A combined clinical and histological assessment of survival of patients with Hodgkin's disease.
This paper reviews a series of 246 patients with Hodgkin's disease treated in the Royal Air Force Medical Service between 1940 and 1966. The clinical and histological staging of the disease in relation to the survival time is evaluated. The variation in the clinical patterns of the disease, together with the histological appearances in the affected glands, can be related to the patient's defence system. A most important clinical factor in assessing prognosis is considered to be the presence or absence of constitutional symptoms. The majority of the patients who had constitutional symptoms on presentation also had many glands involved. It was found in those patients who had no constitutional symptoms at the onset of the disease that there was little difference in survival time between those with glands involved in a single group or region and those with glands involved in many regions, whether above and/or below the diaphragm. Those patients with histologically well differentiated lesions showed a significantly higher survival rate than those in the histologically poorly differentiated groups.


Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: the role of acid-base equilibria.
The recently declared global pandemic of a new human coronavirus called SARS-CoV-2, which causes respiratory tract disease COVID-19, has reached worldwide resonance and global efforts are being made to look for possible cures. Sophisticated molecular docking software, as well as available protein sequence and structure information, offer the ability to test the inhibition of two important targets of SARS-CoV-2, furin (FUR) enzyme, and spike glycoprotein, or spike protein (SP), that are key to host cell adhesion and hijacking. The potential inhibitory effect and mechanism of action of acid-base forms of different antiviral drugs, dominant at physiological pH, chloroquine (CQ), hydroxychloroquine (HCQ), and cinanserin (CIN), which have been shown to be effective in the treatment of SARS-CoV-2 virus, is reported with the special emphasis on their relative abundances. On the other hand, the potential inhibitory effect of the dominant acid-base forms of quercetin (Q) and its oxidative metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H) benzofuranone (BZF), which are constituents of traditional food products believed to exhibit antiviral effects, was also examined. The undertaken study includes the determination of the major energy contributions to the binding energy as well as in-depth analysis of amino acid residues at the active pocket and possible interactions. The approach that we propose here may be an additional strategy for combating the deadly virus by preventing the first step of the virus replication cycle. Preliminary research has shown that the investigated compounds exert an inhibitory effect against the SARS-CoV-2 furin enzyme and spiked glycoprotein through different acid-base forms. These investigations may be helpful in creating potential therapeutic agents in the fight against the SARS-CoV-2 virus. On the other hand, the results we predicted in this computational study may be the basis for new experimental in vitro and in vivo studies.


A novel gedunin-2-hydroxypropyl-β-cyclodextrin inclusion complex improves anti-nociceptive and anti-inflammatory activities of gedunin in rodents.
Gedunin is a bioactive compound, obtained from Entandrophragma angolense (EA), which has limited therapeutic usefulness due to poor aqueous solubility and first-pass effects. Cyclodextrins are cyclic oligosaccharides that form complexes with poorly soluble compounds, thus enhancing their pharmacological activity. In this article, we evaluated the pharmacological activities of gedunin-2-hydroxypropyl-β-cyclodextrin complex (GCD) in rodents. The antinociceptive activity of GCD (50, 100, 200 mg/kg) and Gedunin (50mg/kg) was tested in acetic acid-induced writhing and formalin-induced paw licking in mice. The anti-inflammatory activity was investigated in carrageenan-induced paw oedema and air pouch inflammation models in rats. Leucocytes counts, Tumour Necrosis Factor-alpha (TNF-α) level, nitric oxide, malondialdehyde, reduced glutathione, and myeloperoxidase enzyme activities were assessed in the air pouch exudate. The GCD (200mg/kg) significantly decreased writhing response, reduced licking duration and decreased oedema compared with gedunin and control. Exudate volume and leucocyte count were significantly reduced by GCD (200 mg/kg), it decreased myeloperoxidase activity and inhibited TNF-α release. The carrageenan-induced GSH depletion, increased malondialdehyde and nitrite levels were significantly reversed by GCD (200 mg/kg) relative to gedunin and control. The GCD complex demonstrated significant antinociceptive and anti-inflammatory activities relative to gedunin alone via mechanisms associated with inhibition of oxidative stress and inflammation in rodents.


Testing of Verbal Fluency in Egyptians: Cultural and Educational Challenges.
The importance of verbal fluency tasks as a cornerstone in cognitive assessment is now well acknowledged, as they provide fast, reliable tools for assessment of both verbal and executive function abilities. To investigate the effect of age and education on verbal fluency and to develop a verbal fluency task that is culture-oriented and non-education-based to overcome the problem of illiteracy in Egypt. Two groups of participants were recruited, a normal cognition control group (n=79) and a clinically demented group (n=32). Phonemic verbal fluency was tested by asking participants to generate as many words as they could think of starting with the Arabic letter Haa; category fluency was evaluated using four semantic categories (animals, fruits, vegetables, and names). Animal, vegetable, and name fluency tasks (unlike phonemic fluency and fruit) were not related to age and education, and they had better criterion validity (area under the receiver operating characteristic curve [AUC]=0.96, 0.91, and 0.92, respectively) than did letters and fruits (AUC=0.74 and 0.86, respectively). Our suggested cutoff points are 11 for the animal fluency task (sensitivity=94%, specificity=93%), 11 for vegetables (sensitivity=84%, specificity=88%), and 18 for names (sensitivity=91%, specificity=82%). Animals, vegetables, and names are reliable and appropriate categories to be used for culture-oriented and non-education-based verbal fluency tests.


Naphthalimide-Based Fluorophore for Soft Anionic Interface Monitoring.
A naphthalimide-based low-molecular-mass fluorophore (NA) was designed and synthesized by introducing an azetidine unit onto the aromatic ring of the compound as an electron-donating structure, and a hydrophilic (2-(2-aminoethyl-amino)ethanol) moiety into the "N-imide site" of the core structure. UV-vis absorption and fluorescence measurements revealed that the fluorophore is soluble in water and shows a fluorescent quantum yield of ∼20% and lifetime of ∼3.7 ns in the solvent within a wide pH range. Moreover, the fluorescence emission and anisotropy of the fluorophore as produced are both dependent upon the viscosity and polarity of the medium. Further studies demonstrated that NA can be used as a selective probe to monitor the aggregation of anionic surfactants owing to its accumulation onto the anionic surfaces of the aggregates as formed. Inspired by the discovery, NA was successfully applied for detection of cell membranes and E. coli via monitoring of their negatively charged surfaces, which is important for fast checking of biological contamination of water. Importantly, all the tests could be performed in a visualized manner. We believe that the new, low-molecular-mass fluorophore as created may find applications in chemical and biochemical sensing and imaging.


Mouse retina explants after long-term culture in serum free medium.
The neonatal mouse retina remains viable as an explant in serum-supplemented growth media for more than 4 weeks. Interpretation of drug effects on this tissue is compromised by the enigmatic composition of the serum. We sought to remove this ambiguity by culturing neonatal as well as late postnatal mouse retina in serum-free nutrient medium. In this study three important observations were made, (1) there is histotypic development of neonatal as well as preservation of late postnatal mouse retinal structure during long-term culture in serum-free medium, although the late postnatal tissue tends to show some loss of cells in the outer nuclear layer. (2) Protein expression in explant photoreceptor cells was similar to that in the litter-matched ones, except for green cone opsin and interphotoreceptor retinoid-binding protein, although mRNA of the latter is present at similar amounts as in age-matched in vivo controls. (3) Cells of the inner retina stained by antibodies to calcium-binding proteins display some novel sprouting of processes. The results show that the mouse retina can be cultured as an explant for more than 4 weeks in a serum-free medium. This represents an important step forward because, (1) the possibility of interference of drug effects by unknown serum factors has been eliminated; and (2) the spent culture medium can be analyzed to investigate biomolecules released by the retina in vitro.


Total anomalous pulmonary venous connection in 80 patients: Primary sutureless repair and outcomes.
Total anomalous pulmonary venous connection (TAPVC) is a rare but critical cardiac anomaly, in which pulmonary veins are connected to an abnormal location rather than the left atrium. The prognosis can be extremely poor without intervention, with a mortality of 80% during infancy. The purpose of this research is to summarize the outcomes and relevant risk factors of 80 total anomalous pulmonary venous connection (TAPVC) patients who underwent primary TAPVC sutureless repair and discuss the indications and benefits of primary sutureless repair. This retrospective review included 80 patients with TAPVC who underwent primary sutureless repair at a single institution between January 2015 and December 2020. Patients were subdivided into 4 groups according to Darling's classification. Risk factors that increase the postoperative pulmonary vein flow velocity were explored by Multiple Linear regression. Anatomic TAPVC subtypes included supracardiac 35 (43.8%), cardiac 24 (30%), infracardiac 17 (21.2%), and mixed 4 (5%). Median age at repair was 16.5 days and median weight was 3.5 kg. Preoperative pulmonary venous obstruction (PVO)was presented in 20 (25%) patients. There were 2 early deaths and 1 late death. 2 patients developed postoperative PVO and none required reintervention. Prolonged cardiopulmonary bypass time (CPB) (p = 0.009), preoperative pneumonia (p = 0.022) and gender (p = 0.041) were found to be associated with the increase of postoperative pulmonary vein flow velocity. Under the primary sutureless technique, no statistical difference was observed among the 4 subgroups in terms of postoperative pulmonary vein flow velocity (p = 0.589). The primary sutureless technique may eliminate the differences between subtypes while decrease the postoperative PVO rate, which makes it applicable in any subtypes of TAPVC. Following the favorable outcomes in preventing postoperative PVO in all subtypes in this study, we advocate the indications for primary sutureless repair may expand further to all the TAPVC patients.


Delayed Stroke after Aneurysm Treatment with Flow Diverters in Small Cerebral Vessels: A Potentially Critical Complication Caused by Subacute Vasospasm.
Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.


