Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine.
Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated. The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice. We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals. Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.


Two-component hearing sensations produced by two-electrode stimulation in the cochlea of a deaf patient.
Dissimilarities in perception elicited by stimulation with two electrodes were estimated. A two-dimensional spatial configuration was found to be suitable to represent the dissimilarity data, and the two dimensions could be interpreted as corresponding to the position of the apical and basal electrode of the two-electrode combination. A speech-processing strategy that converts acoustic, first and second formants to two-electrode stimulation is proposed.


Metastatic acral melanoma treatment outcomes: a systematic review and meta-analysis.
Acral melanomas are a unique subset of melanomas occurring on the palms, soles, and nails. There is poor prognosis with surgery alone and no specific guidelines for the treatment of metastatic acral melanoma. This meta-analysis explored the systemic therapy outcomes for metastatic acral melanoma. Medline, Pubmed, EMBASE, and the grey literature were searched from 2010 to August 2020 for studies specifying the treatment outcome of metastatic acral melanoma. Studies were assessed by two investigators. A random-effects meta-analysis was performed and pooled Kaplan-Meier curves for progression-free survival and overall survival were created. Critical appraisal was performed using the Newcastle-Ottawa Scale. Nineteen nonrandomized studies were included, comprising 646 patients with acral melanomas and 1609 patients with nonacral melanomas treated with systemic therapy including chemotherapy, KIT-targeted drugs, as well as anti-CTLA-4 and anti-PD-1 checkpoint inhibitor therapy. Thirteen studies included Kaplan-Meier curves for progression-free survival or overall survival and 11 studies reported treatment responses. Patients with acral melanomas had worse prognosis than nonacral cutaneous melanoma (acral overall survival: median 15 months, 95% CI, 13.7-16.3 months; nonacral cutaneous: median 24 months, 95% CI, 22.6-25.4 months, P < 0.001). Acral melanoma patients treated with anti-PD-1 monotherapy had higher overall survival at 12 months (53%) compared with anti-CTLA-4 monotherapy (34%; P < 0.001). This study provides estimates of treatment response for metastatic acral melanoma, demonstrating low activity across a breadth of approved drug therapies, including anti-PD-1, the most active therapy in melanoma to date. Further research into treatments for metastatic acral melanoma is needed.


Randomized phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules.
Screening CT identifies small peripheral lung nodules, some of which may be pre- or early invasive neoplasia. Secondary end point analysis of a previous chemoprevention trial in individuals with bronchial dysplasia showed reduction in size of peripheral nodules by inhaled budesonide. We performed a randomized, double-blind, placebo-controlled phase IIb trial of inhaled budesonide in current and former smokers with CT-detected lung nodules that were persistent for at least 1 year. A total of 202 individuals received inhaled budesonide, 800 μg twice daily or placebo for 1 year. The primary endpoint was the effect of treatment on target nodule size in a per person analysis after 1 year. The per person analysis showed no significant difference between the budesonide and placebo arms (response rate 2% and 1%, respectively). Although the per lesion analysis revealed a significant effect of budesonide on regression of existing target nodules (P = 0.02), the appearance of new lesions was similar in both groups and thus the significance was lost in the analysis of all lesions. The evaluation by nodule type revealed a nonsignificant trend toward regression of nonsolid and partially solid lesions after budesonide treatment. Budesonide was well tolerated, with no unexpected side effects identified. Treatment with inhaled budesonide for 1 year did not significantly affect peripheral lung nodule size. There was a trend toward regression of nonsolid and partially solid nodules after budesonide treatment. Because a subset of these nodules is more likely to represent precursors of adenocarcinoma, additional follow-up is needed.


Habitus and climate change: Exploring support and resistance to sustainable welfare and social-ecological transformations in Sweden.
We explore peoples' dispositions and practices with regard to social-ecological transformations based on a sustainable welfare policy strategy in Sweden. We draw on Bourdieu's concept of habitus to highlight the relations between social positions, dispositions, and position-takings. Using data from an own survey, we identify habitus types and place these in the space of social positions. We apply principal component analysis to a large set of questions about social, ecological, and climate change related topics and identify eight underlying eco-social dispositions. These are used for cluster analyses that find typical constellations of eco-social dispositions within the Swedish population: variants of eco-social habitus. We find seven habitus types and describe their social characteristics, political preferences, and practices. Finally, the seven habitus are plotted onto the map of social positions, the Bourdieusian social space, highlighting their relations-proximities, tensions, and contestations-to each other. We find evidence that political struggles around social-ecological transformations reproduce existing social structures but are also connected to new "eco-social" divisions that appear between groups in similar positions. In the conclusion we discuss the implications for social-ecological transformations based on sustainable welfare.


Targeted mutagenesis of duplicated genes in soybean with zinc-finger nucleases.
We performed targeted mutagenesis of a transgene and nine endogenous soybean (Glycine max) genes using zinc-finger nucleases (ZFNs). A suite of ZFNs were engineered by the recently described context-dependent assembly platform--a rapid, open-source method for generating zinc-finger arrays. Specific ZFNs targeting dicer-like (DCL) genes and other genes involved in RNA silencing were cloned into a vector under an estrogen-inducible promoter. A hairy-root transformation system was employed to investigate the efficiency of ZFN mutagenesis at each target locus. Transgenic roots exhibited somatic mutations localized at the ZFN target sites for seven out of nine targeted genes. We next introduced a ZFN into soybean via whole-plant transformation and generated independent mutations in the paralogous genes DCL4a and DCL4b. The dcl4b mutation showed efficient heritable transmission of the ZFN-induced mutation in the subsequent generation. These findings indicate that ZFN-based mutagenesis provides an efficient method for making mutations in duplicate genes that are otherwise difficult to study due to redundancy. We also developed a publicly accessible Web-based tool to identify sites suitable for engineering context-dependent assembly ZFNs in the soybean genome.


Death receptor 5 promotes tumor progression in gastric cancer.
Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor stemness. Unlike death receptor 4 (DR4TRAIL-R1), DR5 was expressed in the cytoplasm and nucleus, and was found to be positively correlated with lymphovascular invasion, lymph node metastasis, and TNM stage. Patients with positive DR5 had worse overall survival (OS) (P = 0.006). The multivariate Cox model showed that DR5 is an independent poor prognostic factor (hazard ratio = 1.693). Furthermore, knockdown of DR5 inhibited aggressive behaviors, including proliferation and metastasis in gastric cancer cells, and inhibited lung metastasis in vivo. In summary, nuclear localization of DR5 expression is a poor prognosis factor in gastric cancer and promotes growth, invasion, and metastasis of tumor cells in vitro and in vivo.


Effective gaussian mixture learning for video background subtraction.
Adaptive Gaussian mixtures have been used for modeling nonstationary temporal distributions of pixels in video surveillance applications. However, a common problem for this approach is balancing between model convergence speed and stability. This paper proposes an effective scheme to improve the convergence rate without compromising model stability. This is achieved by replacing the global, static retention factor with an adaptive learning rate calculated for each Gaussian at every frame. Significant improvements are shown on both synthetic and real video data. Incorporating this algorithm into a statistical framework for background subtraction leads to an improved segmentation performance compared to a standard method.


Use of mass isotopomer distributions in secreted lipids to sample lipogenic acetyl-CoA pool in vivo in humans.
Measurement of hepatic fatty acid (FA) and cholesterol synthesis has been limited by lack of access to the precursor pool, cytosolic acetyl-CoA. We present a method for inferring the enrichment of the true hepatic lipogenic precursor pool in humans using the frequency distribution of mass isotopomers within enriched circulating polymers of acetyl-CoA [very low-density lipoprotein (VLDL)-palmitate, VLDL-stearate]. Human subjects were infused intravenously (n = 16) with [1-13C]- or [2-13C]acetate. Oral sulfamethoxazole (SMX) was administered concurrently, and the acetylated conjugate (SMX acetate) was used to estimate independently the hepatic cytosolic acetyl-CoA enrichment. Isotopomer frequencies in VLDL-FA were determined by gas chromatography-mass spectrometry, whereas high-performance liquid chromatography-mass spectrometry was used to measure enrichments in SMX acetate. Based on the excess M2/excess M1 ratio in VLDL-FA, calculated acetyl-CoA enrichments were 5.59 +/- 0.33 molar percent excess (MPE), whereas SMX acetate enrichments were 5.38 +/- 0.31 MPE (the 2 methods were not significantly different). Mass isotopomer-calculated and SMX acetate-measured estimates of acetyl-CoA enrichments correlated very closely in individual subjects (r2 = 0.93; P less than 0.0001). De novo hepatic lipogenesis can be measured using isotopomer-calculated precursor enrichments compared with measured incorporation in specific isotopomers of VLDL-FA. In summary, excess isotopomer frequencies in secreted lipids provide a non-invasive technique for estimating hepatic cytosolic acetyl-CoA enrichments in humans in vivo and correlate closely with enrichments observed using the xenobiotic probe technique. Isotopomeric distributions represent a new strategy for accurate measurement of macromolecule synthesis that may be applicable to other classes of molecules besides lipids.


