer-based patient records as the standard for all patient care records. This project represents the ongoing efforts of The University of Iowa College of Dentistry's collaboration with the University of Uppsala Data Center, Uppsala, Sweden, on a computer-based patient dental record model. ICOHR (Intelligent Computer Based Oral Health Record) is an information system which brings together five important parts of the patient's dental record: medical and dental history; oral status; treatment planning; progress notes; and a Patient Care Database, generated from their clinical care information (the database is also stored in the ICOHR). ICOHR is designed to be integrated into a traditional practice management system. The components of the ICOHR system support the use of various types of clinical care quality management tools, including medical alerts, clinical care guidelines, care modifiers, and diagnostic decision support. Data input is multimodal, so the user may use both voice recognition and direct input with a digitizer board to enter information into the database. ICOHR is designed to be integrated into the clinical environment in an ergonomic fashion in order to facilitate the unobtrusive and efficient acquisition of patient information. ICOHR is currently under clinical evaluation in both private practice and institutional environments. The private practice is a large general dentistry practice with over twenty sites scattered throughout a large metropolitan area. The institutional settings are a College of Dentistry and a Hospital Dentistry program. The evaluations have started in two of the sites and the other site will be phased in during the next six months. Our demonstration of the system will include both prepared presentations of the system's various functions and provide an opportunity for hands-on use of the system for interested attendees.


Baseline Serum Vitamin A and D Levels Determine Benefit of Oral Vitamin A&D Supplements to Humoral Immune Responses Following Pediatric Influenza Vaccination.
Maximizing vaccine efficacy is critical, but previous research has failed to provide a one-size-fits-all solution. Although vitamin A and vitamin D supplementation studies have been designed to improve vaccine efficacy, experimental results have been inconclusive. Information is urgently needed to explain study discrepancies and to provide guidance for the future use of vitamin supplements at the time of vaccination. We conducted a randomized, blinded, placebo-controlled study of influenza virus vaccination and vitamin supplementation among 2 to 8 (inclusive) year old children over three seasons, including 2015-2016 (n = 9), 2016-2017 (n = 44), and 2017-2018 (n = 26). Baseline measurements of vitamins A and D were obtained from all participants. Measurements were of serum retinol, retinol-binding protein (RBP, a surrogate for retinol), and 25-hydroxyvitamin D (25(OH)D). Participants were stratified into two groups based on high and low incoming levels of RBP. Children received two doses of the seasonal influenza virus vaccine on days 0 and 28, either with an oral vitamin supplement (termed A&D; 20,000 IU retinyl palmitate and 2000 IU cholecalciferol) or a matched placebo. Hemagglutination inhibition (HAI) antibody responses were evaluated toward all four components of the influenza virus vaccines on days 0, 28, and 56. Our primary data were from season 2016-2017, as enrollment was highest in this season and all children exhibited homogeneous and negative HAI responses toward the Phuket vaccine at study entry. Responses among children who entered the study with insufficient or deficient levels of RBP and 25(OH)D benefited from the A&D supplement (p < 0.001 for the day 28 Phuket response), whereas responses among children with replete levels of RBP and 25(OH)D at baseline were unaffected or weakened (p = 0.02 for the day 28 Phuket response). High baseline RBP levels associated with high HAI titers, particularly for children in the placebo group (baseline RBP correlated positively with Phuket HAI titers on day 28, r = 0.6, p = 0.003). In contrast, high baseline 25(OH)D levels associated with weak HAI titers, particularly for children in the A&D group (baseline 25(OH)D correlated negatively with Phuket HAI titers on day 28, r = -0.5, p = 0.02). Overall, our study demonstrates that vitamin A&D supplementation can improve immune responses to vaccines when children are vitamin A and D-insufficient at baseline. Results provide guidance for the appropriate use of vitamins A and D in future clinical vaccine studies.


Insecticidal Effect of Solenostemma argel Extracts Against Culex pipiens.
Of the various plant extracts from 10 plant species tested against larvae of Culex pipiens in the laboratory, only extracts from Solenostemma argel exhibited larvicidal activity. A chloroform leaf extract of S. argel exhibited relatively high activity with a lethal concentration causing 50% mortality (LC50) of 15.89 ppm, while chloroform and ethyl acetate extracts of S. argel fruits were 19.70 and 19.52 ppm, respectively. The chloroform fruit extract at 10 ppm reduced the hatchability of Cx. pipiens eggs by 20%, whereas the chloroform leaf extract was found to be less effective (5% reduction). At 10 ppm, adult emergence was reduced by 84% and 75% for chloroform and ethyl acetate extracts of fruits, respectively. Metamorphosis of larvae exposed to chloroform fruit extract (10 ppm) was extended to 15 days, as compared to 10 days for control larvae. It took 12 days at 1 ppm, and 15 days at 6 and 10 ppm for chloroform fruit extract-treated embryos to develop into adult mosquito while it took 10 days in the control treatment. However, 100% toxicity was observed in the embryos of zebrafish, Danio rerio, treated with the ethyl acetate fruit extracts (LC50 of 20 ppm and LC100 of 40 ppm) and chloroform leaf extract (LC50 of 30 ppm and LC100 of 60 ppm). These findings emphasize the need to further isolate the bioactive molecules in S. argel crude extracts that may still be mosquitocidal but produce no, or minimal, adverse effects on nontarget organisms such as zebrafish.


Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses.
Breast cancer is a highly heterogeneous disease. Although differences between intrinsic breast cancer subtypes have been well studied, heterogeneity within each subtype, especially luminal-A cancers, requires further interrogation to personalize disease management. Here, we applied well-characterized and cancer-associated heterocellular signatures representing stem, mesenchymal, stromal, immune, and epithelial cell types to breast cancer. This analysis stratified the luminal-A breast cancer samples into five subtypes with a majority of them enriched for a subtype (stem-like) that has increased stem and stromal cell gene signatures, representing potential luminal progenitor origin. The enrichment of immune checkpoint genes and other immune cell types in two (including stem-like) of the five heterocellular subtypes of luminal-A tumors suggest their potential response to immunotherapy. These immune-enriched subtypes of luminal-A tumors (containing only estrogen receptor positive samples) showed good or intermediate prognosis along with the two other differentiated subtypes as assessed using recurrence-free and distant metastasis-free patient survival outcomes. On the other hand, a partially differentiated subtype of luminal-A breast cancer with transit-amplifying colon-crypt characteristics showed poor prognosis. Furthermore, published luminal-A subtypes associated with specific somatic copy number alterations and mutations shared similar cellular and mutational characteristics to colorectal cancer subtypes where the heterocellular signatures were derived. These heterocellular subtypes reveal transcriptome and cell-type based heterogeneity of luminal-A and other breast cancer subtypes that may be useful for additional understanding of the cancer type and potential patient stratification and personalized medicine.


