The contribution of stem cell factor and granulocyte colony-stimulating factor in reducing neurodegeneration and promoting neurostructure network reorganization after traumatic brain injury.
Traumatic brain injury (TBI) is a major cause of death and disability in young adults worldwide. TBI-induced long-term cognitive deficits represent a growing clinical problem. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are involved in neuroprotection and neuronal plasticity. However, the knowledge concerning reparative efficacy of SCF + G-CSF treatment in post-acute TBI recovery remains incomplete. This study aims to determine the efficacy of SCF + G-CSF on post-acute TBI recovery in young adult mice. The controlled cortical impact model of TBI was used for inducing a severe damage in the motor cortex of the right hemisphere in 8-week-old male C57BL mice. SCF + G-CSF treatment was initiated 3 weeks after induction of TBI. Severe TBI led to persistent motor functional deficits (Rota-Rod test) and impaired spatial learning function (water maze test). SCF + G-CSF treatment significantly improved the severe TBI-impaired spatial learning function 6 weeks after treatment. TBI also caused significant increases of Fluoro-Jade C positive degenerating neurons in bilateral frontal cortex, striatum and hippocampus, and significant reductions in MAP2+ apical dendrites and overgrowth of SMI312+ axons in peri-TBI cavity frontal cortex and in the ipsilateral hippocampal CA1 at 24 weeks post-TBI. SCF + G-CSF treatment significantly reduced TBI-induced neurodegeneration in the contralateral frontal cortex and hippocampal CA1, increased MAP2+ apical dendrites in the peri-TBI cavity frontal cortex, and prevented TBI-induced axonal overgrowth in both the peri-TBI cavity frontal cortex and ipsilateral hippocampal CA1.These findings reveal a novel pathology of axonal overgrowth after severe TBI and demonstrate a therapeutic potential of SCF + G-CSF in ameliorating severe TBI-induced long-term neuronal pathology, neurostructural network malformation, and impairments in spatial learning.


The natural tolerance of the afghan pika (Ochotona rufescens) to morphine.
A lagomorph, the afghan pika, Ochotona rufescens showed no effect whatever following the subcutaneous injection of morphine in doses up to 50 mg per 100 g of body weight, i.e. 250 times the ED50 for the rat. Higher doses were toxic and induced convulsions. However, the pika is responsive to synthetic opiates such as etorphine, pentazocine and phenoperidine. Interestingly enough, morphine antagonized the opiate response elicited by those narcotics to which the animal is sensitive. Pharmacokinetic analysis demonstrated that morphine enters the pika's brain as readily as it does the rat's. In addition, opiate receptor sites, which are present in normal amounts in pika brain retained their high affinity for 3H-etorphine (KD = 0.3 nM), 3H-naloxone (KD = 1.2 nM) and morphine. Moreover, binding of morphine to pika brain homogenates was inhibited in the presence of sodium ions (agonist response). Therefore, the antagonism of phenoperidine action by morphine appeared not to occur at the opiate receptor site; the mechanism of the pika's natural tolerance to morphine may reside in molecular events that normally preceed (metabolism?) or follow (enzyme activation?) the interaction between the drug and its specific recognition sites.


[Use of hyperbaric oxygenation in the therapy of experimental hypothyroidism].
In animal experiments on rabbits the effect of hyperbaric oxygen was studied on the functional state of the myocardium, the cardiac resistance to induced peroxide lipid oxidation, the structural and functional changes in the thyroid gland and the state of microcirculation in the conditions of experimentally induced hypothyrosis. It was demonstrated that hyperbaric oxygen has a favourable effect on the state of myocardium and microcirculation.


Investigating the genetic diversity of CRESS DNA viruses in cats identifies a novel feline circovirus and unveils exposure of cats to canine circovirus.
Circular replication-associated protein (Rep)-encoding single stranded (CRESS) DNA viruses include Circoviruses which have been found in several animal species and in human specimens. Circoviruses are associated with severe disease in pigs and birds and with respiratory and gastrointestinal disorders and systemic disease in dogs. In cats there are only a few anecdotical studies reporting CRESS DNA viruses. In this study, a total of 530 samples (361 sera, 131 stools, and 38 respiratory swabs) from cats, were screened for the presence of CRESS DNA viruses. Overall, 48 (9.0%) of 530 samples tested positive using a pan-Rep PCR. A total of 30 Rep sequences were obtained. Ten sequences of fecal origin were tightly related to each other (82.4-100% nt identity) and more distantly related to mongoose circoviruses (68.3 to 77.2% nt identity). At genome level these circoviruses displayed the highest nt identity (74.3-78.7%) to mongoose circoviruses thus representing a novel circovirus species. Circoviruses from different animal hosts (n = 12) and from humans (n = 8) were also identified. However, six Rep sequences were obtained from serum samples, including canine circoviruses, a human cyclovirus and human and fish-associated CRESS DNA viruses. The presence of these viruses in the sera would imply, to various extent, virus replication in the animal host, able to sustain viremia. Overall, these findings indicate a wide genetic diversity of CRESS DNA viruses in cats and warrant further investigations.


Radioimmunotherapy for first-line and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: an analysis of 215 patients registered in the international RIT-Network.
Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist. Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries. This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 - 88), with 27% above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1%), as part of third-line to eighth-line therapy for relapse (16.4%), and in refractory disease (12.2%). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 - 600 days). The overall response rate was 63.3%. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3% in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively. Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity.


Mathematical modeling of cytotoxic lymphocyte-mediated immune response to hepatitis B virus infection.
Nowak's model of the human immunodeficiency virus (HIV) infection has been extensively and successfully used to simulate the interaction between HIV and cytotoxic lymphocyte- (CTL-) mediated immune response. However, this model is not available for hepatitis B virus (HBV) infection. As the enhanced recruitment of virus-specific CTLs into the liver has been an important novel concept in the pathogenesis of hepatitis B, we develop a specific mathematical model analyzing the relationship between HBV and the CTL-mediated immune response, and the indicator of the liver cell damage, alanine aminotransferase (ALT). The stability condition of the complete recovery equilibrium point at which HBV will be eliminated entirely from the body is discussed. A different set of parameters is used in the simulation, and the results show that the model can interpret the wide variety of clinical manifestations of HBV infection. The model suggests that a rapid and vigorous CTL response is required for resolution of HBV infection.


Revision Total Shoulder Arthroplasty without Humeral Component Removal. A Preliminary Report on the Role of a Platform Humeral Component.
Revision total shoulder arthroplasty to a reverse system without removing the humeral component-- i.e., a platform system--has been in use since 2006. This preliminary report compares the outcomes of revision total shoulder replacement in patients who underwent revision utilizing a platform system as compared to those patients requiring stem removal. The data banks from two academic centers were utilized to review patients who underwent revision total shoulder surgery requiring removal of a well fixed humeral stem and those revised with a well fixed platform humeral stem. All patients underwent revision to reverse total shoulder arthroplasty. Measured variables were pre and postoperative Constant scores, blood loss, operating room time, complications, and cost. The use of a platform system resulted in fewer complications, less operating room time, and a decrease in blood loss (p < 0.05). The Constant scores were not significantly different between the two groups. The cost of implants and operating room time was also less in the platform system group. Revision total shoulder arthroplasty utilizing a platform system that does not require humeral component removal resulted in a significant decrease in complications, blood loss, and operating room time compared with revisions that did not utilize a platform system. The Constant score was similar between the two groups. The overall cost of the procedure was less when the platform system was used.


Transcription factor RFX4 binding to the testis-specific histone H1t promoter in spermatocytes may be important for regulation of H1t gene transcription during spermatogenesis.
The X-box binding protein RFX4 is highly expressed in testis in contrast with other tissues, but its function there is unknown. Another family member abundant in testis, RFX2, has been shown to bind to the X-Box elements in the promoter of the testis specific histone H1t, which is expressed only in pachytene spermatocytes. RFX proteins are known to dimerize, and there is the possibility that the abundant testis RFX4, which is also expressed in pachytene spermatocytes as shown by RT-PCR and Western blotting, may interact with RFX2 in these cells. In EMSA anti-RFX2 polyclonal antibodies produce a supershifted complex with testis extracts and an X-Box probe. On the other hand, RFX4 polyclonal antibodies do not supershift the complex but appear to enhance formation of the complex. RFX4 appears to co-precipitate with RFX2 in immunoprecipitation, and to co-purify with RFX2 in an affinity purification using a biotinylated X-box affinity probe. In ChIP assays RFX4 also binds to the H1t promoter in vivo. These data suggest a possible regulatory role for RFX4 in transcription of the histone H1t gene during spermatogenesis.


Improved Survival After Primary Tumor Surgery in Metastatic Breast Cancer: A Propensity-adjusted, Population-based SEER Trend Analysis.
There is ongoing debate about nonpalliative primary tumor surgery in metastatic breast cancer patients. This issue has become even more relevant with the introduction of increasingly sensitive imaging modalities. Metastatic breast cancer patients were identified in the SEER registry between 1998 and 2009. The effect of primary tumor surgery on overall and cancer-specific mortality using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching was assessed. Overall, 16,247 women with metastatic breast cancer were included. Of those 7600 women underwent primary tumor surgery although 8647 did not have any surgery at all. Primary tumor surgery decreased from 62.0% in 1998 to 39.1% in 2009 (P < 0.001). Primary tumor surgery was associated with decreased overall mortality (hazard ratio (HR) = 0.53, 95% CI 0.50-0.55, P < 0.001) and cancer-specific mortality (HR = 0.51, 95% CI 0.48-0.54, P < 0.001) in the propensity score-matched model. The benefit of primary tumor surgery increased from 1998 to 2009 for overall mortality (1998: HR = 0.72, 95% CI 0.59-0.89, 2009: HR = 0.42, 95% CI 0.35-0.50) and cancer-specific mortality (1998: HR = 0.72, 95% CI 0.58-0.89, 2009: HR = 0.40, 95% CI 0.33-0.48). The present study-the first population-based analysis using propensity score methods-provides evidence of a favorable impact of primary tumor surgery on mortality in metastatic breast cancer patients. Most importantly, the benefit of primary tumor surgery increased over time from 1998 to 2009. Although the final results of ongoing randomized studies are awaited, currently available evidence should be discussed with metastatic breast cancer patients.


