Aberrant expression of SATB2, CDX2, CDH17 and CK20 in hepatocellular carcinoma: a pathological, clinical and outcome study.
Data regarding expression of intestinal markers in hepatocellular carcinoma (HCC) are limited. We determined the clinicopathological associations of cytokeratin (CK)19, a progenitor liver epithelial cell marker as well as biliary epithelial marker, and intestinal immunohistochemical markers expression in HCC and assessed their prognostic value. Tissue sections and/or tissue microarrays (TMAs) from 202 known HCCs were immunostained using CK19, CK20, CDH17, CDX2 and SATB2 antibodies. Haematoxylin and eosin (H&E)-stained slides were reviewed for tumour grading. Clinical and oncological outcomes were retrieved. Associations of staining with clinicopathological features and survival outcomes were evaluated. CK19, CK20, CDH17, CDX2 and SATB2 were positive in 12.8, 5.4, 10.3, 8.6 and 59.9%, respectively. All but SATB2 were strongly associated with higher tumour grade and AFP levels > 400 ng/ml (P < 0.05). CK19-positive HCC were more likely to express CDX2 (P = 0.001), CDH17 (P < 0.001) and/or CK20 (P = 0.012). CK20, CDX2 and CDH17 co-expression was seen in five cases (2.5%). CK19 and SATB2 positivity, tumour size ≥ 5 cm, background cirrhosis, AFP > 400 ng/ml and having no treatment were associated with decreased overall survival by log-rank test and univariable proportional hazards regression. However, in a multivariable model, CK19 and SATB2 positivity were not independent predictors of decreased survival while their association with known poor prognosticators in HCC was evident. HCC can express markers of intestinal differentiation. This phenotypical aberrancy correlates with variable clinicopathological parameters, some of which are independent predictors of poor survival.


Electrophysiological Approaches for the Study of Ion Channel Function.
Ion channels play crucial roles in cell physiology, and are a major class of targets for clinically relevant pharmaceuticals. Because they carry ionic current, the function and pharmacology of ion channels can be studied using electrophysiological approaches that range in resolution from the single molecule to many millions of molecules. This chapter describes electrophysiological approaches for the study of one representative ion channel that is defective in a genetic disease, and that is the target of so-called highly effective modulator therapies now used in the clinic: the cystic fibrosis transmembrane conductance regulator (CFTR). Protocols are provided for studying CFTR expressed heterologously, for CFTR expressed in situ in airway epithelial cells, and for purified or partially purified CFTR protein reconstituted into planar lipid bilayers.


Serotonin (5-HT) precursor loading with 5-hydroxy-l-tryptophan (5-HTP) reduces locomotor activation produced by (+)-amphetamine in the rat.
Evidence suggests that increases in synaptic serotonin (5-HT) can reduce the stimulant properties of amphetamine-type drugs. Here we tested the hypothesis that administration of the 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), along with the peripheral decarboxylase inhibitor benserazide, would decrease locomotor effects of (+)-amphetamine. Drug treatments were administered to conscious male rats undergoing in vivo microdialysis in nucleus accumbens. During dialysis sampling, rats were housed in chambers equipped with photobeams to detect forward locomotion (i.e., ambulation) and repetitive movements (i.e., stereotypy). Extracellular concentrations of dopamine (DA) and 5-HT were measured by high-pressure liquid chromatography with electrochemical detection. 5-HTP (10 & 30 mg/kg, i.p.) plus benserazide (30 mg/kg, i.p.) caused dose-related increases in 5-HT but failed to alter other parameters. (+)-Amphetamine (0.3 & 1.0 mg/kg, i.p.) produced dose-related increases in DA, ambulation and stereotypy. Combined administration of 5-HTP and (+)-amphetamine evoked large elevations in extracellular DA and 5-HT, but caused significantly less ambulation than (+)-amphetamine alone (~50% reduction). Our results confirm that 5-HTP can decrease hyperactivity produced by (+)-amphetamine, even in the presence of elevations in dialysate DA. The data suggest that 5-HTP and (+)-amphetamine may be useful to broadly enhance monoamine function in the clinical setting, while reducing undesirable effects of (+)-amphetamine.


Analysis of early stages of budding inHydra by means of an endogenous inhibitor.
Buds originate inHydra attenuata at a position 1/3 of the body length from the basal disc. The position with respect to the vertical axes is determined first and the position of the bud on the circumference of this budding region is specified later.Bud formation in hydra is reversibly prevented by pre-treatment with an inhibitor purified from hydra tissue (Berking, 1977). Some hours after the end of the treatment with the inhibitor, bud formation is resumed. From the starting or restarting point of development after the inhibitory treatment to the visible beginning of bud formation, 4 intermediary stages were distinguished on the basis of different responses to a second treatment with inhibitor. The pre0treatment is followed immediately by a period of maximal sensitivity to the inhibitor, which varies in length. At the conclusion of this phase the time interval required for the visible appearance of buds is fixed (12 h). In this and the following phase another application of inhibitor can cancel the entire preparatory process from the pre-treatment onwards. A transition to near complete resistance to inhibitor is the basis for defining a third phase. In a fourth phase, immediately before the evagination of the bud starts, the proesence of the inhibitor will again hinder the development. Upon removal of the inhibitor the suppressed buds will appear.


Is There a Role for Anti-factor Xa Activity Assay in Venous Thromboembolism Prophylaxis Management Among Orthopaedic Trauma Patients? Systematic Review and Meta-analysis.
To determine the effect of anti-factor Xa assay dosing of low-molecular-weight heparin (LMWH) on rates of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), bleeding, and mortality among orthopaedic trauma patients. PubMed/MEDLINE, Embase, Ovid, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov , and Scopus were systematically searched from inception of the database to 2021. Prospective, retrospective, and randomized controlled trial studies were included if they compared rates of VTE, DVT, PE, bleeding, and/or mortality between orthopaedic trauma patients receiving anti-factor Xa-based LMWH dosing and those receiving standard dosing. Two independent reviewers screened titles and abstracts for eligibility. Study characteristics including study design, inclusion criteria, and intervention were extracted. Meta-analysis was performed using pooled proportion of events (effect size) with 95% confidence intervals. A random-effects model was used. Heterogeneity was quantified by Higgins I 2 . Heterogeneity and variability between subgroups indicated differences in the pooled estimate represented by a P -value. Six hundred eighty-five studies were identified, and 10 studies including 2870 patients were included. In total, 30.3% and 69.7% received an adjusted and nonadjusted dose of LMWH, respectively. The rate of VTE and DVT were significantly lower in the anti-factor Xa-adjusted cohort, whereas there was no statistically significant difference in rates of PE, bleeding, or mortality between the cohorts. This systematic review and meta-analysis demonstrates that anti-factor Xa activity assay dosing of LMWH among orthopaedic trauma patients leads to a reduction in overall DVT rates, although not PE rates, without an increased risk of bleeding events. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Protective measures must be built in.
Recent high profile thefts from hospitals have highlighted one aspect of the overall problem of security of hospital premises. There are others aspects which NHS staff deal with on a daily basis throughout England and Wales.


Specific quorum sensing molecules are possibly associated with responses to herbicide toxicity in a Pseudomonas strain.
Pesticides contribute to pest control and increase agricultural production; however, they are toxic to non-target organisms, and they contaminate the environment. The exposure of bacteria to these substances can lead to the need for physiological and structural changes for survival, which can be determined by genes whose expression is regulated by quorum sensing (QS). However, it is not yet clear whether these processes can be induced by herbicides. Thus, the aim of this work was to determine whether there is a QS response system in the Pseudomonas fluorescens CMA55 strain that is modulated by herbicides. This strain was isolated from water storage tanks used for washing pesticide packaging and was tested against herbicides containing saflufenacil, glyphosate, sulfentrazone, 2,4-D, and dicamba as active molecules. Our results showed that in the presence of herbicides containing saflufenacil and glyphosate (the latter was not present at the bacterial isolation site) the strain had a profile of QS signaling molecules that may be involved in controlling the production of reactive oxygen species. Alternatively, the same strain, in the presence of sulfentrazone (it was not present at the bacterial isolation site), 2,4-D and dicamba-containing herbicides, presented another profile of molecules that may be involved in different stages of biofilm formation. These findings, as a first screening, suggest that this strain used strategies to activate antioxidant enzymes and biofilm production under the signaling of QS molecules to respond to herbicides, regardless of previous contact, representing a model of phenotypic plasticity for adaptation to agricultural environments that can be used in studies of herbicide bioremediation.


Cartilaginous predictors of residual acetabular dysplasia (RAD) in developmental dysplasia of the hip following closed or open reduction: A systematic review and meta-analysis.
This study was designed to analyze the cartilaginous predictors of residual acetabular dysplasia (RAD) after early treatment of developmental dysplasia of the hip and their diagnostic accuracy. Databases such as PubMed, Embase, Cochrane, and Web of science were searched to screen the literature. The quality of the literature was assessed by the QUADAS-2 tool. Qualitative and quantitative synthesis of literature were performed based on extracted data. For quantitative synthesis studies, the sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve with corresponding confidence intervals were calculated. For the cartilaginous acetabular index (CAI) group, the combined values of sensitivity, specificity, and DOR were 0.80 (95% CI = 0.54-0.93), 0.73 (95% CI = 0.57-0.84), and 10.62 (95% CI = 3.96-28.53), respectively. The corresponding values in the cartilaginous center-edge angle (CCE) group were 0.71 (95% CI = 0.57-0.82), 0.78 (95% CI = 0.66-0.87), and 8.64 (95% CI = 3.08-24.25), respectively. The area under the curve (AUC) of SROC was 0.82 (95% CI = 0.78-0.85) and 0.80 (95% CI = 0.76-0.83) for the CAI and CCE groups. The CAI group had higher sensitivity, DOR, and AUC than the CCE group. Both of these two groups have good diagnostic accuracy, and CAI/L-AI has a little edge over CCE/L-CEA. However, there is still more research needed to determine whether they can be used as independent indications for secondary orthopedic surgery.Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier: [CRD42022338332].


