Early Respiratory Bacterial Detection and Antistaphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis.
Consensus is lacking regarding antistaphylococcal antibiotic prophylaxis use for young children with cystic fibrosis. Prophylaxis is recommended in the United Kingdom, but it is recommended against in the United States. To test the hypothesis that antistaphylococcal antibiotic prophylaxis is associated with a decreased risk of Staphylococcus aureus acquisition but no increased risk of Pseudomonas aeruginosa acquisition. We undertook a longitudinal observational study of children with cystic fibrosis who were recruited from birth (or from their first registry entry in the period) and followed until the age of 4 years (1,500 d) using 2000-2009 data from the UK Cystic Fibrosis Trust and Cystic Fibrosis Foundation registries. Children were excluded if they had a positive culture result for S. aureus or P. aeruginosa, or if they were receiving inhaled antibiotics, at the first encounter. Time to first S. aureus and P. aeruginosa detection in the UK/U.S. cohorts was compared using a Cox proportional hazards model. A UK-based analysis compared the same for those receiving flucloxacillin with those who received no prophylaxis. We included the following covariates: sex, age at registry entry, dornase alfa use, genotype, and center size. The primary analysis comprised 1,074 UK and 3,677 U.S. children. The risk of first detection was greater in U.S. children than in UK children for S. aureus (hazard ratio [HR], 5.79; 95% confidence interval [CI], 4.85, 6.90; P < 0.001) and P. aeruginosa (HR, 1.92; 95% CI, 1.65, 2.24; P < 0.001). In the UK analysis, we compared 278 children receiving flucloxacillin and 306 receiving no prophylaxis. Flucloxacillin was not associated with a reduced risk of S. aureus detection (HR, 1.22; 95% CI, 0.74, 2.0; P = 0.43), but it was associated with an increased risk of P. aeruginosa detection (HR, 2.53; 95% CI, 1.71, 3.74; P < 0.001). None of the covariates significantly affected the risk estimate in either analysis. The risk of first detection of S. aureus and P. aeruginosa was greater in the United States than in the United Kingdom. In the United Kingdom, the risk of first P. aeruginosa detection was increased among those receiving flucloxacillin compared with those who received no prophylaxis. These observational findings should be examined in randomized controlled trials.


Ca(2+) /calmodulin dependent kinase II: a critical mediator in determining reperfusion outcomes in the heart?
Ischaemic heart disease is a major cause of death and disability in the Western world, and a substantial health burden. Cardiomyocyte Ca(2+) overload is known to significantly contribute to contractile dysfunction and myocyte death in ischaemia and reperfusion, and significant advancements have been made in identifying the downstream mediators and cellular origins of this Ca(2+) mismanagement. Ca(2+) /calmodulin-dependent kinase II (CaMKII) is recognized as an important mediator linking pathological changes in subcellular environments to modifications in cardiomyocyte Ca(2+) handling. Activated in response to fluctuations in cellular Ca(2+) and to various post-translational modifications, CaMKII targets numerous Ca(2+) channels/transporters involved in Ca(2+) handling and contractile function regulation. CaMKII is activated early in reperfusion, where it exacerbates Ca(2+) leak from the sarcoplasmic reticulum and promotes the onset of ventricular arrhythmias. Inhibiting CaMKII can increase functional recovery in reperfusion and reduce apoptotic/necrotic death, at least partly through indirect and direct influences on mitochondrial Ca(2+) levels and function. Yet, CaMKII can also have beneficial actions in ischaemia and reperfusion, in part by providing inotropic support for the stunned myocardium and contributing as an intermediate to cardioprotective preconditioning signalling cascades. There is considerable potential in targeting CaMKII as a part of a surgical reperfusion strategy, though further mechanistic understanding of the relationship between CaMKII activation status and the extent of ischaemia/reperfusion injury are required to fully establish an optimal pharmacological approach.


MRI and 18FET-PET Predict Survival Benefit from Bevacizumab Plus Radiotherapy in Patients with Isocitrate Dehydrogenase Wild-type Glioblastoma: Results from the Randomized ARTE Trial.
To explore a prognostic or predictive role of MRI and O-(2-18F-fluoroethyl)-L-tyrosine (18FET) PET parameters for outcome in the randomized multicenter trial ARTE that compared bevacizumab plus radiotherapy with radiotherpay alone in elderly patients with glioblastoma. Patients with isocitrate dehydrogenase wild-type glioblastoma ages 65 years or older were included in this post hoc analysis. Tumor volumetric and apparent diffusion coefficient (ADC) analyses of serial MRI scans from 67 patients and serial 18FET-PET tumor-to-brain intensity ratios (TBRs) from 31 patients were analyzed blinded for treatment arm and outcome. Multivariate Cox regression analysis was done to account for established prognostic factors and treatment arm. Overall survival benefit from bevacizumab plus radiotherapy compared with radiotherapy alone was observed for larger pretreatment MRI contrast-enhancing tumor [HR per cm3 0.94; 95% confidence interval (CI), 0.89-0.99] and for higher ADC (HR 0.18; CI, 0.05-0.66). Higher 18FET-TBR on pretreatment PET scans was associated with inferior overall survival in both arms. Response assessed by standard MRI-based Response Assessment in Neuro-Oncology criteria was associated with overall survival in the bevacizumab plus radiotherapy arm by trend only (P = 0.09). High 18FET-TBR of noncontrast-enhancing tumor portions during bevacizumab therapy was associated with inferior overall survival on multivariate analysis (HR 5.97; CI, 1.16-30.8). Large pretreatment contrast-enhancing tumor mass and higher ADCs identify patients who may experience a survival benefit from bevacizumab plus radiotherapy. Persistent 18FET-PET signal of no longer contrast-enhancing tumor after concomitant bevacizumab plus radiotherapy suggests pseudoresponse and predicts poor outcome.


Quality of Life on the Views of Older Family Carers of People with Dementia.
Older family carers of people with dementia represent an increasing but overlooked population of family carers. This research aimed to explore how these individuals make sense of their own quality of life and to identify the factors that enhance or compromise this. Four focus groups were conducted in 2014 with 19 older family carers in community-based support groups in Nottinghamshire, United Kingdom. Data were transcribed verbatim and analysed using Interpretative Phenomenological Analysis. Thirty-three subthemes emerged and were collated into three superordinate themes: 1) aspects of care and caregiving, 2) feelings and concerns, and 3) satisfaction with life and caregiving. This study identified a broad range of aspects that are of particular importance to the quality of life of older family carers of people with dementia. These findings are expected to inform future research as well as health and social care providers with the aim of improving life quality for this population.


Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.
In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described. The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding). Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.


[Algorithm of life quality evaluation for patients with psychosomatic diseases].
To elaborate the algorithm for evaluation of quality of life (QL) in patients with psychosomatic diseases. AMPI, Spilberger-Khanin anxiety test, the procedures 'general state, activity, mood" and "personality differential". The algorithm of QL evaluation comprises a questionnaire consisting of 48 questions divided into 3 blocks. Quality of the somatic state was assessed by restrictions in exercise, self-care, everyday activity. A psychological component of QL was determined by the presence of depression, anxiety, emotional effects on everyday and professional activity; the social component--by relations in office, family, medical personal. The procedure was standardized, so QL should be considered as high at 97-144 points, good 87-96, satisfactory 44-86, unsatisfactory results were at 26-43 points, poor--at 0-25 points. The proposed technique of QL of psychosomatic patients proved its validity and reliability. Therefore, it can be recommended for design of psychosocial and medical rehabilitative measures as well as for assessment of efficacy of these measures.


DNA replication of bacteriophage T5. 3. Studies on the structure of concatemeric T5 DNA.
The replication of bacteriophage T5 DNA has been shown to proceed via branched concatemeric intermediates. The structures of this concatemeric DNA was studied with respect to single-stranded regions and single-strand interruptions by digestion with S1 nuclease and agarose gel electrophoresis after alkali denaturation. The results were compared with the pattern of 'nicks' in the mature virion DNA, and the possible origins of these nicks are discussed. The structure of T5 concatemeric DNA was also studied by electron microscopy. Replication forks, loops and rare circular structures were observed, all of which were similar to those seen in replicating DNA of other large phages. Phage capsid structures were detected in association with both concatemeric and mature phage length DNA. These observations are discussed in relation to the replication, maturation and packaging of T5 DNA.


The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders.
Marfan syndrome (MFS) is a multisystem genetic disorder with over 3000 mutations described in the fibrillin 1 (FBN1) gene. Like MFS, other connective tissue disorders also require a deeper understanding of the phenotype-genotype relationship due to the complexity of the clinical presentation, where diagnostic criteria often overlap. Our objective was to identify mutations in patients with connective tissue disorders using a genetic multipanel and to analyze the genotype-phenotype associations in a cohort of Mexican patients. We recruited 136 patients with MFS and related syndromes from the National Institute of Cardiology. Mutations were identified using next-generation sequencing (NGS). To examine the correlation between mutation severity and severe cardiovascular conditions, we focused on patients who had undergone Bentall-de Bono surgery or aortic valve repair. The genetic data obtained allowed us to reclassify the initial clinical diagnosis across various types of connective tissue disorders. The transforming growth factor beta receptor 2 (TGFBR2) rs79375991 mutation was found in 10 out of 16 (63%) Loeys-Dietz patients. We observed a high prevalence (65%) of more severe mutations, such as frameshift indels and stop codons, among patients requiring invasive treatments like aortic valve-sparing surgery, Bentall and de Bono procedures, or aortic valve replacement due to severe cardiovascular injury. Although our study did not achieve precise phenotype-genotype correlations, it underscores the importance of a multigenetic panel evaluation. This could pave the way for a more comprehensive diagnostic approach and inform medical and surgical treatment decision-making.


