Defensive hypervariable regions confer superinfection exclusion in microviruses.
Single-stranded DNA phages of the family Microviridae have fundamentally different evolutionary origins and dynamics than the more frequently studied double-stranded DNA phages. Despite their small size (around 5 kb), which imposes extreme constraints on genomic innovation, they have adapted to become prominent members of viromes in numerous ecosystems and hold a dominant position among viruses in the human gut. We show that multiple, divergent lineages in the family Microviridae have independently become capable of lysogenizing hosts and have convergently developed hypervariable regions in their DNA pilot protein, which is responsible for injecting the phage genome into the host. By creating microviruses with combinations of genomic segments from different phages and infecting Escherichia coli as a model system, we demonstrate that this hypervariable region confers the ability of temperate Microviridae to prevent DNA injection and infection by other microviruses. The DNA pilot protein is present in most microviruses, but has been recruited repeatedly into this additional role as microviruses altered their lifestyle by evolving the ability to integrate in bacterial genomes, which linked their survival to that of their hosts. Our results emphasize that competition between viruses is a considerable and often overlooked source of selective pressure, and by producing similar evolutionary outcomes in distinct lineages, it underlies the prevalence of hypervariable regions in the genomes of microviruses and perhaps beyond.


Outcomes associated with nurse practitioners in collaborative practice with general practitioners in rural settings in Canada: a mixed methods study.
The formalized nurse practitioner (NP) role in British Columbia is relatively new with most roles implemented in primary care. The majority of primary care is delivered by physicians using the fee-for-service model. There is a shortage of general practitioners associated with the difficulties of recruitment and retention, particularly in rural and remote locations. The uptake of the primary care NP role has been slow due to challenges in understanding the extent of its contributions. This study aims to identify the outcomes associated with the NP role in collaborative primary care practice. Three case studies where NPs were embedded into rural fee-for-service practices were undertaken to determine the outcomes at the practitioner, practice, community, and health services levels. Interviews, documents, and before and after data, were analyzed to identify changes in practise, access, and acute care service utilization. The results showed that NPs affected how care was delivered, particularly through the additional time afforded each patient visit, development of a team approach with interprofessional collaboration, and a change in style of practise from solo to group practise, which resulted in improved physician job satisfaction. Patient access to the practice improved with increased availability of appointments and practice staff experienced improved workplace relationships and satisfaction. At the community level, access to primary care improved for harder-to-serve populations and new linkages developed between the practice and their community. Acute care services experienced a statistically significant decrease in emergency use and admissions to hospital (P = 0.000). The presence of the NP improved their physician colleagues' desire to remain in their current work environment. This study identified the diversity of needs that can be addressed by the NP role. Namely, the importance of time to enhance patient care and its associated benefits, especially in the fee-for-service model; the value of the NP's role in the community; the acceptance of the clinical competence of NPs by their physician colleagues; the outcomes generated at the practice level in terms of organizational effectiveness and service provision; and substantiated the impact of the role in improving primary care access and reducing acute care utilization.


[HIV resistance in men who have sex with men: a Meta-analysis].
To assess the prevalence of HIV primary drug resistance and drug resistance gene mutations among men who have sex with men (MSM). Methods: We searched eight electronic databases (CNKI, VIP, CBM, Wanfang Database, PubMed, Web of Knowledge, Springer, Medline) for the studies of HIV drug resistance relevant to MSM. Drug resistance and drug resistance mutations data were pooled and analyzed according to statistical test of homogeneity. Subgroups were further divided according to sample size, location, race, quality rating score, sampling time. Results: Forty-three studies were included in this Meta-analysis. The pooled rate of total to protease inhibitor (PI), nucleoside reverse transcriptase inhibitor(NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) were 10.21% (95% CI 8.65% to12.03%), 2.98% (95% CI 2.25% to 3.93%), 4.05% (95% CI 3.14% to 5.21%), 4.42% (95% CI 3.31% to 5.88%), respectively. The pooled rates of PI major mutation, PI secondary mutations, NRTI mutations and NNRTI mutations were 0.55% (95% CI 0.38% to 0.80%), 1.31% (95% CI 0.98% to 1.75%), 0.85% (95% CI 0.51% to 1.40%), 1.19% (95% CI 0.70% to 2.01%), 0.79% (95% CI 0.55% to 1.13%), 1.73% (95% CI 1.21% to 2.46%), 0.86% (95% CI 0.61% to 1.21%), 2.24% (95% CI 1.77% to 2.83%), respectively. Sample size, region, and race were heterogeneous sources; the rate of resistance mutations and gene mutation rate were different in different subgroups. Conclusion: The prevalence of primary drug resistance among MSM was high in Americas and Europe, and it was gradually increased in Asia. We should pay attention to the high incidence of PI secondary mutations.


Left ventricular volume: physical basis for attenuation corrections in radionuclide determinations.
Absolute left ventricular volume has been calculated from gated blood pool studies by estimating an attenuation correction for left ventricular counts. We studied the physical basis of these corrections by evaluating x-ray photon attenuation from CT scans of the thorax (10 second scans, no gating). CT numbers were converted to linear attenuation coefficients (LACs) at 140 keV, and LACs from the center of the left ventricle or esophagus to the chest wall (40 degrees left anterior oblique position) were determined in 12 patients of various body habitus. The mean LACs were virtually identical (0.13 cm-1 +/- 0.02 cm-1 SD), but were less than the LAC of water (0.15 cm-1). However, the esophagus was 66% further from the chest wall than the center of the left ventricle. These results suggest that conventional methods overestimate attenuation and show that LAC variability between individuals can be large. Better methods of attenuation correction may improve count-based estimates of left ventricular volume.


electrochemical generation of a nonheme oxoiron(IV) complex.
The complex [Fe(IV)O(N4Py)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) has been prepared by bulk electrolysis in aqueous CH3CN and CH2Cl2, and its redox properties characterized. Bulk chronocoulometry and spectropotentiometry experiments in CH3CN show that [Fe(II)(N4Py)(NCCH3)]2+ can be oxidized quantitatively to its iron(III) derivative at an applied potential of +0.71 V vs ferrocene and then to the oxoiron(IV) complex (in the presence of added water) at potentials above +1.3 V. The E1/2 value for the Fe(IV/III) couple has been estimated to be +0.90 V from spectropotentiometric titrations in CH3CN and cyclic voltammetric measurements in CH2Cl2.


Transcriptomics data: pointing the way to subclassification and personalized medicine in systemic lupus erythematosus.
To summarize recent studies stratifying SLE patients into subgroups based on gene expression profiling and suggest future improvements for employing transcriptomic data to foster precision medicine. Bioinformatic & machine learning pipelines have been employed to dissect the transcriptomic heterogeneity of lupus patients and identify more homogenous subgroups. Some examples include the use of unsupervised random forest and k-means clustering to separate adult SLE patients into seven clusters and hierarchical clustering of single-cell RNA-sequencing (scRNA-seq) of immune cells yielding four clusters in a cohort of adult SLE and pediatric SLE participants. Random forest classification of bulk RNA-seq data from sorted blood cells enabled prediction of high or low disease activity in European and Asian SLE patients. Inferred transcription factor activity stratified adult and pediatric SLE into two subgroups. Several different endotypes of SLE patients with differing molecular profiles have been reported but a global consensus of clinically actionable groups has not been reached. Moreover, heterogeneity between datasets, reproducibility of predictions as well as the most effective classification approach have not been resolved. Nevertheless, gene expression-based precision medicine remains an attractive option to subset lupus patients.


Reasons and barriers for using a patient portal: survey among patients with diabetes mellitus.
The use of a Web portal for patients with diabetes mellitus to access their own personal health record may result in improved diabetes outcomes. However, the adoption by patients is slow. This may be caused by patient characteristics, but also by the content, layout, and promotion of the portal. Detailed knowledge about this could help increase patients' participation in Web portals. The aim was to study the opinions of patients with diabetes and identify perceived barriers to using a Web portal to optimize its use. We conducted a survey among patients with type 1 and type 2 diabetes mellitus from 62 primary care practices and 1 outpatient hospital clinic in the central area of the Netherlands who all used the same electronic health record with a Web portal. Questionnaires about patient characteristics, opinions about reasons for use or nonuse, and about portal content were sent to 1500 patients with a login and 3000 patients without a login to the Web portal. Patient groups were stratified according to login frequency. Demographic and diabetes-related variables were analyzed with multivariable regression analysis. The total response rate was 66.63% (2391/4399); 1390 of 4399 patients (31.60%) were eligible for analysis. There were 413 regular users (login frequency more than once) and 758 nonusers (no login). Most nonusers (72.4%) stated that the main reason for not requesting a login was that they were unaware of the existence of the portal. Other barriers reported by patients were disinterest in managing their own disease (28.5%, 216/758) and feelings of inadequacy with the use of computers and Internet (11.6%, 88/758). Patients treated by a general practitioner were more frequently nonusers compared to patients treated by an internist (78.8%, 666/846 vs 28.3%, 92/325; P<.001) and more users than nonusers became aware of the Web portal through their physician (94.9%, 392/413 vs 48.8%, 102/209; P<.001). Nonusers perceived specific portal content as not as useful as regular users did, especially access to laboratory values (71.7%, 383/534 vs 92.3%, 372/403), rereading clinic visits (61.3%, 320/522 vs 89.6%, 360/402), e-messaging (52.0%, 262/504 vs 74.6%, 299/401), and uploading results to the glucose diary (45.3%, 229/506 vs 74.0%, 288/400; all P<.001). Our study shows that unawareness of the patient portal is the main barrier of enrollment. Users and nonusers perceive the usefulness of the portal differently and do not have the same recommendations for additional functionalities. To increase patients' participation in a Web portal, the unawareness of its existence and its possibilities need to be addressed by their health care professionals.


