Increased Expression of Epileptiform Spike/Wave Discharges One Year after Mild, Moderate, or Severe Fluid Percussion Brain Injury in Rats.
In this study, we describe increased expression of cortical epileptiform spike/wave discharges (SWD) in rats one year after mild, moderate, or severe fluid percussion traumatic brain injury (fpTBI). Groups of rats consisted of animals that had received mild, moderate, or severe fpTBI, or sham operation one year earlier than electrocorticography (ECoG) recordings. In addition, we included a group of age-matched naïve animals. ECoG was recorded from awake animals using epidural electrodes implanted on the injured hemisphere (right), sham-operated hemisphere (right), or right hemisphere in naïve animals. The SWDs were detected automatically using Fast Fourier Transformation and a novel algorithm for comparing changes in spectral power to control (nonepileptical) ECoG. The fpTBI resulted in increased expression of SWDs one year after injury compared with sham-operated or naïve animals. The number of SWD-containing ECoG epochs recorded in a 1 h recording session were: naïve 12.9 ± 10.3, n = 8, sham 23.6 ± 8.2, n = 10, mild TBI 78.9 ± 23.9, n = 10, moderate TBI 61.3 ± 32.5, n = 12, severe TBI 72.5 ± 28.3, n = 11 (mean ± standard error of the mean). Increased expression of SWDs was not related to injury severity. SWDs were observed to a lesser extent even in sham-operated and naïve animals. The data indicate that fpTBI exacerbates expression of SWDs in the rat and that this increase may be observed at least one year after injury. As others have discussed, the spontaneous occurrence of these epileptiform events in rodents limits the use of this model for investigations of acquired epilepsy, at least of the nonconvulsive type, after TBI.


The proteolytic environment involved in MHC class II-restricted antigen presentation can be modulated by the p41 form of invariant chain.
During biosynthesis, MHC class II associates with invariant chain which exists in two forms, p31 and p41. Both forms of invariant chain prevent peptide binding to class II, facilitate transport, and enhance class II localization to Ag-processing compartments. In spite of these shared functions, presentation of some Ags can be selectively enhanced by expression of p41. Here we show that p41 can function as a protease inhibitor: 1) the functional and biochemical consequences of p41 expression can be mimicked by inhibiting cysteine proteases in vivo; 2) the amount of intracellular active cysteine proteases is dramatically decreased in p41-positive cells; and 3) a polypeptide corresponding to the p41-unique region is a potent inhibitor of cathepsin L in vitro. These data suggest that p41 can enhance Ag presentation by reducing the proteolytic activity of the Ag-processing compartment, thus protecting a subset of antigenic epitopes from excessive degradation.


Quantitative measurement of spastic ankle joint stiffness using a manual device: a preliminary study.
Quantitative measurement of ankle joint stiffness following stroke could prove useful in monitoring the progress of a rehabilitation programme. The objective of this study was to design a manual device for use in the clinical setting. Manual measurement of spastic ankle joint stiffness has historically been conducted using hand-held dynamometers or alternative devices, but some difficulties have been reported in controlling the velocity applied to the ankle during the measurement. In this study, a manually operated device was constructed with a footplate, a torquemeter and a potentiometer. It was mechanically designed to rotate around an approximated axis of the ankle joint and to measure ankle joint angular position and its corresponding resistive torque. Two stroke hemiplegic subjects pariticapted in a pilot study. The results suggested that difficulty in controlling the applied velocity might be complemented by presenting torque data as a function of peak angular velocity in each stretching cycle. Moreover, the results demonstrated that the device could potentially apply a wide range of angular velocities and provide potentially useful clinical information. Quantitative data successfully acquired using this method included the approximate ankle angular position, where the velocity-dependent characteristics of stiffness was notably initiated and its corresponding torque and velocity.


The effects of 2-hydroxy-4-methylthio-butanoic acid supplementation on the rumen microbial population and duodenal flow of microbial nitrogen.
Four multiparous, lactating Holstein cows (average DIM 169.5 ± 20.5 d), fitted with ruminal and duodenal cannulas, were used in a 4 × 4 Latin square with a 2 × 2 factorial arrangement of treatments to investigate the effects of 2-hydroxy-4-methylthio-butanoic acid (HMTBA) when fed with diets differing in metabolizable protein (MP) supply and equal levels of crude protein on milk production and composition, rumen microbial activity, duodenal protein flow, and rumen bacterial community composition in vivo and in vitro. Experimental periods were 28 d in length. Cows were housed in individual tie stalls and were randomly assigned to 4 dietary treatments: low MP or high MP, supplemented with or without 25 g of HMTBA, which was top-dressed once daily at 0930 h. No interactions were observed between HMTBA and level of dietary MP, with the exception of ruminal acetate-to-propionate ratio. Milk yield was not affected by treatment and averaged 23.8 ± 2.06 kg/d. There was a tendency for increased milk protein percent in cows receiving low MP diets, averaging 3.30 ± 0.09% and 3.21 ± 0.09% for low MP and high MP, respectively. The total-tract apparent digestibility of organic matter, neutral detergent fiber, and nitrogen were greater in cows consuming the low MP diet. Rumen pH was lower in cows consuming high MP diets as well as in those consuming HMTBA. Rumen ammonia concentrations tended to be greater in cows consuming HMTBA, and volatile fatty acid concentrations were greater in cows consuming HMTBA. Duodenal dry matter flow, nitrogen flow, and microbial nitrogen flow did not differ between treatments. The bacterial community structure of cows receiving HMTBA was not affected at the phylum level. The relative abundance of bacterial phyla in vivo differed when compared with in vitro conditions for Firmicutes, Bacteroidetes, Proteobacteria, TM7, Tenericutes, Spirochaetes, SR1, and Verrucomicrobia.


Forty-eight hour ice storage of kidneys: importance of cation content.
The importance of the cation content of flush solutions used for simple hypothermic storage has been investigated in a 48 hour canine kidney preservation model. Uniformly successful 48 hour storage was achieved with solution C2. However, inclusion of procaine (0.1 Gm. per 100 ml.) in the flushing solution as in C3 produced significant kidney damage. Without procaine, Sacks solution was no better than was C2 and the latter proved significantly superior to a sodium-based solution having identical anion content and osmolarity. The magnesium content of the sodium appeared to favorably influence the outcome of the kidney storage experiments.


Locus of Heat Resistance (LHR) in Meat-Borne Escherichia coli: Screening and Genetic Characterization.
Microbial resistance to processing treatments poses a food safety concern, as treatment tolerant pathogens can emerge. Occasional foodborne outbreaks caused by pathogenic Escherichia coli have led to human and economic losses. Therefore, this study screened for the extreme heat resistance (XHR) phenotype as well as one known genetic marker, the locus of heat resistance (LHR), in 4,123 E. coli isolates from diverse meat animals at different processing stages. The prevalences of XHR and LHR among the meat-borne E. coli were found to be 10.3% and 11.4%, respectively, with 19% agreement between the two. Finished meat products showed the highest LHR prevalence (24.3%) compared to other processing stages (0 to 0.6%). None of the LHR+E. coli in this study would be considered pathogens based on screening for virulence genes. Four high-quality genomes were generated by whole-genome sequencing of representative LHR+ isolates. Nine horizontally acquired LHRs were identified and characterized, four plasmid-borne and five chromosomal. Nine newly identified LHRs belong to ClpK1 LHR or ClpK2 LHR variants sharing 61 to 68% nucleotide sequence identity, while one LHR appears to be a hybrid. Our observations suggest positive correlation between the number of LHR regions present in isolates and the extent of heat resistance. The isolate exhibiting the highest degree of heat resistance possessed four LHRs belonging to three different variant groups. Maintenance of as many as four LHRs in a single genome emphasizes the benefits of the LHR in bacterial physiology and stress response.IMPORTANCE Currently, a "multiple-hurdle" approach based on a combination of different antimicrobial interventions, including heat, is being utilized during meat processing to control the burden of spoilage and pathogenic bacteria. Our recent study (M. Guragain, G. E. Smith, D. A. King, and J. M. Bosilevac, J Food Prot 83:1438-1443, 2020, https://doi.org/10.4315/JFP-20-103) suggests that U.S. beef cattle harbor Escherichia coli that possess the locus of heat resistance (LHR). LHR seemingly contributes to the global stress tolerance in bacteria and hence poses a food safety concern. Therefore, it is important to understand the distribution of the LHRs among meat-borne bacteria identified at different stages of different meat processing systems. Complete genome sequencing and comparative analysis of selected heat-resistant bacteria provide a clearer understanding of stress and heat resistance mechanisms. Further, sequencing data may offer a platform to gain further insights into the genetic background that provides optimal bacterial tolerance against heat and other processing treatments.


Effect of pharmacological treatment for urinary incontinence in the elderly and frail elderly: A systematic review.
The prevalence and severity of urinary incontinence (UI) increase with age and comorbidity. The benefits of pharmacotherapy for UI in the elderly are questionable. The aim of the present study was to systematically review the efficacy of pharmacological treatment for UI in the elderly and frail elderly. We searched PubMed, EMBASE, Cochrane library and Cinahl databases through October 2013 to identify prospective controlled trials that evaluated pharmacological treatment for UI in persons aged ≥65 years. Elderly persons living in nursing homes were regarded as frail elderly. Outcomes were urinary leakage, quality of life and adverse events. We screened 1038 abstracts and assessed 309 full-text articles. We identified 13 trials of high or moderate quality; 11 evaluated anticholinergic drugs and two evaluated duloxetine. Oxybutynin, the only drug studied in the frail elderly population, had no effect on urinary leakage or quality of life in elderly with urgency UI (UUI). Seven trials evaluated the effects of darifenacin, fesoterodine, solifenacin, tolterodine or trospium. Urinary leakage decreased (standard mean difference: -0.24, 95% confidence interval -0.32-0.15), corresponding to a reduction of half a leakage per 24 h. Common side-effects of treatment were dry mouth and constipation. Data were insufficient for evaluation of the effect on quality of life or cognition. The evidence was insufficient to evaluate the effects of duloxetine. No eligible studies on mirabegron and estrogen were found. Anticholinergics have a small, but significant, effect on urinary leakage in older adults with UUI. Treatment with drugs for UUI in the frail elderly is not evidence based.