Microscopic reconstruction and immunohistochemical analysis of discomalleolar ligament.
Discomalleolar ligament represents the vestiges of the primitive lateral pterygoid muscle which penetrates in the caudal end of Meckel's cartilage; during the development of newborn, the petrotympanic fissure close almost completely leaving inside the discomalleolar ligament. After entering in tympanic cavity, some fibers of the discomalleolar ligament insert to walls of cavity, other fibers continue with the lateral margin of the anterior ligament and insert in the neck of malleus; in contrast, other Authors demonstrated that discomalleolar ligament is an independent structure inserted in proximity of the neck of the malleus. Although the discomalleolar ligament can be considered as a structure of clinical importance, it is not described by anatomy textbooks. Moreover, it is likely that important correlations between temporomandibular diseases and otological symptoms exist. We have studied discomalleolar ligament submitting the specimens to the 3D volume rendering technique, light microscopy, reconstructing a wide light microscopic fields to analyze the real connection between retrodiscal connective tissue and middle ear, and immunofluorescence methods in order to analyze the consistence of ligament. We have shown two types of connections between TMJ and ear: first, with external acoustic meatus and, second, with middle ear through discomalleolar ligament. The different insertion represents a strong support in order to demonstrate that the TMJ disorders can determine variations of tension that are transmitted on the tympanic membrane provoking tinnitus in according to clinical features. Then, we propose that it is necessary to mention, also in anatomy textbook, the discomalleolar ligament as ligament distance of TMJ.


Differential distribution patterns of ammonia-oxidizing archaea and bacteria in acidic soils of Nanling National Nature Reserve forests in subtropical China.
In addition to ammonia-oxidizing bacteria (AOB) the more recently discovered ammonia-oxidizing archaea (AOA) can also oxidize ammonia, but little is known about AOA community structure and abundance in subtropical forest soils. In this study, both AOA and AOB were investigated with molecular techniques in eight types of forests at surface soils (0-2 cm) and deep layers (18-20 cm) in Nanling National Nature Reserve in subtropical China. The results showed that the forest soils, all acidic (pH 4.24-5.10), harbored a wide range of AOA phylotypes, including the genera Nitrosotalea, Nitrososphaera, and another 6 clusters, one of which was reported for the first time. For AOB, only members of Nitrosospira were retrieved. Moreover, the abundance of the ammonia monooxygenase gene (amoA) from AOA dominated over AOB in most soil samples (13/16). Soil depth, rather than forest type, was an important factor shaping the community structure of AOA and AOB. The distribution patterns of AOA and AOB in soil layers were reversed: AOA diversity and abundances in the deep layers were higher than those in the surface layers; on the contrary, AOB diversity and abundances in the deep layers were lower than those in the surface layers. Interestingly, the diversity of AOA was positively correlated with pH, but negatively correlated with organic carbon, total nitrogen and total phosphorus, and the abundance of AOA was negatively correlated with available phosphorus. Our results demonstrated that AOA and AOB were differentially distributed in acidic soils in subtropical forests and affected differently by soil characteristics.


Factors associated with suicide attempts in first-episode psychosis during the first two years after onset.
The risk of suicide in first-episode psychosis (FEP) is high. However, there are many unknowns about this phenomenon and the risk factors associated with higher risk are not well-understood. Therefore, we aimed to determine the baseline sociodemographic and clinical factors associated with suicide attempts in FEP patients over two-years after psychosis onset. Univariate and logistic regression analyses were performed. Between April 2013 and July 2020, 279 patients treated at the FEP Intervention Program at our hospital (Hospital del Mar, Spain) were enrolled and 267 completed the follow-up. Of these, 30 patients (11.2%) made at least one suicide attempt, mostly during the untreated psychosis period (17 patients, 48.6%). Several variables-prior history of suicide attempts and low functionality, depression, and feelings of guilt at baseline-were all significantly associated with suicide attempts. These findings suggest that targeted interventions, especially in prodromal stages, could play a key role in identifying and treating FEP patients with a high suicide risk.


Target insertion depth of nasopharyngeal temperature probes in children: A prospective observational study analyzing magnetic resonance images.
Core temperature monitoring is indispensable to prevent children from perioperative thermal perturbations. Although nasopharyngeal measurements are commonly used in anesthesia and considered to reflect core temperature accurately, standardized target depths for probe insertion are unknown in children. Our primary goal was to determine a target depth of nasopharyngeal temperature probe insertion in children by measuring distances on magnetic resonance imaging (MRI). Secondary aims were to correlate these measurements with biometric variables and facial landmark-distances to derive formulas estimating target depth. We conducted a prospective observational study in children ≤12 years undergoing cranial MRI with anesthesia. We documented patient characteristics and measured the landmark-distances nostril-mandible, nostril-tragus, and philtrum-tragus on patient's faces. On MRI, the target point for the probe tip was considered to be the site of the nasopharyngeal mucosa with the closest proximity to the internal carotid artery. After its determination in the transverse axis and triangulation to the sagittal axis, we measured the distance to the nostril. This distance, defined as target insertion depth, was correlated with the patient characteristics and used for univariate and multiple linear regression analysis. One hundred twenty children with a mean age of 4.5 years were included. The target insertion depth ranged from 61.8 mm in infants to 89.8 mm in 12-year-old children. Height correlated best (ρ = 0.685, 95%-CI: [0.57-0.77]). The best-fit estimation in millimeters, "40.8 + height [cm] × 0.32,″ would lead to a placement in the target position in 67% of cases. A simplified approach by categories of 50-80, 80-110, 110-130, and >130 cm height with target insertion depths of 60, 70, 80, and 85 mm, respectively, achieved similar probabilities. Height-based formulas could be a valuable proxy for the insertion depth of nasopharyngeal temperature probes. Further clinical trials are necessary to investigate their measurement accuracy.


Inhibition of lipid droplet accumulation in macrophages by triterpenoids produced from Torametes orientaris.
Four triterpenoids 1-4 isolated from the fruit body of Torametes orientaris were found to inhibit lipid droplet accumulation in macrophages. From the biochemical analysis, compounds 2 and 3 inhibited selectively cholesteryl ester synthesis in macrophages, while compounds 1 and 4 showed inhibition of both cholesteryl ester and triacylglycerol syntheses.


Comparative Effectiveness of Cardiac Resynchronization Therapy Defibrillators Versus Standard Implantable Defibrillators in Medicare Patients.
Previous analyses have shown that there is lower mortality with cardiac resynchronization therapy defibrillators (CRT-D) in patients with left bundle branch block (LBBB) but demonstrated mixed results in patients without LBBB. We evaluated the comparative effectiveness of CRT-D versus standard implantable defibrillators (ICDs) separately in patients with LBBB and right bundle branch block (RBBB) using Medicare claims data. Medicare records from CRT-D and ICD recipients from 2002 to 2009 that were followed up for up to 48 months were analyzed. We used propensity scores to match patients with ICD to those with CRT-D. In LBBB, 1:1 matching with replacement resulted in 54,218 patients with CRT-D and 20,763 with ICD, and in RBBB, 1:1 matching resulted in 7,298 patients with CRT-D and 7,298 with ICD. In LBBB, CRT-D had a 12% lower risk of heart failure hospitalization or death (hazard ratio [HR] 0.88, 95% confidence interval 0.86 to 0.90) and 5% lower death risk (HR 0.95, 0.92 to 0.97) compared with ICD. In RBBB, CRT-D had a 15% higher risk of heart failure hospitalization or death (HR 1.15, 1.10 to 1.20) and 13% higher death risk (HR 1.13, 1.07 to 1.18). Sensitivity analysis revealed that accounting for covariates not captured in the Medicare database may lead to increased benefit with CRT-D in LBBB and no difference in RBBB. In conclusion, in a large Medicare population, CRT-D was associated with lower mortality in LBBB but higher mortality in RBBB. The absence of certain covariates, in particular those that determine treatment selection, may affect the results of comparative effectiveness studies using claims data.


Molecular dynamics simulations: bring biomolecular structures alive on a computer.
The molecular dynamics (MD) simulations play a very important role in science today. They have been used successfully in binding free-energy calculations and rational design of drugs and vaccines. MD simulations can help visualize and understand structures and dynamics at an atomistic level when combined with molecular graphics programs. The molecular and atomistic properties can be displayed on a computer in a time-dependent way, which opens a road toward a better understanding of the relationship of structure, dynamics, and function. In this chapter, the basics of MD are explained, together with a step-by-step description of setup and running an MD simulation.


Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo--a role in tumour cell survival?
In addition to its role in bone turnover, osteoprotegerin (OPG) has been reported to bind to and inhibit Tumour necrosis factor-related apoptosis inducing ligand (TRAIL). TRAIL is produced in tumours by invading monocytes, inducing apoptosis in neoplastic cells sensitive to this cytokine. OPG production by tumour cells would therefore be a novel mechanism whereby cancer cells evade host defences and gain a growth advantage. In this study we show that OPG produced by breast cancer cells enhances tumour cell survival by inhibiting TRAIL-induced apoptosis. OPG expression by breast cancer cells (MDA-MB 436/231) grown in vitro was examined using PCR and ELISA, and the sensitivity of these cells to TRAIL was determined. The effects of OPG on TRAIL induced apoptosis was investigated by exposing MDA-MB 436 cells to TRAIL, in the presence or absence of OPG, followed by assessment of nuclear morphology. We found that the levels of OPG produced were sufficient to inhibit TRAIL-induced apoptosis, suggesting that OPG may play a role in tumour cell survival. We also examined the expression pattern of OPG in a selection of breast tumours (n=400) by immunohistochemistry, and related OPG expression to the clinico-pathological data for each tumour. OPG expression was found to be negatively correlated with increasing tumour grade. To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours.


Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder.
In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.


Lumbar and ventricular CSF protein, leukocytes, and lactate in suspected bacterial CNS infections.
Protein concentration, leukocyte density, and lactate concentration were studied in 41 pairs of ventricular and lumbar CSF drawn at an interval of less than 24 hours from patients with suspected bacterial CNS infections. The ventriculo-lumbar ratios ranged from 0.003 to 10.2 (median=0.42) for protein and from 0.002 to 53.5 (median=0.17) for leukocytes. The uneven distribution of leukocytes and proteins in the CSF space may produce findings that fail to indicate bacterial CNS infections. Lactate was distributed more homogeneously in the CSF space than protein and leukocytes (ventriculo-lumbar ratio 0.52 to 1.66 [median=0.811).


Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.


Impedimetric sensor for toxigenic Penicillium sclerotigenum detection in yam based on magnetite-poly(allylamine hydrochloride) composite.
We describe a new DNA biosensor for the detection of toxigenic Penicillium sclerotigenum in pure culture or infected yams. The P. sclerotigenum detection takes place on a self-assembled monolayer of a (magnetite)/(poly(allylamine hydrochloride)) (Fe3O4-PAH) composite that serves as an anchoring layer for the DNA hybridization interaction. Electrical impedance spectroscopy (EIS) was used to evaluate and quantify the hybridization degree. The Fe3O4-PAH composite is a good platform for the immobilization of biomolecules, due to the presence of many possible binding sites for nucleotides and to its large surface-to-volume ratio and good biocompatibility. The biosensor was capable of not only qualitatively detecting the presence of the fungus genome at low concentrations, but also shown a good quantitative impedimetric response its electrical resistance was monitored along the time of exposure. A Fe3O4-PAH-probe biosensor would require only small volumes and low concentrations of the analyte when used, for instance, in detecting P. sclerotigenum contamination of food, besides presenting many comparative advantages, such as selectivity, specificity and reproducibility, relative to alternative techniques.


Physiological status and intersex in the endobenthic bivalve Scrobicularia plana from thirteen estuaries in northwest France.
The bivalve Scrobicularia plana, an important species for the structure and functioning of estuarine and coastal mudflats, was studied in thirteen sites from NW France differing by their degree of contamination to document the presence of reproduction impairments (intersex, sex ratio, gonadosomatic indices) in relation to the condition revealed by using hepatosomatic and condition indices. In agreement with recent studies in other European estuaries, intersex was revealed in all the studied estuaries, including sites the chemical and ecological status of which is considered "good" according to the criteria of the European Water Framework Directive. The presence of endocrine disrupting chemicals (EDCs) could result in such disturbances. Our results re-inforce the concern linked to the subtle effects of EDCs, which are active at very low doses, often in the absence of any major sign of toxicity. However at this stage, no clear link may be established between intersex and population effects.


[Synthesis and insulinotropic activity of 2-benzylidenesuccinic acid derivatives].
To design and synthesize new compounds of prandial glucose regulator with more simple structure. The target compounds were synthesized from diethyl succinate and benzaldehyde or 4-fluorobenzaldehyde by four-step reactions. Thus 18 compounds were synthesized. Their structures were comfirmed by NMR, MS and IR. Seventeen compounds had different hypoglycemic activity in mice, among them, 9 compounds had higher hypoglycemic activity and 6 compounds had character of prandial glucose regulator. Part of the compounds have higher hypoglycemic activity deserve to be further investigated.


Measuring transplant center performance: The goals are not controversial but the methods and consequences can be.
Risks of regulatory scrutiny has generated widespread concern about increasingly risk averse transplant center behaviors regarding both donor and candidate acceptance patterns. To address potential unintended consequences threatening access to care, we discuss recent changes in regulatory metrics and potential improvements in quality oversight of transplant centers. Despite many recent changes to one-year patient and graft survival regulatory criteria, the capacity to accurately identify true underperforming centers and avoiding false positive flagging remains an area of great concern. Numerous studies have demonstrated restrictions in transplant volume and access following transplant center flagging. Current regulatory criteria are limited in their capacity to accurately identify poorly performing centers and potentially encourage risk-averse behavior by transplant centers. Efforts to address these concerns should focus on (1) improving risk-adjustment models with better data which captures the acuity of candidate and donor risk, (2) reconsidering primary outcomes measured to assess comprehensive transplant center performance, (3) improving education to address rational or perceived disincentives, and (4) using data more effectively to share best practices.


AAV8 capsid variable regions at the two-fold symmetry axis contribute to high liver transduction by mediating nuclear entry and capsid uncoating.
Adeno-associated virus serotype 8 (AAV8) is a promising vector for liver-directed gene therapy. Although efficient uncoating of viral capsids has been implicated in AAV8׳s robust liver transduction, much about the biology of AAV8 hepatotropism remains unclear. Our study investigated the structural basis of AAV8 liver transduction efficiency by constructing chimeric vector capsids containing sequences derived from AAV8 and AAV2 - a highly homologous yet poorly hepatotropic serotype. Engineered vectors containing capsid variable regions (VR) VII & IX from AAV8 in an AAV2 backbone mediated near AAV8-like transduction in mouse liver, with higher numbers of chimeric genomes detected in whole liver cells and isolated nuclei. Interestingly, chimeric capsids within liver nuclei also uncoated similarly to AAV8 by 6 weeks after administration, in contrast with AAV2, of which a significantly smaller proportion were uncoated. This study links specific AAV capsid regions to the transduction ability of a clinically relevant AAV serotype.


Demonstration of a high-energy, narrow-bandwidth, and temporally shaped fiber regenerative amplifier.
We report a high-energy and high-gain fiber regenerative amplifier for narrow-bandwidth nanosecond laser pulses that uses a Yb-doped photonic crystal fiber. The input pulse energy is 270 pJ for a 3.5 ns laser pulse with 0.3 nm (FWHM) bandwidth. At a pump laser power of 8.6 W at 974 nm, pulse energies up to 746 μJ with 1.2% (rms) energy stability are generated. To the best of our knowledge, this is the highest energy obtained in a fiber-based regenerative amplifier. A high-energy, nearly diffraction-limited, single-mode beam with a high gain of 64 dB shows promise for future application in the front ends of high-power laser facilities.


Left-sided inferior vena cava implications for cardiopulmonary bypass cannulation in open thoracoabdominal aortic aneurysm repair.
A left-sided inferior vena cava poses a unique challenge when cannulating for cardiopulmonary bypass during thoracoabdominal aortic aneurysm repair, and how to effectively and safely do so has not been previously described. A 51-year-old woman with a history of Loeys-Dietz syndrome and a left-sided inferior vena cava underwent open Crawford extent II thoracoabdominal aortic aneurysm repair. Cardiopulmonary bypass cannulation was performed using the right axillary artery, left common femoral artery, and right internal jugular vein. The patient's repair was successful, and she was ultimately discharged back to her home.


Mechanisms of cardiac depression caused by lipoteichoic acids from Staphylococcus aureus in isolated rat hearts.
Lipoteichoic acid (LTA) represents a major virulence factor in gram-positive sepsis. In the present study we perfused isolated rat hearts for 180 minutes with highly purified LTA from Staphylococcus aureus. A progressive decline of left ventricular contractile function paralleled by the expression of myocardial tumor necrosis factor-alpha (TNF-alpha) mRNA and protein as well as the release of TNF-alpha into the perfusate was observed in LTA-perfused hearts. Employment of an anti-TNF-alpha antibody completely prevented the loss in contractile function. When CD14, a prominent pathogen recognition receptor, was blocked by a specific antibody, induction of TNF-alpha mRNA and protein release as well as the associated cardiodepression was diminished in response to LTA. Synthesis of TNF-alpha protein was located to interstitial cells of LTA-challenged hearts as detected by immunohistochemistry. Besides progressive cardiodepression, coronary perfusion pressure (CPP) was moderately increased in LTA-perfused hearts. This was accompanied by the release of thromboxane A2 (TXA2) into the perfusate and the induction of cyclooxygenase (Cox)-2 mRNA and protein in the myocardium. Blocking of TXA2 by the nonspecific Cox inhibitor indomethacin, the thromboxane receptor antagonist daltroban, or the selective Cox-2 inhibitor NS-398 prevented the increase in CPP. LTA causes cardiac depression by activating myocardial TNF-alpha synthesis via CD14 and induces coronary vascular disturbances by activating Cox-2-dependent TXA2 synthesis. These phenomena may contribute to cardiac depression in gram-positive sepsis.