The contribution of glutenin macropolymer depolymerization to the deterioration of frozen steamed bread dough quality.
Depolymerization of glutenin macropolymers (GMP) widely exists in the frozen dough with little effort in elucidating its effects on steamed bread quality. To clarify this, GMP was fractionated from wheat flour and reconstituted to yeast and chemical leavened dough (YLD/CLD). Results showed that with supplementary GMP fraction, depolymerization degree was alleviated in frozen dough. The bread quality loss from freezing was partially counteracted along with better preserved GMP content. Both of dough elasticity and gas retention capability were enhanced in GMP-enriched frozen dough. Gassing power in frozen YLD decreased while remained constant in CLD. Addition of GMP did not affect the gassing power, which allowed interpreting the improved bread qualities from the enhanced dough elasticity and gas retention capability. Based on the improved facts of frozen steamed bread dough quality with additional GMP fractions, this study revealed the pivotal role of GMP depolymerization on the frozen steamed bread dough quality.


Pneumonia and empyema caused by Streptococcus intermedius that shows the diagnostic importance of evaluating the microbiota in the lower respiratory tract.
The bacterial species in the Streptococcus anginosus group (S. constellatus, S. anginosus, S. intermedius) are important causative pathogens of bacterial pneumonia, pulmonary abscesses and empyema. However, the bacteria in this group are primarily oral resident bacteria and unable to grow significantly on ordinary aerobic culture media. We experienced a case of pneumonia and empyema caused by Streptococcus intermedius detected using a 16S rRNA gene sequencing analysis of bronchoalveolar lavage fluid and pleural effusion, but not sputum. Even when applying the molecular method, sputum samples are occasionally unsuitable for identifying the causative pathogens of lower respiratory tract infections.


Vulvar epithelioid sarcoma metastatic to the scalp. A case report and review of the literature.
We report a case of vulvar epithelioid sarcoma with metastases to the scalp, an inguinal lymph node, lungs, liver, and kidneys. Epithelioid sarcoma typically involves the extremities of young men and may be confused histologically with various benign and malignant processes. Only five cases of primary vulvar epithelioid sarcoma have been previously reported. The present case represents the first report of cutaneous metastases from this primary site. We also review the literature pertaining to the clinical, pathologic, and immunohistochemical features of this rare tumor.


Rights to privacy in research: adolescents versus parents.
Conducting research on adolescents raises a number of ethical issues not often confronted in research on younger children. In part, these differences are due to the fact that although assent is usually not an issue, given cognitive and social competencies, the life situations and behavior of youth make it more difficult to balance rights and privacy of the adolescents. In this article, the three ethical principles of beneficence, justice, and respect for persons are discussed in terms of their application to the study of adolescents. Then, seven vignettes are presented to illustrate how these principles apply to real-life situations. How to balance the rights of adolescents and their parents is discussed, using adolescent girls and their parents for illustrative purposes.


Relation between hypermetabolism, cachexia, and survival in cancer patients: a prospective study in 390 cancer patients before initiation of anticancer therapy.
Background: Cachexia is a major cause of death in cancer patients. The role of hypermetabolism in cancer cachexia remains unclear.Objective: We studied the relation between resting energy expenditure (REE), the estimated energy balance, clinical and biological markers of cachexia, and survival.Design: REE was measured with the use of indirect calorimetry in cancer patients before the initiation of anticancer therapies. Hypermetabolic, normometabolic, and hypometabolic patients were identified with the use of Boothby's standard. Weight loss, performance status (PS), C-reactive protein (CRP), albumin, the nutritional risk index, daily energy intake, energy balance (equal to daily energy intakes minus the REE), and survival were recorded.Results: Of 390 enrolled patients, 49% of subjects were hypermetabolic, 30% of subjects were normometabolic, and 21% of subjects were hypometabolic. Mean daily energy intakes did not differ significantly between the 3 groups. Hypermetabolic patients, compared with normometabolic patients, were more likely to have a negative energy balance [45% compared with 32%, respectively; OR: 1.74 (95% CI: 1.05, 2.91); P = 0.024], weight loss >5% [48% compared with 34%, respectively; OR: 1.83 (95% CI: 1.11, 3.04); P = 0.013], PS ≥2 [40% compared with 29%, respectively; OR: 1.70 (95% CI: 1.01, 2.88); P = 0.038], and CRP concentrations ≥10 mg/L [52% compared with 33%, respectively; OR: 2.2 (95% CI: 1.33, 3.66); P = 0.001]. In metastatic patients, compared with normometabolism, hypermetabolism was associated with a reduced median survival [14.6 compared with 21.4 mo, respectively; OR: 1.48 (95% CI: 1.01, 2.17); P = 0.044].Conclusions: Hypermetabolism is correlated with clinical and biological markers of cancer cachexia and is associated with a shorter survival in metastatic cancer patients. The development of therapeutic strategies that aim to blunt hypermetabolism appears warranted. This trial was registered at www.controlled-trials.com as ISRCTN46152275.


Combination of Antimicrobials and Essential Oils as an Alternative for the Control of Salmonella enterica Multiresistant Strains Related to Foodborne Disease.
Due to the increase in bacterial resistance to antimicrobials (AMBs) commonly used in veterinary and human medicine, the new strategies for controlling zoonoses focus on the study of natural products with demonstrated AMB activity, such as essential oils (EOs). The aim of this study was to evaluate the in vitro effect of the combination of enrofloxacin (ENR), ceftiofur (CEF), and trimethoprim-sulfamethoxazole (SXT) with cinnamon, clove, oregano, and red thyme EOs against multiple drug-resistant strains of Salmonella enterica. The minimum inhibitory concentration (MIC) of each product was determined by microdilution and "Checkerboard" methods and their combined effect was evaluated against 15 strains of S. enterica. The results were interpreted by the calculation of fractional inhibitory concentration (FIC) and their respective indexes (FICI). Significant susceptibility of all strains to the four EOs was observed. The results showed a synergistic effect between EOs and AMBs tested, highlighting the upper percentage of total synergies of the SXT with the four EOs (FICI ≤0.5 in 60% of assays), and the most effective combination being the one of ENR and cinnamon. The MIC of cinnamon was reduced from 1250 to 312.5 μg/mL and the MIC of ENR from 2 to 0.031 μg/mL. There was no antagonism in the tested combinations (AMBs-EOs). Our results support the combined use of EOs and AMBs for the control of multiresistant strains of S. enterica with a reduction of the minimum effective dose of AMBs and their adverse effects.


The Role of Health Coaching in Pain and Palliative Care Pharmacy Practice.
Whole-person care is essential in the management of patients with chronic pain and serious illness. Pain, suffering, and comfort do not fall under typical chronic disease management and cannot be boxed nicely into algorithms of evidence-focused, biomarker-based goal achievement like hypertension or diabetes. Current therapies, including surgical, interventional, and analgesic modalities may be only marginally effective, and have brought with them questionable practices, high cost, and an opioid epidemic. Patient-focused goals are gaining favor, and exploration of methods to enhance this approach include health coaching. In the setting of pain management, this would include pain coaching. This commentary will highlight the role of health coaching in the setting of chronic disease and pain management, and the pharmacists' qualifications and potential contributions to health and pain coaching.


Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules.
Nascent MHC class II molecules are associated with the invariant chain and are transported to the endolysosomal pathway, where MHC class II molecules acquire peptide antigens. On the other hand, misfolded endoplasmic reticulum (ER) proteins are generally degraded in the cells and are neither expressed on the cell surface nor secreted. Here, we found that MHC class II molecules associate with some misfolded ER proteins via the peptide-binding groove in competition with invariant chain. The misfolded proteins associated with MHC class II molecules are transported intact to the cell surface without processing to peptides. Furthermore, these complexes efficiently stimulate antigen-specific B cells. These findings reveal that MHC class II molecules function as a chaperone for the cell surface expression of misfolded ER proteins. In addition, we suggest that MHC class II molecules present not only peptides but also intact host-cell-derived proteins on the cell surface. These findings provide new insights into the function of MHC class II molecules.


The DEAD-box RNA helicase DDX41 is a novel repressor of p21WAF1/CIP1 mRNA translation.
The cyclin-dependent kinase inhibitor p21 is an important player in stress pathways exhibiting both tumor-suppressive and oncogenic functions. Thus, expression of p21 has to be tightly controlled, which is achieved by numerous mechanisms at the transcriptional, translational, and posttranslational level. Performing immunoprecipitation of bromouridine-labeled p21 mRNAs that had been incubated before with cytoplasmic extracts of untreated HCT116 colon carcinoma cells, we identified the DEAD-box RNA helicase DDX41 as a novel regulator of p21 expression. DDX41 specifically precipitates with the 3'UTR, but not with the 5'UTR, of p21 mRNA. Knockdown of DDX41 increases basal and γ irradiation-induced p21 protein levels without affecting p21 mRNA expression. Conversely, overexpression of DDX41 strongly inhibits expression of a FLAG-p21 and a luciferase construct, but only in the presence of the p21 3'UTR. Together, these data suggest that this helicase regulates p21 expression at the translational level independent of the transcriptional activity of p53. However, knockdown of DDX41 completely fails to increase p21 protein levels in p53-deficient HCT116 cells. Moreover, posttranslational up-regulation of p21 achieved in both p53+/+ and p53-/- HCT116 cells in response to pharmaceutical inhibition of the proteasome (by MG-132) or p90 ribosomal S6 kinases (by BI-D1870) is further increased by knockdown of DDX41 only in p53-proficient but not in p53-deficient cells. Although our data demonstrate that DDX41 suppresses p21 translation without disturbing the function of p53 to directly induce p21 mRNA expression, this process indirectly requires p53, perhaps in the form of another p53 target gene or as a still undefined posttranscriptional function of p53.