Practical issues of biomarker-assisted targeted therapy in precision medicine and immuno-oncology era.
The concept of precision medicine is not new, as multiplex and very sensitive methods, or next-generation sequencing and matched targeted cancer therapies, have come to clinical practice. Substantial progress has been made from the discovery to the development and clinical application of biomarkers and matched targeted therapies. However, there still remain many challenges and issues to be overcome in each step, from acquisition of tumour tissues through validation of biomarkers to the final decision on targeted therapy. This review will briefly touch on these issues, hoping to provide a better understanding and application of targeted therapy in cancer treatment in the era of precision medicine and immuno-oncology. It also helps to understand that the meaning or value of biomarker(s) and matched targeted therapy changes along with expansion of knowledge and advance of methodology, and constant efforts have to be made in evaluating the meaning and clinical value during the development and after the establishment of biomarkers or the approval of matched targeted therapies, which might be more complicated by the advent of new therapeutic agents and new diagnostic methods.


Pre/postnatal taurine supplementation improves neurodevelopment and brain function in mice offspring: A persistent developmental study from puberty to maturity.
Taurine (TAU) is a sulfur-containing amino acid abundantly found in the human body. Endogenously, TAU is synthesized from cysteine in the liver. However, newborns rely entirely on TAU's dietary supply (milk). There is no investigation on the effect of long-term TAU administration on next-generation neurological development. The current study evaluated the effect of long-term TAU supplementation during the maternal gestational and litter weaning time on several neurological parameters in mice offspring. Moreover, the effects of TAU on mitochondrial function and oxidative stress biomarkers as plausible mechanisms of its action in the whole brain and hippocampus have been evaluated. TAU (0.5 % and 1 % w/v) was dissolved in the drinking water of pregnant mice (Day one of pregnancy), and amino acid supplementation was continued during the weaning time (post-natal day; PND = 21) until litters maturity (PND = 65). It was found that TAU significantly improved cognitive function, memory performance, reflexive motor activity, and emotional behaviors in F1-mice generation. TAU measurement in the brain and hippocampus revealed higher levels of this amino acid. TAU and ATP levels were also significantly higher in the mitochondria isolated from the whole brain and hippocampus. Based on these data, TAU could be suggested as a supplement during pregnancy or in pediatric formula. The effects of TAU on cellular mitochondrial function and energy metabolism might play a fundamental role in the positive effects of this amino acid observed in this investigation.


Macro square wave jerks in a rhesus monkey: physiological and anatomical findings in a case of selective impairment of attentive fixation.
An otherwise normal female rhesus monkey executed large saccadic eye movements (macro square wave jerks) when required to attentively fixate a small visual target (fixation point). The jerks were observed exclusively in this specific testing situation. They occurred periodically at a frequency of 2.04 + - 0.18 Hz to the right side with an amplitude of 23.5 deg. Direction of the jerks was about 3-4 degrees downward from horizontal. These parameters remained constant throughout the several months of daily recording. No jerks were executed during periods when the behaviourally important target was absent or substituted by another, behaviourally non-relevant visual stimulus. The monkey could perform normal visually guided saccades as well as smooth pursuit eye movements, but with the jerks always superimposed, when the monkey paid attention to the visual target. Histologic inspection of the brain revealed the presence of an incapsulated nematode in the cortex of lobulus simplex of the right cerebellar hemisphere, i.e., in a region involved in oculomotor control.


The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications.
Epigenetic gene regulation has emerged as a major mechanism for gene regulation in all eukaryotes. Histones are small, basic proteins that constitute the major protein component of chromatin, and posttranslational modifications (PTM) of histones are essential for epigenetic gene regulation. The different combinations of histone PTM form the histone code for an organism, marking functional units of chromatin that recruit macromolecular complexes that govern chromatin structure and regulate gene expression. To characterize the repertoire of Toxoplasma gondii histone PTM, we enriched histones using standard acid extraction protocols and analyzed them with several complementary middle-down and bottom-up proteomic approaches with the high-resolution Orbitrap mass spectrometer using collision-induced dissociation (CID), higher-energy collisional dissociation (HCD), and/or electron transfer dissociation (ETD) fragmentation. We identified 249 peptides with unique combinations of PTM that comprise the T. gondii histone code. T. gondii histones share a high degree of sequence conservation with human histones, and many modifications are conserved between these species. In addition, T. gondii histones have unique modifications not previously identified in other species. Finally, T. gondii histones are modified by succinylation, propionylation, and formylation, recently described histone PTM that have not previously been identified in parasitic protozoa. The characterization of the T. gondii histone code will facilitate in-depth analysis of how epigenetic regulation affects gene expression in pathogenic apicomplexan parasites and identify a new model system for elucidating the biological functions of novel histone PTM. Toxoplasma gondii is among the most common parasitic infections in humans. The transition between the different stages of the T. gondii life cycle are essential for parasite virulence and survival. These differentiation events are accompanied by significant changes in gene expression, and the control mechanisms for these transitions have not been elucidated. Important mechanisms that are involved in the control of gene expression are the epigenetic modifications that have been identified in several eukaryotes. T. gondii has a full complement of histone-modifying enzymes, histones, and variants. In this paper, we identify over a hundred PTM and a full repertoire of PTM combinations for T. gondii histones, providing the first large-scale characterization of the T. gondii histone code and an essential initial step for understanding how epigenetic modifications affect gene expression and other processes in this organism.


Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer.
Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases (RTKs), is highly expressed in head and neck squamous cell carcinoma (HNSCC) where increased EGFR expression levels in tumors are associated with decreased survival. HNSCC patient responses to EGFR-targeted monotherapies in clinical trials, though significant, have been limited. Tumor signaling pathway components that work in cooperation with EGFR or provide compensation for the loss of EGFR-initiated signaling will be ideal targets for therapies to be used in combination with EGFR-targeted agents. Based on the current understanding of molecular signaling pathways and available agents, ErbB family-targeted and Src family-targeted agents represent strategies for further exploration. Here, we discuss agents targeting ErbB and Src family kinases in clinical development, provide an overview of completed and ongoing clinical trials, and outline a molecular rationale for combining ErbB- and Src-targeted therapeutics.


Area characteristics and admission rates of people with schizophrenia and affective disorders in a German rural catchment area.
Studies in urban areas identified environmental risk factors for mental illness, but little research on this topic has been performed in rural areas. Hospital admission rates were computed for 174 rural municipalities in the catchment area of the state psychiatric hospital in Günzburg in years 2006 to 2009 and combined with structural and socio-economic data. Relationships of overall and diagnosis-specific admission rates with municipality characteristics were analysed by means of negative binomial regression models. Admission rates of patients with a diagnosis of schizophrenia and affective disorder combined decrease with increasing population growth, population density, average income and green areas, while admission rates are positively correlated with commuter balance, income inequality, unemployment rates and traffic areas. Admission rates for schizophrenia are negatively related to population growth, average income and agricultural areas, but positively related to mobility index, income inequality and unemployment rate. Admission rates for affective disorders are negatively related to population growth, population density, average income and green areas, while higher admission rates are correlated with commuter balance, high income inequality, unemployment rate and traffic-related areas. Effects of wealth, economic inequality, population density and structural area characteristics influence psychiatric admission rates also in rural areas.


Review of Serial and Parallel Min-Cut/Max-Flow Algorithms for Computer Vision.
Minimum cut/maximum flow (min-cut/max-flow) algorithms solve a variety of problems in computer vision and thus significant effort has been put into developing fast min-cut/max-flow algorithms. As a result, it is difficult to choose an ideal algorithm for a given problem. Furthermore, parallel algorithms have not been thoroughly compared. In this paper, we evaluate the state-of-the-art serial and parallel min-cut/max-flow algorithms on the largest set of computer vision problems yet. We focus on generic algorithms, i.e., for unstructured graphs, but also compare with the specialized GridCut implementation. When applicable, GridCut performs best. Otherwise, the two pseudoflow algorithms, Hochbaum pseudoflow and excesses incremental breadth first search, achieves the overall best performance. The most memory efficient implementation tested is the Boykov-Kolmogorov algorithm. Amongst generic parallel algorithms, we find the bottom-up merging approach by Liu and Sun to be best, but no method is dominant. Of the generic parallel methods, only the parallel preflow push-relabel algorithm is able to efficiently scale with many processors across problem sizes, and no generic parallel method consistently outperforms serial algorithms. Finally, we provide and evaluate strategies for algorithm selection to obtain good expected performance. We make our dataset and implementations publicly available for further research.


[Post-translational modifications modulate estrogen receptor alpha activity in breast tumors].
Regulation of the proteome by post-translational modifications (PTM) emerges as a major contributing factor to the functional diversity in biology regulating cellular processes. Because PTM are key to the physiologic functions of the proteins involved, it is imperative that we understand the << coding >> that these modifications impart to regulate diverse activities. As estrogen signalling mediates a plethora of PTM not only on the receptors themselves but also on their coregulators, we investigate to << crack >> the ER code. Besides the long-known phosphorylation, other covalent additions such as acetylation, ubiquitination, sumoylation and methylation have been described for estrogen receptors in recent years. These modifications affect receptor stability and activity, and provide potential mechanisms for cell- or-gene-specific regulation. A better understanding of the impact of these PTMs on estrogen receptor should help in the identification of new drugs for breast cancer treatments.