The inflammatory marker suPAR after cardiac arrest.
Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long-term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response. This pilot study aimed at investigating suPAR levels in relation to outcome after CA and mild induced hypothermia. suPAR levels were measured at 6, 36, and 72 hours in patients treated with hypothermia after CA. suPAR levels were analyzed in relation to survival after 6 months. Receiver operating characteristic curve (ROC)-analyses were performed, and area under the curve (AUC) was calculated. Time to return of spontaneous circulation (ROSC) was correlated to suPAR levels. Fifty-five patients (40 male, median 65 years) were included, and 33 (60%) were alive after 6 months. The suPAR levels were significantly higher in nonsurviving patients compared with survivors at 6 and 36 hours (p=0.006 and 0.034 respectively), but not at 72 hours. The suPAR levels increased from 6 to 72 hours (p<0.0001). Time to ROSC correlated positively with suPAR levels at 6 hours (p=0.003) but not at 36 and 72 hours. ROC analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups was substantial, reducing the prognostic value. There was a significant increase in suPAR levels during the first 72 hours after CA.


The Wisdom Project: virtual education in primary care.
This article examines the development of the Wisdom Project, a pilot for the teaching of informatics to primary health care professionals, using an original educational model based on e-mail and Web pages. The article begins by placing the development of the Wisdom Project in the context of changes in medical education and training. The aims and objectives of Wisdom are outlined, and the methodologies for setting up and evaluating the project are described. The article then presents the results of the evaluation, including the identification of significant improvements in knowledge of CD ROMs (P = 0.01), e-mail (P = 0.03), Medline (P = 0.02), operating systems (P = 0.02), Web browsers (P = 0.003) and word processing (P = 0.03). Improvements in evidence-based practice (EBP) did not reach significance. Finally, a number of conclusions are presented, considering the lessons learnt for the future development of such projects.


Ruthenium complexes as antimicrobial agents.
One of the major advances in medical science has been the development of antimicrobials; however, a consequence of their widespread use has been the emergence of drug-resistant populations of microorganisms. There is clearly a need for the development of new antimicrobials--but more importantly, there is the need for the development of new classes of antimicrobials, rather than drugs based upon analogues of known scaffolds. Due to the success of the platinum anticancer agents, there has been considerable interest in the development of therapeutic agents based upon other transition metals--and in particular ruthenium(II/III) complexes, due to their well known interaction with DNA. There have been many studies of the anticancer properties and cellular localisation of a range of ruthenium complexes in eukaryotic cells over the last decade. However, only very recently has there been significant interest in their antimicrobial properties. This review highlights the types of ruthenium complexes that have exhibited significant antimicrobial activity and discusses the relationship between chemical structure and biological processing--including site(s) of intracellular accumulation--of the ruthenium complexes in both bacterial and eukaryotic cells.


Transferring cognitive tasks between brain imaging modalities: implications for task design and results interpretation in FMRI studies.
As cognitive neuroscience methods develop, established experimental tasks are used with emerging brain imaging modalities. Here transferring a paradigm (the visual oddball task) with a long history of behavioral and electroencephalography (EEG) experiments to a functional magnetic resonance imaging (fMRI) experiment is considered. The aims of this paper are to briefly describe fMRI and when its use is appropriate in cognitive neuroscience; illustrate how task design can influence the results of an fMRI experiment, particularly when that task is borrowed from another imaging modality; explain the practical aspects of performing an fMRI experiment. It is demonstrated that manipulating the task demands in the visual oddball task results in different patterns of blood oxygen level dependent (BOLD) activation. The nature of the fMRI BOLD measure means that many brain regions are found to be active in a particular task. Determining the functions of these areas of activation is very much dependent on task design and analysis. The complex nature of many fMRI tasks means that the details of the task and its requirements need careful consideration when interpreting data. The data show that this is particularly important in those tasks relying on a motor response as well as cognitive elements and that covert and overt responses should be considered where possible. Furthermore, the data show that transferring an EEG paradigm to an fMRI experiment needs careful consideration and it cannot be assumed that the same paradigm will work equally well across imaging modalities. It is therefore recommended that the design of an fMRI study is pilot tested behaviorally to establish the effects of interest and then pilot tested in the fMRI environment to ensure appropriate design, implementation and analysis for the effects of interest.


Hb Helsinki: a variant with a high oxygen affinity and a substitution at a 2,3-DPG binding site (beta82[EF6] Lys replaced by Met).
A new haemoglobin, Hb Helsinki, in which beta 82-Lys (EF6) is replaced by Met, was found in a Finnish family. It was associated with familial erythrocytosis, and the oxygen affinity of the blood was higher than normal. The oxygen equilibrium curves of purified Hb Helsinki and HbA from the same haemolysate have been determined under vaious conditions. "Stripped' Hb Helsinki was found to show normal cooperativity, slightly low oxygen affinity and a reduced Bohr effect at physiological pH. However, the organic phosphates, 2,3-diphosphoglycerate (2,3-DPG) and inositol hexaphosphate (IHP) had a very small effect on Hb Helsinki, and the 2,3-DPG binding constant of deoxygenated Hb Helsinki is close to that of oxyhaemoglobin A. Thus, the replacement of Lys by Met at position 82 dramatically changes the nature of the central cavity of the tetramer and the effect of 2,3-DPG on the respiratory function of the molecule.


Considerations in use of microspheres for flow measurements in anesthetized rat.
The results of single injections of different doses of microspheres (60,000, 100,000, and 375,000) demonstrated a significant reduction in measured heart and kidney blood flows as a function of the number of microspheres injected. Measured flow to other organs was unaffected by a single injection of these doses of microspheres. The injection of microspheres at a faster rate (0.8 ml/min microsphere injection; 1.0 ml/min flush) resulted in higher calculated heart flow when compared with the slow rate (0.2 ml/min microsphere injection; 0.25 ml/min flush). A significant decrease (approximately 21%) in measured blood flow to the right side of the brain that was observed in all the groups is due to the occlusion of the right carotid artery by the cannulation procedure. Intra-aortic injection of microspheres resulted in reduced measured brain blood flow when compared with intraventricular injections. Accurate and reliable heart and brain blood flows were not obtained with intra-aortic injection of microspheres. However, intra-aortic injection of microspheres does provide accurate and reliable flow measurements for more distal organs.


[Personal studies on the current spectrum of pathogenic bacteria in otitis externa and chronic otitis media].
From 1985-1987 smears (for Gram staining) and swabs (for culture and antibiogram) were done in 294 patients suffering from chronic otitis media, and in 67 cases of external otitis. Besides the comparison of these two procedures, the microbial spectrum in case of external otitis and chronic otitis media is considered and compared to the literature. Pseudomonas aeruginosa and Staphylococcus aureus are the most frequent pathogens. Often gram-positive rod-shaped bacilli were also found, the pathogenicity of which has been underestimated in the literature up to now. The anaerobes did not play an important role in our patients. The value of gram staining (immediate information and safer antibiotic therapy) is pointed out on the basis of the reported results.


CYP8A1 gene polymorphisms and left main coronary artery disease.
Left main (LM) disease is rare but the most hazardous phenotype of coronary artery disease (CAD). Thus, early detection of participants at high risk of developing left main coronary heart disease (LM-CAD) is crucial. The aim of this study was to identify gene polymorphisms which could distinguish participants who are at high risk of developing LM-CAD. Such a candidate can be the prostaglandin I(2) or prostacyclin (PGI(2)) gene. The DNA of 254 participants (151 participants with angiographically documented LM-CAD and 103 healthy controls) was analyzed for the frequency of C1117A polymorphism in the gene coding CYP8A1. The genotype distribution was different between the LM-CAD and the control group. Particularly, the CC genotype of CYP8A1 was commoner in the LM-CAD than in the healthy group (P < .001). Allele frequencies were also differently distributed between the 2 groups. C allele frequency was higher in LM-CAD group (P = .016). The CC genotype of C1117A polymorphism is associated with higher risk of LM-CAD, which prospectively may have potential importance in screening high-risk populations. However, further investigations in larger populations are required to confirm these findings.