Effects of lunar cycle on fasting plasma glucose, heart rate and blood pressure in type 2 diabetic patients.
The purpose of this study was to investigate the influence of lunar phases on fasting plasma glucose, heart rate, and blood pressure in type 2 diabetic patients. The present cross-sectional study was carried out during four phases, i.e., full moon (FM), first quarter (FQ), new moon (NM), and third quarter (TQ), of the lunar month. The study was conducted on 42 randomly selected patients (22 males and 20 females) from the Diabetes Clinic of Calcutta Medical College. Fasting plasma glucose (FPG) of each subject was determined and heart rate (HR) and blood pressure (BP) were measured at rest and during static exercise conditions, i.e., performance of a standard handgrip dynamometer test. The FPG level during the NM and FM was significantly higher (p < .001) than during the TQ and FQ for both males and females, respectively. The mean HR during static exercise during the NM and FM for both males and females was significantly higher than that during the FQ (p < .05) and TQ (p < .01). It appears from the present study that lunar phases may affect fasting plasma glucose level and cardiovascular functions of aged type 2 diabetic patients both at rest and during exercise.


BAP37 and Prohibitin are specifically recognized by an SV40 T antigen antibody.
We have identified two cellular proteins that are specifically immunoprecipitated by an anti-SV40 T antigen monoclonal antibody. This antibody, PAb419, recognizes an epitope contained within a region of T antigen which we have recently demonstrated is required for the initiation of immortalization by SV40 T antigen, but is not essential for maintenance of the immortal state. The two proteins were identified as BAP37 and Prohibitin. Recent results suggest Prohibitin may enhance the transcriptional inactivation of E2F by the retinoblastoma family of pocket proteins (pRb, p107, p130). BAP37 and Prohibitin are specifically recognized by PAb419 and PAb210, another anti-SV40 T antigen monoclonal antibody, which has an overlapping epitope, but not by other anti-SV40 T antigen monoclonal antibodies, demonstrating the specificity of the interaction.


Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder.
Bipolar disorders (BDs) exhibit high heritability and symptoms typically first occur during late adolescence or early adulthood. Affected individuals may experience alternating bouts of mania/hypomania and depression, with euthymic periods of varying lengths interspersed between these extremes of mood. Clinical research studies have consistently demonstrated that BD patients have disturbances in circadian and seasonal rhythms, even when they are free of symptoms. In addition, some BD patients display seasonal patterns in the occurrence of manic/hypomanic and depressive episodes as well as the time of year when symptoms initially occur. Finally, the age of onset of BD symptoms is strongly influenced by the distance one lives from the equator. With few exceptions, animal models useful in the study of BD have not capitalized on these clinical findings regarding seasonal patterns in BD to explore molecular mechanisms associated with the expression of mania- and depression-like behaviors in laboratory animals. In particular, animal models would be especially useful in studying how rates of change in photoperiod that occur during early spring and fall interact with risk genes to increase the occurrence of mania- and depression-like phenotypes, respectively. Another unanswered question relates to the ways in which seasonally relevant changes in photoperiod affect responses to acute and chronic stressors in animal models. Going forward, we suggest ways in which translational research with animal models of BD could be strengthened through carefully controlled manipulations of photoperiod to enhance our understanding of mechanisms underlying seasonal patterns of BD symptoms in humans. In addition, we emphasize the value of incorporating diurnal rodent species as more appropriate animal models to study the effects of seasonal changes in light on symptoms of depression and mania that are characteristic of BD in humans.


Validation over time of a nomogram including HER2 status to predict the sentinel node positivity in early breast carcinoma.
The molecular subtypes of breast cancer have different axillary status. A nomogram including the interaction covariate between estrogen receptor (ER) and HER2 has been recently published (Reyal et al. PLOS One, May 2011) and allows to identify the patients with a high risk of positive sentinel lymph node (SLN). The purpose of our study was to validate this model on an independent population. We studied 755 consecutive patients treated at Institut Curie for operable breast cancer with sentinel node biopsies in 2009. The multivariate model, including age, tumor size, lymphovascular invasion and interaction covariate between ER and HER2 status, was used to calculate the theoretical risk of positive sentinel lymph node (SLN) for all patients. The performance of the model on our population was then evaluated in terms of discrimination (area under the curve AUC) and of calibration (Hosmer-Lemeshow HL test). our population was significantly different from the training population for the following variables: median tumor size in mm, lymphovascular invasion, positive ER and age. The nomogram showed similar results in our population than in the training population in terms of discrimination (AUC=0.72 [0.68-0.76] versus 0.73 [0.7-0.75] and calibration (HL p=0.4 versus p=0.35). Despite significant differences between the two populations concerning variables which are part of the nomogram, the model was validated in our population. This nomogram is robust over time to predict the likelihood of positive SLN according to molecular subtypes defined by surrogate markers ER and HER2 determined by immunohistochemistry in clinical practice.


Familial malignant osteopetrosis in children: a case report.
The clinical, radiological, pathological and laboratory findings of two brothers with autosomal recessive malignant osteopetrosis are presented. Our findings are similar to characteristics previously reported in the literature about patients with osteopetrosis. The 6-year-old male patient was pale and had petechiae on his arms and legs. He also had macrocephalia, splenomegaly, severe pancytopenia, genu valgus, hypocalcemia, amaurosis, cessation of physical development, generalized bone sclerosis and recurrent infections with a history of multiple incidences of acute otitis media. Generalized bone sclerosis and irregular sclerosis of the maxilla and mandible were seen on radiographs. The oral mucosa was apparently normal but permanent tooth eruption was delayed although there was early loss of deciduous teeth. The recommended treatment was blood transfusion and therapy with antibiotics when necessary; a bone marrow transplant was not possible due to lack of a compatible donor.


Rate of severe ovarian damage following surgery for endometriomas.
There is growing and consistent evidence showing that ovarian reserve is affected following surgical excision of ovarian endometriomas. Of particular concern is the risk of severe ovarian damage leading to unresponsiveness to ovarian hyperstimulation. In this study, we aimed to determine the rate of this complication. Ninety-three women underwent surgery for monolateral endometriomas were recruited. Patients who underwent IVF were selected and, in all cases, follicular growth was monitored by serial transvaginal ultrasonography. The main outcome measure was the rate of ovaries remaining silent when stimulated after surgery for endometriomas. Absence of follicular growth was observed in 12 operated ovaries although this event never occurred in the contralateral gonad (P < 0.001). The frequency (95% confidence interval) of severe ovarian damage following surgery was 13% (7-21%). Severe ovarian damage, occurring in gonads operated on for ovarian endometriomas, is not a rare event.


The relationship between L2 motivation and transformative engagement in academic reading among EAP learners: Implications for reading self-regulation.
This study examined the relationship between L2 motivation and engagement in academic reading skill from the lenses of L2 motivational self-system and transformative experience. More specifically, following the transformative experience (TE) framework, we investigated the level of students' engagement in academic reading skills inside and outside English classes. We also explored what motivational factors act as strong predictors of transformative experience and whether L2 motivation and engagement of students differ across different disciplines. Stratified purposive sampling was followed to recruit 419 undergraduate English for academic purposes (EAP) students studying in different majors. As such, we developed a questionnaire for measuring TE and utilized a pre-established questionnaire to operationalize L2 motivational self-system. We found that L2 motivation significantly covaried with students' level of engagement in English academic reading skill. Furthermore, the results of multiple regression analysis revealed that L2 learning experience and ideal L2 self were strong predictors of transformative engagement; ought-to L2 self played a marginal role in the occurrence of TE. Discipline-wise, Life Sciences students were considerably more motivated than those in Arts and Humanities. However, no significant difference was observed in the extent of transformative engagement among students across disciplinary groups. Implications for EAP instructors, educational authorities, and material and curricula developers are discussed.


Smoking: Its Impact on Urologic Health.
Tobacco use remains the single largest preventable cause of disease and premature death in the United States, and smoking is a leading cause of cancer and death from cancer. There is also evidence that smoking is associated with several urologic diseases. Urologists have a unique opportunity to help our patients lead healthy lifestyles, which includes ending their dependence on nicotine and tobacco. This article points out the various urologic conditions associated with smoking and tobacco use with the intention of providing physicians and patients with knowledge and education regarding this connection.


Association of polybrominated diphenyl ethers in two fat compartments with increased risk of insulin resistance in obese individuals.
Polybrominated diphenyl ethers (PBDEs), a widely utilized class of flame retardants in various commercial products, represent a prominent source of environmental contaminants. PBDEs tend to accumulate in adipose tissue, potentially altering the function of this endocrine organ and increasing risk of insulin resistance. The aim of this study was to compare levels of PBDEs in adipose tissues from two metabolically distinct obese groups; the insulin sensitive (IS) and the insulin resistant (IR). Levels of 28 PBDE congeners were assessed in subcutaneous and omental adipose tissues from 34 obese Qatari individuals (11 IS and 23 IR) using gas chromatography (Trace GC Ultra) coupled to a TSQ Quantum triple Quadrupole mass spectrometer. Correlations of identified PBDEs and mediators of metabolic disease were established and effects of PBDEs treatment on insulin signaling in primary omental preadipocytes were determined. Out of 22 detectable PBDEs in subcutaneous and omental adipose tissues, PBDEs 28, 47, 99 and 153 were predominant in omental adipose tissues from obese Qatari subjects. PBDEs 99, 28, and 47 were significantly higher in IR individuals compared to their IS counterparts. Significant positive correlations were identified between PBDEs 28 and 99 in the omental tissues and with fasting insulin levels. When considering PBDEs congeners, penta congeners were also higher in IR compared to IS individuals, while no significant differences were detected in mono, tri, tertra, hexa, hepta and octa congeners between the two studied groups. Treatment of human omental preadipocytes from insulin sensitive individuals with PBDE28 caused inhibition of phosphorylation of GSK3 α/β (Ser21/Ser9), mTOR (Ser2448), p70 S6 kinase (Thr389) and S6 ribosomal protein (Ser235/Ser236) and activation of PTEN (Ser380) phosphorylation, suggesting inhibition of insulin signaling. This pilot data suggests that accumulation of specific PBDEs in human adipose tissues is associated with insulin resistance in obese individuals. Further investigation of the functional role of PBDEs in the pathology of insulin resistance should help developing therapeutic strategies targeting obese individuals at higher risk.