Six-Month Outcomes in Patients Hospitalized with Severe COVID-19.
Previous work has demonstrated that patients experience functional decline at 1-3 months post-discharge after COVID-19 hospitalization. To determine whether symptoms persist further or improve over time, we followed patients discharged after hospitalization for severe COVID-19 to characterize their overall health status and their physical and mental health at 6 months post-hospital discharge. Prospective observational cohort study. Patients ≥ 18 years hospitalized for COVID-19 at a single health system, who required at minimum 6 l of supplemental oxygen during admission, had intact baseline functional status, and were discharged alive. Overall health status, physical health, mental health, and dyspnea were assessed with validated surveys: the PROMIS® Global Health-10 and PROMIS® Dyspnea Characteristics instruments. Of 152 patients who completed the 1 month post-discharge survey, 126 (83%) completed the 6-month survey. Median age of 6-month respondents was 62; 40% were female. Ninety-three (74%) patients reported that their health had not returned to baseline at 6 months, and endorsed a mean of 7.1 symptoms. Participants' summary t-scores in both the physical health and mental health domains at 6 months (45.2, standard deviation [SD] 9.8; 47.4, SD 9.8, respectively) remained lower than their baseline (physical health 53.7, SD 9.4; mental health 54.2, SD 8.0; p<0.001). Overall, 79 (63%) patients reported shortness of breath within the prior week (median score 2 out of 10 (interquartile range [IQR] 0-5), vs 42 (33%) pre-COVID-19 infection (0, IQR 0-1)). A total of 11/124 (9%) patients without pre-COVID oxygen requirements still needed oxygen 6 months post-hospital discharge. One hundred and seven (85%) were still experiencing fatigue at 6 months post-discharge. Even 6 months after hospital discharge, the majority of patients report that their health has not returned to normal. Support and treatments to return these patients back to their pre-COVID baseline are urgently needed.


A thermodynamic approach to analyzing relative permittivity and solvent mole fraction models, and application to SN1 reactions.
The standard methods for analyzing solvent effects on chemical reactions largely include linear free energy relations that relate kinetic and spectroscopic terms to solvent interactive parameters. The number of these parameters has grown over the years in order to make linear free energy techniques more accurate and cover a wider range of reaction systems. However, even with the myriad of parameters, the details of specific reaction systems make the application of these techniques sometimes unreliable. On the other hand, a thermodynamic approach provides a more precise analysis, and has proven particularly useful for reactions in multi-component solvent systems. In this article we present the mathematical formalism for relating the activation free energy to the bulk thermodynamic properties for a binary (cosolvent) system. We then use this thermodynamic approach, coupled with selected solvent models, to analyze the hydrolysis rates of tert-butyl chloride in the acetonitrile/water solvent system under iso-mole fraction, isodielectric, and isothermal conditions. These analyses allow us to differentiate and quantify bulk electrostatic effects and the effects of close-range solute-solvent interactions.


Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice.
Inhibition of spinal glutamate receptors induces antinociceptive effects in numerous animal models of pain. The present study compares the effects of intrathecally administered N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists on nociceptive responses in the tail flick test. Potency of antagonists at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors was first measured by electrical assays in Xenopus oocytes expressing rat cerebral cortex poly(A)+ RNA. Subsequently, Swiss Webster mice were injected intrathecally with the antagonists and tested for antinociception. The drugs tested were: NBQX and GYKI-52466, selective AMPA receptor antagonists, ketamine, MK-801, R(+) HA-966 and ACEA-0762, selective NMDA receptor antagonists, and ACEA-1031, ACEA-1328 and ACEA-0593, NMDA receptor antagonists that also show inhibition of non-NMDA receptors. Selective NMDA receptor antagonists induced essentially no antinociceptive effects in the tail flick test. Antinociceptive activity generally correlated with inhibition of AMPA receptors. The exception was the non-competitive AMPA receptor antagonist GYKI-52466, which was unexpectedly weak. This may be due to inadequate dosing, because the compound has limited solubility, or may be due to differences in the non-NMDA receptor subtype-selectivity profile of GYKI-52466 as compared to competitive antagonists such as NBQX. Overall, our results suggest that inhibition of spinal non-NMDA receptors is the primary, and necessary, mechanism of antinociception by these drugs in the tail flick test in mice.


Sarcopenia and Frailty in Cirrhosis: Assessment and Management.
Sarcopenia and frailty are frequent in cirrhosis, and both contribute to increased morbidity and mortality. The complex pathogenesis of sarcopenia in cirrhosis is mainly determined by hyperammonemia and malnutrition. Sarcopenia/frailty screening and reevaluation should be undertaken in all cirrhotic patients. Frailty tests are useful in the ambulatory setting, whereas the computed tomography scan is the diagnostic gold standard for sarcopenia. To manage sarcopenia/frailty, a multidisciplinary team should develop a personalized comprehensive care plan that includes patient education, protein/calorie intake goals, late evening meals, exercise programs, and micronutrient replenishment. In selected patients, branched-chain amino acid and testosterone supplements may also be beneficial.


Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation.
To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo. Prostaglandin E(2) (PGE(2)) through activation of EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR(-/-)) mice transplanted with either EP4(+/+) (EP4(+/+)/LDLR(-/-)) or EP4(-/-) (EP4(-/-)/LDLR(-/-)) bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow-derived cells increased the incidence (50% of male EP4(+/+)/LDLR(-/-) mice versus 88.9% of male EP4(-/-)/LDLR(-/-) mice developed AAA; and 22% of female EP4(+/+)/LDLR(-/-) mice versus 83.3% of female EP4(-/-)/LDLR(-/-) mice developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow-derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth muscle cell accumulation within AAA lesions. Deficiency of EP4 on bone marrow-derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE(2) signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation.


Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics.
There is mounting evidence suggesting widespread aberrations in neural connectivity as the underlying neurobiology of autism. Using DTI to assess white matter abnormalities, this study implemented a voxelwise analysis and tract-labeling strategy to test for a structural neural phenotype in autism. Subjects included 15 boys with autism and 8 controls, group-matched on age, cognitive functioning, sex, and handedness. DTI data were obtained by using a 3T scanner. FSL, including TBSS, was used to process and analyze DTI data where FA was chosen as the primary measure of fiber tract integrity. Affected voxels were labeled by using an integrated white matter tractography atlas. Post hoc correlation analyses were performed between FA of each affected fiber tract and scores on the Social Responsiveness Scale. The autism group exhibited bilateral reductions in FA involving numerous association, commissural, and projection tracts, with the most severely affected being the forceps minor. The most affected association tracts were the inferior fronto-occipital fasciculus and superior longitudinal fasciculus. There were no areas of increased FA in the autism group. All post hoc correlation analyses became nonsignificant after controlling for multiple comparisons. This study provides preliminary evidence of reduced FA along many long-range fiber tracts in autism, suggesting aberrant long-range corticocortical connectivity. Although the spatial distribution of these findings suggests widespread abnormalities, there are major differences in the degree to which different tracts are affected, suggesting a more specific neural phenotype in autism.


Assessing emergency department nurses' ability to communicate with angry patients and the factors that influence it.
To assess emergency department (ED) nurses' ability to communicate with angry patients and to explore the factors that influence nurses' communication skills. A cross-sectional survey design. This study was conducted in November and December 2020. Stratified sampling was adopted to recruit ED nurses from 18 tertiary hospitals in western, eastern, and central China to complete an online questionnaire. The Nurses' Communication Ability with Angry Patients Scale (NCAAPS) and the General Self-Efficacy Scale were used to assess ED nurses' communication ability and self-efficacy, respectively. Descriptive statistics, the Mann-Whitney U-test, the Kruskal-Wallis H test, Spearman's correlation analysis, and the generalized linear model were used for data analysis. A total of 679 valid questionnaires were collected. The mean total score for the NCAAPS was (3.79 ± 0.47), while the scores for its four dimensions were (3.87 ± 0.59) for communication skills, (3.82 ± 0.59) for anger perception, (3.79 ± 0.53) for self-preparation, (3.73 ± 0.54) for exploring the cause of anger. The generalized linear regression analysis result showed that a longer employment duration, previous communication ability training, and higher self-efficacy were significantly and independently associated with higher NCAAPS scores (p < 0.05). The mean total score and the four dimensions score for the NCAAPS were moderate. But there is still room for improvement in ED nurses' ability to communicate with angry patients. "Exploring the cause of anger" was the lowest score among the four dimensions. To improve ED nurses' ability to communicate with angry patients, future studies should focus on constructing specific communication training, improving nurses' ability to explore the cause of anger and self-efficacy. The findings of this study provide important insights into ED nurses' ability to communicate with angry patients and can thus guide the future development of intervention programmes to improve this ability among ED nurses.


CRISPR/Cas-mediated Fubp1 silencing disrupts circadian oscillation of Per1 protein via downregulating Syncrip expression.
Most living organisms have physiological and behavioral circadian rhythms controlled by molecular clocks. In mammals, several core clock genes show self-perpetuating oscillation profiles of their messenger RNAs (mRNAs) and proteins through an auto-regulatory transcription-translation feedback loop (TTFL). As a critical component in the molecular clock system, Period 1 (Per1) contributes to the maintenance of circadian rhythm duration predominantly in peripheral clocks. Alterations in Per1 expression and oscillating patterns lead to the development of cancers as well as circadian rhythm abnormalities. In this study, we demonstrate that the phasic profile of Per1 protein was clearly disrupted in CRISPR/Cas-mediated Fubp1-deficient cells. Although Fubp1 does not show rhythmic expression, Fubp1 upregulates the mRNA and protein level of Syncrip, the main post-transcriptional regulator of Per1 protein oscillation. In addition to the diverse physiological functions of Fubp1, including cell-cycle regulation and cellular metabolic control, our results suggest new roles for Fubp1 in the molecular clock system.