All-Solid-State Garnet-Based Lithium Batteries at Work-In Operando TEM Investigations of Delithiation/Lithiation Process and Capacity Degradation Mechanism.
Li7 La3 Zr2 O12 (LLZO)-based all-solid-state Li batteries (SSLBs) are very attractive next-generation energy storage devices owing to their potential for achieving enhanced safety and improved energy density. However, the rigid nature of the ceramics challenges the SSLB fabrication and the afterward interfacial stability during electrochemical cycling. Here, a promising LLZO-based SSLB with a high areal capacity and stable cycle performance over 100 cycles is demonstrated. In operando transmission electron microscopy (TEM) is used for successfully demonstrating and investigating the delithiation/lithiation process and understanding the capacity degradation mechanism of the SSLB on an atomic scale. Other than the interfacial delamination between LLZO and LiCoO2 (LCO) owing to the stress evolvement during electrochemical cycling, oxygen deficiency of LCO not only causes microcrack formation in LCO but also partially decomposes LCO into metallic Co and is suggested to contribute to the capacity degradation based on the atomic-scale insights. When discharging the SSLB to a voltage of ≈1.2 versus Li/Li+ , severe capacity fading from the irreversible decomposition of LCO into metallic Co and Li2 O is observed under in operando TEM. These observations reveal the capacity degradation mechanisms of the LLZO-based SSLB, which provides important information for future LLZO-based SSLB developments.


Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients.
Current studies suggest that short-term exposure of parathyroid glands to fibroblast growth factor 23 (FGF23) reduces parathyroid hormone secretion. However, patients with chronic kidney disease (CKD) develop secondary hyperparathyroidism despite high levels of serum FGF23, indicating a parathyroid FGF23 'resistance'. Here we analyzed the expression of the FGF23 receptors Klotho and FGF receptor 1 (FGFR1) in 88 hyperplastic parathyroid glands from 31 patients with CKD (including 21 renal allograft recipients), and their regulation in isolated bovine and human hyperplastic parathyroid cells. Glandular expression was variable, yet the Klotho and FGFR1 mRNA levels declined in parallel with the decreasing glomerular filtration rate, significantly decreasing over CKD stages. We found no association between the expression of Klotho, FGFR1, and the proliferation marker Ki67. In vitro treatment of bovine cells with FGF23 or calcium reduced the Klotho level, whereas active vitamin D(3) compounds increased its expression. Phosphate and parathyroid hormone had no effect. Treatment had less impact on Klotho in cultured human cells than in the bovine healthy cell model, whereas FGFR1 expression was induced in the hyperplastic cells. Thus parathyroid Klotho and FGFR1 decrease with declining renal function, possibly because of alterations in mineral metabolism related to the failing kidney. This could explain the observed parathyroid resistance to FGF23 in late CKD.


Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism.
Secondary hyperparathyroidism is a common complication in patients with stage 5 chronic kidney disease (CKD), accelerated by hyperphosphatemia. Fibroblast growth factor 23 (FGF-23), a phosphorus-regulating protein, has key roles in several phosphate-wasting disorders. The aim of this study is to examine the association of advanced secondary hyperparathyroidism with circulating FGF-23 levels. Fifteen patients with marked secondary hyperparathyroidism (parathyroid hormone [PTH], 990 +/- 118 pg/mL [ng/L]) were enrolled. All underwent parathyroidectomy with forearm autotransplantation (PTX), and their FGF-23 levels were measured before and after PTX (days 1, 3, 7, and 10) by means of sandwich enzyme-linked immunosorbent assay. Preoperative FGF-23 levels correlated positively with phosphorus (P < 0.05), calcium-phosphorus product (Ca x P; P < 0.0005), and PTH values (P < 0.05). Serum FGF-23 levels decreased time dependently after PTX (P < 0.0005). Both serum phosphorus and Ca x P values decreased similarly after PTX ( P = 0.0001). Furthermore, FGF-23 levels days 1 and 3 correlated linearly with serum phosphorus (P < 0.05; P < 0.005, respectively) and Ca x P values (P < 0.01; P < 0.0001, respectively). FGF-23 levels correlate positively with serum phosphorus, Ca x P, and PTH values in patients with advanced secondary hyperparathyroidism. Complete ablation of progressive parathyroid glands reduces circulating FGF-23 levels, simultaneously decreasing serum phosphorus and Ca x P values. These findings suggest that hyperplastic parathyroid glands, together with hyperphosphatemia, affect abnormal FGF-23 metabolism in patients with stage 5 CKD with advanced secondary hyperparathyroidism.


Trace element changes in sclerotic heart valves from patients are expressed in their blood.
The pathogenesis of some heart diseases has been associated with changes in the balance of certain trace elements. However, whether blood trace element changes exist that are related to changes in the cardiovascular system are, in most cases, unknown. In this study, blood trace element levels were analysed in 46 patients with non-rheumatic aortic valve sclerosis that were previously shown to have a disturbed trace element balance in their valve tissue, including 11/15 elements. Results showed significant changes of blood levels of 8/15 trace elements in these patients when compared with blood levels in 46 healthy controls. Of these elements, Cd and Mg were the only elements that increased in both blood and valves. Cu and Se were increased in blood but decreased in valves, whereas Co and Zn were decreased in blood but increased in valves. Several elements (As, Ca, Fe, Pb, and V) were unchanged in blood although changed in valves. Although Mn and Hg showed changes in blood, this was not evident in the valves. Al and Ag were the only elements that did not change in both blood and valves. Significant covariation in blood and valve levels was only observed for Al and Pb. The recorded pattern of trace element changes indicates a complex competition/exchange between body compartments in this disease, where the increased blood Cu/Zn ratio suggests an ongoing infectious/inflammatory process.


The collisional limit: an important consideration for membrane-associated enzymes and receptors.
Because of the proximity of many bound receptors or enzymes, a membrane surface may become uniformly reactive so that every collision between a ligand and the membrane particle results in a binding or catalytic event. At this limit (the collisional limit), the reaction rate depends on membrane particle (cell) concentration and is independent of receptor concentration. Many receptor systems display properties that satisfy the requirements of a collisionally limited reaction. These include the presence of many receptors per cell. The filling of only a few of these receptors often generates the maximum cellular response, and the remaining receptors have been referred to as spare receptors. However, many receptors are needed to produce the collisional limit, and spare receptors may represent nature's evolution toward a reaction that provides the maximum rate as well as the maximum sensitivity to a ligand. Since receptors or enzymes provided on small membrane fragments will not function at the collisional limit, properties of reconstituted enzymes or receptors may not be extrapolated to the physiological situation. The use of normal bimolecular kinetic or equilibrium equations is inappropriate for reactions limited by collision and can give unusual results that lead to inappropriate conclusions. Determination of whether the collisional limit applies to a membrane-bound system is important for understanding its properties and those of the physiological circumstance.