Protein-lipid nanohybrids as emerging platforms for drug and gene delivery: Challenges and outcomes.
Nanoparticulate drug delivery systems have been long used to deliver a vast range of drugs and bioactives owing to their ability to demonstrate novel physical, chemical, and/or biological properties. An exponential growth has spurred in research and development of these nanocarriers which led to the evolution of a great number of diverse nanosystems including liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), micelles, dendrimers, polymeric nanoparticles (NPs), metallic NPs, and carbon nanotubes. Among them, lipid-based nanocarriers have made the largest progress whether commercially or under development. Despite this progress, these lipid-based nanocarriers suffer from several limitations that led to the development of many protein-coated lipid nanocarriers. To less extent, protein-based nanocarriers suffer from limitations that led to the fabrication of some lipid bilayer enveloping protein nanocarriers. This review discusses in-depth some limitations associated with the lipid-based or protein-based nanocarriers and the fruitful outcomes brought by protein-lipid hybridization. Also discussed are the various hybridization techniques utilized to formulate these protein-lipid nanohybrids and the mechanisms involved in the drug loading process.


Health care reform in Belgium.
Curbing the growth of public sector health expenditures has been the proclaimed government objective in Belgium since the 1980s. However, the respect for freedom of choice for patients and for therapeutic freedom for providers has blocked the introduction of microeconomic incentives and quality control. Therefore--with some exceptions, particularly in the hospital sector--policy has consisted mainly of tariff and supply restrictions and increases in co-payments. These measures have not been successful in curbing the growth of expenditures. Moreover, there remains a large variation in medical practices. While the structure of health financing is relatively progressive from an international perspective, socioeconomic and regional inequalities in health persist. The most important challenge is the restructuring of the basic decision-making processes; i.e. a simplification of the bureaucratic procedures and a re-examination of the role of regional authorities and sickness funds.


"The Wisdom of Age": Perspectives on Aging and Growth among Lesbian Older Adults.
Older lesbian-identified women are a health disparate yet resilient population about whom knowledge is limited and emerging. Among the areas in need of research are older lesbians' experiences of later life and stress-related growth. This article presents the findings from a qualitative study that investigated older lesbians' experiences of adversity and adaptation as they age. In-depth, exploratory interviews were conducted with 12 lesbian-identified women who were between the ages of 65-80. This study applied grounded theory methodology to identify respondents sources of stress and fear, their strengths and coping strategies and how those relate to each other and to their growth in later life. We advance a model of adaptive change that shows how spirituality, social support, and resistance to cultural norms help older lesbian adults cope with loss, illness, and discrimination and develop wisdom in later life. Knowledgeable practitioners can help older lesbian women identify and maintain sources of social support, explore spirituality, and facilitate continuous growth through the end of life. Social workers can advocate for services that are welcoming and affirmative so as to reduce fears of isolation and dependence associated with health decline.


Short-term hemostatic safety of strontium ranelate treatment in elderly women with osteoporosis.
Strontium ranelate offers significant clinical benefits in terms of efficacy, tolerability, and ease of administration in the treatment of postmenopausal osteoporosis. However, there are some data revealing an association between strontium ranelate treatment and increased incidence of venous thromboembolism (VTE), suggesting possible adverse prothrombotic effects of the drug. To assess the effect of strontium ranelate treatment on primary hemostasis, secondary hemostasis, and the natural anticoagulant defense system, together with prothrombotic markers, in elderly women with osteoporosis. This study was designed in a prospective manner. Thirty-five elderly women diagnosed with osteoporosis were included. During a 2 month treatment period, participants received strontium ranelate 2 g. Platelet Function Analyzer-100 (PFA-100) in vitro bleeding time was performed to depict primary hemostasis. Secondary hemostatic parameters including prothrombin time, international normalized ratio, activated partial thromboplastin time, anti-cardiolipine immunoglobulin (Ig) M and IgG, antiphospholipid IgM and IgG, protein C, protein S, antithrombin III, lupus anticoagulant, fibrinogen, thrombin, activated protein C resistance, and plasma levels of d-dimer were assessed. These parameters were tested before and after 2 month treatment with strontium ranelate. Mean +/- SD age of the patients was 72.82 +/- 5.69 years. After 60 days of treatment, there was no statistically significant prolongation in PFA-100 in vitro bleeding time and no statistically significant change in the critical hemostatic parameters in patients receiving strontium ranelate that led to discontinuation of the treatment. None of the subjects developed clinical VTE during the 2 month period of strontium ranelate treatment. The hemostatic safety of strontium ranelate in the elderly population with osteoporosis was shown over 2 months of treatment; however, its long-term hemostatic safety should be evaluated further.


Opposite regulation of uncoupling protein 1 and uncoupling protein 3 in vivo in brown adipose tissue of cold-exposed rats.
Earlier we reported a 14-fold increase of glycogen in the brown adipose tissue (BAT) in rats when the animals were placed back from cold to neutral temperature. To elucidate the mechanism, here we compared the level of glucose transporter 4 (GLUT4) protein, uncoupling protein (UCP) 1 and UCP3 mRNA and protein expressions in the BAT under the same conditions. We found that the increased GLUT4 level in cold was maintained during the reacclimation. After 1 week cold exposure the mRNA and protein content of UCP1 increased parallel, while the protein level of UCP3 decreased, contrary to its own mRNA level.


Immunohistochemical localization of pregnancy-related placental protein 4 in nontumorous tissues and in gynecological tumors.
The aim of the study was to demonstrate the localization of placental protein 4 (PP4) in different nontumorous and tumorous tissues originating from the female genital tract. PP4 immunoreactivity was demonstrated using the peroxidase-antiperoxidase immunohistochemical technique. Tissue samples were obtained from the cervix and body of the uterus, ovary, vulva and from gestational trophoblastic tumors. PP4-positive cells were present in nontumorous tissues with various pathologic findings, and in many but not all benign gynecological tumors. Similar numbers of PP4-positive cells were located in malignant and benign gynecological tumors; however, PP4 staining intensity was greater in the malignant lesions. PP4-positive cells were found in hydatidiform moles and in choriocarcinoma. PP4 was distributed mainly in the cytoplasm, but it was also bound to the cell membrane. We conclude from these studies that PP4 is located in a variety of benign and malignant cells of the female genital tract and that these cells may be the source of plasma PP4 found in patients with these conditions.


FITNESS CONSEQUENCES OF SEASONAL POLYPHENISM IN WESTERN WHITE BUTTERFLIES.
The western white butterfly, Pontia occidentalis, has distinctly different wing phenotypes during spring and summer generations as a result of phenotypic plasticity (seasonal polyphenism). We experimentally generated different seasonal phenotypes in the lab by altering photoperiodic conditions during rearing, and released the resulting butterflies in the field. Mark-recapture studies were then used to estimate the effects of the polyphenism on activity patterns and adult survival in both late-spring (one study) and summer (two studies) conditions. There were no significant effects of rearing treatment on temporal patterns of behavioral activity during either the late-spring or the summer field studies. Recapture probabilities were consistently higher for males than females in all three field studies; in the summer 1992 study, recapture probabilities were higher for long-day (LD) than for short-day (SD) treatment groups. During the late-spring 1992 study, there were no significant differences between LD and SD treatment groups for survival probabilities. In the two summer studies, there were significant effects of photoperiodic treatment on survival probabilities; in the summer 1992 study, LD individuals consistently had higher survival probabilities than SD individuals; in the summer 1991 study, there was a significant interaction between treatment and time period on survival probabilities, such that survival probabilities were higher for LD than for SD individuals in two of four time periods. The consistent differences in survival probabilities between treatment groups in the summer 1992 study can be accounted for by the differences in wing traits between the treatment groups. Micrometeorological data from the study site showed that midday ambient temperatures averaged ~3°C hotter during the 1992 than the 1991 summer study and that ambient conditions during the late-spring 1992 study were relatively warm and sunny for the season. These results document the varying relationships between phenotype and fitness in the temporally fluctuating environments experienced by this population.


New micro-optical methods to study metabolism in periportal and pericentral regions of the liver lobule.
New techniques employing microlight guides allow metabolic events to be studied noninvasively in tiny volumes of liver tissue located in defined regions within the liver lobule. These events include oxygen utilization, carbohydrate metabolism, ethanol oxidation, monooxygenation, glucaronidation, and sulfation. Two-fiber microlight guides are constructed from 80-microns optical fibers and are placed on periportal or pencentral regions of the liver lobule based on the pattern of liver pigmentation. Light of selected wavelengths is transmitted to the liver surface by one fiber, and the resultant fluorescence or reflectance is delivered to a photomultiplier by the second fiber. The experimental strategy is to monitor native fluors which are metabolically linked (e.g., NADH) or to infuse nonfluorescent substrates which are converted to fluorescent products by specific enzyme systems (e.g., 7-ethoxycoumarin for monooxygenation). Alternatively, disappearance of fluorescence can also be employed (e.g., 7-hydroxycoumarin for sulfation or glucuronidation). With these methods, rate-limiting steps in situ (e.g., substrate uptake, enzyme activity, cofactor supply) have been studied for several metabolic systems in periportal and pericentral regions of the liver lobule.