The Relation of Age on HIV-Positive Women's Cluster of Differentiation 4, Antiretroviral Therapy, Papanicolaou Test, Human Papillomavirus test and Visual Inspection with Acetic Acid.
Despite increased life expectancy, mortality rates among women infected with HIV are 3-15 times higher than those in the overall population, HIV-infected women are also excessively affected by HPV and have increased risks of HPV-associated developments. This study's objective is to examine the relation between the ART treatment, CD4 levels, Pap, HPV and VIA tests with p16 detection among HIV-infected women. The data used in this study was collected by survey questionnaire instruments in 2009 in Kenya. Descriptive and explanatory statistics using frequency and chi-square/fisher's exact tests were performed for analysis using SAS-software. The data was stratified by age groups (30-39, 40-49, and 50 years and older). 75.28% of single HIV-positive women between the ages 30-39 participated significantly in the study, with a p-value of <0.0001. 52.24% of HIV-positive women 30-39 years old were most likely to receive ART treatment for less than two years by a margin of 11.2% compared to those who received the treatment for more than two years and those who were off treatment by a margin of 2.24% (p-value of 0.03). The HIV-positive women 30-39 years old had lower CD4 counts of less than 350 cells/μl (44%) and higher CD4 counts of 500 cells/μl or higher (46.64%). 45.3% of the HIV-positive women 30-39 years old were more likely to have positive VIA tests with a p-value of 0.05. 65.87% of HIV-positive women 30-39 years old were most likely to have positive VIA tests with a p-value of <0.05. HIV-positive women 30-39 years old were most likely to have high-risk HPV compared to their older counterparts. This study shows that incorporating screening strategies (Pap tests, VIA tests and HPV genotyping) in conjunction with ART treatment were more effective in preventing cervical cancer in HIV-positive young women 30-39 years old.


Probiotics as efficient immunopotentiators: translational role in cancer prevention.
Accumulating evidences indicate that some diseases are triggered by abnormalities of the gut microbiota. Among these, immune-related diseases can be the promising targets for probiotcs. Several studies have proved the efficacy of probiotics for preventing such diseases including cancers, infections, allergies, inflammatory bowel diseases and autoimmune diseases. Lactobacillus casei strain Shirota (LcS) is one of the most popular probiotics, benefits of which in health maintenance and disease control have been supported by several science-based evidences. This review summarizes human clinical trials with this probiotic against cancer development and also discusses the possible immunomodulatory mechanisms by which LcS exerts anti-cancer activity.


Results of the interprofessional and interdisciplinary Berlin round table on patient-reported outcomes, quality of life, and treatment expectations of patients with gynecological cancer under maintenance treatment.
Patients' reported outcomes and their perspectives around their therapeutic management is a field of continuously increasing relevance in gynecological oncology. We report the results of the Berlin dialog on seven patient-reported parameters and outcomes concerning chemotherapy and maintenance treatment in patients with gynecological cancer. Key opinion leaders in gynecological oncology from different European counties and representatives of leading patients' advocate groups in Berlin held a consensus meeting in Berlin on April 6, 2019. Seven topics of interest were identified in advance around quality of life, iatrogenic toxicity, treatment decision-making processes, sexuality, participation in clinical trials, second opinion, and long-term survivors with the the following standard operating procedure for processing and discussion: (1) agreement on its relevance; (2) literature review, and (3) discussion and consensus statements. All main topics reached a consensus approval. The defined statements emphasized the importance of patients' role in incorporating and establishing quality of life as an outcome parameter in clinical trials. Furthermore, discussants raised the importance of identifying new tools for reflecting patient-reported iatrogenic toxicity as well as emphasizing patients' rights in providing personal information, access to second opinion in the decision-making process, and their participation in clinical trials. The results of this round table meeting could help redefine perspectives on the discussed topics and the importance for therapeutic management as well as for trial designs.


Use of trapezius myocutaneous flaps in the reconstruction of head and neck defects.
The trapezius myocutaneous flap of skin and muscle has, as its major blood supply, the superficial branch of the transverse cervical vessels, which is used as a pedicle. The flap may include the scapular spine as a viable bone graft for mandibular defects. Anatomic and surgical experiences have verified the feasibility of using this flap. The intended vascular pedicle arises separately from the subclavian artery in 25% of these cases. Surgical results using the flap have been excellent. Above the level of the mandible, the flap may lack adequate length. It has been used with success to repair the tongue, floor of the mouth, pharyngeal wall, and skin surface. It is particularly impressive as a method of repairing mandibular defects.


Out-of-season production of 17,20β-dihydroxypregn-4-en-3-one in the roach Rutilus rutilus.
In this study, although the highest production of two physiologically significant progestins in teleosts [17,20β-dihydroxypregn-4-en-3-one (17,20β-P) and 17,20β,21-trihydroxypregn-4-en-3-one (17,20β,21-P)] was observed in the period just prior to spawning in both male and female roach Rutilus rutilus, there was also a substantial production (mean levels of 5-10 ng ml(-1) in blood; and a rate of release of 5-20 ng fish(-1) h(-1) into the water) in males and females in the late summer and early autumn (at least 7 months prior to spawning). During this period, the ovaries were increasing rapidly in size and histological sections were dominated by oocytes in the secondary growth phase [i.e. incorporation of vitellogenin (VTG)]. At the same time, the testes were also increasing rapidly in size and histological sections were dominated by cysts containing mainly spermatogonia type B. Measurements were also made of 11-ketotestosterone (11-KT) in males and 17β-oestradiol and VTG in females. The 3 months with the highest production of 11-KT coincided with the period that spermatozoa were present in the testes. In females, the first sign of a rise in 17β-oestradiol concentrations coincided with the time of the first appearance of yolk globules in the oocytes (in August). The role of the progestins during the late summer and autumn has not been established.


A deficiency screen of the major autosomes identifies a gene (matrimony) that is haplo-insufficient for achiasmate segregation in Drosophila oocytes.
In Drosophila oocytes, euchromatic homolog-homolog associations are released at the end of pachytene, while heterochromatic pairings persist until metaphase I. A screen of 123 autosomal deficiencies for dominant effects on achiasmate chromosome segregation has identified a single gene that is haplo-insufficient for homologous achiasmate segregation and whose product may be required for the maintenance of such heterochromatic pairings. Of the deficiencies tested, only one exhibited a strong dominant effect on achiasmate segregation, inducing both X and fourth chromosome nondisjunction in FM7/X females. Five overlapping deficiencies showed a similar dominant effect on achiasmate chromosome disjunction and mapped the haplo-insufficient meiotic gene to a small interval within 66C7-12. A P-element insertion mutation in this interval exhibits a similar dominant effect on achiasmate segregation, inducing both high levels of X and fourth chromosome nondisjunction in FM7/X females and high levels of fourth chromosome nondisjunction in X/X females. The insertion site for this P element lies immediately upstream of CG18543, and germline expression of a UAS-CG18543 cDNA construct driven by nanos-GAL4 fully rescues the dominant meiotic defect. We conclude that CG18543 is the haplo-insufficient gene and have renamed this gene matrimony (mtrm). Cytological studies of prometaphase and metaphase I in mtrm hemizygotes demonstrate that achiasmate chromosomes are not properly positioned with respect to their homolog on the meiotic spindle. One possible, albeit speculative, interpretation of these data is that the presence of only a single copy of mtrm disrupts the function of whatever "glue" holds heterochromatically paired homologs together from the end of pachytene until metaphase I.


Are ointments better than other vehicles for corticosteroid treatment of psoriasis?
Topical corticosteroids are the most common treatment agent for psoriasis in the United States (U.S.). Conventional dermatologic wisdom holds that ointment preparations provide the highest potency (due to their occlusive nature and moisturizing ability) and are best suited for psoriasis. This article presents evidence challenging the conventional belief that ointment vehicles are necessarily best for psoriasis. A previous systematic review of the efficacy of clinical trials of potent topical corticosteroids did not support greater efficacy or greater delivery of potent topical corticosteroids with ointment vehicles compared to other topical preparations. Moreover, preference studies demonstrate that psoriasis patients often find application of ointment to be messy, raising concerns about both short-term and long-term adherence to treatment. Recent compliance studies demonstrate that poor compliance to topical treatment is common among psoriasis patients and contributes to poor psoriasis treatment outcomes. Non-ointment topical corticosteroid products exhibit excellent efficacy in clinical practice. Much of the poor outcomes in psoriasis, even tachyphylaxis, likely relate less to actual medication failure and more to failure to apply the medication. Topical psoriasis treatment is likely to be more successful when physicians and patients discuss what type of vehicle the patient will use and plan treatment accordingly.


Cumulative Health Risk Behaviors and Adolescent Suicide: The Moderating Role of Future Orientation.
Objectives: In this study, we investigated the association between cumulative health risk behaviors (HRBs) and adolescent suicidal behaviors and the moderating effect of future orientation. Methods: We used data were from 4255 adolescents in grades 9th-12th participating in the National Longitudinal Study of Adolescent Health (Wave I-II). We computed a cumulative HRB index by using 14 HRB indicators covering diet, physical activity, sleep, social media use, safety behaviors, and substance use. We used multilevel mixed-effect logistic regressions to analyze associations among cumulative HRBs, future orientation, and suicidal behaviors, adjusting for sociodemographic characteristics, depression, and complex survey design. We included 3-way interaction terms to explore moderation effect. Results: Cumulative HRBs significantly increased the odds of suicidal ideation (AOR = 1.27, 95% CI = [1.17, 1.37], p <. 001) and suicide attempts (AOR=1.26, 95% CI = [1.09, 1.46], p <. 01) across time. Future orientation moderated the associations between cumulative HRBs and suicide attempts differently across race/ethnicity. Engaging more than 4 cumulative HRBs, black adolescents with low future orientation had significantly higher risks of suicide attempts than those with high future orientation. Conclusions: Findings underline cumulative HRBs as significant risk factors for adolescent suicidal behaviors longitudinally. Suicide interventions targeting HRBs could benefit from nurturing future orientation.


