CSF Proteins as Discreminatory Markers of Tubercular and Pyogenic Meningitis.
Meningitis is still a major cause of illness in many parts of the world. Though substantial improvement has been occurred in the diagnosis of meningitis, conclusive differentiation between tubercular and pyogenic meningitis remains to be an unsolved problem. Patients with meningitis often have severe neurological deficit or die inspite of antibiotic therapy. Thus, improvement in diagnostic test and therapy is required. The objective of the present study was to find a simple biochemical marker for diagnosis of meningitis and differentiation of tubercular and pyogenic meningitis. CSF samples were collected from 90 paediatric patients from Nilofer Hospital, Hyderabad, India, from age group of 4 months to 12 years. CSF samples were collected by performing Lumbar Puncture under aseptic conditions and with required precaution. CSF samples were divided into 3 groups where Group 1 included Control that was without CSF inflammation, Group 2 with Tuberculous Meningitis & Group 3 consisting of Pyogenic Meningitis with 30 samples in each group. Electrophoretic analysis of CSF proteins was performed which separated as bands of pre-albumin, albumin, alpha, beta and gamma globulins. Protein content in CSF was 259 ± 409 mg/dl in tuberculous meningitis, whereas in pyogenic meningitis it was 111 ± 83.94 mg/dl and in control group was 19 ± 13.3 mg/dl. Electrophoretic analysis revealed pre-albumin band to be 2.8 ± 1.2 % in tuberculous meningitis, which was significantly decreased when compared with control and pyogenic meningitis. Albumin band in tuberculous meningitis was 34.8 ± 9.9 %, which was also significantly decreased when compared to control and pyogenic meningitis. Alpha band was 19.7 ± 6.9 % in pyogenic meningitis, but in control and tubeculous meningitis it was 10.4 ± 2.9% and 10.3 ± 5.2% respectively. Beta band was found similar in all the three groups. Gamma band was 33.2 ± 8.08% in tuberculous meningitis, 13.8 ± 4.55% in control and 16.7 ± 13.18% in pyogenic meningitis. Pre-albumin band was found to be decreased and gamma band was shown to be increased in tuberculous meningitis. Alpha band was increased in pyogenic meningitis. Thus, CSF protein fraction separated and quantitated by native Polyacrylamide slab gel electrophoresis, could be used as markers in differentiation of tubercular and pyogenic meningitis.


The growth inhibitory effects of cadmium and copper on the MDA-MB468 human breast cancer cells.
Cadmium chloride is an important occupational and environmental pollutant. However, it can also be anti-carcinogenic under certain conditions. Copper, an essential trace element, has the ability to generate reactive oxygen species and induce cell apoptosis. This study was aimed to determine the growth inhibitory effects of cadmium and copper on the MDA-MB468 human breast cancer cells. By using MTT cell viability test, treatment of monolayer cell cultures with different metal concentrations (1-1000 µM) showed a significant dose dependent decrease (p < 0.05) of viable cells in different times. A considerable cytotoxicity was observed for CdCl2 at 200 µM and 1 µM after 48 and 72 hours incubations, respectively. The highest concentration of CuCl2 (1000 µM) had little cytotoxic effects after 48 hours incubation period, but 1 µM of CuCl2 revealed a considerable cytotoxicity after 72 hours. The maximum synergic cytotoxic effect was observed at 0.5 µM of both metals. The results of the present study indicate that cytotoxic effect of CuCl2 is somehow lesser than that of CdCl2. This may be due to vital role of copper which is not known for cadmium so far.


Tranexamic acid in cardiac surgery: a systematic review and meta-analysis (protocol).
Bleeding during cardiac surgery is associated with increased morbidity and mortality. Tranexamic acid is an antifibrinolytic with proven efficacy in major surgeries. Current clinical practice guidelines recommend intraoperative use in cardiac procedures. However, several complications have been reported with tranexamic acid including seizures. This review intends to summarise the evidence examining the efficacy and safety of tranexamic acid in patients undergoing cardiac surgery. We will search MEDLINE, Embase, PubMED, ACPJC, CINAHL and the Cochrane trial registry for eligible randomised controlled trials, the search dates for all databases will be from inception until 1 January 2019, investigating the perioperative use of topical and/or intravenous tranexamic acid as a stand-alone antifibrinolytic agent compared with placebo in patients undergoing open cardiac surgery. We categorised outcomes as patient critical or patient important. Selected patient-critical outcomes are: mortality (intensive care unit, hospital and 30-day endpoints), reoperation within 24 hours, postoperative bleeding requiring transfusion of packed red blood cells, myocardial infarction, stroke, pulmonary embolism, bowel infarction, upper or lower limb deep vein thrombosis and seizures. Those outcomes, we perceived as clinical experts to be most patient valued and patients were not involved in outcomes selection process. We will not apply publication date, language, journal or methodological quality restrictions. Two reviewers will independently screen and identify eligible studies using predefined eligibility criteria and then review full reports of all potentially relevant citations. A third reviewer will resolve disagreements if consensus cannot be achieved. We will present the results as relative risk with 95% CIs for dichotomous outcomes and as mean difference or standardised mean difference for continuous outcomes with 95% CIs. We will assess the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Formal ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication TRIAL REGISTRATION NUMBER: CRD42018105904.


Development of a Cadaveric Shoulder Motion Simulator with Open-Loop Iterative Learning for Dynamic, Multiplanar Motion: A Preliminary Study.
Ex vivo shoulder motion simulators are commonly used to study shoulder biomechanics but are often limited to performing simple planar motions at quasi-static speeds using control architectures that do not allow muscles to be deactivated. The purpose of this study was to develop an open-loop tendon excursion controller with iterative learning and independent muscle control to simulate complex multiplanar motion at functional speeds and allow for muscle deactivation. The simulator performed abduction/adduction, faceted circumduction, and abduction/adduction (subscapularis deactivation) using a cadaveric shoulder with an implanted reverse total shoulder prosthesis. Kinematic tracking accuracy and repeatability were assessed using maximum absolute error (MAE), root mean square error (RMSE), and average standard deviation (ASD). During abduction/adduction and faceted circumduction, the RMSE did not exceed 0.3, 0.7, and 0.8 degrees for elevation, plane of elevation, and axial rotation, respectively. During abduction/adduction, the ASD did not exceed 0.2 degrees. Abduction/adduction (subscapularis deactivation) resulted in a loss of internal rotation, which could not be restored at low elevation angles. This study presents a novel control architecture, which can accurately simulate complex glenohumeral motion. This simulator will be used as a testing platform to examine the effect of shoulder pathology, treatment, and rehabilitation on joint biomechanics during functional shoulder movements.


Kinetic Stability of Proteins in Beans and Peas: Implications for Protein Digestibility, Seed Germination, and Plant Adaptation.
Kinetically stable proteins (KSPs) are resistant to the denaturing detergent sodium dodecyl sulfate (SDS). Such resilience makes KSPs resistant to proteolytic degradation and may have arisen in nature as a mechanism for organismal adaptation and survival against harsh conditions. Legumes are well-known for possessing degradation-resistant proteins that often diminish their nutritional value. Here we applied diagonal two-dimensional (D2D) SDS-polyacrylamide gel electrophoresis (PAGE), a method that allows for the proteomics-level identification of KSPs, to a group of 12 legumes (mostly beans and peas) of agricultural and nutritional importance. Our proteomics results show beans that are more difficult to digest, such as soybean, lima beans, and various common beans, have high contents of KSPs. In contrast, mung bean, red lentil, and various peas that are highly digestible contain low amounts of KSPs. Identified proteins with high kinetic stability are associated with warm-season beans, which germinate at higher temperatures. In contrast, peas and red lentil, which are cool-season legumes, contain low levels of KSPs. Thus, our results show protein kinetic stability is an important factor in the digestibility of legume proteins and may relate to nutrition efficiency, timing of seed germination, and legume resistance to biotic stressors. Furthermore, we show D2D SDS-PAGE is a powerful method that could be applied for determining the abundance and identity of KSPs in engineered and wild legumes and for advancing basic research and associated applications.


Clinical impact of sepsis at admission to the ICU of a private hospital in Salvador, Brazil.
To describe the clinical characteristics, laboratory data, and clinical outcomes of patients with and without sepsis admitted to the ICU of a private hospital in the city of Salvador, Brazil, and to identify clinical variables related to a worse prognosis in those with sepsis. This was a longitudinal study including all patients admitted to the general ICU of the Hospital Português, in the city of Salvador, Brazil, between June of 2008 and March of 2009. At ICU admission, two groups of patients were identified: with sepsis and without sepsis. Epidemiological, clinical and laboratory data were collected, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated. Of the 144 patients in the study, 29 (20.1%) had sepsis. Among the patients with sepsis, males accounted for 55.2%, the mean age was 73.1 ± 14.6 years, and the mean APACHE II score was 23.8 ± 9.1, compared with 36.3%, 68.7 ± 17.7 years, and 18.4 ± 9.5, respectively, among those without sepsis. There were significant associations between a diagnosis of sepsis and the following variables: APACHE II score; in-hospital mortality; ICU mortality; HR; mean arterial pressure; hematocrit level; white blood cell count; and antibiotic use. The use of life support measures and lower hematocrit levels were associated with a worse prognosis in the patients with sepsis. The patients diagnosed with sepsis presented worse clinical outcomes, probably due to their greater severity. Hematocrit level was the only variable that was a predictor of mortality risk in the patients with sepsis.