A management algorithm and practical oncoplastic surgical techniques for repairing partial mastectomy defects.
In patients undergoing a partial mastectomy, choosing the best method with which to repair the defect is essential to optimizing outcomes and minimizing the potential for postoperative complications. The authors present a management algorithm for repairing partial mastectomy defects based on clinically relevant parameters to allow clinicians to better select the most appropriate indications for the various reparative oncoplastic procedures. The clinicopathologic factors considered in surgical decision-making for reconstruction after partial mastectomy include timing of reconstruction in relation to radiation therapy, status of the tumor margin, extent of breast skin resection, breast size, and whether the cosmetic outcome would be better after a total mastectomy with immediate breast reconstruction, thereby avoiding the need for radiation therapy. Most patients with medium or large breasts will likely benefit from immediate repair, whereas some with small breasts may not. Immediate repair of partial mastectomy defects is preferred with the use of local breast tissue (local tissue rearrangement or breast reduction techniques) because of the simplicity of these approaches and because techniques using local tissue maintain the color and texture of the breast. Waiting to repair a large deformity until after whole-breast radiation therapy usually necessitates a complex transfer of a large volume of autologous tissue, which many patients who undergo breast conservation therapy are not willing to pursue. Use of lower abdominal flaps to repair partial breast defects is generally discouraged. Although the authors' management algorithm and practical oncoplastic techniques should prove useful, it is up to the multidisciplinary breast team and the patient to determine the best approach.


Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells.
Embryonic stem (ES) cells are self-renewing cells that maintain pluripotency to differentiate into all types of cells. Because of their potential to provide a variety of tissues for use in regenerative medicine, there is great interest in the identification of growth factors that govern these unique properties of ES cells. However, the signaling pathways controlling ES cell proliferation remain largely unknown. Since transforming growth factor beta (TGFbeta) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGFbeta signaling by Smad7 or SB-431542 dramatically decreased ES cell proliferation without decreasing ES pluripotency. By contrast, inhibition of bone morphogenetic protein (BMP) signaling by Smad6 did not exhibit such effects, suggesting that activin-Nodal-TGFbeta signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGFbeta or BMP, significantly enhanced ES cell propagation without affecting pluripotency. We also found that activin-Nodal signaling was constitutively activated in an autocrine fashion in serum-free cultured ES cells, and that inhibition of such endogenous signaling by SB-431542 decreased ES cell propagation in serum-free conditions. These findings suggest that endogenously activated autocrine loops of activin-Nodal signaling promote ES cell self-renewal.


ATP binding cassette G1-dependent cholesterol efflux during inflammation.
ATP binding cassette transporter G1 (ABCG1) mediates the transport of cellular cholesterol to HDL, and it plays a key role in maintaining macrophage cholesterol homeostasis. During inflammation, HDL undergoes substantial remodeling, acquiring lipid changes and serum amyloid A (SAA) as a major apolipoprotein. In the current study, we investigated whether remodeling of HDL that occurs during acute inflammation impacts ABCG1-dependent efflux. Our data indicate that lipid free SAA acts similarly to apolipoprotein A-I (apoA-I) in mediating sequential efflux from ABCA1 and ABCG1. Compared with normal mouse HDL, acute phase (AP) mouse HDL containing SAA exhibited a modest but significant 17% increase in ABCG1-dependent efflux. Interestingly, AP HDL isolated from mice lacking SAA (SAAKO mice) was even more effective in promoting ABCG1 efflux. Hydrolysis with Group IIA secretory phospholipase A(2) (sPLA(2)-IIA) significantly reduced the ability of AP HDL from SAAKO mice to serve as a substrate for ABCG1-mediated cholesterol transfer, indicating that phospholipid (PL) enrichment, and not the presence of SAA, is responsible for alterations in efflux. AP human HDL, which is not PL-enriched, was somewhat less effective in mediating ABCG1-dependent efflux compared with normal human HDL. Our data indicate that inflammatory remodeling of HDL impacts ABCG1-dependent efflux independent of SAA.


Current studies on biological tagatose production using L-arabinose isomerase: a review and future perspective.
D-Tagatose is a hexoketose monosaccharide sweetener, which is an isomer of D-galactose and is rarely found in nature. Recently, there has been industrial interest in D-tagatose as a low-calorie sugar-substituting sweetener. This article describes the properties and metabolism of tagatose as well as its commercial importance. The comparison between the biological tagatose production and the chemical production was reviewed based on the example of the glucose isomerization into fructose. The industrial problems facing its commercial application is described and evolving potential solutions are suggested.


Stimulating erythropoiesis: future perspectives.
The introduction of recombinant human erythropoietin (rHuEpo) nearly 20 years ago has revolutionised the management of patients with CKD, providing the opportunity for safe long-term anaemia correction without the attendant risks identified with blood products. Based on our expanding knowledge in this area, there are many exciting and innovative new approaches to anaemia correction that stand on, or are close to, the threshold of yielding products ready for clinical use. Recently, an Epo-related molecule called continuous Epo receptor activator has been licensed in Europe, and other molecules are in various processes of development, including Epo mimetic peptide. The search goes on for orally active antianaemic therapies, and several strategies are being investigated. Furthermore, it is now clear that in addition to the anaemia-correction properties of erythropoiesis-stimulating agents, there is the potential for cytoprotection by prevention of cellular apoptosis. This effect could be used in the prevention of ischaemia-reperfusion injury as well as other conditions associated with acute kidney injury and other disease processes. The aim of this article is to discuss these possible future strategies, focusing in particular on those with a reasonable likelihood of a pharmaceutical product that is likely to be used clinically.


Expanding non-invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y.
Non-invasive prenatal testing (NIPT) based on cell-free DNA in maternal plasma is being expanded to include additional chromosome abnormalities beyond those involving chromosomes 21, 18, 13, X and Y. Review of population cytogenetic data provides insight into the likely number of additional abnormalities detectable. Additional clinically significant and cytogenetically recognizable abnormalities are present in less than 0.1% of newborns but clinically significant, or potentially significant, sub-microscopic imbalances are expected to be present in 1.7%. Cytogenetic studies on chorionic villus samples suggests that after excluding abnormalities involving chromosomes 21, 18, 13, X and Y, approximately 0.6% of NIPT results may be positive for an unbalanced abnormality attributable to mosaicism but most of these will not be confirmed at amniocentesis or in newborns. NIPT has also been developed for specific microdeletion syndromes and initial experience is now available. Laboratory procedures such as deeper sequencing and additional data analytics are rapidly evolving but even with existing protocols, it is already clear that NIPT does not necessarily need to be limited to trisomies 21, 18, 13 and the sex-chromosome abnormalities. Patient educational materials and genetic counseling services need to be available for women offered expanded NIPT.


Overexpression of ephrinB2 in stem cells from apical papilla accelerates angiogenesis.
We aimed to accelerate angiogenesis in pulp regeneration by modulating ephrinB2 expression in stem cells from apical papilla (SCAPs). Stem cells from apical papilla were transducted with ephrinB2-lentiviral expression vector (ephrinB2-SCAPs) in experimental group and green fluorescent protein (GFP-SCAPs) in control group. The transduction efficiency was confirmed by real-time PCR and Western blot assays. MTT assay was performed to detect the proliferative capacity of SCAPs after transduction. In vitro Matrigel assay and in vivo Matrigel plug assay were carried out to evaluate the angiogenic capacity. Results showed that ephrinB2-SCAPs had significantly higher ephrinB2 expression than GFP-SCAPs. EphrinB2-SCAPs upregulated vascular endothelial growth factor (VEGF) secretion under hypoxia. In vitro Matrigel assay demonstrated that human umbilical vein endothelial cells (HUVECs) cocultured with ephrinB2-SCAPs under hypoxia formed vascular-like structures earlier than GFP-SCAPs. Animal experiments confirmed that SCAPs co-transplanted with HUVECs enabled to generate greater amount of blood vessels than SCAPs alone. EphrinB2-SCAPs produced increased number of blood vessels with references to GFP-SCAPs, and those co-transplanted with HUVECs generated vessels with larger and functional tubule volumes. Regulating ephrinB2 expression in SCAPs may act as a new avenue for enhancing angiogenesis in dental pulp regeneration.


Development of Films from Spent Coffee Grounds' Polysaccharides Crosslinked with Calcium Ions and 1,4-Phenylenediboronic Acid: A Comparative Analysis of Film Properties and Biodegradability.
Most polymeric materials are synthetic and derived from petroleum, hence they accumulate in landfills or the ocean, and recent studies have focused on alternatives to replace them with biodegradable materials from renewable sources. Biodegradable wastes from food and agroindustry, such as spent coffee grounds (SCGs), are annually discarded on a large scale and are rich in organic compounds, such as polysaccharides, that could be used as precursors to produce films. Around 6.5 million tons of SCGs are discarded every year, generating an environmental problem around the world. Therefore, it was the aim of this work to develop films from the SCGs polysaccharide fraction, which is comprised of cellulose, galactomannans and arabinogalactans. Two types of crosslinking were performed: the first forming coordination bonds of calcium ions with polysaccharides; and the second through covalent bonds with 1,4-phenylenediboronic acid (PDBA). The films with Ca2+ ions exhibited a greater barrier to water vapor with a reduction of 44% of water permeability vapor and 26% greater tensile strength than the control film (without crosslinkers). Films crosslinked with PDBA presented 55-81% higher moisture contents, 85-125% greater permeability to water vapor and 67-150% larger elongations at break than the films with Ca2+ ions. Film biodegradability was demonstrated to be affected by the crosslinking density, with the higher the crosslinking density, the longer the time for the film to fully biodegrade. The results are promising and suggest that future research should focus on enhancing the properties of these films to expand the range of possible applications.


