Efficacy of combined topiramate/thioctic acid therapy in migraine prophylaxis.
Migraine cannot be cured and the aim, shared with the patient, is to minimise the impact of the illness on the patient's life and lifestyle. The aim of prophylaxis is to reduce the number of migraine attacks. Prophylaxis should be considered when appropriately used acute management gives inadequate control of symptoms. The efficacy and safety of topiramate 50 mg/d and thioctic acid (α-lipoic acid) 300 mg/d either as monotherapy or in combination were investigated as migraine prophylactic agents. Forty secondary school migraineur girls were enrolled in the study. The study was conducted in two phases, a prospective baseline phase and 1-month treatment phase. Combined topiramate/thioctic acid therapy was more effective than either topiramate or thioctic acid monotherapy as a migraine-preventive treatment. Combined topiramate/thioctic acid therapy decreased the mean monthly migraine frequency from 5.86 ± 1.2 to 2.6 ± 0.98 (p ⩽ 0.05), topiramate (50 mg/d) from 5.71 ± 1.4 to 4.75 ± 1.5 and thioctic acid (300 mg/d) from 5.68 ± 1.6 to 5.22 ± 1.8. Reduction in mean monthly migraine days was also significantly greater in the group receiving combined topiramate/thioctic acid (from 12.32 ± 1.85 to 5.74 ± 1.1) compared to those receiving either topiramate 50 mg/d (from 12.7 ± 1.34 to 11.85 ± 1.35) or thioctic acid 300 mg/d (from 12.5 ± 1.72 to 11.65 ± 1.44). The responder rate (% of patients showing ⩾50% reduction in monthly migraine frequency) was 85% in patients receiving combined topiramate/thioctic acid therapy compared to 30% and 20% in patients receiving either topiramate or thioctic acid, respectively. The incidence of adverse events was higher in patients receiving topiramate (50 mg/d) monotherapy. The most common adverse events were nausea, fatigue, paraesthesia and taste perversion. We conclude that combined topiramate/thioctic acid therapy is more effective and better tolerated than topiramate monotherapy. The combination has lower monthly medication costs compared to the traditionally used topiramate 100 mg monotherapy.


Extracellular vesicles and COPD: foe or friend?
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease characterized by progressive airflow limitation. The complex biological processes of COPD include protein hydrolysis tissue remodeling, innate immune inflammation, disturbed host-pathogen response, abnormal cellular phenotype conversion, and cellular senescence. Extracellular vesicles (EVs) (including apoptotic vesicles, microvesicles and exosomes), are released by almost all cell types and can be found in a variety of body fluids including blood, sputum and urine. EVs are key mediators in cell-cell communication and can be used by using their bioactive substances (DNA, RNA, miRNA, proteins and other metabolites) to enable cells in adjacent and distant tissues to perform a wide variety of functions, which in turn affect the physiological and pathological functions of the body. Thus, EVs is expected to play an important role in the pathogenesis of COPD, which in turn affects its acute exacerbations and may serve as a diagnostic marker for it. Furthermore, recent therapeutic approaches and advances have introduced EVs into the treatment of COPD, such as the modification of EVs into novel drug delivery vehicles. Here, we discuss the role of EVs from cells of different origins in the pathogenesis of COPD and explore their possible use as biomarkers in diagnosis, and finally describe their role in therapy and future prospects for their application. Graphical Abstract.


Comprehensive evaluation of matrix factorization methods for the analysis of DNA microarray gene expression data.
Clustering-based methods on gene-expression analysis have been shown to be useful in biomedical applications such as cancer subtype discovery. Among them, Matrix factorization (MF) is advantageous for clustering gene expression patterns from DNA microarray experiments, as it efficiently reduces the dimension of gene expression data. Although several MF methods have been proposed for clustering gene expression patterns, a systematic evaluation has not been reported yet. Here we evaluated the clustering performance of orthogonal and non-orthogonal MFs by a total of nine measurements for performance in four gene expression datasets and one well-known dataset for clustering. Specifically, we employed a non-orthogonal MF algorithm, BSNMF (Bi-directional Sparse Non-negative Matrix Factorization), that applies bi-directional sparseness constraints superimposed on non-negative constraints, comprising a few dominantly co-expressed genes and samples together. Non-orthogonal MFs tended to show better clustering-quality and prediction-accuracy indices than orthogonal MFs as well as a traditional method, K-means. Moreover, BSNMF showed improved performance in these measurements. Non-orthogonal MFs including BSNMF showed also good performance in the functional enrichment test using Gene Ontology terms and biological pathways. In conclusion, the clustering performance of orthogonal and non-orthogonal MFs was appropriately evaluated for clustering microarray data by comprehensive measurements. This study showed that non-orthogonal MFs have better performance than orthogonal MFs and K-means for clustering microarray data.


Influence of food size and food quantity on the feeding of the mussel Dreissena polymorpha.
In common with many other suspension feeders, the freshwater mussel Dreissena polymorpha has a maximum filtration rate at low food concentrations and a maximum ingestion rate at high food concentrations. These high rates, which reflect the potential maximum food uptake of the animal, are called the filtration capacity and the ingestion capacity respectively. The ingestion capacity was attained without forming pseudofaeces with Chlamydomonas reinhardii as food. The incipient limiting level could be calculated as the quotient of these two values. A decrease of the filtration rate at high food concentrations was correlated with changes in pumping activity, which showed more frequent interruptions, or a lower level of water transport. Dreissena can filter out particles of diameter greater than 0.7 μm from the water. Retention reaches a plateau at about 5 μm particle diameter. Scanning electron micrographs of the arrangement of the cilia on the gill filaments are given.


Unique clinical phenotypes of patients with obstructive sleep apnea in a Japanese population: a cluster analysis.
In an attempt to better understand the heterogeneity of individuals with obstructive sleep apnea (OSA), unbiased analytic approaches such as cluster analysis have been used worldwide; however, only a few such studies have been conducted for Asian populations alone, despite the potential racial/ethnic differences. We thus applied this approach to a Japanese population with OSA. In this single-center, retrospective, observational study, our nocturnal polysomnography dataset included the findings for 1,020 patients between May 2016 and December 2020. Of these, 712 patients met the study criteria: aged > 20 years, fully completed questionnaire, no missing data on all-night full polysomnography, and confirmed OSA diagnosis with an apnea-hypopnea index (AHI) > 15 events/h. We employed hierarchical cluster analysis using demographic data, self-reported symptoms, and polysomnographic data. We identified 5 distinct clinical clusters within the OSA patient population, which were labeled as "classic OSA" (20--67 years, obese, high AHI, high Epworth Sleepiness Scale [ESS]), "milder classic OSA" (22--77 years, obese, high AHI, low ESS), "nonobese and minimally symptomatic" (20--88 years, moderate AHI, low ESS), "excessive sleepiness without severe OSA" (26--79 years, moderate AHI, high ESS), and "older adult and severe OSA" 55--92 years, (high AHI, low ESS). Of these, the last 3 clusters were characterized as nonobese. Notably, we identified the cluster with excessive sleepiness despite less severe OSA. We did not identify any clusters with predominant upper-airway obstruction symptoms because the symptoms were prevalent and equally distributed in all clusters. We found some unique clinical phenotypes in nonobese patients with OSA in a Japanese population. Ida H, Suga T, Nishimura M, Aoki Y. Unique clinical phenotypes of patients with obstructive sleep apnea in a Japanese population: a cluster analysis. J Clin Sleep Med. 2022;18(3):895-902.


Mechanism of platelet activation and potential therapeutic effects of natural drugs.
Cardiovascular disease is one of the most concerning chronic diseases in the world. Many studies have shown that platelet overactivation is a very important factor in the occurrence and development of cardiovascular diseases. At present, the widely used antiplatelet drugs have some defects, such as drug resistance and adverse reactions. The purpose of this article is to summarize the main mechanisms and pathways of platelet activation, the main targets of antiplatelet aggregation, and the antiplatelet aggregation components of natural drugs and their mechanisms of action to provide new research ideas for the development and application of antiplatelet drugs. In this review, we systematically searched the PubMed, Google Scholar, Web of Science, and CNKI databases and selected studies based on predefined eligibility criteria. We then assessed their quality and extracted data. ADP, AA, THR, AF, collagen, SDF-1α, and Ca2+ can induce platelet aggregation and trigger thrombosis. Natural drugs have a good inhibitory effect on platelet activation. More than 50 kinds of natural drugs and over 120 kinds of chemical compounds, including flavonoids, alkaloids, saponins, terpenoids, coumarins, and organic acids, have significantly inhibited platelet activation activity. The MAPK pathway, cGMP-PKG pathway, cAMP-PKA pathway, PI3K-AKT pathway, PTK pathway, PLC pathway, and AA pathway are the main mechanisms and pathways of platelet activation. Natural drugs and their active ingredients have shown good activity and application prospects in anti-platelet aggregation. We hope that this review provides new research ideas for the development and application of antiplatelet drugs.


Long-term follow-up in patients with coeliac disease in the pandemic-era: a view from Sheffield the NHS England national centre for adult coeliac disease.
To explore patients' follow-up preferences. Optimal follow-up strategies for patients with coeliac disease remain a subject of debate. Research suggests patients' prefer review by dietitians with a doctor available as required. Patients with coeliac disease under review at our centre, completed a questionnaire assessing their views on what makes follow-up useful based on specific criteria. Bloods tests, symptoms review, dietary assessment, opportunity to ask questions and reassurance. Patients' preferences between follow-up with a hospital doctor, a hospital dietitian, a hospital dietitian with a doctor available, a general practitioner, no follow-up or access when needed were also evaluated. 138 adult patients completed the questionnaire, 80% of patients reported following a strict gluten free diet (mean diagnosis was 7.2 years). Overall, 60% found their follow-up to be 'very useful' valuing their review of blood tests and symptoms (71%) reassurance (60%) and opportunity to ask questions (58%). Follow-up by a dietitian with a doctor available was the most preferred option of review (p<0.001) except when compared to hospital doctor (p=0.75). Novel modalities of follow-up such as telephone and video reviews were regarded as of equal value to face-to-face appointments (65% and 62% respectively). Digital applications were significantly less preferable (38%, p<0.001). Follow-up by a dietitian with a doctor available as needed was the most preferred follow-up method. However, in this study follow-up by a dietitian with doctor available and hospital doctor alone was statistically equivalent. Many patients consider telephone and video follow-up of equal value to face-to-face reviews.