Salt-induced aggregation and fusion of dioctadecyldimethylammonium chloride and sodium dihexadecylphosphate vesicles.
Small dioctadecyldimethylammonium chloride (DODAC) vesicles prepared by sonication fuse upon addition of NaCl as detected by several methods (electron microscopy, trapped volume determinations, temperature-dependent phase transition curves, and osmometer behavior. In contrast, small sodium dihexadecyl phosphate (DHP) vesicles mainly aggregate upon NaCl addition as shown by electron microscopy and the lack of osmometer behavior. Scatter-derived absorbance changes of small and large DODAC or DHP vesicles as a function of time after salt addition were obtained for a range of NaCl or amphiphile concentration. These changes were interpreted in accordance with a phenomenological model based upon fundamental light-scattering laws and simple geometrical considerations. Short-range hydration repulsion between DODAC (or DHP) vesicles is possibly the main energy barrier for the fusion process.


Sex steroid receptor expression in idiopathic pulmonary fibrosis.
Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia, 10 idiopathic organizing diffuse alveolar damage, 7 hypersensitivity pneumonitis, and 3 nonspecific interstitial pneumonitis served as controls. Immunohistochemistry for estrogen receptor α, progesterone receptor (PR), and androgen receptor was performed in all groups. Expression of these receptors was assessed in 4 anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, whereas among the control cases, only 1 nonspecific interstitial pneumonitis case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization, and center of fibroblastic foci; however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for androgen receptor and estrogen receptor α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF.


Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy.
Therapeutic hypothermia (HT) delays the cytokine response in infants with neonatal encephalopathy (NE). To determine if HT delayed the C-reactive protein (CRP) response and altered white blood cell (WBC), neutrophil and platelet count course during the first week of life in infants with NE. Retrospective cohort study. Regional neonatal intensive care unit, UK. 104 term infants with NE (38 normothermia (NT) and 66 HT) born between 1998 and 2010. Infants not exposed to prenatal sepsis risk factors were classified as group 'A' and exposed infants to group 'B'. CRP >10 mg/L was defined as significant response. Time to CRP >10 mg/L, peak CRP, WBC, neutrophil and platelet count. Blood cultures were negative in all the infants. In babies who had CRP response, HT delayed time to CRP >10 mg/L (median (95% CI): group A, HT: 36 h (28.3 to 48.0); NT: 24 h (0.0 to 24.0); p=0.001; group B, HT: 30 h (15.2 to 56.8); NT: 12 h (0.0 to 24.0); p=0.009) and time to peak CRP (median (95% CI): group A, HT: 60 h (60.0 to 72.0); NT: 36 h (0.0 to 48.0); p=0.001; group B, HT: 84 h (62.1 to 120.0); NT: 24 h (0.0 to 36.0); p=0.001). Compared with NT, HT was associated with reduction in slope of CRP elevation by 0.5 (95% CI 0.04 to 0.97), WBC by 2.18×10(9)/L (95% CI 0.002 to 4.35) and platelet count by 32.3×10(9)/L (95% CI 2.75 to 61.8) independent of exposure to sepsis risk, meconium aspiration and severity of asphyxia. Therapeutic hypothermia delayed the initiation of CRP and its peak response, and depressed the WBC and platelet count compared with NT.


Influence of environmental factors on the homoeotic effect ofloboid-ophthalmoptera inDrosophila melanogaster.
This paper deals with the influence of environmental factors, particularly those that may be expected to change the rate of growth in the larval period, on the homoeotic wing-like outgrowths in the eyes of the strainloboid-ophthalmoptera (see Ouweneel, 1969a, b).The penetrance of the homoeotic effect increases with maternal age (Table 1); Delcour (1968) furnished evidence that there is a relation between maternal age and growth rate of tissues in the larva. Penetrance is inversely related to temperature; at low temperatures the development of the whole larva is strongly retarded, but the growth of the eye disc is probably less retarded, so that it grows relatively more than at higher temperatures. It is notable that the temperature-sensitive period (24-60 h after hatching, at 25° C; Fig. 1) precedes, and coincides with, the period of abnormal hyperplasia in the disc (Ouweneel, 1969b).Acetamide, given in the food, enhances the number of facets so that even the wild type eye size may be reached; in proportion to its concentration it moreover strongly increases the penetrance of the wing-like outgrowths. At higher concentrations, however, when eye enlargement is maximal, the penetrance of the outgrowths decreases again (Figs. 2-5). The optimal concentration (at which the penetrance is maximal) is higher at higher temperatures (Figs. 2-5; cf. Fig. 7). The sensitive period for acetamide extends from about 0-55 h after hatching (at 25° C) (Fig. 6). Uracil increases the penetrance of the homoeotic effect (Table 2). Sodium tetraborate seems to increase the penetrance of the homoeotic outgrowths, but to reduce their expressivity slightly at higher concentrations. Starvation (Tabel 3) and farnesol medium prolong the larval period, but do not show clear-cut effects on the homoeotic phenomenon, probably because they only postpone metamorphosis, and do not retard the whole of larval development (compare temperature effect, above). UV irradiation influenced penetrance, but lower dosages had a greater effect than higher ones; the former suppressed the homoeotic effect at early larval ages, but stimulated it at later ages; this points to the occurrence of two separate sensitive periods for UV (Table 4). In all experiments clear-cut sexual differences in sensitivity were observed, which may be ascribed to the sex-linked location of theophthalmoptera modifier (Ouweneel, 1969a).Evidence can be found in the literature that enhanced proliferation is a prerequisite for many homoeotic phenomena in the broad sence (cf. Fig. 8). The present study and previous data show that also homoeotic mutations often interact with agents causing changes in growth rate; it is possible that the basic action of all homoeotic mutations has to do with such changes.


Toxicity profiles and solvent-toxicant interference in the planarian Schmidtea mediterranea after dimethylsulfoxide (DMSO) exposure.
To investigate hydrophobic test compounds in toxicological studies, solvents like dimethylsulfoxide (DMSO) are inevitable. However, using these solvents, the interpretation of test compound-induced responses can be biased. DMSO concentration guidelines are available, but are mostly based on acute exposures involving one specific toxicity endpoint. Hence, to avoid solvent-toxicant interference, we use multiple chronic test endpoints for additional interpretation of DMSO concentrations and propose a statistical model to assess possible synergistic, antagonistic or additive effects of test compounds and their solvents. In this study, the effects of both short- (1 day) and long-term (2 weeks) exposures to low DMSO concentrations (up to 1000 µl l(-1) ) were studied in the planarian Schmidtea mediterranea. We measured different biological levels in both fully developed and developing animals. In a long-term exposure set-up, a concentration of 500 µl l(-1) DMSO interfered with processes on different biological levels, e.g. behaviour, stem cell proliferation and gene expression profiles. After short exposure times, 500 µl l(-1) DMSO only affected motility, whereas the most significant changes on different parameters were observed at a concentration of 1000 µl l(-1) DMSO. As small sensitivity differences exist between biological levels and developmental stages, we advise the use of this solvent in concentrations below 500 µl l(-1) in this organism. In the second part of our study, we propose a statistical approach to account for solvent-toxicant interactions and discuss full-scale solvent toxicity studies. In conclusion, we reassessed DMSO concentration limits for different experimental endpoints in the planarian S. mediterranea.


Genotyping of Candidaalbicans isolates from oropharyngeal candidiasis in head and neck cancer patients in Iran: Molecular epidemiology and SAP2 gene expression.
Multilocus sequence typing is a powerful method for genotyping of clinical isolates of Candidaalbicans. Cross-contamination between the patients is an important reason for nosocomial infections. Oropharyngeal candidiasis (OPC) caused by C. albicans is an important problem in patients with head and neck cancer, in Cancer Institute of Tehran. Here we studied the endemic genotypes of C. albicans isolates and the relationship between geographic distributions, potential cross-contaminations and the expression of SAP2 gene, an important gene in oral candidiasis, with MLST groups. A total of 32 clinical strains of C. albicans isolated from head and neck cancer patients with oropharyngeal candidiasis were subjected to MLST analysis and SAP2 gene expression was analyzed by Real-time PCR. We identified 75 polymorphic sites in 7 loci of C. albicans isolates and 30 diploid sequence types which 27 of them were found as new. After eBURST analysis, our results determined that CC 124 was the most prevalent group among all CCs. SAP2 gene showed high expression in almost all OPC patients' isolates, compared to the control. We found few genetically-related as well as identical isolates among the 32 Candida strains which indicated low cross-contaminations among the patients. There was no relationship between C. albicans MLST profiles and their geographic distribution, cancer type and SAP2 gene expression. This lack of correlation was possibly due to the small understudy population; hence, finding more relevance requires studies with a higher number of samples.


Effective Piezo-Phototronic Enhancement of Flexible Photodetectors Based on 2D Hybrid Perovskite Ferroelectric Single-Crystalline Thin-Films.
2D hybrid perovskites are very attractive for optoelectronic applications because of their numerous exceptional properties. The emerging 2D perovskite ferroelectrics, in which are the coupling of spontaneous polarization and piezoelectric effects, as well as photoexcitation and semiconductor behaviors, have great appeal in the field of piezo-phototronics that enable to effectively improve the performance of optoelectronic devices via modulating the electro-optical processes. However, current studies on 2D perovskite ferroelectrics focus on bulk ceramics that cannot endure irregular mechanical deformation and limit their application in flexible optoelectronics and piezo-phototronics. Herein, we synthesize ferroelectric EA4 Pb3 Br10 single-crystalline thin-films (SCFs) for integration into flexible photodetectors. The in-plane multiaxial ferroelectricity is evident within the EA4 Pb3 Br10 SCFs through systematic characterizations. Flexible photodetectors based on EA4 Pb3 Br10 SCFs are achieved with an impressive photodetection performance. More importantly, optoelectronic EA4 Pb3 Br10 SCFs incorporated with in-plane ferroelectric polarization and effective piezoelectric coefficient show great promise for the observation of piezo-phototronic effect, which is capable of greatly enhancing the photodetector performance. Under external strains, the responsivity of the flexible photodetectors can be modulated by piezo-phototronic effect with a remarkable enhancement up to 284%. Our findings shed light on the piezo-phototronic devices and offer a promising avenue to broaden functionalities of hybrid perovskite ferroelectrics.