The associations between pain intensity, psychosocial variables, and pain duration/recurrence in a large sample of persons with nonspecific spinal pain.
The aims of this study were: (1) to describe and compare pain intensity, disability, cognitive, physical, behavioral, and environmental variables in 4 predefined categories, on the basis of duration and recurrence of nonspecific spinal pain; and (2) to compare disability, cognitive, physical, behavioral, and environmental variables in these 4 predefined categories, after controlling for pain intensity. Postal questionnaires were sent to a random sample of 5000 persons, aged 20 to 50 years, in Sweden. The response rate was 39%. One thousand and twenty-four participants reporting spinal pain were divided into 4 predefined categories (n=100, 215, 172, and 537) based on duration and recurrence of pain. Multivariate analyses of variance and covariance were performed to investigate differences between the 4 pain duration/recurrence groups. The first analyses revealed that the 4 pain duration/recurrence groups differed in pain intensity, disability, 7 cognitive variables, and perceived social support. After controlling for pain intensity, small but significant group differences were identified in depression, catastrophizing, pain expectations, and perceived social support. Higher levels of catastrophizing and pain expectations and lower levels of perceived social support were seen in groups with longer duration of pain. After controlling for pain intensity, categories based on pain duration/recurrence differed in 3 cognitive variables and perceived social support. Pain expectations, catastrophizing and perceived social support were related to longer duration of pain. Between-group differences were small and pain duration/recurrence was not an important explanatory factor.


Biliary cast syndrome following liver transplantation: Predictive factors and clinical outcomes.
Biliary cast syndrome (BCS), the presence of biliary casts and debris causing biliary obstruction, occurs in 4%-18% of orthotopic liver transplant (OLT) recipients. Potential consequences include cholangitis and graft damage or loss. Limited data exist regarding the etiology and outcomes of BCS. The purpose of this study was to evaluate donor and recipient risk factors and determine the impact of BCS. A retrospective review of 355 OLT cases identified 9 BCS patients (2.5%) diagnosed by cholangiography. Twenty-six matched controls were also identified. The warm ischemic time was significantly longer in BCS patients. Other recipient and donor preoperative and intraoperative characteristics, including the donor risk index, revealed no significant differences. Overall patient survival showed a trend toward worse outcomes at 6, 12, and 18 months and end of follow-up in the BCS group. Overall graft survival was also worse in the BCS group at all time periods, with statistical significance demonstrated at 18 months and end of follow-up. The number of therapeutic biliary procedures and hospital readmissions was significantly higher in the BCS group. Twenty-two percent of the BCS patients required repeat OLT versus none of the control patients. In conclusion, BCS is an uncommon complication of OLT. Except for a longer warm ischemic time, recipient and donor factors did not predict the occurrence of BCS. BCS patients showed a significantly worse graft survival, as well as a trend toward worse patient survival. Given the negative impact of BCS on liver transplant outcomes, further studies appear justified.


Inbreeding in the greater white-toothed shrew, Crocidura russula.
We combined mark-and-recapture studies with genetic techniques of parentage assignment to evaluate the interactions between mating, dispersal, and inbreeding, in a free-ranging population of Crocidura russula. We found a pattern of limited and female-biased dispersal, followed by random mating within individual neighborhoods. This results in significant inbreeding at the population level: mating among relatives occurs more often than random, and F(IT) analyses reveal significant deficits in heterozygotes. However, related mating partners were not less fecund, and inbred offspring had no lower lifetime reproductive output. Power analyses show these negative results to be quite robust. Absence of phenotypic evidence of inbreeding depression might result from a history of purging: local populations are small and undergo disequilibrium gene dynamics. Dispersal is likely caused by local saturation and (re)colonization of empty breeding sites, rather than inbreeding avoidance.


Proteolysis of endomorphin-1 by brain synaptic membrane-associated peptidases.
The biotransformation of endomorphin-1 (EM-1) by brain synaptic membranes has been studied. Peptide fragments of EM-1 that were formed during incubation with membrane preparations in vitro were isolated by High-performance liquid chromatography (HPLC) and characterized using determination of amino acid composition. At pH 7.4, two degradation products, EM-1(1-3) and EM-1(1-2), were identified. EM-1 was degraded 77.5% at 30 min incubation with synaptic membranes. The time course of the experiments and the effect of carboxypeptidase inhibitor (CPI) demonstrated that the proteolysis reaction involves the participation of carboxypeptidase activity.


Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes.
Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged β cells resemble those preceding the development of diabetes, the contribution of β cell aging and senescence remains unclear. We generated a β cell senescence signature and found that insulin resistance accelerates β cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and β cell function while decreasing expression of markers of aging, senescence, and senescence-associated secretory profile (SASP). Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.


Enhanced Sampling of Phase Transitions in Coarse-Grained Lipid Bilayers.
Freezing and melting of dipalmitoylphosphatidylcholine (DPPC) bilayers are simulated in both the explicit (Wet) and implicit solvent (Dry) coarse-grained MARTINI force fields with enhanced sampling, via the isobaric, molecular dynamics version of the generalized replica exchange method (gREM). Phase transitions are described with the entropic viewpoint, based upon the statistical temperature as a function of enthalpy, TS(H) = 1/(dS(H)/dH), where S is the configurational entropy. Bilayer thickness, area per lipid, and the second-rank order parameter (P2) are calculated vs temperature in the transition range. In a 32-lipid Wet MARTINI system, transitions in the lipid and water subsystems are strongly coupled, giving rise to considerable structure in TS(H) and the need to specify the state of the water when reporting a lipid transition temperature. For gel lipid + liquid water → fluid lipid + liquid water, we find 292.4 K. The small system is influenced by finite-size effects, but it is argued that the entropic approach is well suited to revealing them, which will be particularly relevant for studies of finite nanosystems where there is no thermodynamic limit. In a 390-lipid Dry MARTINI system, two-dimensional analogues of the topographies of coexisting states ("subphases") seen in pure fluids are found. They are not seen in the 32-lipid Wet or Dry system, but the Dry lipids show a new type of state with gel in one leaflet and tilted gel in the other. Dry bilayer transition temperatures are 333.3 K (390 lipids) and 338 K (32 lipids), indicating that the 32-lipid system is not too small for a qualitative study of the transition. Physical arguments are given for Dry lipid system size dependence and for the difference between Wet and Dry systems.


Importance of isolation and biotypization of Gardnerella vaginalis in diagnosis of bacterial vaginosis.
The natural habitat of Gardnerella vaginalis is a vagina since it could be located among 69% of women who have no signs of vaginal infection and in the vagina of as many as 13.5% girls. G. vaginalis is almost certainly identified among women diagnosed with bacterial vaginosis as well as in the urethra of their sexual partner. The increase in prevalence and concentration of G. vaginalis among patients diagnosed with this syndrome confirms that G. vaginalis plays a significant role in its pathogenesis. In our research, based on Amsel criteria for three or more clinical signs of bacterial vaginosis, it was diagnosed in 20.5% of women with subjective problems of vaginal infection, and in 48.80% of women with subjective symptoms characteristic of this disease. G. vaginalis was isolated from vaginal secretion of women without clinical signs characteristic of bacterial vaginosis. In 2.58% of cases it was solitary, while in 1.28% it was found in combination with other aerobic and anaerobic bacteria and, in 1.28% women combined with Candida albicans. The isolation of G. vaginalis was significantly increased (p<0.05) in the group of women with clinical signs of bacterial vaginosis in comparison to the group of women without these signs. Frequent recurrence of bacterial vaginosis, which is found in 20-30% of women within a three months treatment, is explained as reinfection with other biotype of G. vaginalis, different from a source biotype or as a consequence of wrong treatment. Following Piot biotype scheme, biotypes 2., 3. and 7. G. vaginalis are significantly more often isolated from women who suffer from bacterial vaginosis. Biotype 7. G. vaginalis, isolated from the group of women without clinical signs of bacterial vaginosis, accounted for 2.58% cases. Following Benit biotype scheme, biotypes IVa, IVc and IIc were identified in 12.90% cases, while biotypes IIIa, IIa, Ia, IVb, IIb were found in 6.45% cases. Lipase-positive isolates of G. vaginalis were significantly more frequently accompanied by the syndrome of bacterial vaginosis.


