Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma.
Current therapy for intermediate thickness melanoma involves wide local excision with sentinel lymph node biopsy (SLNB). SLNB provides important prognostic information and immediate regional lymphadenectomy for a positive sentinel lymph node (SLN) may improve survival and identifies patients who are candidates for adjuvant therapy and/or clinical trials. The head and neck site is unique because of its complex lymphatic drainage pattern to multiple nodal basins and because of the risk of site-specific morbidity associated with regional lymphadenectomy when compared to other body sites. The goal of this study is to report the results of SLNB for head and neck cutaneous melanoma in locating the sentinel node and to report on the prognostic implications of SLNB for this cohort of patients. A prospectively entered melanoma database was used to review consecutive patients with head and neck cutaneous melanoma undergoing SLNB at Memorial Sloan-Kettering Cancer Center between 1996 and 2007. The database, along with a retrospective chart review, was used to evaluate the success of SLNB at locating an SLN and the success rate of frozen section and permanent section analysis at diagnosing metastatic disease. Recurrence at all sites including the nodal basin and status at last follow-up was recorded. Characteristics of the patients' primary melanoma were included. Descriptive statistics along with univariate and multivariate survival analysis were performed. Between 1996 and 2007, 234 patients with a diagnosis of head and neck cutaneous melanoma underwent SLNB and had at least 1 month of follow-up. At least 1 SLN was identified in 218 of these patients (93%) by lymphoscintigraphy. In 16 patients, no SLN was found. These patients had a much shorter time to recurrence (4.75 months) than either the SLN-positive group (10.7 months) or the SLN-negative group (26.0 months). They had a disease-specific survival (DSS) in between the SLN-positive and SLN-negative group. Of the patients in whom an SLN was identified, 28 patients (12%) had at least 1 positive SLN. Of these, the SLNs of 14 patients (50%) were identified on frozen section; 14 (50%) could only be identified after further sectioning or immunohistochemical analysis postoperatively. Among 190 patients with a negative SLNB, 12 patients had recurrences in the nodal basin. This resulted in a sensitivity of 70%, a negative predictive value of 94%, and a false-negative rate of 30%. The 3-year disease-free survival for SLN-negative and SLN-positive patients was 84% (p < .031) and 58% (p < .102), respectively. The 3-year melanoma-specific survival was 98% (p < .012) and 75% (p < .201), respectively. The SLN status is an important predictor of survival. The technique, performed in the head and neck is complex and associated with a high false-negative rate.


Relationship of temperament and behaviour measures to the prolactin response to fenfluramine in depressed men.
Low central nervous systems (CNS) serotonin has been linked to aggression, impulsivity and disinhibition in both animal and human studies. Low cerebrospinal fluid (CSF) 5-hydroxindoleacetic acid (5HIAA) has been reported in violent criminals, arsonists and violent suicide attempters. Reduced prolactin response to fenfluramine has been found in aggressive patients and criminal offenders. Cloninger's dimension of harm avoidance is hypothesised to be related to CNS serotonin levels, but studies have reported contradictory results. Forty-eight men with major depression received a fenfluramine challenge as well as a number of measures of temperament and behaviour: the Tridimensional Personality Questionnaire (TPQ); the Eysenck Personality Questionnaire (EPQ); the Barratt Impulsivity Scale (BIS); the Hopkins Symptom Checklist (SCL-90); and clinician-rated personality disorder symptoms. The prolactin response to fenfluramine was not related to EPQ or TPQ measures except the TPQ dimension of reward dependence and the EPQ Lie scale. The prolactin response to fenfluramine was not related to BIS measures or to SCL-90 measures except the SCL-90 somatization scale. The prolactin response to fenfluramine was not related to personality disorder diagnoses or to a measure of repeated self-harm. Thus, in a sample of moderately depressed male outpatients, there was very little relationship between personality, behavioural measures and the prolactin response to fenfluramine. We suggest that alterations in serotonin functioning, when measured using the prolactin response to fenfluramine, may be more commonly linked to behavioural abnormalities in personality-disordered or criminal samples.


Validation of a new prototypic measure of melancholia.
Multiple approaches have been adopted in an attempt to effectively identify and discriminate melancholic and non-melancholic depressive subtypes. We recently developed the Sydney Melancholia Prototype Index (SMPI) which incorporates antecedent and illness course variables as well as symptoms, with clinician-rated and self-rated SMPI versions, and with the former having been shown to have superior sensitivity and specificity in discriminating melancholic from non-melancholic depression. The aim of this study was to further evaluate the capacity of the SMPI to identify melancholia in comparison to DSM-based and clinician-judged assignments. The sample comprised 214 patients diagnosed with melancholic or non-melancholic depression according to a detailed clinical assessment and by the Mini International Neuropsychiatric Structured Interview (MINI) assessing formal DSM-IV melancholia criteria. DSM-IV assignment to melancholic versus non-melancholic depression was contrasted with clinician-judged allocation, the combination of these two strategies ("concordant diagnoses"), and to the SMPI (CR or clinician-rated and SR or self-report versions), with the likely validity of each approach examined against historical ascriptions for melancholia. DSM-IV criteria assigned the highest percentage of the sample with a melancholic diagnosis (64%), whereas the SMPI-SR assigned the smallest percentage with a melancholic diagnosis (37%). DSM-IV assignment was associated with the fewest number of validating variables, whilst SMPI-CR and independent clinician diagnosis were associated with the greatest number of differentiating variables including negative childhood experiences, past and recent stressors, satisfaction with life and perceived social support. These comparative analyses provide further support for the SMPI-CR in identifying and discriminating melancholic depression from non-melancholic depression. Replication of these findings in other samples with independent raters is recommended.


[Buflomedil and the speed of glycolysis. Note I].
An in vitro study was conducted into the speed of glycolysis is human erythrocytes. Incubation with Buflomedil does not change the speed of glycolysis.


Demographic and clinical feature disparity between progress and non-progress patients with vitiligo after COVID-19 vaccination: A cross-sectional study.
There have been several case reports regarding newly developed vitiligo following the coronavirus disease 19 (COVID-19) vaccination. However, the relationship between COVID-19 vaccine and vitiligo progression remains unclear. To explore the relationship between COVID-19 vaccine and vitiligo progression and its potential influencing factors, A cross-sectional study was conducted on 90 patients with vitiligo who received inactivated COVID-19 vaccination. Detailed information covering demographic characteristics (age and sex), vitiligo clinical features (disease subtypes, duration, stage and comorbidities) and disease activity was collected through an electronic questionnaire. Ninety patients with vitiligo included 44.4% males, with an average age of 38.1 years (standard deviation, SD = 15.0). Patients were divided into progress group (29, 32.2%) and normal group (61, 67.8%) based on whether they experienced vitiligo progression after inactivated COVID-19 vaccination. 41.3% of patients in the progress group experienced vitiligo progression within 1 week after vaccination, and disease progression mainly occurred after the first dose inoculation (20, 69.0%). Logistic regression revealed that patients aged <45 years (odds ratio (OR) was 0.87, 95% confidence interval (CI): 0.34-2.22) and male patients (OR = 0.84, 95% CI: 0.34-2.05) had lower risk for vitiligo progression, while patients with segmental vitiligo (SV) subtype (OR = 1.68, 95% CI: 0.53-5.33), with <5 years disease duration (OR = 1.32, 95% CI: 0.51-3.47) had higher risk for vitiligo progression after COVID-19 vaccination, but without statistical significance. Over 30% patients experienced vitiligo progression after inactivated COVID-19 vaccination, and female patients, elder age, shorter disease duration and SV subtype are potential risk factors for vitiligo progression.


Electrical stimulation of the ventral tegmental area and catecholamine metabolism in discrete regions of the rat brain.
Data are presented which show a different pattern of dopamine and noradrenaline utilization in terminal regions of the A9 and A10 dopaminergic systems and in terminal regions of the dorsal noradrenergic bundle after electrical stimulation of the ventral tegmental area and an adjacent area. At the sites of the electrodes an enhanced turnover of noradrenaline was found. These results are discussed relating the location of the electrode sites and the location of the dopaminergic cell bodies A9 and A10 and catecholaminergic fibers passing through the MFB innervating forebrain and limbic structures. It is concluded that activation of parts of the A10 dopaminergic system and the A6 noradrenergic system is correlated with intracranial self-stimulation.


Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease.
Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.


Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model.
Fourth passage rat brain capillary endothelial cell cultures, which no longer possess the tight junctions characteristic of this highly specialized component of the blood-brain barrier, were used to study induction of zonulae occludentes in vitro. These cells, when grown in 50% rat brain astrocyte-conditioned medium and 50% alpha-MEM on an endothelial cell matrix-coated substrate (Cedarlane Labs, Hornby, Ont.), possessed numerous, elaborately complex, tight junctions which were identical to those displayed in vivo by intact brain capillary endothelium. Endothelial cells grown in 50% astrocyte-conditioned medium and 50% alpha-MEM on bare plastic or fibronectin-coated substrate, possessed no tight junctions. Results of this study clearly demonstrate the local control of tight junction biogenesis in brain capillary endothelial cells depends on: (1) an astrocyte-produced factor(s), and (2) a 'competent' (cell-produced) extracellular matrix.


Exploring the bacterial community succession and metabolic profiles of Lonicera japonica Thunb. residues during anaerobic fermentation.
Discarding Lonicera japonica Thunb. (LJT) residues containing many active metabolites create tremendous waste. This study aimed to effectively use LJT residues by anaerobic fermentation. Fermentation significantly decreased the pH values and reduced the abundance of undesirable bacteria (potential pathogenic and biofilm-forming) while increasing Lactobacillus abundance. Compound additive use further improved fermentation quality (significantly increased the lactic acid (LA) content and decreased the pH values and ammonia nitrogen (a-N) content) and nutrient quality (significantly decreased the acid detergent fiber (ADF) content and increased the water-soluble carbohydrate (WSC) content) and optimized the microbial community (increased the Lactobacillus abundance). Fermentation also altered the flavonoids, alkaloids and phenols contents in the residues with minor effects on the functional metabolites amounts. The LJT residues metabolic profile was mainly attributed to its epiphytic bacteria, with a small contribution from the compound additive. Thus, compound additives may improve anaerobic LJT residue fermentation without functionally impairing the metabolites.