[Surgical treatment of endocrine-cell tumors of hepato-pancreatic-duodenal zone (comment of the editor)].
Endocrine-cell tumors of hepatopancreatoduodenal zone are rare diseases. Their rate doesn't exceed 1-4% of all tumors of this location. 79 patients with endocrine-cell tumors of hepatopancreatoduodenal zone were treated, 67 of them underwent surgical treatment (operability was 67.1%) Radical operations were performed in 45 patients (gastropancreatoduodenal resection--17, distal resection of the pancreas--16, tumor enucleation--5, hemihepatectomy--3, liver resection--4). Prognosis of endocrine-cell tumors of hepatopancreatoduodenal zone is relatively favorable. In radically operated patients the presence of metastases to lymph nodes doesn't influence long-term results which are better than ones of chemo- or radiotherapy. Correlation between long-term results of surgery and age of patients, tumor sizes and its histologic structure was not revealed. Radicality of surgery is the only factor influencing prognosis. It is necessary to expand indications for extended operations, and to perform multi-stage operations in some cases of recurrences.


Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications.
The use of nitric oxide (NO) is emerging as a promising, novel approach for the treatment of antibiotic resistant bacteria and biofilm infections. Depending on the concentration, NO can induce biofilm dispersal, increase bacteria susceptibility to antibiotic treatment, and induce cell damage or cell death via the formation of reactive oxygen or reactive nitrogen species. The use of NO is, however, limited by its reactivity, which can affect NO delivery to its target site and result in off-target effects. To overcome these issues, and enable spatial or temporal control over NO release, various strategies for the design of NO-releasing materials, including the incorporation of photo-activable, charge-switchable, or bacteria-targeting groups, have been developed. Other strategies have focused on increased NO storage and delivery by encapsulation or conjugation of NO donors within a single polymeric framework. This review compiles recent developments in NO drugs and NO-releasing materials designed for applications in antimicrobial or anti-biofilm treatment and discusses limitations and variability in biological responses in response to the use of NO for bacterial eradiation.


Telemedicine--a complement to traditional referrals in oral medicine.
Introducing telemedicine into clinical practice has not been without difficulties. Within the framework of the European Union project "Health Optimum," telemedicine consultations with specialists at the Department of Oral & Maxillofacial Surgery at Uppsala University Hospital (Uppsala, Sweden) have been offered to dentists in the public dental health service. The aim is to streamline the consultation process, improve/develop the skills of the participating dentists and dental hygienists, and save time and money for patients, healthcare authorities, and society. Patient records are collected in a database for demonstration and discussion, and the system is also available for referrals. Both medical and dental photographs and x-rays are digitized in the same system. These can be viewed during telemedicine rounds and by the consultants at the hospital prior to a consultation. Secure, interactive conferencing software is used, which provides a quick, easy, and effective way to share video and data over the Internet. Both parties can demonstrate different parts of an image using a pointer or a drawing system. Conference phones are presently used for verbal communication. Ten patients were discussed during telemedicine rounds (3 males and 7 females), all of whom would normally have been referred to a specialist. As a result of the telemedicine round, 2 were referred to a specialist, whereas diagnoses were made for the other 8, and treatment was suggested. The dental health clinic could thus provide treatment without the need for referral to a consultant. The telemedicine system described here allows patient care to be provided rapidly and more economically. Future plans include "live" rounds using a videocamera, providing the possibility to relay real-time information about the intraoral situation. A camera is being developed and should preferably be permanently installed chair side.


Carboxymethyl Cellulose Entrapped in a Poly(vinyl) Alcohol Network: Plant-Based Scaffolds for Cartilage Tissue Engineering.
Cartilage has a limited inherent healing capacity after injury, due to a lack of direct blood supply and low cell density. Tissue engineering in conjunction with biomaterials holds promise for generating cartilage substitutes that withstand stress in joints. A major challenge of tissue substitution is creating a functional framework to support cartilage tissue formation. Polyvinyl alcohol (PVA) was crosslinked with glutaraldehyde (GA), by varying the mole ratios of GA/PVA in the presence of different amounts of plant-derived carboxymethyl cellulose (CMC). Porous scaffolds were created by the freeze-drying technique. The goal of this study was to investigate how CMC incorporation and crosslinking density might affect scaffold pore formation, swelling behaviors, mechanical properties, and potential use for engineered cartilage. The peak at 1599 cm-1 of the C=O group in ATR-FTIR indicates the incorporation of CMC into the scaffold. The glass transition temperature (Tg) and Young's modulus were lower in the PVA/CMC scaffold, as compared to the PVA control scaffold. The addition of CMC modulates the pore architecture and increases the swelling ratio of scaffolds. The toxicity of the scaffolds and cell attachment were tested. The results suggest that PVA/CMC scaffolding material can be tailored in terms of its physical and swelling properties to potentially support cartilage formation.


An opiate binding site in the rat brain is highly selective for 4,5-epoxymorphinans.
In vitro binding studies have demonstrated the existence of multiple opiate receptor types. An additional site in the rat brain (termed the lambda site) is distinct from the established types by its selectivity for 4,5-epoxymorphinans (such as naloxone and morphine). While the lambda site displays a high affinity for naloxone in vivo and in vitro in fresh brain membrane homogenates, these sites rapidly convert in vitro to a state of low affinity. The regional distribution of the lambda site in the brain is strikingly different from that of the classic opiate receptor types.


Antioxidant Potential of Propolis, Bee Pollen, and Royal Jelly: Possible Medical Application.
Honeybees products comprise of numerous substances, including propolis, bee pollen, and royal jelly, which have long been known for their medicinal and health-promoting properties. Their wide biological effects have been known and used since antiquity. Bee products are considered to be a potential source of natural antioxidants such as flavonoids, phenolic acids, or terpenoids. Nowadays, the still growing concern in natural substances capable of counteracting the effects of oxidative stress underlying the pathogenesis of numerous diseases, such as neurodegenerative disorders, cancer, diabetes, and atherosclerosis, as well as negative effects of different harmful factors and drugs, is being observed. Having regarded the importance of acquiring drugs from natural sources, this review is aimed at updating the current state of knowledge of antioxidant capacity of selected bee products, namely, propolis, bee pollen, and royal jelly, and of their potential antioxidant-related therapeutic applications. Moreover, the particular attention has been attributed to the understanding of the mechanisms underlying antioxidant properties of bee products. The influence of bee species, plant origin, geographic location, and seasonality as well as type of extraction solutions on the composition of bee products extracts were also discussed.


Measurement of single channel currents from cardiac gap junctions.
Cardiac gap junctions consist of arrays of integral membrane proteins joined across the intercellular cleft at points of cell-to-cell contact. These junctional proteins are thought to form pores through which ions can diffuse from cytosol to cytosol. By monitoring whole-cell currents in pairs of embryonic heart cells with two independent patch-clamp circuits, the properties of single gap junction channels have been investigated. These channels had a conductance of about 165 picosiemens and underwent spontaneous openings and closings that were independent of voltage. Channel activity and macroscopic junctional conductance were both decreased by the uncoupling agent 1-octanol.


Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma.
Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma. The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot. In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit. Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: Bone Joint J 2020;102-B(12):1752-1759.


Environmental Surveillance Can Dynamically Track Ecological Changes in Enteroviruses.
Environmental surveillance can be used to trace enteroviruses shed from human stool using a sewer network that is independent of symptomatic or asymptomatic infection. In this study, the local transmission of enteroviruses was analyzed using two wastewater treatment plants, which were relatively close to each other (15 km), designated as sentinels. Influent was collected at both sentinels once a month from 2013 to 2016, and viruses were isolated. Using neutralizing tests with type-specific polyclonal antisera and molecular typing, 933 isolates were identified as enteroviruses. Our results showed that the frequency of virus isolation varied for each serotype at the two sentinels in a time-dependent manner. Because echovirus 11 (Echo11) and coxsackievirus B5 isolates showed a high frequency and were difficult to distinguish, they were further grouped into various lineages based on the VP1 amino acid sequences. The prevalence of each lineage was visualized using multidimensional scaling. The results showed that Echo11 isolates of the same lineage were isolated continuously, similar to coxsackievirus B5 isolates of three lineages. Conversely, Echo1, Echo13, Echo18, Echo19, Echo20, Echo29, and Echo33 were isolated only once each. Our findings suggested that if an enterovirus is imported into the population, it may result in small-scale transmission, whereas if there are initially many infected individuals, it may be possible for the virus to spread to a wide area, beyond the local community, over time. In addition, our findings could provide insights into risk assessment of transmission for importation of poliovirus in polio-free countries and regions.IMPORTANCE In this study, we showed that environmental enterovirus surveillance can be used to monitor the propagation of nonpolio enteroviruses in addition to poliovirus detection. Since epidemiological studies of virus transmission based on the past were performed using specimens from humans, there were limitations to research design, such as specimen collection for implementation on a large-scale target population. However, environmental monitoring can dynamically track the ecological changes in enteroviruses in the region by monitoring viruses in chronological order and targeting the population within the area by monitoring viruses over time. We observed differences in the transmission of echovirus 11 and coxsackievirus B5 in the region according to lineage in a time-dependent manner and with a multidimensional scaling pattern.