[Functional deterioration secondary to hospitalization for an acute disease in the elderly. An analysis of its incidence and the associated risk factors].
To determine the incidence of functional impairment at hospital admission and after hospital discharge, and to identify those factors that could be predictors of such impairment in a cohort of elderly people with high level of independence in the basic activities of daily living (BADL). Epidemiologic, longitudinal and prospective study. Acute unit in a geriatric department. The follow-up population was made up by 150 subjects older than 65 years, admitted on account of acute medical conditions from December, 15th, 1995, to December, 15th, 1996, who were independent for walking and independent or with slight dependence for BADL. STUDY PARAMETERS: All patients were evaluated at 48 hours after admission and one month after discharge by means of a protocol including sociodemographic, clinical, attending, functional and mental parameters. The incidence of functional impairment at hospital admission was 70.66%; such impairment persisted one month after discharge in 29.3% of subjects. The most involved activities related to motility. In the analysis of crude data, the following parameters showed association with functional impairment risk one month after discharge: female sex (OR: 2.5), sensorial organ pathology (OR: 2.6), hospital stay longer than 15 days (OR: 7.2), and Lawton Index score (3.8 +/- 2.6 in impaired patients vs. 4.9 +/- 2 in non-impaired patients; p < 0.01). Barthel Index score at admission lower than 60 (OR: 9.5), Cognitive Miniexam score lower than 28 (OR: 4.1), Informant Test score higher than 84 (OR: 2.5) and Geriatric Depression Scale score 9 (OR: 3.1). In the logistic regression model, the following parameters remained as predictors of impairment: sex (OR: 3.3), days of hospital stay (OR: 2.3) and Barthel Index score at admission (OR: 6.1) and Cognitive Miniexam score (OR: 2.7). For our population, sex, hospital stay days, functional impairment in Barthel Index at admission and Cognitive Miniexam score parameters seem to behave as independent variables that can predict functional impairment risk for BADL one month after discharge. These parameters could be useful to select groups of elderly people with impairment risk, who could benefit from specialized interventions leading to prevent/decrease functional impairment secondary to acute disease and hospitalization.


Reporting of informed consent, standard of care and post-trial obligations in global randomized intervention trials: a systematic survey of registered trials.
Ethical guidelines are designed to ensure benefits, protection and respect of participants in clinical research. Clinical trials must now be registered on open-access databases and provide details on ethical considerations. This systematic survey aimed to determine the extent to which recently registered clinical trials report the use of standard of care and post-trial obligations in trial registries, and whether trial characteristics vary according to setting. We selected global randomized trials registered on http://www.clinicaltrials.gov and http://www.controlled-trials.com. We searched for intervention trials of HIV/AIDS, malaria, and tuberculosis from 9 October 2004, the date of the most recent version of the Helsinki Declaration, to 10 April 2007. We collected data from 312 trials. Fifty-eight percent (58%, 95% CI = 53 to 64) of trial protocols report informed consent. Fifty-eight percent (58%, 95% CI = 53 to 64) of trials report active controls. Almost no trials (1%, 95% CI = 0.5 to 3) mention post-trial provisions. Most trials measure surrogate outcomes. Twenty percent (20%, 95% CI = 16 to 25) of trials measure patient-important outcomes, such as death; and the odds that these outcomes are in a low income country are five times greater than for a developed country (odds ratio (OR) 5.03, 95% CI = 2.70 to 9.35, p = < 0.001). Pharmaceutical companies are involved in 28% (CI = 23 to 33) of trials and measure surrogate outcomes more often than nonpharmaceutical companies (OR 2.45, 95% CI = 1.18 to 5.09, p = 0.31). We found a large discrepancy in the quality of reporting and approaches used in trials in developing settings compared to wealthier settings.


Current therapies and future perspectives in subacute sclerosing panencephalitis.
Subacute sclerosing panencephalitis is a progressive neurological disorder of children and young adults caused by a measles virus that became defective by persisting in the host. According to the results of clinical trials, antiviral and/or immunomodulatory therapy can slow the progression of the disease and improve life expectancy in patients. However, its long-term effects and eventual outcome remain debatable due to conflicting results and its lack of effect on the rapidly progressive form of the disease. Possible future therapies for subacute sclerosing panencephalitis are RNAi and antiapoptotic agents, which are currently in the hypothetical and experimental stages of research.


A Feed-Forward Circuit of Endogenous PGC-1α and Estrogen Related Receptor α Regulates the Neuronal Electron Transport Chain.
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a central regulator of cellular and mitochondrial metabolism. Cellular bioenergetics are critically important in "energy-guzzling" neurons, but the components and wiring of the transcriptional circuit through which PGC-1α regulates the neuronal electron transport chain have not been established. This information may be vital for restoring neuronal bioenergetics gene expression that is compromised during incipient Parkinson's neuropathology and in aging-dependent brain diseases. Here we delineate a neuronal transcriptional circuit controlled by endogenous PGC-1α. We show that a feed-forward circuit of endogenous neuronal PGC-1α and the orphan nuclear estrogen-related receptor α (ERRα) activates the nuclear-encoded mitochondrial electron transport chain. PGC-1α not only trans-activated expression of ERRα, but also coactivated ERRα target genes in complexes I, II, IV, and V of the neuronal electron transport chain via association with evolutionary conserved ERRα promoter binding motifs. Chemical activation of this transcriptional program induced transcription of the neuronal electron transport chain. These data highlight a neuronal transcriptional circuit regulated by PGC-1α that can be therapeutically targeted for Parkinson's and other neurodegenerative diseases.


Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain.
This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.


Expression of simian virus 40-rat preproinsulin recombinants in monkey kidney cells: use of preproinsulin RNA processing signals.
The complete rat preproinsulin gene I was cloned into a simian virus 30 (SV 40) vector. Most of the late region of the viral vector, including the SV40 intervening sequences (introns) and all of the major splice junctions, was deleted and replaced by the entire rat insulin gene. The recombinant molecules and a temperature-sensitive helper virus (tsA28) were inoculated into monkey kidney cultures. The formation of stable transcripts of the insulin insert was as efficient as the production of late SV40 mRNA. Analysis of these transcripts indicated that the rat preproinsulin gene nucleotide signals involved in RNA splicing and poly(A) addition were used. Examination of the 5' ends of the mRNAs showed several classes, one of which was the same size as the authentic rat insulinoma mRNA. This suggests that a portion of the transcripts may be initiated or processed faithfully, or both, at their 5' ends within rat insulin sequences. Significant quantities of a protein identified as rat proinsulin were synthesized. Detection of most of the proinsulin in the tissue culture medium suggests that this protein was secreted.