Cold stress triggers freezing tolerance in wheat (Triticum aestivum L.) via hormone regulation and transcription of related genes.
Low temperatures limit the geographic distribution and yield of plants. Hormones play an important role in coordinating the growth and development of plants and their tolerance to low temperatures. However, the mechanisms by which hormones affect plant resistance to extreme cold stress in the natural environment are still unclear. In this study, two winter wheat varieties with different cold resistances, Dn1 and J22, were used to conduct targeted plant hormone metabolome analysis on the tillering nodes of winter wheat at 5 °C, -10 °C and -25 °C using an LC-ESI-MS/MS system. We screened 39 hormones from 88 plant hormone metabolites and constructed a partial regulatory network of auxin, jasmonic acid and cytokinin. GO analysis and enrichment of KEGG pathways in different metabolites showed that the 'plant hormone signal transduction' pathway was the most common. Our study showed that extreme low temperature increased the most levels of auxin, cytokinin and salicylic acid, and decreased levels of jasmonic acid and abscisic acid, and that levels of auxin, jasmonic acid and cytokinin in Dn1 were higher than those in J22. These changes in hormone levels were associated with changes in gene expression in synthesis, catabolism, transport and signal transduction pathways. These results differ from the previous hormone regulation mechanisms, which were mostly obtained at 4 °C. Our results provide a basis for further understanding the molecular mechanisms by which plant endogenous hormones regulate plant freezing stress tolerance.


Prognostic Significance of CD276 in Non-small Cell Lung Cancer.
The expression and significance of CD276 in non-small cell lung cancer (NSCLC) was explored. The BioGPS database was used to analyze the expression level of CD276 in normal tissues. Studies on the expression of CD276 in NSCLC patients using the Oncomine database. The prognostic roles of CD276 in NSCLC was studied using the Kaplan-Meier plotter database. The BioGPS database showed CD276 expression in all the human normal tissues. Compared with normal lung tissue, CD276 gene highly expressed in NSCLC tissue at mRNA level (P<0.05). The expression level of CD276 gene was negatively correlated with overall survival (OS) of NSCLC patients. Subgroup analysis showed that CD276 expression level had a significant effect on OS of patients with lung adenocarcinoma, while in squamous cell carcinoma its expression level had no significant effect on OS. According to the information mined from the tumor gene database, CD276 mRNA was found highly expressed in NSCLC tissue and the expression of CD276 has a significant impact on survival of NSCLC patients, which provides an important theoretical basis for further study of the role of CD276 in the occurrence and development of NSCLC.


Evaluating acceptance of an electronic data management system at a tertiary care institution.
This research reports on satisfaction with the introduction of an electronic document management system in a tertiary hospital environment. A buffet of training and familiarization options were offered: one-on-one training, open house, drop-in, e-learning, classroom training, and self-study. It was found that professions differ in their pattern of satisfaction with training and they also differ in their satisfaction with both the usefulness and the ease of use of the system. Satisfaction among administrators was highest and that among nurses lowest. There was an association between attendance at the open house event and satisfaction with the system.


Machine Learning-Based Model for Predicting Prolonged Mechanical Ventilation in Patients with Congestive Heart Failure.
Mechanical ventilation (MV) is widely used to relieve respiratory failure in patients with congestive heart failure (CHF). Prolonged MV (PMV) is associated with a poor prognosis. We aimed to establish a prediction model based on machine learning (ML) algorithms for the early identification of patients with CHF requiring PMV. Twelve commonly used ML algorithms were used to build the prediction model. The least absolute shrinkage and selection operator (LASSO) regression was employed to select the key features. We examined the area under the curve (AUC) statistics to evaluate the prediction performance. Data from another database were used to conduct external validation. We screened out 10 key features from the initial 65 variables via LASSO regression to improve the practicability of the model. The CatBoost model showed the best performance for predicting PMV among the 12 commonly used ML algorithms, with favorable discrimination (AUC = 0.790) and calibration (Brier score = 0.154). Moreover, hospital mortality could be accurately predicted using the CatBoost model as well (AUC = 0.844). In the external validation, the CatBoost model also showed satisfactory prediction performance (AUC = 0.780), suggesting certain generalizability of the model. Finally, a nomogram with risk classification of PMV was shown in this study. The present study developed and validated a CatBoost model, which could accurately predict PMV in mechanically ventilated patients with CHF. Moreover, this model has a favorable performance in predicting hospital mortality in these patients.


A comparative study of the cytotoxic and genotoxic effects of cisplatin and its analogue, TNO-6, in yeast.
The antitumour drug cisplatin and its analogue, TNO-6, were studied for their cytotoxic, mutagenic and recombinagenic effects in a diploid strain (D7) of the yeast, Saccharomyces cerevisiae. It was observed that the structural change in TNO-6 resulted in reduced cytotoxicity and recombinagenicity (mitotic gene conversion) but increased mutagenic activity compared to the effects of cisplatin at equimolar concentrations. These results indicated that the mechanism through which TNO-6 damages cellular DNA is different from that of cisplatin.


Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands.
A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had K(i) values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D3 versus D2 receptor. Calculated logP values (logP=2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 K(i) value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.


Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia.
The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-/-) mice were severely obese compared with MC4R (+/-) and WT mice (body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-) was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.


Release of L-aspartate by reversal of glutamate transporters.
Aspartate is released in the brain during metabolic inhibition and can activate NMDA receptors. We compared the characteristics of aspartate and glutamate release mediated by reversed operation of GLAST glutamate transporters in salamander retinal glial cells, when high [K(+)](o) solution was applied to mimic the ionic conditions of stroke or glaucoma. In the absence of Cl(-), to isolate the transport-associated current of the transporters, reversed uptake of aspartate and glutamate had similar characteristics. Both were increased strongly by depolarisation, inhibited by the transport inhibitor TBOA (DL-threo-beta-benzyloxyaspartate), and activated in a first order manner by intracellular amino acid (in the presence of 20mM [Na(+)](i)) with an EC(50) of 0.8mM for aspartate and 2.3mM for glutamate. In stroke the extracellular pH shifts acid by around a pH unit: this reduced the release of aspartate and glutamate by reversed uptake by a factor of 8-20. The external Cl(-) concentration had only a small effect on the current associated with reversed uptake of aspartate and glutamate. Tamoxifen, which reduces amino acid release through swelling-activated anion channels in glial cells, was found to inhibit reversed uptake with an IC(50) which was >100 microM. Part of the activation of NMDA receptors which occurs in ischaemia is likely to reflect the release of aspartate by reversed uptake.


Sperm factors associated with the production of equine blastocysts by intracytoplasmic sperm injection (ICSI) using frozen/thawed semen.
Intracytoplasmic Sperm Injection (ICSI) using frozen/thawed sperm is a common procedure to obtain embryos from fertile or subfertile mares and stallions. Stallion-associated factors that impact the efficiency of ICSI have been studied less than those associated with the mare. Three experiments were conducted: Experiment 1: the effect of freezing extender composition and cryoprotectant; Experiment 2: the effect of sperm exposure to seminal plasma prior to freezing (ejaculated vs. epididymal sperm; two-freeze/thaw cycles each); and Experiment 3: the effect of sperm morphologic feature used for fertilization (normal vs. cytoplasmic droplet vs. bent tail); on the blastocyst rate after ICSI. In Experiment 1, stallion sperm was cryopreserved using commercially available extenders containing: a) 2% egg-yolk + milk + 4% glycerol (MFR5); b) 2% egg-yolk + milk + 2% glycerol + 3% methyl formamide (CMMFR5); c) 20% egg-yolk + 4.75% glycerol (LE); or d) 20% egg-yolk + 2% glycerol + 3% methyl formamide (CMLE). Sperm from each of the treatment groups were used for Piezo-driven ICSI on in vitro-matured equine oocytes (n = 321). Extender CMLE resulted in a lower cleavage rate (35%) than the other treatment groups (MFR5: 74%, CMMFR5: 62%, LE: 68%; P < 0.05). Extender MFR5 yielded a higher blastocyst rate per injected oocyte (21/82 [26%]) than the Groups LE (8/77 [10%]), CMLE (4/80 [5%]) or CMMFR5 (4/82 [5%]; P < 0.05). Extender MFR5 also yielded a higher blastocyst rate per cleaved oocyte (34%) than Groups LE, CMLE or CMMFR5 (15%, 14%, 8%; respectively P < 0.05). In Experiment 2, ejaculated (EJ) and epididymal (EPD) sperm from a fertile stallion which was initially cryopreserved in the CMLE extender, was thawed and re-cryopreserved in MFR5 extender for use in ICSI. Sperm from both groups (EJ vs. EPD) were used for ICSI on in vitro matured oocytes (n = 127). Differences were not detected for cleavage rate (EJ: 36/63 [57%] vs. EPD: 49/64 [77%]), blastocyst rate per injected oocyte (EJ: 11/63 [17%] vs. EPD: 11/64 [17%]), or blastocyst rate per cleaved oocyte (EJ: 31% vs. EPD: 22%) between treatment groups (P > 0.05). In Experiment 3, morphologically normal sperm (N), or sperm with proximal droplets (PD) or bent tails (BT), were obtained from a single fertile stallion and were used for ICSI on in vitro matured oocytes (n = 75). No differences were detected among treatment groups for cleavage rate (N: 19/25 [77%] vs. PD: 20/25 [88%] vs. BT: 18/25 [72%]), blastocyst rate per injected oocyte (N: 6/25 [24%] vs. PD: 5/25 [20%] vs. BT: 2/25 [8%]), and blastocyst rate per cleaved oocyte (N: 32% vs. PD: 23% vs. BT: 11%; P > 0.05). In conclusion, the current study indicates that freezing extender composition used for stallion sperm cryopreservation has an impact on the developmental competence of in vitro-matured equine oocytes after ICSI and in vitro culture. Furthermore, we were unable to detect differences on cleavage and blastocyst rates when performing ICSI when using: 1) ejaculated or epididymal sperm; or 2) sperm with different morphologic features. The results from the current study provide additional insight regarding stallion-related factors that should be considered when performing ICSI in horses.