The value of routine pH monitoring in the diagnosis and treatment of laryngopharyngeal reflux.
To assess the need for pH testing in diagnosing laryngopharyngeal reflux (LPR). Case series with planned data collection. Tertiary care center. On the basis of symptoms and/or abnormal endoscopic findings, more than 500 patients underwent 24-hour pharyngeal pH testing at a single center (using the Dx-pH probe) between January 2009 and June 2011. A total of 163 patients not on proton-pump inhibitors at the time of study and with complete data available for analysis (pH results, body mass index, smoking status, pretest reflux symptom index) were divided into 2 groups by positive (n = 70) and negative (n = 93) Ryan Score. The Reflux Symptom Index (RSI) was compared between groups and assessed overall against Ryan Score parameters at different pH thresholds. The diagnostic utility of an RSI ≥ 13 for prediction of Ryan Score was assessed. No significant difference in RSI was seen between Ryan-positive (17.50 ± 11.47) and Ryan-negative (14.95 ± 11.43) patients (P = .161). Overall, RSI correlated poorly with percentage time spent below pH thresholds 6.5, 6.0, 5.5, and 5.0 and upright and supine Ryan parameters at these thresholds (as determined by linear regression analysis). The sensitivity, specificity, positive predictive value, and negative predictive value of RSI ≥ 13 for Ryan positivity were 55.7%, 47.3%, 44.3%, and 58.7%, respectively. Our findings show that in our population of otolaryngology patients, the diagnosis of LPR cannot be reliably made on the basis of symptoms alone. Diagnosis, and in particular treatment decisions, should ideally be made on the basis of a combination of symptoms, signs, and confirmatory testing.


Susceptibility to type 1 diabetes is associated with ApoCIII gene haplotypes.
Type 1 diabetes is a disease of beta-cell destruction leading to insulin deficiency. Genes for type 1 diabetes have been identified; however, much of the genetic risk remains unexplained. Genetic variation within the apolipoprotein CIII (apoCIII) gene alters apoCIII levels, which are increased in type 1 diabetes and induce beta-cell apoptosis. We therefore hypothesize haplotypes within the apoCIII gene are associated with type 1 diabetes. DNA from 584 type 1 diabetic patients and 591 control subjects were genotyped for six single nucleotide polymorphisms (SNPs) in the apoCIII gene (C-641A, C-482T, T-455C, C1100T, C3175G, and T3206G). Two alleles of a haplotype block (promoter SNPs + C3175G) were associated with type 1 diabetes. The A-T-C-C allele frequency was higher in type 1 diabetes (0.19 vs. 0.16, P = 0.05), and the C-C-T-C allele was reduced in type 1 diabetes (0.60 vs. 0.65, P = 0.04). The odds ratio (OR) for A-T-C-C allele increased with 0, 1, and 2 copies (OR of 1.00, 1.24, and 1.60, respectively; P = 0.05) and decreased for the C-C-T-C allele (1.00, 0.97, and 0.73, respectively; P = 0.03). This haplotype block contains an insulin response element. Screening for this haplotype may identify at-risk individuals, and this pathway may offer a target for prevention of type 1 diabetes.


Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?
COVID-19 has rapidly become a pandemic worldwide, causing extensive and long-term health issues. There is an urgent need to identify therapies that limit SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Unbalanced lung inflammation is a common feature in severe COVID-19 patients; therefore, reducing lung inflammation can undoubtedly benefit the clinical manifestations. Histamine H1 receptor (H1 receptor) antagonists are widely prescribed medications to treat allergic diseases, while recently it has emerged that they show significant promise as anti-SARS-CoV-2 agents. Here, we briefly summarize the novel use of H1 receptor antagonists in combating SARS-CoV-2 infection. We also describe the potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. Finally, the opportunities and challenges of the use of H1 receptor antagonists in managing COVID-19 are discussed.


Risk Factors Based on Analysis of Injury Mechanism and Protective Equipment for Ice Hockey Amateur Players.
Considering the increasing popularity of ice hockey in South Korea, types of injuries and protective equipment for amateur club members need to be further studied. The purpose of the study is to investigate various injuries and protective equipment used by amateur players and to analyze different risk factors by collecting information on areas of injury and their mechanisms. The online survey for 102 participants was designed to address the general information of participants, types of injuries, information about ice hockey equipment, and open-ended questions about injuries and equipment. We conducted in-depth face-to-face interviews with five players about their experiences with injury and opinions about the protective equipment. In total, 60% of the survey participants had experienced injuries, including to the knee (22.6%), shoulder (21.6%), ankle (20.6%), and wrist (14.7%), in order of frequency. Types of injury included sprain (33.3%), contusion (31.4%), fracture (17.7%), abrasion (10.8%), and concussion (0.9%). Injury mechanisms included instances in which those with less proficiency in skating would be injured initially from player-to-player contact, and from landing on the ice or crashing into the fence afterward. We acknowledged how important wearing correctly sized equipment is for protection, and we highlighted the need to develop protective gear that accommodates Asian body measurements.


The social brain network and autism.
Available research data in Autism suggests the role of a network of brain areas, often known as the 'social brain'. Recent studies highlight the role of genetic mutations as underlying patho-mechanism in Autism. This mini review, discusses the basic concepts behind social brain networks, theory of mind and genetic factors associated with Autism. It critically evaluates and explores the relationship between the behavioral outcomes and genetic factors providing a conceptual framework for understanding of autism.


The seasonal activity and the effect of mechanical bending and wounding on the PtCOMT promoter in Betula pendula Roth.
In this study, 900-bp (signed as p including nucleotides -1 to -886) and partly deleted (signed as dp including nucleotides -1 to -414) COMT (caffeate/5-hydroxyferulate O-methyltransferase) promoters from Populus tremuloides Michx. were fused to the GUS reporter gene, and the tissue-specific expression patterns of the promoters were determined in Betula pendula Roth along the growing season, and as a response to mechanical bending and wounding. The main activity of the PtCOMTp- and PtCOMTdp-promoters, determined by the histochemical GUS assay, was found in the developing xylem of stems during the 8th-13th week and in the developing xylem of roots in the 13th week of the growing season. The GUS expression patterns did not differ among the xylem cell types. The PtCOMT promoter-induced GUS expression observed in phloem fibres suggests a need for PtCOMT expression and thus syringyl (S) lignin synthesis in fibre lignification. However, the PtCOMTdp-promoter induced GUS expression in stem trichomes, which may contribute to the biosynthesis of phenylpropanoid pathway-derived compounds other than lignin. Finally, a strong GUS expression was induced by the PtCOMT promoters in response to mechanical stem bending but not to wounding. The lack of major differences between the PtCOMTp- and PtCOMTdp-promoters suggests that the deleted promoter sequence (including nucleotides -415 to -886) did not contain a significant regulatory element contributing to the GUS expression in young B. pendula trees.


Investigation of respirable coal mine dust (RCMD) and respirable crystalline silica (RCS) in the U.S. underground and surface coal mines.
Dust is an inherent byproduct of mining activities that raises notable health and safety concerns. Cumulative inhalation of respirable coal mine dust (RCMD) and respirable crystalline silica (RCS) can lead to obstructive lung diseases. Despite considerable efforts to reduce dust exposure by decreasing the permissible exposure limits (PEL) and improving the monitoring techniques, the rate of mine workers with respiratory diseases is still high. The root causes of the high prevalence of respiratory diseases remain unknown. This study aimed to investigate contributing factors in RCMD and RCS dust concentrations in both surface and underground mines. To this end, a data management approach is performed on MSHA's database between 1989 and 2018 using SQL data management. In this process, all data were grouped by mine ID, and then, categories of interests were defined to conduct statistical analysis using the generalized estimating equation (GEE) model. The total number of 12,537 and 9050 observations for respirable dust concentration are included, respectively, in the U.S. underground and surface mines. Several variables were defined in four categories of interest including mine type, geographic location, mine size, and coal seam height. Hypotheses were developed for each category based on the research model and were tested using multiple linear regression analysis. The results of the analysis indicate higher RCMD concentration in underground compared to RCS concentration which is found to be relatively higher in surface coal mines. In addition, RCMD concentration is seen to be higher in the Interior region while RCS is higher in the Appalachia region. Moreover, mines of small sizes show lower RCMD and higher RCS concentrations. Finally, thin-seam coal has greater RCMD and RCS concentrations compared to thicker seams in both underground and surface mines. In the end, it is demonstrated that RCMD and RCS concentrations in both surface and underground mines have decreased. Therefore, further research is needed to investigate the efficacy of the current mass-concentration-based monitoring system.


Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody-Induced Cell Dissociation in Pemphigus Vulgaris.
Pemphigus vulgaris (PV) is a potentially lethal autoimmune disease characterized by blister formation of the skin and mucous membranes and is caused by autoantibodies against desmoglein (Dsg) 1 and Dsg3. Dsg1 and Dsg3 are linked to keratin filaments in desmosomes, adhering junctions abundant in tissues exposed to high levels of mechanical stress. The binding of the autoantibodies leads to internalization of Dsg3 and a collapse of the keratin cytoskeleton-yet, the relevance and interdependence of these changes for loss of cell-cell adhesion and blistering is poorly understood. In live-cell imaging studies, loss of the keratin network at the cell periphery was detectable starting after 60 min of incubation with immunoglobulin G fractions of PV patients (PV-IgG). These rapid changes correlated with loss of cell-cell adhesion detected by dispase-based dissociation assays and were followed by a condensation of keratin filaments into thick bundles after several hours. Dsg3 internalization started at 90 min of PV-IgG treatment, thus following the early keratin changes. By inhibiting casein kinase 1 (CK-1), we provoked keratin alterations resembling the effects of PV-IgG. Although CK-1-induced loss of peripheral keratin network correlated with loss of cell cohesion and Dsg3 clustering in the membrane, it was not sufficient to trigger the internalization of Dsg3. However, additional incubation with PV-IgG was effective to promote Dsg3 loss at the membrane, indicating that Dsg3 internalization is independent from keratin alterations. Vice versa, inhibiting Dsg3 internalization did not prevent PV-IgG-induced keratin retraction and only partially rescued cell cohesion. Together, keratin changes appear very early after autoantibody binding and temporally overlap with loss of cell cohesion. These early alterations appear to be distinct from Dsg3 internalization, suggesting a crucial role for initial loss of cell cohesion in PV.


Neurobiology and the natural history of schizophrenia.
Schizophrenia follows a fairly consistent natural history and longitudinal course of illness, and it can be described in the context of four specific clinical stages-the premorbid, prodromal, deterioration, and chronic/residual stages. Many patients treated in their first episode of schizophrenia respond well to treatment and achieve some symptom remission and level of recovery, but recurrent episodes, often brought on by treatment nonadherence or insufficient treatment, lead to more substantial and lasting neurologic deterioration. This presentation describes the clinical stages of schizophrenia and discusses the possibility for prevention of clinical deterioration with early detection and treatment of the illness and sustained maintenance treatment after episodic remission.


No evidence for loss of alleles at 11p in HBV negative hepatocellular carcinomas.
The aim of the present study was to determine whether loss of DNA sequences at the chromosome arm 11p, where presumed tumor suppressor genes are located, might occur in hepatocellular carcinomas (HCCs) of hepatitis B virus (HBV) negative patients. Normal liver and HCC genotypes were compared at 6 loci on 11p with 7 polymorphic probes detecting 10 restriction length polymorphisms (RFLPs). Each of the 8 paired normal-tumor tissue samples was informative for at least three different loci on 11p13-pter. None of them showed loss of constitutional heterozygosity for those markers. The retainment of 11p alleles suggests that mechanisms other than loss of tumor suppressor genes on llp are involved in hepatocarcinogenesis of HBV negative patients.


[Current modalities of mechanical ventilation for acute respiratory failure in chronic respiratory insufficiency].
Acute respiratory failure in patients with chronic obstructive lung disease is a frequent and serious complication, with a mortality rate of 20 p. 100 and 57 p. 100 of the patients kept under mechanical ventilation for more than two weeks. The main problem with mechanical ventilation is an unavoidable intrinsic positive expiratory pressure and a hyperinflation that can be increased by the different modes of ventilation. All the classical modes of mechanical ventilation may be used, including control-mode ventilation, assist/control-mode ventilation, intermittent mandatory ventilation and ventilation with inspiratory assistance. Another major problem is weaning from mechanical ventilation as it may take a long time or even be impossible, so that the patients stay in intensive care units for ages or require long-term home ventilation. At the moment, there is no way of predicting the outcome of weaning in each individual subjects, and none of the various ventilation procedures has proved superior to the others. Nasal ventilation has recently been introduced in intensive care where it constitutes a major step forward being less invasive; it avoids intubation in 60 p. 100 of the patients but is more exacting for the physicians and nursing staff; finally, it makes it possible to treat acute respiratory failure at an earlier stage than previously.


Integrated catalytic wet air oxidation and aerobic biological treatment in a municipal WWTP of a high-strength o-cresol wastewater.
This study examines the feasibility of coupling a Catalytic Wet Air Oxidation (CWAO), with activated carbon (AC) as catalyst, and an aerobic biological treatment to treat a high-strength o-cresol wastewater. Two goals are pursued: (a) To determine the effect of the main AC/CWAO intermediates on the activated sludge of a municipal WasteWater Treatment Plant (WWTP) and (b) To demonstrate the feasibility of coupling the AC/CWAO effluent as a part of the influent of a municipal WWTP. In a previous study, a high-strength o-cresol wastewater was treated by AC/CWAO aiming to establish the distribution of intermediates and the biodegradability enhancement. In this work, the biodegradability, toxicity and inhibition of the most relevant intermediates detected in the AC/CWAO effluent were determined by respirometry. Also, the results of a pilot scale municipal WWTP study for an integrated AC/CWAO-aerobic biological treatment of this effluent are presented. The biodegradation parameters (i.e. maximum oxygen uptake rate and oxygen consumption) of main AC/CWAO intermediates allowed the classification of the intermediates into readily biodegradable, inert or toxic/inhibitory compounds. This detailed study, allowed to understand the biodegradability enhancement exhibited by an AC/CWAO effluent and to achieve a successful strategy for coupling the AC/CWAO step with an aerobic biological treatment for a high-strength o-cresol wastewater. Using 30%, as COD, of AC/CWAO effluent in the inlet to the pilot scale WWTP, the integrated AC/CWAO-biological treatment achieved a 98% of total COD removal and, particularly, a 91% of AC/CWAO effluent COD removal without any undesirable effect on the biomass.


Analysis of clinical parameter and tumor necrosis factor-alpha levels on keratinized tissue around implant and tooth.
Studies have shown the importance of keratinized tissue around implants to prevent peri-implant diseases. This study aims to analyze the correlation of keratinized tissue around implants and teeth with clinical parameter scores and tumor necrosis factor-alpha (TNF-α) levels. A cross-sectional study of 20 adults with 20 dental implants and 20 contralateral teeth that have functioned suprastructurally for more than 3 months without any systemic diseases. Keratinized tissue around implant and tooth was measured. The clinical examinations included the plaque index (PI), papilla bleeding index (PBI), and pocket depth (PD). Peri-implant sulcus fluid (PISF) and gingival crevicular fluid were collected to measure TNF-α levels. Spearman's test was used to analyze the correlation. Significant differences were found between keratinized tissue around the implant in PI, PBI, and PD (P < 0.05). Differences were found between wide and narrow keratinized tissue around contralateral teeth in PI and PBI (P < 0.05) but not in PD. TNF-α levels were not correlate to keratinized tissue width around implant and contralateral tooth (P > 0.05). Strong correlations were found between each clinical parameter score and the keratinized tissue width of peri-implant tissue in PI, PBI, and PD. The clinical parameter score between wide and narrow keratinized tissue around implant showed strong correlation, particularly in PBI. This shows the importance of adequate keratinized tissue around implant to maintain implant stability.


[An international medical expert committee's participation in uncovering the truth on the liquidation of Polish officers found in mass graves at Katyn in the spring of 1943 and the biography of a Danish participant, Helge Tramsen (1910-1979)].
The article is based on a paper read as a invited speaker at a conference, entitled "Medical experts and expertise in cases of humanitarian crises "convened by the University of Geneva and the Committee of the International Red Cross in April 2007. The article starts with an overview of Polish history from the end of World War I up to the disclosure of the mass graves in the spring of 1943, but is otherwise a translation of the original English lecture with some additions from new findings.in archives. Helge tramsen was born into a bourgois family in Copenhagen. After graduation in medicine from the University of Copenhegen in 1936 he married a British woman and joined the naval medical corps and also embarked on a surgical career.. From 1940 to 1943 he was prosector at the Institute of Forensic Medicine at the University of Copenhagen. After the finding of the mass graves at Katyn, Germany requested from a number of European countries under German control forensic experts to join an international commission to investigate the findings. As the professor of forensic medicine declined perobably due to health reasons Tramsen was sent. During the German occupation of Denmark 1940 to 1945 Tramsen according to family tradition participated in the resistance movement and he consulted with members of the more conservative part of it and was recommended to go to Germany with an added purpose of being able to transport material out of Germany. He went with special plane from Copenhagen to Berlin, where he joined the international group, which later flew to Smolensk via Warszawa. He conducted a post mortem on the body of a Polish officer, selected by himself. Following that he attended in the discussion on the final report, which later in Berlin was handed over to the German minister of health, and which later formed an important part of the official German material accusing the USSR for the killing. During his stay in Berlin he claimed to have collected material, which in his opinion was drawings of the Eder Möwe dams and brought it back to Copenhagen with the severed head of the body of the Polish officer, on which he has carried out the post mortem. After Tramsen's return to Denmark, a British agent obtained his travel report and sent it to London and he later obtained additional information from Tramsen on the unanimous and voluntary conclusion of the experts. No information on the drawings and the head can be found in British archives. According to Tramsen's own account as a naval officer on activities during the occupation, he participated in sabotage actions, but that can not be substantiated by other sources. However, he participated in July 1944 in an attach on a fortress north of Copenhagen, held by the German Navy; the attach failed, and Transen went under ground, but later returned to his flat in Copenhagen, where he was taken prisoner by German security police. As prisoner he underwent torture and was subjected to mocked execution. He was transferred to a concentration camp, but probably due to the intervention by the permanent secretary of the Danish Foreign office, which after the Danish Government has stopped functioning in August 1943 kept the administration running and retained contacts with the German occupation authorities, Tramsen was not sent to a concentration camp in Germany, where survival rates were very low, but to one in Denmark. After the German defeat in May 1945 Tramsen continued his career in surgery, but went into general practice in Copenhagen in 1947, when he also obtained a permanent position in the naval medical service., where he remained until normal retirement in 1970, in the latter part as the highest ranking medical naval officer. He also served as medical chief at the Danish hospital ship Jutlandia serving as Danish contribution to the UN off the coast of Korea during the Korean war. He also attended as representative of the Danish Ministry of Defence the conference on the revision of the Geneva Conventions. No doubt Tramsen feared Soviet retaliation, but on the other hand he also showed courage by giving evidence at the US congressional hearings in 1952, where he confirmed that there had been no German pressure on the participants, and their conclusions had been voluntary and unanimous. He also gave an interview on Radio Free Europe transmitted to Poland in 1962. in which he desribed his experiences in Katyn. In 1971 his eldest daughter died in Warsaw, offially by carbon-monoxid poisoning from a gas heater. In theory it could be an accident, homicide or suicide. He felt it could be a revenge and in his grief he felt responsible and had a nervous break down. He died from a somatic illness in 1979 and during his terminal illness he told about his experiences from the war to a nephew.