CCl4-induced increase of hepatocyte free arachidonate level: pathogenesis and contribution to cell death.
A significant increase of the intracellular level of free arachidonic acid was observed in intact rat hepatocytes after poisoning with very low concentrations of CCl4 (0.129-0.172 mM), shown not to exert direct solvent effect. It seems likely that activation of phospholipase A2 (PLA2) is the mechanism mainly responsible for the rise of cytosolic arachidonate, since the latter is prevented by the PLA2 inhibitors indomethacin and mepacrine. The CCl4-induced delay of arachidonic acid incorporation within the cell membrane phospholipids partly contributes to its intracellular accumulation in the early phases of the poisoning. The lack of any significant protection by metabolic inhibitors (SKF 525A, metyrapone), antioxidant compounds (promethazine, diphenylphenylenediamine DPPD) or antioxidant procedures (rat pretreatment with vitamin E) leads to exclude an involvement of CCl4 biotransformation in the increase of intracellular free arachidonate. Finally, the PLA2 inhibitors employed in this study did not afford protection against the enzymic leakage of CCl4-treated hepatocytes.


Long-term oncologic outcomes of laparoscopic versus open surgery for rectal cancer: a pooled analysis of 3 randomized controlled trials.
To compare long-term oncologic outcomes between laparoscopic and open surgery for rectal cancer and to identify independent predictors of survival. Few randomized trials comparing laparoscopic and open surgery for rectal cancer have reported long-term survival data. Data from the 3 randomized controlled trials comparing curative laparoscopic (n=136) and open surgery (n=142) for upper, mid, and low rectal cancer conducted at the Prince of Wales Hospital, Hong Kong, between September 1993 and August 2007 were pooled together for this analysis. Survival and disease status were updated to February 2012. Survival was calculated using the Kaplan-Meier method, and independent predictors of survival were determined using the Cox regression analysis. The demographic data of the 2 groups were comparable. The median follow-up time of living patients was 124.5 months in the laparoscopic group and 136.6 months in the open group. At 10 years, there were no significant differences in locoregional recurrence (5.5% vs. 9.3%; P=0.296), cancer-specific survival (82.5% vs. 77.6%; P=0.443), and overall survival (63.0% vs. 61.1%; P=0.505) between the laparoscopic and open groups. There was a trend toward lower recurrence rate at 10 years in the laparoscopic group than in the open group among patients with stage III cancer (P=0.078). The Cox regression analysis showed that stage III cancer, lymphovascular permeation, and blood transfusion, but not the operative approach, were independent predictors of poorer cancer-specific survival. This pooled analysis with a follow-up of more than 10 years confirms the long-term oncologic safety of laparoscopic surgery for rectal cancer.


Impaired lung epithelial permeability in hepatitis C virus antibody positive patients detected by 99mTc-DTPA aerosol scintigraphy.
Chronic hepatitis C virus (HCV) infection has been recently identified as an aetiological agent in idiopathic pulmonary fibrosis. The present study was designed to determine the pulmonary clearance rate of 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) in asymptomatic HCV antibody positive (HCV Ab+) patients and the role of 99mTc-DTPA aerosol scintigraphy in the early detection of lung involvement. Twenty-six non-smoker HCV Ab+ and HCV-RNA (+) patients (20 female, six male; aged 43+/-11 years), with no clinical pulmonary symptoms, and normal radiological findings, were studied. Thirty-one healthy non-smoker volunteers (24 female, seven male; aged 40+/-10 years) were taken as a control group. 99mTc-DTPA aerosol inhalation scintigraphy and pulmonary function tests were performed in all patients and in controls. On the basis of the scintigrams the percentage decline in activity per minute (Kep) was evaluated, which represented an accurate parameter of lung membrane permeability. The mean Kep values of healthy controls (0.78+/-0.13 for left lung, 0.79+/-0.14 for right lung) were significantly lower than HCV Ab+ patients (1.10+/-0.31 for left lung, 1.11+/-0.34 for right lung, P<0.001). But no significant change was observed in PFT (P>0.05). We conclude that subclinical alveolitis and/or interstitial lung disease may be present in patients with HCV Ab+, since it is known that an increase in the epithelial permeability of the lung is an early manifestation of interstitial disease.


Human papillomavirus type 16 DNA in oral white sponge nevus.
White sponge nevus (WSN) is a benign hereditary lesion of the mucous membranes. DNA extracted from a biopsy specimen of oral WSN was assayed for the presence of DNA sequences homologous to human papillomavirus (HPV) types 1, 2, 4, 6, 11, 13, 16, and 18 by Southern blot hybridization. Only HPV-16 homologous DNA sequences were detected at a copy number of approximately 200 to 250 genome copies per diploid cell. The viral DNA sequences did not appear to be integrated into the host cell chromosome. The finding of HPV-16 in an inherited lesion such as WSN indicates that caution must be exercised in ascribing a causal association in relation to the demonstration of HPV in other mucosal disorders.


An automated imaging system for radiation biodosimetry.
We describe here an automated imaging system developed at the Center for High Throughput Minimally Invasive Radiation Biodosimetry. The imaging system is built around a fast, sensitive sCMOS camera and rapid switchable LED light source. It features complete automation of all the steps of the imaging process and contains built-in feedback loops to ensure proper operation. The imaging system is intended as a back end to the RABiT-a robotic platform for radiation biodosimetry. It is intended to automate image acquisition and analysis for four biodosimetry assays for which we have developed automated protocols: The Cytokinesis Blocked Micronucleus assay, the γ-H2AX assay, the Dicentric assay (using PNA or FISH probes) and the RABiT-BAND assay.


Transcriptional control of rat heme oxygenase by heat shock.
A heat shock element is located in the 5'-flanking region of the rat heme oxygenase gene (HO gene). The incubation of rat glioma cells at 42 degrees C or with hemin at 37 degrees C increased the levels of heme oxygenase mRNA within 1 h and produced a maximum at 3 h (at least a 20-fold increase). In both treatments, the heme oxygenase activity started to increase after a lag period of about 1 h and reached a maximum value at 5 h. There was an apparent additive effect of both treatments on the heme oxygenase induction. Studies with actinomycin D and cycloheximide suggested that both heat shock and hemin acted at the transcriptional level to induce heme oxygenase. Therefore, we analyzed the transient expression of chimeric fusion genes harboring the promoter of the rat HO gene ligated to the Escherichia coli gene gpt in rat glioma cells and in K1735 mouse amelanotic melanoma cells. The 5'-flanking region of the rat HO gene bearing the heat shock element conferred the heat inducibility of gpt RNA production in both cell lines; however, hemin treatment did not induce gpt RNA. These results indicate that rat heme oxygenase is a heat shock protein and that hemin induces heme oxygenase through a different mechanism from heat shock.


Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas.
This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed low-grade non-Hodgkin's lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration. This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists. Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of > or = 1 year (termed durable response population). For the durable response population, 44% had not progressed at > or = 2.5 to > or = 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease > or = 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy. The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.


Association between Bifidobacterium and Scardovia Wiggsiae and caries-related factors in severe early childhood caries and caries-free Thai children: a quantitative real-time PCR analysis and a questionnaire cross-sectional study.
To quantitatively identify Bifidobacterium, S. wiggsiae and S. mutans in plaque samples obtained from children with severe-ECC and caries-free groups and to analyze their association with caries-related factors retrieved from the questionnaire in each group. To establish the 2 study groups, clinical examination in 122 Thai children, aged 2-5 years, recorded decayed, missing and filled teeth scores (dmft), in addition to plaque and gingival indices. Sixty one children in the caries-free group and 61 in the S-ECC group were identified. A questionnaire was used to assess the parent's attitudes and behavior regarding the child's oral hygiene care and diet. Pooled overnight supra gingival plaque was collected from each child using a sterile toothpick, released in 1 ml of TE buffer, transported on ice to the Laboratory and stored at - 20 °C. DNA was extracted from the plaque based on enzymatic lysis and quantitative real-time PCR using fluorescent dye (SYBR green) in addition to Agarose gel electrophoresis were performed. All laboratory and retrieved from the questionnaire data per child were recorded and statistically analysed. S. wiggsiae (p < 0.005) and S. mutans (p < 0.001) were higher in the S-ECC group. Bifidobacterium, S. mutans, and S. wiggsiae were associated with the dmft score and gingival index (p < 0.001). The dmft scores of children who detected only S. mutans were significantly lower than the dmft scores of children who detected two bacteria; S. mutans + S. wiggsiae (p = 0.028), S. mutans + Bifidobacterium (p = 0.026), and three bacteria; S. mutans + Bifidobacterium + S. wiggsiae (p = 0.007). Children who found all three bacteria (Bi + Sm + Sw) had the highest dmft scores, followed by children who had two bacteria (Bi + Sw, or Bi + Sm, or Sw + Sm). The guardians' education levels, occupations, household income, prolonged bottle feeding, taking of water after bottle or breast feeding, eating sugar-coated crackers or bread with sweetened cream, and premature birth were the factors that related to S-ECC. Levels of S. wiggsiae and S. mutans, guardian's education, family economics, prolonged bottle feeding, eating high sugar-containing snacks and premature birth were associated with S-ECC.


