A national perspective of adult gangliogliomas.
Gangliogliomas (GG) are rare tumors of the nervous system. Patient characteristics and clinical outcomes of low and high-grade GG have been difficult to elucidate in the adult population. This study aims to further elaborate on GG treatment and overall survival utilizing a larger cohort than previously published. The USA National Cancer Database was utilized to evaluate adult (age 18years and older) patients diagnosed with GG between 2004 and 2006. Descriptive statistics and Kaplan-Meier overall survival estimates were provided. A total of 198 adult GG patients were diagnosed between 2004 and 2006. Of these, 181 (91.4%) were low-grade and 17 (8.6%) high-grade GG. Overall, the median age was 36years; approximately 50% of patients were female, and 86.5% Caucasian. Most patients (59%) had near/gross total resection. Radiation and chemotherapy were prescribed in 18 (9.1%) and 11 (5.7%) patients, respectively. Radiation (64.7% versus 3.9%, p<.0001) and chemotherapy (47.1% versus 1.7%, p<.0001) were more frequently given to patients with high-grade tumors than low-grade. The median overall survival of high-grade GG was 44.4months (95% confidence interval [CI]: 10.5-92.5) while the corresponding estimate for low-grade tumors was not reached. Older age (hazard ratio [HR] 1.72, 95% CI: 1.26-2.34) and high tumor grade (HR 3.91, 95% CI: 1.43-10.8) were found to be associated with poor survival. Adult GG have a temporal lobe predilection and overall gross total resection rate of 59%. Older patients with high-grade tumors had an increased hazard of mortality. High-grade GG were significantly more likely to be treated with radiation therapy and chemotherapy.


Relationship between Epstein-Barr virus nuclear antigen and DNA genome number in superinfected and induced lymphoblastoid cell lines.
The relative contents of Epstein-Barr virus (EBV)-associated nuclear antigen (EBNA) and average numbers of EBV genome equivalents per cell were determined (i) in Raji cells superinfected with P3HR-1 virus, (ii) in Raji cells induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and sodium n-butyrate and (iii) in P3HR-1 cells induced by TPA and sodium n-butyrate. This treatment was followed by increases in the percentage of early antigen (in both Raji and P3HR-1 cells) and virus capsid antigen-positive cells (in P3HR-1 cells) and increases of approximately 20-fold in the average number of EBV DNA equivalents in superinfected Raji cells and in TPA- and sodium n-butyrate-induced P3HR-1 cells. However, the content of EBNA in these cells dropped. This was revealed by a decrease in both the complement-fixing antigen content and in the proportion of EBNA-positive cells as determined by anti-complement immunofluorescence. Thus, the positive correlation found previously between the content of EBNA and the number of EBV genome equivalents per cell in proliferating lymphoblastoid cultures does not seem to apply to the situation in either superinfected Raji cells or in P3HR-1 cells induced by TPA and sodium n-butyrate.


Use of antacids, alginates and proton pump inhibitors: a survey of the general Danish population using an internet panel.
Both over-the-counter medicine, such as antacids or alginates, and proton pump inhibitors (PPI) are used for treating acid-related disorders. We sought to describe what characterizes users of these different medicines, including long-term PPI users within the general population. A cross-sectional survey was conducted in an internet panel representative of the Danish adult population in 2012. Data queried included antacid/alginate and PPI use, reason for therapy, co-medication, and presence of upper gastrointestinal symptoms. Long-term PPI use was defined as using PPI ≥1/3 of the last year (∼120 days). Risk of long-term PPI use was estimated by logistic regression. A total of 18,223 people received the questionnaire, of which 52% (9390) responded. Antacid/alginate use was reported by 23%; 16% reported use of only antacid/alginate. PPI use was reported by 13.6%; 6.2% were defined as long-term PPI users. Antacid/alginate users were younger, used less co-medication, had most often started on therapy because of reflux symptoms, and had less often ongoing symptoms. Risk of long-term PPI use appeared to be increased in male gender, by renewing PPI prescription by phone/e-mail, using co-medication, and having started on PPI for several reasons. Combination of antacid/alginate and PPI was reported by approximately 50% of those on therapy with weekly or daily symptoms. 23% of Danish adults were using antacids or alginates and 14% were using PPI, of which one-half were on long-term therapy. Prescription renewal by phone or e-mail and use of other prescription medication were associated with long-term PPI use, indicating a behavioral pattern, in which unnecessary PPI therapy may be maintained.


Human motor fatigability as evoked by repetitive movements results from a gradual breakdown of surround inhibition.
Motor fatigability emerges when demanding tasks are executed over an extended period of time. Here, we used repetitive low-force movements that cause a gradual reduction in movement speed (or 'motor slowing') to study the central component of fatigability in healthy adults. We show that motor slowing is associated with a gradual increase of net excitability in the motor network and, specifically, in primary motor cortex (M1), which results from overall disinhibition. Importantly, we link performance decrements to a breakdown of surround inhibition in M1, which is associated with high coactivation of antagonistic muscle groups. This is consistent with the model that a loss of inhibitory control might broaden the tuning of population vectors such that movement patterns become more variable, ill-timed and effortful. We propose that the release of inhibition in M1 is an important mechanism underpinning motor fatigability and, potentially, also pathological fatigue as frequently observed in patients with brain disorders.


[Relapsing borrelioses fevers: forgotten and new ones].
Relapsing fever borrelioses are widely spread in the endemic regions of Eurasia, Africa, and America as before and account for significant morbidity and mortality; however, these infections have been recently underestimated. The pathogens of the fevers are the Borrelia species transmitted by ticks of the Ornithodoros genus; they genetically differ from the pathogens of Lyme borreliosis--Borrelia burgdorferi sensu lato transmitted by Ixodes ticks. The species Borrelia miyamotoi belongs to the genetic species of Borrelia, the causative agents of relapsing fevers. The authors found Borrelia of this species in the Ixodes ticks of Russia and first showed that B. miyamotoi were able to induce multiple cases in man, which had been earlier diagnosed as erythema-free Ixodes tick-borne borreliosis. The review considers the pathogenesis, clinical picture, diagnosis, and treatment of "old" relapsing fever borrelioses versus the available data on the "new" infection caused by B. miyamotoi. This must assist Russian physicians and scientists both to treat "old" and new tick-borne relapsing borrelioses and to schedule studies of the "new" B. myamotoi infection.


Surgery of the ear and the lateral skull base: pitfalls and complications.
Surgery of the ear and the lateral skull base is a fascinating, yet challenging field in otorhinolaryngology. A thorough knowledge of the associated complications and pitfalls is indispensable for the surgeon, not only to provide the best possible care to his patients, but also to further improve his surgical skills. Following a summary about general aspects in pre-, intra-and postoperative care of patients with disorders of the ear/lateral skull base, this article covers the most common pitfalls and complications in stapes surgery, cochlear implantation and surgery of vestibular schwannomas and jugulotympanal paragangliomas. Based on these exemplary procedures, basic "dos and don'ts" of skull base surgery are explained, which the reader can easily transfer to other disorders. Special emphasis is laid on functional aspects, such as hearing, balance and facial nerve function. Furthermore, the topics of infection, bleeding, skull base defects, quality of life and indication for revision surgery are discussed. An open communication about complications and pitfalls in ear/lateral skull base surgery among surgeons is a prerequisite for the further advancement of this fascinating field in ENT surgery. This article is meant to be a contribution to this process.


Risk analysis of prethreshold retinopathy of prematurity.
To present a new multifactorial algorithm to integrate important risk factors for unfavorable retinal outcome in eyes that reached prethreshold retinopathy of prematurity (ROP) in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study. A computerized risk model (RM-ROP2) was developed from this algorithm to identify high-risk prethreshold eyes for enrollment in the Early Treatment for Retinopathy of Prematurity randomized trial. Data were analyzed from 613 eyes (1 eye per infant) in the natural history cohort of the Multicenter Trial for Cryotherapy for Retinopathy of Prematurity. These eyes were selected from infants in whom 1 or both eyes progressed to prethreshold ROP. Eyes that progressed to threshold ROP and were randomized to cryotherapy were excluded from this study, but control eyes that reached threshold ROP were included. The course of ROP for 1 prethreshold eye for each infant was tracked until the evaluation of its structural outcome at 3 months' postterm. Tables present structural outcome by selected risk characteristics. A multiple logistic risk model is used to summarize the combined effect of all of these known prognostic risk factors as they relate to structural outcome. Eyes were classified by predicted outcome into 10 risk categories, lowest to highest. Both the observed and predicted outcomes in each category showed an increasingly unfavorable outcome when viewed from lowest to highest risk. Prethreshold ROP eyes were then divided into 2 groups, high-risk, eyes (risk, 0.15-1.0) and low-risk eyes (risk, <0.15). High-risk eyes had an unfavorable outcome of 36% at 3 months' postterm; whereas, only 5% of the low-risk eyes had an unfavorable outcome. The model effectively identifies prethreshold ROP eyes that have a relatively high risk and eyes that have a lower risk of an unfavorable structural outcome at 3 months.