Crimean-Congo hemorrhagic fever virus in tortoises and Hyalomma aegyptium ticks in East Thrace, Turkey: potential of a cryptic transmission cycle.
Recent reports have demonstrated the presence of Crimean-Congo hemorrhagic fever virus (CCHFV) genomic material in Hyalomma aegyptium ticks feeding primarily on tortoises belonging to the genus Testudo. This raises the question if these ticks and their hosts play a role in the natural transmission dynamics of CCHFV. However, the studies are limited, and assessing the relevance of H. aegyptium in perpetuating the virus in nature, and a potential spillover to humans remains unknown. This study aimed to detect CCHFV in H. aegyptium ticks and their tortoise hosts in the East Thrace region of Turkey, where H. aegyptium is the most common human-biting tick and where a high density of tortoises of the genus Testudo can be found. During the study period, 21 blood samples from different tortoises (2 T. hermanni and 19 T. graeca), 106 tick pools (containing 448 males, 152 females, 93 nymphs and 60 larvae) collected from 65 tortoises (5 T. hermanni and 60 T. graeca), 38 adult unfed questing ticks (25 males and 13 females, screened individually) and 14 pools (containing 8 nymphs and 266 larvae) of immature unfed questing ticks collected from the ground were screened for CCHFV genome by nested PCR and partial genomes sequenced. As a result of the screening of these 179 samples, 17 (9.5%) were detected as positive as follows: 2 of 21 blood samples (9.52%), 13 (containing 18 nymphs in 3 pools, and 52 males and 8 females in 10 pools) of 106 tick pools from tortoises (12.26%), and 2 of 38 adult questing ticks (5.26%). No positive result was determined in 14 pools of immature questing ticks. Previous studies have shown that reptiles can participate in the transmission of arthropod-borne viruses, but they may contribute to different aspects of the disease ecology and evolution of tick-borne viral pathogens. Our results indicate the presence of CCHFV in questing and feeding H. aegyptium ticks as well as tortoise hosts. This may indicate that CCHFV circulates in a cryptic transmission cycle in addition to the primary transmission cycle that could play a role in the natural dynamic of the virus and the transmission to humans.


Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide.
The filamentous bacteriophage fd bind a cell target with exquisite specificity through its few copies of display peptides, whereas nanoparticles functionalized with hundreds to thousands of synthetically generated phage display peptides exhibit variable and often-weak target binding. We hypothesise that some phage peptides in a hierarchical structure rather than in monomeric form recognise and bind their target. Here we show hierarchial forms of a brain-specific phage-derived peptide (herein as NanoLigand Carriers, NLCs) target cerebral endothelial cells through transferrin receptor and the receptor for advanced glycation-end products, cross the blood-brain-barrier and reach neurons and microglial cells. Through intravenous delivery of NLC-β-secretase 1 (BACE1) siRNA complexes we show effective BACE1 down-regulation in the brain without toxicity and inflammation. Therefore, NLCs act as safe multifunctional nanocarriers, overcome efficacy and specificity limitations in active targeting with nanoparticles bearing phage display peptides or cell-penetrating peptides and expand the receptor repertoire of the display peptide.


Fluorocarbons. Current status and future applications.
This article presents information on medical applications of fluorocarbons. These inert chemicals have a high solubility for the respiratory gases and, in emulsified form, are present in the oxygen-transporting plasma substitutes now undergoing clinical trials. Oxygen content is directly related to arterial partial pressure of oxygen (PaO2). Thus, although oxygen transport of Fluosol-DA 20% (FDA) is only 0.75 ml per 100 ml per 10 kPa, oxygen delivery at the tissues will be adequate in the presence of a high PaO2. FDA has a low viscosity at low shear rates and this, together with a very small emulsion particle size of 0.1 micron, helps provide improved tissue oxygenation in conditions of ischaemic hypoxia. Fluorocarbon plasma substitutes may be employed as 'blood', but may also be used for a wide range of purposes in clinical practice. This review describes some current and potential future applications.


Defective binding of 3-methylcholanthrene to the Ah receptor within C3H/1OT1/2 clone 8 mouse fibroblasts in culture.
C3H/1OT1/2 clone 8 mouse fibroblasts (C3H/1OT1/2 cells) exhibit induction of aryl hydrocarbon hydroxylase (cytochrome P1-450) when exposed in culture to benzo(a)pyrene, benz(a)anthracene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but do not display the induction response when treated with 3-methylcholanthrene (MCA), the classical inducer of cytochrome P1-450. Induction of cytochrome P1-450 is regulated by the Ah receptor which initially binds inducing chemicals in the cytoplasm, after which the inducer x receptor complex translocates into the nucleus. Cytosolic and nuclear forms of the Ah receptor can be detected in C3H/1OT1/2 cells using [3H]TCDD as the radioligand in culture, but specific Ah receptor binding is not detectable within C3H/1OT1/2 cells incubated with [3H]MCA. In contrast, in Hepa-1c1 cells, which exhibit cytochrome P1-450 induction when treated with MCA, cytosolic and nuclear Ah receptor can be detected by incubation of the cells either with [3H]MCA or with [3H]TCDD. Nonradioactive MCA is able to compete with [3H]TCDD for Ah receptor sites in C3H/1OT1/2 cells, but the relative potency of MCA as a competitor is lower within C3H/1OT1/2 cells than in C3H/1OT1/2 cytosol during extracellular incubation. Specific binding of [3H]MCA to Ah receptor can be detected by incubation of [3H]MCA with C3H/1OT1/2 cytosol outside the cell. The selective loss of response to MCA as a cytochrome P1-450 inducer (while retaining response to other inducers) appears to be due to defective interaction of MCA with the Ah receptor within the intracellular environment. The specific molecular alteration which makes the MCA x receptor complex ineffective within C3H/1OT1/2 cells is unknown. Some fibroblast lines other than C3H/1OT1/2 also selectively fail to respond to MCA; thus, this variation in Ah receptor function may not be due to a mutational change in the Ah regulatory gene which codes for the Ah receptor.


Effect of Submucosal Injection of Platelet-rich Plasma on the Rate of Canine Retraction - A Split-mouth Randomized Clinical Study.
The use of platelet-rich plasma (PRP) has gained popularity in orthodontics in the past decade. PRP is an autologous concentration of platelets rich in growth factors and is hypothesized to play a role in orthodontic tooth movement (OTM) due to its bone remodeling capacity. The aim of this study was to determine the effect of PRP on the rate of tooth movement in humans. Fourteen patients requiring bilateral extraction of upper first premolars were included in the study. PRP (×4) was prepared and injected in the alveolar mucosa, distal to canine on experimental sides. Canine retraction was initiated on the same day of PRP injection using NiTi closed coil springs on both sides. The amount of canine retraction was measured and compared between both sides at the 4th, 8th, 12th, and 16th weeks by measuring the distance between lateral incisor and canine on the cast. Results showed mean displacement of 1.355 mm, 1.232 mm, 1.191 mm, and 1.085 mm on experimental side and 1.265 mm, 1.126 mm, 1.031 mm, and 0.879 mm on control side at the 4th, 8th, 12th, and 16th weeks, respectively. Although increased OTM (13.85% or 1.1 times faster) was observed on experimental side at all time intervals compared to the control group, the result was not statistically significant. 4× concentration of PRP does not accelerate OTM significantly.


Effectiveness of interventions to reduce adverse outcomes among older adults following emergency department discharge: Protocol for an overview of systematic reviews.
Background: Older adults are frequent users of Emergency departments (ED) and this trend will continue due to population ageing and the associated increase in healthcare needs. Older adults are vulnerable to adverse outcomes following ED discharge. A number of heterogeneous interventions have been developed and implemented to improve clinical outcomes among this cohort. A growing number of systematic reviews have synthesised evidence regarding ED interventions using varying methodologies. This overview aims to synthesise the totality of evidence in order to evaluate the effectiveness of interventions to reduce adverse outcomes in older adults discharged from the ED. Methods: To identify relevant reviews, the following databases will be searched: Cochrane Database of Systematic reviews, Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Databases of Abstracts of Reviews of Effects, PubMed, MEDLINE, Epistemonikos, Ageline, Embase, PEDro, Scopus, CINAHL and the PROSPERO register. The search for grey literature will include Open Grey and Grey Literature Reports. Systematic reviews of randomised controlled trials will be analysed to assess the effect of ED interventions on clinical and process outcomes in older adults. Methodological quality of the reviews will be assessed using the Assessment of Multiple Systematic Reviews 2 tool. The review will be reported in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Summary of findings will include a hierarchical rank of interventions based on estimates of effects and the quality of evidence. Discussion: This overview is required given the number of systematic reviews published regarding the effectiveness of various ED interventions for older adults at risk of adverse outcomes following discharge from the ED. There is a need to examine the totality of evidence using rigorous analytic techniques to inform best care and potentially develop a hierarchy of treatment options. PROSPERO registration: CRD42020145315 (28/04/2020).


5-year mortality in cardiac surgery patients with low cardiac output syndrome treated with levosimendan: prognostic evaluation of nt-probnp and c-reactive protein.
To determine the clinical risk factors predictive of the 5--year mortality in patients with low cardiac output syndrome (LCOS) after cardiac surgery. In addition, to assess the influence of inflammation and myocardial dysfunction severity, as measured by C--reactive protein (CRP) and N--terminal pro--brain natriuretic peptide (NT--proBNP) concentrations, on outcome. We studied 30 patients who underwent cardiac surgery and developed postoperative LCOS requiring inotropic support for longer than 48 hours after intensive care unit (ICU) admission. All patients received a 24--hour infusion of levosimendan after study enrolment. We measured the following at baseline, 24 h, 48 h and 7 days: clinical data, serum NT--proBNP and serum CRP levels. Patients were followed--up at 5 years for death by any cause. A risk--adjusted Cox proportional hazards regression model was used for statistical analysis. Hazard ratios and their 95% confidence intervals (CI) are presented. The 5--year mortality was 36.6% (n = 11). The predictors of 5--year mortality were the presence of dilated cardiomyopathy (HR = 36.909; 95% CI: 1.901-716.747; P = 0.017), a higher central venous pressure (CVP) at 48 hours (HR = 2.686; 95% CI: 1.383-5.214; P = 0.004), and lower CRP levels on day 7 (HR = 0.963; 95% CI: 0.933-0.994; P = 0.021). NT--proBNP levels showed a trend to higher initial levels in survivors without statistical significance, but were not associated with 5--year mortality. The presence of dilated cardiomyopathy, elevated CVP at 48 h and reduced CRP levels on day 7 predicted 5--year mortality in patients who developed postoperative LCOS after cardiac surgery. NT--proBNP levels in the first postoperative week were not predictors of long--term outcomes.