The effect of TGF-beta1 on immune responses of naïve versus memory CD4+ Th1/Th2 T cells.
The role of TGF-beta1 in the regulation of T cell responses has been perplexing, possibly because it is dependent on the type of T cell being regulated and its cytokine microenvironment. In the present study, we demonstrate that TGF-beta1 has a profound inhibitory effect on naive CD4+ T cell undergoing differentiation under defined neutral, Th1 and Th2 priming conditions. In addition, we show that if CD4+ T cells are primed in the presence of TGF-beta1, they exhibit reduced secondary anti-CD3/anti-CD28-induced and antigen-specific immune responses (even when TGF-beta is absent during the secondary response), which is not due to reduced expression of co-stimulatory molecules or to inadequate IL-2 production. Finally, with respect to the effect of TGF-beta on fully differentiated antigen-specific memory CD4+ T cells, we demonstrate that while antigen-specific activation and cytokine secretion by memory Th1 T cells is inhibited by TGF-beta1, such inhibition is associated with partial down-regulation of IL-12 receptor beta2 chain expression. In contrast, memory Th2 T cells are not subject to TGF-beta1 -mediated suppression. In summary, these studies reveal that TGF-beta1 is a powerful negative regulator of the primary immune response of CD4+ T cells, but only Th1 T cells are subject to such regulation after the memory stage of T cell differentiation has been reached. Thus, these studies define the potential regulatory role of TGF-beta1 in Th1 and Th2 T cell-mediated autoimmunity.


Development of a shuttle vector for Moraxella catarrhalis.
Efforts to perform genetic analysis in Moraxella catarrhalis have been hampered by the lack of a cloning vector. M. catarrhalis strain E22 was previously shown to contain plasmid pLQ510 which lacked a selectable antibiotic resistance marker. Several methods were used to eliminate unnecessary DNA from pLQ510. Then, a 1.2 kb spectinomycin resistance cartridge, a multiple cloning site, and the origin of replication from pACYC184 were cloned into this plasmid backbone to obtain the 7.2 kb plasmid pWW102B. This new plasmid could replicate in M. catarrhalis as well as in both Escherichia coli and Haemophilus influenzae. This shuttle vector was used to clone and express two different M. catarrhalis genes, respectively, encoding an adhesin and a protein involved in serum resistance. When these two plasmids were introduced into appropriate M. catarrhalis mutants, they complemented the phenotypic deficiency of each mutant. This is the first report of functional complementation in trans in this pathogen.


Curcumin in cancer therapy: Exploring molecular mechanisms and overcoming clinical challenges.
Cancer poses a significant global health burden, necessitating the widespread use of chemotherapy and radiotherapy as conventional frontline interventions. Although targeted therapy and immunotherapy have shown remarkable advancements, the challenges of resistance development and severe side effects persist in cancer treatment. Consequently, researchers have actively sought more effective alternatives with improved safety profiles. In recent years, curcumin, a natural polyphenolic phytoalexin, has garnered considerable attention due to its broad spectrum of biological effects. This concise review provides valuable insights into the role of curcumin in cancer therapy, with a focus on elucidating its molecular mechanisms in inducing programmed cell death of tumor cells and suppressing tumor cell metastasis potential. Additionally, we discuss the challenges associated with the clinical application of curcumin and explore current endeavors aimed at overcoming these limitations. By shedding light on the promising potential of curcumin, this review contributes to the advancement of cancer treatment strategies.


National evaluation of the effect of graduated driver licensing laws on teenager fatality and injury crashes.
Automobile crashes remain a prominent cause of death and injury for teenagers in the United States. While it is generally agreed that graduated drivers licensing (GDL) influences crash rates, it is unclear which components have the strongest effect on any specific types of crashes. We analyze the relative effect of different stages of GDL on teenage fatal and injury crash risk via a negative binomial generalized linear model with random state effects. Overall, nighttime, and crashes with multiple teenage passengers are considered. The strongest effects are seen by 16-year-olds, for which a strict permit stage is associated with a 58% reduction in fatal crash risk over a lenient permit stage. Similar reductions are seen for injury crashes. The intermediate stage, involving nighttime and passenger restrictions, is associated with a 44% reduction in fatalities but has relatively little effect on injury crashes. The strongest effects are generally seen for passenger crashes, followed by nighttime, and then overall crashes. This study identifies stronger relationships between GDL and crash risk than has previously been discovered and captures the relative effects of permit and intermediate licensing restrictions, two high-level components of GDL which differ in intent and implementation.


The efficacy and feasibility of fractional CO2 laser therapy for the treatment of urinary incontinence: a multicentric case-control study.
Female urinary incontinence is a significant public health problem. Conservative treatments require high patient compliance, while surgery often leads to more complications and recovery time. Our aim is to evaluate the efficacy of microablative fractional CO<inf>2</inf> laser (CO<inf>2</inf>-laser) therapy in women with urinary incontinence (UI). This is a retrospective analysis of prospectively collected data on women with stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with predominant SUI subjected to four sessions of CO<inf>2</inf>-laser therapy performed once a month, between February 2017 and October 2017, with a 12-month follow-up. The subjective Visual Analogue Scale (VAS) 0-10 was used to score and variables were evaluated at baseline and at one, six and 12 months after initiation of therapy. Finally, results were compared to a control group. The cohort consisted of 42 women. The proportion of patients with vaginal atrophy among those younger than 55 years was substantially lower (3/23; 13%) than among those older than 55 years (15/19; 78.9%). CO<inf>2</inf> laser treatment was associated with a significant improvement in VAS scores recorded one-month, six-months, and one-year, after conclusion of therapy (P<0.001). VAS scores improved significantly in patients with either SUI (26/42; 61.9%) or mixed UI (16/42; 38.1%). No major post treatment complications were registered. Women with vaginal atrophy demonstrated significantly better results (P<0.001). Results confirm the efficacy and a good safety profile, for CO<inf>2</inf> laser treatment in SUI, mostly in women with postmenopausal vaginal atrophy and should be considered as a treatment option for female patients with concomitant SUI and vaginal atrophy.


High-current density alkaline electrolyzers: The role of Nafion binder content in the catalyst coatings and techno-economic analysis.
We report high-current density operating alkaline (water) electrolyzers (AELs) based on platinum on Vulcan (Pt/C) cathodes and stainless-steel anodes. By optimizing the binder (Nafion ionomer) and Pt mass loading (mPt) content in the catalysts coating at the cathode side, the AEL can operate at the following (current density, voltage, energy efficiency -based on the hydrogen higher heating value-) conditions (1.0 A cm-2, 1.68 V, 87.8%) (2.0 A cm-2, 1.85 V, 79.9%) (7.0 A cm-2, 2.38 V, 62.3%). The optimal amount of binder content (25 wt%) also ensures stable AEL performances, as proved through dedicated intermittent (ON-OFF) accelerated stress tests and continuous operation at 1 A cm-2, for which a nearly zero average voltage increase rate was measured over 335 h. The designed AELs can therefore reach proton-exchange membrane electrolyzer-like performance, without relying on the use of scarce anode catalysts, namely, iridium. Contrary to common opinions, our preliminary techno-economic analysis shows that the Pt/C cathode-enabled high-current density operation of single cell AELs can also reduce substantially the impact of capital expenditures (CAPEX) on the overall cost of the green hydrogen, leading CAPEX to operating expenses (OPEX) cost ratio <10% for single cell current densities ≥0.8 A cm-2. Thus, we estimate a hydrogen production cost as low as $2.06 kgH2 -1 for a 30 years-lifetime 1 MW-scale AEL plant using Pt/C cathodes with mPt of 150 μg cm-2 and operating at single cell current densities of 0.6-0.8 A cm-2. Thus, Pt/C cathodes enable the realization of AELs that can efficiently operate at high current densities, leading to low OPEX while even benefiting the CAPEX due to their superior plant compactness compared to traditional AELs.


Kernel estimation of risk surfaces without the need for edge correction.
Kernel estimates of relative risk surfaces can be used to examine the geographical variation of disease risk. These surfaces can be expressed as ratios of bivariate kernel density estimates constructed from case and control data, but care must be taken to avoid excessive bias at the boundaries of the region under study. It is possible to correct this bias, without the complications of explicit edge correction, through the use of a specific smoothing regimen.


Purification, potency and immunogenicity analysis of Vero cell culture-derived rabies vaccine: a comparative study of single-step column chromatography and zonal centrifuge purification.
Continuous Vero cell lines are more suitable for large-scale production of rabies vaccine. The purification of Vero cell-derived rabies vaccine is critical because of the residual cellular DNA and serum proteins. The perfection of techniques using column chromatography with different matrix material, gel filtration and zonal centrifugation is of paramount importance for the optimal purification of rabies vaccine, leaving minimal residual cellular DNA, below the permissible level of 100 pg per dose and serum protein content of 1 ppm. In this study the potency, immunogenicity and safety of Vero cell-derived rabies vaccines were compared following purification by densely or loosely packed DEAE-sepharose CL-6B columns with different bed heights or by zonal centrifugation. The optimal virus recovery and maximum removal of substrate DNA and serum proteins were achieved only when the sepharose CL-6B column bed height was maintained at a thickness of 2-2.5 cm. The rabies virus material was purified by layering over the matrix without applying pressure. DEAE-sepharose CL-6B column purification using a simplified, cost effective technique as described in this study enhances the antigen yield by 50% in comparison with zonal purification.