Alteration of gas phase ion polarizabilities upon hydration in high dielectric liquids.
We investigate the modification of gas phase ion polarizabilities upon solvation in polar solvents and ionic liquids. To this aim, we develop a classical electrostatic theory of charged liquids composed of solvent molecules modeled as finite size dipoles, and embedding polarizable ions that consist of Drude oscillators. In qualitative agreement with ab initio calculations of polar solvents and ionic liquids, the hydration energy of a polarizable ion in both types of dielectric liquid is shown to favor the expansion of its electronic cloud. Namely, the ion carrying no dipole moment in the gas phase acquires a dipole moment in the liquid environment, but its electron cloud also reaches an enhanced rigidity. We find that the overall effect is an increase of the gas phase polarizability upon hydration. In the specific case of ionic liquids, it is shown that this hydration process is driven by a collective solvation mechanism where the dipole moment of a polarizable ion induced by its interaction with surrounding ions self-consistently adds to the polarization of the liquid, thereby amplifying the dielectric permittivity of the medium in a substantial way. We propose this self-consistent hydration as the underlying mechanism behind the high dielectric permittivities of ionic liquids composed of small charges with negligible gas phase dipole moment. Hydration being a correlation effect, the emerging picture indicates that electrostatic correlations cannot be neglected in polarizable liquids.


Claustrum projections to prefrontal cortex in the capuchin monkey (Cebus apella).
We examined the pattern of retrograde tracer distribution in the claustrum following intracortical injections into the frontal pole (area 10), and in dorsal (area 9), and ventral lateral (area 12) regions of the rostral prefrontal cortex in the tufted capuchin monkey (Cebus apella). The resulting pattern of labeled cells was assessed in relation to the three-dimensional geometry of the claustrum, as well as recent reports of claustrum-prefrontal connections in other primates. Claustrum-prefrontal projections were extensive, and largely concentrated in the ventral half of the claustrum, especially in the rostral 2/3 of the nucleus. Our data are consistent with a topographic arrangement of claustrum-cortical connections in which prefrontal and association cortices receive connections largely from the rostral and medial claustrum. Comparative aspects of claustrum-prefrontal topography across primate species and the implications of claustrum connectivity for understanding of cortical functional networks are explored, and we hypothesize that the claustrum may play a role in controlling or switching between resting state and task-associated cortical networks.


Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis.
Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation. Tazarotene (AGN 190168), a retinoic acid receptor (RAR)-specific retinoid, is effective in the treatment of psoriasis, a hyperproliferative and inflammatory skin disease. Because negative regulation of genes appears to be important in the antiproliferative and antiinflammatory action of retinoids, we studied the down-regulation of genes in skin raft cultures by this antipsoriatic retinoid. By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168. MRP-8 and SKALP are overexpressed in psoriatic lesions as compared to the normal epidermis, and they are markers of hyperproliferative keratinocyte differentiation. We also show that MRP-8 expression is retinoid inhibitable in cultured keratinocytes induced to differentiate with 10% serum or IFN-gamma, and that MRP-8 is inhibited by RAR but not by retinoid X receptor-specific retinoids in a dose-dependent manner. Finally, MRP-8, SKALP, and the previously characterized differentiation marker, transglutaminase I, are all down-regulated in vivo in psoriatic lesions after treatment with AGN 190168 in comparison to placebo. Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status.


Can the spotlight of attention be shaped like a doughnut? Evidence from steady-state visual evoked potentials.
Visual attention enables observers to extract and process high-priority information in the visualfield. Controversy remains as to whether or not observers can ignore information that falls within the spatial beam of attention. We used an objective physiological measure, the steady-state visual evoked potential (SSVEP), to investigate this question. A stream of flickering small, uppercase letters was embedded in the center of a stream of large, uppercase letters. A unitary beam would result in no difference of the SSVEP amplitude elicited by the small letter stream when it was attended versus ignored (i.e., when subjects attended the large letter stream). Contrary to this prediction, SSVEP amplitude increased by almost 100% when the small letter stream was attended compared with when it was ignored. The results support the notion that the attentional spotlight can be formed like a doughnut, processing central information differentially depending on whether it is attended or ignored.


Mutants of Escherichia coli defective for replicative transposition of bacteriophage Mu.
We isolated 142 Hir- (host inhibition of replication) mutants of an Escherichia coli K-12 Mu cts Kil- lysogen that survived heat induction and the killing effect of Mu replicative transposition. All the 86 mutations induced by insertion of Tn5 or a kanamycin-resistant derivative of Tn10 and approximately one-third of the spontaneous mutations were found by P1 transduction to be linked to either zdh-201::Tn10 or Tn10-1230, indicating their location in or near himA or hip, respectively. For a representative group of these mutations, complementation by a plasmid carrying the himA+ gene or by a lambda hip+ transducing phage confirmed their identification as himA or hip mutations, respectively. Some of the remaining spontaneously occurring mutations were located in gyrA or gyrB, the genes encoding DNA gyrase. Mutations in gyrA were identified by P1 linkage to zei::Tn10 and a Nalr gyrA allele; those in gyrB were defined by linkage to tna::Tn10 and to a gyrB(Ts) allele. In strains carrying these gyrA or gyrB mutations, pBR322 plasmid DNA exhibited altered levels of supercoiling. The extent of growth of Mu cts differed in the various gyrase mutants tested. Phage production in one gyrA mutant was severely reduced, but it was only delayed and slightly reduced in other gyrA and gyrB mutants. In contrast, growth of a Kil- Mu was greatly reduced in all gyrase mutant hosts tested.


Antidepressants for smoking cessation.
There are two reasons to believe antidepressants might help in smoking cessation. First, depression may be a symptom of nicotine withdrawal, and smoking cessation sometimes precipitates depression. Second, smoking appears to be due, in part, to deficits in dopamine, serotonin and norepinephrine, all of which are increased by antidepressants. The aim of this review is to assess the effectiveness of antidepressant medications in aiding long term smoking cessation. The drugs include bupropion; doxepin; fluoxetine; imipramine; moclobemide; nortriptyline; selegiline; sertraline, tryptophan and venlafaxine. We searched the Cochrane Tobacco Addiction Group trials register which includes trials indexed in Medline, Embase, SciSearch and PsycLit, and other reviews and meeting abstracts. We considered randomized trials comparing antidepressant drugs to placebo or an alternative therapeutic control for smoking cessation. We excluded trials with less than 6 months follow-up. We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effects model. There was one trial each of moclobemide, sertraline and venlafaxine, two of fluoxetine and nortriptyline, and five trials of bupropion, one of which tested long term use to prevent relapse. Nortriptyline and bupropion both increased cessation. In one trial the combination of bupropion and nicotine patch produced higher quit rates than patch alone. Some antidepressants (bupropion and nortriptyline) can aid smoking cessation. It is not clear whether these effects are specific for individual drugs, or a class effect.


Genetic parameters for health traits using data collected from genomic information nucleus herds.
As with many other countries, data availability has been a limitation in Australia for developing breeding values for health traits. A genomic information nucleus of approximately 100 herds across the country, selected on the basis of their record keeping, has recently been established in Australia and is known as Ginfo. The objective of this study was to evaluate the feasibility of developing genomic breeding values for health traits using farmer-collected data from Ginfo herds. Having this genotyped population opens up opportunities to develop new genomic breeding values, such as dairy health traits. In these herds, the 4 most recorded groups of health diseases identified were mastitis, reproductive problems, lameness, and metabolic disorders with incidence levels of 16, 9, 2, and 1.5%, respectively. Heritability estimates from pedigree and genomic analysis ranged from 0.01 to 0.03 for mastitis, 0.005 to 0.02 for reproductive disorders, 0 to 0.02 for lameness, and 0.00 to 0.06 for metabolic disorders. However, although heritability is low, there is sufficient genetic variation to make genetic progress feasible (coefficient of variation ranging from 3 to 26.3%). Genetic correlations between health and milk production traits (0.08 to 0.48) and overall type (-0.00 to 0.57) are unfavorable, but favorable with other economical traits, such as fertility (0.10 to 0.51), survival (-0.16 to -0.37), and somatic cell count (0.07 to 0.55). For a genomic reference population of 11,458 cows, the reliability of genomic predictions is comparatively low (<30%), but is promising for health traits, such as mastitis (∼30%) and a broader-based all disease trait (∼28%), when bulls have daughters in the reference population, but not when they only have genomic information (0 to 18%). Further improvement of the reliabilities of health breeding values continues to be an important objective. The study has provided a good foundation for future research to develop breeding values for health traits.


Developmental changes between ages 13 and 21 years in the extent and magnitude of the BOLD response during decision making.
Developmental neuroimaging results have suggested a progression in focalization in functional activations from childhood to adulthood. The mechanisms underlying this process are thought to be an age-related decrease in activation extent as well as an increased magnitude in task-related areas. The present study aimed to evaluate these notions while controlling for confounders that may bias towards focalization. We used adolescent subjects in small age ranges. In addition, head motion corrections were incorporated in statistical analyses and regions of interest were identified for each participant separately to overcome inter-individual variability in anatomy and functional organization. Activation patterns of 13-, 17- and 21-year-old males were compared during the decision phase of a challenging and complex gambling paradigm. The BOLD amplitude enhanced with increasing age, modulated by task conditions. First, response amplitude during difficult, endogenous relative to exogenous decisions increased with age. This decision difficulty effect was most pronounced in 21-year-olds, both in areas associated with task execution and default mode areas. Second, deciding to pass as opposed to gamble exerted more effort in inferior frontal and parietal areas only by 13- and 17-year-olds. There was neither an age-related decrease in activation extent, nor any qualitative shifts in activated areas as suggested by the focalization hypothesis. These results suggest that although different age groups throughout adolescence engage similar brain areas during decision making, the response magnitude in these areas increases with age particularly during difficult task conditions, providing that confounding factors are controlled.