Magnetic-field-assisted solvothermal growth of single-crystalline bismuth nanowires.
The magnetic-field-assisted approach has been used in the shape-controlled synthesis of single Bi nanocrystals. By tuning the magnetic field strength in the solvothermal process, Bi nanowires with dimension of 40-200 nm and lengths up to tens of micrometers were synthesized. Various techniques such as x-ray diffraction, scanning electron microscopy, transmission electron microscopy and Fourier transform infrared spectrometry have been used to characterize the products obtained. The results show that the magnetic field plays a key role in the crystal growth of the Bi nanowires. All nanowires were highly oriented single crystals with the growth direction along the c-axis.


The effect of preoperative 18F-FDG PET on the surgical decision in early breast cancer: 5-Year follow-up.
The diagnosis, treatment, and management of the breast cancer (BC) require a multidisciplinary approach. In newly diagnosed BC, fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) can detect extra-axillary regional nodal and distant lesions. Between 2010 and 2015, this study included 101 patients with early-stage BC who were examined with 18F-FDG PET before surgery. Patients were divided into two groups: Group 1 consisted of patients with suspected 18F-FDG uptake and Group 2 with the remaining 18F-FDG-negative patients. Differences between these groups were tested using the Pearson chi-square test, Fisher's exact test, Mann Whitney-U test, independent t-test and ROC analysis. They could be followed-up after 2015 for 5 years. All patients were then rediscussed either neoadjuvant therapy or surgery in the oncology board in 2020 with changing neoadjuvant criteria and oncoplastic surgery techniques. Fluorine-18-FDG PET was found to have a sensitivity of 77.8% and a specificity of 90.8% in detecting axillary lymph node metastasis. During the minimum 5-year follow-up, one patient had bone metastasis, 2 patients had a local recurrence, and 3 patients had metastatic lymph nodes in the axilla. In the re-evaluation of the same patients over 5 years, the decrease in mastectomy decision was remarkable (P-value 0.01). We observed that we could not achieve a significant difference in 5-year metastasis/recurrence between the groups. Moreover, due to 18F-FDG-PET high false positivity, it significantly extended the time to surgery (P-value 0.01). In early-stage BC, 18F-FDG PET demonstrated better performance in axillary lymph nodes metastases detection in comparison with other diagnostic imaging methods, even if SLNB remains the gold standard technique.


A standardized method for the analysis of liver sinusoidal endothelial cells and their fenestrations by scanning electron microscopy.
Liver sinusoidal endothelial cells are the gateway to the liver, their transcellular fenestrations allow the unimpeded transfer of small and dissolved substances from the blood into the liver parenchyma for metabolism and processing. Fenestrations are dynamic structures--both their size and/or number can be altered in response to various physiological states, drugs, and disease, making them an important target for modulation. An understanding of how LSEC morphology is influenced by various disease, toxic, and physiological states and how these changes impact on liver function requires accurate measurement of the size and number of fenestrations. In this paper, we describe scanning electron microscopy fixation and processing techniques used in our laboratory to ensure reproducible specimen preparation and accurate interpretation. The methods include perfusion fixation, secondary fixation and dehydration, preparation for the scanning electron microscope and analysis. Finally, we provide a step by step method for standardized image analysis which will benefit all researchers in the field.


A Structure-Aware Hierarchical Graph-Based Multiple Instance Learning Framework for pT Staging in Histopathological Image.
Pathological primary tumor (pT) stage focuses on the infiltration degree of the primary tumor to surrounding tissues, which relates to the prognosis and treatment choices. The pT staging relies on the field-of-views from multiple magnifications in the gigapixel images, which makes pixel-level annotation difficult. Therefore, this task is usually formulated as a weakly supervised whole slide image (WSI) classification task with the slide-level label. Existing weakly-supervised classification methods mainly follow the multiple instance learning paradigm, which takes the patches from single magnification as the instances and extracts their morphological features independently. However, they cannot progressively represent the contextual information from multiple magnifications, which is critical for pT staging. Therefore, we propose a structure-aware hierarchical graph-based multi-instance learning framework (SGMF) inspired by the diagnostic process of pathologists. Specifically, a novel graph-based instance organization method is proposed, namely structure-aware hierarchical graph (SAHG), to represent the WSI. Based on that, we design a novel hierarchical attention-based graph representation (HAGR) network to capture the critical patterns for pT staging by learning cross-scale spatial features. Finally, the top nodes of SAHG are aggregated by a global attention layer for bag-level representation. Extensive studies on three large-scale multi-center pT staging datasets with two different cancer types demonstrate the effectiveness of SGMF, which outperforms state-of-the-art up to 5.6% in the F1 score.


PROPERTIES OF F' STRAINS OF ESCHERICHIA COLI SUPERINFECTED WITH F-LACTOSE AND F-GALATOSE EPISOMES.
Echols, Harrison (University of Wisconsin, Madison). Properties of F' strains of Escherichia coli superinfected with F-lactose and F-galactose episomes. J. Bacteriol. 85:262-268. 1963.-A study of F' superinfection of F' strains of Escherichia coli by F Lac P and F Gal indicates that superinfecting F Lac P may achieve a stable existence along with native F Lac P in approximately 1% of the recipient F' population. The stable presence of F Gal, on the other hand, leads to a displacement or suppression of F Lac P when F Gal is used as a superinfecting agent or as the native episome. The majority of F' bacteria used as recipients neither acquire in stable form the superinfecting F-linked genes nor demonstrate gene activity immediately after attempted transfer, as judged by alkaline phosphatase synthesis directed by an F-transferred P(+) gene. This failure to show gene activity suggests that the F' bacteria which are sterile as recipients exclude transfer rather than inhibit subsequent multiplication.


CINCH (confocal incoherent correlation holography) super resolution fluorescence microscopy based upon FINCH (Fresnel incoherent correlation holography).
FINCH holographic fluorescence microscopy creates high resolution super-resolved images with enhanced depth of focus. The simple addition of a real-time Nipkow disk confocal image scanner in a conjugate plane of this incoherent holographic system is shown to reduce the depth of focus, and the combination of both techniques provides a simple way to enhance the axial resolution of FINCH in a combined method called "CINCH". An important feature of the combined system allows for the simultaneous real-time image capture of widefield and holographic images or confocal and confocal holographic images for ready comparison of each method on the exact same field of view. Additional GPU based complex deconvolution processing of the images further enhances resolution.


Reasoning about climate change.
Why is disbelief in anthropogenic climate change common despite broad scientific consensus to the contrary? A widely held explanation involves politically motivated (system 2) reasoning: Rather than helping uncover the truth, people use their reasoning abilities to protect their partisan identities and reject beliefs that threaten those identities. Despite the popularity of this account, the evidence supporting it (i) does not account for the fact that partisanship is confounded with prior beliefs about the world and (ii) is entirely correlational with respect to the effect of reasoning. Here, we address these shortcomings by (i) measuring prior beliefs and (ii) experimentally manipulating participants' extent of reasoning using cognitive load and time pressure while they evaluate arguments for or against anthropogenic global warming. The results provide no support for the politically motivated system 2 reasoning account over other accounts: Engaging in more reasoning led people to have greater coherence between judgments and their prior beliefs about climate change-a process that can be consistent with rational (unbiased) Bayesian reasoning-and did not exacerbate the impact of partisanship once prior beliefs are accounted for.


Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.
Basic cardiac electrophysiology is foundational to understanding normal cardiac function in terms of rate and rhythm and initiation of cardiac muscle contraction. The primary clinical tool for assessing cardiac electrical events is the electrocardiogram (ECG), which provides global and regional information on rate, rhythm, and electrical conduction as well as changes in electrical activity associated with cardiac disease, particularly ischemic heart disease. This teaching review is written at a level appropriate for first- and second-year medical students. Specific concepts discussed include ion equilibrium potentials, electrochemical forces driving ion movements across membranes, the role of ion channels in determining membrane resting potentials and action potentials, and the conduction of action potentials within the heart. The electrophysiological basis for the ECG is then described, followed by discussion on how ischemia alters cellular electrophysiology and ECG recordings, with particular emphasis on changes in T waves and ST segments of the ECG.


Antimicrobial use and serotype distribution of nasopharyngeal Streptococcus pneumoniae isolates recovered from Greek children younger than 2 years old.
The serotype distribution of 781 nasopharyngeal pneumococcal isolates recovered from 2448 unselected children aged 2-23 months was studied. Only 3.9% of the children for whom cultures were performed attended day care centers. The proportions of pneumococcal isolates that belonged to serotypes related to the 7-, 9- and 11-valent conjugate pneumococcal vaccine were 65%, 66%, and 70%, respectively. The pneumococcal carriage rate among untreated children was 34%; the rates among children treated with antibiotics during the periods 1-30 or 31-60 days before the time of nasopharyngeal sampling were 25% and 36%, respectively. There was a significant positive association between antimicrobial use and carriage of antibiotic-resistant pneumococci, which belonged mainly to vaccine-related serotypes. The proportion of isolates that belonged to vaccine-related serotypes in untreated carriers was 72%; however, the proportions in carriers treated 1-30 days or 31-60 days before sampling were 66% and 56%, respectively. In the nasopharynx, antimicrobial use selects for antibiotic-resistant pneumococci, mainly of vaccine-related serotypes, whereas it may promote an increase in the frequency of colonization with nonvaccine serotypes.