A bottom-up strategy toward a flexible vanadium dioxide/silicon nitride composite film with infrared sensing performance.
Vanadium dioxide (VO2) attracts great attention due to its well-known metal-to-insulator transition. However, traditional VO2 films grown on rigid substrates are inflexible, which limits their applications. In this work, we successfully prepared VO2/silicon nitride (VO2/SN) composite films by a simple template method. The VO2/SN film shows high flexibility, strong infrared absorption, and drastic resistance change (>103) induced by the phase transition. The application of the VO2/SN film is presented by infrared sensing, which shows a high responsivity (720 V W-1) and short response time (409 ms).


Overlapping cytotoxic T-lymphocyte and B-cell antigenic sites on the influenza virus H5 hemagglutinin.
To define the recognition site of cytotoxic T lymphocytes (CTLs) on influenza virus H5 hemagglutinin (HA), an H5 HA-specific CTL clone was examined for the ability to recognize monoclonal antibody-selected HA variants of influenza virus A/Turkey/Ontario/7732/66 (H5N9). On the basis of 51Cr release assays with the variants, a CTL epitope was located near residue 168 of H5 HA. To define the epitope more precisely, a series of overlapping peptides corresponding to this region was synthesized and tested for CTL recognition. The minimum peptide recognized by the CTL clone encompassed residues 158 to 169 of H5 HA. Relative to the H3 HA three-dimensional structure, this CTL epitope is located near the distal tip of the HA molecule, also known as a major B-cell epitope on H3 HA. A single mutation at residue 168 (Lys to Glu) in the H5 HA variants abolished CTL recognition; this same amino acid was shown previously to be critical for B-cell recognition (M. Philpott, C. Hioe, M. Sheerar, and V. S. Hinshaw, J. Virol. 64:2941-2947, 1990). Additionally, mutations within this region of the HA molecule were associated with attenuation of the highly virulent A/Turkey/Ontario/7732/66 (H5N9) (M. Philpott, B. C. Easterday, and V.S. Hinshaw, J. Virol. 63:3453-3458, 1989). When tested for recognition of other H5 viruses, the CTL clone recognized the HA of A/Turkey/Ireland/1378/83 (H5N8) but not that of A/Chicken/Pennsylvania/1370/83 (H5N2), even though these viruses contain identical HA amino acid 158-to-169 sequences. These results suggest that differences outside the CTL epitope affected CTL recognition of the intact HA molecule. The H5 HA site defined in these studies is, therefore, important in both CTL and B-cell recognition, as well as the pathogenesis of the virus.


Desert varnish: the importance of clay minerals.
Desert varnish has been characterized by infrared spectroscopy, x-ray diffraction, and electron microscopy. It is a distinct morphological entity having an abrupt boundary with the underlying rock. Clay minerals comprise more than 70 percent of the varnish. Iron and manganese oxides constitute the bulk of the remainder and are dispersed throughout the clay layer.


Predation danger can explain changes in timing of migration: the case of the barnacle goose.
Understanding stopover decisions of long-distance migratory birds is crucial for conservation and management of these species along their migratory flyway. Recently, an increasing number of Barnacle geese breeding in the Russian Arctic have delayed their departure from their wintering site in The Netherlands by approximately one month and have reduced their staging duration at stopover sites in the Baltic accordingly. Consequently, this extended stay increases agricultural damage in The Netherlands. Using a dynamic state variable approach we explored three hypotheses about the underlying causes of these changes in migratory behavior, possibly related to changes in (i) onset of spring, (ii) potential intake rates and (iii) predation danger at wintering and stopover sites. Our simulations showed that the observed advance in onset of spring contradicts the observed delay of departure, whereas both increased predation danger and decreased intake rates in the Baltic can explain the delay. Decreased intake rates are expected as a result of increased competition for food in the growing Barnacle goose population. However, the effect of predation danger in the model was particularly strong, and we hypothesize that Barnacle geese avoid Baltic stopover sites as a response to the rapidly increasing number of avian predators in the area. Therefore, danger should be considered as an important factor influencing Barnacle goose migratory behavior, and receive more attention in empirical studies.


Thiazetidin-2-ylidenes as four membered N-heterocyclic carbenes: theoretical studies and the generation of complexes with N+ center.
Thiazetidin-2-ylidenes have been designed as four membered N-heterocyclic carbenes (NHCs) using quantum chemical studies. These species are smaller analogs of thiazol-2-ylidenes, possess high singlet stability (57 kcal mol-1) and large nucleophilicity (3.4 eV). The possible existence of these carbenes has been established by synthesizing and crystalizing compounds with NHC→N+←(thiazetidin-2-ylidene) coordination bonds.


Plasma glutathione peroxidase and its relationship to renal proximal tubule function.
Selenium-dependent extracellular glutathione peroxidase (E-GPx) is found in plasma and other extracellular fluids. Previous studies have indicated that patients with chronic renal failure on dialysis have low plasma GPx activity. In this study, dialysis patients had approximately 40% of control plasma GPx activity, while anephric individuals had lowest plasma GPx activities ranging from 2 to 22% of control. The residual plasma GPx activity in anephric individuals could be completely precipitated by anti-E-GPx antibodies, indicating that all plasma GPx activity can be attributed to E-GPx in both normal and anephric individuals. Plasma GPx activity rises rapidly following kidney transplantation, often reaching normal values within 10 days. The plasma GPx activity in some transplanted patients rises to levels higher than the normal range, followed by a return to the normal range. Since E-GPx in the kidney is primarily synthesized in the proximal tubules, we investigated whether nephrotoxic agents known to disrupt proximal tubule function also affected plasma GPx activity. The beta-lactam antibiotic cephaloglycin rapidly caused a decrease in plasma GPx activity in rabbits. In addition, the chemotherapeutic agent ifosfamide caused a decrease in plasma GPx activity in pediatric osteosarcoma patients. Fanconi syndrome associated with either ifosfamide therapy or valproic acid therapy also caused a decrease in plasma GPx activity. Thus plasma GPx activity is related to kidney function and is decreased in certain situations where nephrotoxic drugs are administered. Monitoring plasma GPx activity may have predictive value in evaluating the function of transplanted kidneys or in predicting those patients particularly at risk of nephrotoxic injury associated with certain medications.


A Mathematical Morphology-Based Filter for Noise Reduction and Detail Preservation in Low-Dose Dental CT Images.
During the acquisition on a low-dose radiation computed tomography (CT) scan, images are usually marked by heavy noise and undesired artifacts, which dramatically reduce its applicability in the image processing workflow. A noise reduction and detail preservation filter based on mathematical morphology is presented in this paper. The filter is geared to allow control of an opening operator followed by a systematic contrast limited adaptive histogram equalization (CLAHE) in conjunction with a reconstruction by dilation in last stage. A quantitative metric built on peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and mean-squared error (MSE) were applied to check noise reduction, detail preservation, and performance. The results obtained by the proposed filter were compared with those obtained in the literature, showing very good results: compared with the best-tested filter, the filter had a gain of 7.91% on PSNR, 7.57% on SSIM and 37.8% on MSE.