Percutaneous transhepatic cholangiography.
This is an evaluation of percutaneous transhepatic cholangiography, a technique of over eight years' standing, previously considered by many authorities as both unrewarding and dangerous. The value and risks of the procedure have been examined in 20 patients with obstructive jaundice of uncertain origin and in one further patient with a post-cholecystectomy syndrome. The presence and the nature of extrahepatic obstructive lesions was correctly diagnosed in 10 of 11 patients shown to have this cause for jaundice. The failure to obtain cholangiograms in the remaining 10 patients was correctly correlated with the presence of intrahepatic obstructive disease due to hepatitis or primary biliary cirrhosis. The risks of percutaneous cholangiography seem over-rated, biliary peritonitis occurring in under 5% of patients submitted to the procedure.


Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.
The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.


[The Karachi health resort: synthesis of science and practice].
This article is devoted to the history of one of the oldest Siberian health resorts known as "The Karachi Lake". It describes the stages of its development, the scientific component of the system of spa-and-resort therapy and medico-social rehabilitation of the patients. The detailed analysis of the mechanisms underlying the beneficial action of the natural therapeutic factors, cooperation with the leading research institutions, and the formation of the modern scientific and technical basis have strengthened the position of the resort on the market of the medical, health-promoting, and recreational services due to the development of the new activities in this field.


Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report.
Poor-insight obsessive-compulsive disorder (PI-OCD) is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI), fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3) blockers, making them preferred choices especially in cases of drug-induced nausea.


Nasal lavage fluid and proteomics as means to identify the effects of the irritating epoxy chemical dimethylbenzylamine.
The aims of this study were to describe the changes in the nasal lavage fluid (NLF) protein pattern after exposure to the irritating epoxy chemical dimethylbenzylamine (DMBA) and to identify the affected proteins using a proteomic approach. The protein patterns of NLF from six healthy subjects and eight epoxy workers with airway irritation were analysed using two-dimensional gel electrophoresis (2-DE) before and after exposure to 100 microg m(-3) DMBA for 2 h in an exposure chamber. NLF proteins were identified by (i) comparison with a 2-DE NLF reference database; (ii) N-terminal amino acid sequencing; and (iii) mass spectrometry. In NLF from healthy subjects, the levels of immunoglobulin A increased and the levels of Clara cell protein 16 (CC16) decreased after chamber exposure, while in NLF from epoxy workers, alpha(2)-macroglobulin and caeruloplasmin increased. Two previously unidentified proteins decreased in NLF from epoxy workers after exposure; these were identified as statherin and calgranulin B. In addition, the subjects who developed high counts of eosinophils in their nasal mucosa after chamber exposure had significantly lower levels of immunoglobulin-binding factor (IgBF) before exposure than subjects with low eosinophil infiltration. These results show that short-term exposure to DMBA causes distinct changes in NLF proteins. Moreover, three proteins that have previously not been associated with upper airway irritation were identified: statherin, calgranulin B and IgBF. Further studies are needed to investigate whether these proteins may be used as biomarkers of airway irritation and to give new insight into the ways in which occupational exposure to irritants causes inflammation of the airways.


In vitro homology search array comprehensively reveals highly conserved genes and their functional characteristics in non-sequenced species.
With the increase in genomic and transcriptomic data produced by the recent advancements in next generation sequencers and microarrays, it is now easier than ever to conduct large-scale comparative genomic studies for familiar species. However, there are more than ten million species on earth, and the study of all remaining species is not realistic in terms of cost and time. There have been a number of attempts at using microarrays for cross-species hybridization; however, those approaches only utilized the same probes for each species or different probes designed from orthologous genes. To establish easier and cheaper methods for the large-scale comparative genomic study of non-sequenced species, we developed an in vitro homology search array with the aid of a bioinformatic approach to probe design. To perform large-scale genomic comparisons of non-sequenced species, we chose squid, one of the most intelligent species among Protostomes, for comparison with human genes. We designed a microarray using human single copy genes and conducted microarray experiments with mRNAs extracted from the squid. Multi-copy genes could not be detected using the microarray in this study because their sequence similarity caused cross-hybridization. A search for squid homologous genes among human genes revealed that 68% of the human probes tested showed the expression of squid homolog genes and 95 genes were confirmed to be expressed highly in squid. Functional classification analysis showed that these highly expressed genes comprise DNA binding proteins, which are under pressure of DNA level mutation and, consequently, show high similarity at the nucleotide level. Our array could detect homologous genes in squids and humans in spite of the distant phylogenic relationships between the species. This experimental method will be useful for identifying homologs in non-sequenced species, for the development of genetic resources and for the collection of information on biodiversity, particularly when using the genome of sibling or closely related species.


A Balamuthia survivor.
This case report describes a human survivor of Balamuthia mandrillaris infection. This is a free-living amoeba that can cause infection with the devastating consequence of near universally fatal encephalitis. We report this case to demonstrate the possibility of recovery. A 26-year-old Hispanic male, a landscape gardener, presented to the hospital in March 2010 with a two month history of headache, visual disturbances and new-onset seizures. Brain imaging identified two enhancing central lesions and Balamuthia mandrillaris was later identified by brain biopsy. He received several months of various antimicrobials including miltefosine, a novel use of the drug in this disease at the time. Seven weeks into therapy, considerations were made to switch him to 'comfort care' because of worsening clinical status and seemingly lack of response to treatment. The patient finally demonstrated clinical and radiological improvement after eight weeks with modified therapy, despite experiencing some debilitating toxic effects likely to be related to antibiotics. Two years after his initial presentation he made a complete recovery. Balamuthia mandrillaris amoebic encephalitis is considered an almost universally fatal disease; this case demonstrates the possibility of recovery. This report outlines his treatment, drug toxicities and includes additional information regarding the therapeutic use of the drug miltefosine. Whether his survival is related to the specific antimicrobials used in this case is unknown and further investigation is warranted.


Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis.
Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein-associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis.


Heterogeneous expression of cytokeratins in metastatic mammary adenocarcinoma cells in vitro and in vivo.
The expression of cytokeratins was investigated in rat 13762NF adenocarcinoma cell lines and clones growing in vitro and in vivo. The anti-cytokeratin monoclonal antibody PKK1 used in this study recognized one cytokeratin with a molecular weight of 54,000 in these cells. Immunofluorescence staining of cultured tumor cells with PKK1 detected cytokeratins in less than 1% of the tumor cells isolated from the locally growing parental tumors, but intense cytokeratin staining in the form of fibrils and networks was found in the cell cultures derived from spontaneous metastases. There were variable degrees of staining with the anti-cytokeratin antibody in cultured cells from metastases, indicating phenotypic diversity in the expression of cytokeratins. Staining with PKK1 of frozen sections from locally growing tumors obtained after injecting the cells into the mammary fat pads of syngeneic rats also demonstrated considerable heterogeneity in cytokeratin expression. The anti-cytokeratin reagent stained only a few, isolated cells in frozen sections of tumors established from parental tumor cells, while this reagent stained intensely cells in local tumors and their metastases established from tumor cells cultured from spontaneous lymph node or lung metastases.


Constant relative age and size at sex change for sequentially hermaphroditic fish.
A general problem in evolutionary biology is that quantitative tests of theory usually require a detailed knowledge of the underlying trade-offs, which can be very hard to measure. Consequently, tests of theory are often constrained to be qualitative and not quantitative. A solution to this problem can arise when life histories are viewed in a dimensionless way. Recently, dimensionless theory has been developed to predict the size and age at which individuals should change sex. This theory predicts that the size at sex change/maximum size (L50/L(max)), and the age at sex change/age at first breeding (tau/alpha) should both be invariant. We found support for these two predictions across 52 species of fish. Fish change sex when they are 80% of their maximum body size, and 2.5 times their age at maturity. This invariant result holds despite a 60 and 25 fold difference across species in maximum size and age at sex change. These results suggest that, despite ignoring many biological complexities, relatively simple evolutionary theory is able to explain quantitatively at what point sex change occurs across fish species. Furthermore, our results suggest some very broad generalities in how male fitness varies with size and age across fish species with different mating systems.