Effect of various levels of forage and form of diet on rumen development and growth in calves.
The effect of form of starter grain (coarse vs. ground) and inclusion of various levels of hay on body weight gain and rumen development was evaluated. Two experiments were conducted to determine the effect of form of diet and forage inclusion on intake, growth, feed efficiency, and weaning age in dairy calves. Diets consisted of commercial coarse starter (C), ground starter (G), coarse starter with 7.5% bromegrass hay of consistent particle size (8 to 19 mm) (H1), and coarse starter with 15% hay (H2). In experiment 1, intake was held constant across treatments until weaning, when feed was offered ad libitum. Calves receiving H1 and H2 were heavier and had greater body weight gain and greater feed efficiency than calves receiving C. There were no differences in intake. Total volatile fatty acid concentrations were higher, and the proportion of acetate was lower for calves fed G vs. C. In experiment 2, calves (n = 56) were offered diets on an ad libitum basis and weaned according to intake. There were no differences in body weight gain, average daily gain, feed efficiency, and age at weaning with respect to treatment. Starter and total dry matter intake tended to be greater in calves fed H1 and H2 vs. C. The addition of controlled particle size hay to diets of young calves appears to favorably alter rumen environment, resulting in increased intake and improved feed efficiency. Forage of a consistent particle size can be successfully utilized in starter rations of young calves.


Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity.
Infection of the brain by lentiviruses, including human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus envelope gene has been implicated in the regulation of cell tropism and the host response to infection. Here, we examine the hypothesis that envelope sequence diversity modulates the expression of host molecules implicated in lentivirus-induced brain disease, including matrix metalloproteinases (MMP) and related transcription factors. Infection of primary macrophages by chimeric HIV clones containing brain-derived envelope fragments from patients with HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) showed that MMP-2 and -9 levels in conditioned media were significantly higher for the HAD clones. Similarly, STAT-1 and JAK-1 levels were higher in macrophages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V(1)CSF), the less neurovirulent strain (Petaluma), and a chimera containing the V(1)CSF envelope in a Petaluma background (FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in conditioned media from V(1)CSF- and FIV-Ch-infected macrophages, which was associated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhibitor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expression, in FIV-infected macrophages. Analysis of MMP mRNA and protein levels in brain samples from HIV-infected persons or FIV-infected cats showed that MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression was accompanied by significant increases in STAT-1 and JAK-1 mRNA and protein levels in the same brain samples. The present findings indicate that two lentiviruses, HIV and FIV, have common mechanisms of MMP-2 and -9 induction, which is modulated in part by envelope sequence diversity and the STAT-1/JAK-1 signaling pathway.


[Comprehensive health care: indications from the training of nurses].
This study has the objective of understanding the training of nurses for comprehensive health care. It used data from interviews with teachers, students and service nurses submitted to discourse analysis. There is an understanding of comprehensive care in the training of nurses from the perspective of establishing a healthcare model in which care is directed to the patient. There are reflections regarding the technologies and the form of organization of the work, expressed in a permanent tension: Clinical versus Collective Health as a challenge for comprehensive care. It was identified that building completeness in the formation implies assuming acting in health as an educative principle in a new form of learning-teaching in health, which breaks up with pre-formed, out-of-context knowledge. The conclusion is that comprehensive health care is taken as an object of reflection in the movement for change in the pedagogical practices, and that it is reflected in health attention.


Correcting non-photochemical quenching of Saildrone chlorophyll-a fluorescence for evaluation of satellite ocean color retrievals.
In vivo chlorophyll fluorescence (ChlF) can serve as a reasonable estimator of in situ phytoplankton biomass with the benefits of efficiently and affordably extending the global chlorophyll (Chl) data set in time and space to remote oceanic regions where routine sampling by other vessels is uncommon. However, in vivo ChlF measurements require correction for known, spurious biases relative to other measures of Chl concentration, including satellite ocean color retrievals. Spurious biases affecting in vivo ChlF measurements include biofouling, colored dissolved organic matter (CDOM) fluorescence, calibration offsets, and non-photochemical quenching (NPQ). A more evenly distributed global sampling of in vivo ChlF would provide additional confidence in estimates of uncertainty for satellite ocean color retrievals. A Saildrone semi-autonomous, ocean-going, solar- and wind-powered surface drone recently measured a variety of ocean and atmospheric parameters, including ChlF, during a 60-day deployment in mid-2018 in the California Current region. Correcting the Saildrone ChlF data for known biases, including deriving an NPQ-correction, greatly improved the agreement between the drone measurements and satellite ocean color retrievals from MODIS-Aqua and VIIRS-SNPP, highlighting that once these considerations are made, Saildrone semi-autonomous surface vehicles are a valuable, emerging data source for ocean and ecosystem monitoring.


Inhibition by dopamine of the neurotransmission in the rat vas deferens.
The effects of alpha-adrenoceptor and dopaminoceptor agonists and antagonists were investigated on presynaptic receptors in the prostatic portion of rat vas deferens. The variable studied was the early component (250 msec) of the motor response elicited by field stimulation (single pulses). All the experiments were carried out in the presence of cocaine 30 mumol/l and hydrocortisone 28 mumol/l so as to block the sites of amines loss and 1-propranolol 0.3 mumol/l to block beta-adrenoceptors. Clonidine, noradrenaline (NA) and dopamine (DA) inhibited the motor response in a concentration-dependent manner. DA was 10 and 10(4) times less potent than NA and clonidine respectively. The selective D2 agonist, LY 141865, failed to inhibit the motor response even at a high concentration (30 mumol/l). Yohimbine (0.1, 0.3 and 1 mumol/l) antagonized competitively the effect of clonidine, NA and DA showing similar - log KB values (7.57; 7.68 and 7.09 respectively). Likewise, idaxozan (0.03 mumol/l) blocked the inhibitory effect of DA in the same order of potency (- log KB = 7.81). On the other hand, pimozide 0.21 mumol/l and Schering 23390 3 mumol/l antagonized the inhibitory effect of DA, showing a lower potency than the other antagonists. Taken together, these findings do not support the hypothesis that DA activates a specific population of prejunctional dopaminoceptors to inhibit the motor response elicited by field stimulation in the presence of cocaine, hydrocortisone and 1-propranolol in the prostatic portion of the rat vas deferens. Instead, the population of prejunctional alpha 2-adrenoceptor may be involved.


[Effect of Harrington instrumentation spondylodesis on scoliotic thoracic deformity. A retrospective 5-year analysis].
Harrington-Instrumentation (HI) was the golden standard of scoliosis surgery for more than two decades and is still frequently used. The effects of instrumentation on rib hump reduction in long term follow-up is not well documented. 104 patients with idiopathic thoracic scoliosis were studied with a minimum follow-up of five years (min. 5 y., max. 8 years). The rib-cage deformity was determined as rib hump index (RHi) by measuring the rib hump to the depression. The long term effect of HI was investigated using full standing AP radiographs. Measuring cobb angle (CA), translation (TA) and rotation of apical vetebra (RA) were obtained for every patient preoperatively, postoperatively and at follow-up. Patient were analysed in 3 different groups. Single curve thoracic scoliosis (n = 54) (King III and IV), double curve thoracic/lumbar scoliosis (n = 35) (King I and II) and double curve thoracic scoliosis (n = 15) (King V). With an average preoperative measurement of 62.7 degrees and a postoperative measurement angle of 32.9 degrees the correction of CA achieved is 47.5% (23-73%). The mean thoracic translation improved by 50% (0-100%). Rotation of the scoliosis was not reduced significant. In follow up studies no loss of correction in frontal plane deformity was obtained. The mean RHi in all groups was seen to improve by 25-30% (min. 0%, max. 60%), depending on form of scoliosis. In group of patients King II/III scoliosis (n = 52) the mean RHi increased measurably to 11.5% (min. 0%, max. 50%) correction at long term follow up. In group of patients King I/II scoliosis average RHi was increased from 31% (5-100%) to 21% correction. The mean RHi correction in the group of patients King V scoliosis correction rate of 26% (0-50%) was unchanged at long term follow up. HI leads to a permanent and stable improvement of the frontal plane including apical vertebral translation. HI does not have derotational capabilities. The effect of the rib-cage deformity was less impressive with loss of correction at follow up.


Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.
With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it was decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR). Systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using 'pioglitazone AND India AND human' and 'pioglitazone AND India AND human AND patient' and compared with EMA-AR. Spontaneous reports in World Health Organization VigiBase from India were compared with VigiBase data from other countries. Sixty six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively. The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non-exposed patients was not significantly different in an Indian retrospective cohort study. There were two cases and a series of eight cases of bladder cancer published but none reported in VigiBase. In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed.


[The system of regulation of aldosterone secretion in old rats].
The experiments performed on mature (4-6) and old (28-30 months) rats revealed changes developed in old animals in various links of regulatory system of aldosterone secretion: the decreased hypothalamohypophyseal control of mineralocorticoid secretion, increased sensitivity of glomerular zone to ACTH, vasopressin, K+ and of myocardium skeletal muscle and renal tissue to aldosterone. Changes in tissue sensitivity to aldosterone may be conditioned by the increased affinity of mineralocorticoid receptors to aldosterone in old age.