Measurement of activated factor XII in health and disease.
We investigated a new ELISA for measuring activated factor XII (FXIIa) in plasma. The intra-assay coefficient of variation was 3.5% and 5.1% for plasma containing 2.5 and 8.2 ng/ml FXIIa. The inter-assay coefficient of variation was 6.2% and 6.6%. FXIIa correlated with age in women older than 55 years (r = 0.55, P = 0.0003). Mean levels in the whole population of 160 healthy individuals included in this study were not different between men and women, but women younger than 55 years had lower levels than older women and men of the corresponding age. In a group of 25 healthy centenarians FXIIa was significantly higher (3.2 ng/ ml, 95% CI 2.3-3.6) than in controls (2.1 ng/ml, 95% CI 1.8-2.4). Increased levels were also found in pregnancy, with higher levels in the third trimester (4.7 ng/ml, 95% CI 3.9-5.5) than in the first trimester (2.9 ng/ml, 95% CI 2.2-3.9). FXIIa was unmeasurable in patients with FXII deficiency, but normal in patients with FXI deficiency and C1-inhibitor deficiency. FXIIa was significantly higher than in normal controls in patients with severe sepsis (3.9 ng/ml, 95% CI 2.8-5.4) and septic shock (5.4 ng/ml, 95% CI 3.7-7.7). After treatment with thrombolytic agents, a marked increase of FXIIa was found in patients with myocardial infarction. In conclusion, the immunoassay of FXIIa permits to study more directly the contact phase of blood coagulation in situations in which the involvement of this system may play a pathophysiological role.


First Report of Leaf Spots Caused by Pestalotiopsis nanjingensis on Photinia × fraseri in China.
Photinia × fraseri Dress, belonging to the Rosaceae family, is widely cultivated as an ornamental plant in China. In July 2022, the leaf spot symptoms were observed on over thirty P. × fraseri plants in an approximately 2-hectare park in Xinjian District, Nanchang City, Jiangxi Province, China (28°43'02″ N, 115°44'01″ E), with a disease incidences of roughly 10% . At first, small, grayish-white lesions appeared on the leaf edges, later expanding into 2 to 10 mm circular or irregular spots. These spots turned grayish-white to brown, with dark brown margins. Eventually, some lesions' centers dried and died. For fungal isolation, ten symptomatic leaves were randomly collected. The edges between the diseased and healthy tissues were cut into small pieces (4 × 4 mm). These pieces were then surface-sterilized by dipping in 70% ethanol for 30 s and 1% NaClO for 30 s. Subsequently, they were rinsed three times with sterile distilled water. Leaf pieces were then transferred to potato dextrose agar (PDA) medium and incubated at 25 °C for 3-4 days. Eight isolates with similar colony morphology were collected from diseased leaves. Colonies of this fungus on PDA were nearly round, white, and had sparse aerial mycelium on the surface with black, gregarious conidiomata. The conidia were nearly cylindrical, smooth, hyaline, and 4-septate, measuring 16.7 to 24.3 × 4.2 to 6.6 µm (mean 20.9 × 5.3 µm, n=50). The three middle cells were smooth, doliiform, and brown, with concolorous septa that were darker than the rest of the cell. They measured 11.8 to 17.0 µm long (mean 14.1 µm, n=50). The basal and apical cells were triangular and transparent. The basal cells had a mean length of 4.7 µm and were equipped with a basal appendage, while the apical cells had two appendages with a mean length of 17.7 µm(n=50). The characteristics of these isolates match those of Pestalotiopsis species (Maharachchikumbura et al. 2014). To identify them accurately, three representative isolates, namely JFRL 03-161, JFRL 03-162, and JFRL 03-226, were selected for further analysis. The internal transcriptional spacer (ITS) region, β-tubulin (TUB2) and translation elongation factor 1-alpha (TEF1-α) gene were amplified and sequenced using primers ITS1/ITS4 (White et al. 1990), BT2a/BT2b (Glass and Donaldson 1995), and EF1-526F/EF1-1567R (Maharachchikumbura et al. 2012), respectively. All sequences (ITS: OR342044-OR342046, TUB2: OR343299-OR343301, and TEF1-α: OR343302-OR343304) were deposited in GenBank. A BLASTn homology search revealed 99-100% identity to Pestalotiopsis nanjingensis CSUFTCC16 (ex-type). The sequences included ITS (OK493602, 486/486 nucleotides), TUB2 (OK562377, 438/439 nucleotides), and TEF1-α (OK507972, 478/478 nucleotides). The maximum likelihood analyses were performed for the combined ITS, TUB2 and TEF1-α data sets using IQtree web server (Trifinopoulos et al. 2016). The resulting phylogenetic tree demonstrated a strong association: the three isolates clustered tightly with P. nanjingensis forming a clade with robust 99% bootstrap support. This clustering, consistent with both morphological and molecular characteristics, confirmed the identity of the fungus as P. nanjingensis. To evaluate its pathogenicity, we obtained 3-year-old P. × fraseri 'Red Robin' plants, which were purchased then potted in a controlled climate chamber. We surface sterilized six healthy leaves of P. × fraseri with 70% ethanol and created wounds using a sterile needle. Subsequently, we inoculated a 50 μL conidial suspension (1 × 106 conidia/mL) of the isolate JFRL 03-161 on these wounded leaves. In parallel, another six leaves from P. × fraseri were inoculated with sterile distilled water, serving as the control group. All potted plants were incubated under conditions of 26 °C and 80% humidity. After seven days, all leaves inoculated with isolate JFRL 03-161 displayed symptoms similar to those observed in the field, whereas the control leaves remained unaffected. To fulfill Koch's postulates, we re-isolated P. nanjingensis plants from the symptomatic leaves and identified it based on morphological and molecular characteristics. It has been reported that two species of Pestalotiopsis, namely P. microspora and P. trachicarpicola can caused damage to the leaves of P. × fraseri in China (Xu et al. 2022; Zhu et al. 2021). However, to our best knowledge, this is the first report on leaf spot caused by P. nanjingensis on P. × fraseri in China. Therefore, it is necessary to pay more attention to the leaf spot disease of P. × fraseri caused by Pestalotiopsis species and develop appropriate control strategies.


The pulvinar sign: frequency and clinical correlations in Fabry disease.
Fabry disease is an X-linked lysosomal deficiency of alpha-galactosidase A that results in cellular accumulation of galactoconjugates, mainly globotriaosylceramide, particularly in blood vessels. Neuroradiological findings include ischemic stroke, white matter lesions, vascular abnormalities (vertebrobasilar dolichoectasia and vessel tortuosity), and posterior thalamus involvement (the so called pulvinar sign). The purpose of our study was to investigate the presence of the increased pulvinar signal intensity on T1-weighted imaging - pulvinar sign and its relationship with other clinical findings, in a non-selected cohort of Fabry patients. We performed a prospective analysis of two populations of patients (36 subjects) with Fabry disease. Patients were followed-up at the Department of Internal Medicine of the Bichat Hospital in Paris (France) and at the Neurological Clinic of the University Hospital of Padova (Italy). Brain MR studies of each patient included T1- and T2- weighted images, FLAIR sequences, and in some cases diffusion weighted images. A total of 36 patients (16 males, 20 females) were investigated in 14 families. The pulvinar sign was found in 5 male patients, but not in female patients. Seven patients had had at least one stroke (territorial or lacunar). There was no correlation between stroke and the pulvinar sign. All patients with the pulvinar sign had hypertrophic cardiomyopathy. Four patients out of five with the pulvinar sign were on dialysis or had a kidney transplantation. Our findings suggest that the pulvinar sign is a highly specific sign of Fabry disease, found in male patients with cardiac signs and severe kidney involvement.


Dietary modulation of intestinal nutrient transport in the teleost fish tilapia.
Tilapia (Oreochromis mossambicus) were fed a diet with either 60% carbohydrate (70% grain-4% fish meal) or 17% carbohydrate (11% grain-65% fish meal) for greater than or equal to 4 wk. Intestinal uptake of radiolabeled acetate, D-glucose, and L-proline was measured in brush-border membrane vesicles. As expected, fish fed high carbohydrate had significantly higher D-glucose uptake than those fed low carbohydrate [maximal uptake rate (Vmax), respectively, 84.2 +/- 18.2 vs. 37.4 +/- 10.9 pmol.mg protein-1.s-1; n = 4 batches of vesicles in each case; t test, P less than 0.025]. The change in glucose transport was specific, because in the same batches of vesicles there was no significant diet effect on carrier-mediated uptake of L-proline or acetate. Also as expected, dietary modulation of carrier-mediated transport was effected primarily by alterations in Vmax and not apparent Michaelis constant (Km); Km was not significantly altered by diet for either D-glucose (high carbohydrate vs. low carbohydrate, respectively, 0.34 +/- 0.17 vs. 0.12 +/- 0.03 mM; P greater than 0.2), L-proline (respectively, 0.10 +/- 0.03 vs. mM 0.13 +/- 0.05), or acetate (respectively, 4.8 +/- 1.4 vs. mM 6.5 +/- 2.2).