A high-throughput and multiplex microsphere immunoassay based on non-structural protein 1 can discriminate three flavivirus infections.
The explosive spread of Zika virus (ZIKV) and associated complications in flavivirus-endemic regions underscore the need for sensitive and specific serodiagnostic tests to distinguish ZIKV, dengue virus (DENV) and other flavivirus infections. Compared with traditional envelope protein-based assays, several nonstructural protein 1 (NS1)-based assays showed improved specificity, however, none can detect and discriminate three flaviviruses in a single assay. Moreover, secondary DENV infection and ZIKV infection with previous DENV infection, both common in endemic regions, cannot be discriminated. In this study, we developed a high-throughput and multiplex IgG microsphere immunoassay (MIA) using the NS1 proteins of DENV1-DENV4, ZIKV and West Nile virus (WNV) to test samples from reverse-transcription-polymerase-chain reaction-confirmed cases, including primary DENV1, DENV2, DENV3, WNV and ZIKV infections, secondary DENV infection, and ZIKV infection with previous DENV infection. Combination of four DENV NS1 IgG MIAs revealed a sensitivity of 94.3% and specificity of 97.2% to detect DENV infection. The ZIKV and WNV NS1 IgG MIAs had a sensitivity/specificity of 100%/87.9% and 86.1%/78.4%, respectively. A positive correlation was found between the readouts of enzyme-linked immunosorbent assay and MIA for different NS1 tested. Based on the ratio of relative median fluorescence intensity of ZIKV NS1 to DENV1 NS1, the IgG MIA can distinguish ZIKV infection with previous DENV infection and secondary DENV infection with a sensitivity of 88.9-90.0% and specificity of 91.7-100.0%. The multiplex and high-throughput assay could be applied to serodiagnosis and serosurveillance of DENV, ZIKV and WNV infections in endemic regions.


The prognostic significance of clinical and pathological features in hepatocellular carcinoma.
The prognosis of patients with HCC still remains dismal. The life expectancy of HCC patients is hard to predict because of the high possibility of postoperative recurrence. Many factors, such as patient's general conditions, macroscopic tumor morphology, as well as tumor histopathology features, have been proven of prognostic significance. Female HCC patient often has a better prognosis than male patient, which might be due to the receptor of sex hormones. Younger patients often have tumors with higher invasiveness and metastatic potentials, and their survival and prognosis are worse than the older ones. Co-existing hepatitis status and hepatic functional reserve have been confirmed as risk factors for recurrence. Serum alpha-fetoprotein (AFP) is useful not only for diagnosis, but also as a prognostic indicator for HCC patients. AFP mRNA has been proposed as a predictive marker of HCC cells disseminated into the circulation and for metastatic recurrence. Many pathologic features, such as tumor size, number, capsule state, cell differentiation, venous invasion, intrahepatic spreading, and advanced pTNM stage, are the best-established risk factors for recurrence and important aspects affecting the prognosis of patients with HCC. Marked inflammatory cell infiltration in the tumor could predict a better prognosis. Clinical stage is still the most important factor influencing on the prognosis. Extratumor spreading and lymph nodal metastasis are independent predictors for poor outcome. Some new predictive systems have recently been proposed. Different strategies of treatment might have significant different effects on the patients' prognosis. To date, surgical resection is still the only potentially curative treatment for HCC, including localized postoperative recurrences. Extent of resection, blood transfusion, occlusion of porta hepatis, and blood loss affect the survival and prognosis of HCC patients. Regional therapies provide alternative ways to improve the prognosis of HCC patients who have no opportunity to receive surgical treatment or postoperative recurrence. The combination of these treatment modalities is hopeful to further improve the prognosis. The efficacies of neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy or chemoembolization in preventing recurrence and on the HCC prognosis still remain great controversy, and deserve further evaluation. Biotherapy, including IFN-alpha therapy, will play more important role in preventing recurrence and metastasis of HCC after operation.


Treating Epilepsy Patients with Investigational Anti-COVID-19 Drugs: Recommendations by the Israeli Chapter of the ILAE.
The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy.


KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes.
An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.


Nadir CD4 Is Negatively Associated With Antinuclear Antibody Detection in HCV/HIV-Coinfected Patients.
Hepatitis C virus (HCV) and HIV infections are associated with higher risk of autoimmune diseases and T-cell dysfunction. We evaluate prevalence and factors associated with the presence of autoimmune antinuclear (ANA), anti-smooth muscle actin (aSMA), and anti-liver kidney microsome (aLKM1) antibodies (Ab) in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era. A cross-sectional observational study nested in the ANRS CO13 HEPAVIH cohort (NCT number: NCT03324633). We selected patients with both ANA testing and T-cell immunophenotyping determination during the cohort follow-up and collected aLKM1 and aSMA data when available. Logistic regression models were built to determine factors associated with the presence of auto-Ab. Two hundred twenty-three HCV/HIV-coinfected patients fulfilled selection criteria. Prevalence of ANA and aSMA was 43.5% and 23.2%, respectively, and both were detected in 13.3% of patients. Isolated aSMA were detected in 9.9% and aLKM1 in 2 patients. In multivariable analysis, only a low nadir CD4 T-cell count was significantly associated with ANA detection. ANA and aSMA detection remain frequent in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era, despite fair immune restoration. These results advocate for a close monitoring of ANA before immune checkpoint inhibitor therapy in these patients with greater caution for those with a low nadir CD4 T-cell count.


Outpatient genetic risk assessment in women with breast cancer: one center's experience.
A chart audit at one cancer center, of 193 women with breast cancer, was completed to assess whether a complete family history that may indicate genetic predisposition was obtained and if that information led a provider to suggest risk reduction strategies. A risk management tool, which included a pedigree template, was used. Of the 193 charts reviewed, 88.6% had family history information recorded; 41.5% reported three generations of family history. Risk management was undocumented in 21.8% of the charts reviewed and, for those that were reported (78.2%), 7.25% were referred for genetic counseling. These results suggest that a more detailed assessment of hereditary breast cancer risk incorporating three generations of family history and additional types of cancer need to be integrated into medical oncology practice. An algorithm was developed as a guide to improve the process of evaluation and referral for genetic risk assessment.


Leukotrienes and sex: strange bedfellows?
Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease.


Assessment of physical activity in patients with chronic low back or neck pain.
To investigate physical activity level in patients with chronic low back and neck pain. 32 preoperative patients, 32 outpatients with low back or neck pain and 32 healthy controls were included in study. The physical activity level of the participants was evaluated with the International Physical Activity Questionnaire. The Oswestry Disability Index and Neck Pain Disability Index, Short Form-36, Pittsburgh Sleep Quality Index and Beck Depression Inventory were used for assessment of disability, quality of life, sleep quality and depression. Statistical significant differences was found in disability, sleep quality, depression, physical activity level and quality of life scores between three groups (p < 0.05). All scores of preoperative patients were significantly lower than outpatients except sleep parameter (p < 0.05). Sleep quality, disability and depression scores of patients with chronic neck pain were significantly lower and physical activity level and quality of life scores were significantly higher than patients' with chronic low back pain (p < 0.05). Physical activity modification was found in patients with chronic low back and neck pain. Physical activity level, disability, sleep, depression and quality of life scores of preoperative patients with low back pain more affected than neck patients.


Clinical features and survival impact of EBV-positive diffuse large B-Cell lymphoma with different age cutoffs.
In 2016 WHO classification, EBV +DLBCL of the elderly was replaced by EBV+ DLBCL NOS. This is due to the fact that many young patients of EBV+ DLBCL were found in recent years. In this study, we retrospectively analyzed clinical features and survival outcomes of EBV positive DLBCL patients in different age groups. All the patients treated at a single center. When we use different ages (40, 50 and 60 years old) as cutoffs, the prevalence of EBV positive DLBCL was 12.0%, 12.3% and 13.0% in younger patients and 19.0%, 15.4% and 13.8% in elder patients respectively. Whatever the age cutoff was, EBV positive associated with unfavorable clinical prognosis in elder groups. When we use 40 and 50 years old as age cutoffs, poor impacts of EBV positive on overall survival and progression-free survival were observed only in elder patients, but not in younger patients. It should be noted that when we use 60 years old as age cutoff, the results were the opposite. EBV+ DLBCL patients with age of 40 to 60 years old showed poorer prognostic features than EBV- DLBCL patients; however, patients in other age groups did not show evident differences in prognosis between EBV+ DLBCL patients and EBV- DLBCL patients. This finding was not reported before.


Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis.
Parkinson's disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD. We established inducible PC12 cell lines in which wild-type or mutant alpha-synuclein can be de-repressed by removing doxycycline. Differentiated PC12 cell lines expressing mutant alpha-synuclein showed decreased activity of proteasomes without direct toxicity. Cells expressing mutant alpha-synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A. These data suggest that expression of mutant alpha-synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.


Pulmonary venous remodeling in COPD-pulmonary hypertension and idiopathic pulmonary arterial hypertension.
Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure ( P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide ( P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling ( P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.


Continuous-index hidden Markov modelling of array CGH copy number data.
In recent years, a range of techniques for analysis and segmentation of array comparative genomic hybridization (aCGH) data have been proposed. For array designs in which clones are of unequal lengths, are unevenly spaced or overlap, the discrete-index view typically adopted by such methods may be questionable or improved. We describe a continuous-index hidden Markov model for aCGH data as well as a Monte Carlo EM algorithm to estimate its parameters. It is shown that for a dataset from the BT-474 cell line analysed on 32K BAC tiling microarrays, this model yields considerably better model fit in terms of lag-1 residual autocorrelations compared to a discrete-index HMM, and it is also shown how to use the model for e.g. estimation of change points on the base-pair scale and for estimation of conditional state probabilities across the genome. In addition, the model is applied to the Glioblastoma Multiforme data used in the comparative study by Lai et al. (Lai,W.R. et al. (2005) Comparative analysis of algorithms for identifying amplifications and deletions in array CGH data. Bioinformatics, 21, 3763-3370.) giving result similar to theirs but with certain features highlighted in the continuous-index setting.


Bimanual finger tapping: effects of frequency and auditory information on timing consistency and coordination.
The authors' goal in this study was to probe the basis for an earlier, unexpected finding that preferred-frequency finger tapping tends to have higher frequencies and to be less stable for in-phase than for antiphase tasks. In follow-up experiments, 3 protocols were employed: a preferred-frequency replication in both coordination modes, a metronome-driven matching of the preferred frequencies to each of the coordination modes, and a frequency scaling of both modes. The original findings were affirmed for preferred frequency. Tapping to a metronome had a differential effect on in-phase and antiphase: A more stable coupling across frequencies was exhibited during in-phase. Under frequency scaling, the antiphase pattern decomposed at lower frequencies than did in-phase, but no phase transitions were observed. The loss of stable coordination in both modes was attended by sudden increases in frequency differences between fingers and by phase wandering. The emergence of those effects is discussed in light of asymmetric modifications to the Haken-Kelso-Bunz model (H. Haken, J. A. S. Kelso, & H. Bunz, 1985) and the task constraints of tapping.


Temporal Shift Module (TSM) Based Automatic Fall Detection with Bounding Box Grounding.
Fall detection is one of the important tenets of remote geriatric care operations. Fall is one of the main causes of injury in old individuals leading to fractures, concussions, and different issues that might lead to prompt demise. In a world increasingly making the elderly live in isolation, accurate and real-time detection of falls is very important to remote caregivers to be able to provide timely medical assistance. Recent advancements in vision-based technologies have got promising results; however, these models are often trained on acted datasets and their appropriateness for application in the wild is not well established. In this paper, we propose a vision-based fall detection mechanism that improves the accuracy of in-the-wild complex events. The proposed system is built leveraging Temporal Shift Module (TSM) with a bounding box grounding (BBG) approach for accurate Region Of Interest (ROI) sequence generation when sudden deformation in the shape is observed. Compared to the general 3D CNN based approaches, the proposed model achieves better accuracy while maintaining the level of computational complexity at that of the 2D CNN models. The proposed approach demonstrates promising performance on both acted and in-the-wild datasets.


Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1.
The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.


[Morphology of the blackfly species group macropyga of the genus Prosimulium roubaud, 1906, and re-establishment of the generic name Taeniopterna Enderlein, 1925 for this group (Diptera: Simuliidae)].
The genus Taeniopterna with the types species Melusina macropyga Lundstrom, 1911 was proposed by Enderlein in 1925. Later this taxon was considered as the species group macropyga in the genus Prosimulium Roubaud, 1906 by many authors (Rubzov, 1956; Crosskey et Howard, 1997; Adler et al., 2004, and others). However, differences between this group and the remaining species of Prosimulium s. str. (species group hirtipes/mixtum) seem to be not lesser, than those between other genera (or subgenera) of the tribe Prosimuliini (in our sense), namely Helodon Enderlein, 1921, Urosimulium Contini, 1963, Parahelodon Peterson, 1970, and Distosimulium Peterson, 1970. Taeniopterna differs from other genera of Prosimuliini by the following characters. Imago differs from all other genera in having shortened proboscic (1.5 times shorter than clypeus, while in other genera it is of the same length with clypeus). It differs from all genera except Helodon in having relatively prolonged and lightly pointed distally wings (in other genera wings are wide and rounded distally). Male differs from all other genera of the tribe, except Urosimulium, in having narrow frons between the eyes. It differs from the Urosimulium male by conic gonostyles (in Urosimulium gonostyles bear the large heel). Female differs from all other genera of tribe by very small spermatheca (1/3-1/5 of the lenght of the branch of genital fork (while in other genera spermatheca is equal or longer, than the branch of genital fork) and by the absence of serration on maxillae and mandibles. Female also differs from other genera of the tribe, except Prosimulium, by very long hypogynal valves and by missing or very small and pressed basal tooth of claws (in Helodon, Urosimulium, Parahelodon, and Distosimulium hypogynal valves are short and rounded, basal tooth of claws is moderate or large and put aside). It differs from Prosimulium by smaller head (more narrow than thorax, while in Prosimulium head is near equal by width with thorax) and by absence of sclerotization on the medial edges of hypogynal valves. Larva differs from all other genera of the tribe, except Prosimulium, in having long dorsoventral projections of wide sclerotized band of prothorax (in other genera this band is narrow and without projections). It differs from Prosimulium by another pattern of the hypostomal teeth. Pupa differs from all other genera of the tribe, except Distosimulium, by cocoon covering all the pupal body (in other genera cocoon covers only posterior part of the pupal body). It differs from Distosimulium by long and strong caudal thorns (in Distosimulium caudal thorns are of moderate length and more thin). These and some other characters give the base for the proposition to consider the species group macropyga as a a separate genus Taeniopterna Enderlein, 1925. A list of Taeniopterna species is given.


Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience.
Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow-up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach.


Mechanisms and Factors Associated With Tackle-Related Injuries in South African Youth Rugby Union Players.
The majority of injuries in rugby union occur during tackle events. The mechanisms and causes of these injuries are well established in senior rugby union. To use information from an injury database and assess video footage of tackle-related injuries in youth rugby union matches to identify environmental factors and mechanisms that are potentially confounding to these injuries. Descriptive epidemiological study. Injury surveillance was conducted at the under-18 Craven Week rugby tournament. Tackle-related injury information was used to identify injury events in match video footage (role-matched noninjury tackle events were identified for the cohort of injured players). Events were coded using match situational variables (precontact, contact, and postcontact). Relative risk ratio (RRR; ratio of probability of an injury or noninjury outcome occurring when a characteristic was observed) was reported by use of logistic regression. In comparison with the first quarter, injury risk was greater in the third (RRR = 9.75 [95% CI, 1.71-55.64]; P = .010) and fourth quarters (RRR = 6.97 [95% CI, 1.09-44.57]; P = .040) for ball carriers and in the fourth quarter (RRR = 9.63 [95% CI, 1.94-47.79]; P = .006) for tacklers. Ball carriers were less likely to be injured when they were aware of impending contact (RRR = 0.14 [95% CI, 0.03-0.66]; P = .012) or when they executed a moderate fend (hand-off) (RRR = 0.22 [95% CI, 0.06-0.84]; P = .026). Tacklers were less likely to be injured when performing shoulder tackles (same side as leading leg) in comparison to an arm-only tackle (RRR = 0.02 [95% CI, 0.001-0.79]; P = .037). Ball carriers (RRR = 0.09 [95% CI, 0.01-0.89]; P = .040) and tacklers (RRR = 0.02 [95% CI, 0.001-0.32]; P =.006) were less likely to be injured when initial contact was made with the tackler's shoulder/arm instead of his head/neck. The relative risk of tackle-related injury was higher toward the end of matches. Incorrect technique may contribute to increased injury risk. Implementing recovery strategies between matches, training safe and effective techniques, and improving levels of conditioning may counter the negative effects of fatigue. These findings may assist stakeholders in youth rugby to formulate injury prevention strategies and may improve the preparation of field-side medical staff for managing tackle-related injuries at these or similar tournaments.