The partial molar volumes of anesthetics in lipid bilayers.
The excess volumes of mixing of benzyl alcohol, halothane, and methoxyflurane in water and in suspensions of several lipid bilayers have been determined at 25 degrees C using a novel excess volume dilatometer. The excess volumes of mixing in water were all found to be negative, whereas in lipid suspensions they were all more positive than those in water alone. From known partition coefficients the partial molar volumes of these three solutes in the lipid bilayers were calculated. These values were all close to the molar volumes of the pure anesthetics, as was a value determined for halothane in olive oil. Halothane was studied in dipalmitoylphosphatidylcholine below its phase transition, and was found to exhibit a much larger excess volume than in any other system we studied. The potency of these three anesthetics was determined in tadpoles. It was calculated that at equi-anesthetic doses these three agents caused an expansion in egg lecithin/cholesterol (2:1) bilayers of 0.21 +/- 0.015%. This result is consistent with the hypothesis that general anesthetics act by expanding membranes.


Systematic review: what is the best antibiotic treatment for Staphylococcus aureus intramammary infection of lactating cows in North America?
Staphylococcus aureus is the most prevalent pathogen causing intramammary infections (IMI) in dairy cattle worldwide. New treatment regimens have been evaluated to increase cure rates. A systematic review was conducted to answer this question: what is the best antibiotic treatment for S aureus IMI of lactating cows in North America? Direct comparison between studies (n = 6) was difficult since there was no clinical trial comparing all antibiotics and large variations between study protocols and enrolment and outcome definitions were observed. The best therapeutic option currently available in North America is an extended intramammary therapy for 5 to 8 days.


Gastric neuromodulation with Enterra system for nausea and vomiting in patients with gastroparesis.
Gastric electrical stimulation (GES) has been introduced for treating gastric motility disorders, such as gastroparesis, and obesity. A special method of GES using high frequency-short pulses, called Enterra® Therapy, has been clinically applied to treat nausea and vomiting in patients with gastroparesis. However, its mechanisms are not well understood. General methodologies of GES published in the literature are systematically reviewed and their main effects and application are presented. The major part of this review is focused on Enterra Therapy since this is the only method that has been used clinically. A number of different GES methods have been proposed. GES with long pulses or dual pulses, but not short pulses, are able to alter (enhance or inhibit) such parameters of gastric motility as gastric slow waves and gastric emptying. Synchronized GES has been reported to improve antral contractions. GES with high frequency-short pulses, or Enterra Therapy, is known to improve nausea and vomiting in patients with gastroparesis and has a response rate of 50-70%. Improved gastric accommodation, direct enteric nervous system effects, enhanced vagal activity, and activation of central neurons are believed to be the underlying mechanisms involved in the antiemetic effect of this therapy. GES with high frequency-short pulses effectively reduces nausea and vomiting in patients with gastroparesis. This antiemetic effect could be mediated via enteric, autonomic, and/or central neural mechanisms. Further systematic and controlled studies are needed to improve the efficacy of Enterra Therapy and to understand its mechanisms of action.


[Diagnosis of white spot syndrome virus in farm crawfish in Anhui province and its epidemiological source].
The aims of this study were to find out the pathogen causing high mortality of the crawfish population in Anhui over the past years. To provide the strategy for controlling the spread of the disease, an investigation was conducted to trace the origin of the pathogen. Crawfish samples were tested by nested PCR, to diagnose the White Spot Syndrome Virus (WSSV). Healthy crawfish were inoculated with the supernatant of tissue homogenates. The viral suspension was purified using sucrose density gradients. The gill samples infected with purified virus were then subject to the transmission electron microscopy (TEM). The possible sources, including pond water, feedstuff, crabs, water plants, were investigated. Crawfish samples and commercial feeds exhibited all positive for WSSV. Challenge model on healthy crawfish recovered similar symptoms as the naturally infected ones on 7 to 9 days after inoculation. The viral particles were observed under TEM. Our findings indicated that WSSV was the causative agent that led to high mortality in the crawfish population in this area. These results demonstrated that the exotic viruses are derived from the regions where the frozen feeds were contaminated with WSSV-infected shell debris.


Mce1R of Mycobacterium tuberculosis prefers long-chain fatty acids as specific ligands: a computational study.
The mce1 operon of Mycobacterium tuberculosis, which codes the Mce1 transporter, facilitates the transport of fatty acids. Fatty acids are one of the major sources for carbon and energy for the pathogen during its intracellular survival and pathogenicity. The mce1 operon is transcriptionally regulated by Mce1R, a VanR-type regulator, which could bind specific ligands and control the expression of the mce1 operon accordingly. This work reports computational identification of Mce1R-specific ligands. Initially by employing cavity similarity search algorithm by the ProBis server, the cavities of the proteins similar to that of Mce1R and the bound ligands were identified from which fatty acids were selected as the potential ligands. From the earlier-generated monomeric structure, the dimeric structure of Mce1R was then modeled by the GalaxyHomomer server and validated computationally to use in molecular docking and molecular dynamics simulation analysis. The fatty acid ligands were found to dock within the cavity of Mce1R and the docked complexes were subjected to molecular dynamics simulation to explore their stabilities and other dynamic properties. The data suggest that Mce1R preferably binds to long-chain fatty acids and undergoes distinct structural changes upon binding.


Intratumoral Susceptibility Signals Reflect Biomarker Status in Gliomas.
Susceptibility-weighted imaging (SWI) can be a useful tool to depict vascular structures in brain tumors as well as micro-bleedings, which represent tumor invasion to blood vessels and could also be representative of tumoral angiogenesis. In this study, we investigated the relationship between SWI features and glioma grades, and the expression of key molecular markers isocitrate dehydrogenase 1 (IDH1), O-6-methylguanine-DNA methyltransferase (MGMT), and 1p19q. The gliomas were graded according to the intratumoral susceptibility signals (ITSS). We used the Mann-Whitney test to analyze the relationship between ITSS grades and the pathological level and status of these markers. Additionally, the area under the curve (AUC) was used to determine the predictive value of glioma SWI characteristics for the molecular marker status. In these cases, the ITSS grades of low-grade gliomas (LGG) were significantly lower than those of high-grade gliomas (HGG). Similarly, the ITSS grades of gliomas with IDH1 mutations and MGMT methylation were significantly lower than those of gliomas with Wild-type IDH1 and unmethylated MGMT. However, ITSS grades showed no relationship with 1p19q deletion status, while they did show significant predictive ability for glioma grade, IDH1 mutation, and MGMT methylation. These findings indicate an association between some molecular markers and cerebral microbleeds in gliomas, providing a new avenue for non-invasive prediction of molecular genetics in gliomas and an important basis for preoperative personalized surgical treatment based on molecular pathology.


Nitrate levels and the age of groundwater from the Upper Devonian sandstone aquifer in Fife, Scotland.
The tritium concentrations in 13 groundwater samples from boreholes throughout the Upper Devonian sandstone aquifer of Fife have been measured. Due to atmospheric variations in tritium concentrations over the last century, this radioactive tracer can be used as a groundwater age indicator. In this study, the groundwater tritium concentrations have allowed for the area to be divided into three zones, and the variable chemistry of the groundwater samples, including the problem of recent elevated nitrate levels in the Fife Aquifer, has been interpreted in terms of their relative ages.


CADASIL presenting as status migrainosus and persisting aura without infarction.
Different types of migraine have been reported in 20-40% of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe a novel migrainous manifestation of CADASIL consisting in status migrainosus and persistent aura without infarction. The symptoms resolved after i.v. treatment with lorazepam and mannitol.


Genome-wide identification and expression analysis of the MYB transcription factor in Japanese plum (Prunus salicina).
MYB proteins constitute one of the largest transcription factor families in plants, members of which are involved in various plant physiological and biochemical processes. Japanese plum (Prunus salicina) is one of the important stone fruit crops worldwide. To date, no comprehensive study of the MYB family in Japanese plum has been reported. In this study, we performed genome-wide analysis of MYB genes in Japanese plum including the phylogeny, gene structures, protein motifs, chromosomal locations, collinearity and expression patterns analysis. A total of 96 Japanese plum R2R3-MYB (PsMYB) genes were characterized and distributed on 8 chromosomes at various densities. Collinearity analysis indicated that the segmental duplication events played a crucial role in the expansion of PsMYB genes, and the interspecies synteny analysis revealed the orthologous gene pairs between Japanese plum and other four selected Rosaceae species. The 96 PsMYB genes could be classified into 27 subgroups based on phylogenetic topology, as supported by the conserved gene structures and motif compositions. Further comparative phylogenetic analysis revealed the functional divergence of MYB gene family during evolution, and three subgroups which included only Rasaceae MYB genes were identified. Expression analysis revealed the distinct expression profiles of the PsMYB genes, and further functional predictions found some of them might be associated with the plum fruit quality traits. Our researches provide a global insight into the organization, phylogeny, evolution and expression patterns of the PsMYB genes, and contribute to the greater understanding of their functional roles in Japanese plum.


Microwounding is a pivotal factor for the induction of actin-dependent penetration resistance against fungal attack.
Induced penetration resistance is triggered by failed penetration attempts of nonpathogenic fungi. The resistance mechanism is an important nonhost reaction in plants that can block the invasion of filamentous pathogens such as fungi and oomycetes. However, it remains unclear whether the mechanical stimuli accompanying fungal penetration play a role in induced penetration resistance, whereas the perforation of the cell wall may provide significant stimuli to plant cells. Here, we used microneedles or biolistic bombardment to mimic fungal penetration pegs and a micromanipulation transfer technique of the bio-probe, a germling of Blumeria graminis hordei, to the wounded cells to demonstrate that microwounds derived from fungal penetration attempts may trigger induced penetration resistance in plant cells. When preinoculated with the nonpathogenic fungi Erysiphe pisi and Colletotrichum orbiculare, which were unable to penetrate a barley cell, the penetration of a bio-probe that was transferred by micromanipulation onto the same cell was completely blocked. Fungal penetration was essential to the triggering of induced penetration resistance because a penetration-peg-defective mutant of C. orbiculare completely lacked the ability to trigger resistance. The artificial microwounds significantly, but not completely, blocked the penetration of the bio-probe. Treatment with the actin polymerization inhibitor cytochalasin A or expression of the actin depolymerizing protein HvPro1 caused complete ablation of the induced penetration resistance triggered by either failed fungal penetration or artificial microwounds. These results strongly suggest that microwounding may trigger actin-dependent induced penetration resistance. Manipulation of induced penetration resistance may be a promising target to improve basic disease resistance in plants.