Cardiac Contractility Modulation in Patients with Advanced Heart Failure: A Comprehensive Review of Literature.
Heart failure is a significant cause of morbidity and mortality worldwide. Despite advancements in guideline-directed medical therapy and improvements in device-based therapies, patients with advanced heart failure have high rates of mortality regardless of ejection fraction. For patients with reduced ejection fraction who meet criteria, cardiac resynchronization therapy or implantable cardiac defibrillators are options available to improve outcomes. However, not all heart failure patients meet those criteria. Cardiac contractility modulation is an innovative therapy that serves to improve functional outcomes and quality of life, while also modifying pathologic gene expression and preventing further remodeling. In this article, we aim to discuss the major clinical trials investigating cardiac contractility modulation as a suitable therapy for patients with advanced heart failure.


A Spatial Analysis of Acute Myocardial Infarction Rates in New York State in Relation to Hospitals Along State Jurisdictional Borders.
Patients experiencing acute myocardial infarction (AMI) are likely to visit the nearest hospital providing appropriate services since timely care is a critical determinant in the treatment and progression of AMI. We comparatively examined AMI rates in border and nonborder census tracts. The New York State (NYS) Environmental Public Health Tracking (EPHT) program, in conjunction with the Statewide Planning and Research Cooperative System, will work on developing memoranda of understanding with neighboring states to be able to more comprehensively access NYS residents' out-of-state health records. To determine whether AMI rates in the NYS border census tracts differ from AMI rates in nonborder census tracts as a preliminary exploration of the utilization of out-of-state care for acute health conditions by NYS border residents. We reviewed data on inpatient and emergency department visits in NYS with discharge dates from 2005 to 2014 retrospectively. We used the NYS EPHT tier 1 system database to locate hospitals. We geocoded all cases to NYS 2010 census tracts. We mapped differences between border and nonborder tracts and analyzed resulting spatial patterns. We computed tract-level AMI rates and differences between border and nonborder AMI rates. The age-adjusted AMI rates differed by 8.2 cases per 10 000 people (95% confidence interval, 6.94-12.60). Maps showed patterns of differences in AMI rates, especially along the NYS border with New England and other geographically closer out-of-state hospitals. AMI rates that were geographically closer to out-of-state hospitals were lower, suggesting that people residing in border census tracts are utilizing out-of-state care. Our study adds to literature on the geographical component of health care accessibility and utilization in the context of acute conditions such as AMI and lends impetus to access out-of-state health records to better understand health care facility access and utilization for NYS residents.


A Structural Competency Curriculum for Primary Care Providers to Address the Opioid Use Disorder, HIV, and Hepatitis C Syndemic.
The interrelated epidemics of opioid use disorder (OUD) and HIV and hepatitis C virus (HCV) infection have been identified as one of the most pressing syndemics facing the United States today. Research studies and interventions have begun to address the structural factors that promote the inter-relations between these conditions and a number of training programs to improve structural awareness have targeted physician trainees (e.g., residents and medical students). However, a significant limitation in these programs is the failure to include practicing primary care providers (PCPs). Over the past 5 years, there have been increasing calls for PCPs to develop structural competency as a way to provide a more integrated and patient-centered approach to prevention and care in the syndemic. This paper applies Metzel and Hansen's (1) framework for improved structural competency to describe an educational curriculum that can be delivered to practicing PCPs. Skill 1 involves reviewing the historical precedents (particularly stigma) that created the siloed systems of care for OUD, HIV, and HCV and examines how recent biomedical advances allow for greater care integration. To help clinicians develop a more multidisciplinary understanding of structure (Skill 2), trainees will discuss ways to assess structural vulnerability. Next, providers will review case studies to better understand how structural foundations are usually seen as cultural representations (Skill 3). Developing structural interventions (Skill 4) involves identifying ways to create a more integrated system of care that can overcome clinical inertia. Finally, the training will emphasize cultural humility (Skill 5) through empathetic and non-judgmental patient interactions. Demonstrating understanding of the structural barriers that patients face is expected to enhance patient trust and increase retention in care. The immediate objective is to pilot test the feasibility of the curriculum in a small sample of primary care sites and develop metrics for future evaluation. While the short-term goal is to test the model among practicing PCPs, the long-term goal is to implement the training practice-wide to ensure structural competence throughout the clinical setting.


The Effects of Age and HIV on Neuropsychological Performance.
Both HIV and aging impact performance on neuropsychological testing; however, evidence for differences between HIV effects in younger compared to older subjects (interaction effects) is limited and the findings have been inconsistent. Coexisting morbidities that contribute to cognitive impairment in HIV include those not directly referable to infection, per se, and are more prevalent with advancing age, increasing the likelihood that HIV and age effects may be largely independent. As individuals survive with HIV into geriatric age groups, greater clarity on these relationships is essential. We present cross-sectional data from a large (n = 450) cohort designed to analyze HIV, age, and interaction effects using a well-matched cohort of HIV-negative individuals. Results reveal limited evidence for interaction effects between HIV and age on neuropsychological performance. We conclude that older age does not significantly influence neuropsychological performance among HIV patients when seronegative controls are largely composed of individuals from a similar socioeconomic background.


Comparison of the C2A domain of synaptotagmin-I and annexin-V as probes for detecting cell death.
The induction of apoptosis is frequently accompanied by the exposure of phosphatidylserine (PS) on the cell surface, which has been detected using radionuclide and fluorescently labeled derivatives of the PS-binding protein, Annexin V. The fluorescently labeled protein has been used extensively in vitro as a diagnostic reagent for detecting cell death, and radionuclide-labeled derivatives have undergone clinical trials for detecting tumor cell death in vivo following treatment. We show here that the C2A domain of Synaptotagmin-I, which had been fluorescently labeled at a single cysteine residue introduced by site-directed mutagenesis, detected the same levels of cell death as a similarly labeled Annexin-V derivative, in drug-treated murine lymphoma and human breast cancer cell lines in vitro. However, the C2A derivative showed significantly less binding to viable cells and, as a consequence, up to 4-fold more specific binding to apoptotic and necrotic cells when compared with Annexin-V. C2A offers a potential route for the development of a new generation of more specific imaging probes for the detection of tumor cell death in the clinic.


Higher attentional costs for numerosity estimation at high densities.
Humans can estimate numerosity over a large range, but the precision with which they do so varies considerably over that range. For very small sets, within the subitizing range of up to about four items, estimation is rapid and errorless. For intermediate numerosities, errors vary directly with the numerosity, following Weber's law, but for very high numerosities, with very dense patterns, thresholds continue to rise with the square root of numerosity. This suggests that three different mechanisms operate over the number range. In this study we provide further evidence for three distinct numerosity mechanisms, by studying their dependence on attentional resources. We measured discrimination thresholds over a wide range of numerosities, while manipulating attentional load with both visual and auditory dual tasks. The results show that attentional effects on thresholds vary over the number range. Both visual and auditory attentional loads strongly affect subitizing, much more than for larger numerosities. Attentional costs remain stable over the estimation range, then rise again for very dense patterns. These results reinforce the idea that numerosity is processed by three separates but probably overlapping systems.


Relationships between the generalized functional method and other methods of nonimaging optical design.
The recently developed generalized functional method provides a means of designing nonimaging concentrators and luminaires for use with extended sources and receivers. We explore the mathematical relationships between optical designs produced using the generalized functional method and edge-ray, aplanatic, and simultaneous multiple surface (SMS) designs. Edge-ray and dual-surface aplanatic designs are shown to be special cases of generalized functional designs. In addition, it is shown that dual-surface SMS designs are closely related to generalized functional designs and that certain computational advantages accrue when the two design methods are combined. A number of examples are provided.


Exposure to Different Amounts of Dietary Gluten in Patients with Non-Celiac Gluten Sensitivity (NCGS): An Exploratory Study.
It is unclear whether patients with non-celiac gluten sensitivity (NCGS) can tolerate gluten. We have evaluated the changes of both gastrointestinal symptoms and quality of life for NCGS patients after the re-introduction of dietary gluten. Twenty-two NCGS patients reporting functional gastroenterological symptoms and on gluten-free diet (GFD) for the previous three weeks were exposed to incremental gluten-containing diets. Three groups were compared at baseline (immediately after 3-weeks on GFD) and immediately after the return of symptomatology: (i) a group tolerating a low-gluten diet (3.5 g gluten/day, week 1, n = 8), (ii) a group tolerating a mid-gluten diet (8 g gluten/day, week 2, n = 6), and (iii) a group tolerating a high-gluten diet (13 g gluten/day, week 3, n = 8). Their gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. The most common symptoms were: constipation (46%), abdominal pain (50%) and dyspepsia (38%). A decrease in several short form health survey (SF-36) sub-scores (all p < 0.03) after gluten re-introduction was only observed in the group tolerating the low-gluten diet; the same group showed a lower post-intervention role-emotional SF-36 score (p = 0.01). Most gastrointestinal symptoms remained similar after gluten re-introduction. However, a decrease in the general perception of well-being was only found after gluten re-introduction in the group tolerating a low-gluten diet (p = 0.01); the same was true when comparing the post-intervention general well-being perception among the three groups (p = 0.050). In conclusion, dissimilar responses from patients with NCGS were observed after the re-introduction of gluten, with gluten at a low dosage affecting the quality of life and general well-being of a group of patients, whereas others tolerate even higher doses of dietary gluten.


Superior thyroid cornu syndrome: an unusual cause of cervical dysphagia.
Ossification of a superior thyroid cornu in men may cause pharyngeal airway impingement and result in cervical dysphagia. We report on a clinical case series of this rare condition, called superior thyroid cornu syndrome. This is the first report of a case series of this entity as a possible cause of cervical dysphagia that was successfully treated with an endoscopic procedure. A clinical case series of 12 patients were identified as having superior thyroid cornu syndrome (years 2001 to 2006). Eleven patients were male and 1 was female; their mean age was 54.6 years. They complained of unresolved throat pain, difficulty swallowing, and/or pain on swallowing. On flexible laryngoscopy, there was an asymmetric indentation of the pharynx due to a prominent superior thyroid cornu. Laryngeal manipulation produced the pain and exposed the prominent cornu in the airway. Computed tomographic evidence of calcification of the superior thyroid horn without other abnormality was noted. After maximal medical treatment with proton pump inhibitors, anti-inflammatory agents, nasal steroids, antihistamines, and/or other allergy treatments, 8 of the patients who had persistent symptoms were treated by transoral pharyngotomy and resection of an approximately 2.0 x 0.5-cm segment of a thyroid cornu. Vast improvement in symptoms occurred in 6 patients, and complete symptom resolution occurred in 3 of those 6. Two of 8 patients reported improvement in swallowing, but persistent pain. The follow-up duration was between 2 and 15 months from the time of surgery. Superior thyroid cornu syndrome may be a rare cause of cervical dysphagia. It may be diagnosed by careful laryngoscopy with laryngeal palpation followed by a computed tomography scan. Surgical resection of the affected superior thyroid cornu by transoral pharyngotomy appears to be effective in relief of symptoms.