Immortalization by c-myc, H-ras, and Ela oncogenes induces differential cellular gene expression and growth factor responses.
Early-passage rat kidney cells were immortalized or rescued from senescence with three different oncogenes: viral promoter-driven c-myc, H-ras (Val-12), and adenovirus type 5 E1a. The normal c-myc and H-ras (Gly-12) were unable to immortalize cells under similar conditions. Quantitation of RNA in the ras-immortalized lines demonstrated that the H-ras oncogene was expressed at a level equivalent to that of the normal H-ras gene in established human or rat cell lines. Cell lines immortalized by different oncogenes were found to have distinct growth responses to individual growth factors in a short-term assay. E1a-immortalized cells were largely independent of serum growth factors, whereas c-myc-immortalized cells responded to serum better than to epidermal growth factor and insulin. H-ras-immortalized cells responded significantly to insulin alone and gave a maximal response to epidermal growth factor and insulin. Several cellular genes associated with platelet-derived growth factor stimulation, including c-myc, were expressed at high levels in the H-ras-immortalized cells, and c-myc expression was deregulated, suggesting that the H-ras oncogene has provided a "competence" function. H-ras-immortalized cells could not be morphologically transformed by secondary transfection with a long terminal repeat-c-myc oncogene, but secondary transfection of the same cells with H-ras (Val-12) produced morphologically transformed colonies that had 20- to 40-fold higher levels of H-ras oncogene expression. Thus, transformation in this system is dependent on high levels of H-ras oncogene expression rather than on the presence of activated H-ras and c-myc oncogenes in the same cell.


Role of Doppler ultrasound flowmetry in the diagnosis of breast lumps.
One hundred and five patients with discrete breast lumps were examined with a 10 MHz Doppler ultrasonic flowmeter. Doppler flow signals were analysed on an Angioscan spectrum analyser. Recordings from the opposite normal breast were taken as controls and signals from the two sides compared. In 23 patients signals from the normal breast could not be recorded and therefore results of the remaining 82 patients are reported. These included 39 patients with carcinoma, 20 with fibroadenoma, 12 with cyclical nodularity and 11 with cysts. Malignant lumps exhibited significantly higher peak systolic (S) and minimum diastolic frequencies (D) in comparison to the control breast. Fibroadenoma also had a higher S and D than those of the opposite normal breast. Signals over cysts and cyclical nodularity showed no significant difference from the recordings over the control side. Despite significantly higher systolic and diastolic frequencies in the cancer group in comparison to benign lumps and normal breast, considerable overlap in the values was seen between cancer and other groups. Therefore the patterns on 10 MHz Doppler sonography are not sufficiently specific to discriminate benign from malignant breast lumps.


[The importance of the gender perspective in health interview surveys].
The identification and measurement of the population health needs should be the first step in health planning. In order to guarantee equity criteria, to know the situation of the whole population, and therefore also that of women, is a key issue. Health interview surveys are a good tool for pinpointing the needs of the population, but mainly they are usually focused on health risk factors that explain men's health status such as health behaviours and paid job. These factors often fail to capture aspects that are relevant for women's health, such as household work. The main objective of this paper is to emphasise the importance of a gender perspective in the design and analysis of health interview surveys, and to propose variables that should be included in health surveys in order to better know gender health inequalities. Likewise, this article deals with the gender concept and its importance as a health inequality factor. Gender is an analytical construct based on the social organisation of the sexes that can be used to better understand the conditions and factors influencing women's and men's health beginning by the social roles that each culture and society assigns to people based on their sex. Health is a complex process determined by a wide range of factors: biological, social, environmental and health services related factors. Gender, because of its close relation to all of them, plays a key role. The gender approach is characterised by the analysis of the social relation between men and women, taking into account that sex is a determinant of social inequalities. This paper presents the variables that health interview surveys should include from a gender approach point of view: reproductive work, productive work, social class, social support, self-perceived health status, quality of life, mental health and chronic conditions. In addition, issues related to the wording of questions, data collection and analysis are discussed.


Paving the way for increased e-health record use: elaborating intentions of Gen-Z.
This paper presents the determinants of personal e-health records adoption by the Gen-Z population and reveals barriers to use. Gen-Z members are one of the most prominent users of digital health services that have an influence on older generations' technology adoption but have often been overlooked in scholarly research. A survey of 1,000 Gen-Z university students based on modified UTAUT was used to address this research gap. The analysis revealed the vital role of social influence in paving the way for higher adoption among Gen-Z. Moreover, significant influences of performance expectancy, facilitating conditions, and e-health literacy on behavioural intentions were detected. Effort expectancy was found to be insignificant in impacting Gen-Z's intentions to adopt electronic health record systems. Moreover, privacy concerns acted as a barrier to adoption, yet the offsetting effect of users' trust in health systems was shown to be instrumental in overcoming such privacy-related barriers.


Peroral immunotherapy with yolk antibodies for the prevention and treatment of enteric infections.
Oral administration of specific antibodies is an attractive approach to establish protective immunity against gastrointestinal pathogens in humans and animals. The increasing number of antibiotic-resistant bacteria emphasize the need to find alternatives to antibiotics. Immunotherapy can also be used against pathogens that are difficult to treat with traditional antibiotics. Laying hens are very good producers of specific antibodies. After immunization, the specific antibodies are transported to the egg yolk from which the antibodies then can be purified. A laying hen produces more than 20 g of yolk antibodies (IgY) per year. These antibodies also have biochemical properties that make them attractive for peroral immunotherapy: They neither activate mammalian complement nor interact with mammalian Fc receptors that could mediate inflammatory response in the gastrointestinal tract. Eggs are also normal dietary components and thus there is practically no risk of toxic side effects of IgY. Yolk antibodies have been shown in several studies to prevent bacterial and viral infections.


Large endometrial polyp with sarcomatous stromal components following long-term tamoxifen treatment for breast cancer: a case report and review of the literature.
Tamoxifen is commonly used in the management of patients with breast cancer because of its anti-oestrogenic effects to the breasts. However, tamoxifen acts as an oestrogen agonist on the endometrium increasing the incidence of endometrial polyps, hyperplasia and cancer. In addition, it may be possible that tamoxifen increases the occurrence of uterine body tumours. We describe a rare case of a large endometrial polyp with sarcomatous stromal components in a 73-year-old breast cancer patient treated daily with 20 mg of tamoxifen for four years. The glands of the polyp were lined by benign appearing epithelium. The polyp was twisted and protruded from a dilated cervix at the entrance of the vagina. The patient was treated by removal of the polyp and dilatation and curretage. A postoperative computed tomography scan showed many focal hypodense lesions in the hepatic lobes with a well-defined profile suggestive of metastatic disease and the patient was referred for combined chemotherapy. In conclusion, a case of a mesenchymal malignant neoplasm arising in the uterus of a breast cancer patient treated with tamoxifen is reported and its clinical, histological and immunohistochemical features are discussed. Also, the international literature is reviewed.


Gender differences in tobacco smoking dynamics and the neuropharmacological actions of nicotine.
Previous studies have found gender differences in the dynamics of tobacco smoking and cessation in humans. However the physiological basis for these differences is a subject of much debate. Animal studies have also revealed some gender-dependant differences in the neuropharmacological actions of acute and chronic nicotine. The purpose of this article is to review the clinical and basic science studies that have evaluated sex differences in tobacco use/cessation and the animal literature that has provided some clues regarding the possible underlying basis for these differences. The acute and chronic actions of ovarian steroid hormones on nicotinic receptors could play a direct or indirect role in mediation of gender differences in tobacco use dynamics, however no clear picture has emerged from these studies. The literature supports a general consensus women have a more difficult time with smoking cessation and that perhaps nicotine replacement therapy is less efficacious in female smokers. This could be due to alterations in nicotine pharmacokinetics mediated by estrogen, ovarian hormones acting as non-competitive nicotinic receptor antagonists, or many additional issues. Many studies assume that individuals, regardless of gender, have the same motivation for tobacco use and/or cessation. Individual reasons for smoking may simply override gender differences in the pharmacodynamic/pharmacokinetic actions of nicotine. Many animal studies that have reported gender differences in nicotine sensitivity have not carefully controlled for phase of the estrus cycle, and the results of preclinical studies do not always support conclusions that have been drawn from human studies. Thus there are still many questions that remain to be answered in this important area of research.