Synthesis of 4-trifluoromethyl pyridazines via annulation of pyridinium ylides with trifluoroacetyl diazoester.
A base promoted annulation of pyridinium ylides with trifluoroacetyl diazoester has been reported. Highly functionalized 4-trifluoromethyl pyridazines were synthesized in good yields without the use of any heavy metal catalysts. The developed methodology was compatible with a variety of important functional groups. Mechanistic studies revealed that trifluoroacetylated hydrazone was an active intermediate of this three-component annulation. Synthetic versatility of the method via aminolysis and condensation toward amide- and pyridazino[4,5-c]pyridazine-derivatives has been showcased.


Little genetic variability in resilience among cattle exists for a range of performance traits across herds in Ireland differing in Fasciola hepatica prevalence.
It is anticipated that in the future, livestock will be exposed to a greater risk of infection from parasitic diseases. Therefore, future breeding strategies for livestock, which are generally long-term strategies for change, should target animals adaptable to environments with a high parasitic load. Covariance components were estimated in the present study for a selection of dairy and beef performance traits over herd-years differing in Fasciola hepatica load using random regression sire models. Herd-year prevalence of F. hepatica was determined by using F. hepatica-damaged liver phenotypes which were recorded in abattoirs nationally. The data analyzed consisted up to 83,821 lactation records from dairy cows for a range of milk production and fertility traits, as well as 105,054 young animals with carcass-related information obtained at slaughter. Reaction norms for individual sires were derived from the random regression coefficients. The heritability and additive genetic standard deviations for all traits analyzed remained relatively constant as herd-year F. hepatica prevalence gradient increased up to a prevalence level of 0.7; although there was a large increase in heritability and additive genetic standard deviation for milk and fertility traits in the observed F. hepatica prevalence levels >0.7, only 5% of the data existed in herd-year prevalence levels >0.7. Very little rescaling, therefore, exists across differing herd-year F. hepatica prevalence levels. Within-trait genetic correlations among the performance traits across different herd-year F. hepatica prevalence levels were less than unity for all traits. Nevertheless, within-trait genetic correlations for milk production and carcass traits were all >0.8 for F. hepatica prevalence levels between 0.2 and 0.8. The lowest estimate of within-trait genetic correlations for the different fertility traits ranged from -0.03 (SE = 1.09) in age of first calving to 0.54 (SE = 0.22) for calving to first service interval. Therefore, there was reranking of sires for fertility traits across different F. hepatica prevalence levels. In conclusion, there was little or no genetic variability in sensitivity to F. hepatica prevalence levels among cattle for milk production and carcass traits. But, some genetic variability in sensitivity among dairy cows did exist for fertility traits measured across herds differing in F. hepatica prevalence.


Management of multiple sclerosis. How to improve the quality of life.
Multiple sclerosis manifests itself in a number of ways, affecting many body functions and systems. It is not possible to change the pathologic course of multiple sclerosis at this time, but this does not mean that physicians cannot improve the quality of life for patients with this disease. By participating in regular exercise, patients can maintain their strength and mobility. Spasticity may be controlled with medications, and urologic problems, which not only are often overlooked but also have a major bearing on patients' social and vocational life, should be controlled to the greatest extent possible.


Growth condition-induced precocious activation of p34cdc2 kinase inhibits the expression of developmental competence.
We examined the effect of growth conditions upon mitotic p34cdc2 kinase and developmental competence in Acanthamoeba castellanii. At G2/M of the cell cycle p34cdc2 kinase activity peaks in level, and p34cdc2 is transiently in a complex with newly synthesized cyclin B and phosphorylated on tyrosine (pre-MPF). Developmental competence peaks in level slightly preceding p34cdc2 kinase activation and pre-MPF accumulation. Under adverse growth conditions p34cdc2 kinase activation and transient pre-MPF accumulation occur at a reduced G2 phase length and smaller cell size. Developmental competence is not expressed during the shortened G2 phase. Cycloheximide inhibits the precocious p34cdc2 kinase activation and both the precocious accumulation of cyclin B and tyrosine phosphorylation on p34cdc2. No-codazole inhibits the precocious p34cdc2 kinase activation as well; however, it does not affect the precocious accumulation of pre-MPF. Developmental competence increases in level during artificially elongated G2 phases. The results indicate that, first p34cdc2 kinase activation requires cyclin B in a complex with p34cdc2 and the presence of intact microtubuli, second establishment of competence requires a certain length of G2, and third the regulation of pre-MPF accumulation, and thus of cyclin B expression, plays a role in the relationship among growth condition, cell cycle progression, and expression of the developmental program.


"Saber-sheath" trachea: relation to chronic obstructive pulmonary disease.
Sixty male patients with marked coronal narrowing of the intrathoracic trachea (saber-sheath configuration) were compared with 60 controls. Scores were assigned to patients according to separate clinical and radiographic indexes of chronic obstructive pulmonary disease (COPD). Of the 60 patients with the saber-sheath configuration, 57 (95%) had clinical evidence of COPD compared to only 18% in the control group. Of these 57, 26 (45%) lacked conventional radiographic evidence of COPD. This study establishes a strong correlation between saber-sheath trachea and clinical COPD. The value of this radiographic sign is twofold: (1) as an aid in diagnosing COPD when other convincing radiographic evidence is lacking; and (2) to avoid an erroneous assumption that coronal narrowing is due to a mediastinal mass.


Salivary flow rate, calcium, urea, total protein, and amylase levels in fanconi anemia.
Fanconi anemia (FA) is a genetic disease characterized by a chromosomal instability that develops a progressive pancitopenia, leukemia, and/or solid tumors. Nevertheless, it is unknown if this illness induces changes on the salivary gland parenchyma and function. The aim of this study was to assess the stimulated salivary flow rate (SSFR) and calcium, urea, total protein, and amylase levels in saliva of FA patients. Stimulated whole saliva was collected from 34 randomly selected FA patients and 34 age-matched and sex-matched controls. Both samples were analyzed for salivary flow rate, calcium, urea, total proteins, and amylase. The SSFR was analyzed by gravimetric method and calcium, urea, total protein, and amylase concentrations were realized by chemistry tests. Mean values of SSFR for experimental and control groups were, respectively, 0.5 mL/min and 0.8 mL/min (P<0.05). Calcium concentration was 36% (P<0.05) and urea concentration was 21% (P<0.01) lower in the FA group saliva compared with saliva from the controls. The saliva concentration of amylase was almost equal in both groups. FA patients may exhibit significant changes in SSFR, calcium, and urea concentration of saliva.


A Korean perspective on developing a global policy for advance directives.
Despite the wide and daunting array of cross-cultural obstacles that the formulation of a global policy on advance directives will clearly pose, the need is equally evident. Specifically, the expansion of medical services driven by medical tourism, just to name one important example, makes this issue urgently relevant. While ensuring consistency across national borders, a global policy will have the additional and perhaps even more important effect of increasing the use of advance directives in clinical settings and enhancing their effectiveness within each country, regardless of where that country's state of the law currently stands. One cross-cultural issue that may represent a major obstacle in formulating, let alone applying, a global policy is whether patient autonomy as the underlying principle for the use of advance directives is a universal norm or a construct of western traditions that must be reconciled with alternative value systems that may place lesser significance on individual choice. A global policy, at a minimum, must emphasize respect for patient autonomy, provision of medical information, limits to the obligations for physicians, and portability. And though the development of a global policy will be no easy task, active engagement in close collaboration with the World Health Organization can make it possible.


Enhancement in Proton Conductivity and Thermal Stability in Nafion Membranes Induced by Incorporation of Sulfonated Carbon Nanotubes.
Proton exchange membrane fuel cell (PEMFC) is one of the most promising green power sources, in which perfluorinated sulfonic acid ionomer-based membranes (e.g., Nafion) are widely used. However, the widespread application of PEMFCs is greatly limited by the sharp degradation in electrochemical properties of the proton exchange membranes under high temperature and low humidity conditions. In this work, the high-performance sulfonated carbon nanotubes/Nafion composite membranes (Su-CNTs/Nafion) for the PEMFCs were prepared and the mechanism of the microstructures on the macroscopic properties of membranes was intensively studied. Microstructure evolution in Nafion membranes during water uptake was investigated by positron annihilation lifetime spectroscopy, and results strongly showed that the Su-CNTs or CNTs in Nafion composite membranes significantly reinforced Nafion matrices, which influenced the development of ionic-water clusters in them. Proton conductivities in Su-CNTs/Nafion composite membranes were remarkably enhanced due to the mass formation of proton-conducting pathways (water channels) along the Su-CNTs. In particular, these pathways along Su-CNTs in Su-CNTs/Nafion membranes interconnected the isolated ionic-water clusters at low humidity and resulted in less tortuosity of the water channel network for proton transportation at high humidity. At a high temperature of 135 °C, Su-CNTs/Nafion membranes maintained high proton conductivity because the reinforcement of Su-CNTs on Nafion matrices reduced the evaporation of water molecules from membranes as well as the hydrophilic Su-CNTs were helpful for binding water molecules.


Aetiology of acute gastroenteritis in infancy and early childhood in southern India.
The aetiology of acute gastroenteritis was studied in 50 infants and young children. Bacterial pathogens were isolated in 33, enteropathogenic E. coli (EPEC), Salmonella, and Shigella being the commonest isolates. Rotaviruses were detected in the stools of 13 of the cases. All children with gastroenteritis in whom rotavirus was detected were seen during the months July to December. In 30 children who served as controls, EPEC were isolated in 6, but rotavirus was detected in none. It is concluded that infection with rotaviruses is a significant cause of morbidity in children with gastroenteritis in southern India.