Hemorrhagic chondroid chordoma mimicking pituitary apoplexy.
We describe a hemorrhagic chondroid chordoma involving the sella turcica with suprasellar extension. The CT and MRI appearances mimiked a hemorrhagic pituitary adenoma. Chondroid chordoma is a variant composed of elements of both chordoma and cartilaginous tissue. An uncommon bone neoplasm, located almost exclusively in the spheno-occipital region, it is usually not considered in the differential diagnosis of a tumor with acute hemorrhage in the sellar region. We discuss the clinical and radiological characteristics which may allow one to differentiate chondroid chordoma from other tumors of this area.


Inter-relationship of Pro- and Anti- inflammatory Biomarkers with the development of Type 2 Diabetes Mellitus.
There has been growing evidence that inflammatory markers play a role in the development as well as severity of Type 2 diabetes mellitus (T2DM). This study has been designed to decipher the involvement of C-Reactive Protein (CRP), Tumor Necrosis Factor (TNFα), Interleukin-6 (IL-6) and Interleukin-10 (IL-10) in the etiopathogenesis of T2DM. A total of 480 T2DM cases and 540 healthy controls were recruited for the study. Blood samples were collected from each study subject to measure the serum levels of CRP, TNFα, IL-6 and IL-10. We found that serum levels of CRP in mg/dl (4.2 ± 0.9), TNFα in pg/ml (34.5 ± 8.8), IL-6 in pg/ml (19.2 ± 7.2) in T2DM patients were significantly high as compared to control participants (CRP; 1.4 ± 0.6, TNFα; 12.7 ± 3.4, IL-6; 3.1 ± 1.4; P < 0.0001). The serum levels of IL-10 in pg/ml were lower in T2DM cases compared to controls (4.35 ± 1.2 vs. 9.6 ± 1.2). In addition, we observed a significant association of CRP levels with insulin resistance, obesity and dyslipidemia. Increased TNFα levels were strongly associated with female gender, Poor glycemic control and strong family history of diabetes. Poor glycemic control was significantly associated with elevated IL-6 levels. Moreover, significantly reduced IL-10 levels were found in T2DM patients with sedentary lifestyle; low educational and rural background. This study showed a strong relationship between TNFα, IL-6, CRP, IL-10 and T2DM patients of Kashmiri ethnicity, treated at SMHS Hospital. Thus, supporting other studies and showing that cytokines may be good markers for T2DM development.


Association of diet with dental caries in preschool children.
This article updates the evidence linking dietary factors to dental caries in preschool children and recommends dietary approaches to reduce caries risk. Along with nutritional factors, a comprehensive approach to preventing dental caries in preschool children must include good oral hygiene, appropriate use of fluorides, and access to preventive and restorative dental care.


Lipid composition and 3-hydroxy-3-methylglutaryl-CoA reductase activity of acinar cell carcinoma of rat pancreas.
The lipid composition and 3-hydroxy-3-methylglutaryl-CoA reductase activity of subcutaneous transplantable pancreatic acinar cell tumors on nude mice were compared with those of normal, regenerating, fetal and newborn rat pancreata. The tumors and also the fetal tissues showed decreased concentration in total lipids, increased concentration in sphingomyelin and an increase in cholesterol when compared to normal rat pancreas. The regenerating pancreas showed an intermediate elevation in these lipid parameters. Specifically, only tumor showed an increase in phosphatidylethanolamine/phosphatidylcholine ratio. The tumors and also the fetal tissues showed an increase in hydroxymethylglutaryl-CoA reductase activities, suggesting that the de novo synthesis of cholesterol is a requirement for cell proliferation. The cholesterol metabolism in normal tissues is under metabolic regulation as indicated by decreased hydroxymethylglutaryl-CoA reductase activities and decreased cholesterol concentration in postnatal tissues when compared with the fetal tissues. The fast growing AT3A tumor showed higher hydroxymethylglutaryl-CoA reductase activity when compared to the slow growing AT3B tumor, indicating that the differences in growth rate of the tumors may be related at least in part to differences in their cholesterol metabolism.


Fenbendazole and its synthetic analog interfere with HeLa cells' proliferation and energy metabolism via inducing oxidative stress and modulating MEK3/6-p38-MAPK pathway.
Fenbendazole, a broad-spectrum anti-parasitic drug, can be a potential anti-tumor agent. In this study, we synthesized and purified its derivative, analog 6, intending to achieve improved efficacy in cancer cells and decreased toxicity in normal cells. To evaluate in vitro anti-tumor activities of fenbendazole and analog 6 in different cancer cell lines, a CCK-8 assay was performed, and we found that human cervical cancer HeLa cells were more sensitive to analog 6 than to fenbendazole. Furthermore, we explored the associated mechanism, and our results showed that analog 6 and fenbendazole could induce oxidative stress by accumulating ROS. It not only activated the p38-MAPK signaling pathway, thereby inhibiting the proliferation of HeLa cells and enhancing the apoptosis of HeLa cells, but also significantly induced impaired energy metabolism and restrained their migration and invasion. In addition, the modified analog 6 showed reduced toxicity to normal cells without decreased anti-cancer effect. In conclusion, fenbendazole and analog 6 have multiple targets and strong anti-tumor effects on HeLa cells in vitro and in vivo. The optimized analog 6 could inhibit the viability of HeLa cells with lower toxicity than normal human cells, promising to be developed as an antitumor active compound.


The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients.
One hundred and eighty-six patients with intracranial meningiomas were treated at the Royal Marsden Hospital between 1963 and 1983 with megavoltage photon irradiation (60Co gamma rays and 6-8 Mv. X rays). Survival parameters were measured from the time of referral for radiotherapy. The 10-year actuarial cause-specific survival was 67% for all cases and the actuarial disease-free survival was 61%. Both malignant and also "aggressive benign" histologies were associated with poor long-term survival. Benign angioblastic meningioma was associated with lower actuarial cause specific and disease-free survival compared with other benign histological sub-groups. Prognosis was related to the extent of initial surgical resection. Of those who underwent subtotal or partial tumor resection with post-operative radiotherapy the 10-year actuarial cause-specific survival was 77%, and in inoperable patients treated by radiotherapy alone it was 46%. Radiotherapy alone resulted in improvement of neurological performance (Karnofsky) in 12 out of the 32 (38%) patients with inoperable disease. The 10-year survival of patients referred for irradiation following "complete" surgical resection was only 34% owing to the high incidence of adverse histological sub-types in this treatment sub-group. Based upon univariate analysis, performance status of less than 60 (Karnofsky) and also age greater than 50 years at the time of referral for radiotherapy were adverse prognostic factors. Multivariate analysis revealed that histological type, extent of surgical resection and performance status at the time of presentation for radiotherapy were independent prognostic variables. However age at the time of referral lost significance as an independent variable when analyzed using this method. Patients undergoing complete surgical resection for the typical benign non-aggressive meningioma do not require adjuvant irradiation. The results of this study support the role of radiotherapy for treatment of incompletely resected and inoperable meningioma of all 3 histological types (benign, "aggressive benign", malignant).


Quadricuspid pulmonic valve found on well exam.
Quadricuspid pulmonic valve (QPV) is almost always a benign anomaly and is therefore usually discovered incidentally on radiographic studies or post-mortem at autopsy. Because of its rarity, the true extent of the physiology of QPV is not fully understood, and the few reported cases of it may underestimate its physiological consequences. In this case, we report on a young active-duty solider who presented for a well check-up and was discovered on imaging to have a QPV. We also review the most recent literature and provide recommendations regarding the most effective diagnostic modalities.


Demonstrating disease freedom-combining confidence levels.
Part of the requirements for demonstrating disease freedom usually will be that sufficient testing be done to give a specified confidence of detecting the disease if it were present at a specified level. Often, this requirement is translated into a fixed testing regime that must be followed (an inflexible approach that might not be the most economic or practical solution).A more flexible approach is to specify the capabilities of the various tests that can be used to detect the disease, and let the party hoping to demonstrate disease freedom decide upon the testing regime. The question then arises as to how to combine information that can come from a variety of sources over a period of time to give an overall level of confidence. Two methods are given. The first, an exact method based on multiplying probabilities, would be more appropriate for a survey of an area in which no disease is thought to be present. The second method (more appropriate for a herd-assurance program within an infected area) is a point-based system that takes into account the different sensitivities of the methods used to detect disease and the change in prevalence over time. It allocates points for each test done proportional to the sensitivity of the test and the prevalence at the time of testing.