[Establishment and evaluation of noninvasive diagnostic models for liver fibrosis in patients with chronic hepatitis B].
Objective: To establish the model of liver fibrosis based on noninvasive indices, and to investigate the diagnostic value of this model. Methods: A total of 838 patients with chronic hepatitis B (CHB) who underwent liver biopsy in our hospital from March 2003 to October 2013 were selected, and the results of blood tests and B-ultrasound were collected. The correlation between these indices and liver fibrosis stage was analyzed. A logistic regression analysis was performed to establish a predictive model, and the value of this model was examined in validation group. The t-test, Mann-Whitney U non-parametric test, and chi-square test were used for data analysis. A Spearman rank correlation analysis was used for bivariate correlation analysis, and a dichotomous logistic stepwise regression analysis was used for multivariate analysis. Results: In the model group, a model (FV) consisting of age, platelet count (PLT), γ-glutamyl transferase (GGT), albumin/globulin ratio (A/G), and splenic square area (SSA) was established. The areas under the receiver operating characteristic curve (AUROCs) of the model FV were 0.892, 0.910, and 0.915, respectively, in diagnosing significant liver fibrosis (S2-4), progressive liver fibrosis (S3-4), and early-stage liver cirrhosis (S4), with sensitivities of 77.6%, 83.7%, and 86.0%, respectively, specificities of 89.7%, 84.5%, and 83.7%, respectively, and accuracy of 82.1%, 84.2%, and 84.2%, respectively. There were no significant differences in AUROCs between the validation group and the model group (Z = 0.360, 0.885, and 0.046, all P > 0.05). In all patients, FV had significantly higher AUROCs in the diagnosis of liver fibrosis than FIB4 index and S index (Z = 4.569/3.423, 5.640/4.709, and 4.652/4.439, all P < 0.05). With < 0.374 and ≥ 0.577 as the cut-off values for the exclusion and diagnosis of significant liver fibrosis, 61.1% (512/838) of all patients could avoid liver biopsy, and the accuracy was 92.6% (474/512). Conclusion: The noninvasive model based on age, PLT, GGT, A/G, and SSA can accurately predict liver fibrosis degree in patients with CHB with good reproducibility; therefore, it can be used for dynamic monitoring of liver fibrosis degree in clinical practice.


Production of endometrial matrix metalloproteinases, but not their tissue inhibitors, is modulated by progesterone withdrawal in an in vitro model for menstruation.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are implicated in normal menstruation, but the mechanism of their regulation is not yet clear. Human endometrial stromal cell cultures were established to mimic the events of the late luteal phase of the menstrual cycle: after 6 days of culture with estradiol 17beta (10 nmol/L) and progestin (P, 100 nmol/L), half the cells were subjected to P withdrawal, and medium was harvested on day 10. Decidualization of the cells was verified by PRL immunohistochemistry. Latent MMP-1, -2, -3, and -9 were detected by zymography and quantitated by densitometry, and production of all enzymes was increased on withdrawal of P. This increase was confirmed by enzyme-linked immunosorbent assay for MMP-1. TIMP-1, -2, and -3 also were produced by the cells, with a mean ratio of 3.9:1:1.2, respectively. There was no effect of P withdrawal on either the amount of each TIMP or their relative concentrations. Expression of the messenger RNA for TIMP-1 or TIMP-2 also was not changed by P withdrawal. Thus, withdrawal of P alters the ratio of MMPs to TIMPs in this model in favor of MMPs and, hence, of tissue degradation. However, the focal nature of menstruation-associated MMP activity suggests that P withdrawal is unlikely to be the only factor responsible for in vivo induction of MMPs at menstruation.


Effect of rancid corn oil on some onco/suppressor gene expressions in vivo. A short-term study.
Autooxidation of polyunsaturated fatty acids (PUFAs) of edible oils results in the formation of fatty acid hydroperoxides that can undergo further chemical transformations to yield a variety of re-arranged and chain-cleavage products. Since the oxidation products of PUFAs have been reported to have cytotoxic and mutagenic effects, the consumption of rancid oils and fats represents a possible health hazard for the population. Storage of corn oil at room temperature and in the refrigerator for a forty-eight month period resulted in two different qualities of oil samples, which were characterized by UV, titrimetric (peroxide value, acid value) and GC-MS methods. Earlier it was demonstrated that the increase of expression of certain oncogenes and tumor suppressor genes is a method of choice for the early detection of carcinogen exposure. Treatment of CBA/Calpha inbred mice with the two oil samples showed significantly increased expression of the Ha-ras gene in all the investigated organs (liver, lung, kidney, thymus and spleen) of the rancid corn oil-treated animals. Expression of the c-myc and the p53 genes was also increased after the rancid corn oil-treatment in all the organs but the thymus of the mice. The results suggest that rancid oils, rich in omega-6 unsaturated fatty acids, could be involved not only in tumor promotion but in initiation as well.


The safety dance: biophysics of membrane protein folding and misfolding in a cellular context.
Most biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine.


Analysis of a structured intronic region of the LMP2 pre-mRNA from EBV reveals associations with human regulatory proteins and nuclear actin.
The pre-mRNA of the Epstein-Barr virus LMP2 (latent membrane protein 2) has a region of unusual RNA structure that partially spans two consecutive exons and the entire intervening intron; suggesting RNA folding might affect splicing-particularly via interactions with human regulatory proteins. To better understand the roles of protein associations with this structured intronic region, we undertook a combined bioinformatics (motif searching) and experimental analysis (biotin pulldowns and RNA immunoprecipitations) of protein binding. Characterization of the ribonucleoprotein composition of this region revealed several human proteins as interactors: regulatory proteins hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1), hnRNP U, HuR (human antigen R), and PSF (polypyrimidine tract-binding protein-associated splicing factor), as well as, unexpectedly, the cytoskeletal protein actin. Treatment of EBV-positive cells with drugs that alter actin polymerization specifically showed marked effects on splicing in this region. This suggests a potentially novel role for nuclear actin in regulation of viral RNA splicing.


High-NA fiber point-diffraction interferometer for three-dimensional coordinate measurement.
The numerical aperture (NA) and power of diffraction wave in point-diffraction interferometer (PDI) could significantly limit the measurement range of the system. A fiber point-diffraction interferometer with high NA is proposed for the measurement of absolute three-dimensional coordinates. Based on the single-mode fiber with submicron aperture, the diffraction wave with both high NA and high power is obtained, by which the achievable measurement range of the PDI can be extended. A double-iterative method based on Levenbery-Marquardt algorithm is proposed to determine the three-dimensional coordinates under measurement. Numerical simulation and comparison experiments have been carried out to demonstrate the accuracy and feasibility of the proposed PDI system, with both high measurement precision and nice repeatability achieved.


Determination of RHD zygosity using real-time quantitative PCR.
At present RHD incompatibility is still an obstetric problem despite prophylactic treatment. A very welcome recent technical advance has now made it possible to determine the foetal RHD status in a non-invasive risk-free manner using cell free foetal DNA in maternal plasma. In some cases, however, where there is a high risk that the foetus may be affected by HDN (haemolytic disease of the newborn), it may be of interest to determine whether the father is hetero- or homozygous for the RHD gene, since in the former instance there is only a 50% chance that the pregnancy is affected. It has recently been shown that quantitative PCR assays, in particular real-time Taqman PCR, can be used to determine the RHD gene dosage, and also to determine foetal aneuploidies. We demonstrate that the same real-time Taqman PCR assay we had previously developed for non-invasive analysis of the foetal RHD gene and the foetal Y chromosome from maternal plasma can be used to determine the paternal RHD genotype.


Influence of the Structural Accuracy of Homology Models on Their Applicability to Docking-Based Virtual Screening: The β2 Adrenergic Receptor as a Case Study.
How accurate do structures of the β2 adrenergic receptor (β2AR) need to be to effectively serve as platforms for docking-based virtual screening campaigns? To answer this research question, here, we targeted through controlled virtual screening experiments 23 homology models of the β2AR endowed with different levels of structural accuracy. Subsequently, we studied the correlation between virtual screening performance and structural accuracy of the targeted models. Moreover, we studied the correlation between virtual screening performance and template/target receptor sequence identity. Our study demonstrates that docking-based virtual screening campaigns targeting homology models of the β2AR, in the majority of the cases, yielded results that exceeded random expectations in terms of area under the receiver operating characteristic curve (ROC AUC). Moreover, with the most effective scoring method, over one-third and one-quarter of the models yielded results that exceeded random expectation also in terms of enrichment factors (EF1, EF5, and EF10) and BEDROC (α = 160.9), respectively. Not surprisingly, we found a detectable linear correlation between virtual screening performance and structural accuracy of the ligand-binding cavity. We also found a detectable linear correlation between virtual screening performance and structural accuracy of the second extracellular loop (EL2). Finally, our data indicate that, although there is no detectable linear correlation between virtual screening performance and template/β2AR sequence identity, models built on the basis of templates that show high sequence identity with the β2AR, especially within the ligand-biding cavity, performed consistently well. Conversely, models with lower sequence identity displayed performance levels that ranged from very good to random, with no apparent correlation with the sequence identity itself.


Relationship between estrogen receptor-alpha polymorphism and serum levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, C-reactive protein and homocysteine in postmenopausal women.
Genetic variation in the estrogen receptor-gene (ERalpha) may influence the risk of cardiovascular diseases in postmenopausal women. This effect, at least in part, may be dependent on the decrease in expression of injury and inflammatory markers in the vascular wall. The aim of the present study was to evaluate the relationship between ERalpha PvuII and XbaI polymorphisms and serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP) and homocysteine in postmenopausal women. Subjects of the study were 64 postmenopausal women. PvuII and XbaI ERalpha gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Mean sVCAM-1 level was significantly higher in pp homozygotes in comparison with PP homozygotes and Pp heterozygotes, as well as higher in xx homozygotes in comparison with XX homozygotes and Xx heterozygotes. Levels of sVCAM-1 were also significantly higher in women with px haplotype compared with PX and Px haplotypes. There were no relationships between investigated genotypes or haplotypes and levels of sICAM-1, CRP and homocysteine. The results of our study suggest that genetic variation in ER gene may influence blood levels of VCAM-1 in women after the menopause.