Utility of the Current Procedural Terminology Codes for Prophylactic Stabilization for Defining Metastatic Femur Disease.
Cohorts from the electronic health record are often defined by the Current Procedural Terminology (CPT) codes. The error prevalence of CPT codes for patients receiving surgical treatment of metastatic disease of the femur has not been investigated, and the predictive value of coding ontologies to identify patients with metastatic disease of the femur has not been adequately discussed. All surgical cases at a single academic tertiary institution from 2010 through 2015 involving prophylactic stabilization of the femur or fixation of a pathologic fracture of the femur were identified using the CPT and International Classification of Disease (ICD) codes. A detailed chart review was conducted to determine the procedure performed as documented in the surgical note and the patient diagnosis as documented in the pathology report, surgical note, and/or office visit notes. We identified 7 CPT code errors of 171 prophylactic operations (4.1%) and one error of 71 pathologic fracture fixation s(1.4%). Of the 164 prophylactic operations that were coded correctly, 87 (53.0%) had metastatic disease. Of the 70 pathologic operations that were coded correctly, 41 (58%) had metastatic disease. The error prevalence was low in both prophylactic stabilization and pathologic fixation groups (4.1% and 1%, respectively). The structured data (CPT and ICD-9 codes) had a positive predictive value for patients having metastatic disease of 53% for patients in the prophylactic stabilization group and 58% for patients in the pathologic fixation group. The CPT codes and ICD codes assessed in this analysis do provide a useful tool for defining a population in which a moderate proportion of individuals have metastatic disease in the femur at an academic medical center. However, verification is necessary.


Mycobacterium tuberculosis HBHA protein reacts strongly with the serum immunoglobulin M of tuberculosis patients.
Identification and characterization of serologically active mycobacterial antigens are prerequisites for the development of diagnostic reagents. We examined the humoral immune responses of active tuberculosis (TB) patients against Triton-soluble proteins extracted from Mycobacterium tuberculosis by immunoblotting. A 29-kDa protein reacted with immunoglobulin M (IgM) in the pooled sera of the patients, and its N-terminal amino acid sequence matched that of the heparin-binding hemagglutinin (HBHA). Recombinant full-length HBHA was expressed in Escherichia coli (rEC-HBHA) and M. smegmatis (rMS-HBHA). In immunoblot analysis, the IgM antibodies of the TB patients reacted strongly with rMS-HBHA but not with rEC-HBHA, whereas the IgG antibodies of these patients reacted weakly with both recombinant HBHA proteins. In enzyme-linked immunosorbent assay analysis using rMS-HBHA and 85B as antigens, the mean levels and sensitivities of the anti-HBHA IgM antibodies of the TB patients were significantly higher than those of the anti-antigen 85B IgM antibodies, while the IgG antibodies showed the opposite results. Of interest in this respect, the pooled sera from the TB patients that contained anti-HBHA IgM antibodies neutralized the entry of M. tuberculosis into epithelial cells. These findings suggest that IgM antibody to HBHA may play a role in protection against extrapulmonary dissemination.


Coral skeletons: an explanation of their growth and structure.
Coral skeletons are constructed of aragonitic crystals organized into fan systems. A theoretical model for the growth of such fan systems, which depends upon competition between crystals for space in which to grow, is corroborated by vital staining with sodium alizarinesulfonate. Fan systems of crystals compete with each other to form larger fan systems until large, relatively stable fans are produced. It is these relatively stable fan systems that have been observed in optical thin sections of coral skeletons.


Measurement system for marine animal reflectance functions.
Photonic structures in the skin of pelagic fishes and squids evolved specifically for hiding in the complex light field of the open ocean. To understand the principles under which these structures operate, a detailed characterization of their optical properties is required. An optical scatterometer has been developed to measure one important property, the bidirectional reflectance distribution function (BRDF). The instrument was used to collect reflectance functions from the squid Pterygioteuthis microlampas and fish Sternoptyx sp. Although the animals appear very different to a casual observer, the results reveal interesting similarities in their scattering patterns, suggesting a similar optical strategy for hiding in open water.


Impact of donor-to-recipient weight ratio on survival after heart transplantation: analysis of the United Network for Organ Sharing Database.
Generally accepted donor criteria for heart transplantation limit allografts from donors within approximately 20% to 30% of the recipient's weight. We analyzed the impact of donor-to-recipient weight ratio on survival after heart transplantation. Adult heart transplant recipients reported to the United Network for Organ Sharing from 1999 to 2007 were divided into 3 groups based on donor-to-recipient weight ratio: <0.8, 0.8 to 1.2, and >1.2. Kaplan-Meier methodology was used to estimate survival. Propensity-adjusted Cox regression modeling was used to analyze predictors of mortality. A total of 15 284 heart transplant recipients were analyzed; 2078 had weight ratio of <0.8, 9684 had 0.8 to 1.2, and 3522 had >1.2. Kaplan-Meier survival was not statistically different between groups at 5 years (P=0.26). Among patients with weight ratio <0.8, 5-year survival was lower for recipients with high pulmonary vascular resistance (>4 Woods units; P=0.02). Among recipients with high pulmonary vascular resistance, 5-year survival was similar for those with weight ratio 0.8 to 1.2 and >1.2 (P=0.44). Furthermore, male recipients with elevated pulmonary vascular resistance who received hearts from female donors had a significantly worse survival than males who received hearts from male donors (P=0.01). Propensity-adjusted multivariable analysis demonstrated that weight ratio <0.8 did not predict mortality (hazard ratio, 1.09; 95% CI, 0.94 to 1.27; P=0.21). Five-year survival after propensity matching was not statistically different between those with weight ratio <0.8 versus >/=0.8 (P=0.37). Weight ratio did not predict mortality after heart transplantation. However, recipients with elevated pulmonary vascular resistance who received undersized hearts had poor survival. Furthermore, in the setting of high pulmonary vascular resistance, male recipients who received hearts from female donors had worse survival than those who received hearts from male donors. Extending donor criteria to include undersized hearts in select recipients should be considered.


Impaired temporal processing of tactile and proprioceptive stimuli in cerebellar degeneration.
Performance of timed motor sequences relies on the cerebellum and basal ganglia, which integrate proprioceptive information during the motor task and set internal timing mechanisms. Accordingly, these structures are also involved in other temporal processes, such as the discrimination of the different afferent information in the domain of time. In the present study we tested temporal processing of proprioceptive and tactile stimuli in 20 patients with neurodegenerative cerebellar ataxia and 20 age- and sex-matched healthy subjects. Tactile temporal discrimination threshold was defined as the value at which subjects recognized the two stimuli as asynchronous. Temporal discrimination movement threshold of the first dorsal interosseous and flexor carpi radialis was defined as the shortest interval between two paired electrical stimuli in which the subjects blindfolded perceived two separate index finger abductions and wrist flexions. Both tactile and movement temporal discrimination thresholds were higher in patients with cerebellar ataxia. No correlation was found with disease duration and severity. Our study demonstrates that temporal processing of tactile and proprioceptive stimuli is impaired in patients with cerebellar neurodegeneration and highlights the involvement of cerebellum in temporal processing of somatosensory stimuli of different type.


A Multilayer Approach to the Equation of Motion Coupled-Cluster Method for the Electron Affinity.
We have presented a multilayer implementation of the equation of motion coupled-cluster method for the electron affinity, based on local and pair natural orbitals. The method gives consistent accuracy for both localized and delocalized anionic states and results in many-fold speed-up as compared to the canonical and DLPNO-based implementation of the EA-EOM-CCSD method. We have also developed an explicit fragment-based approach which can lead to even higher speed-up with little loss in accuracy. The multilayer method can be used to treat the environmental effect of both bonded and nonbonded nature on the electron attachment process in large molecules.


Visual outcomes after progressive apodized diffractive intraocular lens implantation.
To assess photopic and mesopic vision in patients implanted with the Bi-Flex® M 677 MY bifocal intraocular lens (IOL). In this prospective clinical study, 25 patients with cataract in both eyes were subjected to cataract surgery and bilateral implantation of the Bi-Flex® M 677MY (Medicontur, Hungary) IOL. Three months after surgery, high-contrast photopic uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were determined. Intermediate at 65 cm (DCIVA) and near at 40 cm (DCNVA) visual acuity were also measured, both with best distance correction. The CSV-1000 test chart was used to assess contrast sensitivity (CS). Defocus curves were constructed under photopic and mesopic conditions, determining binocular best-corrected visual acuity over the range +1.50 D to -4.00 D in 0.50-D steps. A KR-1W Wavefront Analyzer was used to measure pupil size and aberrometric outcomes. Presence and type of dysphotopsia were evaluated with the Likert scale. Mesopic mean pupil diameter was 4.58 ± 0.73 mm. The mean values at 3 months were UDVA 0.03 ± 0.09, CDVA -0.05 ± 0.06, DCIVA 0.20 ± 0.07, and DCNVA 0.11 ± 0.08. Mean CS for the 4 frequencies examined were 1.66 ± 0.16, 1.75 ± 0.14, 1.39 ± 0.22, and 0.96 ± 0.19. Significant differences were observed in defocus curves for photopic and mesopic conditions. A significant correlation between pupil diameter and the dysphotopic photopic was found (r = 0.62; p = 0.02). The evaluated progressive apodized diffractive design IOL provides effective restoration of visual function in far and near vision distance with an adequate intermediate visual quality between -1.00 and -1.50 focus.


[Afferent and efferent innervation of the human fascia lata femoris during prenatal ontogeny].
The broad fascia have been studied in 256 extremities of human embryos and fetuses treated by methods of impregnation after Bielschowsky - Gros and Rasskazova, histologically after Falck - Hillarp - Govyrin, Karnovsky - Roots and by incubation of slices in 2% glyoxylic acid. The first neural elements as fasciculi of neural fibres are discovered in 8-9 week-old embryos. Cholinesterase and catecholamines are detected in nerves of the vegetative neural system on the 11-12th week of the intrauterine life, thus demonstrating the appearance of the mediator stage in functioning the autonomic nervous system. Receptor structures having the appearance of simple branching bushes are revealed in the broad fascia in 3-3.5-month-old fetuses. During prenatal ontogenesis the neural apparatus of the broad fascia is becoming more complex, the number of types and total amount of free and incapsulated receptors are increasing, the latter being revealed in 5-month-old fetuses. At the stage of development free neural terminals predominate, and by the time of birth, the number of incapsulated receptors is increasing. The greatest number of the neural terminals are situated in the anterior and external parts of the broad fascia. Cholinergic and adrenergic neural fibers from plexus in the broad fascia, situating mainly near blood vessels.