Randomized controlled trial of supervised physiotherapy versus a home exercise program after hydrodilatation for the management of primary frozen shoulder.
Hydrodilatation and physiotherapy are commonly used treatments for primary frozen shoulder. Little is known about the optimal form of physiotherapy. This study reports a randomized controlled trial comparing 2 forms of physiotherapy after hydrodilatation. The null hypothesis was that there would be no difference between the 2 groups at 1 year as measured by the Oxford Shoulder Score (OSS). We randomized 41 patients undergoing hydrodilatation for primary frozen shoulder into 2 treatment groups: group 1 (n = 20) underwent supervised physiotherapy in addition to a home exercise program, and group 2 (n = 21) followed a self-directed home exercise program in isolation. Assessment was carried out by a blinded research nurse at baseline, 4 weeks, 3 months, 6 months, and 1 year. The primary outcome measure was the OSS. Other measures were range of movement, visual analog scale pain score, and EQ-5D index. There was no significant difference between the treatment groups at any time point as measured by the OSS or EQ-5D index. In group 1, the OSS improved significantly from 25.00 (95% confidence interval [CI], 21.92-28.08) at baseline to 38.29 (95% CI, 34.01-42.58; P < .0001) at 4 weeks and 43.71 (95% CI, 41.61-45.80; P < .0001) at 1 year. In group 2, the OSS improved significantly from 26.60 at baseline (95% CI, 22.50-30.70) to 40.07 (95% CI, 36.77-43.36; P < .0001) at 4 weeks and 43.00 (95% CI, 39.69-46.31; P < .0001) at 1 year. All outcome measures improved significantly from baseline to 4 weeks. In this group of patients, after a hydrodilatation procedure for the treatment of primary frozen shoulder, there was no significant difference in clinical outcomes between supervised physiotherapy in addition to a home exercise program and a self-directed home exercise program in isolation.


TBHQ alleviates pyroptosis and necroptosis in chicken alveolar epithelial cells induced by fine particulate matter from broiler houses.
Fine particulate matter (PM2.5) from poultry houses has adverse effects on the health of animals and workers. Tert-butylhydroquinone (TBHQ), an antioxidant, is widely used in feed additives. The present study investigated the effects of TBHQ on broiler house PM2.5-induced damage in chicken primary alveolar epithelial cells (AECII) extracted from 16-day-old chicken embryos using the method of differential adhesion. AECII were exposed to PM2.5 and TBHQ alone or in combination, and then, cell membrane integrity, pyroptosis, and necroptosis were detected. Our results showed that PM2.5 from broiler houses caused cell rupture and loss of cell membrane integrity. This result was confirmed by the obvious increases in lactate dehydrogenase (LDH) release and propidium iodide (PI)-positive cells compared to the control group. In addition, the intracellular reactive oxygen species (ROS) levels and the expression levels of pyroptosis-related genes (NLRP3, IL-18, IL-1β) and necroptosis-related genes (RIPK3) were also significantly enhanced. However, TBHQ significantly inhibited intracellular ROS, improved cell viability, and reduced the release of LDH and the number of PI-positive cells compared to those in the PM2.5 group. The expression levels of pyroptosis-related genes (Caspase-1, NLRP3, IL-18, IL-1β) and necroptosis-related genes (RIPK3) were also significantly decreased in the co-treatment group. In summary, these results indicated that TBHQ can alleviate PM2.5-mediated cell pyroptosis and necroptosis in chicken AECII and provide a basis for overcoming the danger that air pollutants from broiler houses pose to the health of chickens.


Successful cardiovascular risk reduction in Type 2 diabetes by nurse-led care using an open clinical algorithm.
To implement a protocol-driven, nurse-led cardiovascular risk reduction clinic using an open clinical algorithm. The primary aim of the clinic was to optimize blood pressure (BP) control; secondary aims were to reduce modifiable cardiovascular risk factors. We studied 110 people with Type 2 diabetes attending a diabetes out-patient centre at University Hospital Aintree, Liverpool. Patients taking one or more antihypertensive drugs were selected for referral to the nurse-led clinic if BP was > 140/85 mmHg; there was no age threshold. An open clinical algorithm was designed to direct the nurse on the use of antihypertensive, statin and aspirin therapy plus lifestyle advice and concordance. Thirty-one percent of patients attending for a first visit to the nurse-led clinic had BP within target when measured to British Hypertension Society standards out of the consultant clinic. Mean BP was 150/76 mmHg compared with 178/88 mmHg (P < 0.001). Subsequently, BP was reduced to 130/68 mmHg (P < 0.001), this reduction being sustained at review 9 months later (mean BP 133/67 mmHg), with 87 (79%) achieving BP <or= 140/85 mmHg. Treatment modalities were adjusted to reduce cardiovascular risk, including antihypertensive medication, lipid-lowering therapy and antiplatelet therapy. High-density lipoprotein-cholesterol improved from 1.2 +/- 0.5 mmol/l to 1.4 +/- 0.5 mmol/l (P = 0.004). The number of patients with microalbuminuria decreased from 41 (47%) to 25 (28%) (P = 0.02), with a fall in urinary albumin:creatinine ratio from 3.0 (1.3-7.9) to 1.8 (1.0-5.0) mg/mmol (P = 0.01). The number of smokers decreased from 22 (20%) to 14 (13%) (P = 0.01). Although not included as an intervention in the protocol, HbA1c improved to 8.1 +/- 1.6% from 8.7 +/- 1.6% (P < 0.001). A protocol-driven, nurse-led clinic using an open clinical algorithm can be used effectively to manage cardiovascular risk reduction in Type 2 diabetes.


Helicobacter pylori seropositivity and its association with incident all-cause and Alzheimer's disease dementia in large national surveys.
Infectious agents were recently implicated in Alzheimer's disease (AD) and etiology of other dementias, notably Helicobacter pylori. We tested associations of H. pylori seropositivity with incident all-cause and AD dementia and with AD-related mortality among US adults in a retrospective cohort study. Data from the National Health and Nutrition Surveys III, phase 1 (1988-1991) and 1999-2000 linked with Medicare and National Death Index registries, were used (baseline age ≥45 y, follow-up to 2013, Npooled = 5927). A positive association between H. pylori seropositivity and AD mortality was found in men (hazard ratioadj, pooled = 4.33, 95% confidence interval: 1.51-12.41, P = .006), which was replicated for incident AD and all-cause dementia, with hazard ratioadj, pooled = 1.45 (95% confidence interval: 1.03-2.04, P = .035) and hazard ratioadj, III = 1.44 (95% confidence interval: 1.05-1.98, P = .022), respectively. These associations were also positive among higher socioeconomic status groups. In sum, H. pylori seropositivity's direct association with AD mortality, all-cause dementia, and AD dementia was restricted to men and to higher socioeconomic status groups.


Extracranial neuroblastomas and neurological complications.
Between October 1989 and March 1997, 25 pediatric inpatients were treated for primary extracranial neuroblastoma (NB; n=20) or ganglioneuroblastoma (GNB; n=5) at the University of Istanbul, Institute of Pediatric Oncology, and these children were the subjects of this retrospective study. Seventeen (68%) of these patients experienced 19 neurological complications during the course of their disease. Fourteen had nervous system metastases or invasion. Nonmetastatic complications, including CNS infections (n=3) and new onset of seizures (n=2) secondary to metabolic encephalopathy were seen in 5 cases. By the time of the final analysis of the results, 8 of the 17 patients with neurological complications had died, 7 had either been lost to follow-up (n=4) or were in the terminal stage of their disease (n=3), and 2 were in remission. Both of the patients who were in remission had dumbbell neuroblastoma (DNB), and 1 of them, with congenital DNB, also had neurological sequelae, characterized by paraplegia and neurogenic bladder. Neurological complications occurred in 68% of NB and GNB cases. Metastatic complications were more common than nonmetastatic complications and had a poor prognosis. Neurological complications were the primary cause of mortality in this study, mortality being related to neurological complications in 63% of cases, and the final outcome was worse than expected. However, regardless of any differences in social, economic and geographic factors and different treatment protocols for NB in different pediatric oncology institutions, neurological complication rates in pediatric NB are similar in all.


Otosclerosis: relationship of spiral ligament hyalinization to sensorineural hearing loss.
The sensorineural component of a mixed hearing loss due to otosclerosis is generally accepted as due to the otosclerotic lesion. The existence of pure cochlear otosclerosis without stapes fixation has been questioned. However, we are documenting 7 such cases in a separate publication. Results of this study, which evaluates 46 temporal bones with clinical or cochlear otosclerosis, demonstrate that the degree of sensorineural loss is directly related to the amount of hyalinization of the spiral ligament. The hyalinization occurs adjacent to active otospongiotic lesions but not next to inactive otosclerotic lesions. Both types of lesions may involve the cochlear endosteum. Small channels through the endosteal bone from the lesion to the spiral ligament have been found. The hyalinization spreads laterally from these channels. The hyalinization is presumably a result of the passage of toxic substances (proteolytic enzymes) from the lesion to the ligament. Strial atrophy is most pronounced on ligaments with the greatest degree of hyalinization. Hyalinization in only one ear produces decreased hearing compared to the other ear.