[Treatment of declining in ovarian reserve by shen-reinforcing and menstrual cycle-regulating therapy combined with western medicine: a clinical observation].
To observe the clinical effect of Shen-reinforcing and menstrual cycle-regulating therapy (SRMCRT) combined with Western medicine (WM) in treating decline in ovarian reserve (DOR). Totally 78 patients with DOR were assigned to the traditional Chinese medicine combined WM group (abbreviated as IM group, 40 cases), and the WM group (38 cases) according to random digit table method. Patients in the WM group were treated with hormone replacement therapy, while those in the IM group additionally received SRMCRT. The therapeutic course for all was 3 consecutive months. The therapeutic efficacy was compared between the two groups. The serum levels of follicle stimulating hormone (FSH), FSH/luteinizing hormone (LH), and estradiol (E2), as well as the development of sinus follicles were compared between before and after treatment in the two groups. The therapeutic effective rate was 92.5% in the IM group, higher than that of the WM group (73.68%, P < 0.05). The serum levels of FSH, FSH/LH, and E2 decreased (P < 0.05) and the number of the sinus follicle increased (P < 0.05) in the two groups after treatment. Besides, IM was superior in decreasing serum levels of FSH and FSH/LH, and increasing the number of the sinus follicle (P < 0.05). SRMCRT was an effective method for treating ROD. IM was superior in decreasing serum levels of FSH and FSH/LH, and increasing the number of the sinus follicle.


Secondary interactions in 3-bromopyridinium tribromoacetate.
The title compound, C(5)H(5)BrN(+).C(2)Br(3)O(2)(-), crystallizes with Z' = 2. The residues pack in two distinct (but interconnected) types of layer, namely, layers parallel to (102), in which the residues are connected by classical N-H...O hydrogen bonds, C-H...O interactions and Br...Br contacts, and anion layers parallel to the ab plane, connected by Br...O interactions. The two formula units are topologically equivalent with respect to all these contacts.


Synthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain.
Human brain organoid systems offer unprecedented opportunities to investigate both neurodevelopmental and neurological disease. Single-cell-based transcriptomics or epigenomics have dissected the cellular and molecular heterogeneity in the brain organoids, revealing a complex organization. Similar but distinct protocols from different labs have been applied to generate brain organoids, providing a large resource to perform a comparative analysis of brain developmental processes. Here, we take a systematic approach to compare the single-cell transcriptomes of various human cortical brain organoids together with fetal brain to define the identity of specific cell types and differentiation routes in each method. Importantly, we identify unique developmental programs in each protocol compared to fetal brain, which will be a critical benchmark for the utility of human brain organoids in the future.


Hepatitis C infection in children with haemophilia: a pilot study.
Many haemophilia patients were infected with hepatitis C virus (HCV) in childhood after transfusion with inadequately or non-virus inactivated clotting factor products. Limited information is available on the clinical course of HCV infection in children. To assess the clinical consequences of hepatitis C in these young patients we performed a pilot study of 31 patients with haemophilia, infected with HCV before the age of 13. Current median age was 20 years. Nineteen (61%) patients had chronic hepatitis C, whereas the remaining 12 patients spontaneously cleared HCV. The median duration of infection was 17 years. Among patients chronically infected with HCV, an enlarged liver and/or spleen on ultrasound was present in 59%, whereas 63% had abnormal aminotransferases and/or gamma-GT values. In conclusion, 39% of the patients infected in childhood cleared HCV spontaneously. The majority of the patients with chronic hepatitis C had ultrasound and/or laboratory abnormalities and these findings may be associated with the presence of chronic liver disease.


Comparison of Lesional Juvenile Myositis and Lupus Skin Reveals Overlapping Yet Unique Disease Pathophysiology.
Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE). We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction. Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of up-regulated genes representing interferon (IFN)-stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions. Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.


Discovering Speed Changes of Vehicles from Audio Data.
In this paper, we focus on detection of speed changes from audio data, representing recordings of cars passing a microphone placed near the road. The goal of this work is to observe the behavior of drivers near control points, in order to check whether their driving is safe both when approaching the speed camera and after passing it. The audio data were recorded in controlled conditions, and they are publicly available for downloading. They represent one of three classes: car accelerating, decelerating, or maintaining constant speed. We used SVM, random forests, and artificial neural networks as classifiers, as well as the time series based approach. We also tested several approaches to audio data representation, namely: average values of basic audio features within the analyzed time segment, parametric description of the time evolution of these features, and parametric description of curves (lines) in the spectrogram. Additionally, the combinations of these representations were used in classification experiments. As a final step, we constructed an ensemble classifier, consisting of the best models. The proposed solution achieved an accuracy of almost 95%, without mistaking acceleration with deceleration, and very rare mistakes between stable speed and speed changes. The outcomes of this work can become a basis for campaigns aiming at improving traffic safety.


Improving Color Accuracy of Colorimetric Sensors.
Accurate measurements of reflectance and color require spectrophotometers with prices often exceeding $3000. Recently, new “color instruments” became available with much lower prices, thanks to the availability of inexpensive colorimetric sensors. We investigated the Node+ChromaPro and the Color Muse, launched in 2015 and 2016 by Variable Inc. Both instruments are colorimeters, combining a colorimetric sensor with LED lighting. We investigated color accuracy compared to a high-end spectrophotometer from BYK Gardner. With different sets of samples we find for the Node an average value of dECMC (1:1) = 1.50, and a maximum of 7.86, when comparing with the 45° geometry of the spectrophotometer. Utilizing measurement data on the Spectral Power Distributions of the LEDs, we developed three methods to improve color accuracy as compared to the spectrophotometer data. We used these methods on different sets of samples with various degrees of gloss, both for training the models underlying the methods and for independent tests of model accuracy. Average color accuracy of the Node+ChromaPro improves from dECMC (1:1) = 1.82 to 1.16 with respect to spectrophotometer data. The percentage of samples with dECMC (1:1) < 1.0 increases from 30.9% (uncorrected) to 64%. With the improved color accuracy, these sensors become useful for many more applications.


Efficacy of LDL apheresis for the treatment of cholesterol crystal embolism: A prospective, controlled study.
This study was performed to evaluate the efficacy and safety of LDL apheresis (LDL-A) for the treatment of cholesterol crystal embolism (CCE) after cardiovascular procedures. We conducted a prospective multicenter study of 34 patients with CCE and 15 historical control patients. The present participants underwent six sessions of LDL-A for 4 weeks and underwent medical therapy with corticosteroids and statins. The mean creatinine concentration and estimated glomerular filtration rate at baseline were 3.82 ± 2.29 mg/dL and 17.8 ± 9.9 mL/min/1.73 m2 , respectively. The prevalence of maintenance dialysis at 24 weeks was significantly lower in the present participants than in the historical controls (3.1% vs. 40.0%, respectively; p < 0.0001), but the mortality rate at 24 weeks was comparable (19% vs. 33%, respectively). Although 45 adverse events occurred in 23 participants, there were no unexpected adverse events. LDL-A for CCE reduces the prevalence of maintenance dialysis 24 weeks later and is well tolerated. This study was registered in the Japan Registry of Clinical Trials (jRCTs022180029) and clinicaltrials.gov (NCT01726868).


Limitations of anthropometry during acute food shortages: high mortality can mask refugees' deteriorating nutritional status.
Longitudinal comparison of anthropometric data from cross-sectional surveys is commonly used to assess nutritional status in relief operations. In a refugee camp in Sudan, assessment indicated a high level of childhood malnutrition, but nutritional status appeared relatively unchanged between cluster sample surveys in January (26.3% below 80% of median weight-for-height) and March 1985 (28.4% below 80% of median weight-for-height). However, in this interval, which was marked by irregular food supplies and relatively low energy (calorie) intake as well as by a high incidence of diarrhoeal disease and measles, nearly 13% of all children in the camp died. This deceptive appearance of stability in nutritional status in the face of high mortality may be explained by ongoing nutritional deterioration ("replacement malnutrition") among surviving children. These findings demonstrate that collection and analysis of mortality data are essential for the correct interpretation of anthropometric results during periods of uncertain food supply.


Novel dual-reflection design applied for ITER core x-ray spectrometer.
A novel dual-reflection configuration is introduced for the International Tokamak Experimental Reactor (ITER) core x-ray spectrometer to fit the allocated space where it will be placed accompanied by moving the detectors backward to reduce the incident radiation dose. The highly oriented pyrolytic graphite, which has a mosaic structure of microscopic crystallites, is chosen for the front reflector motivated by higher x-ray throughput and stronger misalignment tolerance compared to the perfect crystal reflector. In the ITER core x-ray spectrometer, a combination of several reflector-deflected Lines of Sight (LOSs) and a direct LOS is proposed for the first time named X-Ray Crystal Spectroscopy Core (XRCS-Core). The system is optimized to observe lines from externally seeded xenon and the intrinsic tungsten impurity, meeting both port integration needs and measurement requirements. Its spectral performance is simulated using an analytical-raytracing mixed code--XRSA, showing good imaging quality with a spectral resolution higher than 8000. The XRCS-Core system is thought to be applicable in various ITER scenarios through the assessment taking into account the spectrometers' specifications and the chosen lines' emissivity in different plasma parameters.


An image-processing toolset for diffusion tensor tractography.
Diffusion tensor imaging (DTI)-based fiber tractography holds great promise in delineating neuronal fiber tracts and, hence, providing connectivity maps of the neural networks in the human brain. An array of image-processing techniques has to be developed to turn DTI tractography into a practically useful tool. To this end, we have developed a suite of image-processing tools for fiber tractography with improved reliability. This article summarizes the main technical developments we have made to date, which include anisotropic smoothing, anisotropic interpolation, Bayesian fiber tracking and automatic fiber bundling. A primary focus of these techniques is the robustness to noise and partial volume averaging, the two major hurdles to reliable fiber tractography. Performance of these techniques has been comprehensively examined with simulated and in vivo DTI data, demonstrating improvements in the robustness and reliability of DTI tractography.