Intensive insulin protocol implementation and outcomes in the medical and surgical wards at a Veterans Affairs Medical Center.
Hyperglycemia is an important marker for clinical outcomes and mortality in hospitalized patients. New national standards have been established emphasizing the importance of improving inpatient glycemic control in individuals with diabetes or new-onset hyperglycemia. Implementation of these new standards is complex and requires a multidisciplinary team approach. A basal-bolus insulin regimen approach has been shown to improve inpatient glycemic control. Few studies have been published regarding basal-bolus insulin protocol outcomes in the non-intensive care unit (ICU) setting. To evaluate the efficacy of a basal-bolus insulin protocol on inpatient glycemic control in a non-ICU setting, as measured by mean blood glucose and number of hypoglycemic episodes per patient admission. A retrospective, observational, single-center study was conducted to compare blood glucose control pre- (October 2006-March 2007) and postprotocol (November 2007-January 2008) implementation. Inclusion criteria consisted of patient admission to a medical or surgical ward for at least 72 hours, with a diagnosis of diabetes, or presentation with 2 blood glucose readings greater than 180 mg/dL. Patients admitted to the ICU or those not admitted to a medical or surgical ward were excluded. Following protocol implementation, the mean +/- SD blood glucose level increased from 174 +/- 88 mg/dL to 188 +/- 95 mg/dL (p < 0.001) and the hypoglycemic incidents significantly decreased, from 1.11 to 0.51 events per patient admission (p < 0.0025). In this pilot study, implementation of a basal-bolus insulin protocol significantly reduced hypoglycemic events; however, mean blood glucose values increased. These results suggest that a basal-bolus insulin protocol can reduce hypoglycemia; however, factors such as protocol compliance, barriers in overcoming the use of the traditional sliding scale insulin regimens, staff education, and change of work-flow habits can influence the overall efficacy and impact of a basal-bolus insulin protocol on inpatient glycemic control.


Influence of substratum hydration and adsorbed macromolecules on bacterial attachment to surfaces.
The attachment of Pseudomonas fluorescens and an Acinetobacter sp. to hydrogel and polystyrene surfaces was investigated to evaluate the influence of adsorbed water and macromolecules on adhesion. With both organisms, there was a decrease in attachment numbers with increasing water content of the hydrogels. There was also a decrease in attachment with a decrease in water contact angle on untreated, tissue culture and sulfonated polystyrene surfaces; however, the attachment numbers were higher than would be expected on the basis of the hydrogel data. With P. fluorescens, attachment to untreated and tissue culture polystyrene was inhibited by bovine serum albumin, Escherichia coli lipopolysaccharide, and the supernatant from spent medium, both when the conditioning substances were added to the suspension of attaching cells and when they were preadsorbed onto the surfaces. Dextran inhibited attachment only when added to the bacterial suspension. Supernatants from centrifuged natural freshwater samples had no effect. Thus, hydration of a surface and the adsorption of macromolecules can reduce bacterial attachment; however, additional factors relating to the chemical composition of the substratum and polymeric stabilization of suspended cells can affect the adhesion interaction and resultant numbers of attached cells.


Molecular cloning and characterization of human papilloma virus DNA derived from a laryngeal papilloma.
Papilloma virus DNA from a laryngeal papilloma was cloned in phage lambda L 47 and characterized after cleavage with different restriction enzymes. Hybridization with the DNAs of human papilloma virus types 1, 2, 3, 4, 5, and 8 showed no homology under stringent hybridization conditions. Human papilloma virus type 6 DNA, however, was partially identical to laryngeal papilloma virus DNA; different restriction enzyme fragments hybridizing with the other DNA were identified on each genome. The degree of homology was determined by reassociation kinetics to be 25%. According to the present nomenclature, laryngeal papilloma virus therefore represents a different type of human papilloma virus and is tentatively designated as human papilloma virus type 11. Sequences homologous to laryngeal papilloma virus DNA were also found in four of nine additional laryngeal papillomas. Attempt to detect homologous DNA in 12 carcinomas of the larynx were negative.


Benign Hepatic Mesenchymal Hamartoma (HMH) - A Case Report.
A one-year-old male child presented with progressive enlargement of abdomen and loss of appetite which he had suffered from, since 4 months. Physical examination showed a palpable mass in right hypochondrium. Ultrasonography and MRI showed a solid mass arising from right lobe of liver. The resected mass was well encapsulated, yellowish white in colour and it measured 20 x 18 x 17cm. Cut surface showed a Nutmeg like appearance. Histology showed a well-defined, fibrous capsule with numerous ducts which were lined by flat to low cuboidal epithelium and which were surrounded by concentric layers of fibrous tissue which showed myxoid changes at places. Intervening area showed normal appearing hepatocytes with clear cell changes, dilated congested sinusoids, along with extramedullary haematopoiesis. Based on distinctive morphological features, a histological diagnosis of Benign Hepatic Mesenchymal Hamartoma of liver was made. IHC was not done, as no specific marker has been described for making a differential diagnosis. Benign Hepatic Mesenchymal Hamrtoma (HMH) of liver is an extremely rare tumour of childhood and therefore, the case was considered worth documentation.


Generation of two isogenic sickle cell disease induced pluripotent stem cell lines from testicular fibroblasts.
Curative bone marrow transplantation (BMT) therapies for sickle cell disease (SCD) can cause infertility. The Fertility Preservation Program (FPP) in Pittsburgh cryopreserves testicular tissues for SCD patients prior to BMT in anticipation that those tissues can be thawed in the future and matured to produce sperm. Here, we generated and validated two isogenic patient-derived induced pluripotent stem cell (iPSC) lines from testicular biopsy fibroblasts of a 12-year-old SCD patient.


Migraine.
Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.


Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.
SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.


Genetic variant of IL28B rs12979860, as predictive marker of interferon-based therapy in Pakistani population.
Hepatitis C virus (HCV) genotypes and genetic variants of interleukin 28B (IL28B) are significantly associated with interferon plus ribavirin treatment of HCV infection. We investigated the distribution of HCV genotypes and single-nucleotide polymorphisms (SNPs) of IL28B (rs12979860 and rs8099917) in Pakistani population. IL28B genotyping was performed by allele-specific PCR and restriction fragment length polymorphism PCR in 140 chronic hepatitis C patients (CHC) and 120 healthy controls. HCV genotype 3 (HCVG3) was the most prevalent genotype, 71.4% (n = 100/140) and with the highest treatment response of 90% (n = 90/100). The overall treatment response of all the HCV genotypes was 82% (n = 115/140). The distribution of IL28B rs12979860CC genotype in treatment responder and non-responder groups was 40.8% (n = 47/115) and 16% (n = 4/25) respectively. IL28B rs12979860CC genotype demonstrated a significant correlation (p = 0.019) with interferon-based therapy of HCV infection. However, there was no observed association of IL28B rs8099917 polymorphism with treatment response in CHC patients (p = 0.264). In conclusion, HCV genotypes and IL28B rs12979860 are predictive markers for the efficiency of interferon plus ribavirin combinational therapy of HCV infection. We recommend the inclusion of testing for these markers in the clinical criteria for decision making for HCV therapy in Pakistani population.


Kinetic analysis of the three-step steroid aromatase reaction of human cytochrome P450 19A1.
Cytochrome P450 19A1 (P450 19A1), the aromatase, catalyzes the conversion of androgens to estrogens through a sequential three-step reaction, generating 19-hydroxy and 19-aldehyde intermediates en route to the product estrogen. A procedure for the heterologous expression and purification of P450 19A1 in Escherichia coli was developed (k(cat) of 0.06 s(-1) for the conversion of androstenedione to estrone). Binding of the substrate and intermediates show low micromolar dissociation constants and are at least two-step processes. Rates of reduction of the iron were fast in the presence of substrate, either intermediate, or product. P450 19A1 is a distributive rather than a processive enzyme, with the sequential reaction allowing free dissociation of the intermediates as revealed by pulse-chase experiments. Conversion of androstenedione to estrone (under single turnover conditions) generated a progress curve showing changes in the concentrations of the substrate, intermediates, and product. A minimal kinetic model containing the individual rate constants for the steps in P450 19A1 catalysis was developed to globally fit the time course of the overall reaction, the dissociation constants, the two-step ligand binding, the distributive character, the iron-reduction rates, and the steady-state conversion of the 19-hydroxy androstenedione and 19-aldehyde androstenedione intermediates to estrone.


The Trick of the Hedgehog: Case Report and Short Review About Archaeopsylla erinacei (Siphonaptera: Pulicidae) in Human Health.
Fleas are ectoparasites of various animals, including Homo sapiens Linnaeus, 1758 (Primates: Hominidae). Among the species relevant to the human health field, either due to their dermatopathological potential or because of their role as vectors of microorganisms responsible for infectious diseases, such as plague or murine typhus, are the human flea, oriental rat flea, closely related cat and dog fleas, and chigoe flea. However, other species can accidentally infest humans. We have herein reported two unusual cases of humans infested and bitten by Archaeopsylla erinacei, the hedgehog flea. This species has been identified using stereomicroscopy, on the base of key characteristics. Furthermore, a brief literature review has revealed that hedgehog fleas could carry human-infectious agents, such as Rickettsia felis Bouyer et al. 2001 (Rickettsiales: Rickettsiaceae) or Bartonella henselae Regnery et al.1992 (Rhizobiales: Bartonellaceae). Using molecular biology, we thus tested nine A. erinacei specimens taken from these patients, for several bacteria species commonly associated with hematophagous arthropods, implicated in human pathology. However, all our samples were proven negative. The role of A. erinacei in human epidemiology has never been evaluated to date. This report sought to remind us that these fleas can be accidental parasites in humans. In addition, recent findings pertaining to bacteria of medical interest that are present in these insects should be brought to the fore, given that the question of their role as vectors in human infections remains unanswered and deserves further investigation.