[Effect of certain factors on the determination of the biological activity of amphotericin B].
Sensitivity of the test-microbe to amphotericin B was studied. It was shown that composition of the nutrient medium, the innoculum amount and preincubation may significantly change the conditions of determination of the test-microbe sensitivity to amphotericin B and affect the accuracy of the microbiological method of determination of the antibiotic activity. The size of the inhibition growth zones of the test-microbe at amphotericin B concentrations within 0.06 to 1000 gamma/ml were measured. The angle of the dose response curve was the least at amphotericin B concentrations within 0.06 to 1.0 gamma/ml. Therefore, they were most suitable for plotting the standard curves. The population growth character of a number of test-cultures was investigated. A new test-culture, i.e., C. scotti Tul-I was proposed as one being most sensitive to amphotericin B, having prolong lag-phase of the population growth, forming even growth and clear inhibition zones.


Applicability of the 12-Item Short-Form Health Survey in patients with progressive systemic sclerosis.
To evaluate the applicability of the 12-Item Short-Form Health Survey (SF-12) as an instrument to measure health-related quality of life in a sample of patients with progressive systemic sclerosis (PSS) through the analysis of its reproducibility and its correlation with functional and clinical parameters. A test-retest reproducibility study for the comparative analysis of the intraclass correlation coefficients (ICCs) of the SF-12 and the SF-36. A total of 46 patients diagnosed with PSS were studied, regardless of the presence of respiratory symptoms. The physical component summary 12 (PCS-12) score had an ICC of 0.47 (95%CI: 0.05-0.71; p < 0.02), whereas the mental component summary (MCS-12) score had an ICC of 0.72 (95%CI: 0.49-0.84; p < 0.001). The PCS-36 score had an ICC of 0.88 (95%CI: 0.78-0.93; p < 0.001), and the MCS-36 score also had an ICC of 0.88 (95%CI: 0.78-0.93; p < 0.001). The SF-12 is a reliable instrument for measuring health-related quality of life in patients with PSS, since it has been proven to be reproducible. However, this version of the SF-12 should only be used in clinical research settings.


Topical delivery of roxithromycin solid-state forms entrapped in vesicles.
Recently, considerable interest developed in using newer/improved antibiotics for the treatment of Acne vulgaris. During this study, different roxithromycin solid-state forms (i.e. crystalline and amorphous) were encapsulated into vesicle systems (niosomes, proniosomes, ufosomes and pro-ufosomes) for dermis targeted delivery. Characterization of the vesicles was done with transmission electron microscopy, light microscopy, droplet size, droplet size distribution, pH, zeta-potential and entrapment efficiency percentage. Finally, comparative release and topical diffusion studies were performed, to evaluate if targeted topical delivery was obtained and if the roxithromycin solid-state amorphous forms resulted in improved topical delivery. Vesicle systems containing different roxithromycin (2%) solid-state forms were successfully prepared and characterized. The vesicles showed optimal properties for topical delivery. All carrier systems had topical delivery to the epidermis-dermis, whilst no roxithromycin was found in the receptor compartment or stratum corneum-epidermis. The niosomes were the leading formulation and the two amorphous forms had better topical delivery than the crystalline form. Successful targeted delivery of roxithromycin was obtained in the dermis, where the activity against Propionibacterium acnes is needed. The amorphous forms seemed to have held their solid-state form during formulation and in the vesicles, showing improved topical delivery in comparison to the crystalline form.


Daphnia's phototaxis as an indicator in ecotoxicological studies: A review.
Animal-based sensors have been increasingly applied to many water monitoring systems and ecological studies. One of the staple organisms used as living sensors for such systems is Daphnia. This organism has been extensively studied and, with time, used in many toxicological and pharmaceutical bioassays, often used for exploring the ecology of freshwater communities. One of its behaviours used for evaluating the state of the aquatic environment is phototaxis. A disruption in the predicted behaviour is interpreted as a sign of stress and forms the basis for further investigation. However, phototaxis is a result of complex processes counteracting and interacting with each other. Predator presence, food quality, body pigmentation and other factors can greatly affect the predicted phototactic response, hampering its reliability as a bioindicator. Therefore, a holistic approach and meticulous documentation of the methods are needed for the correct interpretation of this behavioural indicator. In this review, we present the current methods used for studying phototaxis, the factors affecting it and proposed ways to optimise the reliability of the results.


Two-Dimensional Materials in Biosensing and Healthcare: From In Vitro Diagnostics to Optogenetics and Beyond.
Since the isolation of graphene in 2004, there has been an exponentially growing number of reports on layered two-dimensional (2D) materials for applications ranging from protective coatings to biochemical sensing. Due to the exceptional, and often tunable, electrical, optical, electrochemical, and physical properties of these materials, they can serve as the active sensing element or a supporting substrate for diverse healthcare applications. In this review, we provide a survey of the recent reports on the applications of 2D materials in biosensing and other emerging healthcare areas, ranging from wearable technologies to optogenetics to neural interfacing. Specifically, this review provides (i) a holistic evaluation of relevant material properties across a wide range of 2D systems, (ii) a comparison of 2D material-based biosensors to the state-of-the-art, (iii) relevant material synthesis approaches specifically reported for healthcare applications, and (iv) the technological considerations to facilitate mass production and commercialization.


Impact of rural settings on the interpersonal and personal processes associated with young people supporting a peer who experienced a traumatic event.
There is limited research into informal support processes amongst young people supporting a peer through a traumatic event and how this process occurs specifically within a rural setting. The aim of this research was to understand how the contextual environment impacts on the personal and interpersonal processes of rural-based young people supporting a peer who experienced a traumatic event. Qualitative interviews were conducted with 22 young people (aged 14-19), who resided in Gippsland, Victoria, Australia. A substantive theory was developed using Charmaz's (1) Constructivist grounded theory methodology. Young people who shared responsibility for supporting their peer went back to life as normal and felt connected to their community, whereas young people who maintained sole responsibility, experienced mental health problems, disconnected from their community and felt like an outsider. The contextual environmental factors (i.e., service accessibility, limited transport, and internet blackspots) impacted both negatively and positively on young people's ability to provide support as well as influenced whether they felt safe share responsibility. This theory implies that providing pathways to reconnecting with place and community, are essential in guiding young people back to their foundations of support. Integrating these insights can create new service models in rural areas, whilst also creating opportunities to form healthy foundations of support.


Increasing Incidence of Pelvic Sepsis Following Ileal Pouch-Anal Anastomosis for Ulcerative Colitis in Denmark: A Nationwide Cohort Study.
The risk of pelvic sepsis following IPAA for ulcerative colitis may have changed with changes in medical and surgical treatment, but data are scarce. This study aims to examine temporal changes in the risk of pelvic sepsis following IPAA for ulcerative colitis and to ascertain risk factors associated with pelvic sepsis. This is a nationwide cohort study. This study was conducted in Denmark from 1996 to 2013. Patients were operated on with an IPAA for ulcerative colitis. Pelvic sepsis was defined and validated as the occurrence of anastomotic leakage, pelvic abscesses or fistulas, or an operation for these conditions, recorded in a nationwide registry. Cumulative risks were calculated by using death as a competing risk. Multivariate Cox regression was used to examine the effects of calendar periods (1996-1999, 2000-2004, 2005-2009, and 2010-2013) on hazards ratios for pelvic sepsis, adjusting for age, sex, comorbidity, annual hospital volume, pelvic sepsis in the 12 months preceding surgery, operative stage (1-, 2-, modified 2-, or 3-stage), laparoscopy, and preoperative treatment with biological medicine within 12 weeks before surgery. Of 1456 patients, 244 (16.8%) experienced pelvic sepsis. The 1-year risk increased by calendar period (1996-1999: 2.5%, 2000-2004: 4.5%, 2005-2009: 7.4%, and 2010-2013: 9.6%). The adjusted hazard ratio for pelvic sepsis increased by an average 4.4% (95% CI, 1.3-7.6) per year in the study period. In general, patients were older and had more comorbidities at IPAA in recent years than in earlier years, and more had experienced pelvic sepsis in the 12 months preceding the operation. This study was register based. There were no data on important clinical variables to determine the causes of an increased risk over calendar periods. In this nationwide cohort study, the 1-year risk of pelvic sepsis following primary IPAA for ulcerative colitis increased 4-fold from 1996 to 2013. See Video Abstract at http://links.lww.com/DCR/A956.


Congenital Heart Surgery Nomenclature and Database Project: double outlet right ventricle.
Double outlet right ventricle (DORV) is a type of ventriculoarterial connection in which both great vessels arise entirely or predominantly from the right ventricle. Although the presence of aortic-mitral discontinuity and bilateral coni are important descriptors, they should not serve as absolute prerequisites for the diagnosis of DORV. The morphology of DORV is encompassed by a careful description of the ventricular septal defect (VSD) with its relationship to the semilunar valves, the great artery relationships to each other, the coronary artery anatomy, the presence or absence of pulmonary outflow tract obstruction (POTO) and aortic outflow tract obstruction (AOTO), the tricuspid-pulmonary annular distance, and the presence or absence of associated cardiac lesions. The preferred surgical treatment involves the connection of the left ventricle to the systemic circulation by an intraventricular tunnel repair connecting the VSD to the systemic semilunar valve. This ideal surgical therapy is not always possible due to the presence of confounding anatomical barriers. A multitude of alternative surgical procedures has been devised to accommodate these more complex situations. A framework for the development of the DORV module for a pediatric cardiac surgical database is proposed.


Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis.
The disruption of homeostasis between proliferation and apoptosis in the colonic epithelium contributes to the pathogenesis of human ulcerative colitis. Mice lacking the transcriptional corepressor myeloid translocation gene related-1 (Mtgr1) display impaired secretory cell lineage development in the small intestine and an increase in proliferation in the crypts of both the small and large intestines. Despite the increase in proliferating cells, the colons of Mtgr1-null mice have a normal cell lineage distribution and normal architecture. To uncover colonic phenotypes in Mtgr1(-/-) mice, we stressed the colonic epithelium with low-molecular-weight dextran sodium sulfate (DSS), which is a well-studied model of murine ulcerative colitis. Mtgr1-null mice were given 3% DSS in their drinking water for 4 days and the colons examined at various times thereafter for ulceration and for changes in proliferation and apoptosis. Treatment with DSS resulted in severe colitis in Mtgr1(-/-) mice, at least partially due to increased epithelial apoptosis rates. Transplantation of wild-type and Mtgr1-null bone marrow into irradiated wild-type mice demonstrated that the severe DSS-induced ulceration seen in Mtgr1-null mice was due to a colonic, rather than a hematologic, defect. Importantly, the epithelium of DSS-treated Mtgr1-null mice failed to completely regenerate, showing changes consistent with chronic colitis, even 10 weeks after a single DSS treatment. These findings suggest that Mtgr1 has an important role in crypt survival and regeneration after colonic epithelial ulceration.


A breakdown in macromolecular synthesis preceding differentiation in Streptomyces coelicolor A3(2).
A transitory cessation of growth was recorded in Streptomyces coelicolor A3(2) at the end of vegetative mycelium formation on solid medium. In the same phase a striking reduction in protein and nucleic acid synthesis was detected. Growth and macromolecular synthesis resumed, nearly reaching the original values, when morphological differentiation occurred. It is concluded that a physiological stress occurs within the bacterial population just before the onset of the morphological differentiation.


Titration of transport and modifier sites in the red cell anion transport system.
This work demonstrates the existence of titratable transport and modifier sites in the anion transport system of human red cells. Effects of alkaline extracellular pH on chloride exchange were studied up to pH 13 at 0 degrees C. The studies revealed two sets of reversible titratable groups. One set, having a pK of or approximately 11, appeared to be identical with the inhibitory halide-binding modifier site. Deprotonation of this site stimulated anion transport. The apparent dissociation constants of chloride and iodide at this modifier site were 0.3 and 0.06 M, respectively, and it was confirmed that the organic sulfonate NAP-taurine inhibits anion transport reversibly by a high-affinity interaction with halide-binding modifier sites at the extracellular side of the membrane. Other groups, with apparent pK of or approximately 12 at chloride concentrations above 0.1 M, were named as "transport sites" because transport function depended totally on their protonation. The apparent pK decreased when extracellular halide concentrations was lowered below 0.1 M. It was dependent of the intracellular chloride concentration, and was equally sensitive to extracellular pH of 13, was fully reversible. Hydroxyl ions were not transported to an appreciable extent by the anion exchange system. The pK values of both sets of groups make it likely that they are both arginyl residues, functioning as anion recognition sites similar to the role of functionally essential arginyl residues observed with numerous enzymes.


The pilot trial of the prevention of the increase in electrical taste thresholds by zinc containing fluid infusion during chemotherapy to treat primary lung cancer.
It is well known that there are various adverse effects during chemotherapy for cancer treatment. A taste disorder is also seen in 35-70% of patients. It has been reported that a zinc deficiency is associated with the development of these alterations in taste sensation. The purpose of this pilot study was to determine whether the zinc including infusion had the effect on taste disorder in patients with lung cancer. Taste disorder was evaluated as the increase in electrical taste thresholds using an electrogustometer. The plasma zinc concentration was also measured. Although there was no significant correlation, the increase in taste thresholds was detected in many patients who had a low zinc concentration even before receiving chemotherapy. Moreover, after 2 weeks of chemotherapy, almost all patients who did not have a zinc containing infusion showed development of taste disorder (5/5, 100% at chorda tympani area; 4/5, 80% at glossopharyngeal area), whereas no development of taste disorder was observed in those patients receiving a zinc containing infusion. These results suggest the possibility that the administration of zinc during chemotherapy could be a useful supportive therapy for preventing taste disorder and to help maintain a better quality of life.


3'-phosphoinositides regulate the coordination of speed and accuracy during chemotaxis.
The PI3K/PTEN pathway, as the regulator of 3'-phosphoinositide (3'-PI) dynamics, has emerged as a key regulator of chemoattractant gradient sensing during chemotaxis in Dictyostelium and other cell types. Previous results have shown 3'-PIs to be important for regulating basal cell motility and sensing the direction and strength of the chemoattractant gradient. We examined the chemotaxis of wild-type cells and cells lacking PTEN or PI3K1 and 2 using analytical methods that allowed us to quantitatively discern differences between the genotype's ability to sense and efficiently respond to changes in gradient steepness during chemotaxis. We found that cells are capable of increasing their chemotactic accuracy and speed as they approach a micropipette in a manner that is dependent on the increasing strength of the concentration gradient and 3'-PI signaling. Further, our data show that 3'-PI signaling affects a cell's ability to coordinate speed and direction to increase chemotactic efficiency. Using to our knowledge a new measurement of chemotactic efficiency that reveals the degree of coordination between speed and accuracy, we found that cells also have the capacity to increase their chemotactic efficiency as they approach the micropipette. Like directional accuracy and speed, the increase in chemotactic efficiency of cells with increased gradient strength is sensitive to 3'-PI dysregulation. Our evidence suggests that receptor-driven 3'-PI signaling regulates the ability of a cell to capitalize on stronger directional inputs and minimize the effects of inaccurate turns to increase chemotactic efficiency.


A look into the future: can minimal residual disease guide therapy and predict prognosis in chronic lymphocytic leukemia?
Over the past 2 decades, dramatic improvements in the efficacy of treatments for chronic lymphocytic leukemia have led to progressively higher percentages of clinical complete remissions. A molecular eradication of the leukemia has become not only a desirable, but also an achievable, end point that needs to be evaluated within clinical trials. The assessment of complete remission only at the clinical and morphological level is insufficient, at least for physically fit patients. The detection of minimal residual disease (MRD) in chronic lymphocytic leukemia has become feasible using PCR-based or flow cytometric techniques that reproducibly allow reaching the detection level of less than 1 leukemic cell per 10 000 leukocytes (10(-4)), the level currently defined as MRD(-) status. Emerging data indicate that the MRD status during and at the end of treatment is one of the most powerful predictors of progression-free and overall survival. This predictor appears to be independent of clinical response, type or line of therapy, and known biological markers. For these reasons, the time is ripe to test the use of MRD as a surrogate marker of clinical end points and as a real-time marker of efficacy and/or resistance to the administered therapies. In the near future, clinical trials will determine whether MRD assessment can be used for guiding therapy, either to improve quality of responses through consolidation or to prevent relapses through preemptive therapies based on the reappearance of MRD.


Study of a Functional Polymorphism in the PER3 Gene and Diurnal Preference in a Colombian Sample.
Polymorphisms in human clock genes have been evaluated as potential factors influencing circadian phenotypes in several populations. There are conflicting results for the association of a VNTR in the PER3 gene and diurnal preference in different studies. The objective of this study was to investigate the association between diurnal preference and daytime somnolence with the PER3 VNTR polymorphism (rs57875989) in healthy subjects from Colombia, a Latin American population.A total of 294 undergraduate university students from Bogotá, Colombia participated in this study. Two validated self-report questionnaires, the Composite Scale of Morningness (CSM) and the Epworth Sleep Scale (ESS) were used to assess diurnal preference and daytime somnolence, respectively. Individuals were genotyped for the PER3 VNTR using conventional PCR. Statistical comparisons were carried out with PLINK and SNPStats programs. The PER3 VNTR polymorphism was not associated with either diurnal preference or daytime somnolence in this population. No significant differences in mean scores for those scales were found between PER3 VNTR genotypes. In addition, there were no differences in allelic or genotypic frequencies between chronotype categories. This is consistent with several negative findings in other populations, indicating that the proposed influence of this polymorphism in diurnal preference, and related endophenotypes of neuropsychiatric importance, needs further clarification. This is the first report of molecular genetics of human circadian phenotypes in a Spanish-speaking population.


mRNA bivalent booster enhances neutralization against BA.2.75.2 and BQ.1.1.
The emergence of the highly divergent SARS-CoV-2 Omicron variant has jeopardized the efficacy of vaccines based on the ancestral spike. The bivalent COVID-19 mRNA booster vaccine within the United States is comprised of the ancestral and the Omicron BA.5 spike. Since its approval and distribution, additional Omicron subvariants have been identified with key mutations within the spike protein receptor binding domain that are predicted to escape vaccine sera. Of particular concern is the R346T mutation which has arisen in multiple subvariants, including BA.2.75.2 and BQ.1.1. Using a live virus neutralization assay, we evaluated serum samples from individuals who had received either one or two monovalent boosters or the bivalent booster to determine neutralizing activity against wild-type (WA1/2020) virus and Omicron subvariants BA.1, BA.5, BA.2.75.2, and BQ.1.1. In the one monovalent booster cohort, relative to WA1/2020, we observed a reduction in neutralization titers of 9-15-fold against BA.1 and BA.5 and 28-39-fold against BA.2.75.2 and BQ.1.1. In the BA.5-containing bivalent booster cohort, the neutralizing activity improved against all the Omicron subvariants. Relative to WA1/2020, we observed a reduction in neutralization titers of 3.7- and 4-fold against BA.1 and BA.5, respectively, and 11.5- and 21-fold against BA.2.75.2 and BQ.1.1, respectively. These data suggest that the bivalent mRNA booster vaccine broadens humoral immunity against the Omicron subvariants.