Trauma Exposure and Functional Movement Characteristics of Male Tactical Athletes.
Tactical athletes commonly experience high levels of physical stress, which may increase their risk of musculoskeletal injury. It is critical to understand psychological predictors of functional movement (FM), which may help prevent musculoskeletal injury in this population. To determine the associations of combat and trauma exposure with FM characteristics of male tactical athletes. Secondary objectives were to explore confounding influences of age and physical injury history as well as the mediating role of bodily pain. Cross-sectional study. Research laboratory. Eighty-two healthy, male, active-duty US Navy Explosive Ordnance Disposal personnel (age = 34.0 ± 6.7 years). Participants completed measures of combat exposure, trauma exposure, physical injury history, and bodily pain. We assessed FM characteristics (ie, Functional Movement Screen [FMS], Y-Balance Test), from which we derived a composite functional status (CFS) measure. Hypotheses were tested using correlational and multiple regression (causal-steps) models. In unadjusted models, trauma exposure was inversely associated with the FMS (P = .005) and CFS (P = .009) scores. In adjusted models, these relationships were robust to the confounding influences of age and physical injury history. Trauma exposure and bodily pain were substantive, independent predictors of FMS and CFS in causal-steps models (all P values < .05), implying additive rather than mediated effects (R2adj = 0.18-0.20). Combat exposure did not predict FM characteristics. To our knowledge, this is the first evidence of the influence of trauma exposure on the FM characteristics of male tactical athletes, independent of age, physical injury, and bodily pain. This program of research may help to advance the prevention and treatment of musculoskeletal injuries in the tactical environment.


An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target.
Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signals that are often constitutively activated in many cancerous or transformed cells and some stromal cells in the tumor microenvironment. Persistent STAT3 activation in malignant cells stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. STAT3 undergoes activation through phosphorylation on tyrosine 705, which facilitates its dimerization. Dimeric STAT3 translocates to the nucleus, where it regulates the transcription of genes involved in cell proliferation, survival, etc. In the present study, a synthetic deguelin analogue SH48, discovered by virtual screening, inhibited the phosphorylation, nuclear translocation, and transcriptional activity of STAT3 in H-ras transformed human mammary epithelial MCF-10A cells (MCF10A-ras). We speculated that SH48 bearing an α,β-unsaturated carbonyl group could interact with a thiol residue of STAT3, thereby inactivating this transcription factor. Non-electrophilic analogues of SH48 failed to inhibit STAT3 activation, lending support to the above supposition. By utilizing a biotinylated SH48, we were able to demonstrate the complex formation between SH48 and STAT3. SH48 treatment to MCF10A-ras cells induced autophagy, which was verified by staining with a fluorescent acidotropic probe, LysoTracker Red, as well as upregulating the expression of LC3II and p62. In conclusion, the electrophilic analogue of deguelin interacts with STAT3 and inhibits its activation in MCF10A-ras cells, which may account for its induction of autophagic death.


Cancer incidence, mortality and survival: trends in four leading sites.
Cancer mortality rates in the United States have stabilized in the past few years after rising for more than 50 years. Incidence and mortality rates for all cancers tend to be higher among men than women, among blacks than whites and among those over age 65. In 1994 cancer of the lung, prostate, breast, and colon/rectum (colorectal) will account for an estimated 57 percent of all new cancer cases and 55 percent of cancer deaths. Analysis of incidence, mortality and survival rates of these four major cancers indicate some encouraging trends. That is, even though age-adjusted incidence rates continue to increase, it appears that educational and screening efforts are having a positive influence on mortality rates. Lung cancer incidence has declined in recent years following a decrease in smoking among men that began some 20 years ago; evidence also indicates a start of a declining trend in their mortality from this disease, as well. Lung cancer incidence and mortality rates among women, however, continue to rise. In 1986 lung cancer became the leading cause of cancer deaths among women. Increased use and improved techniques of cancer detection for prostate, breast and colorectal cancers are resulting in larger numbers of these cancers being detected at early stages when they are more readily treatable. It is hoped that such activities will ultimately reduce mortality for these three major cancer sites.


Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro.
Activation of the mitochondrial ATP-sensitive K+ channel (mitoKATP) and its regulation by PKC are critical events in preconditioning induced by ischemia or pharmaceutical agents in animals and humans. The properties of the human cardiac mitoKATP channel are unknown. Furthermore, there is no evidence that cytosolic PKC can directly regulate the mitoKATP channel located in the inner mitochondrial membrane (IMM) due to the physical barrier of the outer mitochondrial membrane. In the present study, we characterized the human cardiac mitoKATP channel and its potential regulation by PKC associated with the IMM. IMM fractions isolated from human left ventricles were fused into lipid bilayers in symmetrical potassium glutamate (150 mM). The conductance of native mitoKATP channels was usually below 80 pS ( approximately 70%), which was reduced by ATP and 5-hydroxydecanoic acid (5-HD) in a dose- and time-dependent manner. The native mitoKATP channel is activated by diazoxide and inhibited by ATP and 5-HD. The PKC activator phorbol 12-myristate 13-acetate (2 microM) increased the cumulative open probability of the mitoKATP channel previously inhibited by ATP (P < 0.05), but its inactive analog 4alpha-phorbol 12,13-didecanoate had no effect. Western blot analysis detected an inward rectifying K+ channel (Kir6.2) immunoreactive protein at 56 kDa and PKC-delta in the IMM. These data provide the first characterization of the human cardiac mitoKATP channel and its regulation by PKC(s) in IMM. This local PKC control mechanism may represent an alternative pathway to that proposed previously for cytosolic PKC during ischemic/pharmacological preconditioning.


Thermoregulatory-induced compromise of muscle blood flow in ponies during intense exercise in the heat: a contributor to the onset of fatigue?
Cardiac output (Q) and tissue blood flows (BF) were measured in four ponies at rest, after 30 min of moderate exercise (ME) (approximately 30% VO2max) and following moderately intense exercise (M-IE) (approximately 65%) until fatigue, in a mildly hot (MH) environment (dry bulb temperature = 41 degrees C, wet bulb temperature = 27.5 degrees C). Exercise at both intensities resulted in increases in Q (15.6 +/- 1.7 [rest] vs. 35.8 +/- 2.6 [ME] vs. 48.6 +/- 3.9 [M-IE] l/min) and VO2 (4.7 +/- 0.9 vs. 24.5 +/- 1.2 vs. 55.8 +/- 5.8 ml/kg/min). When compared to ME, M-IE resulted in decreases in BF to the skin (approximately 15%), nonworking muscle (46%), fat (93%), gut (56%), kidneys (57%), CNS (31-66%) and an increase in BF to respiratory (68%), limb (98.5%) and cardiac (50%) muscles. In contrast, BF to working muscle during ME in thermoneutral (TN) conditions (McConaghy et al. 2002) was higher than found during ME in MH. We calculated that limb BF was approximately 25% lower for ME in MH vs. ME in TN. Similarly, we estimated that limb BF during M-IE in MH was approximately 25% lower than for M-IE in TN. Attenuation of the increases in muscle BF during exercise in the heat may be a determinant of the onset of fatigue.


Identification of Shp-2 as a Stat5A phosphatase.
Stat5A, a member of the signal transducers and activators of transcription (Stat) family, is activated upon a single tyrosine phosphorylation. Although much is known about the activation process, the mechanism by which the tyrosine-phosphorylated Stat5A proteins are inactivated is largely unknown. In this report, we demonstrate that down-regulation of the tyrosine-phosphorylated Stat5A was via dephosphorylation. Using tyrosine-phosphorylated peptides derived from Stat5A, we were able to purify protein-tyrosine phosphatase Shp-2 from cell lysates. Shp-2, but not Shp-1, specifically interacted with Stat5A in vivo, and the interaction was tyrosine phosphorylation-dependent. Moreover, Shp-2 was able to accelerate Stat5A dephosphorylation, and dephosphorylation of Stat5A was dramatically delayed in Shp-2-deficient cells. Therefore, we conclude that Shp-2 is a Stat5A phosphatase, which down-regulates the active Stat5A in vivo.


Alg14 organizes the formation of a multiglycosyltransferase complex involved in initiation of lipid-linked oligosaccharide biosynthesis.
Protein N-glycosylation begins with the assembly of a lipid-linked oligosaccharide (LLO) on the endoplasmic reticulum (ER) membrane. The first two steps of LLO biosynthesis are catalyzed by a functional multienzyme complex comprised of the Alg7 GlcNAc phosphotransferase and the heterodimeric Alg13/Alg14 UDP-GlcNAc transferase on the cytosolic face of the ER. In the Alg13/14 glycosyltransferase, Alg14 recruits cytosolic Alg13 to the ER membrane through interaction between their C-termini. Bioinformatic analysis revealed that eukaryotic Alg14 contains an evolved N-terminal region that is missing in bacterial orthologs. Here, we show that this N-terminal region of Saccharomyces cerevisiae Alg14 localize its green fluorescent protein fusion to the ER membrane. Deletion of this region causes defective growth at 38.5°C that can be partially complemented by overexpression of Alg7. Coimmunoprecipitation demonstrated that the N-terminal region of Alg14 is required for direct interaction with Alg7. Our data also show that Alg14 lacking the N-terminal region remains on the ER membrane through a nonperipheral association, suggesting the existence of another membrane-binding site. Mutational studies guided by the 3D structure of Alg14 identified a conserved α-helix involved in the second membrane association site that contributes to an integral interaction and protein stability. We propose a model in which the N- and C-termini of Alg14 coordinate recruitment of catalytic Alg7 and Alg13 to the ER membrane for initiating LLO biosynthesis.