Fentanyl Concentration in Drug Checking Samples and Risk of Overdose Death in Vancouver, Canada.
The proliferation of fentanyl and its analogs in illegal, unregulated drug markets remains a major driver of the overdose crisis in North America. Drug checking services have been implemented as a harm reduction strategy to address the crisis. However, little is known about their potential utility as a mechanism for monitoring population-level risk of overdose stemming from changing fentanyl concentration in unregulated drugs over time. Therefore, this study assessed the relationship between median fentanyl concentration in expected opioid drug checking samples and the death rate due to illicit drug toxicity over time in Vancouver, Canada. Monthly population-based rates of death due to illicit drug toxicity were drawn from provincial coroner records. Monthly median percent fentanyl concentration was calculated using a validated quantification model from point-of-care Fourier-transform infrared spectra among expected opioid samples that tested positive for fentanyl at community drug checking services. A time-series analysis using generalized additive modeling was conducted to examine the association between monthly median fentanyl concentration and monthly death rate due to illicit drug toxicity, controlling for calendar month. Analyses were conducted in 2021-2022. Between January 2019 and October 2020, 577 deaths due to illicit drug toxicity occurred in Vancouver, and the observed monthly rate ranged from 1.75 to 7.65 deaths per 100,000 population. A significant, positive association was observed between monthly median fentanyl concentration and monthly death rate due to illicit drug toxicity, adjusting for calendar month (chi-square=52.21, p<0.001). Findings suggest a role for point-of-care drug checking as a tool for monitoring evolving overdose risk at the population level.


Outcomes of Inside-out Meniscal Repair in the Setting of Multiligament Reconstruction in the Knee.
Limited evidence exists for meniscal repair outcomes in a multiligament reconstruction setting. Purpose/Hypothesis: The purpose of this study was to assess outcomes and failure rates of meniscal repair in patients who underwent multiligament reconstruction compared with patients who underwent multiligament reconstruction but lacked meniscal tears. The authors hypothesized that the outcomes of meniscal repair associated with concomitant multiligament reconstruction would significantly improve from preoperatively to postoperatively at a minimum of 2 years after the index surgery. Secondarily, they hypothesized that this cohort would demonstrate similar outcomes and failure rates compared with the cohort that did not have meniscal lesions at the time of multiligament reconstruction. Cohort study; Level of evidence, 3. Inclusion criteria for the study included radiographically confirmed skeletally mature patients of at least 16 years of age who underwent multiligamentous reconstruction of the knee without previous ipsilateral osteotomy, intra-articular infections, or intra-articular fractures. Patients were included in the experimental group if they underwent inside-out meniscal suture repair with concurrent multiligament reconstruction. Those included in the control group (multiligament reconstruction without a meniscal tear) underwent multiligament reconstruction but did not undergo any type of meniscal surgery. Lysholm, Western Ontario and McMaster Universities Osteoarthritis Index, Short Form-12 physical component summary and mental component summary, Tegner activity scale, and patient satisfaction scores were recorded preoperatively and postoperatively. The failure of meniscal repair was defined as a retear of the meniscus that was confirmed arthroscopically. There were 43 patients (16 female, 27 male) in the meniscal repair group and 62 patients (25 female, 37 male) in the control group. Follow-up was obtained in 93% of patients with a mean of 3.0 years (range, 2.0-4.7 years). There was a significant improvement between all preoperative and postoperative outcome scores ( P < .05) for both groups. The meniscal repair group had significantly lower preoperative Lysholm and Tegner scores ( P = .009 and P = .02, respectively). There were no significant differences between any other outcome scores preoperatively. The failure rate of the meniscal repair group was 2.7%, consisting of 1 symptomatic meniscal retear. There was no significant difference in any postoperative outcome score at a minimum 2-year follow-up between the 2 groups. Good to excellent patient-reported outcomes were reported for both groups with no significant differences in outcomes between the cohorts. Additionally, the failure rate for inside-out meniscal repair with concomitant multiligament reconstruction was low, regardless of meniscus laterality and tear characteristics. The use of multiple vertical mattress sutures and the biological augmentation resulting from intra-articular cruciate ligament reconstruction tunnel reaming may be partially responsible for the stability of the meniscal repair construct and thereby contribute to the overall improved outcomes and the low failure rate of meniscal repair, despite lower preoperative Lysholm and Tegner scores in the meniscal repair group.


Managing information: today's integrated healthcare enterprises.
Managed care forces healthcare providers to focus simultaneously on costs and outcomes. To support the new priorities, providers are creating new business models, moving rapidly to merge, and forming alliances. The industry is witnessing the rise of integrated healthcare delivery systems that encompass hospitals, physician groups, ambulatory clinics, HMO and PPO plans, and other provider facilities.


Carotid Plaque Morphological Classification Compared With Biomechanical Cap Stress: Implications for a Magnetic Resonance Imaging-Based Assessment.
Two approaches to target plaque vulnerability-a histopathologic classification scheme and a biomechanical analysis-were compared and the implications for noninvasive risk stratification of carotid plaques using magnetic resonance imaging were assessed. Seventy-five histological plaque cross sections were obtained from carotid endarterectomy specimens from 34 patients (>70% stenosis) and subjected to both a Virmani histopathologic classification (thin fibrous cap atheroma with <0.2-mm cap thickness, presumed vulnerable) and a peak cap stress computation (<140 kPa: presumed stable; >300 kPa: presumed vulnerable). To demonstrate the implications for noninvasive plaque assessment, numeric simulations of a typical carotid magnetic resonance imaging protocol were performed (0.62×0.62 mm(2) in-plane acquired voxel size) and used to obtain the magnetic resonance imaging-based peak cap stress. Peak cap stress was generally associated with histological classification. However, only 16 of 25 plaque cross sections could be labeled as high-risk (peak cap stress>300 kPa and classified as a thin fibrous cap atheroma). Twenty-eight of 50 plaque cross sections could be labeled as low-risk (a peak cap stress<140 kPa and not a thin fibrous cap atheroma), leading to a κ=0.39. 31 plaques (41%) had a disagreement between both classifications. Because of the limited magnetic resonance imaging voxel size with regard to cap thickness, a noninvasive identification of only a group of low-risk, thick-cap plaques was reliable. Instead of trying to target only vulnerable plaques, a more reliable noninvasive identification of a select group of stable plaques with a thick cap and low stress might be a more fruitful approach to start reducing surgical interventions on carotid plaques.


Preoperative symptom type influences the 30-day perioperative outcomes of carotid endarterectomy and carotid stenting in the Society for Vascular Surgery Vascular Registry.
The objective of this study was to determine the effect of presenting symptom types on 30-day periprocedural outcomes of carotid endarterectomy (CEA) and carotid artery stenting (CAS) in contemporary vascular practice. Retrospective review was undertaken of the Society for Vascular Surgery Vascular Registry database subjects who underwent CEA or CAS from 2004 to 2011. Patients were grouped by discrete 12-month preprocedural ipsilateral symptom type: stroke, transient ischemic attack (TIA), transient monocular blindness (TMB), or asymptomatic (ASX). Risk-adjusted odds ratios (ORs) were used to compare the likelihood of the 30-day outcomes of death, stroke, and myocardial infarction (MI) and the composite outcomes of death + stroke and death + stroke + MI. Symptom type significantly influences risk-adjusted 30-day outcomes for carotid intervention. Presentation with stroke predicted the poorest outcomes (death + stroke + MI composite: OR, 1.3; 95% confidence interval [CI], 0.83-2.03 vs TIA; OR, 2.56; 95% CI, 1.18-5.57 vs TMB; OR, 2.12; 95% CI, 1.46-3.08 vs ASX), followed by TIA (death + stroke + MI composite: OR, 1.97; 95% CI, 0.91-4.25 vs TMB; OR, 1.63; 95% CI, 1.14-2.33 vs ASX). For both CAS and CEA patients, presentation with stroke or TIA predicted a higher risk of periprocedural stroke than in ASX patients. Presentation with stroke predicted higher 30-day risk of death with CAS but not with CEA. MI rates were not affected by presenting symptom type. The 30-day outcomes for the TMB and ASX patient groups were equivalent in both treatment arms. Presenting symptom type significantly affects the 30-day outcomes of both CAS and CEA in contemporary vascular surgical practice. Presentation with stroke and TIA predicts higher rates of periprocedural complications, whereas TMB presentation predicts a periprocedural risk profile similar to that of ASX disease.


Identification and characterization of a constitutive HSP75 in sea urchin embryos.
An antiserum against a hsp of the 70-kDa family was prepared, by means of a fusion protein, which was able to detect a constitutive 75-kDa hsc in the sea urchin P. lividus. This hsc was present both during oogenesis and at all developmental stages. A two-dimensional electrophoresis has revealed four isolectric forms of this 75-kDa hsc. The amino acid sequence of the fragment used to prepare the anti-hsp70 antibodies revealed a 43% identity with the corresponding part of sea urchin sperm receptor, and in mature eggs a brighter immunofluorescence was seen all around the cell cortex where the receptor for sea urchin sperm is localized. In oocytes the hsp75 was localized in the cytoplasms but not in the nuclei. In the embryos a higher hsp75 concentration was found in the portion facing the lumen of the cells which invaginate at gastrulation.