Autofluorescence imaging of NADH and flavoproteins in the rat brain: insights from Monte Carlo simulations.
There has been recently a renewed interest in using Autofluorescence imaging (AF) of NADH and flavoproteins (Fp) to map brain activity in cortical areas. The recording of these cellular signals provides complementary information to intrinsic optical imaging based on hemodynamic changes. However, which of NADH or Fp is the best candidate for AF functional imaging is not established, and the temporal profile of AF signals is not fully understood. To bring new theoretical insights into these questions, Monte Carlo simulations of AF signals were carried out in realistic models of the rat somatosensory cortex and olfactory bulb. We show that AF signals depend on the structural and physiological features of the brain area considered and are sensitive to changes in blood flow and volume induced by sensory activation. In addition, we demonstrate the feasibility of both NADHAF and Fp-AF in the olfactory bulb.


The Transient IFN Response and the Delay of Adaptive Immunity Feature the Severity of COVID-19.
COVID-19 patients show heterogeneous and dynamic immune features which determine the clinical outcome. Here, we built a single-cell RNA sequencing (scRNA-seq) dataset for dissecting these complicated immune responses through a longitudinal survey of COVID-19 patients with various categories of outcomes. The data reveals a highly fluctuating peripheral immune landscape in severe COVID-19, whereas the one in asymptomatic/mild COVID-19 is relatively steady. Then, the perturbed immune landscape in peripheral blood returned to normal state in those recovered from severe COVID-19. Importantly, the imbalance of the excessively strong innate immune response and delayed adaptive immunity in the early stage of viral infection accelerates the progression of the disease, indicated by a transient strong IFN response and weak T/B-cell specific response. The proportion of abnormal monocytes appeared early and rose further throughout the severe disease. Our data indicate that a dynamic immune landscape is associated with the progression and recovery of severe COVID-19, and have provided multiple immune biomarkers for early warning of severe COVID-19.


Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19.
Overall mental health depends in part on the blood-brain barrier, which regulates nutrient transfer in-and-out of the brain and its central nervous system. Lactoferrin, an innate metal-transport protein, synthesized in the substantia nigra, particularly in dopaminergic neurons and activated microglia is vital for brain physiology. Lactoferrin rapidly crosses the blood-brain barrier via receptor-mediated transcytosis and accumulates in the brain capillary endothelial cells. Lactoferrin receptors are additionally present on glioma cells, brain micro-vessels, and neurons. As a regulator of neuro-redox, microglial lactoferrin is critical for protection/repair of neurons and healthy brain function. Iron imbalance and oxidative stress are common among patients with neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, dementia, depression, and multiple sclerosis. As an endogenous iron-chelator, lactoferrin prevents iron accumulation and dopamine depletion in Parkinson's disease patients. Oral lactoferrin supplementation could modulate the p-Akt/PTEN pathway, reduce Aβ deposition, and ameliorate cognitive decline in Alzheimer's disease. Novel lactoferrin-based nano-therapeutics have emerged as effective drug-delivery systems for clinical management of neurodegenerative disorders. Recent emergence of the Coronavirus disease-2019 (COVID-19) pandemic, initially considered a respiratory illness, demonstrated a broader virulence spectrum with the ability to cross the blood-brain barrier and inflict a plethora of neuropathological manifestations in the brain - the Neuro-COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are widely reported in Parkinson's disease, Alzheimer's disease, dementia, and multiple sclerosis patients with aggravated clinical outcomes. Lactoferrin, credited with several neuroprotective benefits in the brain could serve as a potential adjuvant in the clinical management of Neuro-COVID-19.


Effectiveness of Oral Health Educational Methods among School Children Aged 5-16 Years in Improving their Oral Health Status: A Meta-analysis.
Oral health is an essential component of health throughout life. Two major oral diseases, dental caries and gingival conditions are prevalent in young population. School-based oral health education (OHE) programs with recognized technology and traditional lecturing could be strategic in promotion of oral health behavior in developed and developing countries. The aim of the study is to summarize existing evidence in order to evaluate the effectiveness of OHE programs in school children aged 5-16 years in improving their oral health status. Clinical trials with school children between 5 and 16 years were included. Eligible studies were those which had outcomes as caries, plaque and gingival indices, and oral hygiene status. Articles published from 2010 to 2019 in English language from PubMed, Directory of Open Access Journal (DOAJ), and Google Scholar were searched. Forty-one articles were identified and relevance was determined by examining title and full article. Nine articles were included for qualitative synthesis and seven were eligible for meta-analysis. The risk of bias was assessed by Cochrane Handbook. A meta-analysis was done using Review Manager 5.3 software. After the meta-analysis results for cumulative mean difference was found as 0.05 (-0.17, 0.27), -0.37 (-0.74, 0.00), -0.20 (-0.33, -0.07), and -0.17 (-0.73, 0.38) for plaque status, Oral Hygiene Index-Simplified (OHI-S), debris status, and dental caries, respectively showing a significant difference favoring the experimental group than traditional group. Interventions given by various aids like lectures, albums, models, flipcharts, leaflets, E-programs, games, drawings, and presentations proved effective in improving oral hygiene status and dental caries, but no reduction in plaque levels and gingival inflammation as compared to oral health talk/counseling by dentists. Gurav KM, Shetty V, Vinay V, et al. Effectiveness of Oral Health Educational Methods among School Children Aged 5-16 Years in Improving their Oral Health Status: A Meta-analysis. Int J Clin Pediatr Dent 2022;15(3):338-349.


Penile length and somatometric parameters: a study in healthy young Turkish men.
The purpose of this study was to determine average penile length and to investigate the relationship between penile length and somatometric parameters in a group of young, healthy Turkish men. A total of 1,132 men were included in the study. The age, height and weight of the subjects were recorded. Penile length was measured in both flaccid and stretched states. The correlation between penile length and somatometric parameters was analysed. The mean age of the subjects was 20.3±0.9 years. The mean penile length in flaccid and stretched states was 9.3±1.3 and 13.7±1.6 cm, respectively (P<0.001). There was a positive correlation between flaccid and stretched penile length (r=0.800, P<0.001). The mean testicular volume was 22.0±2.8 cm(3). A weak positive correlation was detected between penile length and mean testicular volume (r=0.143 for flaccid penile length and r=0.140 for stretched penile length, P<0.001 for both). Similarly, weak positive correlations were found between penile length (both flaccid and stretched) and height, weight and body mass index, respectively (P<0.001, for all). These results demonstrate that somatometric parameters are correlated with penile length. We believe that further studies would provide more information about the causal relationship.


Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells.
Epstein-Barr virus (EBV) isolates show sequence divergence in the BamHI YH region of the genome which encodes the nuclear antigen EBNA 2, a protein thought to be involved in the initiation of virus-induced B-cell transformation; type A isolates (such as B95-8 EBV) encode a 82- to 87-kilodalton EBNA 2A protein, whereas type B isolates (such as AG876 EBV) encode an antigenically distinct 75-kilodalton EBNA 2B protein. In the present work 12 type A isolates and 8 type B isolates have been compared for their ability to transform resting human B cells in vitro into permanent lymphoblastoid cell lines. Although the kinetics of initial focus formation was not markedly dependent upon the EBNA 2 type of the transforming virus, on subsequent passage type A virus-transformed cells (type A transformants) yielded cell lines much more readily than did type B transformants. Direct comparison between the two types of transformant revealed clear differences in several aspects of growth phenotype. Compared with type A transformants, cell lines established with type B virus isolates consistently displayed an unusual growth pattern with poor survival of individual cells shed from lymphoblastoid clumps, a lower growth rate and a greater sensitivity to seeding at limiting dilutions, and a significantly lower saturation density that could not be corrected by supplementation of the medium with culture supernatant containing B-cell growth factors. This is the first direct evidence that, in EBV-transformed B-cell lines, the EBNA 2 protein plays a continuing role in determining the cellular growth phenotype.


Progressive Paraparesis after CABG Surgery.
CABG is one of the most common cardiac surgeries all over the world. Similar to other surgeries, it may be associated with some undesirable complications including neurologic complications which might cause morbidity and mortality after surgery. We will describe a case of Progressive Paraparesis after CABG Surgery and review its etiology, diagnosis and management.