Understanding the accuracy of modelled changes in freshwater provision over time.
Accurate modelling of changes in freshwater supplies is critical in an era of increasing human demand, and changes in land use and climate. However, there are concerns that current landscape-scale models do not sufficiently capture catchment-level changes, whilst large-scale comparisons of empirical and simulated water yield changes are lacking. Here we modelled annual water yield in two time periods (1: 1985-1994 and 2: 2008-2017) across 81 catchments in England and validated against empirical data. Our objectives were to i) investigate whether modelling absolute or relative change in water yield is more accurate and ii) determine which predictors have the greatest impact on model accuracy. We used the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) Annual Water Yield model. In this study, absolute values refer to volumetric units of million cubic metres per year (Mm3/y), either at the catchment or hectare level. Modelled annual yields showed high accuracy as indicated by the low Mean Absolute Deviation (MAD, based on normalised data, 0 is high and 1 is low accuracy) at the catchment (1: 0.013 ± 0.019, 2: 0.012 ± 0.020) and hectare scales (1: 0.03 ± 0.030, 2: 0.030 ± 0.025). But accuracy of modelled absolute change in water yield showed a more moderate fit on both the catchment (MAD = 0.055 ± 0.065) and hectare (MAD = 0.105 ± 0.089) scales. Relative change had lower accuracy (MAD = 0.189 ± 0.135). Anthropogenic modifications to the hydrological system, including water abstraction contributed significantly to the inaccuracy of change values at the catchment and hectare scales. Quantification of changes in freshwater provision can be more accurately articulated using absolute values rather than using relative values. Absolute values can provide clearer guidance for mitigation measures related to human consumption. Accuracy of modelled change is related to different aspects of human consumption, suggesting anthropogenic impacts are critically important to consider when modelling water yield.


Scale-free dynamics in the core-periphery topography and task alignment decline from conscious to unconscious states.
Scale-free physiological processes are ubiquitous in the human organism. Resting-state functional MRI studies observed the loss of scale-free dynamics under anesthesia. In contrast, the modulation of scale-free dynamics during task-related activity remains an open question. We investigate scale-free dynamics in the cerebral cortex's unimodal periphery and transmodal core topography in rest and task states during three conscious levels (awake, sedation, and anesthesia) complemented by computational modelling (Stuart-Landau model). The empirical findings demonstrate that the loss of the brain's intrinsic scale-free dynamics in the core-periphery topography during anesthesia, where pink noise transforms into white noise, disrupts the brain's neuronal alignment with the task's temporal structure. The computational model shows that the stimuli's scale-free dynamics, namely pink noise distinguishes from brown and white noise, also modulate task-related activity. Together, we provide evidence for two mechanisms of consciousness, temporo-spatial nestedness and alignment, suggested by the Temporo-Spatial Theory of Consciousness (TTC).


Genome Engineering Using Adeno-associated Virus: Basic and Clinical Research Applications.
In addition to their broad potential for therapeutic gene delivery, adeno-associated virus (AAV) vectors possess the innate ability to stimulate homologous recombination in mammalian cells at high efficiencies. This process--referred to as AAV-mediated gene targeting--has enabled the introduction of a diverse array of genomic modifications both in vitro and in vivo. With the recent emergence of targeted nucleases, AAV-mediated genome engineering is poised for clinical translation. Here, we review key properties of AAV vectors that underscore its unique utility in genome editing. We highlight the broad range of genome engineering applications facilitated by this technology and discuss the strong potential for unifying AAV with targeted nucleases for next-generation gene therapy.


Folic acid supplementation and preterm birth: results from observational studies.
Folic acid (FA) supplementation is recommended worldwide in the periconceptional period for the prevention of neural tube defects. Due to its involvement in a number of cellular processes, its role in other pregnancy outcomes such as miscarriage, recurrent miscarriage, low birth weight, preterm birth (PTB), preeclampsia, abruptio placentae, and stillbirth has been investigated. PTB is a leading cause of perinatal mortality and morbidity; therefore its association with FA supplementation is of major interest. The analysis of a small number of randomized clinical trials (RCTs) has not found a beneficial role of FA in reducing the rate of PTBs. The aim of this review was to examine the results from recent observational studies about the effect of FA supplementation on PTB. We carried out a search on Medline and by manual search of the observational studies from 2009 onwards that analyzed the rate of PTB in patients who received supplementation with FA before and/or throughout pregnancy. The results from recent observational studies suggest a slight reduction of PTBs that is not consistent with the results from RCTs. Further research is needed to better understand the role of FA supplementation before and during pregnancy in PTB.


Nanobiotechnology-based strategies in alleviation of chemotherapy-mediated cardiotoxicity.
The cardiovascular diseases have been among the most common malignancies and the first leading cause of death, even higher than cancer. The cardiovascular diseases can be developed as a result of cardiac dysfunction and damages to heart tissue. Exposure to toxic agents and chemicals that induce cardiac dysfunction has been of interest in recent years. The chemotherapy drugs are commonly used for cancer therapy and in these patients, cardiovascular diseases have been widely observed that is due to negative impact of chemotherapy drugs on the heart. These drugs increase oxidative damage and inflammation, and mediate apoptosis and cardiac dysfunction. Hence, nanotechnological approaches have been emerged as new strategies in attenuation of chemotherapy-mediated cardiotoxicity. The first advantage of nanoparticles can be explored in targeted and selective delivery of drugs to reduce their accumulation in heart tissue. Nanostructures can deliver bioactive and therapeutic compounds in reducing cardiotoxicity and alleviation toxic impacts of chemotherapy drugs. The functionalization of nanostructures increases their selectivity against tumor cells and reduces accumulation of drugs in heart tissue. The bioplatforms such as chitosan and alginate nanostructures can also deliver chemotherapy drugs and reduce their cardiotoxicity. The function of nanostructures is versatile in reduction of cardiotoxicity by chemotherapy drugs and new kind of platforms is hydrogels that can mediate sustained release of drug to reduce its toxic impacts on heart tissue. The various kinds of nanoplatforms have been developed for alleviation of cardiotoxicity and their future clinical application depends on their biocompatibility. High concentration level of chitosan nanoparticles can stimulate cardiotoxicity. Therefore, if nanotechnology is going to be deployed for drug delivery and reducing cardiotoxicity, the first pre-requirement is to lack toxicity on normal cells and have high biocompatibility.


Real-time prescription surveillance and its application to monitoring seasonal influenza activity in Japan.
Real-time surveillance is fundamental for effective control of disease outbreaks, but the official sentinel surveillance in Japan collects information related to disease activity only weekly and updates it with a 1-week time lag. To report on a prescription surveillance system using electronic records related to prescription drugs that was started in 2008 in Japan, and to evaluate the surveillance system for monitoring influenza activity during the 2009-2010 and 2010-2011 influenza seasons. We developed an automatic surveillance system using electronic records of prescription drug purchases collected from 5275 pharmacies through the application service provider's medical claims service. We then applied the system to monitoring influenza activity during the 2009-2010 and 2010-2011 influenza seasons. The surveillance system collected information related to drugs and patients directly and automatically from the electronic prescription record system, and estimated the number of influenza cases based on the number of prescriptions of anti-influenza virus medication. Then it shared the information related to influenza activity through the Internet with the public on a daily basis. During the 2009-2010 influenza season, the number of influenza patients estimated by the prescription surveillance system between the 28th week of 2009 and the 12th week of 2010 was 9,234,289. In the 2010-2011 influenza season, the number of influenza patients between the 36th week of 2010 and the 12th week of 2011 was 7,153,437. The estimated number of influenza cases was highly correlated with that predicted by the official sentinel surveillance (r = .992, P < .001 for 2009-2010; r = .972, P < .001 for 2010-2011), indicating that the prescription surveillance system produced a good approximation of activity patterns. Our prescription surveillance system presents great potential for monitoring influenza activity and for providing early detection of infectious disease outbreaks.


Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.
In type 1 diabetes (T1D), reactive oxygen species (ROS) and proinflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic β cells while promoting autoreactive T cell maturation. Superoxide-deficient nonobese diabetic mice (NOD.Ncf1(m1J)) are resistant to spontaneous diabetes, revealing the integral role of ROS signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-Mϕ) from NOD and NOD.Ncf1(m1J) mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-κB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1(m1J) BM-Mϕ exhibited a 2- and 10-fold decrease in TNF-α and IFN-β proinflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mϕ. Optimal expression of IFN-α/β is not solely dependent on superoxide synthesis, but requires p47(phox) to function in a NOX-independent manner to mediate type I interferon synthesis. Interestingly, MHC-II I-A(g7) expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-A(g7) downregulation. These findings suggest that defective innate immune-pattern-recognition receptor activation and subsequent decrease in TNF-α and IFN-β proinflammatory cytokine synthesis necessary for autoreactive T cell maturation may contribute to the T1D protection observed in NOD.Ncf1(m1J) mice.


Brain maturation and epilepsy.
At full term, both glutamate and gamma-amino-butyric acid (GABA) are excitatory; cortical synapses are beginning to appear, there is little myelin in the cerebral hemispheres, and long tracts hardly start to develop. Neonatal myoclonic encephalopathy can result from premature activation of N-methyl-D-aspartate (NMDA) transmission. Benign neonatal seizures and migrating partial seizures in infancy could involve excessive or premature excitability of deep cortical layers. Benign rolandic epilepsy and continuous spike waves in slow sleep are consistent with an excess of both excitatory and inhibitory cortical synapses. West and Lennox-Gastaut syndromes express age-related diffuse cortical hyperexcitability, the pattern depending on the age of occurrence; synchronization of spikes is becoming possible with maturation of the myelin. Idiopathic generalized epilepsy is itself modulated by maturation that causes frontal hyperexcitability generating myoclonic-astatic seizures, between the ages of infantile and juvenile myoclonic epilepsies. Physiological delay of hippocampo-neocortical pathways maturation could account for the delayed occurrence of mesial temporal epilepsy following infantile damage, whereas premature maturation could contribute to fronto-temporal damage characteristic of fever-induced epileptic encephalopathy in school-age children, a dramatic school-age epileptic encephalopathy.