MicroRNAs from Holarrhena pubescens stems: Identification by small RNA Sequencing and their Potential Contribution to Human Gene Targets.
Holarrhena pubescens is an effective medicinal plant from the Apocynaceae family, widely distributed over the Indian subcontinent and extensively used by Ayurveda and ethno-medicine systems without apparent side effects. We postulated that miRNAs, endogenous non-coding small RNAs that regulate gene expression at the post-transcriptional level, may, after ingestion into the human body, contribute to the medicinal properties of plants of this species by inducing regulated human gene expression to modulate. However, knowledge is scarce about miRNA in Holarrhena. In addition, to test the hypothesis on the potential pharmacological properties of miRNA, we performed a high-throughput sequencing analysis using the Next Generation Sequencing Illumina platform; 42,755,236 raw reads have been generated from H. pubescens stems from a library of small RNA isolated, identifying 687 known and 50 new miRNAs led. The novel H. pubescens miRNAs were predicted to regulate specific human genes, and subsequent annotations of gene functions suggested a possible role in various biological processes and signaling pathways, such as Wnt, MAPK, PI3K-Akt, and AMPK signaling pathways and endocytosis. The association of these putative targets with many diseases, including cancer, congenital malformations, nervous system disorders, and cystic fibrosis, has been demonstrated. The top hub proteins STAT3, MDM2, GSK3B, NANOG, IGF1, PRKCA, SNAP25, SRSF1, HTT, and SNCA show their interaction with human diseases, including cancer and cystic fibrosis. To our knowledge, this is the first report of uncovering H. pubescens miRNAs based on high-throughput sequencing and bioinformatics analysis. This study has provided new insight into a potential cross-species control of human gene expression. The potential for miRNA transfer should be evaluated as one possible mechanism of action to account for the beneficial properties of this valuable species.


Fibrinogen, factor VII clotting activity and coronary artery disease severity.
To asses the relationship between fibrinogen, factor VII coagulant (VIIc) activity and extent of coronary artery disease, we studied 43 white males shown to have greater than 50% stenosis of at least one major coronary artery. Thirty six had a definite history of myocardial infarction at least 3 months earlier and were classified as having 1, 2 or 3 vessel disease while 7 had 2 or 3 vessel disease, but no prior infarction. Groups were similar with regard to age, body mass index and blood pressure. In those with documented prior infarction, there was a significant relationship between the extent of atheroma and coagulation variables factor VIIc and fibrinogen. However, given a similar degree of atheroma, patients with prior infarction had significantly higher levels of factor VIIc activity compared with patients without such a history. These results corroborate those from prospective studies confirming a significant role for the coagulation system in the clinical manifestation of coronary artery disease.


Streamlined plug-in aerosol prototype for reconfigurable manufacture of nano-drug delivery systems.
The significant advances in nano-drug delivery systems (NDDS) for anticancer agents have led to the development of computational techniques, such as machine learning and neural networks to identify the optimal architectural and compositional design in a wide variety of therapeutic nanoformulations. On the other hand, few studies have examined downsized plug-in reaction-ware embodied in an autonomous platform for the instant reconfigurable production of engineered nanomaterials to guide optimal NDDS designs and delivery strategies. This paper describes an on-demand system for an electrically operable, continuously processible material produced by sequential spray pyrolysis and vibrating spray for single-pass NDDS assembly. In particular, a mild chemotherapeutic NDDS consisting of amorphous boron nitride (a-BN; a stable base material for loading), doxorubicin (DOX; an anticancer drug), and folic acid-chitosan conjugate (FACHI; a targeting and antiopsonic agent), called a-BN-DOX@FACHI, was fabricated using the developed system. a-BN-DOX@FACHI was assessed for the pH-responsive release of DOX, targeting of the folate receptor, and its resistance to opsonization and macrophage phagocytosis. a-BN-DOX@FACHI was found to be a mild cancer chemotherapeutic with reasonable biosafety. Integrating a metal ablation device with the developed on-demand system enabled the reconfiguration of NDDS from a-BN-DOX@FACHI to a-BN-Au-DOX@FACHI or a-BN-Pt-cisplatin@bovine serum albumin to add a photothermal effect with a range of architectures and compositions.


Urinary microRNAs can predict response to abiraterone acetate in castration resistant prostate cancer: A pilot study.
Despite novel agents have been introduced to treat castration resistant prostate cancer (CRPC) during the last decade, up to one-third of CRPC patients face primary resistance to new generation compounds. Therefore, sensitive molecular tools are urgently needed for reliable treatment selection and response prediction. This study aimed to evaluate urinary miRNAs and blood circulating androgen receptor (AR) transcript level as a tool for noninvasive outcome prediction for CRPC patients undergoing abiraterone acetate (AA) therapy. Prostate cancer-specific miR-148a, -365, -375, and -429 were analyzed in 129 urine samples collected from 100 CRPC patients before and during AA therapy via quantitative reverse transcription PCR. To test the prognostic value, urinary miRNA levels alone, as well as combined with AR level were associated with progression-free survival (PFS) and overall survival (OS). Level of urinary miR-375 was the highest in CRPC in comparison to noncancerous controls, as well as in combination with miR-429 was predictive for short PFS in AA-treated patients (HR = 2.2, 95% CI: 1.1-4.2, p = 0.023). Especially high prognostic power of all analyzed miRNAs was observed in CRPC cases with high blood AR levels. For PFS prediction a tandem of miR-429 and high AR reached HR of 5.0 (95% CI: 2.2-11.8, p < 0.001), while for prediction of OS the best combination was demonstrated by miR-148a and AR with HR of 3.1 (95% CI: 1.4-7.1, p = 0.006). Urinary miRNAs could be used as prognostic biomarkers for CRPC patients to predict response to AA therapy, especially for the cases with high blood AR levels.


Effects of medial meniscal slope and medial posterior tibial slope on the locations of meniscal tears: A retrospective observational study.
The aim of this study was to analyze the relationship between medial posterior tibial slope (MPTS) and medial meniscus slope (MMS) with the location of meniscal lesions. We hypothesize that meniscuses with greater MPTS and MMS are more likely to have lesions in posterior horn.A total of 292 patients underwent arthroscopic surgery between January 2014 to September 2019 due to knee osteoarthritis (OA) and meniscal lesions were reviewed. Based upon the location of meniscal tears, patients were categorized as group B (tears in posterior horn) and group A (other sites). MPTS and MMS were measured from magnetic resonance imaging (MRI) slices. Osteoarthritis grade was evaluated in anteroposterior radiographs by the criteria defined by Kellgeren and Lawrence. Demographic data, OA grade, MPTS, and MMS for the 2 groups were compared and analyzed.The group A had 29 (39%) male and 45 (61%) female subjects with a mean age of 57.07 ± 6.79 years. Group B consists of 74 (34%) male and 144 (66%) female subjects with a mean age of 58.90 ± 7.594 years. (P = .067 and P = .458 for age and sex, respectively). In group A, 31 knees (42%) were determined to be Kellgren-Lawrence grade one, 32 knees (43%) grade two, and 11 knees (15%) grade three. In group B, 86 knees (39%) were categorized in grade one, 85 knees (39%) in grade two, and 47 knees (26%) in grade three (P = .085). The mean MPTS was 5.06 ± 2.11 degree for group A and 6.15 ± 2.37 degree for group B (P = .001). The mean MMS for group A was lower than group B (1.38 ± 2.12 degree vs 3.14 ± 2.92 degree; P < .000)This study demonstrated that increased MPTS and MMS may be considered as the risk factors for medial meniscal posterior horn tears.


Anatomopathology of the normal and abnormal AV conduction system.
The specialized conduction system of the heart is responsible for both congenital and acquired disorders of cardiac rhythm. Sinoatrial disorders may result from disruption of nodal cells and takeover by subsidiary pacemaker cells. AV block may occur congenitally or result from the ravages of ischemic heart disease. Clinically overt or concealed accessory pathway conduction via various types of bypass tracts are responsible for the genesis of many supraventricular arrhythmias. Anatomohistologic correlations provide the analytic basis for many disturbances of rhythm.


Spontaneous subcapsular renal hematoma: diagnosis and management.
Spontaneous subcapsular or perinephric hematoma in the absence of anticoagulation, arteritis or trauma is most likely due to an underlying renal tumor. Eight such patients recently have been evaluated and after nephrectomy 5 had small tumors undetectable by imaging techniques, including computerized tomography or angiography. In 1 patient a tumor was demonstrated preoperatively by angiography and in only 2 was a tumor not found. In the absence of an apparent etiology, patients with spontaneous renal bleeding and a normal contralateral kidney should undergo radical nephrectomy because of the extremely high incidence of small undetectable occult tumors, often less than 2 cm. in size.


Cytochemical analysis of organelle degradation in phagosomes and apoptotic cells of the mucoid epithelium of mice.
The activity of mitochondrial cytochrome oxidase and peroxisomal catalase in the phagolysosomes and apoptotic bodies of mucoid epithelial cells was analysed. Tissue from 2-6 day old mice was used. The activity of acid phosphatase in lysosomes was also estimated. Cytochrome oxidase was demonstrated in well-preserved mitochondria inside phagosomes. Mitochondria in cells exhibiting apoptotic death also show activity of cytochrome oxidase. The enzyme activity in swollen mitochondria ceases before the membranes of the cristae disappear completely. Apoptotic bodies are phagocytosed by sister mucoid cells and, later on, they are digested inside the cell. Phagosomes which contain already degraded mitochondria show still active catalase in sequestered peroxisomes. The acid phosphatase involved in degradation of phagocytosed material originates from endocytosed lysosomes and primary and secondary lysosomes which fuse with the membranes of phagosomes.


Tumor cell interactions in vitro microtubules, 100 angstrom filaments, and contractile microfilaments of tumor cells involved in "emperipolesis".
An increase in the number of examples of emperiopolesis, i.e., cells within cells, was observed subsequently to addition of Bt2cAMP to spinner flask cultures of JB-1-E tumor cells. A conspicuous arrangement of microtubules and 100 angstrom filaments in the tumor cells involved in emperiopelesis was observed. Absence of emperipolesis in cultures treated with cytochalasin B indecates a possible role of the contractile microfilaments in the events leading to emperiopolesis. The significance of and the term emperipolesis are discussed.