Heterosexual men's pupillary responses to stimuli depicting cisgender males, cisgender females, and gynandromorphs.
Gynandromorphophilia is the sexual attraction and arousal to feminine individuals assigned male at birth, who may or may not have breasts, and who retain their penises. Previous research has suggested that some capacity for gynandromorphophilia may characterize all males who are gynephilic (i.e., sexually attracted and aroused to adult cisgender females). This study examined Canadian cisgender gynephilic men's (n = 65) pupillary responses and subjective ratings of sexual arousal when presented with nude images of cisgender males, cisgender females, and gynandromorphs with, and without, breasts. Subjective arousal to cisgender females was highest, followed by subjective arousal to gynandromorphs with breasts, gynandromorphs without breasts and cisgender males. However, subjective arousal to gynandromorphs without breasts and to cisgender males did not differ significantly. Participants' pupils dilated more to images of cisgender females than to all other stimulus categories. Participants' pupils dilated more to gynandromorphs with breasts than to cisgender males, but pupillary response to gynandromorphs without breasts and cisgender males did not differ significantly. If the capacity for gynandromorphophilic attraction is a cross-culturally invariant aspect of male gynephilia, then these data suggest that this capacity may only extend to gynandromorphs with breasts and not gynandromorphs without breasts.


Comparison of mid-term effectiveness and safety of one-anastomosis gastric bypass and sleeve gastrectomy in patients with super obesity (BMI ≥ 50 kg/m2).
There is no consensus regarding the optimal bariatric procedure in patients with super obesity [body mass index (BMI) ≥ 50 kg/m2]. This study compared the outcomes of one-anastomosis gastric bypass (OAGB) with those of sleeve gastrectomy (SG) in these patients. This retrospective study was conducted based on the prospectively maintained data in a cohort of 557 patients with super obesity, who underwent either SG (n = 348) or OAGB with a 200-cm BPL (n = 154) or a 160-cm BPL (n = 55) by the same surgical team from March 2013 to 2017. Patients undergoing OAGB had greater weight loss in comparison to those managed by SG during the first, second, and third years of follow-up. Comparing the OAGB and SG groups within 3 years after surgery, the total weight loss was 36.5 vs. 33.2% (P < 0.001) and the ΔBMI was 20.1 vs. 18.1 kg/m2 (P < 0.001), respectively. The resolution of diabetes mellitus, hypertension and dyslipidemia were similar after the two procedures. The operative time and length of hospital stay were longer in the OAGB group, and incidence of complications, requiring either readmission or reoperation, was significantly higher after OAGB, in comparison to SG. There was no significant difference in the postoperative weight loss results, resolution of comorbidities, or the incidence of complications between the OAGB-160 and OAGB-200 groups, with the exception of protein-calorie malnutrition requiring revision surgery, which was exclusively observed in the OAGB-200 group. Although OAGB provides superior mid-term weight loss, SG remains the first option for patients with super obesity, due to the safer surgical profile and comparable metabolic improvement.


Characterization of two novel splice site mutations in human factor VII gene causing severe plasma factor VII deficiency and bleeding diathesis.
The molecular basis of severe type I factor (F)VII deficiency was investigated in two Algerian patients. One patient, a 13-year-old-girl who has suffered from severe bleeding since birth, was homozygous for a 7-bp deletion (nt 7774-7780) and a 251-bp insertion (nt 7773-7781) of mitochondrial origin, in IVS 4 acceptor splice site. The other patient, an infant who died from massive intracranial haemorrhage, was homozygous for a transversion in the IVS 7 donor splice site (T9726+2-->G) and a missense mutation in exon 8 (G10588-->A; Arg224-->Gln). In both cases, the deleterious mutations are probably the splice site junction abnormalities impairing mRNA processing. These three lesions have not yet been reported.


Paramecium mitochondrial DNA sequences and RNA transcripts for cytochrome oxidase subunit I, URF1, and three ORFs adjacent to the replication origin.
A 2-kb region adjacent to the replication origin (ori) and a 3-kb region located between the small and large ribosomal RNAs of Paramecium mitochondrial (mt) DNA have been sequenced and the locations of their transcripts determined. The ori segment contains four transcripts, some of which are overlapping, which encode a known protein and two other open reading frames. The other segment encodes, on separate transcripts, the cytochrome c oxidase subunit one gene (COI) and the URF1 gene (ND1) common to most mt genomes. All these genes have the same orientation and do not contain introns. The COI gene is the most divergent of those known and has an internal 108 amino acid 'insert' not found in COI genes from other organisms. With these data it is possible to define a probable Paramecium mt genetic code. With the exception that TGA codes for tryptophan and the use of different start codons, Paramecium mtDNA appears to follow the universal code. GTA possibly can be used as a start codon.


[Variations in enzyme activities in different sporulation conditions of Bacillus megaterium].
Glucose dehydrogenase and alkaline phosphatase activities have been studied for various conditions of sporulation of Bacillus megaterium KM (carbon, nitrogen, phosphate starvation). Glucose dehydrogenase appears in all conditions of sporulation, even with excess of glucose or gluconate. Alkaline phosphatase, usually dereprimed in phosphate starvation, does not increase during sporulation of Bacillus megaterium when phosphate is present.


Protective effect of Renshen Yangrong Decoction (人参养荣汤) on bone marrow against radiation injury in mouse.
To explore the effect of Renshen Yangrong Decoction (人参养荣汤, RYD) in protecting bone marrow from radiation injury. One hundred and eighty Kuming mice were subjected to the three tests for anti-radiation injury effect evaluation, i.e. the test of peripheral white blood cell (WBC) count, the test of bone marrow nucleated cell count, and the bone marrow micronucleus test, using 60 mice for each test. The mice in each test were divided into 6 groups: the blank control group, the model control group, the positive control group treated by Shiyiwei Shenqi Tablet (十一味参芪片, 1.0 g/kg), and three RYD groups treated with high (42.0 g/kg), moderate (21.0 g/kg), and low (10.5 g/kg) doses of crude drugs of RYD, with 10 mice in each group. The treatment was given by gastrogavage perfusion continuously for 7-14 days before mice received (60)Co-γ ray radiation and continued until the end of the experiment. The body weights of the mice were monitored, the changes in peripheral WBC and bone marrow nucleated cells were counted, and the variation in bone marrow micronucleated cells was observed on the respective appointed days. A significant decrease in body weight, peripheral WBC count, and bone marrow nucleated cell count, as well as marked changes in bone marrow micronucleated cells were observed in the mice after radiation, indicating that the radiation injury model was successfully established. As compared with the model control group, the decrease in body weight, peripheral WBC count, and bone marrow nucleated cell count, as well as the increase in bone marrow micronucleus cell count in the high dosage RYD treated group were obviously inhibited or lessened (P<0.05 or P<0.01). RYD showed obvious protective effect in mice with bone marrow injury induced by radiation.


In vitro and in silico studies to explore structural features of flavonoids for aldehyde oxidase inhibition.
Aldehyde oxidase (AO), an important enzyme in the biotransformation of drugs and xenobiotics, is inhibited by flavonoids. This enzyme can metabolize both aldehydes and N-heterocycles. In this work, a set of 15 flavonoids was assessed for inhibitory activity on the AO oxidation of vanillin as an aldehyde substrate. Spectrophotometrically determined IC50 values showed that myricetin, quercetin, and epicatechin were the most potent inhibitors. The results also revealed that the inhibition of vanillin oxidation by flavonoids was stronger than that of phenanthridine oxidation (an N-heterocyclic substrate) as reported previously. In order to investigate the important structural features responsible for the inhibitory effects of the studied flavonoids, a quantitative structure-activity relationship (QSAR) analysis was performed. This study showed that the size of the flavonoids was the most important factor inversely affecting their potencies. The QSAR model can be used more broadly to predict the AO inhibitory activity of flavonoid-like structures for application in food-drug and drug-drug interaction studies.


Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy.
Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by intraperitoneal administration of SB-269970 hydrochloride two hours prior to and sixteen hours after partial hepatectomy and by intraperitoneal administration of SB-258719 sixteen hours after partial hepatectomy. Animals were sacrificed at different time points until 72 h after partial hepatectomy. Liver regeneration was evaluated by [(3)H]-thymidine incorporation into hepatic DNA, the mitotic index in hematoxylin-eosin (HE) sections and by immunochemical detection of Ki67 nuclear antigen. Reversion of 5-HT7 blockade was performed by intraperitoneal administration of AS-19. Serum and liver tissue lipids were also quantified. Liver regeneration peaked at 24 h ([(3)H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and at 32 h (mitotic index in HE sections) in the control group of rats. 5-HT7 receptor blockade had no effect on liver regeneration when applied 2 h prior to partial hepatectomy. Liver regeneration was greatly attenuated when blockade of 5-HT7 receptor was applied (by SB-258719 and SB-269970) at 16 h after partial hepatectomy and peaked at 32 h ([(3)H]-thymidine incorporation into hepatic DNA and mitotic index by immunochemical detection of Ki67) and 40 h (mitotic index in HE sections) after partial hepatectomy. AS-19 administration totally reversed the observed attenuation of liver regeneration. In conclusion, 5-HT7 receptor is a novel type of serotonin receptor implicated in hepatocyte proliferation.