Initial treatment of early-stage small-sized non-small cell lung cancer for octogenarians: a population-based study.
The objectives of this study is to figure out the appropriate initial treatment and criteria for clinical decision for early-stage small-sized non-small cell lung cancer (NSCLC) among octogenarians. Elderly patients (≥80 years) with stage I NSCLC (<3 cm) were identified between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. Patients were divided into four cohorts regarding treatment modalities, and overall survival and cancer-specific survival were evaluated via Kaplan-Meier analysis and Cox proportional hazard model. The propensity score matching method was introduced in the subgroup analysis stratified by four clinical characteristics to identify the preferable treatment. A total of 7861 patients were included with a median overall survival of 43 months (range 1-155 months). In younger patients (80-85 years), lobectomy was superior in improving the survival (versus segmentectomy, HR = 0.68, 95%CI 0.55-0.84; versus wedge resection, HR = 0.77; 95%CI 0.67-0.88). While in those over 85 years, lobectomy was superior to wedge resection (HR = 0.72; 95%CI 0.53-0.98), and all other treatments were comparable. As stratified by T stage in those over 85 years, lobectomy was superior to wedge resection (P = 0.023) for T1 disease, and the four treatments were all comparable in overall survival for T2 disease. In conclusions, the favored treatment of early stage NSCLC for octogenarians may be evaluated by age and T stage. Lobectomy might be preferred in patients between 80 and 85 years whenever possible. Among those over 85 years, radiotherapy might lead to a comparable prognosis and could be recommended as the prior treatment, while should surgery be recommended, lobectomy might be preferred for T1 disease and wedge resection for T2 disease.


Physical Activity Adherence Related to Body Composition and Physical Fitness in Spanish Older Adults: 8 Years-Longitudinal EXERNET-Study.
The multiple benefits of physical activity (PA) compared to the current lack of adherence to this behavior in older people makes it necessary to identify the factors related to its long-term dropout, therefore, the aim of this study was: (i) to study the evolution of behavior change for PA through stages of change (SoC) after 8 years and, to identify the associated factors related to the worsening of SoC for PA. A total of 714 Spanish older adults (>65 years) participated in the Longitudinal elderly EXERNET study 8 years follow-up. SoC for PA from Transtheoretical model of behavior change (TTM), body composition [BMI, fat mass, lean mass, waist circumference (WC), and hip circumference (HC)] and physical fitness (EXERNET battery fitness tests) were recorded. A multivariate binary logistic regression model was used to identify the potential predictive factors of worsening SoC for PA. Three hundred and sixty participants (50.4%) worsening their SoC for PA after 8 years. Predictors factors associated with worsening of SoC were: HC (OR = 1.022; 95% CI: 1.001, 1.044), Lower body strength (OR = 0.940; 95% CI: 0.887, 0.997) and aerobic endurance at the 6 min-walk test (OR = 0.997; 95% CI: 0.995, 0.999). This study highlights that we need to identify adults with high HC, lower body strength and lower aerobic endurance to design a tailored PA program. Identifying the determinants of losing adherence to PA will help in the creation, design, and evaluation of exercise programs with the goal of reducing older adults' drop-outs rates.


Subcutaneous Immunotherapy and Sublingual Immunotherapy: Comparative Efficacy, Current and Potential Indications, and Warnings--United States Versus Europe.
Subcutaneous immunotherapy and sublingual immunotherapy are effective for allergic rhinitis and allergic asthma and with some support for use in selected patients with atopic dermatitis. The sequence of immunologic responses is the same, irrespective of the route of administration, and similar disease modification has been demonstrated. However, there are differences between the two approaches. The most important is the greatly reduced likelihood of sublingual immunotherapy producing systemic reactions. There are major drawbacks for sublingual immunotherapy in regard to dosing. Finally, there is the question of relative clinical efficacy, with the currently available data favoring subcutaneous immunotherapy.


Melanoma, Darwinian medicine and the inner world.
A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation. An added dimension has now emerged--the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8(+) T-cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed. The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed.


Synthesis of fluorescent substrates for protein tyrosine phosphatase assays.
Two fluorescent substrates for protein tyrosine phosphatase (PTPase) reaction were prepared by conjugation of commercially available O-phosphotyrosine and dansyl chlorides. They were hydrolyzed by CD45 tyrosine phosphatase, and proved to be useful for PTPase assay.


Palatal perforations: past and present. Two case reports and a literature review.
Syphilis and cocaine abuse are posing a growing public health problem on a global and national scale. Clinicians are increasingly likely to come across associated oral manifestations. We present two cases of palatal perforations caused by tertiary syphilis and cocaine abuse respectively. The literature review discusses issues specific to palatal perforations and those general to both conditions. The purpose of the report is to focus attention on syphilis and cocaine abuse as rising problems for the dental profession.


Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment.
Congenital cytomegalovirus (CMV) infection is a cause of sensorineural hearing loss (SNHL) in children, but the magnitude of its contribution is uncertain. Quantifying the impact of congenital CMV infection requires an evidence-based assessment using a standard case definition of hearing loss. To determine the frequency of bilateral moderate to profound SNHL in children with congenital CMV infection and to estimate the CMV-attributable fraction of bilateral moderate to profound SNHL. A systematic review of studies of children with congenital CMV infection ascertained in an unbiased manner through universal newborn screening for CMV using viral culture in urine or saliva specimens in combination with a review of the literature on congenital CMV infection and hearing loss, including articles of all types. Approximately, 14% of children with congenital CMV infection develop SNHL of some type, and 3-5% develop bilateral moderate to profound SNHL. Among all children with bilateral moderate to profound SNHL, we estimate that 15-20% of cases are attributable to congenital CMV infection. Congenital CMV infection is one of the most important causes of hearing loss in young children, second only to genetic mutations, and is potentially preventable.


Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic refractory heart failure. Concomitant relief of pulmonary congestion and elevation of pump output demonstrated by improvements in symptomatology, exercise tolerance, hemodynamics and echocardiography.
The long-term efficacy of the new oral vasodilator, prazosin (PZ), was evaluated in nine patients with refractory heart failure due to chronic coronary heart disease. Ventricular function was assessed by cardiac catheterization, echocardiography, and treadmill testing; symptomatic evaluation was carried out for two to four months. One hour following 2-7 mg PZ, control left ventricular filling pressure was reduced (32 to 18 mm Hg, P less than 0.001) and cardiac index was elevated (1.95 to 2.89 L/min/m2, P less than 0.001) for a 6-hour period. After two weeks of PZ 2 to 7 mg four times daily, echographic end-diastolic dimension fell (5.7 to 5.4 cm, P less than 0.001) while shortening fraction increased (27.6 to 30.2%, P less than 0.005). Treadmill exercise duration increased from 209 to 317 seconds (P less than 0.001). Symptoms diminished throughout the duration of follow-up (mean 94 days) with improvement in NYHA functional class (3.7 to 2.2, P less than 0.001). Thus, prazosin possesses sustained nitroprusside-like balanced dilator actions on the systemic arterial and venous systems and is effective in the ambulatory management of chronic severe heart failure.


Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST-elevation myocardial infarction.
Microparticles (MP) are small membrane vesicles, released from activated, damaged and apoptotic endothelial cells (EMP) or platelets (PMP) that may actively modulate inflammation, coagulation and vascular function. We tested the hypothesis that the number of circulating EMP or PMP in acute myocardial infarction correlates with the myocardium at risk (MaR) and infarct size (IS). EMP were quantified in plasma samples of 36 patients (age: 63±10 years) with first time ST-elevation myocardial infarction (STEMI) using flow cytometry. EMP were defined as CD31(+)/CD42(-) MP and CD144(+) MP and PMP as CD31(+)/CD42(+) MP. MaR and IS was determined by cardiovascular magnetic resonance imaging one week after the index event. Plasma levels of CD31(+)/CD42(-) EMP were 251.0±178.8/μl and CD144(+) 106.3±33.7/μl. PMP levels were 579.2±631.8/μl. MaR was 31.0±11.2% of the left ventricle and IS was 11.4±7.1% of the left ventricle. Patients with STEMI in the left anterior descending artery had higher levels of CD31(+)/CD42(-) EMP and PMP than those with other infarct-related arteries (p<0.05). The numbers of CD31(+)/CD42(-) EMP and PMP correlated to MaR, but not to IS. Circulating EMP and PMP correlate to the size of MaR in patients with STEMI suggesting that they reflect the severity of the endothelial injury and platelet activation during myocardial ischemia.


[Value of simulation in pediatrics].
The authors present the concepts of simulation and its utilization in pediatrics. Simulation in medicine is a teaching method that has not yet been developed in Europe and has not spread in pediatrics in France. Motivations for simulation are first and foremost ethical: "Never the first time on patients!" Simulation also provides benefits in teaching communication skills and theoretical concepts. It is an essential means to maintain patient safety by limiting the risk of errors. It covers teaching procedures requiring realistic models such as in teaching communication and crisis resource management. Simulation can also be used for teaching disclosure of bad news, using actors. Simulation skills are acquired during debriefing, when the supervisor acts as a facilitator. Evaluation is mandatory in simulation, dependent on the how realistic the models are and on the performance of a procedure or multidisciplinary team management. Performance can be objectively assessed only with validated tools. Simulation will become a mandatory teaching method in medicine.