Hepatoid adenocarcinoma of the lung.
Lung adenocarcinomas with a mixture of tubular or papillary pattern, sheet-like or trabecular architecture, eosinophilic cytoplasm with centrally located nuclei and alpha-fetoprotein-producing cells have been described as hepatoid adenocarcinomas. Hepatoid adenocarcinomas are mainly found in the stomach but rare cases in other organs have been described. Immunostaining for alpha-fetoprotein (AFP), hepatocyte paraffin 1 (HepPar-1) and thyroid transcription factor-1 (TTF-1) helps in the diagnostic workup. Tumor behavior is still not entirely known but it seems to be associated with early metastases. We report on a 66-year-old, heavy-smoker male patient who had a 10-month history of respiratory complaints and weight loss. At the time he was hospitalized, respiratory failure was already established. The computed tomography corresponded to a collapsed right lung due to a poorly defined expanding mass. The bronchoscopy revealed narrowing of the inferior and medium lobar bronchi. The patient developed irreversible shock and died. At the right lung inferior lobe was extensively replaced by a grayish diffuse neoplasia in a "pneumonia-like" gross pattern. Metastatic disease was found in the right adrenal gland and thoracic and abdominal lymph nodes. Microscopic dissemination through lymphatics, pleura, and airways was detected. Histological examination revealed a poorly differentiated adenocarcinoma with hepatoid features. Immunohistochemmistry stains were positive for keratin 7, polyclonal carcinoembryonic antigen (CEA) in a diffuse pattern, AFP and HepPar-1 antibody. TTF-1 showed a diffuse granular cytoplasmic staining of the neoplastic cells, and only focal nuclear positivity. Multiple bilateral emboli originated from deep venous thrombosis were present in large and medium branches of the pulmonary artery and contributed to the cause of death.


Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency.
21-Hydroxylase deficiency resulting in congenital adrenal hyperplasia (CAH) is a HLA-linked autosomal recessive disorder that has a wide range of phenotypic expression. Two homologous 21-hydroxylase genes (21-OHA and 21-OHB) occur within the Class III region of the major histocompatibility complex, but only one (21-OHB) appears to function in adrenal steroidogenesis. Our restriction maps, and initial sequence data from White et al. (Pediatr Res 20:274A (1986)) for the two human 21-OH genes reveal a high degree of homology between these genes and a reading frame shift mutation in the 21-OHA gene respectively. Among fourteen control subjects, the intragenic restriction patterns of the 21-OHA and 21-OHB genes are invariant. The few restriction fragment length polymorphisms (RFLPs) found in some controls result from polymorphic restriction sites outside the 21-OH genes. In patients with CAH, several different mechanisms for mutation of the 21-OHB gene have been described: deletion of the unique sequences of the 21-OHB gene, conversion of the unique sequences of the 21-OHB gene to those of 21-OHA, and mutations of 21-OHB which do not result in a detectable alteration of restriction pattern (e.g., point mutations). Duplication of the 21-OHA gene has been found in some patients with attenuated CAH; however, the significance of this finding remains unclear.


Comparison of direct and bystander effects induced by ionizing radiation in eight fish cell lines.
To determine bystander and direct effects of ionizing radiation on eight fish cell lines. Fish cell lines were irradiated at a range of doses from 0.5 - 5 Gy. The Irradiated Cell Conditioned Medium (ICCM) was then harvested and placed onto a HPV-G, reporter cell line as well as onto autologous fish cell lines. Cloning efficiency (CE) was the end point used. The HPV-G reporter cell line was chosen because this cell line is capable of transmitting and producing the bystander effect. Four of the eight fish cell lines were clonogenic. These, with the exception of RTG-2 cells, showed increased CE when ICCM was tested on unirradiated autologous cells or on HPV-G cells. ICCM from RTG-2 cells reduced survival. The non-clonogenic cells ICCM tested on HPV-G all showed increased CE. The results show that both bystander signal production and cellular response varies depending on the cell line and that in general signals from established fish cells do not produce death inducing bystander effects. Thus, the comparison of the effect from fish cell ICCM on autologous cells or HPV-G human cells allowed us to separate signal production from response. In almost all cases, for both non-clonogenic and clonogenic fish cell lines, the HPV-G recipient cell line showed an increase in percent survival compared to controls while the clonogenic fish cell lines do not appear to respond.


Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach.
Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted these phagocytic cells in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to >92%, depending on therapy and schedule. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue. Vascular endothelial growth factor (VEGF) is one of the major inducers of tumour angiogenesis and is also required for macrophage recruitment. The strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Immunohistologic evaluation of the tumours showed significant depletion of F4/80+ and MOMA-1+ and a less pronounced depletion of CD11b+ TAMs. Blood vessel staining (CD31) and quantification of the vessels as well as TAMs and tumour-associated dendritic cells (TADCs) in the A673 model showed reduction rates of 85 to >94%, even 9 days after the end of therapy. In addition, CD11c+ TADCs, which have been shown to potentially differentiate into endothelial-like cells upon stimulation by tumour released growth and differentiation factors, were similarly reduced by clodrolip or antibody treatment. These results validate clodrolip therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination and as a tool to study the role of macrophages and dendritic cells in tumorigenesis.


Optical measurement of the refractive index, layer thickness, and volume changes of thin films.
Preparation, measurement, and calculation methods are discussed for the determination of the complex index of refraction, the layer thickness, and induced volume changes of thin layers (due to a phase change, for example). The principle of the calculation is fitting a curve in the reflectance-transmittance plane measured on a range of layer thicknesses, instead of fitting the reflectance and transmittance as a function of independently measured layer thicknesses. This general method is applied to thin films of GaSb and InSb, in which a laser-induced amorphous-to-crystalline transition can be used in optical recording. The information essential for optical recording applications is measured quickly by making use of a stepwise prepared layer thickness distribution, while the complex refractive index and the layer thicknesses can also be calculated unambiguously.


Combined Reactive and Volitional Step Training Improves Balance Recovery and Stepping Reaction Time in People With Parkinson's Disease: A Randomised Controlled Trial.
Falls are frequent and devastating events for people with Parkinson's disease (PD). Here, we investigated whether laboratory-based reactive step training combined with home-based volitional step training was effective in improving balance recovery and stepping ability in people with PD. Forty-four people with idiopathic PD were randomized into intervention or control groups. Intervention participants performed unsupervised volitional step training using home-based exergames (80+ minutes/week) for 12 weeks and attended reactive step training sessions in which they were exposed to slip and trip perturbations at 4 and 8 weeks. Control participants continued their usual activities. Primary outcomes were balance recovery following an induced-trip/slip and choice stepping reaction time (CSRT) at the 12-week reassessment. Secondary outcomes comprised sensorimotor, balance, cognitive, psychological, complex stepping (inhibitory CSRT and Stroop Stepping Test [SST]), gait measures, and falls experienced in everyday life. At reassessment, the intervention group had significantly fewer total laboratory-induced falls and faster CSRT compared to the control group (P < .05). The intervention group also had significantly faster inhibitory CSRT and SST movement times and made fewer mistakes in the SST (P < .05). There were no significant differences in the rate of every day falls or other secondary outcome measures between the groups. Combined volitional and reactive step training improved balance recovery from an induced-perturbation, voluntary stepping time, and stepping accuracy in cognitively challenging tests in people with PD. Further research is required to determine whether such combined step training can prevent daily-life falls in this population.


[Apico-aortic valved conduit for aortic stenosis in patients who could not tolerate median sternotomy].
This report presents 3 cases treated with an apico-aortic valved conduit. Cases 1, 2:A 67-year-old female patient and a 60-year-old male patient what had undergone coronary artery bypass grafting were admitted to our hospital for severe aortic stenosis. Computed tomography showed a severe calcified ascending aorta, and coronary angiography revealed patent bypass graft. Case 3:A 71-year-old male patient that had esophagectomy with retrosternal colonic interposition for esophagus cancer after distal gastrectomy. In addition, he had experienced anterior mediastinal drainagic therapy for anastomotic leak. All 3 patients were treated by implantation of an apico-aortic valved conduit. Operation:This procedure was performed through the 5th intercostal space under a beating heart with cardiopulmonary bypass. Postoperative courses were uneventful. All patients are still alive without procedure-related events. This surgical procedure can be an effective alternative when conventional aortic valve replacement cannot be performed for aortic stenosis patients.


Optical changes and writing on hydrotalcite supported gold nanoparticles.
Gold nanoparticles (AuNP) incorporated into hydrotalcite (HT), provide an interesting type of pigment in which temperature can modulate the plasmon resonance and the aggregation phenomenon. As inferred from microscopy techniques, the preferential binding sites are located at the border of the HT external basal surface, leading to aggregates of gold nanoparticles displaying characteristic plasmon resonance and interference bands around 520 and 700 nm, respectively. The thermally induced color changes in the HT-supported gold material arise from the competition between of nanoparticles aggregation and fusion processes, as characterized by TEM and STM. A laser beam can also induce such changes, allowing the writing of optical information on this type of material.


A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.
As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin-cell penetrating peptide-sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood-brain barrier (BBB) and glioma cells with the internalization and lysosomal escaping ability of CPP. Based on the systematic investigation of structure-activity relations on the cellular level, we constructed TF-CPP-SSL rationally by conjugating TF and CPP moieties to the liposomes via PEG3.4K and PEG2.0K, respectively, and found the optimum densities of TF and CPP were 1.8% and 4%, respectively. These liposomes had the highest targeting efficacy for brain microvascular endothelial cell and C6 cell uptake but avoided capture by normal cells. Fluorescence resonance energy transfer technology and coculture models of BBB and glioma C6 cells indicated that TF-CPP-SSL was transported across the BBB without drug leakage, liposome breakup, or cleavage of ligand. TF-CPP-SSL offered advantages for crossing the BBB and entering into glioma C6 cells. Real-time confocal viewing revealed that TF-CPP-SSL was entrapped in endosomes of glioma C6 cells and then escaped from lysosomes successfully to release the liposomal contents into the cytosol. Entrapped contents, such as doxorubicin, could then enter the nucleus to exert pharmacological effects.