MRI-directed, wire-localized breast excisions: incidence of malignancy and recommendations for pathologic evaluation.
Magnetic resonance imaging (MRI) has an evolving role in the evaluation of breast lesions and is currently being used for the screening of high-risk patients (eg, women with a personal or family history of breast cancer), for the evaluation of extent of disease in patients with a current diagnosis of cancer, and for patients with suspicious, but indeterminate, findings by other imaging modalities. If a suspicious lesion detected by MRI is not well visualized by another method, an MRI-directed core biopsy or breast excision may be performed. MRI cannot be used to verify the lesion in the specimen because MRI lesion detection is dependent on uptake of gadolinium after intravenous injection. Accordingly, these breast excisions present unique challenges to pathologists. The purpose of this report is to define the surgical pathology issues involved in processing MRI-localized excisions. Retrospective review of 85 consecutive MRI-directed breast excisions from 77 patients was performed. Malignant lesions were present in 20 (24%) of 85 excisions, including 10 cases of invasive carcinoma (median size, 0.4 cm), 9 cases of ductal carcinoma in situ, and 1 case of lymphoma. Most of the malignancies (85% or 17/20) had no associated gross finding and only 5 (25%) of 20 of these malignancies were associated with a definite finding on the specimen radiograph. This study demonstrates that gross examination and specimen radiography do not identify most of the malignancies in MRI-localized biopsies and, therefore, optimal processing requires complete microscopic examination of these specimens.


Robust learning from noisy, incomplete, high-dimensional experimental data via physically constrained symbolic regression.
Machine learning offers an intriguing alternative to first-principle analysis for discovering new physics from experimental data. However, to date, purely data-driven methods have only proven successful in uncovering physical laws describing simple, low-dimensional systems with low levels of noise. Here we demonstrate that combining a data-driven methodology with some general physical principles enables discovery of a quantitatively accurate model of a non-equilibrium spatially extended system from high-dimensional data that is both noisy and incomplete. We illustrate this using an experimental weakly turbulent fluid flow where only the velocity field is accessible. We also show that this hybrid approach allows reconstruction of the inaccessible variables - the pressure and forcing field driving the flow.


Nurses' experiences of performing cardiopulmonary resuscitation in intensive care units: a qualitative study.
To describe the nurses' experiences of performing cardiopulmonary resuscitation in intensive care units. Research in the area of resuscitation is primarily concentrated on medical and biophysical aspects. The subjective experiences of those who perform cardiopulmonary resuscitation and their emotions are more seldom addressed. Qualitative descriptive design. Qualitative semi-structured interviews were used (n = 8). Data were analysed with content analysis. Three categories describe the experiences of nurses: training and precardiopulmonary resuscitation; chaos and order during cardiopulmonary resuscitation; and debriefing postcardiopulmonary resuscitation. The study results indicate that the health care staff find it necessary to practice cardiopulmonary resuscitation, as it provides them with a basic feeling of security when applying it in actual situations. We argue that postcardiopulmonary resuscitation debriefing must be viewed in the light of its eigenvalue with a specific focus on the staff's experiences and emotions, and not only on the intention of identifying errors. Debriefing is of the utmost importance for the nurses. Clinical leaders may make use of the findings of this study to introduce debriefing forums as a possible standard clinical procedure.


Validation of NRG Oncology's prognostic nomograms for oropharyngeal cancer in the Veterans Affairs database.
To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population-based sample. The authors tested nomograms for estimating progression-free survival (PFS) and overall survival (OS) in patients from the Veterans Health Administration with previously untreated locoregionally advanced OPSCC, diagnosed between 2008 and 2017, managed with definitive radiotherapy with or without adjuvant systemic therapy. Covariates were age, performance status, p16 status, T/N category, smoking history, education history, weight loss, marital status, and anemia. We used multiple imputation to handle missing data and performed sensitivity analyses on complete cases. Validation was assessed via Cox proportional hazards models, log-rank tests, and c-indexes. A total of 4007 patients met inclusion criteria (658 patients had complete data). Median follow-up time was 3.20 years, with 967 progression events and 471 noncancer deaths. Each risk score was associated with poorer outcomes per unit increase (PFS score, hazard ratio [HR], 1.42 [1.37-1.47]; OS score, HR, 1.40 [1.34-1.45]). By risk score quartile, 2-year PFS estimates were 89.2%, 78.5%, 65.8%, and 48.3%; OS estimates were 92.6%, 83.6%, 73.9%, and 51.3%, respectively (P < .01 for all comparisons). C-indices for models of PFS and OS were 0.65 and 0.67, for all patients, respectively (0.69 and 0.73 for complete cases). The nomograms slightly overestimated PFS and OS in the overall cohort but exhibited high agreement in complete cases. NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy.


[Correction of the inclination of the condylar guidance by changing the Bennett angle on the Dentatus articulator].
Since there is an interrelationship between construction-related inclination of condylar guidance and the Bennett angle with the Dentatus articulator, Lauritzen suggested that the inclination of condylar guidance be adjusted 1 degree in the opposing direction for every 5 degrees alteration in the Bennett angle. This method was rejected because calculations of the interdependence of condylar guidance and Bennett angle showed the results, in some cases, to be worse than when the angle was not adjusted. An exact correction procedure was described.


A hypothesis concerning the aetiology of venous thrombosis.
The historical background against which a new hypothesis must be discussed is presented, and the main threads of thinking about thrombosis are isolated so far as they can be. The interplay between such ideas as pus, white thrombus, white blood corpuscles, platelets, fibrin, and red blood cells, is traced: the origins of our concepts of blood circulation, stasis and slow blood flow, and vessel wall damage, are likewise dug up. The new hypothesis rearranges concepts which are not themselves actually or entirely new: instead of postulating that reduced blood flow results in 'silting' of presumably lifeless blood cells, it proposes that slow flow is more likely to injure venous endothelium by metabolic deprivation: and, in place of 'passive' silting, it postulates attachment of white blood cells and platelets to the damaged endothelium by virtue of their phagocytic or reparative function/s. This implies that thrombi are likely to form wherever living blood cells pass through veins whose endothelium is dying or dead from impaired nutrition (or other cause). The death of endothelium may be widespread, as in the agonal state, or, very limited, as in venous valve pockets when stasis is prolonged. The hypothesis is novel in that it seeks to explain thrombogenesis in functional or physiological terms, rather than in terms of purely biochemical pathogenesis.


4-(4-Nitro-phen-oxy)butanol.
The crystal structure of the title compound, C(10)H(13)NO(4), features inter-molecular O-H⋯O(nitro) hydrogen bonding, which links mol-ecules into supra-molecular chains running parallel to the bc diagonal. There is also π-π stacking between 4-nitro-phenyl groups, the inter-planar distance between the nitro-benzene rings being 3.472 (2) Å.


Improving Quality of Life in Heart Failure.
Heart failure has substantial effects on health-related quality of life. Maintaining or improving quality of life is an important goal of heart failure therapy, and many patients value better quality of life over greater longevity. The symptoms and functional severity of heart failure, medical comorbidities, and depression are the strongest predictors of poor quality of life. Guideline-recommended medical and behavioral interventions for HF, including exercise training and cardiac rehabilitation, self-care interventions, and treatment of depression, can help to improve quality of life. Heart failure is, in most cases, a progressive condition with a poor prognosis. However, poor quality of life is not inevitable, and a variety of medical, surgical, and nonpharmacological interventions can help to maintain or improve quality of life in patients with heart failure.


Ex-vivo immunophenotyping and high dimensionality UMAP analysis of leucocyte subsets in tuberculous lymphadenitis.
Tuberculous lymphadenitis (TBL) is defined by reduced proinflammatory cytokines and elevated CD4+, CD8+ T cells and decreased CD8+ cytotoxic markers. However, ex-vivo phenotyping of diverse leucocytes in TBL has not been done. We show activated and atypical B cells, myeloid dendritic cells (mDCs), classical, non-classical and intermediate monocytes, T regulatory (T regs) cells, CD4+ T cell effector memory RA (TEMRA), CD4+ effector and CD8+ central memory phenotypes were significantly increased in TBL compared to LTB individuals. In contrast, classical memory and plasma B cells, plasmacytoid DCs (pDCs), CD8+ TEMRA, CD4+ naïve and central memory cells were significantly decreased in TBL compared to LTB individuals. Some of the leucocyte frequencies (atypical memory B cells, pDCs, myeloid-derived suppressor cells, CD4+ effector and CD8+ central memory was increased; activated memory and plasma B cell, mDCs, classical, non-classical, intermediate monocytes, T regs, CD4+ TEMRA, CD4+, CD8+ naïve and effector memory cells and CD8+ central memory cells were decreased) were significantly modulated after anti-TB treatment among TBL individuals. UMAP analysis show that leucocyte subsets or islands expressing specific markers were significantly different in TBL baseline and post-treatment individuals. Overall, we suggest altered frequencies of diverse leucocytes influences the disease pathology and protective immunity in TBL individuals.


Fast, cheap and feasible: Implementation of pediatric telemedicine in a public hospital during the Covid-19 pandemic.
In Brazil, telemedicine was allowed as an exception during the coronavirus disease (COVID-19) pandemic. Despite its recognized value and availability, telemedicine is not universally used, suggesting that some barriers prevent its adoption and acceptance within the community. This study aims to describe the implementation of a low-cost telemedicine service in a pediatric hospital in Brazil. Retrospective descriptive study reporting the first three months (April to June 2020) of the experience of implementing a low-cost telemedicine emergency care program in a public tertiary hospital. The service was available to patients up to 18 years of age enrolled in this hospital. A tool for assessing the severity of the patient was developed, the aim of standardizing the procedure, while maintaining quality and safety. Guardian's satisfaction was assessed with a questionnaire sent after teleconsultations. 255 teleconsultations were carried out with 140 different patients. Of the total consultations, 182 were from 99 patients that had performed the Real-Time Polymerase Chain Reaction (RT-PCR) test for the new coronavirus (SARS-Cov-2) or had direct contact with a person known to be positive for COVID-19. Only 26 (14%) were referred to an in-person consultation. No deaths, adverse events or delayed diagnosis were recorded. 86% of the patients who answered the satisfaction questionnaire were satisfied and 92% would use telemedicine again. This study presents an innovative implementation of a telemedicine program in a public and exclusively pediatric tertiary service, serving as a reference for future implementation in other public services in Brazil and developing countries.