Selectivity mechanisms in MscS-like channels: From structure to function.
The E. coli mechanosensitive (MS) channel of small conductance (EcMscS) is the prototype of a diverse family of channels present in all domains of life. While EcMscS has been extensively studied, recent developments show that MscS may display some characteristics not widely conserved in this protein subfamily. With numerous members now electrophysiologically characterized, this subfamily of channels displays a breadth of ion selectivity with both anion and cation selective members. The selectivity of these channels may be relatively weak in comparison to voltage-gated channels but their selectivity mechanisms represent great novelty. Recent studies have identified unexpected residues important for selectivity in these homologs revealing different selectivity mechanisms than those employed by voltage gated K(+), Na(+), Ca(2+) and Cl(-) channels whose selectivity filters are housed within their transmembrane pores. This commentary looks at what is currently known about MscS subfamily selectivity and begins to unravel the potential physiological relevance of these differences.


Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study.
To investigate in vivo the survival of retinal ganglion cells (RGC) 4 to 14 days after optic nerve (ON) transection alone or in combination wih a single intraocular injection of neurotrophin-4 (NT-4), neurotrophin-3 (NT-3), or brain-derived neurotrophic factor (BDNF). In adult rats, RGCs were labeled with fluorogold (FG) applied to their main targets in the brain. Seven days later, the left ON was intraorbitally transected, and, in several groups of animals, the left eye received a sham injection or was injected with 5 microliters of 1% bovine serum albumin-phosphate-buffered saline alone or containing 5 micrograms of NT-4, NT-3, or BDNF. Four, 5, 7, 9, 12 and 14 days after ON transection, the retinas were examined under fluorescence microscopy to estimate RGC survival. In control retinas, the mean densities (cells/mm2+/-SEM) of FG-labeled RGCs were 2421+/-55 (n=20). Four days after axotomy, the densities of RGCs were similar to those observed in control retinas, but 5 and 7 days after axotomy, the mean densities had decreased to 2028+/-63 (n=6) and 1568+/-50 (n=6) respectively. In the group of retinas with sham injection, with vehicle alone or with NT-3, RGC densities also decreased by 7 days to 1261+/-71 (n=5), 1506+/-98 (n=10), and 1474+/-125 (n=4), respectively. However, similar densities to those observed in control retinas were observed 7 days after ON transection in the groups of retinas treated with NT-4 (2505+/-91; n=7) or BDNF (2380+/-74; n=7). Fourteen days after axotomy, RGC densities decreased to 521+/-39 (n=10). Comparable densities were found in groups that underwent axotomy and either sham injection (533+/-51; n=5), injection of vehicle (588+/-19; n=10), or NT-3 treatment (634+/-62; n=6). However, at this time, higher densities were observed in the groups treated with NT-4 839+/-39 (n=8) or BDNF 1321+/-120 (n=7). Axotomy-induced RGC death first appears by day 5 and reaches 80% of the original RGC population by day 12. NT-4 and BDNF administered intraocularly at the time of axotomy exert a neuroprotective effect on axotomy-induced RGC death, thus increasing the population of surviving RGCs and delaying the onset of RGC of axotomy-induced RGC death by approximately 3 days. Intraocular administration of NT-3 did not modify the survival of RGCs after injury.


Development of a Bone-Mimetic 3D Printed Ti6Al4V Scaffold to Enhance Osteoblast-Derived Extracellular Vesicles' Therapeutic Efficacy for Bone Regeneration.
Extracellular Vesicles (EVs) are considered promising nanoscale therapeutics for bone regeneration. To date, EVs are typically procured from cells on 2D tissue culture plastic, an artificial environment that limits cell growth and does not replicate in situ biochemical or biophysical conditions. This study investigated the potential of 3D printed titanium scaffolds coated with hydroxyapatite to promote the therapeutic efficacy of osteoblast-derived EVs. Ti6Al4V titanium scaffolds with different pore sizes (500 and 1000 µm) and shapes (square and triangle) were fabricated by selective laser melting. A bone-mimetic nano-needle hydroxyapatite (nnHA) coating was then applied. EVs were procured from scaffold-cultured osteoblasts over 2 weeks and vesicle concentration was determined using the CD63 ELISA. Osteogenic differentiation of human bone marrow stromal cells (hBMSCs) following treatment with primed EVs was evaluated by assessing alkaline phosphatase activity, collagen production and calcium deposition. Triangle pore scaffolds significantly increased osteoblast mineralisation (1.5-fold) when compared to square architectures (P ≤ 0.001). Interestingly, EV yield was also significantly enhanced on these higher permeability structures (P ≤ 0.001), in particular (2.2-fold) for the larger pore structures (1000 µm). Furthermore osteoblast-derived EVs isolated from triangular pore scaffolds significantly increased hBMSCs mineralisation when compared to EVs acquired from square pore scaffolds (1.7-fold) and 2D culture (2.2-fold) (P ≤ 0.001). Coating with nnHA significantly improved osteoblast mineralisation (>2.6-fold) and EV production (4.5-fold) when compared to uncoated scaffolds (P ≤ 0.001). Together, these findings demonstrate the potential of harnessing bone-mimetic culture platforms to enhance the production of pro-regenerative EVs as an acellular tool for bone repair.


How alcohol advertising and sponsorship works: Effects through indirect measures.
We tested whether incidental exposure to alcohol marketing messages in sporting events: (i) influenced automatic evaluation of brands and alcohol in general; and (ii) if these processes occur through deliberative (conscious) or non-conscious processes. Using an experimental design, participants watched a sport event containing: (i) a prototypical alcohol brand; (ii) a brand unrelated to alcohol; or (iii) a non-prototypical alcohol brand. One hundred and nine participants were randomly assigned to either a cognitively depleting task to impair motivation for effortful conscious processing before watching the excerpt, or a control task. We measured indirect (implicit) and direct (explicit) attitudes toward alcohol and brands, and self-report measures assessing affective response toward the event, involvement in processing the message and identifications toward the playing teams. We found a positive main effect of incidental exposure to alcohol brands on indirect measures of attitudes toward alcohol as well as the specific brand. No effect of cognitive fatigue on indirect measure toward brands and alcohol was observed. Incidental exposure to alcohol marketing messages appear to impact indirect measures of attitudes toward the brand and alcohol in general, and seems to rely on non-conscious automatic processes.


Impact of prescription card service and mail-order drug programs on employers' prescription drug costs.
A study indicates that prescription card service and mail-order drug programs cost employers more money than a traditional indemnity offering because of the significant increase both in the number of claimants and in the paid charges per claimant. Focusing attention only on cost, however, may hamper the overall quality of care delivered under a health benefits program.


Prevalence of spinocerebellar ataxia 36 in a US population.
To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States. A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the NOP56 gene. Fragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56 in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment. In a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort.


Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience.
Ethanol and caffeine are 2 common psychoactive dietary components. We have recently shown that low-dose ethanol plus caffeine results in a 70% to 80% reduction of infarct volume after reversible common carotid/middle cerebral artery (CCA/MCA) occlusion in rats. The combination (caffeinol) was effective after either oral pretreatment or intravenous administration starting up to 2 hours after stroke onset. Ethanol alone aggravated ischemic damage, while caffeine alone was without effect. Daily caffeinol for 2 weeks before ischemia eliminated the neuroprotection seen with acute treatment (tolerance). The purpose of our present study was to further characterize the properties of caffeinol as a possible treatment for ischemic stroke. The transient CCA/MCA occlusion model was used in all experiments. Five sets of experiments were conducted (1) to test the effectiveness of various doses of ethanol (0.2 to 0.65 g/kg) and caffeine (3 to 10 mg/kg) in the caffeinol mixture; (2) to test whether the neuroprotective dose of caffeinol can improve behavioral dysfunction; (3) to test whether chronic ethanol or caffeine before ischemia will affect efficacy of caffeinol treatment; (4) to test whether the protective effect of caffeinol can be improved by pairing it with 35 degrees C hypothermia; and (5) to test whether caffeinol affects frequency of hemorrhage after administration of recombinant tissue plasminogen activator (rtPA) in ischemic animals. Doses as low as 0.2 g/kg of ethanol and 6 mg/kg of caffeine in the caffeinol were effective in reducing cortical infarct volume and behavioral dysfunction after transient CCA/MCA occlusion. Daily exposure to ethanol but not caffeine before CCA/MCA occlusion eliminated the therapeutic efficacy of acute caffeinol treatment, similar to the tolerance observed after chronic exposure to caffeinol. The therapeutic effect of caffeinol could be further improved by pairing it with mild intraischemic hypothermia, and caffeinol did not increase hemorrhagic infarction when given in combination with rtPA. Low doses of caffeinol, equivalent to no more than 2 to 3 cups of strong coffee and 1 cocktail, are consistently and highly neuroprotective, are well tolerated, can be added to other therapies to increase the effect of each, and do not interfere with or complicate rtPA therapy. Caffeinol is an appropriate candidate for clinical trial in stroke patients, although it may be less effective in patients with regular alcohol intake.


Costimulation of adenylyl cyclase and phospholipase C by a mutant alpha 1B-adrenergic receptor transgene promotes malignant transformation of thyroid follicular cells.
Proliferation of thyroid follicular cells is controlled by three intra-cellular cascades [cAMP, inositol 1,4,5-triphosphate (IP3)/Ca2+/diacylglycerol (DAG), and tyrosine kinases] that are activated by distinct extracellular signals and receptors. We had previously generated a transgenic mouse model in which the cAMP cascade was permanently stimulated in thyroid cells by an adenosine A2a receptor (Tg-A2aR model). In the present work, we have generated a transgenic model characterized by the chronic stimulation of both adenylyl cyclase and phospholipase C in thyroid follicular cells. The bovine thyroglobulin gene promoter was used to direct the expression of a constitutively active mutant of the alpha 1B adrenergic receptor, which is known to couple to both cascades in transfected cell lines. The expression of the transgene resulted, as expected, in the activation of phospholipase C and adenylyl cyclase, as demonstrated by the direct measurement of IP3 and cAMP in thyroid tissue. The phenotype resulting from this dual stimulation included growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and the development of malignant nodules invading the capsule, muscles, and blood vessels. Differentiated metastases were found occasionally in old animals. The development of malignant lesions was more frequent and of earlier onset than in our previous Tg-A2aR model, in which only the cAMP cascade was stimulated. These observations demonstrate that the cAMP and IP3/Ca2+/DAG cascades can cooperate in vivo toward the development of thyroid follicular cell malignancies.