Beyond the bundle--journey of a tertiary care medical intensive care unit to zero central line-associated bloodstream infections.
We set a goal to reduce the incidence rate of catheter-related bloodstream infections to rate of <1 per 1,000 central line days in a two-year period. This is an observational cohort study with historical controls in a 25-bed intensive care unit at a tertiary academic hospital. All patients admitted to the unit from January 2008 to December 2011 (31,931 patient days) were included. A multidisciplinary team consisting of hospital epidemiologist/infectious diseases physician, infection preventionist, unit physician and nursing leadership was convened. Interventions included: central line insertion checklist, demonstration of competencies for line maintenance and access, daily line necessity checklist, and quality rounds by nursing leadership, heightened staff accountability, follow-up surveillance by epidemiology with timely unit feedback and case reviews, and identification of noncompliance with evidence-based guidelines. Molecular epidemiologic investigation of a cluster of vancomycin-resistant Enterococcus faecium (VRE) was undertaken resulting in staff education for proper acquisition of blood cultures, environmental decontamination and daily chlorhexidine gluconate (CHG) bathing for patients. Center for Disease Control/National Health Safety Network (CDC/NHSN) definition was used to measure central line-associated bloodstream infection (CLA-BSI) rates during the following time periods: baseline (January 2008 to December 2009), intervention year (IY) 1 (January to December 2010), and IY 2 (January to December 2011). Infection rates were as follows: baseline: 2.65 infections per 1,000 catheter days; IY1: 1.97 per 1,000 catheter days; the incidence rate ratio (IRR) was 0.74 (95% CI=0.37 to 1.65, P=0.398); residual seven CLA-BSIs during IY1 were VRE faecium blood cultures positive from central line alone in the setting of findings explicable by noninfectious conditions. Following staff education, environmental decontamination and CHG bathing (IY2): 0.53 per 1,000 catheter days; the IRR was 0.20 (95% CI=0.06 to 0.65, P=0.008) with 80% reduction compared to the baseline. Over the two-year intervention period, the overall rate decreased by 53% to 1.24 per 1,000 catheter-days (IRR of 0.47 (95% CI=0.25 to 0.88, P=0.019) with zero CLA-BSI for a total of 15 months. Residual CLA-BSIs, despite strict adherence to central line bundle, may be related to blood culture contamination categorized as CLA-BSIs per CDC/NHSN definition. Efforts to reduce residual CLA-BSIs require a strategic multidisciplinary team approach focused on epidemiologic investigations of practitioner- or unit-specific etiologies.


Cloning, DNA sequence, and expression of the Rhodobacter sphaeroides cytochrome c2 gene.
The Rhodobacter sphaeroides cytochrome c2 functions as a mobile electron carrier in both aerobic and photosynthetic electron transport chains. Synthetic deoxyoligonucleotide probes, based on the known amino acid sequence of this protein (Mr 14,000), were used to identify and clone the cytochrome c2 structural gene (cycA). DNA sequence analysis of the cycA gene indicated the presence of a typical procaryotic 21-residue signal sequence, suggesting that this periplasmic protein is synthesized in vivo as a precursor. Synthesis of an immunoreactive cytochrome c2 precursor protein (Mr 15,500) was observed in vitro when plasmids containing the cycA gene were used as templates in an R. sphaeroides coupled transcription-translation system. Approximately 500 base pairs of DNA upstream of the cycA gene was sufficient to allow expression of this gene product in vitro. Northern blot analysis with an internal cycA-specific probe identified at least two possibly monocistronic transcripts present in both different cellular levels and relative stoichiometries in steady-state cells grown under different physiological conditions. The ratio of the small (740-nucleotide) and large (920-nucleotide) cycA-specific mRNA species was dependent on cultural conditions but was not affected by light intensity under photosynthetic conditions. Our results suggest that the increase in the cellular level of the cytochrome c2 protein found in photosynthetic cells was due, in part, to increased transcription of the single-copy cyc operon.


ALK and GSK3: Shared Features of Neuroblastoma and Neural Crest Cells.
Neuroblastoma is one of the most common and deadly childhood cancers. Neuroblastoma arises from transformed cells of the neural crest lineage. Outcomes of the disease vary greatly, ranging from spontaneous regression to aggressive metastases. While this variability may reflect the inherent migratory capabilities and multipotency of neural crest cells, there have been few direct comparisons between neuroblastoma and embryonic neural crest cells, in part because of the limited in vivo accessibility of the mammalian neural crest lineage. Our recent studies demonstrate a novel link between anaplastic lymphoma kinase (ALK) and glycogen synthase kinase 3 (GSK3). Our work suggests that ALK-dependent regulation of GSK3 via tyrosine phosphorylation may alter the substrate specificity of GSK3, thus regulating cytoskeletal dynamics in migrating neural crest cells.


Sequential streaming, binaural cues and lateralization.
Interaural time differences (ITDs) and interaural level differences (ILDs) associated with monaural spectral differences (coloration) enable the localization of sound sources. The influence of these spatial cues as well as their relative importance on obligatory stream segregation were assessed in experiment 1. A temporal discrimination task favored by integration was used to measure obligatory stream segregation for sequences of speech-shaped noises. Binaural and monaural differences associated with different spatial positions increased discrimination thresholds, indicating that spatial cues can induce stream segregation. The results also demonstrated that ITDs and coloration were relatively more important cues compared to ILDs. Experiment 2 questioned whether sound segregation takes place at the level of acoustic cue extraction (ITD per se) or at the level of object formation (perceived azimuth). A difference in ITDs between stimuli was introduced either consistently or inconsistently across frequencies, leading to clearly lateralized sounds or blurred lateralization, respectively. Conditions with ITDs and clearly perceived azimuths induced significantly more segregation than the condition with ITDs but reduced lateralization. The results suggested that segregation was mainly based on a difference in lateralization, although the extraction of ITDs might have also helped segregation up to a ceiling magnitude.


Flavivirus Concentrates Host ER in Main Replication Compartments to Facilitate Replication.
Flavivirus remodels the host endoplasmic reticulum (ER) to generate replication compartments (RCs) as the fundamental structures to accommodate viral replication. Here, a centralized replication mode of flavivirus is reported, i.e., flavivirus concentrates host ER in perinuclear main replication compartments (MRCs) for efficient replication. Superresolution live-cell imaging demonstrated that flavivirus MRCs formed via a series of events, including multisite ER clustering, growth and merging of ER clusters, directional movement, and convergence in the perinuclear region. The dynamic activities of viral RCs are driven by nonstructural (NS) proteins and are independent of microtubules and actin. Moreover, disrupting MRCs formation by small molecule compounds inhibited flavivirus replication. Overall, the findings reveal unprecedented insight into dynamic ER reorganization by flavivirus and identify a new inhibition strategy.


Plasmodium vivax aldolase-specific monoclonal antibodies and its application in clinical diagnosis of malaria infections in China.
Most rapid diagnostic tests (RDTs) currently used for malaria diagnosis cannot distinguish the various Plasmodium infections. The development of a Plasmodium vivax specific RDTs with high sensitivity to sufficiently differentiate the two most common Plasmodium infections would be very crucial for disease treatment and control. Plasmodium vivax aldolase gene (PvALDO) was amplified from the extracted genomic DNA and constructed into pET30a vector. Plasmodium vivax aldolase protein was successfully expressed in Escherichia coli in soluble form and the overall purity was over 95% after one-step affinity chromatography purification. The purified products were used for the immunization of mice and rabbits. Rabbit polyclonal antibodies generated were deployed to develop a novel antibody-capture ELISA for hybridoma screening. Three PvALDO specific mAbs (14C7, 15F1 and 5H7) with high affinities were selected and used in immunochromatographic test strips. Clinical blood samples (n=190) collected from Yunnan (China) were used for evaluation and the RDT's sensitivity for P. vivax was 98.33% (95% Confidence Interval (CI): 91.03% to 99.72%) compared with microscopic examination. There was specificity of 99.23% (95% CI: 95.77% to 99.87%) for P. vivax. Only one Plasmodium falciparum sample was detected among the P. falciparum samples (n=20). All Plasmodium malariae samples (n=2) as well as healthy uninfected samples (n=108) were negative. Overall performance of this RDT was excellent with positive predictive value (PPV) and negative predictive value (NPV) of 98.33% and 99.23%, respectively, at 95% CI and a very good correlation with microscopic observations (kappa value, K=0.9757). Test strips show high sensitivity even at 6.25 ng/ml of recombinant P. vivax aldolase (rPvALDO). This study further elucidates the possibility of developing aldolase-specific RDTs which can differentiate the different Plasmodium infections and improve accurate diagnosis of malaria. This RDT could adequately differentiate between P. vivax and P. falciparum infections. The novel mAb screening method developed here could find application in the screening of highly specific antibodies against other antigens.