Identification of struggling readers or at risk of reading difficulties with one-minute fluency measures.
To identify readers who are struggling or at risk of reading difficulties, reference standards in oral reading fluency (ORF) are used to conduct an assessment that is based on a widely reported method known as curriculum-based measurement (CBM), which itself is based on 1-min fluency measures. The purpose of this study was to evaluate students' ORF (with a 1-min fluency measure) to characterize their fluency and to determine references of appropriate development in reading at the 50th percentile. For this study, a database of readings made available by the Learning Studies Research Laboratory was used. This database consisted of 365 readings by elementary-school students from the third to fifth grades in two cities in the interior of the state of São Paulo from two different public school systems that use the same teaching methodology. The data consisted of digital audio recordings of the passage "The Umbrella" (text suitable for schooling levels) of the Protocol for Assessment of Reading Comprehension procedure. For this procedure, three steps were performed: step 1-listening to the 365 readings and assessing the scores for the number of words read correctly per minute; step 2-the calculation of the mean and percentiles for each grade; and step 3-the adaptation of the reference table to indicate students eligible to receive reading fluency intervention. Third-year students who correctly read 86 or more words per minute, fourth-year students who correctly read 104 or more words per minute, and fifth-year students who correctly read 117 or more words per minute were considered students who had made adequate progress in reading. It was possible to classify students based on the 1-min fluency measures, with reference intervals of words read correctly per minute per school year (for the third, fourth, and fifth years) for those who were making adequate progress in reading and reference intervals for those who were considered readers who were struggling or at risk of reading difficulties.


Teaching authorship and publication practices in the biomedical and life sciences.
Examination of a limited number of publisher's Instructions for Authors, guidelines from two scientific societies, and the widely accepted policy document of the International Committee of Medical Journal Editors (ICMJE) provided useful information on authorship practices. Three of five journals examined (Nature, Science, and the Proceedings of the National Academy of Sciences) publish papers across a variety of disciplines. One is broadly focused on topics in medical research (New England Journal of Medicine) and one publishes research reports in a single discipline (Journal of Bacteriology). Similar elements of publication policy and accepted practices were found across the policies of these journals articulated in their Instructions for Authors. A number of these same elements were found in the professional society guidelines of the Society for Neuroscience and the American Chemical Society, as well as the ICMJE Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Taken together, these sources provide the basis for articulating best practices in authorship in scientific research. Emerging from this material is a definition of authorship, as well as policy statements on duplicative publication, conflict of interest disclosure, electronic access, data sharing, digital image integrity, and research requiring subjects' protection, including prior registration of clinical trials. These common elements provide a foundation for teaching about scientific authorship and publication practices across biomedical and life sciences disciplines.


ABO blood group system, age, sex, risk factors and cardiac infarction.
In a retrospective study in 3100 patients of different ages the relationship between blood group and cardiac infarction was investigated in 450 patients. The patients were divided in two age groups: those who were 65 yr old and older and younger patients (age less than 65 yr). The predominance of blood group A in patients with cardiac infarction was highly significant in both age groups (P less than 0.005, two-tailed Chi-square test). Step-wise excluding all patients with at least one of the risk factors, hypertension, hyperuricemia, diabetes mellitus, smoking, and hyperlipemia similar results were found: the predominance of blood group A in the elderly patients with cardiac infarction was even higher than before excluding the risk factors (P less than 0.001). The predominance of blood group A was also demonstrated at a lower level in younger patients with cardiac infarction (P less than 0.05). Our investigation strongly suggests the existence of a genetic factor associated with blood group A and independent of the other risk factors which is also responsible for a greater incidence of cardiac infarction.


Ti-Cp functionalization by deposition of organic/inorganic silica nanoparticles.
In orthopaedics and cardiovascular surgery, titanium has become the metal of choice, due to its excellent mechanical properties and biocompatibility. In many surgical operations, chemicals and/or biomolecules (such as antibiotics or growth factors) are used in conjunction with prostheses, so as to avoid or stimulate targeted biological events. Often, immobilization instead of release of such molecules is preferred to optimize their effects, thus avoiding ectopic transformations. A versatile method for the functionalization of pure Ti is shown here, which allows the covalent immobilization of polypeptides. In order to avoid the hydrolysable Ti-O-Si bond found in directly silanized Ti, we use organic/inorganic silica colloids, derived from commercially available 25 nm Ludox silica nanoparticles. Prior to deposition onto Ti-Cp, the silica nanoparticles are functionalized by a propylsemicarbazide moiety by silanization. After spin-coating onto the Ti substrates, the colloids were shown by SEM to form a uniform layer, and to be very strongly adsorbed; the reactivity of the supported semicarbazide (Sc) functionalities being maintained. Chemoselective reaction of semicarbazide groups on the surface with aldehyde moieties present on the polypeptide of interest was chosen in this work due to its efficiency, to its compatibility with the proteinogenic amino acids and in particular cystein and to the use of mild experimental conditions. Aldehyde groups are also easily introduced onto polypeptides by synthesis, oxidation of N-terminal Ser residue or polysaccharide moieties of glycoproteins. Biological assays with MC3T3-E1 osteoblasts revealed an excellent cytocompatibility as shown by the assessment of cell viability, vitality and morphology.


Effect of hazelnut type, hydrocolloid concentrations and ultrasound applications on physicochemical and sensory characteristics of hazelnut-based milks.
Effect of hazelnut type, hydrocolloid concentrations and ultrasound applications on physicochemical and sensory characteristics of hazelnut-based milks was studied. Hazelnut- based milks were prepared in three different formulas (F1, F2 and F3) by using raw kernels (Group G1) and roasted hazelnut (Group G2) kernels and homogenized after heat treatment by applying ultrasound (US) (20 KHz, 100 W) with two different durations (5 and 10 min). Physicochemical and structural properties of the samples were extremely affected by heat treatments and US applications. Homogenization process after heat treatment improved protein solubility, zeta potential values for the samples belonged both groups. Homogenized hazelnut-based milk samples showed a significant reduction of particle size. Hazelnut type significantly affected the sensory characteristics of the hazelnut-based milks. Using of gellan gum (GG) and Carboxy methyl cellulose (CMC) together in hazelnut- based milk formulas decreased the stability of the samples.


Prevalence of multidimensional frailty and pre-frailty in older people in different settings: A systematic review and meta-analysis.
Frailty is a common condition in older people. The epidemiological data available, however, are mainly based on the physical frailty phenotype. An extensive literature has suggested that frailty should be identified using a multidimensional approach. Based on these recommendations, we estimated the prevalence of frailty and pre-frailty in the older population, using the multidimensional prognostic index (MPI), a common tool for defining multidimensional frailty. We searched several databases until 10th May 2021 for studies reporting the prevalence of frailty according to MPI values. MPI was categorized, where possible, in < 0.33 (robustness), 0.33-0.66 (pre-frailty) and > 0.66 (frailty) or using a RECursive Partition and AMalgamation approach. A meta-analysis of the prevalence, with the correspondent 95% confidence intervals (CIs) of pre-frailty and frailty was performed stratified by setting (population-based, ambulatory, nursing home, and hospital). Among 177 papers initially screened, we included 57 studies for a total of 56,407 older people. The mean age was 78.6 years, with a slight prevalence of women (58%). The overall prevalence of multidimensional frailty (MPI-3) was 26.8% (95%CI: 22.1-31.5), being higher in nursing home setting (51.5%) and lower in population-based studies (13.3%). The prevalence of pre-frailty (MPI-2) was 36.4% (95%CI: 33.1-39.7), being higher in hospital setting (39.3%) and lower in nursing home (20%). In conclusion, frailty and pre-frailty, according to a multidimensional definition, are common in older people affecting, respectively, one person over four and one over three. Our work further strengths the importance of screening frailty in older people using a multidimensional approach.


The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway.
Although diverse antipsychotic drugs have been developed for the treatment of schizophrenia, most of their mechanisms of action remain elusive. Regulator of G-protein signaling 4 (RGS4) has been reported to be linked, both genetically and functionally, with schizophrenia and is a physiological substrate of the arginylation branch of the N-degron pathway (Arg/N-degron pathway). Here, we show that the atypical antipsychotic drug clozapine significantly inhibits proteasomal degradation of RGS4 proteins without affecting their transcriptional expression. In addition, the levels of Arg- and Phe-GFP (artificial substrates of the Arg/N-degron pathway) were significantly elevated by clozapine treatment. In silico computational model suggested that clozapine may interact with active sites of N-recognin E3 ubiquitin ligases. Accordingly, treatment with clozapine resulted in reduced polyubiquitylation of RGS4 and Arg-GFP in the test tube and in cultured cells. Clozapine attenuated the activation of downstream effectors of G protein-coupled receptor signaling, such as MEK1 and ERK1, in HEK293 and SH-SY5Y cells. Furthermore, intraperitoneal injection of clozapine into rats significantly stabilized the endogenous RGS4 protein in the prefrontal cortex. Overall, these results reveal an additional therapeutic mechanism of action of clozapine: this drug posttranslationally inhibits the degradation of Arg/N-degron substrates, including RGS4. These findings imply that modulation of protein post-translational modifications, in particular the Arg/N-degron pathway, may be a novel molecular therapeutic strategy against schizophrenia.


Study on the interaction between bovine serum albumin and 4'-azido-2'-deoxyfluoroarabinocytidine or analogs by spectroscopy and molecular modeling.
The binding of 4'-azido-2'-deoxyfluoroarabinocytidine (FNC) or analogs (cytidine and 5'-cytidylate monophosphate) to bovine serum albumin (BSA) was investigated by fluorescence, UV-vis absorption spectroscopy and molecular modeling. The three compounds quenched the intrinsic fluorescence of BSA and the results revealed the presence of static quenching mechanism. The positive ΔH and positive ΔS for the systems suggested that the hydrophobic forces stabilized the interaction between the compounds and protein. Results also showed that FNC was the weakest quencher.