The role of endoscopic sinus surgery for the treatment of nasal polyposis.
Nasal polyposis remains a significant challenge to the treating physician. The functional endoscopic surgery technique provides a tool by which the clinician can accurately diagnose, meticulously and atraumatically perform surgery, and precisely provide postoperative care and follow-up for patients with nasal polyp disease.


Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase.
Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/β-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases of myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of the R1845W mutation. This study shows that a higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was suppressed by expression of Thin (herein referred to as Abba), an E3 ubiquitin ligase. This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities, including extensive loss of thick filaments with selective A-band loss, and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Furthermore, the impaired muscle morphology associated with the mutant allele was suppressed by expression of Abba. These findings suggest that modification of the ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.


C. vulgaris growth batch tests using winery waste digestate as promising raw material for biodiesel and stearin production.
The recovery of high added value compound from waste stream is fundamental to keep biotechnological processes sustainable. In this study, anaerobic digestion of two highly produced organic waste was integrated with microalgae-based processes both to treat liquid digestate and recover high value compounds. Chlorella vulgaris growth was assessed for lipids accumulation and subsequent recovery, using two types of digestate: organic waste and sewage sludge digestate (DIG-OFMSW) and wine lees digestate (DIG-WL). Growth tests were carried out in batch mode and results showed a slightly higher final biomass concentration from DIG-WL (1.36 ± 0.09 g l-1) compared to DIG-OFMSW (1.05 ± 0.13 g l-1) and a clearly different lipids accumulation yield (28.86 ± 0.05% in DIG-WL compared to 6.1 ± 0.2% of DIG-OFMSW, on total solids). Lipid characterization showed a high oleic acid accumulation (69.52 ± 0.50%w/w in DIG-WL) that positively influence biodiesel properties and a low linolenic acids content (below 0.30%w/w) that comply with European law EN14214 for biodiesel (linolenic acid content lower than 12%w/w). In addition, due to the high concentration of palmitic and stearic acids detected at the end of test, this oil can be used as new substrate to produce stearin, normally produced from palm oil.


[Surgical treatment of bronchiectasis].
While the prevalence of bronchiectasis has decreased significantly over recent decades in developed countries, resection for bronchiectasis still plays an important part in thoracic surgery practice in some countries, such as Portugal. Between 1994 and 2004, 51 patients (29 female and 22 male) with a mean age of 38.6 years (range 4-65 years) underwent pulmonary resection for bronchiectasis. Mean duration of symptoms was 4.8 years. Surgery was indicated because of unsuccessful medical therapy in 25 patients (49.1%), haemoptysis in 12 (23.5%), lung mass in 9 (17.6%) and lung abscess in 5 (9.8%). The surgical treatment was pulmonectomy in 7 patients, bilobectomy in 3, lobectomy in 36 and segmentectomy in 5. There was no operative mortality. Complications occurred in 8 patients and the morbidity rate was 15.7%. Follow-up was complete in 45 (88.2%) patients with a mean of 3.4 years. Overall, 35 (77.7%) patients were asymptomatic after surgery, symptoms were improved in 7 (15.6%), and unchanged or worse in 3 (6.7%). Unsuccessful medical therapy was still our main indication for surgery of bronchiectasis, despite aggressive anti- biotic therapy. Surgical resection was performed with acceptable morbidity and morbidity and markedly improved symptoms in the majority of patients.


The prevalence of childhood atopic eczema in a general population.
Atopic eczema has become more common during recent decades, but few studies have looked at its prevalence in the general community. Our purpose was to ascertain the prevalence of atopic eczema, its age of onset, and its relationship to breast-feeding and ear piercing in a general practice population. Children (N = 1104), aged 3 to 11 years, were identified from a computerized register in a socially and ethnically mixed English general practice population of 13,314. Of these, 1077 children (97.6% recruitment) were interviewed with parents or guardians, and the resultant data were recorded on a survey form. The lifetime occurrence of atopic eczema was 20% in boys (12% in the past year) and 19% in girls (11% in the past year). Prevalence in the past year was 10% to 14% in boys aged 3 to 11 years but fell in girls from 15% at 3 to 5 years to 8% at 9 to 11 years. Atopic eczema developed in the first 12 months of life in 60% of the children who had the condition, and it developed in the first 6 months of life in three quarters of these children. Ear piercing had been performed in 35% of girls and 3% of boys and was most prevalent in social classes 3, 4, and 5. More than half the girls aged 9 to 11 years had pierced ears. Breast-feeding did not affect the prevalence of atopic eczema. The lifetime prevalence of atopic eczema was 20% in children aged 3 to 11 years. There was no evidence that ear piercing perpetuated eczema in this age group. Breast-feeding did not protect against the development of atopic eczema.


Molecular Characterization of Upper Tract Urothelial Carcinoma in the Era of Next-generation Sequencing: A Systematic Review of the Current Literature.
While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic molecular alterations. To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC. A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies. Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC. We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type.


Recovery of functional deficits following early donor age ventral mesencephalic grafts in a rat model of Parkinson's disease.
It has previously been reported that dopaminergic grafts derived from early donor age, embryonic age 12-day-old (E12) rat embryos produced a fivefold greater yield of dopamine neurons than those derived from conventional E14 donors. The present study addresses whether E12 grafts are able to ameliorate lesion-induced behavioral deficits to the same extent as E14 grafts. In a unilateral rat model of Parkinson's disease, animals received grafts derived from either E12 or E14 donor embryos, dispersed at four sites in the lesioned striatum. Both E12 and E14 grafts were able to induce recovery on both amphetamine and apomorphine rotation tests, and to ameliorate deficits in the cylinder, stepping test, and corridor tests, but were unable to restore function in the paw reaching task. E12 grafts were equivalent to E14 grafts in their effects on lesion-induced deficits. However, E12 grafts resulted in cell yields greater than previously reported for untreated primary tissue, with mean TH-positive cell counts in excess of 25,000 neurons, compared with E14 TH cell counts of 4000-5000 cells, representing survival rates of 75% and 12.5%, respectively, based on the expected adult complement. The equivalence of graft induced behavioral recovery between the two graft groups is attributed to a threshold number of cells, above which no further improvement is seen. Such high dopamine cell survival rates should mean that multiple, functioning grafts can be derived from a single embryonic donor, and if similar yields could be obtained from human tissues then the goal of one embryo per patient would be achieved.


Variation in Patient-Described Barriers to and Facilitators of Diabetes Management by Individual-Level Characteristics: A Cross-Sectional, Open-Ended Survey.
This study analyzed patient-described barriers and facilitators related to diabetes management, focusing on how these differ by glycemia and across individual characteristics. A cross-sectional telephone survey was conducted with adult patients with diabetes in Alberta, Canada, asking two open-ended questions to describe the most helpful and difficult components of their diabetes management. Responses were analyzed using directed content analysis using the Theoretical Domains Framework as a template. The most frequently cited facilitator was care context and information, and the most frequently cited barriers were cognitive challenges and structural barriers, with patient-perceived barriers and facilitators varying by individual-level factors.


Modified cerium-based and Gomori-based cerium methods for light microscopic phosphatase histochemistry: the cerium-perhydroxide-diaminobenzidine-nickel (Ce-H2O2-DAB-Ni and Ce/Ce-H2O2-DAB-Ni) two-step procedures.
Some modified cerium-based and Gomori-based cerium methods for the demonstration of phosphatase activity in cryostat sections were described. Dextrane as stabilizing agent was added to the incubation media for ATPase, 5'-Nase, and TPPase. The oxidation of the CeIII-phosphate primary reaction product in a separate step by H2O2 before the DAB incubation yielded an increase of the intensity of the DAB-based visualization reaction (Ce-H2O2-DAB-Ni two step method). The sensitivity of the histochemical enzyme reaction was remarkably increased if CeIII-ions were employed as amplifying agent (Ce/Ce-H2O2-DAB-Ni two-step method). A new suitable DAB medium consisting of 0.015% DAB, 2.0% Ni-sulphate, 15% methanol, and 0.005% H2O2 in 0.1 mol/l acetate buffer, pH = 5.2, was used. The disadvantage of diffuse background staining has been overcome by addition of 15% methanol to the DAB solution. Electrovalently bound CeIII (cerophilia) was removed by treatment of the incubated sections with CeIII-citrate (CeIII-complexation). In addition, a novel membrane floating incubation for sections is proposed. At present, the modified procedures are some of the most sensitive modes for the demonstration of phosphatases and improve the earlier described cerium-DAB one-step technique (Halbhuber et al. 1988b).


Heart Rate Variability in Nonlinear Rats with Different Orientation and Exploratory Activity in the Open Field.
The basic behavioral activity of nonlinear rats was evaluated from the sum of crossed peripheral and central squares and peripheral and central rearing postures in the open fi eld test. This index was low (<20 episodes), intermediate (20-29 episodes), or high (>30 episodes). Male rats with high score of orientation and exploratory activity were characterized by higher indexes of total heart rate variability than rats with low or intermediate activity. Specimens with a greater contribution of VLF waves into the total power spectrum of heart rate variability were shown to dominate among the rats with high behavioral activity. Our results are consistent with the notions of a suprasegmental nature of VLF waves.


A cascade associative memory model with a hierarchical memory structure.
The introduction of a hierarchical memory structure into a cascade associative memory model for storing hierarchically correlated patterns improves the storage capacity and the size of the basins of attraction remarkably. A learning algorithm groups descendants (second-level patterns) according to their ancestors (first-level ones), and organizes the memory structure in a weight matrix where the groups are memorized separately. The weight matrix is, thus, in the form of a pile of covariance matrices, each of which is responsible for recalling only the descendants of each ancestor. Putting it simply, the model is multiplex associative memory. The recalling process proceeds as follows: the model first recalls the ancestor of a target descendant. Then, the dynamics with dynamic threshold combines the ancestor and the weight matrix to activate the covariance matrix for recalling only the descendants of the ancestor. This mechanism suppresses the cross-talk noise generated by the descendants of the other ancestors, and the recalling ability is enhanced.