Mental health conditions in Lesbian, Gay, Bisexual, Transgender, Queer and Asexual youth in Brazil: A call for action.
Lesbian, Gay, Bisexual, Transgender, Queer, and Asexual (LGBTQA+) youth have a greater chance of experiencing stressful life events when compared to cisgender heterosexual peers, which can lead to mental health problems. We aimed to estimate the prevalence of mental disorders among LGBTQA+ youths from two large cities in Brazil. Participants were 13-22 years old youths from the 3rd wave of the Brazilian High-Risk Cohort for Psychiatric Disorders (n = 1475). Mental disorders were assessed using the Development and Well-Being Behavior Assessment. Sexual orientation and gender identity were assessed using a self-report confidential questionnaire. Data were analyzed through logistic regressions (adjusting for sociodemographic) using sampling weights to account for attrition and our oversampling high-risk design. 15.18% of the sample described themselves as LGBTQA+. The LGBTQA+ group presented higher rates of anxiety disorders (30.14% vs. 13.37%; OR = 3.37; 95%CI:2.51-4.50), depressive disorders (27.75% vs. 15.34%; OR = 2.17; 95%CI:1.60-2.93) and post-traumatic stress disorder (4.98% vs. 2.25%; OR = 4.20; 95%CI:2.24-7.82), if compared with the cisgender heterosexual group. No difference was found for conduct disorders (2.97% vs. 5.21%; OR = 0.82; 95%CI:0.35-1.65) or attention deficit hyperactivity disorder (5.92% vs. 3.28%; OR = 1.56; 95%CI:0.83-2.79). Although recruitment was performed at 57 schools in the two cities, sampling was non-probabilistic and included only urban areas, which might bias prevalence estimates and group comparisons. Our results elucidate the mental health disparities between LGBTQA+ people and cisgender heterosexuals in Brazil. It highlights the need to promote the inclusion of this population in policy formulation and support actions to mitigate the suffering related to sexual orientation and gender identity.


Are teachers at higher risk of HIV infection than the general population in Burkina Faso?
In order to assess the human immunodeficiency virus (HIV) prevalence among teachers in Burkina Faso, we carried out a national survey in 336 primary and secondary schools from urban and rural areas. Among 2088 teachers who agreed to participate, 1498 (71.7%) provided urine for HIV testing. The crude prevalence of HIV among teachers was 2.8% (95% confidence interval [CI]: 2.0-3.6), with no difference between teachers from primary schools (2.9%, 95%CI: 2.1-4.0) and those from secondary schools (2.5%, 95%CI: 0.5-4.5). Age- and area-standardized HIV prevalence was 1.0% (95%CI: 0.4-1.2) in male teachers, 2.5 times lower than among men in the general population (as assessed from a concomitant Demographic Health Survey), and it was 3.5% (95%CI: 2.5-5.2) in female teachers, 1.7 times higher than in Demographic Health Survey women. This finding calls for the implementation of specific HIV prevention programmes in the education sector targeting women more specifically.


Evaluation of the proacrosin/acrosin system and its mechanism of activation in human sperm extracts.
Acrosin is an acrosomal protease synthesized as a proenzyme and activated into beta-acrosin during the acrosome reaction. In the present study, a set of sensitive assays was developed to identify the proacrosin/acrosin system and to evaluate its activation pattern in human sperm extracts. Immunocytochemical analysis with monoclonal antibody (Mab) AcrC5F10 showed specific staining on the acrosome of permeabilized ejaculated and capacitated spermatozoa. Acrosome reaction was associated with a decrease in staining. AcrC5F10 specifically recognized a 55-kDa band (proacrosin) in Western immunoblots. Activation studies showed enzymatically active intermediates of 39 and 35 kDa after zymography. Immunoreactive bands of 52, 43, 34, 21-26 and 16 kDa were identified in the activation patterns developed with AcrC5F10. Activation was completely inhibited in the presence of 9 mM CaCl(2) or 100 mM benzamidine. A multiple sequence alignment revealed partial conservation of putative cleavage sites in the proacrosin sequence. The tests described allow the detection of human proacrosin in spermatozoa and sperm protein extracts, as well as the evaluation of the proenzyme activation pattern. They can be used to study the effect of inhibitors upon proenzyme activation. In addition, alterations in proacrosin activation in semen samples with abnormal acrosin enzymatic activity can be analyzed using these assays.


Horst Otto Stoeckel: Clinician, Administrator, Researcher.
Horst Otto Stoeckel was born September 26, 1930, in Lodz, Poland, which was part of the newly founded Second Republic of Poland until it was occupied by Nazi Germany in 1939. After World War II, his family immigrated to Meiningen, Germany, where he obtained his primary and secondary education. He attended Humboldt University and the University Hospital Charité of Berlin for his medical degree. Profs Theodor Brugsch, Karl Lohmann, and Friedrich Dost were important individuals who helped develop his interest in quantitative clinical pharmacology and pharmacokinetics. Prior to anesthesiology, Stoeckel trained in surgery, internal medicine, and obstetrics and gynecology in addition to clinical anesthesiology at a community hospital in East Germany. He completed 2 years of obligatory training to become an anesthesia specialist at the Teaching Hospital Hufeland and the Research Institute for Lung Diseases at Berlin-Buch. He also received training in anesthesia at the Humboldt University of Berlin. After escaping East Berlin through the Brandenburg Gate in August 1961, he obtained a position at the University of Heidelberg and obtained his West German board certification in anesthesiology in 1962. In the following 12-year period, Stoeckel was married, was promoted, passed his "habilitation" or lectureship period, started a family, and was granted the title of "Professor." His administrative career began in February 1974 when he was selected as the first Chair of Anesthesiology at the University of Bonn, a position he held for 22 years. He also served as Dean of the medical school from 1980 to 1981. As Chair, he developed three areas: patient care, teaching, and research. He developed a long-term research program in the field of "Quantitative Clinical Pharmacology in Anesthesia and the Quantitative Modeling and Control in Anesthesia," which required an interdisciplinary team of specialists in biochemistry, physics, and modern analytical methods. Over 20 years, the group's research program led to the discovery of basic algorithms providing the foundation of the automatic regulation of dosing control by the closed-loop feedback system, which is a concept important to the target-controlled infusion of intravenous and inhalation anesthetics. Following his career as a clinician, administrator, and researcher, he pursued a second career as a collector and museum founder.


Receptive fields in the body-surface map in adult cortex defined by temporally correlated inputs.
Receptive fields (RFs) obtained at specific cortical sites can be used to define a topographic map of the body surface in adult mammalian somatosensory cortex. This map is not static, and RFs at particular cortical sites can change in size and location throughout adult life. Conversely, the cortical loci at which a given skin surface is represented can shift hundreds of micrometres across the cortex in the koniocortical field, area 3b (refs 1-12). This plasticity suggests that RFs derive not from rigid anatomical connections, but by the selection of a subset of a large number of inputs. We have proposed that inputs are selected on the basis of temporal correlation 11-15. Here we test this idea by altering the correlation of inputs from two adjacent digits on the adult owl monkey hand by surgically connecting the skin surfaces of the two fingers (the formation of syndactyly). This manipulation increases the correlation of inputs from skin surfaces of adjacent fingers. The striking discontinuity between the zones of representation of adjacent digits on the somatosensory cortex disappeared. These results support the hypothesis that the topography of the body-surface map in the adult cortex is influenced by the temporal correlations of afferent inputs.


Antiviral Drugs for Viral Pneumonia.
How to cite this article: Bansal T. Antiviral Drugs for Viral Pneumonia. Indian J Crit Care Med 2023;27(8):600.


Sparteine as an anticonvulsant drug: Evidence and possible mechanism of action.
Sparteine is a quinolizidine alkaloid extracted from Lupinus that has numerous pharmacological properties both in humans and animal models. In the central nervous system, sparteine reduces locomotor activity, has light analgesic effects, also has no effects on short-term memory or spatial learning and does not induce changes in behavior or electroencephalographic (EEG) activity. However, the anticonvulsant profile of sparteine is not fully characterized in experimental animals and there are no data in humans. Therefore, the present review focuses on the experimental evidence supporting the anticonvulsant action of sparteine in models of acute seizures and status epilepticus (SE), as well as its possible mechanisms of action. The evidence that supports the anticonvulsant effect of (-)-Sparteine sulfate includes the inhibition of seizures induced by maximal electro-stimulation, a delay in the onset of convulsive behavior and the prolongation of survival time in mice treated with pentylenetetrazole (PTZ). Additionally, sparteine delays the onset of convulsive behavior and decreases the severity and mortality of rats treated with PTZ and pilocarpine. Sparteine decreases amplitude and frequency or blocks the epileptiform activity induced by PTZ, pilocarpine and kainic acid. Sparteine may decrease hyperexcitability through the activation of the M2 and M4 subtypes of mAChRs, which is a probable mechanism of action that together with its systemic effects may favor its anticonvulsant effects against seizures and SE.


Pain assessment tools for use in infants: a meta-review.
Identifying pain in infants is challenging due to their inability to self-report pain, therefore the availability of valid and reliable means of assessing pain is critical. This meta-review sought to identify evidence that could guide the selection of appropriate tools in this vulnerable population. We searched Scopus, Medline, Embase, CINAHL, MIDRIS, EMCare and Google Scholar for eligible systematic reviews. Eligible reviews documented psychometric properties of available observational tools used to assess pain in infants. A total of 516 reviews were identified of which 11 met our inclusion criteria. We identified 36 pain assessment tools (evaluated in 11 reviews) of which seven were reported in at least three reviews. The level of evidence reported on the psychometric properties of pain assessment tools varied widely ranging from low to good reliability and validity, whilst there are limited data on usability and clinical utility. Currently, no observer administered pain assessment tool can be recommended as the gold standard due to limited availability and quality of the evidence that supports their validity, reliability and clinical utility. This meta-review attempts to collate the available evidence to assist clinicians to decide on what is the most appropriate tool to use in their clinical practice setting. It is important that researchers adopt a standard approach to evaluating the psychometric properties of pain assessment tools and evaluations of the clinical utility in order that the highest level of evidence can be used to guide tool selection.