Are immediate postoperative X-Rays valuable in evaluating complications of primary total hip arthroplasty?
This study aimed to investigate the complications of primary total hip arthroplasty based on immediate postoperative X-rays. The overall quality and cost of X-rays were assessed. The institutional database was queried to identify all patients who underwent total hip arthroplasty in a single institution between January 1, 2018, and December 31, 2018. Immediate postoperative X-rays were reviewed to identify the complications such as periprosthetic fractures, dislocation, and fixation failure. The quality and cost of X-ray were assessed. The complications were categorized as "known" and "unknown" according to the intraoperative fluoroscopic results. A total of 518 total hip arthroplasties were included in this study. Based on intraoperative fluoroscopy, periprosthetic fractures were found in 10 (2%) THAs. Compared to the X-rays taken immediately after surgery, 9 periprosthetic fractures (recorded as "known") were found and 1 was not (recorded as "unknown"). There was no significant difference between intraoperative fluoroscopy and X-rays (P > 0.05). Of the 518 X-rays, 225 (43%) were of suboptimal quality. The cost of a single portable pelvic X-ray was $647. In total hip arthroplasty, X-rays taken immediately after surgery rarely reveal unknown complications. The X-rays are often of suboptimal quality, have minimal clinical utility, and are less cost-effective.


Facial palsy as a manifestation of COVID-19: A systematic review of cases.
Facial palsy is a rare complication of the COVID-19 infection. Herein, we conducted a systematic review of all published cases of facial palsy post-COVID-19 infection in an attempt to educate the general population and medical practitioners regarding the likely occurrence of facial palsy in COVID-19 patients, its detection, effective treatment plan, and prognosis of the condition. We searched PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) from December 1, 2019 to September 21, 2021. We included 49 studies bearing accounts of 75 cases who had facial palsy. The mean age of patients was 42.9 ± 19.59 years, with a male-to-female ratio of 8:7. The majority of the cases were reported from Brazil (n = 14), USA (n = 9), Turkey (n = 9), and Spain (n = 9). Noticeably, 30.14% of COVID-19 patients were diagnosed with Guillain-Barré syndrome. In total, 22.97% of patients complained of bilateral facial paralysis (n = 17), whereas ipsilateral paralysis was observed in 77.03% (n = 57). These were common complaints of Lagophthalmos, otalgia, facial drooping, dysarthria, and compromised forehead wrinkling. The treatment regimen mainly included the use of corticosteroids (n = 51) (69.86%), antivirals (n = 23) (31.51%), IVIG (n = 18) (24.66%), antibiotics (n = 13) (17.81%), antiretroviral (n = 9) (12.33%), and antimalarial (n = 8) (10.96%) medications. In all, 35.62% of patients (n = 26) adhered to a combination of antiviral and corticosteroid-based therapy. Positive treatment outcomes were observed in 83.58% (n = 56) of cases. In contrast, 10 patients (14.93%) showed nonsignificant recovery, out of which 3 (4.48%) died from the disease. The association of facial palsy with COVID-19 is controversial and therefore requires further investigation and published work to confirm a causal relationship. However, physicians should not overlook the likelihood of facial palsy post-COVID-19 infection and treat it accordingly.


Probing Metabolism in the Intact Retina Using Stable Isotope Tracers.
Vertebrate retinas have several characteristics that make them particularly interesting from a metabolic perspective. The retinas have a highly laminated structure, high energy demands, and they share several metabolic features with tumors, such as a strong Warburg effect and abundant pyruvate kinase M2 isoform expression. The energy demands of retinas are both qualitatively and quantitatively different in light and darkness and metabolic dysfunction could cause retinal degeneration. Stable isotope-based metabolic analysis with mass spectrometry is a powerful tool to trace the dynamic metabolic reactions and reveal novel metabolic pathways within cells and between cells in retina. Here, we describe methods to quantify retinal metabolism in intact retinas and discuss applications of these methods to the understanding of neuron-glia interaction, light and dark adaptation, and retinal degenerative diseases.


Treating the right patient at the right time: an innovative approach to the management of atrial fibrillation.
The Canadian Cardiovascular Society Access to Care Working Group recently published a series of commentaries on access to cardiovascular care in Canada. These commentaries included proposed minimally acceptable wait times for patients with atrial fibrillation (AF) to be assessed by a cardiologist or an electrophysiologist. To improve access to medical care for the patient with AF, a nurse clinician-based AF clinic was established in the Calgary Health Region (Alberta) in 2005. More than 330 patients had been referred at the time of writing. The time from referral to initial nurse assessment was 38+/-31 days, to physician review and establishment of a management plan was 66+/-49 days and to in-person specialist physician assessment was 80+/-55 days. These wait times are markedly shorter than historical wait times to see an arrhythmia specialist in the Calgary Region. As experience increased, wait times continued to shorten significantly. Preliminary data suggest that early assessment and patient education may reduce emergency department visits and hospitalizations for AF. This experience suggests that a nurse clinician-based AF clinic may provide earlier access to medical care and may improve health outcomes in the long term.


Bluetongue virus, an exceptionally potent interferon inducer in mice.
The attenuated American BT-8 strain of bluetongue virus is 5 to 10 times more potent an interferon inducer than any other viral or nonviral agent reported to date, including as much as 600,000 units/ml of plasma by 8 h after intravenous injection.


Early Cerebral Infarction after Aneurysmal Subarachnoid Hemorrhage.
Aneurysmal subarachnoid hemorrhage (SAH) is a serious disease with high case fatality and morbidity. Early cerebral infarction has been suggested as a risk factor for poor outcome. We aimed to assess the pattern of early and delayed cerebral infarction after aneurysmal subarachnoid hemorrhage. We prospectively enrolled consecutive aneurysmal subarachnoid hemorrhage (SAH) patients presenting to an academic neurosurgical referral center (Prince of Wales Hospital, the Chinese University of Hong Kong) in Hong Kong. Cerebral infarction occurred in 24 (48 %) patients, in which 14 (28 %) had early cerebral infarction and 14 (28 %) had delayed cerebral infarction. Early anterior cerebral infarction occurred in a similar proportion of anterior and posterior circulation aneurysms (24 % vs. 21 %), whereas posterior circulation aneurysm patients had a higher proportion of early posterior cerebral infarction compared with anterior circulation aneurysm patients (18 % vs. 2 %). In conclusion, early cerebral infarction was common and different from delayed cerebral infarction.


Dust mite induces multiple polar T cell axes in human skin.
House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new-onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model AD's emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown. To assess whether HDM APT reproduces AD. Positive HDM APTs (n = 15) from patients with and without AD were evaluated, using genomic and immunohistochemistry studies, against intrapersonal control skin. APT lesions showed higher T cell and dendritic cell infiltrates vs. Seven hundred and forty-three up- and 326 downregulated genes were differentially expressed in HDM APT (fold change >2 and false discovery rate < 0.05), with increased expression of Th2, Th9, Th17/Th22 polar cytokines (i.e. IL-5, IL-13, IL-9, IL-17, IL-22). While HDM caused significant Th2 skewing, it also illustrated differences in Th2 induction and barrier defects; thus, HDM APT does not fully simulate AD. Given its widespread availability and sensitization rates, HDM may potentially be a useful tool that represents select aspects of AD, psoriasis, or contact dermatitis.


Effects of clinically significant weight loss with exercise training on insulin resistance and cardiometabolic adaptations.
To determine response rates for clinically significant weight loss (CWL) following different aerobic exercise training amounts and whether enhanced cardiometabolic adaptations are observed with CWL compared to modest weight loss (MWL) or neither. Participants (N = 330) performed 6 months of aerobic training at 4 kcal per kilogram per week (KKW), 8 KKW, or 12 KKW (50%, 100%, and 150% of recommended levels respectively). Weight loss was categorized as CWL (≥5%) or MWL (3.0% to 4.9%) or neither. The CWL response rate was greater in the 8 KKW group (20.2%, CI: 13.0% to 27.5%) compared to 4 KKW (10.3%, CI: 4.6% to 16.0%), but not compared to the 12 KKW group (14.6%, CI: 7.6% to 21.6%). Reductions in HOMA-IR were observed in participants with CWL (-0.60, CI: -0.98 to -0.22) and with MWL (-0.48, CI: -0.87 to -0.10), but not those who achieved neither (-0.06, CI -0.22 to 0.10). No changes between groups were observed for cholesterol, fitness, or blood pressure. Low response rates for CWL were observed following training, even at levels above recommended levels. Achieving MWL with exercise may represent a reasonable initial weight loss target since the improvement in insulin resistance with MWL is similar to what is achieved with CWL.


Using integrated analysis from multicentre studies to identify RNA methylation-related lncRNA risk stratification systems for glioma.
N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether RNA methylation-related long noncoding RNAs (lncRNAs) affect the prognosis of glioma. We summarized 32 m6A/m5C/m1A-related genes and downloaded RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed (DE-) RNA methylation-related lncRNAs in order to construct a prognostic signature of glioma and in order to determine their correlation with immune function, immune therapy and drug sensitivity. In vitro and in vivo assays were performed to elucidate the effects of RNA methylation-related lncRNAs on glioma. A total of ten RNA methylation-related lncRNAs were used to construct a survival and prognosis signature, which had good independent prediction ability for patients. It was found that the high-risk group had worse overall survival (OS) than the low-risk group in all cohorts. In addition, the risk group informed the immune function, immunotherapy response and drug sensitivity of patients with glioma in different subgroups. Knockdown of RP11-98I9.4 and RP11-752G15.8 induced a more invasive phenotype, accelerated cell growth and apparent resistance to temozolomide (TMZ) both in vitro and in vivo. We observed significantly elevated global RNA m5C and m6A levels in glioma cells. Our study determined the prognostic implication of RNA methylation-related lncRNAs in gliomas, established an RNA methylation-related lncRNA prognostic model, and elucidated that RP11-98I9.4 and RP11-752G15.8 could suppress glioma proliferation, migration and TMZ resistance. In the future, these RNA methylation-related lncRNAs may become a new choice for immunotherapy of glioma.