Management of Retrograde Peri-Implantitis Using an Air-Abrasive Device, Er,Cr:YSGG Laser, and Guided Bone Regeneration.
The placement of an implant in a previously infected site is an important etiologic factor contributing to implant failure. The aim of this case report is to present the management of retrograde peri-implantitis (RPI) in a first maxillary molar site, 2 years after the implant placement. The RPI was treated using an air-abrasive device, Er,Cr:YSGG laser, and guided bone regeneration (GBR). A 65-year-old Caucasian male presented with a draining fistula associated with an implant at tooth #3. Tooth #3 revealed periapical radiolucency two years before the implant placement. Tooth #3 was extracted, and a ridge preservation procedure was performed followed by implant rehabilitation. A periapical radiograph (PA) showed lack of bone density around the implant apex. The site was decontaminated with an air-abrasive device and Er,Cr:YSGG laser, and GBR was performed. The patient was seen every two weeks until suture removal, followed by monthly visits for 12 months. The periapical X-rays, from 6 to 13 months postoperatively, showed increased bone density around the implant apex, with no signs of residual clinical or radiographic pathology and probing depths ≤4 mm. The etiology of RPI in this case was the placement of an implant in a previously infected site. The use of an air-abrasive device, Er,Cr:YSGG, and GBR was utilized to treat this case of RPI. The site was monitored for 13 months, and increased radiographic bone density was noted.


Nuclear entry of hyperbranched polylysine nanoparticles into cochlear cells.
Gene therapy is a potentially effective therapeutic modality for treating sensorineural hearing loss. Nonviral gene delivery vectors are expected to become extremely safe and convenient, and nanoparticles are the most promising types of vectors. However, infrequent nuclear localization in the cochlear cells limits their application for gene therapy. This study aimed to investigate the potential nuclear entry of hyperbranched polylysine nanoparticles (HPNPs) for gene delivery to cochlear targets. Rat primary cochlear cells and cochlear explants generated from newborn rats were treated with different concentrations of HPNPs. For the in vivo study, HPNPs were administered to the rats' round window membranes. Subcellular distribution of HPNPs in different cell populations was observed with confocal microscope 24 hours after administration. Nuclear entry was observed in various cochlear cell types in vitro and in vivo. In the primary cochlear cell culture, concentration-dependent internalization was observed. In the cochlear organotypic culture, abundant HPNPs were found in the modiolus, including the spiral ganglion, organ of Corti, and lateral wall tissues. In the in vivo study, a gradient distribution of HPNPs through different layers of the round window membrane was observed. HPNPs were also distributed in the cells of the middle ear tissue. Additionally, efficient internalization of HPNPs was observed in the organ of Corti and spiral ganglion cells. In primary cochlear cells, HPNPs induced higher transfection efficiency than did Lipofectamine(™). These results suggest that HPNPs are potentially an ideal carrier for gene delivery into the cochlea.


Vocational/educational services in a medical rehabilitation facility: outcomes in spinal cord and brain injured patients.
Records of 86 patients were reviewed to study whether adding on-site professional vocational/educational staff to a multidisciplinary medical rehabilitation program made an impact on vocational/educational outcomes in patients with spinal cord and brain injuries. Differences in such outcomes between the 2 patient groups were also explored. Patients who participated in an inpatient program prior to the addition of on-site vocational/educational staff were compared to those who participated after professional staff were added. Vocational/educational placement rates increased from 19% or lower to as high as 78% in cases where vocational/educational services were appropriate.


Quantification of carbamazepine and its 10,11-epoxide metabolite in rat plasma by UPLC-UV and application to pharmacokinetic study.
A rapid, selective and sensitive UPLC-UV method was developed and validated for the quantitative analysis of carbamazepine and its epoxide metabolite in rat plasma. A relatively small volume of plasma sample (200 μL) is required for the described analytical method. The method includes simple protein precipitation, liquid-liquid extraction, evaporation, and reconstitution steps. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) with a gradient mobile phase consisted of 60:40 going to 40:60 (v/v) water-acetonitrile at a flow rate of 0.5 mL/min. The total run time was as low as 6 min, representing a significant improvement in comparison to existing methods. Excellent linearity (r(2) > 0.999) was achieved over a wide concentration range. Close to complete recovery, short analysis time, high stability, accuracy, precision and reproducibility, and low limit of quantitation were demonstrated. Finally, we successfully applied this analytical method to a pre-clinical oral pharmacokinetic study, revealing the plasma profiles of both carbamazepine and carbamazepine-10,11-epoxide following oral administration of carbamazepine to rats. The advantages demonstrated in this work make this analytical method both time- and cost-efficient approach for drug and metabolite monitoring in the pre-clinical/clinical laboratory.


Inflammation in CNS neurodegenerative diseases.
Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.


On the origin of the helper component of tobacco vein mottling virus: translational initiation near the 5' terminus of the viral RNA and termination by UAG codons.
The nature of the polypeptide products encoded by the 5'-terminal region of the RNA of the potyvirus, tobacco vein mottling virus (TVMV), was investigated. Single-stranded DNA probes complementary to either nucleotides 1100-2100 or 2100-2820 from the 5' terminus of the RNA were prepared by subcloning recombinant plasmids in bacteriophage M13. These were hybridized to TVMV RNA, the DNA:RNA hybrids translated in a reticulocyte lysate cell-free translation system (hybrid-arrested translation), and the products analyzed by electrophoresis on SDS-containing polyacrylamide gels. The hybrids produced altered patterns of polypeptides which indicated that the major product, P75, was translated from the 5' terminus of the RNA. The N-terminal portion (molecular weight approximately 35,000) of P75 did not react with antisera to any of the five known potyviral proteins, suggesting the existence of a previously unidentified cistron at the 5' terminus. Translation of additional RNA sequences produced a polypeptide with a molecular weight of 68,000 which was immunoprecipitable by antiserum to TVMV helper component, establishing the coding region for helper component near the 5' terminus. Limited DNA sequence analysis of the region encoding the C terminus of P75 revealed an open reading frame of 369 nucleotides followed by a pair of UAG Codons. Pulse-chase experiments demonstrated that in the first 10 min of incubation, the only polypeptide initiated was P75, suggesting that products downstream from P75 arose from in vitro fragmentation of TVMV RNA and translation of the RNA fragments.


In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis.
A number of investigators have reported augmented expression of PDGF in lungs with idiopathic pulmonary fibrosis (IPF) or with other types of pulmonary fibrosis. To accomplish such a regulation of PDGF activity, we constructed an expression plasmid of the extracellular domain of PDGF receptor beta chain (XR), which lacks intracellular tyrosine kinase domain and transmembrane portions, and estimated the therapeutic effects of XR gene transfer through the trachea on bleomycin-induced lung fibrosis of C57BL/6 mice using the hemagglutinating virus of Japan(HVJ)-liposome method. The XR gene transfer ameliorated the increases in the wet weight and hydroxyproline content and the histopathologic changes of the lung induced by bleomycin. These findings suggest that PDGF plays a crucial role in the pathogenesis of pulmonary fibrosis, and that XR gene transfer using the HVJ-liposome method may limit the progression of pulmonary fibrosis.


The Impact of COVID-19 on Young People's Mental Health in the UK: Key Insights from Social Media Using Online Ethnography.
There is increasing evidence of the psychological impact of COVID-19 on various population groups, with concern particularly focused on young people's mental health. However, few papers have engaged with the views of young people themselves. We present findings from a study into young people's discussions on social media about the impact of COVID-19 on their mental health. Real-time, multi-platform online ethnography was used to collect social media posts by young people in the United Kingdom (UK), March 2020-March 2021, 1033 original posts and 13,860 associated comments were analysed thematically. Mental health difficulties that were described as arising from, or exacerbated by, school closures, lost opportunities or fraught family environments included depression, anxiety and suicidality. Yet, some also described improvements to their mental health, away from prior stressors, such as school. Young people also recounted anxiety at the ramifications of the virus on others. The complexities of the psychological impact of COVID-19 on young people, and how this impact is situated in their pre-existing social worlds, need recognising. Forging appropriate support necessitates looking beyond an individualised conceptualisation of young people's mental health that sets this apart from broader societal concerns. Instead, both research and practice need to take a systemic approach, recognising young people's societal belonging and social contexts.


Challenges to Engaging Older Adults in a Group-Based Walking Intervention: Lessons From the Residents in Action Trial.
This qualitative research explored older adults' perceptions of participating in group-based walking programs set in independent-living retirement village contexts. Semistructured interviews were conducted with a subset of participants from the Residents in Action Trial. Data were analyzed through a combination of deductive and inductive thematic analysis. Findings were interpreted from a social identity perspective. Five themes were identified: (a) varying levels of social cohesion in retirement villages; (b) degree of shared identity between residents; (c) health, mobility, and preferred pace; (d) devotion to spouse; and (e) busy lives. When designing group-based walking interventions in retirement villages, it is important to consider community-level social cohesion and degree of relatedness between village residents. When attempting to build a sense of shared identity and relatedness between group members, researchers and policy makers should consider differing backgrounds, capabilities, schedules, and interests of participants.


Fabrication of two-layer integrated phase mask for single-beam and single-exposure fabrication of three-dimensional photonic crystal.
In this paper, we report a new design and fabrication of an integrated two-layer phase mask for five-beam holographic fabrication of three-dimensional photonic crystal templates. The phase mask consists of two layers of orthogonally oriented gratings produced in a polymer. The vertical spatial separation between two layers produces a phase shift among diffractive laser beams, which enables the holographic fabrication of inter-connected three-dimensional photonic structures. A three-dimensional photonic crystal template was fabricated using the two-layer phase mask and was consistent with simulations based on the five beam interference. The reported method simplifies the fabrication of photonic crystals and is amendable for massive production and chip-scale integration of three-dimensional photonic structures.