Wetlands, wild Bovidae species richness and sheep density delineate risk of Rift Valley fever outbreaks in the African continent and Arabian Peninsula.
Rift Valley fever (RVF) is an emerging, vector-borne viral zoonosis that has significantly impacted public health, livestock health and production, and food security over the last three decades across large regions of the African continent and the Arabian Peninsula. The potential for expansion of RVF outbreaks within and beyond the range of previous occurrence is unknown. Despite many large national and international epidemics, the landscape epidemiology of RVF remains obscure, particularly with respect to the ecological roles of wildlife reservoirs and surface water features. The current investigation modeled RVF risk throughout Africa and the Arabian Peninsula as a function of a suite of biotic and abiotic landscape features using machine learning methods. Intermittent wetland, wild Bovidae species richness and sheep density were associated with increased landscape suitability to RVF outbreaks. These results suggest the role of wildlife hosts and distinct hydrogeographic landscapes in RVF virus circulation and subsequent outbreaks may be underestimated. These results await validation by studies employing a deeper, field-based interrogation of potential wildlife hosts within high risk taxa.


Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat.
We examined the temporal relationship between portacaval anastomosis (PCA), weight gain, changes in skeletal muscle mass and molecular markers of protein synthesis, protein breakdown, and satellite cell proliferation and differentiation. Male Sprague-Dawley rats with end to side PCA (n=24) were compared with sham-operated pair-fed rats (n=24). Whole body weight, lean body mass, and forelimb grip strength were determined at weekly intervals. The skeletal muscle expression of the ubiquitin proteasome system, myostatin, its receptor (the activin 2B receptor) and its signal, cyclin-dependent kinase inhibitor (CDKI) p21, insulin-like growth factor (IGF)-I and its receptor (IGF-I receptor-alpha), and markers of satellite cell proliferation and differentiation were quantified. PCA rats did not gain body weight and had lower lean body mass, forelimb grip strength, and gastrocnemius muscle weight. The skeletal muscle expression of the mRNA of ubiquitin proteasome components was higher in PCA rats in the first 2 wk followed by a lower expression in the subsequent 2 wk (P<0.01). The mRNA and protein of myostatin, activin 2B receptor, and CDKI p21 were higher, whereas IGF-I and its receptor as well as markers of satellite cell function (proliferating nuclear cell antigen, myoD, myf5, and myogenin) were lower at weeks 3 and 4 following PCA (P < 0.05). We conclude that PCA resulted in uninhibited proteolysis in the initial 2 wk. This was followed by an adaptive response in the later 2 wk consisting of an increased expression of myostatin that may have contributed to reduced muscle protein synthesis, impaired satellite cell function, and lower skeletal muscle mass.


Experimental and DFT studies on competitive heterocyclic rearrangements. Part 2: a one-atom side-chain versus the classic three-atom side-chain (Boulton-Katritzky) ring rearrangement of 3-acylamino-1,2,4-oxadiazoles.
The experimental investigation of the base-catalyzed rearrangements of 3-acylamino-1,2,4-oxadiazoles evidenced a new reaction pathway which competes with the well-known ring-degenerate Boulton-Katritzky rearrangement (BKR). The new reaction consists of a one-atom side-chain rearrangement that is base-activated, occurs at a higher temperature than the BKR, and irreversibly leads to the corresponding 2-acylamino-1,3,4-oxadiazoles. An extensive DFT study is reported to elucidate the proposed reaction mechanism and to compare the three possible inherent routes: (i) the reversible three-atom side-chain ring-degenerate BKR, (ii) the ring contraction-ring expansion route (RCRE), and (iii) the one-atom side-chain rearrangement. The results of the computational investigation point out that the latter route is kinetically preferred over the RCRE and can be considered as the ground-state analogue of a previously proposed C(3)-N(2) migration-nucleophilic attack-cyclization (MNAC) photochemically activated pathway. The MNAC consists of the formation of a diazirine intermediate, involving the exocyclic nitrogen, that eventually evolves into a carbodiimide intermediate (migration); the latter undergoes a single intramolecular nucleophilic attack-cyclization step leading to the final 2-acylamino-1,3,4-oxadiazole.


Raoultella planticola bacteremia following consumption of seafood.
Raoultella planticola is a Gram-negative bacillus commonly found in water, soil and aquatic environments. There have only been 16 cases of R planticola infection documented in the literature to date. R planticola possesses the ability to convert histidine to histamine and can produce symptoms of scombroid poisoning when poorly prepared seafood is consumed in large amounts. The present report describes a case involving a 56-year-old woman who presented with R planticola bacteremia and symptoms consistent with cholangitis four days after consuming a seafood salad containing squid and octopus. She was successfully treated with intravenous ceftriaxone followed by oral ciprofloxacin. Recent chemotherapy, proton pump inhibitor use and altered biliary flow secondary to hepatic metastases may have been contributing factors to the pathogenesis of disease.


Vivid and Fully Saturated Blue Light-Emitting Diodes Based on Ligand-Modified Halide Perovskite Nanocrystals.
CsPbX3 (X = I, Br, Cl) perovskite nanocrystals (NCs) have recently emerged as emitting materials for optoelectronic and display applications owing to their easily tunable emissions, high photoluminescence quantum yield (PLQY), and vivid color purity (full width at half maximum of approximately 20 nm). However, the lagging quantum yields of blue-emitting perovskite NCs have resulted in low efficiency compared to green or red perovskite light-emitting diodes (PeLEDs); moreover, the long insulating ligands (such as oleylamine and oleic acid) inhibit charge carrier injection. In this study, we demonstrated a facile ligand-mediated post-treatment (LMPT) method for high-quality perovskite NCs with changing optical properties to allow fine-tuning of the target emission wavelength. This method involves the use of a mixed halide ion-pair ligand, di-dodecyl dimethyl ammonium bromide, and chloride, which can induce a reconstruction through a self-anion exchange. Using the LMPT method, the PLQY of the surface-passivated blue-emitting NCs was dramatically enhanced to over 70% within the 485 nm blue emission region and 50% within the 467 nm deep-blue emission region. Through this treatment, we achieved highly efficient blue-PeLED maximum external quantum efficiencies of 0.44 and 0.86% within the 470 and 480 ± 2 nm electroluminescence emission regions, respectively.


Lipid peroxidation, tissue necrosis, and metabolic and mechanical recovery of isolated reperfused rat heart as a function of increasing ischemia.
Isolated Langendorff-perfused rat hearts, after 30 min of preperfusion, were submitted to increasing times of global normothermic ischemia (1, 2, 5, 10, 20 and 30 min) or to the same times of ischemia followed by 30 min of reperfusion. Analysis of malondialdehyde, ascorbic acid, oxypurines, nucleosides, nicotinic coenzymes and high-energy phosphates was carried out by HPLC on neutralized perchloric acid extracts of freeze-clamped tissues. In addition, maximum rate of intraventricular pressure development and cardiac output of malondialdehyde, lactate dehydrogenase, oxypurines and nucleosides were monitored during both preperfusion and reperfusion. Besides decreasing energy metabolites and nicotinic coenzyme pool, prolonged ischemia produced oxidation of significant amounts of hypoxanthine and xanthine to uric acid and generation of detectable levels of malondialdehyde (0.002 micromol/g dry weight). After oxygen and substrate readmission, tissue and perfusate malondialdehyde increased only if previous ischemia was longer than 5 min, while lactate dehydrogenase was detected in perfusate of reperfused hearts following 10, 20, and 30 min of ischemia. Highest values of tissue malondialdehyde and total malondialdehyde output were recorded in reperfused hearts subjected to 30 min of ischemia (0.043 micromol/g dry weight and 0.069 micromol/30 min/g dry weight, respectively). Since tissue malondialdehyde was observed without detectable lactate dehydrogenase release in perfusate, it might be stated that malondialdehyde generation (i.e., lipid peroxidation) temporally preceded lactate dehydrogenase release (i.e., tissue necrosis). In reperfused hearts, evaluation of myocardial energy state and of mechanical recovery allowed us to determine times of ischemia beyond which reperfusion did not positively affect these metabolic and functional parameters. Main findings are that, under these experimental conditions, lipid peroxidation might be the cause and not the consequence of tissue necrosis and that duration of ischemia might be the factor deciding effectiveness of reperfusion.


Gene content and diversity of the loci encoding biosynthesis of capsular polysaccharides of the 15 serovar reference strains of Haemophilus parasuis.
Haemophilus parasuis is the causative agent of Glässer's disease, a systemic disease of pigs, and is also associated with pneumonia. H. parasuis can be classified into 15 different serovars. Here we report, from the 15 serotyping reference strains, the DNA sequences of the loci containing genes for the biosynthesis of the group 1 capsular polysaccharides, which are potential virulence factors of this bacterium. We contend that these loci contain genes for polysaccharide capsule structures, and not a lipopolysaccharide O antigen, supported by the fact that they contain genes such as wza, wzb, and wzc, which are associated with the export of polysaccharide capsules in the current capsule classification system. A conserved region at the 3' end of the locus, containing the wza, ptp, wzs, and iscR genes, is consistent with the characteristic export region 1 of the model group 1 capsule locus. A potential serovar-specific region (region 2) has been found by comparing the predicted coding sequences (CDSs) in all 15 loci for synteny and homology. The region is unique to each reference strain with the exception of those in serovars 5 and 12, which are identical in terms of gene content. The identification and characterization of this locus among the 15 serovars is the first step in understanding the genetic, molecular, and structural bases of serovar specificity in this poorly studied but important pathogen and opens up the possibility of developing an improved molecular serotyping system, which would greatly assist diagnosis and control of Glässer's disease.