The acute kidney injury to chronic kidney disease transition in a mouse model of acute cardiorenal syndrome emphasizes the role of inflammation.
Acute cardiorenal syndrome is a common complication of acute cardiovascular disease. Studies of acute kidney injury (AKI) to chronic kidney disease (CKD) transition, including patients suffering acute cardiovascular disease, report high rates of CKD development. Therefore, acute cardiorenal syndrome associates with CKD, but no study has established causation. To define this we used a murine cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) model or sham procedure on male mice. CA was induced with potassium chloride while CPR consisted of chest compressions and epinephrine eight minutes later. Two weeks after AKI was induced by CA/CPR, the measured glomerular filtration rate (GFR) was not different from sham. However, after seven weeks the mice developed CKD, recapitulating clinical observations. One day, and one, two, and seven weeks after CA/CPR, the GFR was measured, and renal tissue sections were evaluated for various indices of injury and inflammation. One day after CA/CPR, acute cardiorenal syndrome was indicated by a significant reduction of the mean GFR (649 in sham, vs. 25 μL/min/100g in CA/CPR animals), KIM-1 positive tubules, and acute tubular necrosis. Renal inflammation developed, with F4/80 positive and CD3-positive cells infiltrating the kidney one day and one week after CA/CPR, respectively. Although there was functional recovery with normalization of GFR two weeks after CA/CPR, deposition of tubulointerstitial matrix proteins α-smooth muscle actin and fibrillin-1 progressed, along with a significantly reduced mean GFR (623 in sham vs. 409 μL/min/100g in CA/CPR animals), proteinuria, increased tissue transforming growth factor-β, and fibrosis establishing the development of CKD seven weeks after CA/CPR. Thus, murine CA/CPR, a model of acute cardiorenal syndrome, causes an AKI-CKD transition likely due to prolonged renal inflammation.


Substance P expression correlates with severity of diarrhea in cryptosporidiosis.
Cryptosporidiosis, caused by Cryptosporidium parvum, is self-limited in immunocompetent hosts but may cause chronic diarrhea in patients with acquired immunodeficiency syndrome (AIDS). Substance P (SP), a neuropeptide belonging to the tachykinin family, is expressed in gastrointestinal tract and can cause electrogenic chloride anion secretion. Therefore, we studied SP mRNA and protein expression in jejunal tissue samples of patients with AIDS with naturally occurring chronic cryptosporidiosis and healthy volunteers with mild cryptosporidiosis or asymptomatic infection after experimental C. parvum challenge. SP mRNA was associated with symptoms in cryptosporidiosis. SP protein levels were greater in symptomatic than asymptomatic volunteers. Similarly, greater expression of SP mRNA and protein were noted in patients with AIDS with chronic cryptosporidiosis versus immunocompetent volunteers with self-limited infection. This study demonstrates a direct correlation between SP levels and disease severity and may imply that SP plays a role in diarrhea mediation.


Caveolin-1 expression in papillary thyroid carcinoma: correlation with clinicopathological parameters and BRAF mutation status.
We aimed to investigate the role of caveolin-1 in papillary thyroid carcinoma pathogenesis. Case series with chart review. Institute for the Application of Nuclear Energy. We evaluated the expression of caveolin-1 in papillary thyroid carcinoma (PTC) by Western blot (WB) and compared the findings with immunohistochemical (IHC) expression of both epithelial and stromal caveolin-1 on the corresponding histological specimens. The results were related to clinicopathological features and BRAF mutation status. Caveolin-1 expression was found in malignant thyroid epithelium and more abundantly in tumor stroma but varied in both compartments within and between PTC subtypes. Caveolin-1 expression in the epithelium was more intense in classical PTC than in the other histological types. On the contrary, stromal caveolin-1 expression was stronger in the follicular, solid, and trabecular PTC variants than in classical PTC. Trends for down-regulation of caveolin-1 expression in epithelium and up-regulation in stroma from the classical via follicular to the solid variant were observed. The relation of WB and IHC results with clinicopathological parameters showed lower caveolin-1 tissue content in BRAF mutated tumors (P < .05), a positive correlation of epithelial caveolin-1 expression with lymph node metastasis (P < .05), and a negative association of stromal caveolin-1 expression with the degree of neoplastic infiltration and BRAF status. Altered expression of caveolin-1 in the thyroid epithelial and stromal compartments may be involved in the pathogenesis of PTC. The potential clinical significance of caveolin-1 expression, as well as its relation to BRAF mutation status, deserves further investigation.


Construction and validity of educational technology about the human papillomavirus vaccine for adolescents.
to construct and validate an educational technology in comic book format about the human papillomavirus vaccine aimed at adolescents. a methodological study, with a quantitative approach, through the agreement method. It was carried out in two phases: educational technology construction and content validity. Participants are expert judges in the health field. Data collection took place in a virtual environment, through a questionnaire. Data analysis was performed by calculating the Content Validity Index. A Content Validity Index of at least 80% was accepted. the comic book's overall Content Validity Index was 82%, reaching the minimum limit established to be validated. comics are fundamental in the teaching-learning process, aiming to catch adolescents' attention. Therefore, it is characterized as a valid tool to inform, in a playful manner, about the human papillomavirus vaccine.


Formulation Design, Optimization and Pharmacodynamic Evaluation of Sustained Release Mucoadhesive Microcapsules of Venlafaxine HCl.
The objective of present research work was to design and characterize the venlafaxine HCl-loaded sodium alginate-based mucoadhesive microcapsules by ionic gelation technique using HPMC K100M as mucoadhesive polymer. The Placket-Burman Design was applied for preliminary screening of the formulations and systematic optimization by using Box-Behnken Design. The prepared microcapsules were characterized for drug content, entrapment efficiency, micromeritic properties, particle size, swelling index, mucoadhesive strength, in vitro drug release and in vivo antidepressant activity. FTIR and differential scanning calorimetry studies showed no incompatibility. Surface morphology studies revealed spherical nature of the prepared microcapsules. In vitro drug release studies revealed sustained release by diffusion mechanism. Further, the microcapsules were effective in reducing the depression induced by forced swimming test in Sprague-Dawley rats compared to the pure drug. The microcapsules were found to be stable under accelerated stability conditions, which suggest them as better alternative delivery systems for enhanced therapeutic efficacy of antidepressant drug, venlafaxine HCl.


Microanatomical and immunohistochemical study of the human lateral antebrachial cutaneous nerve of forearm at the antecubital fossa and its clinical implications.
Changes in the intraneural anatomy with age can cause poor prognosis of nerve repair in patients after nerve injury. The occurrence of Complex Regional Pain Syndrome-Type II, secondary to peripheral nerve injury, is common. The purpose of this study is to asses changes in cross-sectional anatomy of the lateral antebrachial cutaneous nerve of forearm (LCNF) at the antecubital fossa in the fascicular, nonfascicular components (adipose and nonadipose tissue), and sympathetic fibers area with respect to age. For the purpose of the study, 32 human (37-88 years) fresh cadaveric LCNF were collected from left-antecubital fossae and processed for histological, morphometric analysis [total cross-sectional (Asc), fascicular (Af), and nonfascicular area (Anonf)], and immunohistochemical method (tyrosine hydroxylase) for sympathetic fibers. The LCNF's average total cross-sectional area was 3.024 mm(2), and fascicular area was 0.582 mm(2). The average number of fascicles per mm(2) was 3.09. The cross-sectional area in the nerve was mainly occupied by nonfascicular connective tissue (80.75%). There was increased adipose tissue deposition (48.48% of Asc) and decreased collagen fibers (32.24% of Asc) in interfascicular domains without any definite relationship with age. The average sympathetic fiber area was 0.026 mm(2) within the nerve fascicular area without any correlation with age. In LCNF, there was more adipose tissue and less collagen fibers deposition in the interfascicular domains of all age cases, and this may act as an obstacle for nerve fiber regeneration on using LCNF as an interpositional nerve graft.