Do parasites confer a disadvantage to hybrids? : A case study ofAlburnus alburnusxRutilus rubilio, a natural hybrid of Lake Mikri Prespa, Northern Greece.
This paper is the second of three studies of a natural hybrid,Rutilus rubilioxAlburnus alburnus found in Lake Mikri Prespa in Northern Greece. It compares the parasite load of the hybrid to that of its parents, focussing onDactylogyrus spp.,Diplozoon sp.,Bolbophorus confusus andPomphorhynchus bosniacus. The hybrid's gill tissue is parasitised almost exclusively by the parentalDactylogyrus. It follows that theDactylogyrus group constitutes an excellent biological marker for hybridisation. Furthermore, the hybrid is characterised by the following two features: 1. high susceptibility to parasitic infections, 2. important role of ecological components in the recruitment of parasites: for monoxenous parasites (Dactylogyrus spp.), the spatial position of the hybrid and for heteroxenous parasites (P. bosniacus), the trophic position. The parasitology of this particular hybrid may be useful as a model for the properties and fitness of hybrids in general.


PIRCHE-II: an algorithm to predict indirectly recognizable HLA epitopes in solid organ transplantation.
Human leukocyte antigen (HLA) mismatches between donors and recipients may lead to alloreactivity after solid organ transplantation. Over the last few decades, our knowledge of the complexity of the HLA system has dramatically increased, as numerous new HLA alleles have been identified. As a result, the likelihood of alloreactive responses towards HLA mismatches after solid organ transplantation cannot easily be assessed. Algorithms are promising solutions to estimate the risk for alloreactivity after solid organ transplantation. In this review, we show that the recently developed PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) algorithm can be used to minimize alloreactivity towards HLA mismatches. Together with the use of other algorithms and simulation approaches, the PIRCHE-II algorithm aims for a better estimated alloreactive risk for individual patients and eventually an improved graft survival after solid organ transplantation.


Anti-apoptotic HAX-1 suppresses cell apoptosis by promoting c-Abl kinase-involved ROS clearance.
The anti-apoptotic protein HAX-1 has been proposed to modulate mitochondrial membrane potential, calcium signaling and actin remodeling. HAX-1 mutation or deficiency results in severe congenital neutropenia (SCN), loss of lymphocytes and neurological impairments by largely unknown mechanisms. Here, we demonstrate that the activation of c-Abl kinase in response to oxidative or genotoxic stress is dependent on HAX-1 association. Cellular reactive oxygen species (ROS) accumulation is inhibited by HAX-1-dependent c-Abl activation, which greatly contributes to the antiapoptotic role of HAX-1 in stress. HAX-1 (Q190X), a loss-of-function mutant responsible for SCN, fails to bind with and activate c-Abl, leading to dysregulated cellular ROS levels, damaged mitochondrial membrane potential and eventually apoptosis. The extensive apoptosis of lymphocytes and neurons in Hax-1-deficient mice could also be remarkably suppressed by c-Abl activation. These findings underline the important roles of ROS clearance in HAX-1-mediated anti-apoptosis by c-Abl kinase activation, providing new insight into the pathology and treatment of HAX-1-related hereditary disease or tumorigenesis.


A hybridization chain reaction based assay for fluorometric determination of exosomes using magnetic nanoparticles and both aptamers and antibody as recognition elements.
Exosomes represent a new generation of biomarkers for the early diagnosis of hepatic carcinoma. A fluorometric assay is presented that is based on the hybridization chain reaction and magnetic nanoparticles for the highly sensitive determination of exosome (from HepG2 cells). Antibody as the recognition element was modified on the surface of magnetic nanoparticles. Antibody was used to capture the exosome. The Probe 1 was consisted of aptamer sequence and trigger sequence. Aptamer sequence will bind with the surface protein of exosome. The trigger sequence will hybridize with the probe2 (FAM-labeled) and the probe3 (FAM-labeled). So the product of the hybridization chain reaction will present a strong fluorescence signal. The fluorescence product of hybridization chain reaction will link with magnetic nanoparticles through the 'magnetic nanoparticles-antibody-exosome-aptamer' structure. The product can be separated from the matrix due to the present of the magnetic nanoparticles. The excitation was set at 490 nm. The fluorescence value of the emission spectra at 519 nm was set as the signal response. The linear range of this assay is from 1000 to 107 particles·mL-1. The detection limit is 100 particles·mL-1. This assay was applied to the determination of exosome from the hepatic carcinoma cells. Graphical abstractIn the presence of exosmes, the hybridization chain reaction was triggered and strong green fluorescence will be produced. Moreover, the magnetic particles can separate the products from the matrix.


Intestinal calcium absorption, serum phosphate, and parathyroid hormone in patients with chronic renal failure and osteodystrophy before and during hemodialysis.
In 34 patients with chronic renal failure (CRF), fractional 47calcium absorption (Fa47Ca) was measured by an external counting method. A significant correlation was found with impairment of renal function, as expressed by the creatinine clearance. There was also a significant correlation of Fa47Ca with the serum phosphate (SeP) level and of immunoreactive parathyroid hormone (iPTH) with renal function. When the relationship of both SeP and Fa47Ca with creatinine clearance was excluded, no partial correlation between SeP and Fa47Ca appeared to exist. A significant increase of Fa47Ca and serum Ca and a significant decrease of SeP and iPTH were found in 12 patients 2 to 15 months after they were put on intermittent hemodialysis. The possible influence of SeP on intestinal calcium absorption is discussed, and it is suggested that impairment of intestinal absorption of calcium is not a main factor in development of renal osteodystrophy.


Connections of the auditory forebrain in the pigeon (Columba livia).
Ascending auditory efferents in birds terminate mainly within Field L2, a cytoarchitectonically distinct region of the caudomedial telencephalon. The organization of Field L2, and that of its flanking regions, L1 and L3, was investigated with 14C-2-deoxyglucose (14C-2-DG), cytochrome oxidase, and both retrograde and anterograde tracing techniques. Field L2 was found to contain a high concentration of cytochrome oxidase. Following auditory stimulation, 14C-2-DG autoradiography revealed that Field L2 consists of two adjacent but seemingly discontinuous zones, designated Field L2a, which lies ventromedially, and Field L2b, which lies dorsolaterally. Termination of thalamic efferents: The thalamic auditory nuclei ovoidalis (Ov) and semilunaris parovoidalis (SPO) project predominantly upon Field L2, and possibly sparsely upon L1, L3 and the overlying hyperstriatum ventrale (HV). Ov subnuclei project upon L2a and SPO projects predominantly upon L2b. The topography of the projections is inverted along the ventromedial-to-dorsolateral axis of L2, and is in accord with an inverted tonotopic representation of frequencies; high frequencies (< 3.5 kHz) being found in the more ventromedial parts of L2a, and low frequencies and broad band responses in L2b. Intra- and extratelencephalic connections: Field L2a also receives a substantial projection from HV, but the efferent projections of L2a appear confined to adjacent "neostriatal" regions. The subsequent projections of L2b were not identified in this study. L1 and L3 project predominantly to the dorsal neostriatum (Nd) caudolateral to Field L, and have fewer projections to the caudomedial paleostriatum and anterior hyperstriatum accessorium. Nd projects massively upon the ventromedial nucleus of the intermediate archistriatum (Aivm), which has bilateral projections upon the caudomedial telencephalon and is the origin of a major descending pathway having dense terminations surrounding the ovoidalis complex (Ov and SPO), MLd, the lateral lemniscal nuclei, and sparse terminations within SPO itself. It is suggested that within the telencephalon the major components of the auditory pathway consist of cell groups which collectively correspond to the populations of neurons found within the auditory cortex of mammals.


JNK3 enzyme binding to arrestin-3 differentially affects the recruitment of upstream mitogen-activated protein (MAP) kinase kinases.
Arrestin-3 was previously shown to bind JNK3α2, MKK4, and ASK1. However, full JNK3α2 activation requires phosphorylation by both MKK4 and MKK7. Using purified proteins we show that arrestin-3 directly interacts with MKK7 and promotes JNK3α2 phosphorylation by both MKK4 and MKK7 in vitro as well as in intact cells. The binding of JNK3α2 promotes an arrestin-3 interaction with MKK4 while reducing its binding to MKK7. Interestingly, the arrestin-3 concentration optimal for scaffolding the MKK7-JNK3α2 module is ∼10-fold higher than for the MKK4-JNK3α2 module. The data provide a mechanistic basis for arrestin-3-dependent activation of JNK3α2. The opposite effects of JNK3α2 on arrestin-3 interactions with MKK4 and MKK7 is the first demonstration that the kinase components in mammalian MAPK cascades regulate each other's interactions with a scaffold protein. The results show how signaling outcomes can be affected by the relative expression of scaffolding proteins and components of signaling cascades that they assemble.


Infrared spectroscopy as a novel tool to diagnose onychomycosis.
The determination of causative organisms of onychomycosis is still not optimal. There remains a need for a cheap, fast and easy-to-perform diagnostic tool with a high capacity to distinguish between organisms. To determine whether attenuated total-reflectance Fourier transform infrared (ATR-FTIR) spectroscopy can detect and differentiate causative agents in culture-based, ex vivo nail and in vivo nail models. A methodological study was conducted. Both the ex vivo nail model and in vivo pilot study were carried out in an academic university hospital. Analysis of cultured fungi revealed spectral differences for dermatophytes (1692-1606 and 1044-1004 cm-1 ) and nondermatophytes and yeasts (973-937 cm-1 ), confirmed by dendrograms showing an excellent separation between samples from different genera or species. Exploration of dermatophytes, nondermatophytes and yeasts growing on ex vivo nails exposed prominent differences from 1200 to 900 cm-1 . Prediction models resulted in a 96·9% accurate classification of uninfected nails and nails infected with dermatophytes, nondermatophytes and yeasts. Overall correct classification rates of 91·0%, 97·7% and 98·6% were obtained for discrimination between dermatophyte, nondermatophyte and yeast genera or species, respectively. Spectra of in vivo infected and uninfected nails also revealed distinct spectral differences (3000-2811 cm-1 , 1043-950 cm-1 and 1676-1553 cm-1 ), illustrated by two main clusters (uninfected vs. infected) on a dendrogram. Our data suggest that ATR-FTIR spectroscopy may be a promising, fast and accurate method to determine onychomycosis, including identification of the causative organism, bypassing the need for lengthy fungal cultures.