Analysis of human anti-diphtheria antibodies by isoelectric focusing: evidence for restricted clonal heterogeneity of anti-fragment A antibodies.
The in vivo human humoral response to diphtheria toxoid-tetanus toxoid booster immunization was studied by isoelectric focusing analysis of sera obtained after immunization. The anti-diphtheria toxoid (immunoglobulin G [IgG]-Dip), anti-fragment A (IgG-Frag A), and anti-tetanus toxoid antibodies from 20 donors post-booster immunization were focused by using agarose isoelectric focusing and visualized by development with radiolabeled antigens. The quantities of the IgG-Dip and IgG-Frag A antibodies correlated with the number of bands seen on the isoelectric focusing pattern in that more bands were found in the spectrotypes of donors with high serum levels of antibody. No difference was apparent in the antibody spectrotypes obtained from sera of donors at successive times post-booster immunization. Individual heterogeneity of the different donors' spectrotypes was often found for IgG-Frag A antibodies, but a close comparison of several different donors revealed antibodies with the same spectrotype patterns. Thus, individual clones of antibody were revealed in humans after in vivo immunization, particularly when antibodies against antigens of restricted epitope size were analyzed. Additionally, the sharing of certain antibody spectrotypes among several individuals raised the possibility that certain antibody clones may be preferentially expressed in the human population.


Measurement of High-Sensitivity Cardiac Troponin in Pulmonary Embolism: Useful Test or a Clinical Distraction.
The ability to predict death or other unfavorable outcomes after an acute pulmonary embolism (PE) is challenging, with current available risk score models having relatively unsatisfactory prognostic performance in this area. For example, the simplified pulmonary embolism severity index (sPESI), the most frequently used stratification tool, misclassifies a significant percentage of low- and high-risk patients. This gap in care, along with the increasing clinical availability of high-sensitivity cardiac troponin (hs-cTn) laboratory tests and the recent emphasis on detecting myocardial injury, may foster further evaluation of hs-cTn testing in patients with acute PE. Our analysis of the current scientific literature on hs-cTn in patients with acute PE identified that hs-cTn testing may provide valuable information for predicting future adverse outcomes and mortality, independently from baseline clinical risk assessment. Although the risk of an adverse event is indeed higher in patients with higher sPESI scores, cTns retain their prognostic value also in those at low risk, suggesting that a combination of hs-cTn with sPESI may provide an incremental value over assessment of either variable alone. Accordingly, the future development of updated risk stratification models, with the inclusion of laboratory tests such as hs-cTn, may represent an enhanced approach for risk stratification in patients with acute PE. Additional research, however, is needed to verify whether the combination of cTns, specifically as measured with hs-cTn assays, with other biomarkers may further improve the current capacity to efficiently manage patients with acute PE.


Less gap imbalance with restricted kinematic alignment than with mechanically aligned total knee arthroplasty: simulations on 3-D bone models created from CT-scans.
Background and purpose - Mechanical alignment techniques for total knee arthroplasty (TKA) introduce significant anatomic alteration and secondary ligament imbalances. We propose a restricted kinematic alignment (rKA) protocol to minimize these issues and improve TKA clinical outcomes.Patients and methods - rKA tibial and femoral bone resections were simulated on 1,000 knee CT scans from a database of patients undergoing TKA. rKA was defined by the following criteria: independent tibial and femoral cuts within 5° of the bone neutral mechanical axis, with a resulting HKA within 3° of neutral. Imbalances in the extension space, flexion space at 90°, medial compartment and lateral compartment were calculated and compared with measured resection mechanical alignment (MA) results. 2 MA techniques were simulated for rotation using the surgical transepicondylar axis (TEA) and 3° to the posterior condyles (PC).Results - Extension space imbalances ≥ 3 mm occurred in 33% of TKAs with MA technique versus 8.3% with rKA (p < 0.001). Similarly, more frequent flexion space imbalance ≥ 3mm was created by MA technique (TEA 34% or 3° PC 15%) versus rKA (6.4%, p < 0.001). Using MA with TEA or PC, there were only 49% and 63% of the knees respectively with < 3 mm of imbalance throughout the extension and flexion spaces and medial and lateral compartments versus 92% using rKA (p < 0.001).Interpretation - significantly fewer imbalances are created using rKA versus MA for TKA. rKA may be the best compromise, by helping the surgeon to preserve native knee ligament balance during TKA and avoid residual instability, whilst keeping the lower limb alignment within a safe range.


Enzymatic semisynthesis of [LeuB30] insulin.
Experimental conditions for the preparation of [LeuB30] insulin by coupling of des-AlaB30 insulin with Leu-OBu(t) were determined using Achromobacter protease I and trypsin as catalysts. Successful coupling required a large excess of the amine component (0.8 M), a high concentration of organic cosolvent (35-50%) and neutral pH of the reaction mixture. The coupling yield of Achromobacter protease I after 24 h at 37 degrees C was almost the same or a little higher than that at 25 degrees C. With trypsin, the coupling yield at 37 degrees C after 24 h was considerably lower than at 25 degrees C. This was partly ascribed to the difference in concentration of organic cosolvent at 37 degrees C and 25 degrees C; 35% and 50%, respectively, or possibly of enzyme stability at these temperatures. The maximum product yield was about 90% with both enzymes under optimal conditions. A preparative scale experiment was performed with Achromobacter protease I; the yield of [LeuB30] insulin was 51% using porcine insulin as the starting material. This semisynthetic insulin was identified by HPLC and amino acid analysis. No difference was observed in CD spectra between [LeuB30] insulin and human insulin.


Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients.
Fifty patients with newly diagnosed lepromatous leprosy were allocated randomly to one of five groups and treated with either a month-long standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a single dose of 600 mg of rifampin, a month-long regimen with the dapsone (DDS) and clofazimine (CLO) components of the standard MDT, or a single dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline (MINO), with or without the addition of 800 mg of ofloxacin (OFLO). At the end of 1 month, clinical improvement accompanied by significant decreases of morphological indexes in skin smears was observed in about half of the patients of each group. A significant bactericidal effect was demonstrated in the great majority of patients in all five groups by inoculating the footpads of mice with organisms recovered from biopsy samples obtained before and after treatment. Rifampin proved to be a bactericidal drug against Mycobacterium leprae more potent than any combination of the other drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a degree of bactericidal activity similar to that of a regimen daily of doses of DDS-CLO for 1 month, suggesting that it may be possible to replace the DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with or without OFLO. However, gastrointestinal adverse events were quite frequent among patients treated with CLARI-MINO, with or without OFLO, and may be attributed to the higher dosage of CLARI or MINO or to the combination of CLARI-MINO plus OFLO. In future trials, therefore, we propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of MINO, and 400 mg of OFLO.


[Topical organization of somatic projections to the cerebral cortex of the seal Callorhinus ursius].
Somatotopic projections in the cerebral cortex of the fur seal (Callorhinus ursinus) were determined by microelectrode recordings of the multiple unit activity. Somatosensory cortical area is restricted rostrally by postcruciate and coronal sulci, caudally by anterior suprasylvain sulcus and dorsomedially by ansate sulcus. The somatotopic map in this area is oriented in such a way that the head projection is positioned ventrolaterally and that of the hindlimb dorsomedially. The projection area of the forelimb is immersed in the coronal sulcus. Marked disproportions are observed in the projections of different parts of the soma; the head projection has a relatively large magnification factor and within it the vibrissae are presented with the largest magnification.


Immunology of articular cartilage.
The extracellular matrix of articular cartilage is, in part, comprised of 2 macromolecular moieties, collagen and proteoglycans. This article discusses the role of an autoimmune response to these macromolecules in both inflammatory synovitis and osteoarthritis (OA). Autoimmunity to Type II collagen involving "arthrogenic epitope(s)", expressed on the Type II collagen molecule, as well as cell mediated immune responses to collagen may be relevant in the overall development of destruction of articular cartilage. In OA, a role for inflammation and the immune response to connective tissue macromolecules has been suggested by recent investigations. In this regard, autoimmunity plays a part in the progression of the degeneration of articular cartilage in OA.


Chemotherapeutic medications and their emergent complications.
Patients with complications of chemotherapy, either acute or chronic, are frequently encountered in the emergency department (ED). Some patients present with complaints immediately after chemotherapy administration, whereas others may show subtle, secondary signs or may have no signs or symptoms of chemotoxicity. An increased index of suspicion prompts early recognition, diagnosis, and prevention of further iatrogenic injury. This article reviews characteristic hypersensitivity reactions, typical organ system dysfunction, and treatment strategies for adult patients who present to the ED with complications after chemotherapy.


PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.
Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.


DNA copy number aberrations associated with the clinicopathological features of colorectal cancers: Identification of genomic biomarkers by array-based comparative genomic hybridization.
The aim of the present study was to investigate the chromosomal aberrations that are linked with the crucial clinicopathological features of colorectal cancer (CRC) and its prognosis by array-based comparative genomic hybridization (CGH). Fresh-frozen tumor tissues of 94 cases of CRC were analyzed by using bacterial artificial chromosome (BAC) CGH slides spotted with 4030 human BAC clones, which covered the whole range of the human genome at an average interval of 0.83 mega base pairs. DNA copy number aberrations (DCNAs) were identified in association with clinicopathological features: a gain of 8q24.3 and losses of 9q33.1 and 20p12.2 were associated with lymph node metastasis, gain of 8q24.3 and loss of 9q33.1 with disease stage, gain of 8q21.11 and loss of 10q21.3 with lymphovascular invasion and losses of 3p25.1, 10p15.3, 12q15 and 17p13.1 for venous invasion. These aberrations can be regarded as genomic biomarkers to predict the clinical outcome of patients with CRC, and are expected to serve to individualize the treatment of CRC patients.