RNA aptamer inhibitors of a restriction endonuclease.
Restriction endonucleases (REases) recognize and cleave short palindromic DNA sequences, protecting bacterial cells against bacteriophage infection by attacking foreign DNA. We are interested in the potential of folded RNA to mimic DNA, a concept that might be applied to inhibition of DNA-binding proteins. As a model system, we sought RNA aptamers against the REases BamHI, PacI and KpnI using systematic evolution of ligands by exponential enrichment (SELEX). After 20 rounds of selection under different stringent conditions, we identified the 10 most enriched RNA aptamers for each REase. Aptamers were screened for binding and specificity, and assayed for REase inhibition. We obtained eight high-affinity (Kd ∼12-30 nM) selective competitive inhibitors (IC50 ∼20-150 nM) for KpnI. Predicted RNA secondary structures were confirmed by in-line attack assay and a 38-nt derivative of the best anti-KpnI aptamer was sufficient for inhibition. These competitive inhibitors presumably act as KpnI binding site analogs, but lack the primary consensus KpnI cleavage sequence and are not cleaved by KpnI, making their potential mode of DNA mimicry fascinating. Anti-REase RNA aptamers could have value in studies of REase mechanism and may give clues to a code for designing RNAs that competitively inhibit DNA binding proteins including transcription factors.


Grain Boundaries Boost Oxygen Evolution Reaction in NiFe Electrocatalysts.
In a polycrystalline material, the grain boundaries (GBs) can be effective active sites for catalytic reactions by providing an electrodynamically favorable surface. Previous studies have shown that grain boundary density is related to the catalytic activity of the carbon dioxide reduction reaction, but there is still no convincing evidence that the GBs provide surfaces with enhanced activity for oxygen evolution reaction (OER). Combination of various electrochemical measurements and chemical analysis reveals the GB density at surface of NiFe electrocatalysts directly affects the overall OER. In situ electrochemical microscopy vividly shows that the OER occurs mainly at the GB during overall reaction. It is observed that the reaction determining steps are altered by grain boundary densities and the meaningful work function difference between the inside of grain and GBs exists. High-resolution transmission electron microscopy shows that extremely high index planes are exposed at the GBs, enhancing the oxygen evolution activity. The specific nature of GBs and its effects on the OER demonstrated in this study can be applied to the various polycrystalline electrocatalysts.


Cerebral ultrasound findings in infants exposed to crack cocaine during gestation.
Prenatal exposure to cocaine has been associated with a wide spectrum of structural abnormalities in infant brains. The growing use of crack, a smokable and extremely addictive form of cocaine, could exacerbate the situation. The purpose of this study was to determine the frequency, type and severity of cerebral lesions detected by transfontanellar US in newborns exposed to crack during gestation. This was a retrospective study, involving a review of the medical records of children who were born to crack-using women and who were subjected to transfontanellar US imaging during their first days of life. Transfontanellar US revealed abnormalities in 45/129 newborns examined (34.9%). The changes detected were subependymal cysts in 24 infants (18.6%), lenticulostriate vasculopathy in 18 infants (14%), subependymal hemorrhage in 9 infants (7%), and choroid plexus cysts in 9 infants (7%). All of the abnormalities found by US examination were discrete and likely without clinical significance for the babies. However, prospective studies with a long period of tracking are needed to determine whether there are later consequences on the neurodevelopment of children with prenatal exposure to crack.


Transposition of the great arteries: a myocardial perfusion PET-CT study.
We report the case of a 20-year-old woman with surgically corrected transposition of the great arteries, pulmonary valve defects, and absence of left coronary ostium at a previous cardiac catheterization. Because of worsening dyspnea, she underwent myocardial perfusion PET/CT study with 13N-ammonia at rest and during pharmacological stress, which showed extensive ischemia in the left coronary territory and signs of severe left ventricle dysfunction. Quantitative PET data showed impaired regional coronary flow reserve (<2.0) in the left coronary territory, thus allowing a precise and reliable evaluation of the myocardial perfusion defect because of the absence of left coronary ostium.


Trigeminal Lipomatosis: A Rare Cause of Intractable Neuralgia.
Lipomatosis of nerve, earlier known as fibrolipomatous hamartoma is a rare condition which predominantly affects peripheral nerves, cranial nerve involvement being extremely uncommon. Preoperative consideration of this entity is of paramount importance as its inadvertent complete surgical resection may inevitably result in significant neurological deficit. We report a case of trigeminal lipomatosis in a young patient with trigeminal neuralgia.


Pain in chronic pancreatitis: the role of neuropathic pain mechanisms.
Pain mechanisms in patients with chronic pancreatitis are incompletely understood and probably multifactorial. Recently, evidence from experimental human pain research has indicated that in many of these patients pain processing in the central nervous system is abnormal and mimics that seen in neuropathic pain disorders. The current review focuses on several lines of evidence supporting this hypothesis. Hence, the spontaneous and postprandial pain in chronic pancreatitis may reflect the characteristic pain features seen in patients with neuropathic pain. Biochemical and histopathological findings in tissues from patients with chronic pancreatitis are similar to those observed in patients with other nerve fibre lesions. Experimental studies have shown that patients with chronic pancreatitis show signs of spinal hyper-excitability counter-balanced by segmental and descending inhibition. Changes in the brain with cortical reorganisation to gut stimulation and increased activity in specific electroencephalographic features characteristic for neuropathic pain are also seen in patients with chronic pancreatitis. Finally, principles involved in the treatment of pancreatic pain have many similarities with those recommended in neuropathic pain disorders. In conclusion, a mechanism-based understanding of pain in chronic pancreatitis may have important implications for the treatment.


Elements of Program Design in Medicare's Value-based and Alternative Payment Models: a Narrative Review.
Increasing emphasis on value in health care has spurred the development of value-based and alternative payment models. Inherent in these models are choices around program scope (broad vs. narrow); selecting absolute or relative performance targets; rewarding improvement, achievement, or both; and offering penalties, rewards, or both. We examined and classified current Medicare payment models-the Hospital Readmissions Reduction Program (HRRP), Hospital Value-Based Purchasing Program (HVBP), Hospital-Acquired Conditions Reduction Program (HACRP), Medicare Advantage Quality Star Rating program, Physician Value-Based Payment Modifier (VM) and its successor, the Merit-Based Incentive Payment System (MIPS), and the Medicare Shared Savings Program (MSSP) on these elements of program design and reviewed the literature to place findings in context. We found that current Medicare payment models vary significantly across each parameter of program design examined. For example, in terms of scope, the HRRP focuses exclusively on risk-standardized excess readmissions and the HACRP on patient safety. In contrast, HVBP includes 21 measures in five domains, including both quality and cost measures. Choices regarding penalties versus bonuses are similarly variable: HRRP and HACRP are penalty-only; HVBP, VM, and MIPS are penalty-or-bonus; and the MSSP and MA quality star rating programs are largely bonus-only. Each choice has distinct pros and cons that impact program efficacy. Unfortunately, there are scant data to inform which program design choice is best. While no one approach is clearly superior to another, the variability contained within these programs provides an important opportunity for Medicare and others to learn from these undertakings and to use that knowledge to inform future policymaking.


Intracanal removal and apical extrusion of filling material after retreatment using rotary or reciprocating instruments: A new approach using human cadavers.
This study compared intracanal removal of filling as well as the frequency and volume of extruded material after retreatment with either HyFlex or Reciproc instruments in mandibular teeth from cadavers. The root canals of 14 pairs of contralateral single-rooted teeth in mandibles of cadavers were instrumented with Reciproc R40 and filled using lateral compaction. The mandibles were scanned in a micro-computed tomographic (micro-CT) device before and after retreatment procedures. The contralateral teeth were assigned to two groups (n = 14) according to the retreatment protocol using either HyFlex or Reciproc instrument systems. In the HyFlex group, the HyFlex Remover instrument was worked 3 mm short of the working length (WL), followed by HyFlex CM 40.04 and 50.04 at the WL. In the Reciproc group, the R50 instrument was worked up at the coronal two thirds, followed by two more cycles until the WL was reached. Pre- and post-operative micro-CT images were analysed for extrusion and intracanal removal of filling material. After retreatment, extrusion of filling material occurred in 11 (78%) and 14 (100%) teeth from HyFlex and Reciproc groups respectively (p > .05). A similar volume of extruded material was observed after retreatment with both systems (p > .05). A significant decrease in the intracanal filling volume was verified after retreatment with both tested systems (p < .05). However, residual filling material was found in all root canals, regardless of the system. The amount of filling material removed (HyFlex = 80.8%; Reciproc = 65.9%) and the operation time was similar between systems (p > .05). A high frequency of filling material extrusion was observed after retreatment with the two systems in a cadaver model, with no significant difference between them. Both protocols obtained similar efficacy in filling material removal procedures, although none completely cleaned the canals.


Molecular Genetics Analysis of 70 Chinese Families With Muscular Dystrophy Using Multiplex Ligation-Dependent Probe Amplification and Next-Generation Sequencing.
Background: Muscular dystrophy (MD) includes multiple types, of which dystrophinopathies caused by dystrophin (DMD) mutations are the most common types in children. An accurate identification of the causative mutation at the genomic level is critical for genetic counseling of the family, and analysis of genotype-phenotype correlations, as well as a reference for the development of gene therapy. Methods: Totally, 70 Chinese families with suspected MD probands were enrolled in the study. The multiplex ligation-dependent probe amplification (MLPA) was first performed to screen large deletions/duplications of DMD exons in the patients, and then, next-generation sequencing (NGS) was carried out to detect small mutations in the MLPA-negative patients. Results: Totally, 62 mutations of DMD were found in 62 probands with DMD/BMD, and two compound heterozygous mutations in LAMA2 were identified in two probands with MDC1A (a type of congenital MD), indicating that the diagnostic yield was 91.4% by MLPA plus NGS for MD diagnosis in this cohort. Out of the mutations, 51 large mutations encompassing 47 (75.8%) deletions and four duplications (6.5%) were identified by MLPA; 11 small mutations including six (9.7%) nonsense, two (3.2%) small deletions, two splice-site mutations (3.2%), and one small insertion (1.6%) were found by NGS. Large mutations were found most frequently in the hotspot region between exons 45 and 55 (70.6%). Out of the 11 patients harboring point mutations in DMD, 8 were novel mutations. Additionally, one novel mutation in LAMA2 was identified. All the novel mutations were analyzed and predicted as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guideline. Finally, 34 DMD, 4 BMD, 24 BMD/DMD, and 2 MDC1A were diagnosed in the cohort. Conclusion: Our data indicated that the MLPA plus NGS can be a comprehensive and effective tool for precision diagnosis and potential treatment of MD and is particularly necessary for the patients at very young age with only two clinical indicators (persistent hyperCKemia and typical myopathy performance on electromyogram) but no definite clinical manifestations.