Plasma skin resurfacing: personal experience and long-term results.
This article presents a comprehensive clinical approach to plasma resurfacing for skin regeneration. Plasma technology, preoperative protocols, resurfacing technique, postoperative care, clinical outcomes, evidence-based results, and appropriate candidates for this procedure are discussed. Specific penetration depth and specific laser energy measurements are provided. Nitrogen plasma skin regeneration is a skin-resurfacing technique that offers excellent improvement of mild to moderate skin wrinkles and overall skin rejuvenation. It also provides excellent improvement in uniformity of skin color and texture in patients with hyperpigmentation with Fitzpatrick skin types 1 through 4.


Size does matter: cre-mediated somatic deletion efficiency depends on the distance between the target lox-sites.
Cre/lox recombination in vivo has become an important tool to induce chromosomal rearrangements like deletions. Using a combination of Ds transposition and Cre/lox recombination in two independent experiments on chromosomes 6 and 7 of tomato, two sets of somatic deletions up to a size of 200 kb were obtained. The efficiency of somatic deletion decreased with increasing deletion size. The largest germinally transmitted deletion had a size of only 55 kb. The results show that Cre-mediated deletion in somatic cells is less efficient when the lox sites are separated over larger distances. A further drop of the deletion efficiency after germinal transmission of the larger deletions can be explained by the probable loss of genes that are of vital importance to gametophyte function. Plasmid rescue of an 8.4 kb circularised deleted DNA showed that the Cre-mediated deletion takes place in tomato as expected. Since the circular Cre-deleted DNA could only be PCR amplified in plant cells where the deletion was not complete, the double-stranded DNA circle is assumed to be instable.


Atrial septal defect and pulmonary hypertension in professional soccer player.
This study reports a rare case of late diagnosis of atrial septal defect (ASD) with pulmonary hypertension (PH) through two-dimensional echocardiography (ECHO) in a professional soccer player who resumed high-performance sports activity after surgery.


Characterizing jasmonate regulation of male fertility in Arabidopsis.
Coordination of events leading to fertilization of Arabidopsis flowers is tightly regulated, with an essential developmental cue from jasmonates (JAs). JAs coordinate stamen filament elongation, anther dehiscence, and pollen viability at stage 12 of flower development, the stage immediately prior to flower opening. Characterization of JA-biosynthesis and JA-response mutants of Arabidopsis, which usually have a complete male sterility phenotype, has contributed to the understanding of how JAs work in these reproductive processes. These mutants have also been fundamental to the identification of JA-dependent genes acting in male reproductive tissues that accomplish fertilization. The list of JA-dependent genes continues to grow, as does the necessity to characterize novel JA mutant and related transgenic plants. It is therefore instructive to place these genes and mutants in the framework of established JA responses. Here, we describe the phenotypic characterization of flowers that fail to respond to the JA signal. We also measure gene expression in male reproductive tissues of flowers with the aim of identifying their role in JA-dependent male fertility.


A world overview--one-hundred-twenty-seven years of research on toxic cyanobacteria--where do we go from here?
CyanoHABs are an intermittent but repeated occurrence throughout the world. They have been documented to impact water quality through production of compounds affecting taste and odor. Selected species within about 40 genera can produce potent toxins that can cause chronic, acute and acute lethal poisonings to wild and domestic animals and humans. Direct and indirect evidence indicates that the incidence, duration and intensity of CyanoHABs is increasing throughout the world, due largely to a decline in the quality of water supplies. While significant effort has gone into defining the chemistry and toxicology of cyanotoxins, a worldwide effort from scientists and environmental agencies to map their occurrence and environmental health risk is needed. An unprioritized listing for those efforts is suggested below (Ramsdell et al. (eds.) 2005): 1. Improved Ability to Detect HAB Species and Analyze CyanoHAB Toxins. 2. Improved Capability for Monitoring and Forecasting CyanoHABs in a Cost Effective and Timely Manner. 3. Improved Protection of Human Health. 4. Improved Protection of Endangered Species and Improved Ecological Health. 5. Improved Prevention and Mitigation Strategies. 6. Improved Economic Cost Estimates of CyanoHAB Events. 7. Improved Economics for Aquaculture and Shellfish Safety. 8. An Educated and Informed Public.


Exploration of multifaceted molecular mechanism of angiotensin-converting enzyme 2 (ACE2) in pathogenesis of various diseases.
Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.


Estimating Total Labor Input for Supporting Informed Economic Policy Decisions.
The article provides the methodology for assessing the total labor input in the economy on the basis of a symmetric input-output table. The main directions of its use in modern economics are outlined taking into account the surveyed world experience. The study presents an analysis of estimates of total labor costs in the Russian economy calculated industry-by-industry.


Effect of oxygen pressure during culture on survival of mouse thyroid allografts.
A marked increase in the percentage of mouse thyroids that retained function 20 days after transplantation across a major histocompatibility barrier and the percentage that lacked generalized infiltration was observed when the grafts received hyperbaric oxygen during a 4-day culture period. Perfusion of the donor animal before thyroidotomy and the addition of fetal calf serum to the culture medium did not have a significant effect on graft survival, but the percentage of grafts lacking generalized infiltration was slightly increased by the addition of hydrocortisone to the culture medium.


Effects of widely used drugs on micronutrients: a story rarely told.
Vitamins and trace elements are essential to the body, however, deficiencies are frequently observed in the general population. Diet is mostly responsible for these deficiencies but drugs also may play a significant role by influencing their metabolism. These effects are rarely assessed in clinical practice, in part because of limited data available in the literature. Drug-induced micronutrient depletions, however, may be the origin of otherwise unexplained symptoms that might sometimes influence medication compliance. We present various examples of widely prescribed drugs that can precipitate micronutrient deficiencies. This review aims at sensitizing physicians on drug-micronutrient interactions. High-risk population groups also are presented and supplementation protocols are suggested.


On acoustic fields of complex scatters based on physics-informed neural networks.
This paper proposes a modeling method for scattered acoustic fields under complex structures based on Physics-informed Neural Networks (PINNs), with particular attention to the acquisition of training sets and the embedding of physical governing equations. First, using acoustic simulation softwares to obtain the scattered acoustic field under various models, and select the scattered acoustic field data at several moments as the training sets. Then, according to the characteristics of the simulated model, the corresponding physical equations have been embedded in the loss function of the network. We tested the method by predicting the propagation of ultrasonic waves and the scattering of acoustic fields with various simple scatterers. Furthermore, we also use PINN to simulate the scattered acoustic field of the real complex damaged structure. The results show that the mean square error (MSE) between prediction and ground truth is in the order of 10-4, which illustrate PINN can effectively simulate the propagation and reflection of ultrasonic waves, and can also simulate the scattered acoustic field of complex structures accurately. The meshless and accurate characteristics of PINN provide a reliable alternative for the theoretical prediction of complex and continuous scattered acoustic fields.


[Clinical and genetic analysis of a rare case with mosaic partial trisomy 5p syndrome].
To determine the size and origin of a small supernumerary marker chromosome (sSMC) identified in a patient featuring developmental retardation. High-throughput sequencing for copy number variation (CNV-seq) was carried out to delineate the sSMC identified upon G-banded chromosomal karyotyping. The genotype-phenotype correlation was explored by database retrieval and literature analysis. The patient was found to have a karyotype of mos 47,XX,+mar[36]/46,XX[23]. CNV-seq has identified a 18 Mb duplication at 5p14.1-p12 (hg19: 27,399,261-46,083,784)x2.6 with a mosaicism rate of approximately 60%. Patients with mosaic partial trisomy 5p may have extensive clinical manifestations, and the ratio of trisomy 5p cells is correlated with clinical severity of this syndrome.


Glycoprotein hormones tied but not tethered like other cysteine-knot cytokines.
A new crystal structure of the pituitary glycoprotein human follicle-stimulating hormone (hFSH) in complex with a fragment of the human FSH receptor (hFSHR(1-250)) ectodomain has been determined. The hFSH receptor is a Class A rhodopsin-like G-protein-coupled receptor (GPCR). The structure serves as a template for the modeling of the related luteinizing hormone (LH) and thyroid-stimulating hormone (TSH) receptors and explains why these hormones do not cross-react with the FSH receptor. Unexpectedly, the FSH receptor ectodomain in complex with FSH is a dimer but, unlike other cysteine-knot cytokines, FSH does not participate in a receptor-receptor tether. A host of biochemical data can now be placed in the context of the new structure, and will provide new insights that could lead to the development of small-molecule contraceptives and more-active or bifunctional versions of hormones for FSH receptor and other related receptors.


Comprehensive properties of a novel fiber reinforced composite with a UEDMA-based resin matrix.
The traditional fiber reinforced composite (FRC) contains bisphenol A glycidyl methacrylate (bis-GMA) in the resin matrix, which is thought to have some disadvantages. This research aimed at replacing bis-GMA with another monomer-urethane dimethacrylate (UEDMA), with the desired properties for dental use still retained. Four groups were prepared with light-curing (n = 30), one Control group with a bis-GMA-based resin matrix and three experimental groups with UEDMA-based matrices (Exper 1, Exper 2 and Exper 3 with a varying UEDMA weight percentage). Specimens were stored in dry conditions for 24 h or in deionized water for 1, 3, 6 or 12 months prior to the tests. Water sorption (n = 6), Vicker's hardness (n = 6) and flexural properties (n = 6) after each storage time were investigated. Scanning electron microscopy (SEM) images were taken at the fracture sites after 3-point bending. All the results were statistically analyzed (α = 0.05). The Exper 1 group exhibited the lowest weight increase after water storage among the experimental groups. As for dry conditions, 1- and 6-month storage, different resin matrix compositions made no significant difference to hardness, while for 3- and 12-month storage, "Control" possessed the highest hardness. The Control group's strength and modulus, Exper 1 and Exper 2's modulus were stable during water storage. Compared to other experimental groups, Exper 1 had the highest strength and modulus values with most of the storage times. SEM images showed relatively good adhesion between the fiber and the matrix. With all the tested properties considered, the Exper 1 group had superior performance among all the three experimental groups.