Radial astrocyte synchronization modulates the visual system during behavioral-state transitions.
Glial cells support the function of neurons. Recent evidence shows that astrocytes are also involved in brain computations. To explore whether and how their excitable nature affects brain computations and motor behaviors, we used two-photon Ca2+ imaging of zebrafish larvae expressing GCaMP in both neurons and radial astrocytes (RAs). We found that in the optic tectum, RAs synchronize their Ca2+ transients immediately after the end of an escape behavior. Using optogenetics, ablations, and a genetically encoded norepinephrine sensor, we observed that RA synchronous Ca2+ events are mediated by the locus coeruleus (LC)-norepinephrine circuit. RA synchronization did not induce direct excitation or inhibition of tectal neurons. Nevertheless, it modulated the direction selectivity and the long-distance functional correlations among neurons. This mechanism supports freezing behavior following a switch to an alerted state. These results show that LC-mediated neuro-glial interactions modulate the visual system during transitions between behavioral states.


Environmental enrichment rescues survival and function of adult-born neurons following early life stress.
Adverse experiences early in life are associated with the development of psychiatric illnesses. The hippocampus is likely to play pivotal role in generating these effects: it undergoes significant development during childhood and is extremely reactive to stress. In rodent models, stress in the pre-pubertal period impairs adult hippocampal neurogenesis (AHN) and behaviours which rely on this process. In normal adult animals, environmental enrichment (EE) is a potent promoter of AHN and hippocampal function. Whether exposure to EE during adolescence can restore normal hippocampal function and AHN following pre-pubertal stress (PPS) is unknown. We investigated EE as a treatment for reduced AHN and hippocampal function following PPS in a rodent model. Stress was administered between post-natal days (PND) 25-27, EE from PND 35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a conditioned stimulus (CS) following a trace fear protocol and reduced the survival of 4-week-old adult-born neurons throughout the adult hippocampus. Furthermore, we show that fewer adult-born neurons were active during recall of the CS stimulus following PPS. All effects were reversed by EE. Our results demonstrate lasting effects of PPS on the hippocampus and highlight the utility of EE during adolescence for restoring normal hippocampal function. EE during adolescence is a promising method of enhancing impaired hippocampal function resulting from early life stress, and due to multiple benefits (low cost, few side effects, widespread availability) should be more thoroughly explored as a treatment option in human sufferers of childhood adversity.


DNA-repair pathway inhibitors for the treatment of ovarian cancer.
Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide.Three-quarters of women present when the disease has spread through-put the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy, with or without taxanes. Although initial responses to chemotherapy are often good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy agents. Increased understanding about the molecular basis of ovarian cancer has lead to the development of novel agents, which work in different ways to conventional chemotherapy. These include DNA-repair pathway inhibitors, the commonest of which are the PARP (poly (ADP-ribose) polymerase) inhibitors. It is therefore important to compare their effectiveness and side effects of these novel agents to assess their role in the treatment of advanced ovarian cancer, especially as treatment of advanced disease is aiming to improve length of survival and quality of life (QoL). To compare the effectiveness and harmful effects of interventions, which inhibit DNA-repair pathways, in the treatment of ovarian cancer. RCTs were identified by searching The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2009), The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, MEDLINE (1990 to June 2009), EMBASE (1990 to June 2009), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature. Adult women with histologically proven ovarian cancer who were randomised to treatment groups which either compared DNA-repair pathway inhibitors with no treatment or DNA-repair pathway inhibitors together with conventional chemotherapy compared with conventional chemotherapy alone. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. Searches for additional data and information were also performed by two independent review authors. No trials were found and therefore no data were analysed, so only information on excluded references was collected. The search strategy identified 473 unique references of which 461 were excluded on the basis of title and abstract. The remaining 12 articles were retrieved in full, but none satisfied the inclusion criteria. However, two ongoing randomised phase II clinical trials were identified from the clinical trials databases that met our inclusion criteria, but no preliminary data were available. There are to date no published RCT data on the effectiveness and side effects of DNA-repair pathways inhibitors used alone or in association with conventional chemotherapy in the treatment of ovarian cancer. On-going trials have been identified and results are awaited and will be included in future updates of this review.


[Lactase deficiency in children of the first year of life].
In the article the new aspects of development of lactose malabsorbtion at children of the first year of life are resulted. The oligosaccharides and glycosydases of female milk have the certain importance in development of this pathology.


Feeding back surveillance data to prevent hospital-acquired infections.
We describe the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance system. Elements of the system critical for successful reduction of nosocomial infection rates include voluntary participation and confidentiality; standard definitions and protocols; identification of populations at high risk; site-specific, risk- adjusted infection rates comparable across institutions; adequate numbers of trained infection control professionals; dissemination of data to health-care providers; and a link between monitored rates and prevention efforts.


Unbinding transition in lipid multibilayers induced by copper(II) ions.
We describe our observations on an unbinding transition in a multilamellar dispersion of phosphatidylcholine (PC) vesicles induced by copper(II) ions. The small-angle X-ray measurements clearly show that the increasing amount of CuCl2 in the millimolar concentration range continuously increases the amount of the unbound bilayers in the gel phase. Moreover, this phenomenon becomes more pronounced when the samples are heated above the so-called pretransition temperature between the gel and the ripple gel phase. The proposed reason for the latter is the increased repulsive electrostatic interaction due to the appearance of the surface modulation in the ripple gel phase. The observed effects reveal a new aspect of the unbinding phenomena since only the transition induced by the steric repulsion due to the layer fluctuations has been considered so far. Here, we show that the unbinding can also be triggered by the change in the electrostatic interactions. These findings are connected to the physical basis of the crucial role of copper(II) ions in biological processes such as neurodegenerative diseases and cell evolution.


Supply-side harm reduction strategies: Bolivia's experiment with social control.
Harm reduction approaches to drug control have almost exclusively focussed on consumers in northern countries. This article supports recent analysis that indicates that such policies also hold relevance for producer countries by drawing on recent policy innovations in Bolivia. When Evo Morales, the president of the national coca grower confederation, was elected the country's first indigenous president in 2005, he promised to fundamentally change 25 years of the U.S.-funded "drug war" that had generated repeated human rights violations. The new policy, which implicitly incorporates harm reduction principles combined with respect for human rights, recognizes coca leaf's traditional use and cultural importance and relies on vigorous local organizations to implement a community-based programme called social control. Results to date indicate that Bolivia's social control experience has reduced violence in coca growing communities, ensured small farmers a subsistence income from coca and increased sovereignty, while making a modest contribution to containing expansion of coca cultivation. The programme has registered 50,000 farmers who are allowed to cultivate limited quantities of coca to supply traditional users and helped them gain secure title to their land. This registration is combined with satellite surveillance to guarantee that farmers do not exceed limits established by law. To date, the programme's reach is incomplete and coca is still diverted to the drug trade. Nonetheless, the approach may offer lessons for other drug producer countries, particularly where strong socio-political organizations are found in combination with closeknit communities holding shared cultural values.


[Ultracytochemistry of cyclic AMP metabolism].
The paper is concerned with the role of cyclic nucleotides in physiological and pathological processes of the cell vital activity. Principles of histochemical detection of adenylate cyclase and phosphodiesterase of cAMP are discussed. Electron-histochemical data on ultrastructural localization of these two enzymes are reviewed and practical recommendations are given for their electron-histochemical detection.


Do lifestyle, anthropometric and demographic factors associated with muscle strength differ in a UK and Japanese cohort? An exploratory analysis.
Muscle weakness is associated with adverse clinical outcomes including disability and mortality. We report demographic, anthropometric and lifestyle correlates of grip strength in UK and Japanese population-based cohorts. To report prevalence of low grip strength according to 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and 2019 Asian Working Group for Sarcopenia (AWGS 2019) thresholds and to consider correlates of grip strength in Eastern and Western populations. UK (1572 men; 1415 women) and Japanese (519 men; 1027 women) participants were recruited from two cohorts harmonised by consensus. Muscle strength was measured by grip strength dynamometry. Potential correlates of grip strength were examined using sex-stratified linear regression; univariate correlates (p < 0.05) were included in mutually adjusted models. Mean (SD) age was 66.2 (2.8) and 65.8 (12.3) in UK and Japanese cohorts, respectively. Prevalence of low grip strength was higher in Japanese participants (EWGSOP2 5.4% versus 2.4%, AWGS 2019 9.0% versus 3.7%). In both cohorts and sexes, univariate correlates of lower grip strength were older age, shorter height, not consuming alcohol, leaving education earlier and greater comorbidity. Apart from older age and shorter height, the only factors related to lower grip strength in mutually adjusted analyses were greater comorbidity among UK participants (kg difference in grip strength (95%CI) per additional comorbidity - 0.60(- 0.98, - 0.21) among men and - 0.50(- 0.86, - 0.13) among women) and not consuming alcohol among Japanese men (- 1.33(- 2.51, - 0.15)). Correlates of muscle strength were similar in both cohorts. A global approach to age-related muscle weakness prevention may be appropriate.


Anterior segment complications of argon laser therapy.
Similar complications have been reported with both xenon arc and argon laser photocoagulation. Emphasis has been placed on complications in the posterior segment. However, with the argon laser, anterior segment complications such as iritis, focal iris atrophy, inequality of pupil size, posterior synechiae, anterior subcapsular and cortical lens opacities and corneal leukomata may occur. The majority of these complications may be prevented by adequate dilatation of the pupil, patient cooperation, and selective use of retrobulbar anesthesia.


Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur.
Nitric oxide regulates bone turnover by osteoblasts and osteoclasts. Nitric oxide production is impaired by the T-786C eNOS single nucleotide polymorphism, with a substitution of the nucleotide thymine by cytosine at a locus 786 base pairs upstream of the eNOS gene. This leads to vasoconstriction, platelet aggregation, reduced angiogenesis, and reduced bone formation, all of which may be associated with osteonecrosis of the hip. We studied relationships between the T-786C eNOS polymorphism and idiopathic and secondary necrosis of the head of the femur in order to better understand the pathophysiology of osteonecrosis. With use of polymerase chain reaction methodology, the T-786C eNOS polymorphism was compared in ninety-five patients with femoral head necrosis (including thirty-six nonsmokers with idiopathic necrosis and fifty-nine patients with secondary necrosis) and seventy-two healthy normal adult controls. Homozygosity for the mutant eNOS allele (TT) was present in eight (22%) of thirty-six patients with idiopathic osteonecrosis as compared with one (3%) of thirty-six race, gender, and age-matched controls; heterozygosity (TC) was present in nineteen patients (53%) as compared with ten controls (28%); and the wild-type normal genotype (CC) was present in nine patients (25%) as compared with twenty-five controls (69%) (p = 0.0004). Logistic regression revealed that the T-786C eNOS mutant allele was positively associated with idiopathic osteonecrosis of the femoral head (odds ratio, 6.0; 95% confidence interval, 2.51 to 14.4). The fifty-nine patients with secondary osteonecrosis did not differ from fifty-two race, gender, and age-matched controls in terms of the distribution of the T-786C eNOS polymorphism (p = 0.19) or in terms of mutant allele frequency (30% compared with 21%; p = 0.15). The thirty-six patients with idiopathic osteonecrosis differed from the fifty-nine patients with secondary osteonecrosis in that they were more likely to have mutant eNOS genotypes (p = 0.033) and to have a higher mutant T allele frequency (49% compared with 30%; p = 0.009). The T-786C eNOS polymorphism and resultant reduction of nitric oxide production is associated with, and may contribute to, the pathogenesis of idiopathic osteonecrosis of the femoral head. Prognostic Level III. See Instructions to Authors for a complete description of levels of evidence.


[The effect of beta-receptor antagonists and diuretics and their combination on blood pressure and pressure-rate product during ergometric work in hypertensive patients (author's transl)].
1. Hypertensive patients are particularly endangered by disproportionately high increases in blood pressure during daily physical and emotional activity. For this reason, antihypertensive drugs should also be able to influence there pressure changes. 2. Therefore the ability of the beta-receptor antagonist acebutolol (400 mg/die) and of the diuretic mefrusid (25 mg/die) to reduce exercise-induced increases in blood pressure and pressure-rate product during and after standardized ergometric work (50--100 watts) was compared in a within-patient study of 42 outpatients with arterial hypertension (stage 1 to 2, WHO) aged 18 to 50 years. 3. Both drugs resulted in a significant reduction of systolic (p less than 0.05-p less than 0.001) and diastolic (p less than 0.05-p less than 0.001) blood pressure at rest. However, systolic and diastolic blood pressure (p less than 0.001) and pressure-rate product (p less than 0.001) during exercise were only significantly reduced by acebutolol. 4. The strongest blood pressure lowering effect under all conditions could be proven for the free and fixed combination of acebutolol and mefrusid. 5. From these findings it is concluded: (1) beta-adreno-receptor blocking agents are the drugs of first choice in the baseline therapy of mild to moderate arterial hypertension, (2) diuretic drugs potentiate the antihypertensive effect of beta-blocking agents. 6. This therapeutic regimen is recommended especially for hypertensives with ischemic heart disease, because diuretics fail to reduce pressure-rate product as a measure of myocardial O2-consumption.


Titin M-line insertion sequence 7 is required for proper cardiac function in mice.
Titin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the M-line, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (ΔMex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. ΔMex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation-contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation-contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.


Nicotine gum vs. placebo gum: comparisons of withdrawal symptoms and success rates.
Our data and that of researchers in the area clearly provide evidence for nicotine-specific withdrawal and its relief with nicotine gum. In addition, outcome efficacy is enhanced when nicotine gum is combined with behavioral treatment. Nicotine gum appears to be valuable both as a systematic tool and as a means of combatting short- and long-term nicotine seeking that contribute to maintenance of smoking and the inability to quit.


STAT5 in Cancer and Immunity.
Signal transducers and activators of transcription 5 (STAT5a and STAT5b) are highly homologous proteins that are encoded by 2 separate genes and are activated by Janus-activated kinases (JAK) downstream of cytokine receptors. STAT5 proteins are activated by a wide variety of hematopoietic and nonhematopoietic cytokines and growth factors, all of which use the JAK-STAT signalling pathway as their main mode of signal transduction. STAT5 proteins critically regulate vital cellular functions such as proliferation, differentiation, and survival. The physiological importance of STAT5 proteins is underscored by the plethora of primary human tumors that have aberrant constitutive activation of these proteins, which significantly contributes to tumor cell survival and malignant progression of disease. STAT5 plays an important role in the maintenance of normal immune function and homeostasis, both of which are regulated by specific members of IL-2 family of cytokines, which share a common gamma chain (γ(c)) in their receptor complex. STAT5 critically mediates the biological actions of members of the γ(c) family of cytokines in the immune system. Essentially, STAT5 plays a critical role in the function and development of Tregs, and consistently activated STAT5 is associated with a suppression in antitumor immunity and an increase in proliferation, invasion, and survival of tumor cells. Thus, therapeutic targeting of STAT5 is promising in cancer.


Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers.
Virus load and liver damage, as measured by quantitative polymerase chain reaction and histology activity index, were related to genotype and core promoter mutations in 43 chronic hepatitis B virus (HBV) carriers of East Asian origin. T-1762 mutants were more frequent in genotype C strains and were associated with more inflammation (P=.0036) and fibrosis (P=.0088) of the liver but not with hepatitis B e antigen (HBeAg) status or virus load. Conversely, precore mutations were associated with less liver inflammation (P=. 08), which was linked to HBeAg negativity and lower viral replication. Carriers with genotype C were more often HBeAg positive (P=.03) with precore wild type strains and more-severe liver inflammation (P=.009) than were those with genotype B. These findings suggest that pathogenic differences between genotypes may exist and that the T-1762 mutation may be useful as a marker for progressive liver damage but seem to contradict that down-regulation of HBeAg production is the major effect of this mutation.


Cardiovascular Disease and COVID-19 Vaccines: A Systematic Review and Analysis of Published Cases.
As vaccination against COVID-19 became more widespread, side-effects that were not initially detected during clinical trials became more prominent. The aim of this systematic review is to discuss reports of adverse cardiovascular events associated with COVID-19 vaccination. Databases were searched from inception up to August 2022 to identify case reports and case series reporting on patients with cardiovascular disease after COVID-19 vaccination. This study assessed 150 published cases. Of these, 109 were case reports and 41 were case series. The majority of patients were male (n=302, 86.6%), with a mean age of 27.6 ± 16.7 years. Of the included patients, 268 (76.6%) had myocarditis, 50 (14.6%) had myopericarditis, 8 (2.3%) had pericarditis, and only 4 (1.1%) had stress-induced cardiomyopathy. Moreover, 30 (8.6%) and 11 (3.1%) were diagnosed with arrhythmia and ischaemic heart disease, respectively. Ultimately, cardiovascular complications after COVID-19 vaccination include myocarditis, myopericarditis, ischaemic heart disease and arrhythmia. The young population, especially young male patients, could be more vulnerable to myocarditis.


Alleles associated with physical activity levels are estimated to be older than anatomically modern humans.
The purpose of this study was to determine the estimated mutation age and conservation of single-nucleotide polymorphisms (SNPs) associated with physical activity (PA) in humans. All human SNPs found to be significantly associated with PA levels in the literature were cross-referenced with the National Heart, Lung, and Blood Institute's Grand Opportunity Exome Sequencing Project to find estimated African-American (AA) and European-American (EA) mutation age. As a secondary measure of mutation age, SNPs were searched for in Hawk's mutation age prediction database which utilizes linkage equilibrium. To determine conservation among hominids, all SNPs were searched in the University of California, Santa Cruz Genome Browser, which contains Neanderthal and chimpanzee reference genomes. Six of the 104 SNPs associated with PA regulation were exon-located missense variants found in IFNAR2, PPARGC1A, PML, CTBP2, IL5RA, and APOE genes. The remaining 98 SNPs were located in non-protein coding regions. Average AA and EA estimated mutation age of the exon-located SNPs were 478.4 ± 327.5 kya and 542.1 ± 369.4 kya, respectively. There were four selective sweeps (suggestive of strong positive selection) of SNPs in humans when compared to Neanderthal or chimpanzee genomes. Exon-located PA candidate SNPs are older than the hypothesized emergence of anatomically modern humans. However, 95% of PA associated SNPs are found in intron and intergenic location. Across all SNPs, there seems to be a high level of conservation of alleles between humans, Neanderthals, and chimpanzees. However, the presence of four selective sweeps suggests there were selection pressures or drift unique to Homo sapiens that influenced the development of mutations associated with PA regulation.