Adapting Medication for Type 2 Diabetes to a Low Carbohydrate Diet.
Healthcare professionals in the primary care setting need to be competent to safely adapt diabetes medications when patients with Type 2 Diabetes (T2D) alter their diet. Safe prescribing practice is supported through an understanding of the clinical evidence, basic science, and pharmacology of medications. This review article supports clinicians in the practical application of this knowledge to achieve safe practice. Traditional medical training and clinical practice for chronic disease has long revolved around the teaching of intensifying therapy and evidenced based prescribing, a crucial skill when chronic disease progresses. Now that we are witnessing remission of Type 2 Diabetes through nutritional interventions specifically low carbohydrate diets (LCD) we must apply the same effort and thought to de-prescribing as the underlying metabolic condition improves. There is minimal guidance in the literature on how to actively de-prescribe. The American Diabetes Association in their Standards of Medical Care in Diabetes-2021 acknowledges low carbohydrate nutritional therapy (LCD) as a viable option in the management of Type 2 Diabetes (T2D). Thus, the goal of our paper is to help close the gap between the clinical evidence, basic science, and pharmacology of T2D medications to the practical application and teamwork needed to facilitate safe medication reduction in the primary care setting when applied to a LCD. The LCD is an increasingly popular and effective option for managing T2D and can lead to an improvement in the condition, reduced medication burden, and contribute to significant weight loss. Safe initiation of a LCD in patients on medications requires significant monitoring and medication adjustments to decrease and eliminate the risk of hypoglycemia and hypotension. The health care team including clinicians in primary care, nursing, pharmacy and nutrition need to be competent in adjusting diabetes and antihypertensive medications to achieve safe and effective care. The most immediate and important adjustments are to insulin, sulfonylureas, SGLT2 inhibitors, blood pressure medications and diuretics. Interdisciplinary care teams can individualize therapy while following the guidance, which includes monitoring blood glucose and blood pressure closely, decreasing medications that can cause hypoglycaemia and hypotension, evaluating blood glucose and blood pressure data responses regularly, and open access communication with the team. The article is an international consensus document on de-prescribing that was put together by a multidisciplinary team of clinicians.


Ranking of psychosocial and traditional risk factors by importance for coronary heart disease: the Copenhagen City Heart Study.
To rank psychosocial and traditional risk factors by importance for coronary heart disease. The Copenhagen City Heart Study is a prospective cardiovascular population study randomly selected in 1976. The third examination was carried out from 1991 to 1994, and 8882 men and women free of cardiovascular diseases were included in this study. Events were assessed until April 2013. Forward selection, population attributable fraction, and gradient boosting machine were used for determining ranks. The importance of vital exhaustion for risk prediction was investigated by C-statistics and net reclassification improvement. During the follow-up, 1731 non-fatal and fatal coronary events were registered. In men, the highest ranking risk factors for coronary heart disease were vital exhaustion [high vs. low; hazard ratio (HR) 2.36; 95% confidence interval (CI), 1.70-3.26; P < 0.001] and systolic blood pressure (≥160 mmHg or blood pressure medication vs. <120 mmHg; HR 2.07; 95% CI, 1.48-2.88; P < 0.001). In women, smoking was of highest importance (≥15 g tobacco/day vs. never smoker; HR 1.74; 95% CI, 1.43-2.11; P < 0.001), followed by vital exhaustion (high vs. low; HR 2.07; 95% CI, 1.61-2.68; P < 0.001). Vital exhaustion ranked first in women and fourth in men by population attributable fraction of 27.7% (95% CI, 18.6-36.7%; P < 0.001) and 21.1% (95% CI, 13.0-29.2%; P < 0.001), respectively. Finally, vital exhaustion significantly improved risk prediction. Vital exhaustion was one of the most important risk factors for coronary heart disease, our findings emphasize the importance of including psychosocial factors in risk prediction scores.


Axillary web syndrome: an underappreciated complication of sentinel node biopsy in melanoma.
Axillary web syndrome (AWS) is known to occur after axillary dissection and has been reported after axillary sentinel lymph node biopsy (ASLNB) for breast cancer. However, the incidence and outcomes of AWS after ASLNB for melanoma are unknown. A retrospective review of prospectively collected, clinically node-negative patients undergoing ASLNB for melanoma at a single institution during a 14-year period was conducted to determine the incidence of AWS. Features pertaining to patients (age and gender), primary tumor (location, Breslow's depth), and nodes (number removed, positive node rate) were correlated with the occurrence of AWS. Of the 465 patients undergoing ASLNB, 21 (4.5%) developed AWS postoperatively. In comparison, the incidence of other complications in this population were infection 3%, bleeding 1.5%, wound dehiscence .8%, lymphocele 5%, and lymphedema .4%. There was no statistical difference between patients with or without AWS in terms of tumor thickness, location of primary (upper extremity vs trunk), average number of sentinel nodes removed, positive SLNB rates (10% vs 12%), patient age, or gender. All cases of AWS resolved with expectant management; none required surgical intervention. AWS is a notable complication of ASLNB for melanoma, with an incidence as high or higher than "standard" complications. AWS should, therefore, be included in the preoperative discussion of possible complications of ASLNB. Traditional patient, tumor, and nodal factors are not predictive of AWS. Patients should be counseled that AWS usually responds to symptomatic treatment and resolves with time.


Lipopolysaccharide enhances the production of vascular endothelial growth factor by human pulp cells in culture.
We investigated whether vascular endothelial growth factor (VEGF) production by human pulp cells (HPC) is regulated by lipopolysaccharide (LPS) in relation to the pathogenesis of pulpitis. Although HPC incubated with medium alone only marginally expressed VEGF mRNA and produced a low level of VEGF as detected by enzyme-linked immunosorbent assay, the VEGF mRNA expression and VEGF production were markedly enhanced upon stimulation with LPS from Escherichia coli. Prevotella intermedia LPS, phorbol 12-myristate 13-acetate, and interleukin-6 also induced VEGF mRNA expression in HPC. A simian virus 40-infected HPC line also exhibited increased VEGF mRNA expression in response to E. coli LPS, but lung and skin fibroblasts did not. Fetal bovine serum (FBS) increased the sensitivity of HPC to LPS in a dose-dependent manner. HPC did not express membrane CD14 on their surfaces. However, the anti-CD14 monoclonal antibody MY4 inhibited VEGF induction upon stimulation with LPS in HPC cultures in the presence of 10% FBS but not in the absence of FBS. LPS augmented the VEGF production in HPC cultures in the presence of recombinant human soluble CD14 (sCD14). To clarify the mechanisms of VEGF induction by LPS, we examined the possible activation of the transcription factor AP-1 in HPC stimulated with LPS, by a gel mobility shift assay. AP-1 activation in HPC was clearly observed, whereas that in skin fibroblasts was not. The AP-1 inhibitor curcumin strongly inhibited LPS-induced VEGF production in HPC cultures. In addition, a protein synthesis inhibitor, cycloheximide, inhibited VEGF mRNA accumulation in response to LPS. These results suggest that the enhanced production of VEGF in HPC induced by LPS takes place via an sCD14-dependent pathway which requires new protein synthesis and is mediated in part through AP-1 activation.


Nasal glioma and encephalocele: diagnosis and management.
To review the biology of nasal glioma and encephalocele and to present an algorithm for preoperative evaluation and surgical management. Retrospective review and analysis. Tertiary care medical center: 1970 to 2002. Sixteen patients with glioma (n = 10) and encephalocele (n = 6). Age at the time of presentation, sex, signs and symptoms, imaging findings, surgical approach, pathology, complications, rate of recurrence, and follow-up were recorded. Ten patients presented with nasal glioma with a mean age of 9 months. All patients underwent surgical excision. No complication was encountered with a mean follow-up of 3.5 years. Six patients presented with encephaloceles with a mean age of 15.5 months. All patients underwent surgical excision. Complications included cerebrospinal fluid leak (n = 1) and epiphora (n = 1). Follow-up was 1 to 14 years (mean, 4 years). Nasal glioma and encephalocele are rare, benign, congenital lesions with a potential for intracranial extension. Evaluation should include a complete rhinologic and neurologic examination. Preoperative imaging with a thin-cut axial and coronal computed tomography scan and/or multiplanar magnetic resonance imaging is essential. Surgical intervention should be performed soon after diagnosis to alleviate the increased risk of meningitis. A frontal craniotomy approach is recommended if intracranial extension is identified based on preoperative evaluation, followed by an extracranial resection. If there is no evidence of intracranial extension, a conservative extracranial approach is recommended.