Differential Expression Profiling of Microspores During the Early Stages of Isolated Microspore Culture Using the Responsive Barley Cultivar Gobernadora.
In barley, it is possible to induce embryogenesis in the haploid and uninucleate microspore to obtain a diploid plant that is perfectly homozygous. To change developmental fates in this fashion, microspores need to engage in cellular de-differentiation, interrupting the pollen formation, and restore totipotency prior to engaging in embryogenesis. In this work, we used the barley cultivar Gobernadora to characterize the transcriptome of microspores prior to (day 0) and immediately after (days 2 and 5) the application of a stress pretreatment. A deep RNA-seq analysis revealed that microspores at these three time points exhibit a transcriptome of ∼14k genes, ∼90% of which were shared. An expression analysis identified a total of 3,382 differentially expressed genes (DEGs); of these, 2,155 and 2,281 DEGs were respectively identified when contrasting expression at days 0 and 2 and at days 2 and 5. These define 8 expression profiles in which DEGs share a common up- or down-regulation at these time points. Up-regulation of numerous glutathione S-transferase and heat shock protein genes as well as down-regulation of ribosomal subunit protein genes was observed between days 0 and 2. The transition from microspores to developing embryos (days 2 vs. 5) was marked by the induction of transcription factor genes known to play important roles in early embryogenesis, numerous genes involved in hormone biosynthesis and plant hormonal signal transduction in addition to genes involved in secondary metabolism. This work sheds light on transcriptional changes accompanying an important developmental shift and provides candidate biomarkers for embryogenesis in barley.


Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors.
Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target. We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing. We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.


soxR, a locus governing a superoxide response regulon in Escherichia coli K-12.
The nfo (endonuclease IV) gene of Escherichia coli is induced by superoxide generators such as paraquat (methyl viologen). An nfo'-lacZ operon fusion was used to isolate extragenic mutations affecting its expression. The mutations also affected the expression of glucose 6-phosphate dehydrogenase, Mn2(+)-superoxide dismutase (sodA), and three lacZ fusions to soi (superoxide-inducible) genes of unknown function. The mutations were located 2 kilobases clockwise of ssb at 92 min on the current linkage map. One set of mutations, in a new gene designated soxR, caused constitutive overexpression of nfo and the other genes. It included insertions or deletions affecting the carboxyl end of a 17-kilodalton polypeptide. In a soxR mutant, the expression of sodA, unlike that of nfo, was also regulated independently by oxygen tension. Two other mutants were isolated in which the target genes were noninducible; they had an increased sensitivity to killing by superoxide-generating compounds. One had a Tn10 insertion in or near soxR; the other had a multigene deletion encompassing soxR. Therefore, the region functions as a positive regulator because it encodes one or more products needed for the induction of nfo. Regulation is likely to be at the level of transcription because the mutations were able to affect the expression of an nfo'-lac operon fusion that contained the ribosome-binding site for lacZ. Some mutant plasmids that failed to suppress (or complement) constitutivity in trans had insertion mutations several hundred nucleotides upstream of soxR in the general region of a gene for a 13-kilodalton protein encoded by the opposite strand, raising the possibility of a second regulatory gene in this region. The result define a new regulon, controlled by soxR, mediating at least part of the global response to superoxide in E. coli.


Comparison of triptorelin acetate vs triptorelin pamoate in the treatment of Central precocious puberty (CPP): a retrospective study.
The aim of this study is to compare the clinical and biochemical outcomes of triptorelin acetate (TPA) versus triptorelin pamoate (TPP) treatment in girls with central precocious puberty. A total of 60 patients with idiopathic CPP were retrospectively recruited. Thirty girls were treated with triptorelin acetate 3.75 mg/month (TPA group) and thirty girls in a second group received triptorelin pamoate 3.75 mg/4 weeks (TPP group). Patient follow-up at 12 and 24 months included GnRH Test at 12 months and baseline LH at 24 months. Patients were monitored with pelvic ultrasound, X-Ray of the hand and wrist and anthropometric evaluations. A total of 60/60 girls showed a good response to both formulations. Significant reductions in basal and LH peaks, estradiol values, breast pubertal stage, progression of bone age and growth velocity rate after 12 months treatment were obtained in both groups, demonstrating the equivalence of the two formulations in regulating the hypothalamic-pituitary-gonadal (HPG) axis. Triptorelin pamoate provided a more effective and significant reduction in LH peak after 12 months in comparison with triptorelin acetate more effective in reducing ovarian volume and endometrial thickness. Both formulations were equivalent, even though the LH peak was significantly lower in girls treated with triptorelin pamoate.


Levels of state and trait anxiety in patients referred to ophthalmology by primary care clinicians: a cross sectional study.
There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale. Cross sectional study. 322 participants and 80 control participants. State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality. Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory. State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p<0.04), but similar for trait anxiety (p>0.1). Rasch analysis highlighted that the questionnaire results needed to be split into "anxiety-absent" and "anxiety-present" items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls. State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients.


[Verapamil binding with the blood erythrocytes and cardiac output in myocardial infarct patients].
In 14 patients with myocardial infarction the degree of verapamil binding with blood erythrocytes after a single oral administration (80 mg/kg) and the dependence pharmacological effect, the minute heart output (+ % MOC), on verapamil content in plasma and erythrocytes were studied. Intraindividual variability of verapamil distribution coefficients between erythrocytes and plasma (RBC/Ptot) is 9.7 +/- 2,3%, and it differs reliably from values of inter-individual variability of this index (33.7 +/- 3.3%).


The role of the champion in infection prevention: results from a multisite qualitative study.
Although 20% or more of healthcare-associated infections can be prevented, many hospitals have not implemented practices known to reduce infections. We explored the types and numbers of champions who lead efforts to implement best practices to prevent hospital-acquired infection in US hospitals. Qualitative analyses were conducted within a multisite, sequential mixed methods study of infection prevention practices in Veteran Affairs and non-Veteran Affairs hospitals in the USA. The first phase included telephone interviews conducted in 2005-2006 with 38 individuals at 14 purposively selected hospitals. The second phase used findings from phase 1 to select six hospitals for site visits and interviews with another 48 individuals in 2006-2007. It was possible for a single well-placed champion to implement a new technology, but more than one champion was needed when an improvement required people to change behaviours. Although the behavioural change itself may appear to be an inexpensive and simple solution, implementation was often more complicated than changing technology because behavioural changes required interprofessional coalitions working together. Champions in hospitals with low-quality working relationships across units or professions had a particularly challenging time implementing behavioural change. Merely appointing champions is ineffective; rather, successful champions tended to be intrinsically motivated and enthusiastic about the practices they promoted. Even when broad implementation is stymied, champions can implement change within their own sphere of influence. The types and numbers of champions varied with the type of practice implemented and the effectiveness of champions was affected by the quality of organisational networks.


Cross-species comparison of fluoxetine metabolism with fish liver microsomes.
Pharmaceuticals discharged in municipal wastewater are of emerging concern because of their potential for inducing biological effects in aquatic organisms. Selective serotonin reuptake inhibitors (SSRIs), pharmaceuticals prescribed to treat chronic depression, have been detected in receiving and wastewaters. Fluoxetine is a highly prescribed model SSRI used to assess impacts of antidepressants on aquatic organisms. In this study, in vitro hepaticfluoxetine metabolism was determined in several model fish species: rainbow trout, goldfish, zebrafish and killifish. Incubation of fluoxetine with hepatic microsomes from trout pre-treated with carbamazepine showed a time-dependant loss of fluoxetine, concomitant with an increase in norfluoxetine, the major mammalian demethylated metabolite. However, fluoxetine was not well metabolized in reactions with hepatic microsomes from untreated fish. Fluoxetine loss was greater than norfluoxetine production, indicating that norfluoxetine is not the predominant fluoxetine biotransformation product in fish. Furthermore, norfluoxetine was often undetected, possibly indicating that fluoxetine demethylation is a minor metabolic pathway in fish. Inter-species differences in fluoxetine metabolism were not evident because of high intra-species variability, although killifish appeared to have the highest hepatic metabolic capacity for fluoxetine. Fluoxetine metabolism in mammals is catalyzed by cytochrome P450 (CYP) enzymes. Trout were exposed to knownCYP inducers, carbamazepine and 3-methylcholanthrene, to assess potential induction of hepatic fluoxetine metabolism. Microsomes from 3-methylcholanthrene treated fish did not induce detectable changes in fluoxetine concentrations in vitro, indicating that fish CYP1s are not involved in fluoxetine metabolism; the CYPs involved are still unclear. Identification of metabolites other than norfluoxetine warrants further investigation.


A novel ATR-FTIR approach for characterisation and identification of ex situ immobilised species.
We demonstrate a novel method to analyse ex situ prepared protein chips by attenuated total reflection Fourier IR spectroscopy (ATR-FTIR), which circumvents tedious functionalisation steps of internal reflection elements (IREs), and simultaneously allows for complementary measurements by other analytical techniques. This concept is proven by utilising immobilised metal affinity capture (IMAC) chips containing about 10 mum thick films of copolymers coated with nitrilotriacetic acid (NTA) groups, which originally was manufactured for surface enhanced laser desorption ionisation (SELDI) spectrometry. Three immobilisation steps were analysed by ATR-FTIR spectroscopy: 1) NTA complexation with nickel(II) ions 2) binding of two histidine (His)-tagged synthetic peptides of 25 (25-His6) and 48 (48-His6) amino acids to the NTA-groups and 3) attachment of a ligand, mesyl amide, to the surface-bound 48-His6. Despite interference from H(2)O, both amide I and II were well resolved. Utilising peptide adsorption in the thick copolymer matrix yields a high saturation peptide concentration of approximately 100 mg mL(-1) and a dissociation constant of 116+/-11 muM, as determined by a detailed analysis of the Langmuir adsorption isotherm. The mesyl amide ligand was directly seen in the raw ATR-FTIR spectrum with specific peaks in the fingerprint region at 1172 and 1350 cm(-1). Several aspects of the fine structure of the amide I band of the peptide were analysed: influences from secondary structure, amino side chains and competing contamination product. We believe that this approach has great potential as a stand-alone or complementary analytical tool for determination of the chemical composition of functionalised surfaces. We emphasise further that with this approach no chemical treatment of IREs is needed; the chips can be regenerated and reused, and applied in other experimental set-ups.


Biocontrol potential of essential oil monoterpenes against housefly, Musca domestica (Diptera: Muscidae).
Housefly (Musca domestica L.), one of the most common insects in human settlements, has been associated as vectors for various food-borne pathogens, causing food spoilage and disease transmission. The control of housefly was attempted using plant monoterpenes; menthone, menthol, menthyl acetate, limonene, citral and 1,8-cineole, against different life stages of housefly. Bioefficacy against housefly adults revealed highest repellent activity by menthol (95.6 percent) and menthone (83.3 percent). Against housefly larvae, menthol with an LC90 of 0.02 µl/cm(2) in contact toxicity assay and menthone with a LC90 value of 5.4 µl/L in fumigation assay were found to be most effective control agent. With respect to pupicidal activity, superior performance was shown by menthol, citral and 1,8-cineole in contact toxicity assay and citral and 1,8-cineole in fumigation assay. Limonene was found to be the poorest performer in all the assays. Overall, highest efficacy observed for menthol and menthone in various bioassays was in agreement with the results of essential oil activity obtained previously. Significant activity of monoterpenes against various life stages of housefly demonstrates their potential as excellent insecticides with prospects of monoterpenes being developed into eco-friendly and acceptable products for housefly control.


Splicing factor SRSF1 is essential for CD8 T cell function and host antigen-specific viral immunity.
Cytotoxic CD8 T cells are crucial for the host antigen-specific immune response to viral pathogens. Here we report the identification of an essential role for the serine/arginine-rich splicing factor (SRSF) 1 in CD8 T cell homeostasis and function. Specifically, SRSF1 is necessary for the maintenance of normal CD8 T lymphocyte numbers in the lymphoid compartment, and for the proliferative capacity and cytotoxic function of CD8 T cells. Furthermore, SRSF1 is required for antigen-specific IFN-γ cytokine responses in a viral infection challenge in mice. Transcriptomics analyses of Srsf1-deficient T cells reveal that SRSF1 controls proliferation, MAP kinase signaling and IFN signaling pathways. Mechanistically, SRSF1 controls the expression and activity of the Mnk2/p38-MAPK axis at the molecular level. Our findings reveal previously unrecognized roles for SRSF1 in the physiology and function of cytotoxic CD8 T lymphocytes and a potential molecular mechanism in viral immunopathogenesis.


Ontogeny of canine intrathoracic cardiac nervous system.
The functional cardiac innervation of 61 puppies from nine different litters (2-8 littermates), ranging in age from 1 day to 7 wk, was investigated. The efferent sympathetic nervous system exerted minimal effects on the heart of 1-day-old puppies, gradually influencing the heart more thereafter such that by 7 wk of life it was functionally mature. In contrast, efferent parasympathetic cardiac innervation was well developed at birth, maturing thereafter such that by 4-7 wk of age its capacity to modulate the heart was similar to that found in adults. The right- and left-sided efferent sympathetic and parasympathetic intrathoracic nervous systems induced similar cardiac modulation throughout this period of development. Cardiac myocyte beta-adrenergic receptors were partially functional at birth, as determined by responses elicited by supramaximal doses of the beta-agonist isoproterenol. Responses elicited by isoproterenol became greater over the following 7 wk of life, when they were found to be similar to those elicited in adults. By 1 wk of age, synaptic mechanisms in intrathoracic sympathetic ganglia involved in cardiac regulation were relatively well developed, with cardiopulmonary-cardiac reflexes present but not functionally mature at that age. It is concluded that maturation of the efferent sympathetic nervous system modulating the canine heart depends to a large extent on the ontogeny of cardiac beta-adrenergic receptors rather than the ontogeny of synapses in intrathoracic ganglia. Furthermore, even though functional cardiac efferent parasympathetic innervation is present before efferent sympathetic innervation, both reach maturity at about the same age.


Anti-Helicobacter pylori therapy followed by celecoxib on progression of gastric precancerous lesions.
To evaluate whether celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, could reduce the severity of gastric precancerous lesions following Helicobacter pylori (H pylori) eradication. H pylori-eradicated patients with gastric precancerous lesions randomly received either celecoxib (n = 30) or placebo (n = 30) for up to 3 mo. COX-2 expression and activity was determined by immunostaining and prostaglandin E(2) (PGE(2)) assay, cell proliferation by Ki-67 immunostaining, apoptosis by TUNEL staining and angiogenesis by microvascular density (MVD) assay using CD31 staining. COX-2 protein expression was significantly increased in gastric precancerous lesions (atrophy, intestinal metaplasia and dysplasia, respectively) compared with chronic gastritis, and was concomitant with an increase in cell proliferation and angiogenesis. A significant improvement in precancerous lesions was observed in patients who received celecoxib compared with those who received placebo (P < 0.001). Of these three changes, 84.6% of sites with dysplasia regressed in patients treated with celecoxib (P = 0.002) compared with 60% in the placebo group, suggesting that celecoxib was effective on the regression of dysplasia. COX-2 protein expression (P < 0.001) and COX-2 activity (P < 0.001) in the gastric tissues were consistently lower in celecoxib-treated patients compared with the placebo-treated subjects. Moreover, it was also shown that celecoxib suppressed cell proliferation (P < 0.01), induced cell apoptosis (P < 0.01) and inhibited angiogenesis with decreased MVD (P < 0.001). However, all of these effects were not seen in placebo-treated subjects. Furthermore, COX-2 inhibition resulted in the up-regulation of PPARgamma expression, a protective molecule with anti-neoplastic effects. H pylori eradication therapy followed by celecoxib treatment improves gastric precancerous lesions by inhibiting COX-2 activity, inducing apoptosis, and suppressing cell proliferation and angiogenesis.


Growth of human basophil lines derived from chronic myelocytic leukaemia cells in vitro: ultrastructure and X-ray microanalysis studies.
Mononuclear cells from the peripheral blood of patients with chronic myelocytic leukaemia were grown and expanded in liquid culture in the presence of Con A-conditioned medium. An accelerated development of cells of the basophilic lineage was observed and resulted in the appearance of 85% mature basophils after 14 days of incubation. Transmission electron microscopy of developing basophils showed changes in the nucleus and active granule formation in the cytoplasm. By scanning electron microscopy, the immature cells were relatively smooth in comparison with the mature basophils which showed membranous microvilli. The chemical content of the cells at different days of culture was detected by X-ray microanalysis. Immature cells were characterized by a high level of phosphorus with a low level of sulphur. As maturation progressed, the amount of phosphorus decreased, while the level of the sulphur increased, reaching its highest peak in the mature basophils. The different amount of sulphur found in the cells during the maturational process most probably represents the amount of heparin located in the cell granules. This finding may be useful for studying the influence of growth factors on the development and differentiation of human basophils.


Myosin II activity facilitates microtubule bundling in the neuronal growth cone neck.
The cell biological processes underlying axon growth and guidance are still not well understood. An outstanding question is how a new segment of the axon shaft is formed in the wake of neuronal growth cone advance. For this to occur, the highly dynamic, splayed-out microtubule (MT) arrays characteristic of the growth cone must be consolidated (bundled together) to form the core of the axon shaft. MT-associated proteins stabilize bundled MTs, but how individual MTs are brought together for initial bundling is unknown. Here, we show that laterally moving actin arcs, which are myosin II-driven contractile structures, interact with growing MTs and transport them from the sides of the growth cone into the central domain. Upon Myosin II inhibition, the movement of actin filaments and MTs immediately stopped and MTs unbundled. Thus, Myosin II-dependent compressive force is necessary for normal MT bundling in the growth cone neck.


Transfusion-associated graft-versus-host disease: A concise review.
Transfusion-associated graft-versushost disease (TA-GVHD) represents a rare fatal event observed in immunocompromised patients and immunocompetent individuals. The main clinical features of this transfusion reaction are pancitopenia and multiorgan failure (skin, liver, gut). The possible pathogenesis includes donor T lymphocyte proliferation in blood, their engraftment and host tissue attack. The purpose of this narrative review was analyzing the international guidelines for irradiation of cellular blood components to prevent TA-GVHD. A literature search was conducted using PubMed articles published between January 2000 to July 2018. American, Australian, British and Japanese transfusion guidelines have been compared regarding clinical indications. The contribution of manuscripts has been focused on recipients of Haematopoietic Stem Cell Transplantation, severe cellular immunodeficient patients, fetuses and neonates, immunocompentent individuals. Furthermore, 348 cases of TA-GVHD in the last five decades have been documented according to a recent systematic review. The standard of care to prevent this complication is gamma or x irradiation of cellular blood products. New treatments with pathogen inactivation appear safe and effective against proliferating white blood cells and T cells. Further clinical and biological studies are necessary to better characterize immunocompetence of T cells and select alternative preventive strategies.


The Burden of Human Parechoviruses Among Children in Oman: A retrospective study.
This study aimed to evaluate the burden, clinical and laboratory features and outcomes of human parechoviruses (HPeVs) infection among children in Oman. This retrospective study included children (aged <18 years) with molecularly proven HPeV infection who were managed at Sultan Qaboos University Hospital, Muscat, Oman, between January 2017 and December 2019. Data were obtained from the patients' medical records and analysed to describe their demographics, clinical and laboratory features, management and outcomes. HPeV was detected in 61 patients, 44 (72%) of whom were males. The median age of these patients was nine months (interquartile range [IQR]: 6-15 months). HPeV was detected throughout the year without any significant peaks. Majority of the patients (n = 51, 84%) had co-infection with other viruses. Forty-eight (79%) children with HPeV infection required hospitalisation, and their median length of hospital stay was five days (IQR: 3-8 days). Ex-prematurity (n = 10, 16%) was the commonest comorbidity among this group. Fever (n = 41, 67%) and cough (n = 41, 67%) were the commonest presenting symptoms among the children. Two-thirds of the HPeV-infected children in this cohort were managed for lower respiratory tract infection; none was managed for meningitis. Gastroenteritis was not common in this cohort; only eight children had diarrhoea. All children made a full recovery. HPeVs infection does not show a clear seasonality in Oman. Most of the children were aged <2 years and had a viral co-infection. The outcomes of HPeV infection were favourable, with no mortalities, but a thorough follow-up for neurological outcomes was lacking.


[Diagnosis and tactics in the surgical treatment of double aortic arch].
Within the period of from 1978 to 1989, in 19 patients staying in the clinic, a double aortic arch (DAA) was diagnosed by means of roentgenologic investigation, esophagography, angiography. In comparison of the findings of esophagography and angiography, in 2 patients, atresia, of the left arch segment was revealed, in 9 patients, a double arch was associated with Fallot's tetrad (FT), in 4--with the interventricular septum defect (IVSD). All the patients were operated on. In 6 patients with isolated DAA, the lesser arch was transected: in 5--the left, in 1--the right one. In 13 patients with associated DAA and congenital heart defect (CHD), the simultaneous DAA transection and a palliative operation (in 9), or a radical correction of CHD (in 4) were performed. Two patients with FT 3 years later, underwent the second stage successful radical correction of a defect. A long-term result of treatment is good.


Anti-Oligomannose Antibodies as Potential Serum Biomarkers of Aggressive Prostate Cancer.
[Table: see text] This study bridges a carbohydrate microarray discovery and a large-scale serological validation of anti-oligomannose antibodies as novel serum biomarkers of aggressive prostate cancer (PCa). Experimentally, a Man9-cluster-specific enzyme-linked immunosorbent assay was established to enable sensitive detection of anti-Man9 antibodies in human sera. A large-cohort of men with PCa or benign prostatic hyperplasia (BPH) whose sera were banked at Stanford University was characterized using this assay. Subjects included patients with 100% Gleason grade 3 cancer (n = 84), with Gleason grades 4 and/or 5 cancer (n = 204), and BPH controls (n = 135). Radical prostatectomy Gleason grades and biochemical (PSA) recurrence served as key parameters for serum biomarker evaluation. It was found that IgGMan9 and IgMMan9 were widely present in the sera of men with BPH, as well as those with cancer. However, these antibody reactivities were significantly increased in the subjects with the largest volumes of high grade cancer. Detection of serum IgGMan9 and IgMMan9 significantly predicted the clinical outcome of PCa post-radical prostatectomy. Given these results, we suggest that IgGMan9 and IgMMan9 are novel serum biomarkers for monitoring aggressive progression of PCa. The potential of oligomannosyl antigens as targets for PCa subtyping and targeted immunotherapy is yet to be explored.


Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome.
Caspase-11 is a cytosolic sensor and protease that drives innate immune responses to the bacterial cell wall component, LPS. Caspase-11 provides defence against cytosolic Gram-negative bacteria; however, excessive caspase-11 responses contribute to murine endotoxic shock. Upon sensing LPS, caspase-11 assembles a higher order structure called the non-canonical inflammasome that enables the activation of caspase-11 protease function, leading to gasdermin D cleavage and cell death. The mechanism by which caspase-11 acquires protease function is, however, poorly defined. Here, we show that caspase-11 dimerization is necessary and sufficient for eliciting basal caspase-11 protease function, such as the ability to auto-cleave. We further show that during non-canonical inflammasome signalling, caspase-11 self-cleaves at site (D285) within the linker connecting the large and small enzymatic subunits. Self-cleavage at the D285 site is required to generate the fully active caspase-11 protease (proposed here to be p32/p10) that mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production. This study provides a detailed molecular mechanism by which LPS induces caspase-11-driven inflammation and cell death to provide host defence against cytosolic bacterial infection.


The amygdala theory of autism.
Brothers (Brothers L. Concepts in Neuroscience 1990;1:27-51) proposed a network of neural regions that comprise the "social brain", which includes the amygdala. Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality. In this paper we review the evidence for a social function of the amygdala. This includes reference to the Kluver-Bucy syndrome (which Hetzler and Griffin suggested may serve as an animal model of autism). We then review evidence for an amygdala deficit in people with autism, who are well known to have deficits in social behaviour. This includes a detailed summary of our recent functional magnetic resonance imaging (fMRI) study involving judging from the expressions of another person's eyes what that other person might be thinking or feeling. In this study, patients with autism or AS did not activate the amygdala when making mentalistic inferences from the eyes, whilst people without autism did show amygdala activity. The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism. We conclude that the amygdala theory of autism contains promise and suggest some new lines of research.


Reactivation of p53 in cells expressing hepatitis B virus X-protein involves p53 phosphorylation and a reduction of Hdm2.
Multifunctional activities of the hepatitis B virus X-protein (HBx) in cells have been largely implicated in the development of liver cancer; one of these activities is the loss of p53 function by sequestering p53 in the cytoplasm. We have previously found that doxorubicin increased the p53 levels in cells containing p53-binding HBx protein and restored the p53-mediated transcriptional activity that was suppressed by HBx. Here, we investigated the mechanism underlying p53 reactivation. We found that six phosphorylation sites of the Serine residues of p53 were efficiently phosphorylated in HBx-expressing ChangX-34 cells, suggesting that the binding of HBx to the p53 protein does not interfere with the phosphorylation of p53 by signaling kinases. In addition, doxorubicin caused a dramatic reduction of Hdm2 mRNA and protein levels in cells expressing HBx. Intriguingly, reactivation of p53 was accompanied with a nuclear accumulation of p53 and the phosphorylated p53 at Serine15 was only detected in nuclear fraction, but not in cytosolic fraction of doxorubicin-treated ChangX-34 cells. Functional restoration of the p53 protein in HBx-expressing cells occurs according to the dual effects of doxorubicin: a significant reduction of Hdm2 expression and a nuclear accumulation of the phosphorylated p53 protein. Thus, proper usage of doxorubicin as an effective antitumor agent may be reevaluated and can be extended to tumors primarily caused by infection of DNA tumor viruses.


Strongyloidiasis in childhood.
Strongyloides stercoralis is an intestinal nematode of man that is still regularly encountered in many parts of the United States. Strongyloidiasis should be considered in any child with unexplained eosinophilia, steatorrhea, protein-losing enteropathy, or chronic diarrhea, especially if associated with weight loss, growth failure, or recurrent upper abdominal pain. This parasite should be ruled out in any patient from an endemic region who is to be treated with corticosteroids of immunosuppressive agents. Microscopical examination of duodenal fluid, Baermann's fecal extraction technique, or the Haradi-Mori stool culture method may be required to make a diagnosis because the organism is not routinely found in concentrated feces even after multiple examinations in some infected individuals. A diagnosis of strongyloidiasis is important because the disease is curable.


Communication in Neglected Tropical Diseases' elimination: A scoping review and call for action.
Although the practice of communication is often called upon when intervening and involving communities affected by NTDs, the disciplinary framework of health communication research has been largely absent from NTD strategies. To illustrate how practices conceptualized and developed within the communication field have been applied in the context of NTD elimination, we conducted a scoping review focusing on two diseases currently targeted for elimination by the WHO: lymphatic filariasis and Chagas disease. We examined studies published between 2012 and 2020 in five electronic databases. Selected articles were required to (i) have explicit references to communication in either the abstract, title, or key words; (ii) further elaborate on the search terms (communication, message, media, participation and health education) in the body of the article; and (iii) sufficiently describe communication actions associated to those terms. Using the C-Change Socio-Ecological Model for Social and Behavior Change Communication as a reference, the articles were analysed to identify communication activities, theoretical frameworks, and/or rationales involved in their design, as well as their intended level of influence (individual, interpersonal, community, or enabling environment). A total of 43 articles were analysed. Most interventions conceptualized communication as a set of support tools or supplemental activities delivering information and amplifying pre-defined messages aimed at increasing knowledge, encouraging community involvement, promoting individual behavior change, or securing some degree of acceptability of proposed strategies. Although important attempts at further exploring communication capabilities were identified, particularly in participation-based strategies, for most studies, communication consisted of an underdeveloped and under-theorized approach. We contend that a more complex understanding of the capacities offered by the health communication field could help attain the biomedical and social justice goals proposed in NTD elimination strategies. Three ways in which the field of health communication could further enhance NTD efforts are presented: informing interventions with theory-based frameworks, exploring the political complexity of community participation in specific contexts, and identifying conceptualizations of culture implied in interventions' design. This article is a call to action to consider the resources offered by the health communication field when researching, designing, or implementing NTD interventions.