Bacteriological Profile of Chronic Rhinosinusitis and Adenotonsillitis: Evaluating the Role of Biofilm Production and Multidrug Resistance.
There is significant evidence that the etiology of chronic otorhinolaryngology infections such as chronic rhinosinusitis, adenotonsillitis, and otitis media depends on biofilms. As biofilm-forming bacteria can be resistant to the immune system, antibiotics, and other treatments, biofilm infections are often chronic. To identify the genus and species of the clinical isolates obtained from the swabs collected from the patients with chronic infections of the nasal and paranasal sinus, nasopharynx, and oropharynx and to evaluate phenotypic and genotypic methods for the detection of biofilms and antimicrobial resistance among the isolated organisms. A total of 100 patients with chronic rhinosinusitis and adenotonsillitis participated in this study. Various clinical samples from the nasal cavity, nasopharynx, and oropharynx were obtained and subjected to microbiological analysis and biofilm-forming capacity by three methods: tube methods, Congo red staining, and microtiter plate method. The various specific genes were amplified by polymerase chain reaction. The amplified gene products were separated by gel electrophoresis. This was a prospective cohort study conducted on a total of 100 patients with chronic rhinosinusitis and adenotonsillitis. The age of the study participants was between 7 and 53 years with a mean age of 29.22 ± 15.03. This study included 54 (54%) nasal tissue samples and 46 (46%) adenotonsillar tissue. The frequently cultured organisms are coagulase-negative staphylococci (17%), E. coli (10%), Citrobacter (10%), and Klebsiella (7%). Staphylococcus aureus (4), and Methicillin-resistant Staphylococcus aureus (3) produced strong biofilm. Acenobacter (3), Citrobacter (4), and E. coli (4) showed moderate biofilm production. Coagulase-negative Staphylococcus aureus (11), E. coli (6), and Klebsiella (7) showed weak biofilm formation. Citrobacter (6), and Coagulase negative Staphylococcus aureus (6) were negative for biofilm production. Staphylococcus aureus expressed mecA gene (3) and Panton-Valentine Leukocidin gene (2), Pseudomonas expressed mucA gene (2), Citrobacter expressed blaCARB-2 (4) qnrA gene (2), E. coli expressed bla SHV (2) and bla TEM1 gene (2) and Klebsiella expressed Kfu (2) and uge (1). Acenobacter was negative for blaIMP1, blaVIM2 genes. This study adds to the information on the common pathogens-forming biofilms in various nasal pathologies and adenotonsillitis. The knowledge that a particular organism has a higher biofilm-forming capacity will help to sensitize the physician that factors such as biofilms may be at play and take appropriate measures.


[Apoptosis-modulating effects of heat shock proteins: the influence of Hsp27 chaperone on TBA Bcl-2 family proteins in Jurkat cell line].
The in vitro phosphorylated and non-phosphorylated Hsp27 forms concentrations and Bcl-2 proteins affected by Hsp27 inhibition were studied in Jurkat-line tumor cells and healthy donor mononuclear lymphocytes by Western blotting technique. The Hsp27 inhibition causes the increase of intracellular Bax protein concentration and the decrease of Bcl-2 level leading to an increase of apoptotic changes in Jurkat line cells.


Expression of hepatic UDP-glucuronosyltransferase 1A1 and 1A6 correlated with increased expression of the nuclear constitutive androstane receptor and peroxisome proliferator-activated receptor alpha in male rats fed a high-fat and high-sucrose diet.
Rats that consumed a high-fat and high-sucrose (HF1) diet or a high-fat (HF2) diet developed hepatic steatosis. The alteration in nutritional status affected hepatic cytochrome P450 and UDP-glucuronosyltransferase (UGT) levels. Messenger RNA and protein levels of UGT1A1 and UGT1A6 in the liver but not the jejunum were increased in male rats fed the HF1 diet. These protein levels did not increase in HF2-fed male rats or HF1-fed female rats. In contrast, the CYP1A2 protein level was decreased in the HF1 but not HF2 diet group, whereas CYP2E1 and CYP4A protein levels were elevated in the HF2 but not HF1 diet group. No significant difference in the organic anion transporter polypeptide (Oatp) 1, Oatp2, multidrug resistance-associated protein (Mrp) 2, or Mrp3 protein levels was found between the standard and HF1 diet groups of male rats. Consumption of the HF1 diet affected the in vivo metabolism of acetaminophen (APAP) such that the area under the APAP-glucuronide plasma concentration-time curve was elevated 2.1-fold in male rats but not female rats. In liver cell nuclei of male rats but not female rats, constitutive androstane receptor (CAR) and proliferator-activated receptor alpha (PPARalpha) protein levels were significantly enhanced by intake of the HF1 diet. Additionally, administration of the PPARalpha agonist clofibrate to male rats up-regulated UGT1A1 and UGT1A6 and down-regulated CYP1A2 in the liver. Taken together, these results indicate that nutritional status may gender-specifically influence the expression and activation of CAR and PPARalpha in liver cell nuclei, and this effect appears to be associated with alterations in UGT1A1 and UGT1A6 expression.


Thousand and one ways to quantify and compare protein abundances in label-free bottom-up proteomics.
How to process and analyze MS data to quantify and statistically compare protein abundances in bottom-up proteomics has been an open debate for nearly fifteen years. Two main approaches are generally used: the first is based on spectral data generated during the process of identification (e.g. peptide counting, spectral counting), while the second makes use of extracted ion currents to quantify chromatographic peaks and infer protein abundances based on peptide quantification. These two approaches actually refer to multiple methods which have been developed during the last decade, but were submitted to deep evaluations only recently. In this paper, we compiled these different methods as exhaustively as possible. We also summarized the way they address the different problems raised by bottom-up protein quantification such as normalization, the presence of shared peptides, unequal peptide measurability and missing data. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans-Peter Mock.


An online technique for estimating cerebral carbon dioxide reactivity.
A technique for measuring cerebral reactivity using transcranial pulsed Doppler ultrasound is described; the system includes a spectrum analyser and capnometer. Data acquisition and manipulation is under software control. Main stem middle cerebral artery blood velocity is monitored continuously using the transcranial Doppler technique, whilst the operator initiates data collection and controls the inspired gas composition. The calculation of cerebral CO2 reactivity is based upon linear regression analysis of normalized, time-averaged middle cerebral velocity on end-tidal pCO2 and is displayed graphically. Measurement of middle cerebral CO2 reactivities can be completed within 15 min. Results from two subjects, a healthy volunteer and a patient with occlusive disease, are shown to illustrate the technique.


Effects of Al on the splenic immune function and NE in rats.
Norepinephrine (NE) regulates the splenic immune function and it may be related to the effects of Aluminum (Al) on the splenic immune function. Here, the aim of this study was to further explore the effects of aluminum trichloride (AlCl3) on the splenic immune function and its relationship with NE. Forty male Wistar rats were orally exposed to AlCl3 (0, 64.18, 128.36 and 256.72 mg/kg BW) through drinking water for 120 days. The CD3(+), CD4(+), CD8(+) T lymphocytes, the T and B lymphocytes proliferation rates and serum NE concentration were examined. The correlation analysis between splenic immune function and NE were done. The results showed that the CD3(+), CD4(+), CD8(+) T lymphocytes and the T and B lymphocytes proliferation rates decreased and NE concentration increased in AlCl3-treated rats. NE was negatively correlated with proportions of CD3(+), CD4(+) T lymphocytes and T and B lymphocytes proliferation rates, but not correlated with CD8(+) T lymphocytes. The results suggest that AlCl3 suppresses the splenic immune function and NE plays important role in this process.


Preparation of β-Hydroxyketones (Aldols) from the Alkylation of O-Silyl Aryl Cyanohydrins with Epoxides.
β-Hydroxyketones (aldols) are prepared from the alkylation-deprotection of O-silylated aryl cyanohydrins with epoxides. Key to the success of the method was the suppression of an in situ cyclic imidate formation that occurs upon initial opening of the epoxide ring.


Characterization of the structure and self-assembly of two distinct class IB hydrophobins.
Hydrophobins are small proteins secreted by fungi that accumulate at interfaces, modify surface hydrophobicity, and self-assemble into large amyloid-like structures. These unusual properties make hydrophobins an attractive target for commercial applications as emulsifiers and surface modifying agents. Hydrophobins have diverse sequences and tertiary structures, complicating attempts to characterize how they function. Here we describe the atomic resolution structure of the unusual hydrophobin SLH4 (86 aa, 8.4 kDa) and compare its function to another hydrophobin, SC16 (99 aa, 10.2 kDa). Despite containing only one charged residue, SLH4 has a similar structure to SC16 yet has strikingly different rodlet morphology, propensity to self-assemble, and preferred assembly conditions. Secondary structure analysis of both SC16 and SLH4 suggest that during rodlet formation residues in the first intercysteine loop undergo conformational changes. This work outlines a representative structure for class IB hydrophobins and illustrates how hydrophobin surface properties govern self-assembly, which provides context to rationally select hydrophobins for applications as surface modifiers. KEY POINTS: • The atomic-resolution structure of the hydrophobin SLH4 was determined using nuclear magnetic resonance spectroscopy. • The structure of SLH4 outlines a representative structure for class IB hydrophobins. • The assembly characteristics of SLH4 and SC16 are distinct, outlining how surface properties of hydrophobins influence their function.


The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis.
Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in their absence; this dual capacity ensures that cell growth is restricted to the correct paracrine environment and is thereby strictly controlled. Recently our laboratory demonstrated that c-Myc-induced apoptosis requires the CD95 death receptor pathway and that insulin-like growth factor (IGF-1) signalling suppresses this killing. To investigate further the links between c-Myc and IGF-1 pathways in CD95-induced apoptosis, we examined the effects of c-Myc and a downstream IGF-1 survival kinase, Akt, on killing mediated by CD95 and its recruited effector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-caspase-8, which narrows the point at which c-Myc exerts its action downstream of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8. These results restrict the possible mechanisms by which CD95-induced apoptosis is modulated by death signals and survival factors.