Innervation of the placenta and uterus: competition between cytotrophoblasts and nerves?
In normal pregnancy, invasion of the uterus by trophoblasts is followed by dramatic elimination of the rich uterine innervation present in the non-pregnant state, and by remodeling of maternal spiral arteries. In general, the healthy survival of vascular smooth muscle requires innervation, but whether denervation plays a role in stripping of vascular smooth muscle from spiral arteries in normal pregnancy has not been explored. We propose that the temporal and spatial association of trophoblast invasion with denervation in pregnancy may involve competitive interaction between the invading trophoblast and persisting neurons. We suggest feasible experiments to explore the possible effects of such trophoblast-nerve competition on spiral artery remodeling.


Congenital retinal macrovessels: description of three cases and review of the literature.
Congenital retinal macrovessels are large aberrant branches of retinal arteries or veins that cross the macula. We present three patients with a unilateral congenital retinal macrovessel and we conduct a review of the literature. A 22-year-old man complaining of chronic headache as well as two other men, 18 and 23 years old, respectively, during a routine ophthalmological examination, were found with a unilateral congenital retinal macrovessel each. A thorough ophthalmological examination was performed, including colour fundus photography in all three patients and fluorescein angiography in two of the patients. We followed them up for five years. Investigation revealed a unilateral venous congenital retinal macrovessel in all patients. Clinical findings and visual acuity remained unchanged throughout the entire follow-up period. No complications were recorded. Congenital retinal macrovessels are rare and they tend to remain stable. Visual acuity is preserved in most cases. Complications occur only occasionally and have been described in the literature. Differential diagnosis from other arteriovenous malformations affecting multiple organs is necessary.


A neural model of schemas and memory encoding.
The ability to rapidly assimilate new information is essential for survival in a dynamic environment. This requires experiences to be encoded alongside the contextual schemas in which they occur. Tse et al. (Science 316(5821):76-82, 2007) showed that new information matching a preexisting schema is learned rapidly. To better understand the neurobiological mechanisms for creating and maintaining schemas, we constructed a biologically plausible neural network to learn context in a spatial memory task. Our model suggests that this occurs through two processing streams of indexing and representation, in which the medial prefrontal cortex and hippocampus work together to index cortical activity. Additionally, our study shows how neuromodulation contributes to rapid encoding within consistent schemas. The level of abstraction of our model further provides a basis for creating context-dependent memories while preventing catastrophic forgetting in artificial neural networks.


Stereoselective alkylidenation of ketones with 2-(p-toluenesulfinyl)benzyl iodide: synthesis of enantiomerically pure trisubstituted epoxides.
Alkylidenation of arylmethyl, dialkyl, and cyclic ketones with 2-( p-toluenesulfinyl)benzyl iodide in the presence of NaN(SiMe3)2 takes place with a high or complete control of the facial selectivity at the carbonyl group (up to 98% de) and the carbanion (>98% de), respectively, yielding mixtures of only two optically pure trisubstituted epoxides ( E/Z ratio ranges between 2:1 and >50:1). Removal of the p-tolylsulfinyl group with t-BuLi provides the corresponding (E)-3-phenyl-2,2-disubstituted epoxides without affecting their optical purity.


Future Research Directions for the Insurance Hypothesis regarding Food Insecurity and Obesity.
This commentary discusses Nettle et al.'s "The Insurance Hypothesis" linking food insecurity to a high body mass index (BMI). Discussion about how the relationship between race/ethnicity and obesity in the United States is consistent with this hypothesis is presented. Potential ways forward to elucidate the validity of this hypothesis in humans through rigorous controlled trials is highlighted.


Neutrophils in COVID-19: recent insights and advances.
Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to acute respiratory distress syndrome (ARDS), multi-organ failure and death, posing significant threat to human health. Studies have found that pathological mechanisms, such as cytokine storms caused by uncontrolled innate immune system activation, release of damage-associated molecular patterns during tissue injury and a high incidence of thrombotic events, are associated with the function and dysfunction of neutrophils. Specifically, the increased formation of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs) has been shown to be closely linked with the severity and poor prognosis in patients with COVID-19. Our work focuses on understanding the increased number, abnormal activation, lung tissue infiltration, and elevated neutrophil-to-lymphocyte ratio in the pathogenesis of COVID-19. We also explore the involvement of NETs and LDNs in disease progression and thrombosis formation, along with potential therapeutic strategies targeting neutrophil and NETs formation.


Association between antithrombin and mortality in patients with COVID-19. A possible link with obesity.
Despite anticoagulation, usually with heparin, mortality for thromboembolic events in COVID-19 remains high. Clinical efficacy of heparin is due to its interaction with antithrombin (AT) that may be decreased in COVID-19. Therefore, we correlated AT levels with outcomes of COVID-19. We recruited 49 consecutive patients hospitalized for COVID-19. AT levels were significantly lower in 16 non-survivors than in 33 survivors (72.2 ± 23.4 versus 94.6 ± 19.5%; p = 0.0010). A multivariate Cox regression analysis showed that low AT (levels below 80%) was a predictor of mortality (HR:3.97; 95%CI:1.38 to 11.43; p = 0.0103). BMI was the only variable that showed a significant difference between patients with low and those with normal AT levels (32.9 ± 7.9 versus 27.5 ± 5.9%; p = 0.0104). AT levels were significantly lower in obese patients than in subjects with normal weight or overweight (77.9 ± 26.9 versus 91.4 ± 26.9 versus 91.4 ± 17.1%; p = 0.025). An inverse correlation between AT levels and BMI was documented (r:-0.33; p = 0.0179). Our data first suggest that AT is strongly associated with mortality in COVID-19. In addition, AT may be the link between obesity and a poorer prognosis in patients with COVID-19. Other studies should confirm whether AT may become a prognostic marker and a therapeutic target in COVID-19.


Synergistic Effect of Whitlockite Scaffolds Combined with Alendronate to Promote Bone Regeneration.
Due to the increasing aging of society, the number of patients suffering from senile diseases is increasing. Patients suffering from osteoporosis, which is a representative senile disease, take a long time to recover from fractures, and the resulting mortality rate is very high. Alendronate (Ald), which is widely used as a treatment for osteoporosis, alleviates osteoporosis by inhibiting osteoclasts. In addition, whitlockite (WH) promotes the osteogenic differentiation of bone cells and improves bone regeneration. Therefore, we intended to bring about a synergistic effect by using these substances together. In this study, a scaffold composed of gelatin/heparin was fabricated and applied to effectively use WH and Ald together. A scaffold was constructed using gelatin and heparin was used to effectively utilize the cations released from WH. In addition, it formed a porous structure for effective bone regeneration. In vitro and in vivo osteoclast inhibition, osteogenic differentiation, and bone regeneration were studied using the prepared scaffolds. The inhibition of osteoclast was much higher when WH and Ald were applied in combination rather than individually. The highest level of osteogenic differentiation was observed when both substances were applied simultaneously. In addition, when applied to bone regeneration through the mouse calvarial defect model, combined treatment showed excellent bone regeneration. Therefore, this study showed the synergistic effect of WH and Ald, and it is suggested that better bone regeneration is possible by applying this treatment to bones with fractures that are difficult to regenerate.


Associations of professional quality of life and social support with health in clinical nurses.
To explore the associations of the professional quality of life and social support with health in nurses. Physical and mental health may be associated with absence from work among nurses. Few studies have explored the associations of professional quality of life and social support on the physical and mental health of nurses. This was a cross-sectional study. In total, 294 nurses were recruited from a hospital in Southern Taiwan. A self-report questionnaire was used to collect data. Burnout, secondary traumatic stress and social support from relatives or friends were important factors of physical and mental health. Interactions between support from relatives or friends and secondary traumatic stress are important factors in physical health. Reducing burnout and secondary traumatic stress is important for physical and mental health of nurses. Increasing social support from relatives or friends may be useful to reduce the negative effects of secondary traumatic stress on the physical health of nurses. Nurse managers could design interventions to reduce and prevent nurses from being influenced by burnout and secondary traumatic stress. Educating nurses to build effective social networks with relatives or friends and to seek support when experiencing secondary traumatic stress may also be needed.


Ultrastructural effects of Nifurtimox on rat adrenal cortex related to reductive biotransformation.
Nifurtimox (Nfx) (4(5-nitrofurfurylidene)amino)-3-methylthiomorpholine-1, 1-dioxide) is a drug used against Chagas' disease, a parasitic sickness afflicting several million Latin Americans. Nfx administration to Sprague-Dawley male rats (220-250 g) at a dose of 100 mg/kg caused pronounced alterations in the adrenal cortex involving the fasciculata and reticularis zones but which were not evident in the glomerulosa. Alterations observed involved mitochondria, nuclei, Golgi apparatus, and the endoplasmic reticulum but were more intense in the mitochondria. There is Nfx nitroreductase activity in the adrenal microsomal, mitochondrial, and cytosolic-rich fractions but most of it is in the mitochondrial-rich fraction. Activity in the first two fractions requires NADPH and that in the cytosol is only observed in the presence of hypoxanthine as substrate. Enzymatic activity in all fractions is inhibited by oxygen. CO does not inhibit mitochondrial Nfx nitroreductase and inhibits only 10% of the microsomal enzyme activity. Hypoxanthine-dependent cytosolic activity is inhibited by allopurinol. Present results suggest that Nfx is activated to damage-producing reactive metabolites by nitroreductive biotransformation in rat adrenal organelles. Mitochondrial and microsomal bioactivation would occur at the level of the flavoenzyme P-450 reductase rather than at P-450 itself, and cytosolic bioactivation would be mediated by xanthine oxidase. Epidemiological studies on adrenal function in patients undergoing Nfx treatment would be necessary to establish the potential toxicological relevance of these findings.