The time trends of cognitive impairment incidence among older Chinese people in the community: based on the CLHLS cohorts from 1998 to 2014.
to examine a 16-year trend in cognitive impairment (CI) incidence and associated factors among older Chinese people. aged 60 and above whose cognitive function were normal at their first test. a secondary analysis that identified subjects from the database of Chinese Longitudinal Healthy Longevity Survey (CLHLS). The database contained mixed longitudinal cohorts of older Chinese people surveyed in 1998, 2000, 2002, 2005, 2008-09, 2011-12 and 2014. The cognitive function of subjects was tested using the Chinese Mini-Mental State Examination (CMMSE) in each wave. The unique individual code identified a mixed cohort of 17,896 subjects who had multiple CMMSE measures over a 16-year period and available covariates for the analysis. CI was defined as the CMMSE score below 18 points. Crude and age-standardised incidence of CI by gender were calculated by year of survey. Risk factor adjusted time trends in the incidence were examined using multilevel regression models. age-standardised CI incidence decreased from 58.77‰ to 10.09‰ (P < 0.001) from 1998 to 2014, and this decrease remained after adjusting for covariates. About 15.8% in the observed decline was explained by higher education, and 7.9% was due to health practice (regular exercise, physical activity and cognitive activity), beyond age and gender effects. the CI incidence among older Chinese people decreased from 1998 to 2014. Lower education level and less frequent health practices mentioned above were important risk factors in CI prevention.


Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study.
The long-term respiratory sequelae of infants born extremely preterm (EP) and now graduating from neonatal intensive care remains uncertain. To assess the degree of respiratory morbidity and functional impairment at 11 years in children born EP (i.e., at or less than 25 completed weeks of gestation) in relation to neonatal determinants and current clinical status. Pre- and postbronchodilator spirometry were undertaken at school in children born EP and classroom control subjects. Physical examination and respiratory health questionnaires were completed. Multivariable regression was used to estimate the predictive power of potential determinants of lung function. Spirometry was obtained in 182 of 219 children born EP (129 with prior bronchopulmonary dysplasia [BPD]) and 161 of 169 classmates, matched for age, sex, and ethnic group. Children born EP had significantly more chest deformities and respiratory symptoms than classmates, with twice as many (25 vs. 13%; P < 0.01) having a current diagnosis of asthma. Baseline spirometry was significantly reduced (P < 0.001) and bronchodilator responsiveness was increased in those born EP, the changes being most marked in those with prior BPD. EP birth, BPD, current symptoms, and treatment with beta-agonists are each associated independently with lung function z-scores (adjusted for age, sex, and height) at 11 years. Fifty-six percent of children born EP had abnormal baseline spirometry and 27% had a positive bronchodilator response, but less than half of those with impaired lung function were receiving any medication. After extremely preterm birth, impaired lung function and increased respiratory morbidity persist into middle childhood, especially among those with BPD. Many of these children may not be receiving appropriate treatment.


[Primary coblat therapy and secondary surgery for supra-glottal carcinoma (author's transl)].
This statistical study concerned 218 carcinomas of the laryngeal vestibule and margin treated at the Curie Foundation between 1958 and 1967, by primary cobalt therapy followed when necessary by secondary total laryngectomy. It shows that cobalt therapy alone gives excellent results in early forms (T1 and T2) even in the presence of N1 or N2 nodes. By contrast, the proportion of cures is much lower in T3 and T4 forms. Secondary total laryngectomy was used in only 25 cases out of 127 failures. The postoperative course was often difficult (4 fatal complications and 3 pharyngostomies) but 7 of the patients were cured at 5 years. The use of a surgical technique with minimal trauma and in particular respecting the integrity of the carotid gutters has been associated, in a more recent series, with a notable improvement in the results obtained (one cure out of 2 at 3 years).


Cell proliferation and apoptosis in the fusion of human primary and secondary palates.
The markers of cell proliferation (Ki-67) and apoptosis [caspase-3, TdT-mediated biotin-dUTP nick-end labelling (TUNEL)] and the expression of syndecan-1 and heat shock protein 70 (Hsp70) were analyzed immunohistochemically in 11 developing human palates, from developmental weeks 6 to 10. During fusion of the primary palate, the proportion of proliferating cells decreased from 42 to 32% and the proportion of apoptotic cells decreased from 11 to 7% in the medial-edge epithelium. At later stages, the proportions of both types of cells decreased in the ectomesenchyme, except for proliferating cells in its non-condensing part. At developmental weeks 9-10, the epithelial seam in the secondary palate comprised 28% proliferative cells and 5% apoptotic cells. While condensing ectomesenchyme contained more apoptotic cells than proliferating cells, the opposite was observed for the non-condensing ectomesenchyme. Co-expression of syndecan-1 and Hsp70 was detected in cells budding from the epithelial seam. Our study indicates similar principles for human primary palate and secondary palate fusion, and parallel persistence of proliferation and apoptotic activity. While proliferation enables growth and fusion of different palatal primordia, apoptosis results in the removal of of large numbers epithelial cells at the fusion point. The disintegration of seam remnants seems to be executed through the processes of change in protein content and cell migration, probably leading to cell death as their final outcome.


Paranoia--an unusual presentation of hydrocephalus.
Hydrocephalus commonly occurs after traumatic brain injury. Normal pressure hydrocephalus after traumatic brain injury is usually associated with a failure to progress in therapy and a plateauing or regression of functional abilities. Behavior disturbances are commonly seen as unfortunate sequelae of traumatic brain injury. However, normal pressure hydrocephalus has not been reported to cause aberrant, antisocial behavior. This case report details the course of a patient who sustained a traumatic brain injury and, subsequently, developed normal pressure hydrocephalus associated with paranoia, delusions, and violent behavior.


Sleep patterns and obesity in childhood.
To highlight the recent findings on sleep-obesity associations in children. We focus on sleep duration, sleep timing and chronotype, and describe the potential mechanisms underlying sleep-obesity associations. Poor sleep is increasingly common in children and associations between short sleep duration in early childhood and obesity are consistently found. Less is known about the infancy period, and the findings in adolescents are inconsistent. Sleep timing patterns may also contribute to obesity risk. Variable and shifted sleep schedules and evening chronotypes have recently been linked to adiposity in adults; less is known about children. Further, there is little understanding regarding the mechanisms of association. The timing of eating, dietary intake, obesogenic eating behaviors, and changes in appetite-regulating hormones have been identified as possible mechanisms for sleep-obesity associations and may be promising avenues for future research. Longitudinal and experimental work with children is needed to determine the nature of associations. Beyond sleep duration, sleep timing patterns may contribute to obesity risk. Biological and behavioral processes have been proposed as mechanisms that may explain the association. Understanding the pathways through which poor sleep patterns could increase obesity risk in children may provide novel avenues for intervention.


The Relationship Between Household Microfinance Group Participation and Vaccine Adherence Among Children in Rural Western Kenya.
High childhood vaccine adherence is critical for disease prevention, and poverty is a key barrier to vaccine uptake. Interventions like microfinance programs that aim to lift individuals out of poverty could thus improve vaccine adherence of the children in the household. BIGPIC Family Program in rural Western Kenya provides group-based microfinance services while working to improve access to healthcare and health screenings for the local community. The aim of the present paper is to evaluate the association between household participation in BIGPIC's microfinance program and vaccine adherence among children in the household. We hypothesize that microfinance group participation will have a positive impact on vaccine adherence among children in the household. From 2018 to 2019, we surveyed a sample of 300 participants from two rural communities in Western Kenya, some of whom were participants in the BIGPIC Family's microfinance program. The primary outcome of interest was vaccine adherence of children in the household. Log-binomial models were used to estimate the relationship between microfinance group participation and vaccine adherence, adjusted for key covariates. We also assessed whether the relationship differed by gender of the adult respondent. Microfinance group members were more likely to have all children in their households fully vaccinated [aPR (95% CI): 1.68 (1.20,2.35)] compared to non-microfinance group members. Further, the association was stronger when women were the microfinance members [PR (95% CI): 1.87 (1.27,2.76)] compared to men [PR (95% CI): 1.24 (0.81,1.90)]. Microfinance participation was associated with higher childhood vaccine adherence in rural Western Kenya. Microfinance interventions should be further explored as strategies to improve child health and well-being in low- and middle-income countries.


Adherence to oral therapies among patients with renal cell carcinoma: Post hoc analysis of the ECOG-ACRIN E2805 trial.
As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non-adherence. ECOG-ACRIN E2805 was a double-blind, placebo-controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient-completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log-binomial regression was used to identify correlates of non-adherence (<80% of prescribed pills reported as taken). Mean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non-adherence was associated with race/ethnicity (non-Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80). Among patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase. This trial is registered with ClinicalTrials.gov, number NCT00326898.


Enhanced presynaptic mitochondrial energy production is required for memory formation.
Some of the prominent features of long-term memory formation include protein synthesis, gene expression, enhanced neurotransmitter release, increased excitability, and formation of new synapses. As these processes are critically dependent on mitochondrial function, we hypothesized that increased mitochondrial respiration and dynamics would play a prominent role in memory formation. To address this possibility, we measured mitochondrial oxygen consumption (OCR) in hippocampal tissue punches from trained and untrained animals. Our results show that context fear training significantly increased basal, ATP synthesis-linked, and maximal OCR in the Shaffer collateral-CA1 synaptic region, but not in the CA1 cell body layer. These changes were recapitulated in synaptosomes isolated from the hippocampi of fear-trained animals. As dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, we examined its role in the increased mitochondrial respiration observed after fear training. Drp1 inhibitors decreased the training-associated enhancement of OCR and impaired contextual fear memory, but did not alter the number of synaptosomes containing mitochondria. Taken together, our results show context fear training increases presynaptic mitochondria respiration, and that Drp-1 mediated enhanced energy production in CA1 pre-synaptic terminals is necessary for context fear memory that does not result from an increase in the number of synaptosomes containing mitochondria or an increase in mitochondrial mass within the synaptic layer.