Exploring the link between cancer policies and cancer survival: a comparison of International Cancer Benchmarking Partnership countries.
Cancer policy differences might help to explain international variation in cancer survival, but empirical evidence is scarce. We reviewed cancer policies in 20 International Cancer Benchmarking Partnership jurisdictions in seven countries and did exploratory analyses linking an index of cancer policy consistency over time, with monitoring and implementation mechanisms, to survival from seven cancers in a subset of ten jurisdictions from 1995 to 2014. All ten jurisdictions had structures in place to oversee or deliver cancer control policies and had published at least one major cancer plan. Few cancer plans had explicit budgets for implementation or mandated external evaluation. Cancer policy consistency was positively correlated with improvements in survival over time for six of the seven cancer sites. Jurisdictions that scored the highest on policy consistency had large improvements in survival for most sites. Our analysis provides an important first step to systematically capture and evaluate what are inherently complex policy processes. The findings can help guide policy makers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes.


Dabigatran etexilate is efficacious in consumptive coagulopathy and pain associated with venous malformations.
Consumptive coagulopathy treatment and pain management are crucial for patients with venous malformations (VMs). Dabigatran etexilate, a non-vitamin K antagonist oral anticoagulant, has known advantages compared with low-molecular-weight heparin and vitamin K antagonists, including oral administration, a more consistent pharmacokinetics/pharmacodynamics profile, a better safety profile, and no need for coagulation surveillance. In the present study, we tested the efficacy and safety of dabigatran etexilate for consumptive coagulopathy treatment and pain management for patients with VMs. To investigate the efficacy and safety of dabigatran etexilate in treating localized intravascular coagulation (LIC) associated with VM, we retrospectively collected data for 19 outpatients with VM and LIC, who had been treated with dabigatran etexilate from September 2019 to June 2021. The patients provided oral informed consent and underwent biologic blood testing, routine examinations, and determination of coagulation function before and after treatment. The dosage of dabigatran etexilate was 110 mg twice daily for adults and 55 mg twice daily for children. All 19 patients had benefited from dabigatran etexilate treatment with coagulation improvement and pain relief. Pain had improved in all 16 evaluable patients. The fibrinogen and D-dimer levels had improved in 18 of 19 patients. The fibrin degradation product level had improved in 10 of 14 patients. None of patients reported lesion regression, appearance changes, or improvement in mobility. No significant differences were found in the D-dimer, fibrinogen, and fibrin degradation product levels between the short-term (<10 days) and long-term (≥10 days) use of the medication. Dabigatran etexilate was well tolerated by all patients. No bleeding event had occurred during follow-up. The results of our study have confirmed the efficacy and safety of dabigatran etexilate in treating pain and LIC in patients with VMs. Dabigatran etexilate is a suitable choice preoperatively to modify coagulation function and pain in patients with VMs.


Can early household exposure influence the development of rhinitis symptoms in infancy? Findings from the PARIS birth cohort.
Allergic rhinitis (AR) has become the most prevalent chronic allergic disorder in childhood, and the role of environment has been questioned, particularly in early life. To investigate the risk factors for rhinitis symptoms in infants included in the PARIS (Pollution and Asthma Risk: an Infant Study) birth cohort. Infants were invited to participate at age 18 months in a health examination conducted by a pediatrician. Allergic rhinitis was defined as the presence of rhinitis symptoms (runny nose, blocked nose, sneezing in the absence of a cold) combined with biological atopy (elevated total immunoglobulin E [IgE], specific IgE, or eosinophilia) and nonallergic rhinitis (NAR) as symptoms without biological atopy. Information about indoor exposures and lifestyle was collected during a telephone interview when the child was 1 month of age. Risk factors for AR and NAR were studied by using a polytomous regression model. The prevalence of AR and NAR was 70/1,850 (3.8%) and 99/1,850 (5.4%), respectively. Allergic rhinitis and NAR did not share similar risk factors. Male sex (odds ratio [OR] = 1.99 [1.19-3.32]), parental history of AR (OR = 1.89 [1.16-3.08]), low socioeconomic class (OR = 2.23 [1.05-4.72] for low vs high level), and the presence of cockroaches in the home (OR = 3.15 [1.67-5.96]) were risk factors for AR. Conversely, the presence of particle-board furniture less than 12 months old in the child's bedroom was associated with an increased risk of NAR (OR = 1.87 [1.21-2.90]). This study should raise awareness about the impact of indoor exposures, particularly with regard to cockroaches and particle-board furniture, because they could influence the occurrence of noninfectious rhinitis.


Effect of Statewide Social Distancing and Stay-At-Home Directives on Orthopaedic Trauma at a Southwestern Level 1 Trauma Center During the COVID-19 Pandemic.
To compare orthopaedic trauma volume and mechanism of injury before and during statewide social distancing and stay-at-home directives. Retrospective. Level 1 trauma center. One thousand one hundred thirteen patients sustaining orthopaedic trauma injuries between March 17 and April 30 of years 2018, 2019, and 2020. Statewide social distancing and stay-at-home directives. Number of consults, mechanism of injury frequency, and type of injury frequency. During the COVID-19 pandemic, orthopaedic trauma consult number decreased. Injuries due to gunshot wounds increased and those due to automobile versus pedestrian accidents decreased. Time-to-presentation increased and length of stay decreased. Operative consults remained unchanged. Orthopaedic trauma injuries continued to occur during the COVID-19 pandemic at an overall decreased rate, however, with a different distribution in mechanism and type of injury. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Vocational experiences and career support opportunities among Canadian men with moderate and severe haemophilia.
The purpose of this research was to provide haemophilia treatment centres (HTCs) with guidance for the potential development of appropriate and timely interventions related to employment and vocational counselling and supports. A multi-method approach was employed, where initial focus groups (n = 13) and review of the literature were used to construct a structured survey instrument (n = 75). Focus group participants made choices about employment with keen awareness of how their bleeding disorder might limit them physically; they described the role of social networks in career choices; and they wrestled with issues of disclosure. Among survey respondents, 47% per cent of respondents reported that haemophilia had a small negative impact, 27% felt that it had a moderate negative impact and 13% indicated that it had a very large negative impact. One-third of respondents had at some point received employment-related advice from a member of their haemophilia treatment centre team. Roughly two-thirds of respondents suggested that vocational advice would be "somewhat" or "very" useful at present. Canadian men with haemophilia continue to experience challenges related to employment and career development. There appears to be an opportunity for HTCs to incorporate additional supports on these topics into the range of services which they currently provide.


Safety assessment of hydroxypropyl methylcellulose as a food ingredient.
Hydroxypropyl methyl cellulose (HPMC; CAS No. 9004-65-3) is an odorless and tasteless, white to slightly off-white, fibrous or granular, free-flowing powder that is a synthetic modification of the natural polymer, cellulose. It is used in the food industry as a multipurpose food ingredient. HPMC is approved by FDA as both a direct and an indirect food additive, and is approved for use as a food additive by the EU. The JECFA has evaluated the food uses of HPMC and established an acceptable daily intake (ADI) of 'not specified' for such uses. Based on the no-observed-adverse-effect level (NOAEL) of 5000 mg/kg body weight/day from a 90-day feeding study in rats, a tolerable intake for ingestion of HPMC by humans of 5 mg/kg body weight/day is posited and, as such, is more than 100-fold greater than the estimated current consumption of 0.047 mg/kg body weight/day.


Metabolic analysis of canine peripheral blood mononuclear cells treated ex vivo with dexamethasone.
In dogs, hyperadrenocorticism (HAC) is associated with insulin resistance and diabetes does progress with HAC. There are significant differences in the transcriptomic and proteomic patterns of activated T cells, which parallel the findings in muscle tissues. The aim of this study was to assess how glucocorticoids affect intracellular metabolites in canine peripheral blood mononuclear cells (CnPBMCs) using dexamethasone. A total of 96 metabolites were identified by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). After incubation with dexamethasone, the metabolites glucose 1-phosphate, glucose 6-phosphate, fructose 6-phosphate, sedoheptulose 7-phosphate and acetyl-CoA were significantly increased. However, ATP, CTP, dATP, pyruvic acid and NADP(+) were significantly decreased. These results show that a glucocorticoid reduces the catabolic reaction of glucose and accordingly decreases the glucose requirements of CnPBMCs.


Concordance between glomerular filtration rate estimation equations and 4-hour urinary creatinine clearance in critically ill patients with severe trauma.
There is a growing body of evidence that the equations used to estimate the glomerular filtration rate (GFR) are not suitable in critically ill patients, a population whose GFR fluctuates continuously. Glomerular filtration is usually estimated by measuring urine creatinine clearance (CrCl) at various time points. The aim of our study was to evaluate the performance of the most widely used GFR calculators in the subpopulation of critically ill patients admitted for severe trauma, and to compare the results against determinations of CrCl in urine collected over a 4-h period (4h-CrCl). Observational study in patients hospitalized for severe trauma. We measured the 4h-CrCl and estimated GFR using the Cockcroft-Gault, modified Jelliffe, MDRD, t-MDRD, and CKD-EPI equations, adjusting the results for body surface area (BSA) (ml/min/1.73m2). Data were analysed using R version 4.0.4. A total of 85 patients were included. Median age was 51 years, and 68 were men (78.82%). The mean BSA-adjusted 4h-CrCl (4h-ClCr/1.73m2) was 84.5 ml/min/1.73m2. We found that GFR estimated using the t-MDRD equation correlated significantly with 4h-CrCl/1.73m2. The Cockcroft-Gault equation correlated significantly with 4h-CrCl/1.73m2 when GFR was greater than 130ml/min/m2. In ICU patients, glomerular filtration can be reliably estimated by determining urine CrCl, but GFR calculators are not accurate in this population.