Characterization of TAG-63 and its role on axonal transport in C. elegans.
Model organisms are increasingly used to study and understand how neurofilament (NF)-based neurological diseases develop. However, whether a NF homolog exists in C. elegans remains unclear. We characterize TAG-63 as a NF-like protein with sequence homologies to human NEFH carrying various coiled coils as well as clustered phosphorylation sites. TAG-63 also exhibits features of NFL such as a molecular weight of around 70 kD, the lack of KSP repeats and the ability to form 10 nm filamentous structures in transmission electron micrographs. An anti-NEFH antibody detects a band at the predicted molecular weight of TAG-63 in Western blots of whole worm lysates and this band cannot be detected in tag-63 knockout worms. A transcriptional tag-63 reporter expresses in a broad range of neurons, and various anti-NFH antibodies stain worm neurons with an overlapping expression of axonal vesicle transporter UNC-104(KIF1A). Cultured neurons grow shorter axons when incubating with drugs known to disintegrate the NF network and rhodamine-labeled in vitro reconstituted TAG-63 filaments disintegrate upon drug exposure. Speeds of UNC-104 motors are diminished in tag-63 mutant worms with visibly increased accumulations of motors along axons. UNC-104/TAG-63 and SNB-1/TAG-63 not only colocalize in neurons but also revealed positive BiFC (bimolecular fluorescence assay) signals. In summary, we identified and characterized TAG-63 in C. elegans, and demonstrate that lack of this protein limits axonal transport efficiencies. Additionally, this study would aid in developing NF-related disease models in the future.


The evolutionary potential of influenza A virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase.
Antigenic evolution of the influenza A virus (IAV) hemagglutinin (HA) gene limits efforts to effectively control the spread of the virus in the population. Efforts to understand the mechanisms governing HA antigenic evolution typically examine the HA gene in isolation. This can ignore the importance of balancing HA receptor binding activities with the receptor-destroying activities of the viral neuraminidase (NA) to maintain viral fitness. We hypothesize that the need to maintain functional balance with NA significantly constrains the evolutionary potential of the HA. We use deep mutational scanning and show that variation in NA activity significantly reshapes the HA fitness landscape by modulating the overall mutational robustness of HA. Consistent with this, we observe that different NA backgrounds support the emergence of distinct repertoires of HA escape variants under neutralizing antibody pressure. Our results reveal a critical role for intersegment epistasis in influencing the evolutionary potential of the HA gene.


Pretreatment Masseter Muscle Volume Predicts Survival in Locally Advanced Nasopharyngeal Carcinoma Patients Treated with Concurrent Chemoradiotherapy.
Muscle loss is a significant indicator of cancer cachexia and is associated with a poor prognosis in cancer patients. Given the absence of comparable studies, the current retrospective study sought to examine the correlation between the total masseter muscle volume (TMMV) before treatment and the survival outcomes in locally advanced nasopharyngeal cancer (LA-NPC) patients who received definitive concurrent chemoradiotherapy (CCRT). A three-dimensional segmentation model was used to determine the TMMV for each patient by analyzing pre-CCRT magnetic resonance imaging. The optimal TMMV cutoff values were searched using receiver operating characteristic (ROC) curve analyses. The primary and secondary endpoints were the relationship between the pre-CCRT TMMV measures and overall survival (OS) and progression-free survival (PFS), respectively. Ninety-seven patients were included in this study. ROC curve analyses revealed 38.0 cc as the optimal TMMV cutoff: ≤38.00 cc (n = 42) and >38.0 cc (n = 55). Comparisons between the two groups showed that the TMMV>38.0 cc group had significantly longer PFS [Not reached (NR) vs. 28; p < 0.01] and OS (NR vs. 71; p < 0.01) times, respectively. The results of the multivariate analysis demonstrated that the T-stage, N-stage, number of concurrent chemotherapy cycles, and TMMV were independent associates of PFS (p < 0.05 for each) and OS (p < 0.05 for each) outcomes, respectively. The findings of the current retrospective research suggest that pretreatment TMMV is a promising indicator for predicting survival outcomes in LA-NPC patients receiving definitive CCRT.


The comet assay: a sensitive method for detecting DNA damage in individual cells.
The comet assay is a sensitive and rapid method for DNA strand break detection in individual cells, and the year 2009 represents the 25th anniversary of the first description of this methodology in 1984. Over time this method has been improved, but is still not completely standardized, and variations are currently in widespread use with emphasis on applications in research and genetic toxicology. Here we review the principles of the comet assay and cite key studies that have focused on this assay in the past 25 years. In addition, we present an example of how the comet assay was used in our laboratory for studying the induction of DNA damage in human lung cancer cells after differing doses of the cytosine analog 5-aza-2'-deoxycytidine (5-aza-CdR). Finally, some insights into the potential of this assay in cancer research and work in related fields are offered.


A specific microdomain ("glycosynapse 3") controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of alpha3beta1 integrin with CD9.
Cell motility is highly dependent on the organization and function of microdomains composed of integrin, proteolipid/tetraspanin CD9, and ganglioside (Ono, M., Handa, K., Sonnino, S., Withers, D. A., Nagai, H., and Hakomori, S. (2001) Biochemistry 40, 6414-6421; Kawakami, Y., Kawakami, K., Steelant, W. F. A., Ono, M., Baek, R. C., Handa, K., Withers, D. A., and Hakomori, S. (2002) J. Biol. Chem. 277, 34349-34358), later termed "glycosynapse 3" (Hakomori, S., and Handa, K. (2002) FEBS Lett. 531, 88-92, 2002). Human bladder cancer cell lines KK47 (noninvasive and nonmetastatic) and YTS1 (highly invasive and metastatic), both derived from transitional bladder epithelia, are very similar in terms of integrin composition and levels of tetraspanin CD9. Tetraspanin CD82 is absent in both. The major difference is in the level of ganglioside GM3, which is several times higher in KK47 than in YTS1. We now report that the GM3 level reflects glycosynapse function as follows: (i) a stronger interaction of integrin alpha3 with CD9 in KK47 than in YTS1; (ii) conversion of benign, low motility KK47 to invasive, high motility cells by depletion of GM3 by P4 (D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol) treatment or by knockdown of CD9 by the RNA interference method; (iii) reversion of high motility YTS1 to low motility phenotype like that of KK47 by exogenous GM3 addition, whereby the alpha3-to-CD9 interaction was enhanced; (iv) low GM3 level activated c-Src in YTS1 or in P4-treated KK47, and high GM3 level by exogenous addition caused Csk translocation into glycosynapse, with subsequent inhibition of c-Src activation; (v) inhibition of c-Src by "PP2" in YTS1 greatly reduced cell motility. Thus, GM3 in glycosynapse 3 plays a dual role in defining glycosynapse 3 function. One is by modulating the interaction of alpha3 with CD9; the other is by activating or inhibiting the c-Src activity, possibly through Csk translocation. High GM3 level decreases tumor cell motility/invasiveness, whereas low GM3 level enhances tumor cell motility/invasiveness. Oncogenic transformation and its reversion can be explained through the difference in glycosynapse organization.


GFR determined by nonradiolabeled iothalamate using capillary electrophoresis.
Traditional measurements of glomerular filtration rate (GFR) in clinical practice include the measurement of serum creatinine or creatinine clearance. Increasing evidence concerning the limitation of these measurements in clinical practice and clinical trials has resulted in efforts to develop technologies that improve measurement of GFR. Recent efforts in that regard have used radioisotopic labeling of markers of GFR, such as 125I-iothalamate, and 51Cr-ethylenediaminetetraacetic acid. Limitations of these technologies include radiation exposure as well as cost considerations for the management of radioisotopes, including safety, disposal, mailing, and deteriorating activity that results in short shelf life. We report a test that used 0.5 mL Conray dye injected subcutaneously and subsequent measurement of the nonisotopic (cold) iothalamate by capillary electrophoresis in blood and urine. GFR using cold iothalamate compared with standard clearance using 125I-iothalamate was 0.99. The method is cost-effective and allows for avoiding exposure to isotopes, as well as problems such as the disposal and short shelf life of isotopes. This technology could allow for replacement of 125I-iothalamate as a marker for GFR.


Coexistence of arthritis, subcutaneous fat necrosis, and pseudocyst of pancreas.
A 29-year-old woman was observed with subcutaneous fat necrosis, arthritis, and a giant pseudocyst of the pancreas. Surgical removal of the cyst resulted in a remission of the inflammatory process in the joints as well as within the subcutaneous tissue.


Chemical reduction kinetics of nitrate in aqueous solution by Mg/Cu bimetallic particles.
Synthesized magnesium/copper (Mg/Cu) bimetallic particles have shown good potential for use in the reduction of nitrate from aqueous solutions. This study was conducted to investigate the main factors affecting the kinetics of nitrate reduction by Mg/Cu particles (<100 microm) in uncontrolled reaction conditions. The Mg/Cu bimetallic particles removed the majority of the various nitrate concentrations tested (50, 100, 150, 200 and 300 mg L(-1)) within a short period. The time required for the removal of 90.6% of the NO3(-) from a 100 mg L(-1) solution was about 20 min using 2 gL(-1) bimetallic Mg/Cu at an initial solution pH of 6. The activation energy (Ea) for nitrate reduction by Mg/Cu over the temperature range of 5 to 60 degrees C was 14.21 kJ mol(-1). The experimental results of the kinetic analysis from batch studies indicated that a higher initial nitrate concentration yielded a greater reaction-rate constant and the denitrification rate increased with increase Mg/Cu dosage.


Cerebral blood flow velocity and pulsation in neonatal respiratory distress syndrome and periventricular hemorrhage.
The present study addressed the hypotheses that cerebral ischemia and/or excessive cerebral blood pulsation contribute to periventricular hemorrhage in preterm newborns with respiratory distress and that the pulse width is a valuable tool to estimate the contribution of cerebral blood pulsation. These hypotheses were tested by following preterm newborns at risk for respiratory distress and periventricular hemorrhage. We monitored for cerebral blood flow velocity (CBFV), cerebral pulse width, and cerebral pulsatility index; for patent ductus arteriosus, capillary Pco2, heart rate (HR) and behavior; and for the occurrence of respiratory distress and periventricular hemorrhage (PVH). The data obtained were analyzed with linear regression with the mode of respiration (spontaneous or supported) and postnatal age as additional covariates. We observed that (a) respiratory distress, either uncomplicated or complicated by PVH, correlates with a low CBFV and a high cerebral pulsatility index; (b) PVH also correlates with a high cerebral pulse width; (c) the increased pulse width precedes the onset of the hemorrhage; and (d) these CBF alterations can be partly attributed to ductal shunting and are ameliorated by mechanical ventilation.