Computational identification of protein kinases and kinase-specific substrates in plants.
The protein phosphorylation catalyzed by protein kinases (PKs) plays an essential role in almost all biological progresses in plants. Thus, the identification of PKs and kinase-specific substrates is fundamental for understanding the regulatory mechanisms of protein phosphorylation especially in controlling plant growth and development. In this chapter, we describe the computational methods and protocols for the identification of PKs and kinase-specific substrates in plants, by using Vitis vinifera as an example. First, the proteome sequences and experimentally identified phosphorylation sites (p-sites) in Vitis vinifera were downloaded. The potential PKs were computationally identified based on preconstructed Hidden Markov Model (HMM) profiles and ortholog searches, whereas the kinase-specific p-sites, or site-specific kinase-substrate relations (ssKSRs) were initially predicted by the software package of Group-based Prediction System (GPS) and further processed by the iGPS algorithm (in vivo GPS) to filter potentially false positive hits. All primary data sets and prediction results of Vitis vinifera are available at: http://ekpd.biocuckoo.org/protocol.php.


Successful treatment of dermatomyositis-related rapidly progressive interstitial pneumonitis with sequential oral cyclophosphamide and azathioprine.
Interstitial lung disease (ILD) is a major complication of idiopathic inflammatory myopathies (IIM). We report the successful use of oral cyclophosphamide, followed by azathioprine maintenance, in the treatment of a patient with dermatomyositis-related rapidly deteriorating ILD, resistant to steroid. Prompt recognition and early aggressive immunosuppressive therapy may improve the outlook of this condition.


Zinc supplementation modifies brain tissue transcriptome of Apis mellifera honeybees.
Bees are the most important group of pollinators worldwide and their populations are declining. In natural conditions, Apis mellifera depends exclusively on food from the field to meet its physiological demands. In the period of scarcity, available resources are insufficient and artificial supplementation becomes essential for maintaining the levels of vitamins, proteins, carbohydrates, and minerals of colonies. Among these minerals, zinc is essential in all living systems, particularly for the regulation of cell division and protein synthesis, and is a component of more than 200 metalloenzymes. The total RNA extracted from the brain tissue of nurse bees exposed to different sources and concentrations of zinc was sequenced. A total of 1,172 genes in the treatment that received an inorganic source of zinc and 502 genes that received an organic source of zinc were found to be differentially expressed among the control group. Gene ontology enrichment showed that zinc can modulate important biological processes such as nutrient metabolism and the molting process. Our results indicate that zinc supplementation modulates the expression of many differentially expressed genes and plays an important role in the development of Apis mellifera bees. All the information obtained in this study can contribute to future research in the field of bee nutrigenomics.


Semi-automated measurement of vascular tortuosity and its implications for mechanical thrombectomy performance.
Few studies have examined the geometry of endovascular mechanical thrombectomy pathways. Here we examine the tortuosity and angulations of catheter pathways from the aortic arch to the termination of the internal carotid artery (ICA) and its association with thrombectomy performance. We included 100 consecutive anterior circulation large vessel occlusion thrombectomy patients over 12 months. Computed tomography angiograms (CTA) were used for 3D segmentation of catheter pathway from the aortic arch to ICA termination. Tortuosity index (TI) and angulations of the catheter pathway were measured in a semi-automated fashion. TI and angulation degree were compared between sides and correlated with age and procedural measures. We analyzed 188 catheter pathways in 100 patients. Severe angulation (≤ 30°) was present in 5.8% and 39.4% of common carotid artery (CCA) and extracranial ICA segments, respectively. Five pathways (2.6%) had 360° loop. CCA and extracranial ICA tortuosity had a weak but significant correlation with age (r = 0.17, 0.21, p value = 0.05, 0.02 respectively), time from groin puncture to the site of occlusion (r = 0.29, 0.25, p values = 0.008, 0.026 respectively), and fluoroscopy time (r = 0.022, 0.31, p values = 0.016, 0.001 respectively). There was a significant difference in the pattern of angulation (p value = 0.04) and tortuosity between right and left side in CCA segment (TI = 0.20 ± 0.086 vs. 0.15 ± 0.82, p value < 0.001). There was a significant difference in CCA angulation between right and left sides. TI of extracranial CCA and ICA correlated with age and influenced time from groin puncture to the occlusion site and total fluoroscopy time.


Rapid diagnostic service for patients with haematuria.
To assess the feasibility of a clinic for the investigation of haematuria, with open access to general practitioners. A total of 395 patients (198 men and 197 women), with mean age 51 years (range 19-73), were referred from 13 general practitioner clinics. All investigations were performed at the patient's first visit at which time either a provisional or a definitive diagnosis was made. Urinary tract infection was the most common diagnosis. Of all the patients, 43 (11%) had a malignancy of whom nine presented with microscopic haematuria. Fifty-nine per cent of patients were discharged after their first visit and 26% were placed on the waiting list for in-patient procedures. An open access clinic such as this is efficient and easily run. The high incidence of pathological abnormalities makes it a worthwhile facility.


CT and MR demonstration of nabothian cysts mimicking a cystic adnexal mass.
The CT and magnetic resonance appearance of prominent nabothian cysts is presented. Although small nabothian cysts are common gynecologic findings, they at times reach 2-4 cm in diameter and may simulate a cystic adnexal mass.


Retinal detachment repair with perfluoro-N-octane endotamponade in an infant with juvenile X-linked retinoschisis.
We present a case of successful surgical management of an infant with X-linked retinoschisis with a giant retinal tear and retinal detachment of the right eye. A 10-month-old male presented with retinoschisis of both eyes and a retinal detachment of the right eye. The patient underwent two-stage pars plana vitrectomy utilizing perfluoro-N-octane to stabilize the detached retina and facilitate posterior hyaloid separation. Retained perfluoro-N-octane tamponade was later exchanged with silicone oil. The retina remained attached at last follow up. Retinal detachment repair in infants presents unique challenges. This is a safe and effective strategy for complex retinal detachment repair in the infant population.


Alterations in vitamin A and E levels in liver and testis of wild ungulates from a lead mining area.
In animals, exposure to metal pollution can induce oxidative stress via several mechanisms. This stress might then cause adverse effects on functions such as male reproductive capacity. Antioxidant vitamins A and E play an important role in maintaining organism functions under stressed conditions. This study assessed the effect of different metals and metalloids on levels of vitamins A and E in livers and testis (n = 67 and 36) of red deer and in livers (n = 22) of wild boar. The study compared animals residing within and outside a polluted mining area. Red deer from mined areas showed significant reductions in liver retinyl docosahexaenoate and retinyl docosapentaenoate. Free retinol, α-tocopherol, and retinyl palmitate in the testis were also lower. This might indicate that increased internal usage of these antioxidants is occurring as deer try to maintain the integrity and function of reproductive tissue. Wild boar from mined areas also showed significant reductions in liver retinyl stearate but increased free retinol levels. This might suggest that vitamin A is being mobilized to a greater degree to cope with the induced oxidative stress caused by exposure to metal pollution. Additionally, a significant negative relationship between liver α-tocopherol and bone lead (Pb) in boar might indicate some long-term effects of Pb on antioxidant levels. Results suggest that vitamin A and E status can be altered as a consequence of exposure to Pb pollution and that complex differences in this response probably exist between species.


Chronic bacterial prostatitis (NIH type II): diagnosis, therapy and influence on the fertility status.
In only approximately 10% of men with symptoms of chronic prostatitis/chronic pelvic pain syndrome bacterial infection of the prostate can be demonstrated by the Meares and Stamey 4-glass or the pre- and post-prostate massage (PPM) two-glass test. Chronic bacterial prostatitis is mainly caused by Gram-negative uropathogens. The role of Gram-positives, atypicals and anaerobes is still debatable. For treatment, fluoroquinolones are considered the drugs of choice because of their favourable pharmacokinetic properties and their antimicrobial spectrum. As relapse and re-infection are a major problem in chronic bacterial prostatitis, only the results of studies with a follow up period of at least 6 months are meaningful. Analysing the concentrations of various fluoroquinolones in prostatic and seminal fluid as well as in prostatic tissue, it becomes, however, obvious that fluoroquinolones differ not only in plasma concentrations, but also in their penetration ability to these sites. Nevertheless, the concentrations at the site of infection of most fluoroquinolones with this indication should be sufficient for the treatment of chronic bacterial prostatitis caused by susceptible pathogens. On the other hand, male accessory gland infection has been linked to male infertility. However, there is still a lack of evidence showing that bacterial prostatitis would have a negative impact on sperm quality.


In vitro penetration of fresh and vitrified swine oocytes by homologous spermatozoa using different incubation systems.
The present study consisted of two experiments. In the first one, ejaculates from four boars were used to compare in vitro penetration (IVP) rates of fresh and vitrified swine oocytes by homologous spermatozoa in four treatments: fresh oocytes in conventional incubation (CO2 incubator) (FC), vitrified oocytes in conventional incubation (VC), fresh oocytes in submarine (bag) incubation (FS) and vitrified oocytes in submarine incubation (VS). The IVP rates for FC, VC, FS and VS were 46.5, 44.3, 36.9 and 33.1%, respectively. Analysis through Chi-square tests identified no differences in IVP rates between FC and VC and between FS and VS (P > 0.05), but IVP rate for FC was greater (P < 0.05) than those for both FS and VS. Besides IVP rate for VC did not differ (P > 0.05) from those for FC and FS, but it was greater than that for VS (P < 0.05). Logistic regression analysis identified differential effects of treatments dependant on individual boars. The second experiment evaluated the influence of semen storage period on the semen quality of the two boars associated with greater IVP rate in the first experiment. Semen quality was estimated by IVP rate using the VC treatment and by the following methods: sperm motility, sperm morphology, hypoosmotic swelling test (HOST) and thermal stress test (TST). According to analysis using Chi-square tests, IVP rate did not differ (P > 0.05), for the first boar, between 0 (100.0%) and 24 h of semen storage (98.1%) nor after 48 and 72 h (66.0 and 59.3%, respectively), but IVP rates were greater during the 0-24 h period compared with the 48-72 h period (P < 0.05). For the second boar, IVP rate at 0 h (50.6%) was greater (P < 0.05) than at 24, 48 and 72 h of semen storage (34.3, 28.3 and 24.0%, respectively), with no further differences observed after 24 h (P > 0.05). Logistic regression analysis identified that the effect of storage on IVP rate was influenced by the effect of individual boars. No differences in semen quality during the storage period were identified by conventional methods of semen evaluation, for either boar (P > 0.05) using analysis of variance with repeated measures. These results indicate that IVP test can be used to estimate boar fertility, even when vitrified oocytes are used (if using conventional CO2 incubators) or using an alternative submarine incubation system (if using fresh oocytes). The IVP test was the only method of semen evaluation that identified the reduction in semen quality up to 72 h of storage.


Down-regulation of nestin in mesenchymal stem cells derived from peripheral blood through blocking bone morphogenesis pathway.
Different signaling pathways are implicated in proliferation and differentiation of stem cells. Bone Morphogenesis Pathway (BMP) signaling was known to display an important function in osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs). In the present study, the authors investigated whether blocking BMP signaling was associated with down regulation of Nestin expression as neural stem cell marker in peripheral blood derived mesenchymal stem cells (PB-MSCs). At first, MSCs were isolated from peripheral blood by plastic adherent ability and flow cytometry analysis. After reaching the confluence, the cells were treated with medium containing Noggin as antagonist of BMP signaling upon 8 days. Real time PCR analysis indicated that the expression of Nestin was diminished in PB-MSCs by attenuating BMP signaling. The obtained results suggested that BMP signaling might have a regulatory function on the Nestin expression in mesenchymal stem cells.


[When is surgical resection of the primary tumor indicated in metastatic prostate cancer and what is the scientific rationale?]
Similar to other tumour entities, analyses of cancer databases giving hope that patients with advanced prostate cancer with osseous metastases benefit from cytoreductive surgery. Prospective clinical trials are in the process of proving this hypothesis. This review article focuses on molecular genetic pathways and clinical data.


Prevalence of Undiagnosed Sleep Apnea in Patients With Atrial Fibrillation and its Impact on Therapy.
This study sought to evaluate the proportion of patients with atrial fibrillation (AF) who also have undiagnosed sleep apnea and examine the impact of its diagnosis on adherence to sleep apnea therapies. Sleep apnea is a modifiable risk factor for AF. However, the proportion of patients with AF who also have undiagnosed sleep apnea and the impact of its diagnosis on therapy have not been well studied. This prospective study included 188 consecutive patients with AF without a prior diagnosis of sleep apnea who were scheduled to undergo AF ablation. Participants underwent home sleep apnea testing, completed a sleep apnea screening questionnaire (STOP-BANG [Snoring; Tiredness, Fatigue, or Sleepiness During the Daytime; Observation of Apnea and/or Choking During Sleep; Hypertension; Body Mass Index >35 kg/m2; Age >50 Years; Neck Circumference >40 cm; and Male Sex]) and were followed for ≥2 years to evaluate the impact of diagnosis on therapy. Home sleep apnea testing was positive in 155 of 188 patients (82.4%); among those 155, 127 (82%) had a predominant obstructive component and 28 (18%) had mixed sleep apnea with a 15.2 ± 7.4% central component. Sleep apnea severity was mild in 43.8%, moderate in 32.9%, and severe in 23.2%. The sensitivity and specificity of a STOP-BANG questionnaire were 81.2% and 42.4%, respectively. In a multivariate analysis, STOP-BANG was not predictive for sleep apnea (odds ratio: 0.54; 95% confidence interval: 0.17 to 1.76; p = 0.31). Therapy with continuous positive airway pressure ventilators was initiated in 73 of 85 patients (85.9%) with moderate or severe sleep apnea, and 68 of the 73 patients (93.1%) remained complaint after a mean follow-up period of 21 ± 6.2 months. Sleep apnea is exceedingly prevalent in patients with AF who are referred for ablation, with a large proportion being undiagnosed due the limited predictive value of sleep apnea symptoms in this AF population. Screening for sleep apnea resulted in high rate of long-term continuous positive airway pressure adherence.


A multi-metric assessment of drought vulnerability across different vegetation types using high resolution remote sensing.
Drought impact monitoring is of crucial importance in light of climate change. However, we lack an understanding of the concomitant responses of ecosystems to a variety of drought characteristics and the links between drought and ecosystem anomaly characteristics for a comprehensive set of vegetation types to provide needed information for water management. In response, this study presents a new framework that allows us to explore the relationship between drought and its impact on ecosystems in greater detail. Specifically, our framework focuses on estimating jointly the hydrological and ecosystem temporal evolution and anomalies around a drought event using four pairs of metrics: onset-onset, duration-duration, intensity-intensity, and severity-severity of drought and vegetation damage. Additionally, we incorporated a metric on vegetation vulnerability based on changes in damage severity along a gradient of increasing drought severity. Based on this framework, we evaluated drought vulnerability patterns of various vegetation types across the Netherlands and Belgium in 2018 at high spatiotemporal resolution. Our results reveal a differential vulnerability of vegetation between ecosystems with increasing drought severity, which could aid future drought impact predictions. In particular, mosaic grasslands and tree/shrub croplands are highly sensitive to increasing drought severity. Individual characteristics (onset, duration, intensity and severity) of drought and vegetation damage behave differently in various vegetation types. For instance, broadleaved forests respond faster than other forests, while mixed forests suffer less damage than other types. The early warning threshold to drought for most vegetation types is around a Standardized Precipitation Evapotranspiration Index (SPEI) value of -1. The characterization of a suite of drought response characteristics through our impact analysis framework can be used in a wide variety of regions to understand current and possible future responses to drought.


Occurrence of epidermal growth factor receptors in human adnexal tumors and their prognostic value in advanced ovarian carcinomas.
Ninety-eight different malignant adnexal tumors were analyzed for the presence of epidermal growth factor (EGF)-specific binding sites and binding parameters were calculated by Scatchard plot analysis [G. Scatchard, Ann. N.Y. Acad. Sci. 51, 660-672 (1949)]. Thirty-four biopsies were EGF receptor (EGF-R) positive with dissociation constants (KD) of 0.5-12 X 10(-9) M and binding capacities (Bmax) of 2-250 fmol/mg. One tumor had a KD of 60 X 10(-9) M and a Bmax of 1660 fmol/mg. The correlation of EGF-R status with clinical parameters showed no significant differences in primary, metastatic, or recurrent tumors, histological subtype, tumor differentiation, and tumor residual after primary surgery. As an inverse correlation, EGF-R-positive tumors are 39% and EGF-R-negative tumors 60% progesterone receptor positive. A response to chemotherapy was noticed in 50% of EGF-R-positive ovarian carcinomas with a mean survival time of patients of 28 months. The response rate of EGF-R negative ovarian carcinomas was 12% with a mean survival time of 16 months. Regarding the treatment schedule the major differences were noticed in the cis-platinum plus cyclophosphamide treatment group. These results suggest that the biology of ovarian carcinomas is influenced by growth factors and their receptors, which can be used as prognostic factors.


Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets.
The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bicarbonate buffer solution (pH 5.5-7.5; 5-50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4-8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ∆pH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.


In vitro and in vivo comparison of argon-pumped and diode lasers for photodynamic therapy using second-generation photosensitizers.
Three prototype microchannel-cooled stacked diode array lasers were compared with the currently used conventional argon ion laser-pumped tunable dye lasers for suitability as light sources in photodynamic therapy (PDT) treatment. The PDT response of Chinese hamster ovary (CHO-K1) cells in culture and SMT-F tumor bearing mice treated with chloro-aluminum sulfonated phthalocyanin (CASPc), benzoporphyrin derivative mono-acid (BPD-MA), and lutetium texaphyrin (Lutex) was determined using each laser light source. Survival of the CHO cells was measured using a cloning assay. Tumor regression/eradication was used to assess response in the mice. Both sources of laser light produced comparable PDT responses in the two systems tested. It would be possible to replace the currently used argon ion laser-pumped dye laser systems with the diode lasers tested.


The effect of ephrin-A1 on resistance to Photofrin-mediated photodynamic therapy in esophageal squamous cell carcinoma cells.
Esophageal squamous cell carcinoma (ESCC), the most prevalent cell type of esophageal cancer, remains a dismal disease with poor prognosis. Photodynamic therapy (PDT) is a minimally invasive treatment option for early esophageal cancer. To explore possible factors involved in resistance to PDT in esophageal cancer cells, we selected PDT-resistant subcell lines by repeated treatment of CE48T/VGH (CE48T) ESCC cells with Photofrin-PDT and then analyzed the global gene modulations in the PDT-resistant cells by whole-genome microarray. More than 700 genes reached a fold change greater than 1.5 in each of the PDT-resistant cells compared to parental cells. Among these genes, both tumor necrosis factor (TNF) and EFNA1 genes were significantly upregulated in resistant cell lines. However, they were significantly downregulated in Photofrin-PDT-treated cells compared to untreated cells. The observations made in the microarray analysis were further confirmed by quantitative PCR. We observed that recombinant tumor necrosis factor alpha (TNF-α) activated the gene expression of EFNA1 at both the messenger RNA (mRNA) level and the protein level in CE48T cells. Functional analysis showed that when incubated with oligomeric and monomeric ephrin-A1 simultaneously, ESCC cells became significantly resistant to Photofrin-PDT. Functional analysis further suggested that transmembrane and soluble ephrin-A1 may cooperate to enhance resistance to Photofrin-PDT in ESCC cells.


Frequent Development of Broadly Neutralizing Antibodies in Early Life in a Large Cohort of Children With Human Immunodeficiency Virus.
Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after human immunodeficiency virus (HIV) infection compared to adults. We evaluated plasma from 212 antiretroviral therapy-naive children with HIV (1-3 years old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity, and immunoglobulin (Ig)G subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay. One-year-old children demonstrated neutralization breadth comparable to chronically infected adults, whereas 2- and 3-year-olds exhibited significantly greater neutralization breadth (P = .014). Likewise, binding antibody responses increased with age, with levels in 2- and 3-year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. It is interesting to note that the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, which suggests that most children may develop a polyclonal neutralization response. These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.