Toxoplasma gondii induces autophagy and apoptosis in human umbilical cord mesenchymal stem cells via downregulation of Mcl-1.
Autophagy and apoptosis are critical for controlling Toxoplasma gondii (T. gondii) infection. T. gondii infection during pregnancy can damage the fetus and cause birth defects; however, the molecular mechanisms of this process are poorly understood. This study aims to determine the activities of autophagy and apoptosis as well as their regulatory mechanisms during T. gondii infection by using human umbilical cord mesenchymal stem cells (hUC-MSCs) as a model of congenital diseases. LC3B, a hallmark protein of autophagy was incrementally upregulated with the infection duration, whereas p62 was downregulated in T. gondii-infected hUC-MSCs. Concurrent to this result, the invasion of T. gondii into hUC-MSCs increased in a time-dependent manner. The expression levels of Bcl-2 family proteins including Bcl-2, Bcl-xL, Bim, Bax, Bid and Bak were not altered; however, Mcl-1 levels in hUC-MSCs were dramatically decreased upon T. gondii infection. In addition, at 24 h post-infection, cleaved PARP and cleaved caspase-3 protein levels were elevated in hUC-MSCs. Importantly, Mcl-1 overexpression reduced the levels of autophagy- and apoptosis-related proteins in T. gondii-infected hUC-MSCs. Mcl-1 proteins were primarily expressed in the fraction containing mitochondria and strongly interacted with Beclin-1 under normal conditions; however, these interactions were remarkably attenuated by T. gondii infection. These results suggest that mitochondrial Mcl-1 is an essential signaling mediator regulating the activation of autophagy and apoptosis during T. gondii infection.


Utility of a nonlinear joint dynamical framework to model a pair of coupled cardiovascular signals.
We have recently proposed a correlated model to provide a Gaussian mixture representation of the cardiovascular signals, with promising results in identifying rhythm disturbances. The approach provides a transformation of the data into a set of integrable Gaussians distributed over time. Looking into the model from a new joint modeling perspective, it is capable of assembling a filtered estimation, and can be used to derive temporal information of the waveforms. In this paper, we present a step-by-step derivation of the joint model putting correlation assumptions together to conclude a minimal joint description for a pair of ECG-ABP signals. We then probe novel applications of this model, including Kalman filter based denoising and fiducial point detection. In particular, we use the joint model for denoising and employ the denoised signals for pulse transit time (PTT) estimation. We analyzed more than 70 h of data from 76 patients from the MIMIC database to illustrate the accuracy of the algorithm. We have found that this method can be effectively used for robust joint ECG-ABP noise suppression, with mean signal-to-noise ratio (SNR) improvement up to 23.2 (12.0) dB and weighted diagnostic distortion measures as low as 2.1 (3.3)% for artificial (real) noises, respectively. In addition, we have estimated the error distributions for QT interval, systolic and diastolic blood pressure before and after filtering to demonstrate the maximal preservation of morphological features (ΔQT: mean ± std = 2.2 ± 6.1 ms; ΔSBP: mean ± std = 2.3 ± 1.9 mmHg; ΔDBP: mean ± std = 1.9 ± 1.4 mmHg). Finally, we have been able to present a systematic approach for robust PTT estimation (r = 0.98, p <; 0.001, mean ± std of error = -0.26 ± 2.93 ms). These findings may have important implications for reliable monitoring and estimation of clinically important features in clinical settings. In conclusion, the proposed framework opens the door to the possibility of deploying a hybrid system that integrates these algorithmic approaches for index estimation and filtering scenarios with high output SNRs and low distortion.


[Risk factors in child asthma].
To evaluate six risk factors in a population of low economic level. 40 asthmatic children were studied, 21 masculine and 19 feminine, with a 9.3 years old half age +/- 3.22 years. A group control is included (22 children) without asthma and without allergic symptoms. I intragroup study. In the control group the tobacco atmosphere overcame the prospective frequency (p < 0.05), circumstance that didn't happen to the group of patient. Intragroup studies. There were not significant differences among the parameters studied in both groups, except for the frequency of family antecedents. The genetic factor is decisive for the initial asthma. The genotypic studies has found the chromosomic locus that regulate their expression. The environmental factors, particularly the tobacco pre and postnatal, they are decisive in the early precipitation of the beginning of the asthma.


A wearable device perspective on the standard definitions of disability progression in multiple sclerosis.
Multiple sclerosis (MS) is a leading cause of disability among young adults, but standard clinical scales may not accurately detect subtle changes in disability occurring between visits. This study aims to explore whether wearable device data provides more granular and objective measures of disability progression in MS. Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a longitudinal multicenter observational study in which 400 MS patients have been recruited since June 2018 and prospectively followed up for 24 months. Monitoring of patients included standard clinical visits with assessment of disability through use of the Expanded Disability Status Scale (EDSS), 6-minute walking test (6MWT) and timed 25-foot walk (T25FW), as well as remote monitoring through the use of a Fitbit. Among the 306 patients who completed the study (mean age, 45.6 years; females 67%), confirmed disability progression defined by the EDSS was observed in 74 patients, who had approximately 1392 fewer daily steps than patients without disability progression. However, the decrease in the number of steps experienced over time by patients with EDSS progression and stable patients was not significantly different. Similar results were obtained with disability progression defined by the 6MWT and the T25FW. The use of continuous activity monitoring holds great promise as a sensitive and ecologically valid measure of disability progression in MS.


Volcanic ash layers illuminate the resilience of Neanderthals and early modern humans to natural hazards.
Marked changes in human dispersal and development during the Middle to Upper Paleolithic transition have been attributed to massive volcanic eruption and/or severe climatic deterioration. We test this concept using records of volcanic ash layers of the Campanian Ignimbrite eruption dated to ca. 40,000 y ago (40 ka B.P.). The distribution of the Campanian Ignimbrite has been enhanced by the discovery of cryptotephra deposits (volcanic ash layers that are not visible to the naked eye) in archaeological cave sequences. They enable us to synchronize archaeological and paleoclimatic records through the period of transition from Neanderthal to the earliest anatomically modern human populations in Europe. Our results confirm that the combined effects of a major volcanic eruption and severe climatic cooling failed to have lasting impacts on Neanderthals or early modern humans in Europe. We infer that modern humans proved a greater competitive threat to indigenous populations than natural disasters.


Near-Atomic-Thick Bismuthene Oxide Microsheets for Flexible Aqueous Anodes: Boosted Performance upon 3D → 2D Transition.
Aqueous batteries provide safety, but they usually suffer from low energy and short lifetimes, limiting their use for large-scale energy storage. Two-dimensional materials with infinite lateral dimensions have inherent properties such as high surface area and remarkable power density and cycling stability that are shown to be critical for the next generation of energy storage systems. Here, ultrathin bismuthene oxide with a large aspect ratio is studied as an anode material for rechargeable aqueous metal-ion batteries. The metal oxides are prepared via a novel electrochemical system allowing for a smooth, high-quality transition of bismuthene to bismuthene oxide in a short time. This anodic system is shown to overcome major limiting factors of such batteries, including low capacity and irreversible and unstable redox reactions in aqueous electrolytes. The essential energy storage properties of two-dimensional (2D) microsheets, without the addition of conductive additives and binders, are compared with those of the corresponding three-dimensional (3D) structures. Notably, the battery performance of 2D microsheets is significantly better than that of nanoparticles from all examined aspects, including power density and potential and cycling stability, while exhibiting a capacity density close to their theoretical value. Moreover, 2D microsheets have shown impressive mechanical flexibility related to the ultrathin thickness of individual microsheets and strong interaction between them after film deposition. Combining the excellent energy storage properties of bismuthene oxide, the simple electrode preparation procedure, the inherent flexing characteristic, and the nontoxicity of both the battery material and the electrolyte makes this 2D material an exceptional candidate for large-scale wearable green electronics.


Other immunosuppressive agents for focal segmental glomerulosclerosis.
A prolonged course with corticosteroids represents the first therapeutic approach for nephrotic patients with focal segmental glomerulosclerosis (FSGS). In patients with contraindications to steroids or in those who do not respond to steroids or cyclosporine, cytotoxic agents, mycophenolate mofetil (MMF), plasmapheresis, and low-density lipoprotein (LDL) apheresis have been tried as alternative treatments. A short-term treatment with cytotoxic agents often is ineffective in steroid-resistant patients However, an aggressive and prolonged treatment with cytotoxic agents combined with corticosteroids proved to be effective in more than half of steroid-resistant children. In adults, the response to cytotoxic agents was good in steroid-responsive patients, but was poor in steroid-resistant patients. Better results were observed when cytotoxic therapy was prolonged for several months. The problem with these drugs is that long-term immunosuppression may be complicated by severe side effects including a major risk for cancer. Uncontrolled studies reported that MMF can induce some reduction of proteinuria, but complete remission of proteinuria was rare and no data on long-term follow-up evaluation with this drug are available. Good results have been reported with plasmapheresis, immunoadsorption, and lipopheresis. However, all the reports were uncontrolled, small sized, and with short-term follow-up evaluation. In conclusion, there are several therapeutic options for patients who respond to steroids and have further relapses of nephrotic syndrome, but how to treat steroid-resistant patients is still a matter of debate. Nevertheless, a 6-month trial with cytotoxic agents or MMF can be offered to steroid-resistant patients to identify the few patients who respond to these agents. The preliminary results with plasmapheresis or lipopheresis are promising but further studies are needed to assess the role of these treatments.