Escherichia coli uracil DNA glycosylase: NMR characterization of the short hydrogen bond from His187 to uracil O2.
Uracil DNA glycosylase (UDG) cleaves the glycosidic bond of deoxyuridine in DNA using a hydrolytic mechanism, with an overall catalytic rate enhancement of 10(12)-fold over the solution reaction. The nature of the enzyme-substrate interactions that lead to this large rate enhancement are key to understanding enzymatic DNA repair. Using (1)H and heteronuclear NMR spectroscopy, we have characterized one such interaction in the ternary product complex of Escherichia coli UDG, the short (2.7 A) H bond between His187 N(epsilon)(2) and uracil O2. The H bond proton is highly deshielded at 15.6 ppm, indicating a short N-O distance and exhibits a solvent exchange rate that is 400- and 10(5)-fold slower than free imidazole at pH 7.5 and pH 10, respectively. Heteronuclear NMR experiments at neutral pH show that this H bond involves the neutral imidazole form of His187 and the N1-O2 imidate form of uracil. The excellent correspondence of the pK(a) for the disappearance of the H bond (pK(a) = 6.3 +/- 0.1) with the previously determined pK(a) = 6.4 for the N1 proton of enzyme-bound uracil indicates that the H bond requires negative charge on uracil O2 [Drohat, A. C., and Stivers, J. T. (2000) J. Am. Chem. Soc. 122, 1840-1841]. Although the above characteristics suggest a short strong H bond, the D/H fractionation factor of phi = 1.0 is more typical of a normal H bond. This unexpected observation may reflect a large donor-acceptor pK(a) mismatch or the net result of two opposing effects on vibrational frequencies: decreased N-H bond stretching frequencies (phi < 1) and increased bending frequencies (phi > 1) relative to the O-H bonds of water. The role of this H bond in catalysis by UDG and several approaches to quantify the H bond energy are discussed.


Priming with T helper cell epitope peptides enhances the antibody response to the envelope glycoprotein of HIV-1 in primates.
The induction of a memory immune response to HIV, mediated by any kind of effector mechanism, requires the induction of T cell help. In previous studies performed in different murine MHC haplotypes, three immunodominant T cell epitopes (T1, T2, and TH4.1) had been identified in the HIV envelope glycoprotein. Moreover, these peptides were proliferative T cell epitopes in humans. In this study, rhesus monkeys, Macaca mulatta, were primed with these three peptides either in combination or given separately. Half of the monkeys had a proliferative response to one or more of the priming peptide(s). Those monkeys who had a T cell proliferative response also had a high antibody response after one boost with a suboptimal dose of the native protein gp 160, whereas three of four control monkeys who had received only the native protein immunization gave no detectable antibody response, and one displayed a very weak response. For reasons that are unclear, antibodies only to the gp41 portion of gp 160 could be detected in the sera. Thus, the peptides can prime Th cells in primates for an enhanced antibody response on first exposure to the whole protein. The three peptides belong to highly conserved and nonglycosylated regions of the envelope protein. The fact that the peptides acted as immunogenic T cell proliferative and helper epitopes in nonhuman primates is very encouraging for including them in future vaccine studies in humans.


Use of electronic visual recording to aid assessment of dietary intake of Australian Aboriginal children living in remote communities.
To assess the feasibility of using electronic visual recording in combination with food records to evaluate dietary intake in Aboriginal infants and children. All foods and drinks consumed by the child over four consecutive days were recorded in daily food records and pictures or videos. Feasibility was assessed by determining i) proportion of meals reported to be consumed; ii) cost of data collection; iii) day-to-day variation in energy intake and; iv) acceptability of the method. Dietary intake data was collected from three girls and five boys aged 11 months to eight years, five over four days and three during one day, at a cost of $3,300 per child. One-third of the 89 meals reported to be consumed through the food records were electronically recorded. Most photographs were taken in the first two days with the number of meals electronically recorded decreasing each day over the four-day period. There was a large day-to-day variation in energy intake. Use of electronic recording to aid individual usual dietary intake data collection was feasible. Collection periods spread over 1-2 weeks may be more appropriate due to the large variance in day-to-day dietary intake.


Is the focus of attention in working memory expanded through practice?
This article reinvestigates the claim by P. Verhaeghen, J. Cerella, and C. Basak (2004) that the focus of attention in working memory can be expanded from 1 to 4 items through practice. Using a modified version of Verhaeghen et al.'s n-back paradigm, Experiments 1 and 3 show that a signature of a one-item focus, the time cost for switching between items in working memory, persists over practice. Verhaeghen et al. reported a shift over practice from a step function to a linear slope of reaction times over set size and argued that it reflects the expansion of the focus. With an improved counterbalancing scheme, a continuously increasing slope was found even without practice in Experiment 2. The results question the hypothesis that the focus is expanded through practice. They are in line with predictions from a model that distinguishes a one-item focus from a direct-access region holding about 4 items.


A qualitative study exploring the nurse telephone follow-up of patients returning home with a colostomy.
The aim of this study was to explore and describe the content of telephone intervention conversations conducted by an enterostomal nurse with patients discharged home with a colostomy. People discharged home with a new colostomy often encounter stoma-related difficulties. Postdischarge care with telephone follow-up by an enterostomal nurse is a helpful way to provide support for patients and ensure continuity of care. There is a paucity of studies reporting the content of telephone follow-up of colostomy patients. Information on the content of such follow-up is important in helping to formulate telephone call protocols that can help these patients. A qualitative exploratory study conducted in a university-based cancer centre in China. The contents of 25 intervention phone calls to colostomy patients from January-August 2009 were subject to qualitative content analysis. Five themes emerged from the qualitative content analysis: 'education for stoma care', 'access to stoma care', 'encouraging stoma self-care', 'resuming normal living' and 'general postoperative problems'. Colostomy patients experienced stoma-related problems and difficulties after discharge, most of which could be effectively managed via telephone follow-up by an enterostomal nurse. The telephone follow-up satisfied patients' need for information and facilitated their adjustment to the permanent stoma. The findings suggested that patients had unmet needs after discharge and needed follow-up on returning home. This study provides important information to guide practice and education. The themes extracted from the qualitative content analysis provide a useful framework to guide the nurse in discussing care with the stoma patients and ensuring patients' adjustment to the permanent stoma. Further work can be done using this framework to develop protocols as standards of care and education materials when educating nurse specialists in stoma care.


14 examples of how LLMs can transform materials science and chemistry: a reflection on a large language model hackathon.
Large-language models (LLMs) such as GPT-4 caught the interest of many scientists. Recent studies suggested that these models could be useful in chemistry and materials science. To explore these possibilities, we organized a hackathon. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.


Genomic signatures of inbreeding in a critically endangered parrot, the kākāpō.
Events of inbreeding are inevitable in critically endangered species. Reduced population sizes and unique life-history traits can increase the severity of inbreeding, leading to declines in fitness and increased risk of extinction. Here, we investigate levels of inbreeding in a critically endangered flightless parrot, the kākāpō (Strigops habroptilus), wherein a highly inbred island population and one individual from the mainland of New Zealand founded the entire extant population. Genotyping-by-sequencing (GBS), and a genotype calling approach using a chromosome-level genome assembly, identified a filtered set of 12,241 single-nucleotide polymorphisms (SNPs) among 161 kākāpō, which together encompass the total genetic potential of the extant population. Multiple molecular-based estimates of inbreeding were compared, including genome-wide estimates of heterozygosity (FH), the diagonal elements of a genomic-relatedness matrix (FGRM), and runs of homozygosity (RoH, FRoH). In addition, we compared levels of inbreeding in chicks from a recent breeding season to examine if inbreeding is associated with offspring survival. The density of SNPs generated with GBS was sufficient to identify chromosomes that were largely homozygous with RoH distributed in similar patterns to other inbred species. Measures of inbreeding were largely correlated and differed significantly between descendants of the two founding populations. However, neither inbreeding nor ancestry was found to be associated with reduced survivorship in chicks, owing to unexpected mortality in chicks exhibiting low levels of inbreeding. Our study highlights important considerations for estimating inbreeding in critically endangered species, such as the impacts of small population sizes and admixture between diverse lineages.