[Changed phosphodiesterase activity of leukocytes in atopic eczema].
Leukocytes of patients with atopic eczema exhibit a variety of biochemical abnormalities, particularly an alteration in cyclic nucleotide metabolism. The basic defect is an elevation of phosphodiesterase activity in these cells, which leads to a diminished modulation of cellular immune function by cAMP. This, in turn, leads to an elevation of IgE synthesis and enhanced release of inflammatory mediators from mast cells and basophils. The phosphodiesterase defect offers new approaches to the treatment of atopic eczema.


Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate.
L-carnitine L-tartrate (LCLT) supplementation beneficially affects markers of postexercise metabolic stress and muscle damage. However, to date, no study has determined the dose response of LCLT to elicit such responses. Therefore, the purpose of this study was to determine the effects of different doses of LCLT on criterion variables previously shown to be responsive to LCLT supplementation. Eight healthy men (22 +/- 3 y, 174 +/- 5 cm, 83.0 +/- 15.3 kg) were supplemented with 0 g, 1 g, and 2 g of LCLT for 3 weeks and then performed a bout of resistance exercise (5 sets of 15-20 repetition maximum with a 2-min rest between sets) with associated blood draws. This procedure was performed in a balanced, randomized, repeated measures design. Serum carnitine concentrations increased (p < or = 0.05) following the 1 g and 2 g doses, with the 2-g dose providing the highest carnitine concentrations. The 1- and 2-g doses reduced postexercise serum hypoxanthine, serum xanthine oxidase, serum myoglobin, and perceived muscle soreness. In conclusion, both the 1- and 2-g doses were effective in mediating various markers of metabolic stress and of muscle soreness. Use of LCLT appears to attenuate metabolic stress and the hypoxic chain of events leading to muscle damage after exercise.


[Prostate cancer prevention: a review of the literature].
This study analyzes recommendations for the prevention of prostate cancer reported in the specific literature on this topic. The method consisted of a review of this matter, adopting a qualitative approach, examined through the theme content analysis technique. Based on the following analysis categories: primary prevention, secondary prevention and masculinity and prevention, the discussion of the study findings concludes that: (a) the recommendations are either diverse or present some controversies among the various viewpoints; (b) the output of scientific papers in the collective health field is sparse on this matter; (c) the development of a more interdisciplinary approach is required for dealing with this matter and (d) few sources take the specific characteristic of maleness into account for recommendations on the prevention of prostate cancer.


Retiree medical--round 2.
The second round of changes resulting from FAS 106 will be less dramatic than the first. But employers can anticipate that overall retiree health care costs will be reduced, averting the need to increase pensions or other retiree benefits. A fixed dollar benefit design will justify a lower accounting cost.


[The impact of the highest mediastinal lymph node metastasis on postoperative recurrense and survival in non-small cell lung cancer patients].
Objective: To examine whether the highest mediastinal lymph node (HMLN) metastasis had an influence on postoperative recurrence and survival among non-small cell lung cancer (NSCLC) patients with N2 lymph node metastasis. Methods: A total of 261 patients who underwent radical resection of lung cancer and systematic lymph node dissection in the Department of Thoracic Surgery of Peking University First Hospital from January 2007 to December 2016 were retrospectively analyzed. There were 180 males and 81 females, aged (61.5±9.4) years (range: 31 to 83 years). There were 128 cases of HMLN-positive and 133 cases of HMLN-negative. They were pathologically confirmed N2 stage NSCLC and postoperative recurrence and survival were followed up. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS) curves according to whether HMLN metastasize or not. The Cox proportional hazards regression model was used for the prognostic analysis. Results: The median DFS and the median OS of the whole group were 28 months and 44 months, respectively. The median DFS in HMLN-positive and HMLN-negative patients was 19 months and 33 months, respectively (P=0.005). The median OS of HMLN-positive and HMLN-negative group was 37 months and 49 months, respectively (P=0.005). Multivariate analysis showed that pneumonectomy and visceral pleural invasion were independent risk factors for both postoperative OS (HR=1.85, 95%CI: 1.25 to 2.72, P=0.002; HR=1.82, 95%CI: 1.30 to 2.56, P=0.007) and DFS (HR=1.61, 95%CI: 1.10 to 2.35, P=0.014; HR=1.77, 95%CI: 1.27 to 2.46,P=0.001). HMLN metastasis and lymphovascular invasion were independent risk factors for only postoperative DFS (HR=1.39, 95%CI: 1.03 to 1.87, P=0.030; HR=1.40, 95%CI: 0.99 to 1.81, P=0.042). Conclusions: For patients of pN2 stage NSCLC, both postoperative recurrence and long-term survival were significantly worse in the HMLN metastatic group. In addition, pneumonectomy and visceral pleural invasion were unfavorable factors that affected both recurrence and overall survival. HMLN metastasis and lymphovascular invasion could shorten the postoperative time for DFS.


Allelochemicals: A source for developing economically and environmentally friendly plant growth regulators.
Allelochemicals are specific secondary metabolites that can exhibit autotoxicity by inhibiting the growth of the same plant species that produced them. These metabolites have been found to affect various physical processes during plant growth and development, including inhibition of seed germination, photosynthesis, respiration, root growth, and nutrient uptake, with diverse mechanisms involving cell destruction, oxidative homeostasis and photoinhibition. In some cases, allelochemicals can also have positive effects on plant growth and development. In addition to their ecological significance, allelochemicals also possess potential as plant growth regulators (PGRs) due to their extensive physiological effects. However, a comprehensive summary of the development and applications of allelochemicals as PGRs is currently lacking. In this review, we present an overview of the sources and categories of allelochemicals, discuss their effects and the underlying mechanisms on plant growth and development. We showcase numerous instances of key phytohormonal allelochemicals and non-phytohormonal allelochemicals, highlighting their potential as candidates for the development of PGRs. This review aims to provide a theoretical basis for the development of economical, safe and effective PGRs utilizing allelochemicals, and emphasizes the need for further research in this area.


Hepatitis C virus infection, Linxian, China.
Bloodborne viruses may have spread in rural China during the past 25 years, but population-based prevalence estimates are lacking. We examined the frequency of hepatitis C virus (HCV) and HIV type 1 (HIV-1) among residents of Linxian, a rural community in Henan Province. In 2000, blood was collected from participants (> or = 55 years of age) who had enrolled in a population-based nutritional intervention trial in 1985. We randomly selected 500 participants for HCV testing and 200 participants for HIV-1 testing. For HCV, 48 (9.6%) of 500 participants were positive by enzyme immunoassay and recombinant immunoblot assay (95% confidence interval, 7.0%-12.2%), and prevalence was lowest in the most geographically isolated participants. Among the HCV-infected participants, 42 had a specimen available from 1985, of which 16 (38.1%) were positive for HCV. For HIV-1, 0/200 participants were positive. We conclude that HCV is now a common infection among older adults in Linxian, China.


Confirmatory Factor Analysis and Differential Relationships of the Two Subdomains of Negative Symptoms in Chronically Ill Psychotic Patients.
Research suggests a two factor structure for negative symptoms in patients with psychotic disorders: social amotivation (SA) and expressive deficits (ED). Applying this two-factor structure in clinical settings may provide valuable information with regard to outcomes and to target treatments. We aimed to investigate 1) whether the factor structure is also supported in chronically ill patients with a psychotic disorder and 2) what the relationship is between these factors and functioning (overall functioning and living situation), depressive symptoms and quality of life. 1157 Patients with a psychotic disorder and a duration of illness of 5 years or more were included in the analysis (data selected from the Pharmacotherapy Monitoring Outcome Survey; PHAMOUS). A confirmatory factor analysis was performed using items of the Positive and Negative Syndrome Scale that were previously identified to reflect negative symptoms (N1-4, N6, G5, G7, G13, G16). Subsequently, regression analysis was performed on outcomes. The results confirmed the distinction between SA (N2, N4, G16) and ED (N1, N3, N6, G5, G7, G13) in chronically ill patients. Both factors were related to worse overall functioning as measured with the Health of the Nation Outcome Scales, ED was uniquely associated with residential living status. Higher scores for SA were associated with more depressive symptoms and worse quality of life. Thus, SA is most strongly related to level of social-emotional functioning, while ED are more related to living situation and thereby are indicative of level of everyday functioning. This subdivision may be useful for research purposes and be a valuable additional tool in clinical practice and treatment development.


Downregulation of microRNA miR-526a by enterovirus inhibits RIG-I-dependent innate immune response.
Retinoic acid-inducible gene I (RIG-I) is an intracellular RNA virus sensor that induces type I interferon-mediated host-protective innate immunity against viral infection. Although cylindromatosis (CYLD) has been shown to negatively regulate innate antiviral response by removing K-63-linked polyubiquitin from RIG-I, the regulation of its expression and the underlying regulatory mechanisms are still incompletely understood. Here we show that RIG-I activity is regulated by inhibition of CYLD expression mediated by the microRNA miR-526a. We found that viral infection specifically upregulates miR-526a expression in macrophages via interferon regulatory factor (IRF)-dependent mechanisms. In turn, miR-526a positively regulates virus-triggered type I interferon (IFN-I) production, thus suppressing viral replication, the underlying mechanism of which is the enhancement of RIG-I K63-linked ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein, while ectopic miR-526a expression inhibits the replication of EV71 virus. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and suggest a novel mechanism for the evasion of the innate immune response controlled by EV71. RNA virus infection upregulates the expression of miR-526a in macrophages through IRF-dependent pathways. In turn, miR-526a positively regulates virus-triggered type I IFN production and inhibits viral replication, the underlying mechanism of which is the enhancement of RIG-I K-63 ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein; cells with overexpressed miR-526a were highly resistant to EV71 infection. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and propose a novel mechanism for the evasion of the innate immune response controlled by EV71.


Trends in R-X bond dissociation energies (R = Me, Et, i-Pr, t-Bu; X = H, CH3, OCH3, OH, F): a surprising shortcoming of density functional theory.
The performance of a variety of high-level composite procedures, as well as lower-cost density functional theory (DFT)- and second-order perturbation theory (MP2)-based methods, for the prediction of absolute and relative R-X bond dissociation energies (BDEs) was examined for R = Me, Et, i-Pr and t-Bu, and X = H, CH(3), OCH(3), OH and F. The methods considered include the high-level G3(MP2)-RAD and G3-RAD procedures, a variety of pure and hybrid DFT methods (B-LYP, B3-LYP, B3-P86, KMLYP, B1B95, MPW1PW91, MPW1B95, BB1K, MPW1K, MPWB1K and BMK), standard restricted (open-shell) MP2 (RMP2), and two recently introduced variants of MP2, namely spin-component-scaled MP2 (SCS-MP2) and scaled-opposite-spin MP2 (SOS-MP2). The high-level composite procedures show very good agreement with experiment and are used to evaluate the performance of the lower-level DFT- and MP2-based procedures. The best DFT methods (KMLYP and particularly BMK) provide very reasonable predictions for the absolute heats of formation and R-X BDEs for the systems studied. However, all of the DFT methods overestimate the stabilizing effect on BDEs in going from R = Me to R = t-Bu, leading in some cases to incorrect qualitative behavior. In contrast, the MP2-based methods generally show larger errors (than the best DFT methods) in the absolute heats of formation and BDEs, but better behavior for the relative BDEs, although they do tend to underestimate the stabilizing effect on BDEs in going from R = Me to R = t-Bu. The potentially less computationally expensive SOS-MP2 method offers particular promise as a reliable method that might be applicable to larger systems.


Regulation of plant immune receptor accumulation through translational repression by a glycine-tyrosine-phenylalanine (GYF) domain protein.
Plant immunity is tightly regulated to ensure proper defense against surrounding microbial pathogens without triggering autoimmunity, which negatively impacts plant growth and development. Immune receptor levels are intricately controlled by RNA processing and post-translational modification events, such as ubiquitination. It remains unknown whether, and if yes, how, plant immune receptor homeostasis is regulated at the translational level. From a mutant, snc1-enhancing (muse) forward genetic screen, we identified MUSE11/EXA1, which negatively regulates nucleotide-binding leucine-rich repeat (NLR) receptor mediated defence. EXA1 contains an evolutionarily conserved glycine-tyrosine-phenylalanine (GYF) domain that binds proline-rich sequences. Genetic and biochemical analysis revealed that loss of EXA1 leads to heightened NLR accumulation and enhanced resistance against virulent pathogens. EXA1 also associates with eIF4E initiation factors and the ribosome complex, likely contributing to the proper translation of target proteins. In summary, our study reveals a previously unknown mechanism of regulating NLR homeostasis through translational repression by a GYF protein.


Third-year undergraduate nursing students' perceptions of high-fidelity simulation.
High-fidelity simulation, with the potential to enhance cognitive, associative, and autonomous skills, can help students develop clinical reasoning. This study examined third-year students' (N = 300) perceptions about the implementation of high-fidelity simulation into an existing clinical course. Data were collected using an evaluation form completed by students after the simulation. Students perceived high-fidelity simulation as enjoyable, with an appropriate degree of challenge yet possessing congruency with concepts studied in the course. Students' transient feelings of confusion were interpreted as a natural component of the problem solving process as they analyzed, clustered, and interpreted cues to respond to rapid changes in the simulated patient's clinical condition. Debriefing was viewed as an important component and assisted in clarifying students' knowledge and rationale for practice. Further research is required on the relationship between the degree of confusion and its impact on learning and whether high-fidelity simulation increases the ability to reason in the clinical setting.


Tracheal rupture: a rare complication related to foreign body aspiration.
A one-year-old patient admitted following foreign body aspiration and referred following cardiopulmonary resuscitation in a local hospital was diagnosed to have tracheobronchial rupture. We first assumed puncture of the mucous membrane of the left main bronchus by the tip of the tube. Later, we thought that the rupture might have been caused by rigid bronchoscopy. Etiology and treatment are discussed and recent literature reviewed.


Glutamine affects glutathione recycling enzymes in a DMBA-induced breast cancer model.
Malignancy depletes host glutathione (GSH) levels to increase treatment-related toxicity and increases itself to resist the treatments. Our previous studies have shown that dietary glutamine (GLN) prevented 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors through enhancing gut GSH release and reducing tumor GSH level. In addition, GSH synthesis, metabolism, and recycling are accomplished in gamma-glutamyl cycle. We hypothesized that the GLN prevention might be through a differential regulation of the gamma-glutamyl cycle enzymes. Female Sprague-Dawley rats were randomized into DMBA-tumor bearing, DMBA-treated, and control groups subdivided into GLN and water groups. GLN supplementation was given at 1 g/kg/day by gastric gavage. The activities and messenger RNA levels of gamma-glutamyl transpeptidase (GTP), gamma-glutamylcysteine synthetase (GCS), 5-oxo-L-prolinase (OPase), gamma-glutamyl transferase (GTF), and glutaminase (GLNase) were determined in gut mucosa and breast tumor using specific enzyme assays and semiquantitative reverse transcription polymerase chain reaction. GLN upregulated gut GTP, GCS, OPase, and GLNase in DMBA-tumor bearing, DMBA-treated, and/or control rats; however, it downregulated these enzymes in the tumor. The paradoxical effect of GLN on key GSH recycling enzymes in the gut versus tumor suggests that dietary supplemental GLN could be used in the clinical practice to increase the therapeutic index of cancer treatments by protecting normal tissues from, and sensitizing tumor cells to, chemotherapy and radiation-related injury.


Can a brief two-hour interdisciplinary communication skills training be successful in undergraduate medical education?
To pilot-test feasibility, acceptance and learning-outcomes of a brief interdisciplinary communication skills training program in undergraduate medical education. A two-hour interdisciplinary communication skills program with simulated patients was developed and pilot-tested with clinical students at Hamburg University. Five psychosocial specialties facilitated the training. Composite effects were measured qualitatively and quantitatively. Eighty students volunteered to participate in the pilot-program (intervention-group). Their evaluations of the program were very positive (1.1 on a six-point scale). Benefits were seen in feedback, increase of self-confidence, cross-disciplinary clinical and communication experience. Students who did not volunteer (n=206) served as the control-group. The intervention-group performed significantly better (p=0.023) in a primary care communication examination and female students performed better than males. Clinical teachers evaluated the pilot-training very positively with regard to learning-outcomes and feasibility. The positive results from the pilot-training led to implementation into the regular curriculum. A two-hour interdisciplinary communication skills training program is beneficial for medical students with regard to communication competencies, self-confidence and learning-outcomes. The training is feasible within given time-frames and limited staff resources. The high teaching load for small-group-training are split between five specialties. The concept might be an interesting option for other faculties.


Tracking geometrical descriptors on 3-D deformable surfaces: application to the left-ventricular surface of the heart.
Motion and deformation analysis of the myocardium are of utmost interest in cardiac imaging. Part of the, research is devoted to the estimation of the heart function by analysis of the shape changes of the left-ventricular endocardial surface. However, most clinically used shape-based approaches are often two-dimensional (2-D) and based on the analysis of the shape at only two cardiac instants. Three-dimensional (3-D) approaches generally make restrictive hypothesis about the actual endocardium motion to be able to recover a point-to-point correspondence between two surfaces. The present work is a first step toward the automatic spatio-temporal analysis and recognition of deformable surfaces. A curvature-based and easily interpretable description of the surfaces is derived. Based on this description, shape dynamics is first globally estimated through the temporal shape spectra. Second, a regional curvature-based tracking approach is proposed assuming a smooth deformation. It combines geometrical and spatial information in order to analyze a specific endocardial region. These methods are applied both on true 3-D X-ray data and on simulated normal and abnormal left ventricles. The results are coherent and easily interpretable. Shape dynamics estimations and comparisons between deformable object sequences are now possible through these techniques. This promising framework is a suitable tool for a complete regional description of deformable surfaces.


Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): The First Randomized Trial.
Intraparenchymal hemorrhages occur in a proportion of severe traumatic brain injury TBI patients, but the role of surgery in their treatment is unclear. This international multi-center, patient-randomized, parallel-group trial compared early surgery (hematoma evacuation within 12 h of randomization) with initial conservative treatment (subsequent evacuation allowed if deemed necessary). Patients were randomized using an independent randomization service within 48 h of TBI. Patients were eligible if they had no more than two intraparenchymal hemorrhages of 10 mL or more and did not have an extradural or subdural hematoma that required surgery. The primary outcome measure was the traditional dichotomous split of the Glasgow Outcome Scale obtained by postal questionnaires sent directly to patients at 6 months. The trial was halted early by the UK funding agency (NIHR HTA) for failure to recruit sufficient patients from the UK (trial registration: ISRCTN19321911). A total of 170 patients were randomized from 31 of 59 registered centers worldwide. Of 82 patients randomized to early surgery with complete follow-up, 30 (37%) had an unfavorable outcome. Of 85 patients randomized to initial conservative treatment with complete follow-up, 40 (47%) had an unfavorable outcome (odds ratio, 0.65; 95% confidence interval, CI 0.35, 1.21; p=0.17), with an absolute benefit of 10.5% (CI, -4.4-25.3%). There were significantly more deaths in the first 6 months in the initial conservative treatment group (33% vs. 15%; p=0.006). The 10.5% absolute benefit with early surgery was consistent with the initial power calculation. However, with the low sample size resulting from the premature termination, we cannot exclude the possibility that this could be a chance finding. A further trial is required urgently to assess whether this encouraging signal can be confirmed.