The electroclinical features and surgical outcomes of inferior perisylvian epilepsy.
To summarize the clinical and electrophysiological observations of epilepsy originating from the inferior perisylvian cortex, and analyze the potential epileptic networks underlying the semiological manifestations. We retrospectively analyzed patients with refractory inferior perisylvian epilepsy (IPE) who had undergone resective surgery, and then reviewed the demographic, clinical, neuroelectrophysiological, neuroimaging, surgical, histopathological, and follow-up data of the patients from the respective medical records. The selected patients were then categorized in accordance with the results of semiological analysis. Quantitative 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) analysis was performed to investigate the underlying neural network. Of the 18 IPE patients assessed in this study, ipsilateral frontotemporal epileptic discharges or its onsets were the dominant interictal or ictal scalp EEG observations. In addition, oroalimentary or manual automatism was the most frequently documented manifestation, followed by facial tonic or clonic movements. Moreover, the semiological analysis identified and classified the patients into 2 patterns, and the PET statistical analyses conducted on these 2 groups revealed differences in the neural network between them. Inferior perisylvian epilepsy possesses semiological manifestations similar to those of mesial temporal lobe epilepsy or rolandic opercular epilepsy, hence these conditions should be carefully differentiated. Performing lesionectomy or cortectomy, sparing the mesial temporal structures, was found to be an effective and safe treatment modality for IPE.


Effect of vitamin D therapy on bone mineral density in patients with diabetic nephropathy; a randomized, double-blind placebo controlled clinical trial.
Diabetes compromises bone strength resulting increased risk of osteoporosis. Objective of this study was to determine the effect of vitamin D given to patients with early diabetic renal disease on BMD and BMC. Patients with diabetic nephropathy were recruited. Treatment group received 50,000 IU of vitamin D3 intramuscularly and the control group was given an equal volume of distilled water (0.25 mL) monthly for six months. Baseline BMD, BMC in the total body, lumbar spine and proximal femur were measured by DXA. After six months measurements were repeated. When trial period was over, a randomly selected subgroup of patients (25 from each group) was followed up for further six-months and measurements were repeated. Selected patients were randomly assigned to two groups. After six months, the treatment group total body BMD, total body BMC and BMDs of spine, femoral neck and total hip regions increased by 2.0%, 2.2%, 1.8%, 2.1% and 2.6% (P < 0.05 for all within-group differences), respectively. In the Control group, BMD or BMC of any region mentioned above did not change significantly during the initial 6 months (P < 0.05 for the between-groups differences). After 6 months of stopping treatment, a statistically significant reduction of total BMD and BMC was observed in the treatment group (P = 0.009). This study showed that treatment with high dose vitamin D significantly influences total body BMC, total body BMD, BMDs of spine, femoral neck and hip among patients with diabetic nephropathy.


Is there too much variability in technical neurosurgery decision-making? Virtual Tumour Board of a challenging case.
Decades into the era of evidence-based medicine, most neurosurgeons are aware that the vast majority of our day-to-day patient care decisions are not guided by class I evidence, especially those related to surgical procedures. We rely on common sense, personal bias based on our residency training and personal experience. A 35-year-old man presented with a 6-month history of visual loss, cognitive decline and endocrine dysfunction. Imaging showed the culprit lesion to be a cystic suprasellar tumour with a mural nodule. Opinions regarding the optimal surgical approach were sought from 40 colleagues in the senior neurosurgeon's own hospital and other centres worldwide, who suggested 37 different approaches. A right pterional image-guided craniotomy successfully allowed for drainage of the cyst and resection of the nodule. The pathology was adamantinomatous craniopharyngioma. The patient had an excellent surgical recovery and a good outcome.


Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-β peptides.
Carboxyterminally elongated and aminoterminally truncated Aβ peptides as well as their pyroglutamate and oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to characterize aminoterminally truncated or oxidized Aβ38, Aβ40, and Aβ42 peptide species in immunoprecipitated human cerebrospinal fluid (CSF). We invented a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and used the Aβ-SDS-PAGE/immunoblot for subsequent analysis of CSF Aβ peptide patterns. In the present study, we identified the aminoterminally truncated Aβ peptides 2-40 and 2-42 as well as oxidized forms of Aβ1-38 and Aβ1-42 in CSF. Our protocol allowed the quantification of a pattern of Aβ peptides 1-38(ox), 2-40, and 2-42 in addition to the well known panel of Aβ 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42 in a group of seven patients with peripheral polyneuropathy. In the present approach, we could broaden the range of quantifiable Aβ peptides described in previous studies (i.e., 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42) by Aβ 1-38(ox), 2-40, and 2-42. An exact analysis of CSF Aβ peptides regarding their carboxy- and aminoterminus as well as posttranslational modification seems promising with respect to diagnostic and pathogenic aspects.


Point-of-Care Ultrasound Diagnosis of Acute High Altitude Illness: A Case Report.
With the advent of high-quality portable ultrasound machines, point-of-care ultrasound (POCUS) has gained interest as a promising diagnostic tool for patients with high altitude illness. Although POCUS is used successfully in hospital environments to detect interstitial pulmonary edema and increased intracranial pressure, the relationship between specific sonographic criteria and high altitude illness is still unclear. We report the case of a healthy 32-y-old male who developed acute respiratory distress and neurologic impairment at 4321 m while participating in a high altitude medical research expedition. We discuss the potential of POCUS to diagnose acute high altitude illness by lung ultrasound, optic nerve sheath diameter measurement, and echocardiography. Ultrasound in combination with clinical findings helped us to exclude relevant differential diagnoses, start on-site treatment, and organize an evacuation. We used serial clinical and ultrasound examinations to assess the patient over time. Although its role in high altitude medicine needs further investigation, we believe that POCUS can be a valuable tool to aid clinical decision-making in remote, high altitude environments.


Stroke in sickle cell disease and the promise of recent disease modifying agents.
Sickle cell disease (SCD) is an inherited hemoglobinopathy affecting approximately 100,000 individuals in the United States. Cerebrovascular disease is among the most common and debilitating complications of SCA, with 53% experiencing silent cerebral infarct by age 30 and 3.8% experiencing overt stroke by age 40 years. This review highlights the burden of cerebrovascular disease in SCD, including both stroke and silent cerebral infarct (SCI). We then discuss the pathophysiology of stroke and cerebral fat embolism in the absence of a patent foramen ovale. This review also reveals that options for primary and secondary stroke prevention in SCD are still limited to hydroxyurea and blood transfusion, and that the role of aspirin and anticoagulation in SCD stroke has not been adequately studied. Limited data suggest that the novel disease-modifying agents for SCD management may improve renal dysfunction, leg ulcers, and lower the abnormally high TCD flow velocity. Further research is urgently needed to investigate their role in stroke prevention in SCD, as these novel agents target the main stroke contributors in SCD - hemolysis and vaso-occlusion. This literature review also explores the role of healthcare disparities in slowing progress in SCD management and research in the United States, highlighting the need for more investment in patient and clinician education, SCD management, and research.


Iohexol in urography.
Thirty patients injected intravenously with a nonionic contrast medium, iohexol, for urography were compared with 30 patients similarly injected with sodium iothalamate. Comparable radiographic results were obtained in these patients with normal renal function. Few minor responses were observed with the iohexol, suggesting that it may prove to be an attractive contrast medium for this purpose.


Inhibitory Activity and Mechanism Investigation of Hypericin as a Novel α-Glucosidase Inhibitor.
α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC50) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10-5 M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.


Usefulness of transtelephonic documentation of the electrocardiogram during sporadic symptoms suggestive of cardiac arrhythmias.
One hundred patients with sporadically occurring symptoms suggesting cardiac arrhythmias were evaluated with the aid of a transtelephonic electrocardiographic recording device (Cardiomemo). In 83 patients, 124 episodes with symptoms were documented and a correlation with electrocardiographic findings could be established. Forty of these patients (48%) had a cardiac arrhythmia and 43 (52%) had a normal heart rhythm. It appears that, for the assessment of sporadically occurring symptoms, transtelephonic electrocardiographic recording is a valuable supplement to 24-hour ambulatory electrocardiographic monitoring.


Leukoaraiosis and pulse-wave encephalopathy: observations with phase-contrast MRI in mild cognitive impairment.
To test the pathogenic hypothesis of a breakdown in the vital buffering of the arterial pulsations behind leukoaraiosis (LA) in mild cognitive impairment (MCI). Seventy-one elderly patients with MCI underwent a combined structural and dynamic MR examination (3D T1-weighted and fast-FLAIR T2-weighted sequences, phase contrast sequences). Arterial indices of pulsatility (IP) and composite indicators of the amplitude transfer function between cerebrospinal fluid and cerebral venous flow (Icsf/veins) were used to assess the large artery stiffness and the intracranial compliance respectively. Cerebral total arterial blood flow (tCBF), superficial and deep venous flow rates were also measured. Intracranial dynamic parameters and potential confounders including age, gender and vascular risk factors were compared between two groups respectively with and without significant LA. The only dynamic changes on multivariate analyse were an IP increase, a lowering of deep venous outflow and Icsf/veins in patients with LA. There was a significant interaction between IP and Icsf/veins in the logistic regression: as compared with patients with low IP (suggestive of high large artery compliance) and high Icsf/veins (suggestive of high intracranial compliance), the adjusted odds ratios for the presence of LA were 9 (95% CI 1-64, P=0.02) in cases of both high IP and Icsf/veins, 10 (95% CI 1-64, P=0.02) in cases of both high IP and low Icsf/veins and 19 (95% CI 3-127, P=0.002) in cases of both low IP and Icsf/veins. LA may reflect an arteriosclerotic and/or resistive pulse wave encephalopathy in MCI.