Protease 2A induces stress granule formation during coxsackievirus B3 and enterovirus 71 infections.
Stress granules (SGs) are granular aggregates in the cytoplasm that are formed under a variety of stress situations including viral infection. Previous studies indicate that poliovirus, a member of Picornaviridae, can induce SG formation. However, the exact mechanism by which the picornaviruses induce SG formation is unknown. The localization of SG markers in cells infected with coxsackievirus B3 (CVB3) or enterovirus 71 (EV71) and in cells expressing each viral protein was determined via immunofluorescence assays or plasmid transfection. Eight plasmids expressing mutants of the 2A protease (2A(pro)) of CVB3 were generated using a site-directed mutagenesis strategy. The cleavage efficiencies of eIF4G by CVB3 2A(pro) and its mutants were determined via western blotting assays. In this study, we found that CVB3 infection induced SG formation, as evidenced by the co-localization of some accepted SG markers in viral infection-induced granules. Furthermore, we identified that 2A(pro) of CVB3 was the key viral component that triggered SG formation. A 2A(pro) mutant with the G122E mutation, which exhibited very low cleavage efficiency toward eIF4G, significantly attenuated its capacity for SG induction, indicating that the protease activity was required for 2A(pro) to initiate SG formation. Finally, we observed that SGs also formed in EV71-infected cells. Expression of EV71 2A(pro) alone was also sufficient to cause SG formation. Both CVB3 and EV71 infections can induce SG formation, and 2A(pro) plays a crucial role in the induction of SG formation during these infections. This finding may help us to better understand how picornaviruses initiate the SG response.


Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity.
We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with Ki constants ranging from 9.4 μM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional π-π interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases.


The prevalence of depression among parents of children/adolescents with type 1 diabetes: A systematic review and meta-analysis.
Emerging research indicates that depression among parents of children/adolescents with type 1 diabetes mellitus (T1DM) has increased significantly. However, the prevalence rates reported by different studies vary substantially. Seven databases were systematically searched (Pubmed, Embase, MEDLINE, Scopus, Web of Science, Cochrane Library, PsycInfo) from the inception to 15th October 2022. We pooled prevalence rates from each study with a random-effect model. We conducted a stratified meta-analysis to identify the potential sources of heterogeneity among studies. The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was utilized to evaluate the quality of evidence. Twenty-two studies were included, with a total of 4639 parents living with type 1 diabetic children. Overall, the pooled prevalence rate of depression or depressive symptoms was 22.4% (95%CI 17.2% to 28.7%; I 2 = 96.8%). The prevalence was higher among mothers (31.5%) than fathers (16.3%) as well as parents of children (aged < 12 years) with T1DM (32.3%) than those with adolescents (aged ≥ 12 years) (16.0%). Our research suggests that more than 1 in 5 parents of type 1 diabetic children/adolescents worldwide suffer from depression or depressive symptom. Depression screening and interventions are required for parents of children with T1DM. https://www.crd.york.ac.uk/prospero/, identifier (CRD42022368702).


Human T cells expressing BEND3 on their surface represent a novel subpopulation that preferentially produces IL-6 and IL-8.
BEN domain-containing protein 3 (BEND3) has no transmembrane region, is localized in the cytoplasm, and is involved in chromatin function and transcription. We here identified a novel subpopulation of human T cells that expressed BEND3 on their cell surface (BEND3(+) T cells). BEND3(+) T cells consisted of approximately 3% of T cells in the peripheral blood, were present in both CD4(+) and CD8(+) T cells, and were also observed in cord blood. The stimulation of BEND3(+) T cells through the TCR/CD3 complex led to the production of various kinds of cytokines; however, the levels of IL-6 and IL-8 produced by BEND3(+) T cells were higher than those by BEND3(-) T cells. The proportion of BEND3(+) T cells was also increased in some patients with inflammatory diseases. Taken together, these results indicate that BEND3(+) T cells are a new subpopulation of T cells in terms of their cytokine profile. Further analyses on BEND3(+) T cells may be of importance and useful in understanding human T cell immunology.


Treatment of Dientamoeba fragilis infection with paromomycin.
Treatment with paromomycin (25-35 mg/kg/d for 7 days) was evaluated prospectively in 15 children with Dientamoeba fragilis infection after 1-month follow-up. At the end of the study, parasitologic effectiveness and clinical improvement were observed in 12/15 (80%) and 13/15 (87%) patients, respectively. Paromomycin appears to be an effective drug for treatment of D. fragilis infection in children.


Serum levels of tumor necrosis factor-alpha in patients with psoriasis before, during and after narrow-band UVB phototherapy.
Narrow-band UVB (NB-UVB) phototherapy is widely used worldwide for moderate and severe psoriasis, which is a chronic autoimmune inflammatory disease characterized by skin infiltrates of Th1-, Th17- and Th22-cells releasing locally pro-inflammatory cytokines. We investigate serum levels of tumor necrosis factor-α (TNF-α) in psoriatic patients before and after NB-UVB phototherapy. Twenty-eight subjects with moderate/severe plaque type psoriasis were enrolled. The severity of skin involvement was rated according to the Psoriasis Area and Severity Index (PASI) score at baseline (T0) and after 4 (T1) and 12 (T2) weeks of NB-UVB treatment. At the same time points, blood samples were taken for evaluation of TNF-α levels. NB-UVB phototherapy was administered twice weekly on non-consecutive days until 12 weeks. The median PASI score significantly decreased from 12.0 at baseline (T0), to 6.9 after 4 weeks (T1, P<0.001) and to 0 after 12 weeks (T2, P<0.001). TNF-a serum levels significantly increased in respect to the baseline after 12 weeks of therapy. NB-UVB phototherapy is highly effective against psoriasis but, as it increases the TNF-α serum level, it seems unlikely that it can decrease the chronic inflammatory state that is thought to be responsible of the systemic co-morbidities of psoriasis.


Insulin: A connection between pancreatic β cells and the hypothalamus.
Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.


Division of labour in the black garden ant (Lasius niger) leads to three distinct proteomes.
Task specialization in social insects leads to striking intra-specific differences in behaviour, morphology, physiology and longevity, but the underlying mechanisms remain not yet fully understood. Adult colonies of black garden ants (Lasius niger) have a single queen fertilized by one or a small number of males. The inter-individual genetic variability is thus relatively low, making it easier to focus on the individual molecular differences linked to the division of labour. Mass spectrometry-based proteomics enabled us to highlight which biological functions create the difference between queens, foragers and nest-workers. The proteome of each caste reflected nicely their social role: e.g., reproduction for queens, pesticide resistance for foragers - that are the most exposed to environmental risk factors - and, interestingly, digestion for nest-workers, thus highlighting proteomic profiles differences even among workers. Furthermore, our exploratory approach suggests energy trade-off mechanisms - in connection with the theory of social immunity - that might explain the difference in longevity between queens and workers. This study brings evidence that proteomics is able to highlight the subtle mechanisms of molecular regulation induced by social organization.


Thalidomide-induced Stroke in a Child With Thalassemia Major.
β-thalassemia major is a hereditary anemia resulting from defects in β-globin production. It is also characterized by a hypercoagulable state with an increased risk of thrombosis. Thalidomide, a drug known for its immunomodulating and antiangiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells. An increasing incidence of thromboembolic events in thalidomide-treated patients has been reported. This is often in the context of thalidomide combinations with other drugs, including steroids and particularly anthracycline-based chemotherapy, and with very low incidence of thrombosis with single-agent thalidomide treatment. We report a case of stroke in a β-thalassemic child who had received a course of thalidomide.


A Diagnostic Conundrum: Ectopic Nasal Ossification, Submucosal Alveolar Cleft, Absent Posterior Atlantal Arch, and Corpus Callosum Lipoma.
A 19-year-old woman was referred for nasal breathing and aesthetic concerns regarding her nose. A computed tomography scan revealed a massive osseous shield anterior to the piriform aperture. Furthermore, there was a submucosal median alveolar cleft, and the posterior arch of C1 was missing. The magnetic resonance imaging brain scan revealed a curvilinear lipoma of corpus callosum. The ectopic nasal bone was removed by open rhinoplast,y and nasal function and aesthetics were restored. The described features defy conventional clinical diagnosis and severity classifications and present a diagnostic conundrum somewhere between a mild form of frontonasal dysplasia, oculoauriculofrontonasal syndrome, and Pai syndrome.


Luminal polyamines stimulate repair of gastric mucosal stress ulcers.
The purpose of this study was to examine whether luminal polyamines can substitute for tissue polyamines in the healing process of gastric mucosal stress ulcers. Rats were fasted 22 h, placed in restraint cages, and immersed in water to the xiphoid process for 6 h. Animals were killed either immediately or at 4, 12, or 24 h after the period of stress. Stress significantly increased ornithine decarboxylase (ODC) activity and tissue polyamine content. Mucosal polyamine levels peaked 4 h after stress and remained significantly elevated for 12 h. The healing process, which was significant by 12 h, was inhibited by DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC. DFMO totally prevented the marked increases in ODC and polyamine levels that usually followed stress. Oral administration of polyamines, putrescine, cadaverine, spermidine, or spermine, immediately after stress increased the normal rate of healing and prevented the inhibition of repair caused by DFMO. Spermidine or spermine accelerated healing better than putrescine or cadaverine. The delayed recovery of mucosal DNA, RNA, and protein content after stress in the DFMO-treated rats was also significantly prevented by exogenous polyamines. The reduced amounts of gastric mucosal spermidine and spermine in rats treated with DFMO returned toward control levels after administration of exogenous spermidine (100 mg/kg). These results show that 1) increased levels of polyamines provided by ODC are absolutely required for normal healing of gastric mucosal stress ulcers, 2) the polyamines are active from the luminal side, and 3) polyamines accelerate healing at least partly through a mechanism involving cell renewal.