2022 Annual Report of the National Poison Data System® (NPDS) from America's Poison Centers®: 40th Annual Report.
This is the 40th Annual Report of America's Poison Centers National Poison Data System (NPDS). As of 1 January, 2022, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.72 [4.40, 9.27] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. In 2022, 2,483,183 closed encounters were logged by NPDS: 2,064,875 human exposures, 50,381 animal exposures, 363,099 information requests, 4,790 human confirmed nonexposures, and 38 animal confirmed nonexposures. Total encounters showed a 12.9% decrease from 2021, and human exposure cases decreased by 0.771%, while health care facility (HCF) human exposure cases increased by 0.214%. All information requests decreased by 48.4%, medication identification (Drug ID) requests decreased by 21.2%, and medical information requests showed a 76.92% decrease, although these remain twice the median number before the COVID-19 pandemic. Drug Information requests showed a 52.4% decrease, due to declining COVID-19 vaccine calls to PCs but still comprised 5.55% of all information contacts. Human exposures with less serious outcomes have decreased 1.70% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.41% per year since 2000.Consistent with the previous year, the top 4 substance classes most frequently involved in all human exposures were analgesics (11.5%), household cleaning substances (7.23%), antidepressants (5.61%), and cosmetics/personal care products (5.23%). Antihistamines (4.81%) replaced sedatives/hypnotics/antipsychotics as the 5th substance class. As a class, analgesic exposures increased most rapidly, by 1,514 cases/year (3.26%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were household cleaning substances (10.3%), analgesics (9.54%), cosmetics/personal care products (9.49%), dietary supplements/herbals/homeopathic (6.65%), and foreign bodies/toys/miscellaneous (6.61%). NPDS documented 3,255 human exposures resulting in death; 2,622 (80.6%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage the increasing number of more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.


Toward a theory of deaf ethnos: deafnicity -- D/deaf (Homaemon - Homoglosson - Homothreskon).
Should ethnicity be used to interpret relations between the Deaf community and the hearing people? Recent scholarship questioning the merits of Deaf ethnicity suggests a need to reexamine the use of ethnicity when describing Deaf identity and culture. This article provides an overview of key contributions to race and ethnicity discourse in the 20th century, identifies epistemological and ontological errors to avoid, suggests adherence to the classical Greek concept of ethnos as an alternative to ethnie, and argues for the continuing significance of Deaf ethnicity. Specifically, I propose that Deaf ethnicity is a triadic relational nexus that approximates communities of origin, language, and religion. This is expressed as Deafnicity approximately D/deaf (Hómaemon * Homóglosson * Homóthreskon). Deafnicity offers a promising alternative for examining relations between Deaf and hearing communities, exploring variance between nationalized Deaf communities, and expanding our understanding of audism.


Exon recognition and nucleocytoplasmic partitioning determine AMPD1 alternative transcript production.
Two mature transcripts are produced from the rat AMP deaminase 1 (AMPD1) gene, one that retains exon 2 and one from which exon 2 has been removed. The ratio of these two transcripts is controlled by stage-specific and tissue-specific signals (I. Mineo, P. R. H. Clarke, R. L. Sabina, and E. W. Holmes, Mol. Cell. Biol. 10:5271-5278, 1990; R. L. Sabina, N. Ogasawara, and E. W. Holmes, Mol. Cell. Biol. 9:2244-2246, 1989). By using transfection studies with native, mutant, and chimeric minigene constructs, two steps in RNA processing that determine the ratio of these two transcripts have been identified. The first step is recognition of this exon in the primary transcript. The primary transcript is subject to alternative splicing in which exon 2 is either recognized and thereby included in the mature mRNA or is ignored and retained in a composite intron containing intron 1-exon 2-intron 2. The following properties of the primary transcript influence exon recognition. (i) Exon 2 is intrinsically difficult to recognize, possibly because of its small size (only 12 bases) and/or a suboptimal 5' donor site at the exon 2-intron 2 boundary. (ii) Intron 2 plays a permissive role in recognition of exon 2 because it is removed at a relatively slow rate, presumably because of the suboptimal polypyrimidine tract in the putative 3' branch site. The second step in RNA processing that influences the ratio of mature transcripts produced from the AMPD1 gene occurs subsequent to the ligation of exon 2 to exon 1. An RNA intermediate, composed of exon 1-exon 2-intron 2-exon 3, is produced in the first processing step, but it is variably retained in the nucleus. Retention of this intermediate in the nucleus is associated with accumulation of the mature mRNA containing exon 2, while cytoplasmic escape of this intermediate is reactions, exon recognition and nucleocytoplasmic partitioning, determine the relative abundance of alternative mRNAs derived from the AMPD1 gene.


Protein preparation, crystallization and preliminary X-ray analysis of human adrenal gland protein AD-004.
The adrenal gland protein AD-004 was identified in the human adrenal gland. Full-length AD-004 contains 172 amino acids, with a predicted molecular weight of about 20 kDa. In attempts to crystallize human AD-004, the gene was subcloned into a modified pET vector, pET21-DEST, with an N-terminal His(5) tag using the Gateway cloning system, followed by protein expression in Escherichia coli strain BL21(DE3). The protein was purified in two steps to near-homogeneity and was crystallized. The crystals belong to space group P6(1) or P6(5), with unit-cell parameters a = b = 99.56, c = 57.19 A. A complete 2.0 A data set has been collected at a rotating-anode X-ray source and structure determination is under way.


Glucocorticoids and the Brain after Critical Illness.
Treatment for critical illness typically focuses on a patient's short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut-brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.


Characterization of de novo transcriptome for waterhemp (Amaranthus tuberculatus) using GS-FLX 454 pyrosequencing and its application for studies of herbicide target-site genes.
Waterhemp is a model for weed genomics research in part because it possesses many interesting biological characteristics, rapidly evolves resistance to herbicides and has a solid foundation of previous genetics work. To develop further the genomics resources for waterhemp, the transcriptome was sequenced using Roche GS-FLX 454 pyrosequencing technology. Pyrosequencing produced 483 225 raw reads, which, after quality control and assembly, yielded 44 469 unigenes (contigs + singletons). A total of 49% of these unigenes displayed highly significant similarities to Arabidopsis proteins and were subsequently grouped into gene ontology categories. Blast searches against public and custom databases helped in identifying and obtaining preliminary sequence data for all of the major target-site genes for which waterhemp has documented resistance. Moreover, sequence data for two other herbicide targets [4-hydroxyphenylpyruvate dioxygenase (HPPD) and glutamine synthetase], where resistance has not yet been reported in any plant, were also investigated in waterhemp and six related weedy Amaranthus species. These results demonstrate the enormous value of 454 sequencing for gene discovery and polymorphism detection in a major weed species and its relatives. Furthermore, the merging of the 454 transcriptome data with results from a previous whole genome 454 sequencing experiment has made it possible to establish a valuable genomic resource for weed science research.