Evaluation of posterior lens capsule by 20-MHz ultrasound probe in traumatic cataract.
To investigate the accuracy of echography with a 20-MHz probe for evaluation of posterior lens capsule in traumatic cataract before surgery. Prospective interventional case series. This study consisted of 43 eyes with traumatic cataract that were scheduled to undergo surgery. In all cases, cataract was dense enough to prevent visualization of the posterior lens capsule. Echography was performed using a 20-MHz probe to detect rupture of the posterior lens capsule. All patients subsequently underwent cataract extraction and intraoperative findings of the posterior lens capsule were compared with the preoperative echographic findings. This study included 43 eyes of 43 patients (38 men and 5 women) with a mean age of 35.6 ± 15.3 years (range, 4-68 years). The trauma was either blunt (4 eyes) or sharp (39 eyes); there was closed globe injury in 2 eyes and open globe injury in 41 eyes. By 20-MHz echography, posterior border of the crsytalline lens was clearly visualized in all 43 eyes. By 20-MHz echographic imaging, rupture of the posterior lens capsule was identified in 17 eyes (39.5%). During cataract surgery, it was noted that 14 eyes (32.6%) had rupture of the posterior lens capsule. Sensitivity, specificity, positive predictive value, and negative predictive value were 93%, 86%, 76%, and 96%, respectively, for 20-MHz echography to detect rupture of the posterior lens capsule. Also, the positive likelihood ratio, negative likelihood ratio, and odds ratio were 6.7, 0.08, and 81, respectively. Echography with 20-MHz probe is an accurate imaging modality for detection of posterior lens capsule rupture in traumatic cataract preoperatively. This technique helps ophthalmologists have an appropriate surgical plan before operating.


Generation of polyclonal antiserum for the detection of methylarginine proteins.
This report describes an approach for the study of the biology of methylarginine proteins based on the generation of immunological reagents capable of recognizing the methylarginine status of cellular proteins. Two forms of an immunizing peptide were prepared based upon an amino acid sequence motif found most prevalently among verified dimethylarginine-containing proteins. One form of the peptide was constructed with 7 arginine residues alternating with 8 glycine residues. None of the arginines used in the synthesis were methylated. The alternative form of the peptide was synthesized with the identical repeating GRG sequence, but with asymmetrical dimethylarginine at each arginine residue. A methylarginine-specific antiserum was generated using the latter peptide. ELISA and western blotting of glycine arginine-rich peptides, each synthesized with or without asymmetric dimethylarginine, demonstrate the methyl specificity of the antiserum. The methylarginine-specific antibody co-localizes with the highly methylated native nucleolin protein conspicuously concentrated in the nucleolus. The methylarginine-specific antiserum recognizes a GRG peptide and bacterially expressed RBP16 only after incubation of the peptide or RBP16 with recombinant protein arginine methyltransferase 1, or cell extracts, respectively. Proteins isolated from cells in different developmental states exhibit different patterns of reactivity observed by western blots. Finally, the methylarginine-specific reagent interacts specifically with the methylarginine of cellular hnRNPA1 and human fragile X mental retardation protein expressed in cultured PC12 cells. An immunological reagent capable of detecting the methylarginine status of cellular methylproteins will facilitate the cellular and molecular analysis of protein arginine methylation in a wide variety of research and biomedical applications.


Effects of Unfiltered Cigarettes on Smoking Behavior and Toxicant Exposure: Protocol for a Randomized Crossover Clinical Trial.
Plastic filters on cigarette butts are a widespread source of nonbiodegradable, toxic environmental waste. State and local legislation to ban the sale of single-use cigarettes may be considered to prevent this waste, but scientific evidence on the impact of switching smokers to unfiltered cigarettes on smoking behavior and toxicant exposures is needed to inform this policy. We have designed an open-label, randomized, 9-week, crossover clinical trial of adult filtered-cigarette smokers who switch to unfiltered cigarettes. Our objective is to understand the impact of switching smokers of filtered cigarettes to unfiltered cigarettes on smoking behavior and toxic exposures. This trial involves a 1-week baseline period; a 2-week period of smoking filtered or unfiltered cigarettes, where groups are randomly assigned; a 3-week washout period; another 1-week baseline period; and a 2-week crossover period of smoking the opposite condition (ie, filtered or unfiltered cigarettes) for a sufficient sample size of 40 participants. We will determine changes in (1) observed topography (ie, puff count, interpuff interval, and puff volume) and cigarettes smoked per day, via butt counts and self-report, (2) expired carbon monoxide and excretion of urinary cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and volatile organic compounds, and (3) participants' knowledge and attitudes toward unfiltered cigarettes, satisfaction with smoking, and intention to quit if they were not able to smoke filtered cigarettes. This study was funded in June 2018 and approved by the relevant Institutional Review Boards in July 2018. This study has enrolled 37 participants as of October 2020. Data analysis is currently underway, and trial results are expected to be published in spring 2021. This pilot proof-of-principle study will inform the design of a larger, future research project that can provide robust scientific evidence on our research question. Such a large study could inform possible state or local legislation to ban the sale of single-use filtered cigarettes in order to mitigate the environmental impact of discarded single-use plastic filters. ClinicalTrials.gov NCT03749876; https://clinicaltrials.gov/ct2/show/NCT03749876. DERR1-10.2196/19603.


Cisplatin-induced germ cell apoptosis in mouse testes.
The purpose of this study was to investigate whether exposure of male mice to cisplatin induces apoptosis in male germ cells and the possible role of apoptosis in cisplatin-induced testicular damage. Forty-eight male BALB/c mice were divided into cisplatin and control groups. The mice from the cisplatin group received a single intraperitoneal injection of cisplatin of either 1, 5, or 10 mg/kg. The control group received a single intraperitoneal injection of saline alone. The testes were removed on days 1, 3, and 7 after cisplatin administration, respectively. Following histological examination, apoptotic indices (AIs) were measured within seminiferous tubules of the mouse testes by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. A low incidence of spontaneous apoptosis was observed in controls, particularly in spermatogonia and spermatocytes of the mouse testes. After cisplatin administration, both increased Als and decreased spermatozoa and spermatids were found in the seminiferous tubules of the mouse testes. Cisplatin-induced apoptosis was found in spermatogonia, spermatocytes, and spermatids of the mouse testes. In comparison to the control values, AIs increased 2.6- to 6.8-fold in cisplatin-treated mouse testes. AIs reached the highest level on day 1 following 1 mg/ kg, on day 3 following 5 mg/kg, and on day 7 following treatment of 10 mg/kg cisplatin. The study showed that cisplatin-induced germ cell apoptosis in the mouse testes was related to both the dose response and the time course of response. It is suggested that cisplatin-induced germ cell apoptosis may result in decreased spermatogenesis, and the higher dose of cisplatin may delay the occurrence of apoptosis in the mouse testes.


Surgical treatment of spontaneous common carotid dissection: a case report.
Cervical carotid dissection is more common in extracranical vessel: internal carotid artery dissection (ICAD) is typical, vertebral artery dissection is uncommon, common carotid artery dissection (CCAD) is rare and even a more rare cause of ischemic stroke. Cervical artery dissections account up to 20-25% of ischemic strokes in young patients. Isolated and spontaneous common carotid artery dissection without aortic damage is unique. Indeed in the Literature 8 cases were identified. MRI and CTA were the most commonly used for diagnosis and follow-up. A 67-year-old came to our observation reporting burning pain in the right latero-cervical region in supine position, irradiated in the temporal region and recurrent episodes of migraine with aura (scintillating scotoma), in the last 3 months. The last Doppler Ultrasound control, performed after the onset of symptoms, showed an highlighted dissection wall with double lumen at the origin of the bulb and the internal carotid artery on the right. Aortic arch arteriography confirmed the diagnosis. The patient underwent surgery (longitudinal arteriotomy, removing four miointimal flaps, fastening the distal common carotid artery with 3 Kunlin's points). Any neurological or vascular problems after surgery were noticed. The pathogenesis can be related to a combination of an intrinsic weakness in the arterial wall and an external trigger. The diagnosis of CAD is made with MRI (78.0%), conventional angiography (31.1%), CTA (14.7%), and ultrasound (11.3%). No evidence-based guidelines exists for treatment of CCAD. In our patient surgical CEA treatment was the optimal solution.


[Treatment of carpal acroparesthesias (author's transl)].
Topical steroid treatment of the carpal tunnel syndrome gives outstanding results in mild or moderately severe types of nerve lesion. In many patients in whom there was improvement of function and cessation of pain, not everything was achieved that we consider to be the aim of an ideal treatment. Normalisation of nerve function and the elimination of the pathophysiological mechanism responsible for the compression often make surgical treatment essential.


Assessment of cellular proliferation in tumors by PET using 18F-ISO-1.
This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-(18)F-fluoroethoxy)-5-methylbenzamide ((18)F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms. Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent (18)F-ISO-1 PET. Tumor (18)F-ISO-1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of (18)F-ISO-1 and human dosimetry were evaluated. Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor-to-muscle ratio correlated significantly with Ki-67 (τ = 0.27, P = 0.04, and τ = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor-to-normal-tissue ratio (τ = 0.07, P = 0.56) or distribution volume ratio (τ = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of (18)F-ISO-1 were encountered. The presence of a significant correlation between (18)F-ISO-1 and Ki-67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials.