Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes.
Ovarian failure is heterogeneous, both in cause and in phenotype. Women whose menses cease prior to age 40 years and have menopausal FSH levels are traditionally considered by clinicians to have the diagnosis of "premature ovarian failure" (POF). In fact, however, the ovarian function in this disorder is in reality a continuum of impairment in ovarian responsiveness. For this reason the term "primary ovarian insufficiency" (POI) has been suggested to be more accurate. It would be yet more desirable to classify this disorder on the basis of aberrant embryonic differentiation rather than the state of ovarian function. Genes that exert known hormonal effects (FSH, FSHR, LH, LHR, CYP17, CYP19) primarily affect follicle function, as do BMP15, GDF9, and GPR3. These genes mutations have occasionally been found in humans, but none are common. Still other genes expressed during oogenesis appear more likely to be characterized by lack of germ cell formation. These include DNA binding proteins and transcription factors like NOBOX and LHX8, and RNA binding proteins like NANOS. Plausible causative mutations have been identified in a few women (NOBOX, GDF9, LDX8), but even then only 1-2% of cases show a perturbation. Thus, considerable heterogeneity-phenotypic as well as etiologic-exists in ovarian failure, irrespective of whether follicles do or do not develop. Analysis of other genes is necessary, including many likely to show novel mechanisms of action.


Cell size and communication: role in structural and electrical development and remodeling of the heart.
With the advent of new information about alterations of cardiac gap junctions in disease conditions associated with arrhythmias, there have been major advances in the genetic and metabolic manipulation of gap junctions. In contrast, in naturally occurring cardiac preparations, little is known about cell-to-cell transmission and the subcellular events of propagation or about structural mechanisms that may affect conduction events at this small size scale. Therefore, the aim of this article is to review results that produce the following unifying picture: changes in cardiac conduction due to remodeling cardiac morphology ultimately are limited to changes in three morphologic parameters: (1) cell geometry (size and shape), (2) gap junctions (distribution and conductivity), and (3) interstitial space (size and distribution). In this article, we consider changes in conduction that result from the remodeling of cell size and gap junction distribution that occurs with developmental ventricular hypertrophy from birth to maturity. We then go on to changes in longitudinal and transverse propagation in aging human atrial bundles that are produced by remodeling interstitial space due to deposition of collagenous septa. At present, experimental limitations in naturally occurring preparations prevent measurement of the conductance of individual gap junctional plaques, as well as the delays in conduction associated with cell-to-cell transmission. Therefore, we consider the development of mathematical electrical models based on documented cardiac microstructure to gain insight into the role of specific morphologic parameters in generating the changes in anisotropic propagation that we measured in the tissue preparations. A major antiarrhythmic implication of the results is that an "indirect" therapeutic target is interstitial collagen, because regulation of its deposition and turnover to prevent or alter microfibrosis can enhance side-to-side electrical coupling between small groups of cells in aging atrial bundles.


The novel carbohydrate epitope L3 is shared by some neural cell adhesion molecules.
The monoclonal L3 antibody reacts with an N-glycosidically linked carbohydrate structure on at least nine glycoproteins of adult mouse brain. Three out of the L3 epitope-carrying glycoproteins could be identified as the neural cell adhesion molecules L1 and myelin-associated glycoprotein, and the novel adhesion molecule on glia. Expression of the L3 carbohydrate epitope is regulated independently of the protein backbone of these three glycoproteins. Based on the observation that out of three functionally characterized L3 epitope-carrying glycoproteins three fulfill the operational definition of an adhesion molecule, we would like to suggest that they form a new family of adhesion molecules that is distinct from the L2/HNK-1 carbohydrate epitope family of neural cell adhesion molecules. Interestingly, some members in each family appear to be unique to one family while other members belong to the two families.


Influence of Chinese cultural health beliefs among Malaysian Chinese in a suburban population: a survey.
In a multiethnic nation, it is not uncommon for doctors to encounter patients of different cultural backgrounds. Often, patients' cultural beliefs influence their perception of health and illnesses, and their treatment option. Many Chinese cultural beliefs are influenced by the Taoist concept of yin-yang balance. We interviewed 50 Malaysian Chinese from the general public of a suburban population in order to unravel the impact of Chinese cultural health beliefs on their decision-making, and this was compared with the opinions of 50 Chinese medical students from second to final year. Convenience sampling was then applied. From the survey, 78 percent of the general public believed that 'too much heat' or 'too much coldness' in the body could cause diseases. Compared to the medical students, a significantly higher number of the respondents held such beliefs, including the beliefs that abdominal colic is due to excessive 'wind' in the abdomen, consuming certain food can dispel wind from the body, and the importance of observing taboos during the confinement period after delivery. The majority of respondents from both groups believed that it is acceptable to combine both traditional Chinese medicine and modern medicine. There is a discrepancy in the extent to which these beliefs influence the perception of health and illnesses among the general public and among medical students. Healthcare providers need to be aware of such beliefs and practices regarding traditional Chinese medicine among their Chinese patients.


Approaches for disease prioritization and decision-making in animal health, 2000-2021: a structured scoping review.
This scoping review identifies and describes the methods used to prioritize diseases for resource allocation across disease control, surveillance, and research and the methods used generally in decision-making on animal health policy. Three electronic databases (Medline/PubMed, Embase, and CAB Abstracts) were searched for articles from 2000 to 2021. Searches identified 6, 395 articles after de-duplication, with an additional 64 articles added manually. A total of 6, 460 articles were imported to online document review management software (sysrev.com) for screening. Based on inclusion and exclusion criteria, 532 articles passed the first screening, and after a second round of screening, 336 articles were recommended for full review. A total of 40 articles were removed after data extraction. Another 11 articles were added, having been obtained from cross-citations of already identified articles, providing a total of 307 articles to be considered in the scoping review. The results show that the main methods used for disease prioritization were based on economic analysis, multi-criteria evaluation, risk assessment, simple ranking, spatial risk mapping, and simulation modeling. Disease prioritization was performed to aid in decision-making related to various categories: (1) disease control, prevention, or eradication strategies, (2) general organizational strategy, (3) identification of high-risk areas or populations, (4) assessment of risk of disease introduction or occurrence, (5) disease surveillance, and (6) research priority setting. Of the articles included in data extraction, 50.5% had a national focus, 12.3% were local, 11.9% were regional, 6.5% were sub-national, and 3.9% were global. In 15.2% of the articles, the geographic focus was not specified. The scoping review revealed the lack of comprehensive, integrated, and mutually compatible approaches to disease prioritization and decision support tools for animal health. We recommend that future studies should focus on creating comprehensive and harmonized frameworks describing methods for disease prioritization and decision-making tools in animal health.


Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate.
To cure localized prostate cancer, the entire prostate must be eliminated, which is what all forms of treatment must achieve. Although there is no better way to cure localized disease than total surgical removal, the challenge is whether this can be accomplished with acceptable morbidity. To evaluate quality of life following radical retropubic prostatectomy, patient reported outcomes of 62 men who underwent radical retropubic prostatectomy at this institution were recorded during the first 18 months of followup. By 18 months 93% of the patients were dry (wearing no pads) and 93% to 98% characterized urinary bothersomeness as none or small. Potency, defined as the ability to achieve unassisted intercourse with or without the use of sildenafil, improved gradually and by 18 months 86% of the patients were potent and 84% considered sexual bothersomeness as none or small. In an effort to improve the outcome of radical prostatectomy, the surgical procedures on these 62 patients were videotaped prospectively. The videotapes were reviewed 18 months after the study was initiated and 4 specific steps in the surgical procedure were correlated with patient reported outcomes. Surgeons who wish to improve their outcomes should consider using this technique to identify in their own hands other important arbitrary variations that may improve results. The probability of maintaining an undetectable prostate specific antigen was evaluated in men with similar pathological stages of disease who were or were not potent following surgery. Men who were potent had the same outcome as those who were impotent, supporting the premise that preservation of sexual function does not compromise cancer control. Cancer control and quality of life following brachytherapy were analyzed and the following conclusions were made: 1) high dose intensification is necessary if radiation therapy is expected to cure prostate cancer but I doubt that any form of radiotherapy will produce durable cancer control for 20 to 30 years; 2) although brachytherapy is rarely adequate as monotherapy, I am not certain that brachytherapy combined with external beam radiotherapy is any better than 3-dimensional conformal therapy alone and the side effects are uncertain, and 3) I believe that a prostate specific antigen nadir of less than 0.2 ng./ml. is necessary to confirm an adequate response to radiation. I believe that there is no better way to cure organ confined cancer than total surgical removal. Today continence and potency rates should be high. If not, a review of intraoperative videotapes of successful and unsuccessful cases can improve results. In men treated with radiotherapy stringent criteria for treatment response and quality of life outcomes are needed.


Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination.
Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients' CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research.


Examining chronic care patient preferences for involvement in health-care decision making: the case of Parkinson's disease patients in a patient-centred clinic.
Patient-centred care is a recommended model of care for Parkinson's disease (PD). It aims to provide care that is respectful and responsive to patient preferences, values and perspectives. Provision of patient-centred care should entail considering how patients want to be involved in their care. To understand the participation preferences of patients with PD from a patient-centred care clinic in health-care decision-making processes. Mixed-methods study with early-stage Parkinson's disease patients from a patient-centred care clinic. Study involved a modified Autonomy Preference Index survey (N=65) and qualitative, semi-structured in-depth interviews, analysed using thematic qualitative content analysis (N=20, purposefully selected from survey participants). Interviews examined (i) the patient preferences for involvement in health-care decision making; (ii) patient perspectives on the patient-physician relationship; and (iii) patient preferences for communication of information relevant to decision making. Preferences for participation in decision making varied between individuals and also within individuals depending on decision type, relational and contextual factors. Patients had high preferences for communication of information, but with acknowledged limits. The importance of communication in the patient-physician relationship was emphasized. Patient preferences for involvement in decision making are dynamic and support shared decision making. Relational autonomy corresponds to how patients envision their participation in decision making. Clinicians may need to assess patient preferences on an on-going basis. Our results highlight the complexities of decision-making processes. Improved understanding of individual preferences could enhance respect for persons and make for patient-centred care that is truly respectful of individual patients' wants, needs and values.


Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic chagasic cardiomyopathy treated with amiodarone or sotalol.
This study assessed the role of electrophysiologic testing to identify therapeutic strategies for the treatment of patients with sustained ventricular tachycardia (VT) and chronic chagasic cardiomyopathy treated with amiodarone or sotalol. One hundred fifteen patients [69 men (60%); mean age 52 +/- 10 years] with chagasic cardiomyopathy presenting with symptomatic VT were studied after loading with Class III antiarrhythmic drugs; 78 had a history of sustained VT, and 37 with symptomatic nonsustained VT had sustained VT induced at baseline electrophysiologic study. All but 12 patients also underwent baseline electrophysiologic study. Mean left ventricular ejection fraction was 0.49 +/- 0.14. Based on results of electrophysiologic study after loading with Class III drugs, patients were divided into three groups: group 1 (n = 23) had no sustained VT induced; group 2 (n = 45) had only tolerated sustained VT induced; and group 3 (n = 47) had hemodynamically unstable sustained VT induced. After a mean follow-up of 52 +/- 32 months, total mortality rate was 39.1%; it was significantly higher in group 3 than in groups 2 and 1 [69%, 22.2%, and 26%, respectively, P < 0.0001, hazard ratio (HR) 10.4, 95% confidence interval (CI) 3.8, 21.8]. There was no significant difference in total mortality rate between groups 1 and 2 (P = 0.40, HR 1.5, 95% CI 0.75, 4.58). Cardiac mortality and sudden cardiac death rates also were higher in group 3 patients. In patients with chagasic cardiomyopathy and sustained VT, electrophysiologic testing can predict long-term efficacy of Class III antiarrhythmic drugs. This may help in the selection of patients for implantable cardioverter defibrillator therapy.


Phylogenetic characterization of East African cassava mosaic begomovirus (Geminiviridae) isolated from Manihot carthaginensis subsp. glaziovii (Müll.Arg.) Allem., from a non-cassava growing region in Tanzania.
Manihot carthaginensis subsp. glaziovii (Müll.Arg.) Allem., a wild relative of cassava, native to Brazil, is one of the popular agroforestry trees used for hedges and/or boundary plants surrounding homesteads and farms and also harbours cassava mosaic begomoviruses (CMBs) and cassava brown streak ipomoviruses. Sequences of the DNA-A component of East African cassava mosaic virus (EACMV) isolates from M. carthaginensis subsp. glaziovii (Müll.Arg.) Allem., collected from non-cassava growing areas of Tanzania were characterized. Thirteen full length DNA-A sequences were analysed together with 15 already reported EACMV sequences and six CMB species reference genomes. The results show 96 to 100% nucleotide sequence identity with EACMV isolates from Kenya. Phylogenetic analysis revealed that EACMV isolates from M. carthaginensis subsp. glaziovii (Müll.Arg.) Allem, belong to a single cassava mosaic begomovirus species. The EACMV monophyletic clade is distinct from all other CMB species. The presence of Cassava infecting begomoviruses in wild cassava relative growing from traditionally non cassava growing region serve as inoculum sources for cassava-infecting begomoviruses and therefore their eradication is key in the sustainable management of CMBs, especially in the non-cassava growing areas.


Attitudes of nursing degree students towards end of life processes. A cultural approach (Spain-Senegal).
The concept of death is abstract, complex and has a number of meanings. Thus, its understanding and the approach taken to it depend, to a large extent, on aspects such as age, culture, training and religion. Nursing students have regular contact with the process of death and so it is of great interest to understand the attitudes they have towards it. As we live in a plural society it is even more interesting to not only understand the attitudes of Spanish students but, also, those of students coming from other countries. In the present article, we seek to identify and compare the attitudes held by nursing degree students at Hekima-Santé University (Senegal) and the University of Huelva (Spain) about end of life processes. The study identifies elements that condition attitudes and coping with death, whilst considering curricular differences with regards to specific end of life training. A descriptive, cross-sectional and multi-center study was conducted. The overall sample (N = 142) was divided into groups: Hekima-Santé University (Dakar, Senegal) and the University of Huelva (Huelva, Spain). The measurement instruments used were an ad-hoc questionnaire and Bugen´s Coping with Death Scale. Statistically significant differences (p = 0.005, 95%CI) were found in relation to overall Bugen Scale scores. We can confirm that specialized end of life training (University of Huelva, Spain) did not lead to better coping when compared with a population whose academic curriculum did not provide specific training and who engaged in more religious practices (Hekima-Santé University, Senegal). In cultures where religion not only influences the spiritual dimension of the individual, but acts in the ethical and moral system and consequently in the economic, educational and family sphere, the accompaniment at the end of life transcends the formative plane. Considering the plural society in which we live, the training that integrates the Degree in Nursing with regard to the care of the final process, must be multidimensional in which spirituality and faith are integrated, working emotional and attentional skills, as well as cultural competence strategies in this process.


Anaesthesia of conjoined twins.
Conjoined twins have been a source of fascination to the public and the medical profession for centuries. Their birth was initially viewed as an ominous sign of impending disaster. Since Middle Ages into the 19th century they were regarded as monstrosities and were exhibited at circuses and sideshows. The frequency of conjoined twins is approximately 1 in 50,000 gestation, but many of them die in utero, are terminated or stillborn. The true incidence is estimated to be 1 in 200,000 live births. This article gives an overview of Siamese twins and of the prenatal diagnosis in assessing the prognosis, anaesthetic and post-natal surgical management and outcome. Anaesthesia for conjoined twins surgery, whether prior to or for separation, is an enormous challenge to the anaesthesiologist. The site and complexity of the conjunction affect management of the airway, an intravenous access, the extent of blood and number of surgical specialties involved. Preoperative assessment and planning with interdisciplinary communication and cooperation is vital to the success of the operations. Meticulous attention to detail, monitoring and vigilance are mandatory.


Measuring sodium intake: research and clinical applications.
Although most current guidelines recommend a daily sodium intake of less than 2.3 g/day, most people do not have a reliable estimate of their usual sodium intake. In this review, we describe the different methods used to estimate sodium intake and discuss each method in the context of specific clinical or research questions. We suggest the following classification for sodium measurement methods: preingestion measurement (controlled intake), peri-ingestion measurement (concurrent), and postingestion measurement. On the basis of the characteristics of the available tools, we suggest that: validated 24-h recall methods are a reasonable approach to estimate sodium intake in large epidemiologic studies and individual clinical counselling sessions, methods (such as single 24-h urine collection, single-time urine collection, or 24-h recall methods), are of value in population-level estimation of mean sodium intake, but are less suited for individual level estimation and a feeding-trial design using a controlled diet is the most valid and reliable method for establishing the effect of reducing sodium to a specific intake target in early phase clinical trials. By considering the various approaches to sodium measurement, investigators and public health practitioners may be better informed in assessing the health implications of sodium consumption at the individual and population level.


Blinding and Patient-Reported Outcome Completion Rates in US Food and Drug Administration Cancer Trial Submissions, 2007-2017.
Patient-reported outcomes (PROs) are commonly included in submissions to the United States Food and Drug Administration (FDA). Open-label designs are frequent in cancer trials. Between-arm differences in PRO missingness may affect results. We sought to compare PRO completion rates between study arms in randomized open-label and double-blind cancer trials. Randomized, controlled trials for oncology and malignant hematology products submitted to the FDA in fiscal years 2007-2017 were identified using internal FDA databases. Applicant study reports were reviewed to assess PRO use and reporting of completion rates. Completion rates were collected for each PRO and compared between arms. Results were summarized using descriptive statistics. Ninety-six trials for anticancer products from 2007 to 2017 contained PROs. Fifty-one (53.1%) were randomized, controlled trials with useable information on PRO completion. The median completion rate for investigational arms was 89.7% (range = 33.7-100.0%) and 88.2% (range = 11.0-100.0%) for control arms. At six months, seven double-blind trials had gaps of at least 10% in at least one PRO between arms; in four trials, these gaps favored the control arm (median difference = 11.5%, range = 10.0-17.0%). For open-label trials, four trials had such gaps, all of which favored the investigational arm (median difference = 28.5%, range = 10.0-69.0%). Among trials that provided interpretable PRO completion information, completion rates were high. Most trials had comparable completion rates between arms. However, when large between-arm completion rate differences existed, differences favoring the experimental arm were more common in open-label trials compared with double-blind trials. Procedures must be put in place to improve reporting of PRO completion and reduce missingness, particularly in open-label trials.


Physiological characterization of vestibular efferent brainstem neurons using a transgenic mouse model.
The functional role of efferent innervation of the vestibular end-organs in the inner ear remains elusive. This study provides the first physiological characterization of the cholinergic vestibular efferent (VE) neurons in the brainstem by utilizing a transgenic mouse model, expressing eGFP under a choline-acetyltransferase (ChAT)-locus spanning promoter in combination with targeted patch clamp recordings. The intrinsic electrical properties of the eGFP-positive VE neurons were compared to the properties of the lateral olivocochlear (LOC) brainstem neurons, which gives rise to efferent innervation of the cochlea. Both VE and the LOC neurons were marked by their negative resting membrane potential <-75 mV and their passive responses in the hyperpolarizing range. In contrast, the response properties of VE and LOC neurons differed significantly in the depolarizing range. When injected with positive currents, VE neurons fired action potentials faithfully to the onset of depolarization followed by sparse firing with long inter-spike intervals. This response gave rise to a low response gain. The LOC neurons, conversely, responded with a characteristic delayed tonic firing upon depolarizing stimuli, giving rise to higher response gain than the VE neurons. Depolarization triggered large TEA insensitive outward currents with fast inactivation kinetics, indicating A-type potassium currents, in both the inner ear-projecting neuronal types. Immunohistochemistry confirmed expression of Kv4.3 and 4.2 ion channel subunits in both the VE and LOC neurons. The difference in spiking responses to depolarization is related to a two-fold impact of these transient outward currents on somatic integration in the LOC neurons compared to in VE neurons. It is speculated that the physiological properties of the VE neurons might be compatible with a wide-spread control over motion and gravity sensation in the inner ear, providing likewise feed-back amplification of abrupt and strong phasic signals from the semi-circular canals and of tonic signals from the gravito-sensitive macular organs.


Prevalence and impact of founder mutations in hereditary breast cancer in Latin America.
Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the in-flux of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53.


Review of Artificial Intelligence Techniques in Imaging Data Acquisition, Segmentation, and Diagnosis for COVID-19.
The pandemic of coronavirus disease 2019 (COVID-19) is spreading all over the world. Medical imaging such as X-ray and computed tomography (CT) plays an essential role in the global fight against COVID-19, whereas the recently emerging artificial intelligence (AI) technologies further strengthen the power of the imaging tools and help medical specialists. We hereby review the rapid responses in the community of medical imaging (empowered by AI) toward COVID-19. For example, AI-empowered image acquisition can significantly help automate the scanning procedure and also reshape the workflow with minimal contact to patients, providing the best protection to the imaging technicians. Also, AI can improve work efficiency by accurate delineation of infections in X-ray and CT images, facilitating subsequent quantification. Moreover, the computer-aided platforms help radiologists make clinical decisions, i.e., for disease diagnosis, tracking, and prognosis. In this review paper, we thus cover the entire pipeline of medical imaging and analysis techniques involved with COVID-19, including image acquisition, segmentation, diagnosis, and follow-up. We particularly focus on the integration of AI with X-ray and CT, both of which are widely used in the frontline hospitals, in order to depict the latest progress of medical imaging and radiology fighting against COVID-19.


Past trials influence perception of ambiguous motion quartets through pattern completion.
There are many celebrated examples of ambiguous perceptual configurations such as the Necker cube that abruptly and repeatedly "switch" among possible perceptual states. When such ambiguous configurations are presented intermittently, observers tend to see the same perceptual state on successive trials. The outcome of each trial apparently serves to "prime" the outcome of the following. We sought to determine how long the influence of a past trial persists by using ambiguous motion quartets as stimuli. We found large, significant effects of all four most recent trials, but the results were not consistent with any priming model. The results could be explained instead as perceptual completion of two kinds of temporal patterns, repeating and alternating. We conclude that the visual system does not passively remember perceptual state: it analyzes recent perceptual history and attempts to predict what will come next. These predictions can alter what is seen.


From childhood to adult age: 18-year longitudinal results and prediction of the course of mental disorders in the community.
This prospective longitudinal study of a representative community sample of children and adolescents (N = 269) examined the long-term course and predictive power of psychiatric symptoms in childhood/adolescence for diagnostic outcome (ICD-10) 18 years later at adult age. At both cross-sectional assessments, baseline (1980-1984) and the 18-year follow-up (2001-2004), psychiatric symptoms were assessed using the 'Standardized Psychiatric Interview' (Goldberg et al. in Br J Prev Soc Med 24:18-23, 1970). At follow-up, study participants were reassessed with the standardized M-CIDI (Wittchen and Pfister in Manual und Durchführungsbeschreibung des DIA-X-M-CIDI, Swets and Zeitlinger, Frankfurt, 1997) interview. The participation rate at 18-year follow-up was 82% of those alive. The frequency of clinically relevant depressive symptoms and symptoms of anxiety or phobia was considerably higher when the participants were younger (baseline assessment at childhood, adolescent age) as compared to their scores in adult age. Increased levels of somatic symptoms, fatigue, irritability, sleep disturbances, depression, anxiety and worry as well as phobic symptoms in childhood/adolescence were related to a higher risk of suffering from a psychiatric disorder in adulthood. Depressive symptoms predicted both mood disorders and substance use disorders in adulthood. Phobias predicted later anxiety disorders. These data spanning almost two decades add significant information to the existing literature on the course of mental disorders in the community during the transition from adolescence to adulthood.


Condylocephalic nailing of proximal femoral fractures.
The use of a closed nailing technique for elderly patients with intertrochanteric fractures has resulted in a substantially improved mortality. The incidence of fixation failures and degree of shortening are similar to that experienced with sliding screw and sliding nail plate systems. However, since rotational deformities may occur, the procedure is most beneficial for debilitated patients with intertrochanteric fractures, who represent substantial surgical risks. In general, subtrochanteric fractures occur in a younger group of patients. Since the proximal fragment is usually much larger and the quality of bone superior in this group of patients, the fixation failure rate was extremely low and significant loss of rotatory reduction did not occur. The body of experience gained in recent years with closed nailing techniques for femoral shaft and tibial fractures is directly applicable to the closed nailing of intertrochanteric and subtrochanteric fractures. Extremely comminuted fractures or long oblique fractures may shorten, and rotatory reduction and control must always be a concern. These difficulties must be weighed against the advantages of a negligible infection rate and extremely low nonunion and implant failure rates.


The anti-tumor function of the IKK inhibitor PS1145 and high levels of p65 and KLF4 are associated with the drug resistance in nasopharyngeal carcinoma cells.
We and others have previously shown that the canonical nuclear factor kappa-B (NF-κB) pathway is essential to nasopharyngeal carcinoma (NPC) tumor development and angiogenesis, suggesting that the NF-κB pathway, including its upstream modulators and downstream effectors, are potential therapeutic targets for NPC. The inhibitor of upstream IκB kinase (IKK), PS1145, is a small molecule which can specifically inhibit the IκB phosphorylation and degradation and the subsequent nuclear translocation of NF-κB. The present study aims to determine the anti-tumor activity of PS1145 on NPC. Our results showed that PS1145 significantly inhibited the growth of tumorigenic NPC cell lines, but not in the normal nasopharyngeal epithelial cell line. Results in the in vivo study showed that low concentration of PS1145 (3 mg/kg) could significantly suppress the subcutaneous tumor formation in the nude mice bearing NPC xenografts. Apparent adverse effects were not observed in the animal study. Drug resistance against PS1145 seems to be associated with the increased levels of active NF-kB p65 and change of expression levels of kruppel-like factor 4. As can be seen, PS1145 appears to be a safe agent for animal experiments and its effects are tumor-specific, and the proteins associated with the drug resistance of PS1145 are implied.


Topical modes in the preparation of human spleen specimens for routine scanning electron microscopy studies.
Various preparatory techniques were used to improve scanning electron microscopy images of the fine structure of vascular, cellular, and cordalreticular components of normal human spleens. The progressive method of fixation (GTGO) applied in the present study, allowed air drying of the tissues and rendered the specimens conductive even in newly fractured surfaces. Vascular perfusion proved necessary only in studies of the splenic blood vessels, while a simple immersion of tissue blocks in the washing solution resulted in better images of the white pulps. Interstitial (transsplenic) perfusion was found to be superior to vascular perfusion for routine preparation of spleen tissues, and freeze-cracking did not necessarily lead to improved images of the specimen's surfaces. Combined with proper washing and shaping protocols, the GTGO procedure is shown to be a superior mode of specimen preparation, abolishing most traditional artifacts and obtaining clear images of the complex splenic tissue.


Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.
Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.


Local Accumulation of Lymphocytes in the Intima of Human Aorta Is Associated with Giant Multinucleated Endothelial Cells: Possible Explanation for Mosaicism of Atherosclerosis.
Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into the intimal layer of the arterial wall through the endothelium. In adult humans, the luminal surface of the arterial wall is a heterogeneous monolayer of cells with varying morphology including typical endothelial cells (ECs) and multinucleated variant endothelial cells (MVECs). We hypothesized that distribution of MVECs in the endothelial monolayer can be related to the distribution pattern of early atherosclerotic lesions. We obtained en face preparations of intact adult (22-59 years old) aortic wall sections that allowed us to study the endothelial monolayer and the subendothelial layer. We compared the distribution of MVECs in the endothelial monolayer with the localization of early atherosclerotic lesions in the subendothelial layer, which were characterized by lipid accumulation and immune cell recruitment. In primary culture, MVECs demonstrated increased phagocytic activity compared to mononuclear ECs. Moreover, we have shown that unaffected aortic intima contained associates formed as a result of aggregation and/or fusion of LDL particles that are non-randomly distributed. This indicated that MVECs may be involved in the accumulation of LDL in the subendothelial layer through increased transcytosis. Interaction of LDL with subendothelial cells of human aorta in primary culture increased their adhesive properties toward circulating immune cells. Study of unaffected aortic intima revealed non-random distribution of leukocytes in the subendothelial layer and increased localization of CD45+ leukocytes in the subendothelial layer adjacent to MVECs. Together, our observations indicate that MVECs may be responsible for the distribution of atherosclerotic lesions in the arterial wall by participating in LDL internalization and immune cell recruitment.


Effect of tadalafil on penile nitric oxide synthase and corporal smooth muscle in rats under dutasteride treatment.
Aim: To investigate the effect of tadalafil in rats administered with daily dutasteride.Methods: Twenty-four Sprague-Dawley male rats were allocated to three groups as control (group C), dutasteride (group D) and dutasteride plus tadalafil (group D + T). After a month of treatment, serum samples were obtained from rats to measure dihydrotestosterone and total testosterone. Nitric oxide (NO) synthase (NOS) immunoreactivity and levels of NOS enzyme isoforms, NO and cyclic guanosine monophosphate (cGMP) were evaluated in the harvested penile tissues. Also, corporal smooth muscle and collagen were examined.Results: Staining intensities of neuronal NOS and endothelial NOS were significantly lower in group D (p < .05). They were similar between group C and group D + T. Immunoreactivity of inducible NOS was observed higher in group D than group C (p = .01) whereas group D + T had the highest iNOS (p<.001). ELISA revealed similar outcomes in terms of NOS enzyme isoform levels. The mean of smooth muscle to collagen ratio was the lowest in group D (p < .001) and it was similar among group C and group D + T (p = .072). Group D had the lowest cGMP and NO levels (p < .05) and they did not differ between group C and group D + T (p>.05). Group D and group D + T had significantly decreased dihydrotestosterone and increased testosterone, compared to group C (p < .001). They were similar between group D and group D + T.Conclusion: Daily treatment with tadalafil improves dutasteride-induced changes in rat penis.


Oral leukoplakia: Transmission electron microscopic correlation with clinical types and light microscopy.
Leukoplakia, is a precancerous lesion that is most commonly encountered in the oral cavity. The grade of dysplasia is presumed to be the most important indicator of malignant potential. There are many promising aspects in advanced methods for the evaluation of oral precancer and cancer. Among these methods, electron microscopic examination predicts the true biologic potential more accurately than conventional histology and has some success in the early detection of potentially malignant lesions. It has been reported in the literature that there is some correlation between clinical, histopathological, and transmission electron microscopic features. In this cohort study (prospective research), from the total of 9 subjects, 3 had homogenous leukoplakia, 3 had ulcerative type of oral leukoplakia, and 3 had nodular type of oral leukoplakia. Two patients were selected as control patients. Transmission electron microscopic examination was carried for all the cases and controls. All the findings were correlated with clinical features and light microscopy. Clinically and histologically, mild leukoplakia showed break in basement membrane, which can only be observed under transmission electron microscope (TEM). Additional dysplastic features were observed under transmission electron microscope, which are indicative of neoplastic process. Thus, it is finally concluded that nodular leukoplakia seems to be the most severe clinical type of leukoplakia showing highest risk of malignant transformation. Homogenous leukoplakia might show break in basement membrane under TEM.


Prion propagation by Hsp40 molecular chaperones.
Molecular chaperones regulate essential steps in the propagation of yeast prions. Yeast prions possess domains enriched in glutamines and asparagines that act as templates to drive the assembly of native proteins into beta-sheet-rich, amyloid-like fibrils. Several recent studies highlight a significant and complex function for Hsp40 co-chaperones in propagation of prion elements in yeast. Hsp40 co-chaperones bind non-native polypeptides and transfer these clients to Hsp70s for refolding or degradation. How Hsp40 co-chaperones bind amyloid-like prion conformers that are enriched in hydrophilic residues such as glutamines and asparagines is a significant question in the field. Interestingly, selective recognition of amyloid-like conformers by distinct Hsp40s appears to confer opposing actions on prion assembly. For example, the Type I Hsp40 Ydj1 and Type II Hsp40 Sis1 bind different regions within the prion protein Rnq1 and function respectively to inhibit or promote [RNQ(+)] prion assembly. Thus, substrate selectivity enables distinct Hsp40s to act at unique steps in prion propagation.


A Comparative Analysis of Phytochemicals, Metal Ions, Volatile Metabolites in Heart Wood, Stem Bark and Leaves of Salix alba L. along with in Vitro Antioxidant, Antacid, Antimicrobial Activities for Sake of Environment Conservation by Substitution of Stem Bark With Leaf.
The genus of Salix is used in food, medicine and nutraceuticals, and standardized by using the single marker compound Salicin only. Stem bark is the official part used for the preparation of various drugs, nutraceuticals and food products, which may lead to overexploitation and damage of tree. There is need to search substitution of the stem bark with leaf of Salix alba L. (SA), which is yet not reported. Comparative phytochemicals viz. Salicin, Procyanidin B1 and Catechin were quantified in the various parts of SA viz. heart wood (SA-HW), stem bark (SA-SB) and leaves (SA-L) of Salix alba L.by using newly developed HPLC method. It was observed that SA-HW and SA-L contained far better amount of Salicin, Procyanidin B and Catechin as compared to SA-SB (SA-HW~SA-L≫SA-SB). Essential and toxic metal ions of all three parts were analysed using newly developed ICP-OES method, where SA-L were founded as a rich source of micronutrients and essential metal ions as compared to SA-SB and SA-HW. GC-MS analysis has shown the presence of fatty acids and volatile compounds. The observed TPC and TFC values for all three parts were ranged from 2.69 to 32.30 mg GAE/g of wt. and 37.57 to 220.76 mg QCE/g of wt. respectively. In DPPH assay the IC50 values of SA-SB, SA-HW, and SA-L were 1.09 (±0.02), 5.42 (±0.08), and 8.82 (±0.10) mg/mL, respectively. The order of antibacterial activities against E. coli, S. aureus, P. aeruginosa, and B. subtilis strains was SA-L>SA-HW>SA-SB with strong antibacterial activities against S. aureus, and B. subtilis strains. The antacid activities order was SA-L>SA-SB>SA-HW. The leaves of SA have shown significant source of nutrients, phytochemicals and medicinal properties than SA-HW and SA-SB. The leaves of SA may be considered as substitute of stem bark to save the environment or to avoid over exploitation, but after the complete pharmacological and toxicological studies.


Degradation of Biofumigant Isothiocyanates and Allyl Glucosinolate in Soil and Their Effects on the Microbial Community Composition.
Brassicales species rich in glucosinolates are used for biofumigation, a process based on releasing enzymatically toxic isothiocyanates into the soil. These hydrolysis products are volatile and often reactive compounds. Moreover, glucosinolates can be degraded also without the presence of the hydrolytic enzyme myrosinase which might contribute to bioactive effects. Thus, in the present study the stability of Brassicaceae plant-derived and pure glucosinolates hydrolysis products was studied using three different soils (model biofumigation). In addition, the degradation of pure 2-propenyl glucosinolate was investigated with special regard to the formation of volatile breakdown products. Finally, the influence of pure glucosinolate degradation on the bacterial community composition was evaluated using denaturing gradient gel electrophoresis of 16S rRNA gene amplified from total community DNA. The model biofumigation study revealed that the structure of the hydrolysis products had a significant impact on their stability in the soil but not the soil type. Following the degradation of pure 2-propenyl glucosinolate in the soils, the nitrile as well as the isothiocyanate can be the main degradation products, depending on the soil type. Furthermore, the degradation was shown to be both chemically as well as biologically mediated as autoclaving reduced degradation. The nitrile was the major product of the chemical degradation and its formation increased with iron content of the soil. Additionally, the bacterial community composition was significantly affected by adding pure 2-propenyl glucosinolate, the effect being more pronounced than in treatments with myrosinase added to the glucosinolate. Therefore, glucosinolates can have a greater effect on soil bacterial community composition than their hydrolysis products.


The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals.
The beta-3 adrenergic receptor gene (ADRB3) is part of the adrenergic system, which is known to play a key role in energy metabolism. The association between the Trp64Arg variant in the ADRB3 and body mass index (BMI) has been widely examined, but previous studies have been small and results have been inconsistent. We assessed the association between the ADRB3 Trp64Arg variant and BMI in a large UK population-based cohort of 4854 middle-aged men and women. We also performed a meta-analysis of 97 studies, involving 44 833 individuals, to place our findings in context. Although we found no significant difference in BMI (0.20 kg/m(2), P=0.40) between the Trp64Trp homozygotes and Arg64 allele carriers in our UK population-based cohort, the meta-analysis showed significant association between the Arg64Trp variant and BMI, with Arg64-allele carriers having a 0.24 kg/m(2) (P=0.0002) higher BMI compared with noncarriers. However, we also found substantial heterogeneity among the studies (P=2.2 x 10(-14)). The difference in East Asians (0.31 kg/m(2), P=0.001) was 3.9 times larger than that in Europeans in whom no significant association was observed (0.08 kg/m(2), P=0.36). This was consistent with the chronological cumulative decrease in the effect size, which decreased steadily in Europeans and reached nonsignificance after 11 studies in 1996. In East Asians, the cumulative effect size decreased after the first reports, but reached a steady state at a significant effect size of 0.24 kg/m(2) in 2000. Although the funnel plot indicated no apparent publication bias, smaller studies tended to report greater differences in BMI, compared with larger studies. Collectively, these data suggest that the Trp64Arg ADRB3 genetic variant might be associated with BMI in East Asians, but not Europeans. More generally, our study shows the importance of meta-analyses in the field of genetic association studies for common traits. Each genetic variant makes only a small contribution to variation in BMI, and large sample sizes are needed to reliably assess and interpret gene-phenotype associations.


The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy.
The gut microbiome is implicated as a marker of response to immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes. NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021).


A metronidazole metabolite in human urine and its risk.
Metronidazole is a drug used for the treatment of trichomonal vaginitis, amebiasis, giardiasis, and certain anaerobic bacterial infections in humans. Acetamide and N-(2-hydroxyethyl)oxamic acid are metabolites of metronidazole in the rat, and we find small amounts of both metabolites in the urine of human patients taking the drug. Although acetamide is carcinogenic for rats, we do not believe that our finding further defines metronidazole's risk for humans. That risk can only be estimated from surveillance of people previously exposed to the drug.


Comparison of two MR grading systems for correlation between grade of cervical neural foraminal stenosis and clinical manifestations.
To compare the reliability of two recently reported MR grading systems of cervical neural foraminal stenosis (CNFS) and their correlation with clinical manifestations. We evaluated 188 patients (male : female = 80 : 108; mean age of 41 years) who visited our institution and underwent oblique sagittal MRI of the cervical spine. Two radiologists evaluated the MRI findings for the presence and grade of CNFS at the narrowest point, with the grading systems (Park, Kim and mKim systems) suggested by Park et al and Kim et al. More than one positive neurologic sign and more than one neurologic clinical symptom was considered a positive neurologic manifestation of each foraminal stenosis. Interobserver agreement between the two readers was analyzed using kappa statistics. Non-parametric correlation analysis (Spearman's correlation) was used to evaluate the correlation coefficients (R) to assess the relationship between CNFS grade and clinical manifestations. Both the Park and mKim systems demonstrated a relatively high correlation (R = 0.714-0.764) between the CNFS grade and clinical manifestation, while the Kim system yielded a moderate correlation (by Reader 2). The Park and mKim systems demonstrated higher correlation values at the level of C6-7 than C4-5, while the Kim system showed no difference in correlation at the cervical spine level. Both the Park and mKim systems provide a reliable, reproducible CNFS diagnosis, while the Kim system has a slightly inferior reliability. The Park and mKim systems had a similar, relatively high clinical correlation. Grades 2 and 3 of the Park system and Grade 2 in the Kim and mKim systems exhibited a similar clinical significance. Patients with a grade of 0 (using each system) consistently exhibit negative neurologic manifestation.


Anisotropic topological surface states on high-index Bi2Se3 films.
A high-index topological insulator thin film, Bi2 Se3 (221), is grown on a faceted InP(001) substrate by molecular-beam epitaxy (see model in figure (a)). Angle-resolved photoemission spectroscopy measurement reveals the Dirac cone structure of the surface states on such a surface (figure (b)). The Fermi surface is elliptical (figure (c)), suggesting an anisotropy along different crystallographic directions. Transport studies also reveal a strong anisotropy in Hall conductance.


[Some aspects of teaching-service integration].
This article analyzes the situation of the nursing educator and the three roles she should carry out: teaching, nursing service and research. Besides these roles are those she should carry out as human being in a social context. The internal and external motivation and the conflicts and feelings that cause an educator to avoid carrying out some of these roles are analyzed. No answer is given for the questions raised; however, it is suggested that an intense, humble study of experience, with self analysis, would help the nursing educator to be more realistic and to come to an equilibrium.


Bilateral ganglion cysts at L4/5 causing central canal stenosis and producing sciatica and neurogenic claudication: a case report.
Symptomatic bilateral juxtafacet ganglion cysts are relatively uncommon in the degenerated spine. The literature describes 16 cases of bilateral ganglion or synovial cysts, none reported sciatica and neurogenic claudication simultaneously. We present a case of a 60-year-old woman who presented with symptoms of bilateral sciatica and neurogenic claudication. Magnetic resonance imaging of the lumbar spine revealed bilateral lesions related to the facet joints at the L4/5 level, causing bilateral lateral recess stenosis and narrowing of the central canal due to encroachment of these bilateral lesions at the same level. She underwent an elective central canal decompression of the L4/5 level and excision of the facet cysts bilaterally with lateral recess decompression, which resulted in good relief of both the radicular and claudication symptoms.


Ethylene involvement in the regulation of heat stress tolerance in plants.
Because of the rise in global temperature, heat stress has become a major concern for crop production. Heat stress deteriorates plant productivity and alters phenological and physiological responses that aid in precise monitoring and sensing of mild-to-severe transient heat stress. Plants have evolved several sophisticated mechanisms including hormone-signaling pathways to sense heat stimuli and acquire heat stress tolerance. In response to heat stress, ethylene, a gaseous hormone, is produced which is indispensable for plant growth and development and tolerance to various abiotic stresses including heat stress. The manipulation of ethylene in developing heat stress tolerance targeting ethylene biosynthesis and signaling pathways has brought promising out comes. Conversely increased ethylene biosynthesis and signaling seem to exhibit inhibitory effects in plant growth responses from primitive to maturity stages. This review mainly focuses on the recent studies of ethylene involvement in plant responses to heat stress and its functional regulation, and molecular mechanism underlying the plant responses in the mitigation of heat-induced damages. Furthermore, this review also describes the crosstalk between ethylene and other signaling molecules under heat stress and approaches to improve heat stress tolerance in plants.


Design of LVFFARK and LVFFARK-functionalized nanoparticles for inhibiting amyloid β-protein fibrillation and cytotoxicity.
Aggregation of amyloid β-protein (Aβ) into amyloid oligomers and fibrils is pathologically linked to Alzheimer's disease (AD). Hence, the inhibition of Aβ aggregation is essential for the prevention and treatment of AD, but the development of potent agents capable of inhibiting Aβ fibrillogenesis has posed significant challenges. Herein, we designed Ac-LVFFARK-NH2 (LK7) by incorporating two positively charged residues, R and K, into the central hydrophobic fragment of Aβ17-21 (LVFFA) and examined its inhibitory effect on Aβ42 aggregation and cytotoxicity by extensive physical, biophysical, and biological analyses. LK7 was observed to inhibit Aβ42 fibrillogenesis in a dose-dependent manner, but its strong self-assembly characteristic also resulted in high cytotoxicity. In order to prevent the cytotoxicity that resulted from the self-assembly of LK7, the peptide was then conjugated to the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to fabricate a nanosized inhibitor, LK7@PLGA-NPs. It was found that LK7@PLGA-NPs had little cytotoxicity because the self-assembly of the LK7 conjugated on the NPs was completely inhibited. Moreover, the NPs-based inhibitor showed remarkable inhibitory capability against Aβ42 aggregation and significantly alleviated its cytotoxicity at a low LK7@PLGA-NPs concentration of 20 μg/mL. At the same peptide concentration, free LK7 showed little inhibitory effect. It is considered that several synergetic effects contributed to the strong inhibitory ability of LK7@PLGA-NPs, including the enhanced interactions between Aβ42 and LK7@PLGA-NPs brought on by inhibiting LK7 self-assembly, restricting conformational changes of Aβ42, and thus redirecting Aβ42 aggregation into unstructured, off-pathway aggregates. The working mechanisms of the inhibitory effects of LK7 and LK7@PLGA-NPs on Aβ42 aggregation were proposed based on experimental observations. This work provides new insights into the design and development of potent NPs-based inhibitors against Aβ aggregation and cytotoxicity.


Neurotrophic factors are required by mature sympathetic neurons for survival, transmission and connectivity.
1. Two neuronal growth factors, nerve growth factor (NGF) and neurotrophin 3 (NT3), have been studied for their action on the developing and mature sympathetic nervous system. 2. Antibodies to each factor have proved useful as reagents for the detection and quantification of NGF and NT3. They have also proved valuable in uncovering the functional roles of each factor by their ability to neutralize the endogenous molecules. 3. Nerve growth factor acts on postnatal neurons to control neurotransmission, connectivity and survival. Like NGF, NT3 is synthesized by effector tissues and is retrogradely transported by post-ganglionic neurons to prevent cell death. However, the two factors have been shown to have quite distinct functions in mature neurons, indicating the existence of different signalling pathways. This differential action extends to secondary influences on satellite glia. 4. Pathological consequences result from excessive growth factor synthesis leading, in the hypertensive rat, to hyperinnervation and elevated blood pressure. Satellite glial cell synthesis of the factors and their receptors following peripheral nerve damage appears to be responsible for the establishment of inappropriate neuronal connections between sympathetic nerve terminals and sensory somata. 5. It is concluded that these potent factors control, by both coincident and independent mechanisms, sympathetic neuronal function throughout the life of the animal.


Cardiac preload, afterload, and heart failure.
The performance of the heart is regulated by the level of myocardial contractility and the cardiac preload and afterload. These factors, previously of interest primarily to basic scientists, are now clinically important for an understanding of both cardiac function and therapeutics. In this brief review, the essence of these concepts is summarized and related to the treatment of cardiac failure.


Healthcare Transformation Towards Personalized Medicine - Chances and Challenges.
The paper introduces a structured approach to transforming healthcare towards personalized, preventive, predictive, participative precision (P5) medicine. It highlights the promising methodological paradigm changes, accompanied by related organizational and technological ones. In the latter context, the deployment of artificial intelligence and autonomous systems is crucial beside miniaturization and mobility. Beside their opportunities, those advanced technologies also bear risks to be managed. Beside the relationships between technology and human actors, the behavior of intelligent and autonomous systems from a humanistic and ethical perspective is in the center of considerations. The different existing approaches for guaranteeing the intended properties are presented and compared for deriving a common set of necessary principles to be met for P5 medicine.


Statistical invalidation of the Hubble law.
An optimal nonparametric technique for elimination of the observation cutoff bias, on the assumption of a given theoretical cosmology, is applied to the redshift-magnitude and redshift-angular diameter relationships in objectively specified large galaxy samples. The estimates obtained on the assumptions of linear and square redshift-distance laws are uniformly and strongly favorable to the square law. The question of whether the relative inferiority of the linear law can scientifically be ascribed to ancillary extragalactic phenomena is addressed by nonparametric crosstesting of the alternative hypotheses. Each law is used to predict the results of a statistical analysis based on the alternative law by using the given data and computer simulations. The result is that the square law predicts with statistical exactitude the results of the analyses of the linear law; but the linear law predicts with near certainty that the fit of the square law will be much worse than is observed. In the absence of independent validation of a variety of ancillary hypotheses that have been adduced in connection with the linear law, it seems necessary to conclude that the Hubble law lacks an objective statistical foundation.


Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice.
Increased arterial stiffness and blood pressure are characteristic of humans and adult mice with reduced elastin levels caused by aging or genetic disease. Direct associations have been shown between increased arterial stiffness and hypertension in humans, but it is not known whether changes in mechanical properties or increased blood pressure occur first. Using genetically modified mice with elastin haploinsufficiency (Eln(+/-)), we investigated the temporal relationship between arterial mechanical properties and blood pressure throughout postnatal development. Our results show that some mechanical properties are maintained constant regardless of elastin amounts. The peak diameter compliance for both genotypes occurs near the physiologic pressure at each age, which acts to provide maximum pulse dampening. The stress-strain relationships are similar between genotypes and become nonlinear near the systolic pressure for each age, which serves to limit distension under high pressure. Our results also show that some mechanical properties are affected by reduced elastin levels and that these changes occur before measurable changes in blood pressure. Eln(+/-) mice have decreased aortic diameter and compliance in ex vivo tests that are significant by postnatal day 7 and increased blood pressure that is not significant until postnatal day 14. This temporal relationship suggests that targeting large arteries to increase diameter or compliance may be an effective treatment for human hypertension.


Control of buckling in colloidal droplets during evaporation-induced assembly of nanoparticles.
Micrometric grains of anisotropic morphology have been achieved by evaporation-induced self-assembly of silica nanoparticles. The roles of polymer concentration and its molecular weight in controlling the buckling behavior of drying droplets during assembly have been investigated. Buckled doughnut grains have been observed in the case of only silica colloid. Such buckling of the drying droplet could be arrested by attaching poly(ethylene glycol) on the silica surface. The nature of buckling in the case of only silica as well as modified silica colloids has been explained in terms of theory of homogeneous elastic shell under capillary pressure. However, it has been observed that colloids, modified by polymer with relatively large molecular weight, gives rise to buckyball-type grains at higher concentration and could not be explained by the above theory. It has been demonstrated that the shell formed during drying of colloidal droplet in the presence of polymer becomes inhomogeneous due to the presence of soft polymer rich zones on the shell that act as buckling centers, resulting in buckyball-type grains.


Crystal structure of the third extracellular domain of CD5 reveals the fold of a group B scavenger cysteine-rich receptor domain.
Scavenger receptor cysteine-rich (SRCR) domains are ancient protein modules widely found among cell surface and secreted proteins of the innate and adaptive immune system, where they mediate ligand binding. We have solved the crystal structure at 2.2 A of resolution of the SRCR CD5 domain III, a human lymphocyte receptor involved in the modulation of antigen specific receptor-mediated T cell activation and differentiation signals. The first structure of a member of a group B SRCR domain reveals the fold of this ancient protein module into a central core formed by two antiparallel beta-sheets and one alpha-helix, illustrating the conserved core at the protein level of genes coding for group A and B members of the SRCR superfamily. The novel SRCR group B structure permits the interpretation of site-directed mutagenesis data on the binding of activated leukocyte cell adhesion molecule (ALCAM/CD166) binding to CD6, a closely related lymphocyte receptor homologue to CD5.


Qualitative and quantitative analysis of agricultural dust in working environment.
The presented quantitative and qualitative analysis of dust in agricultural working environment is a continuation of the process of recognizing the exposure to dust among private farmers. The study covers the following: determination of respirable fraction of dust in the respiratory zone (on the background of total dust) while performing individual farming activities which constitute an annual work cycle, organic and mineral components of settled dust for basic groups of farming activities, and the main mineral pathogenic component - free silica in airborne and settled dust. The study was conducted on 5 farms specialising in: cultivation of cereals, root plants, vegetables, dairy cattle and swine breeding and mixed production. The analysis of settled dust covered 17 types of dust accompanying field work and farm/indoor activities. Studies of airborne dust were conducted on farmers while performing 40 main work activities which contributed to the annual work cycle. Results of the study confirmed the following: agricultural work activities are accompanied by a high level of dustiness and showed the presence of a respirable fraction in airborne dust of up to 25%, a higher level of pathogenic free silica SiO(2) in settled dust samples in the working environment of a farmer, compared to dust in respiratory zone, a comparable level of SiO(2) in total and respirable airborne dust, and a high level of organic component in settled dust at work activities with plant material. These results indicated that the evaluation of farmers' exposure to dust should be based on the examination of samples taken in the respiratory zone while performing individual work activities


Validity and Reliability of the Indonesian Version of SF-36 Quality of Life Questionnaire on Patients with Permanent Pacemakers.
to construct and validate Indonesian version of SF-36. this is a cross-sectional study, which consist of 2 stages process: 1) language and cultural adaption; and 2) validity and reliability evaluation. We evaluated 32 pacemaker patients during language and cultural adaptation stage and 20 pacemaker patients during validity and reliability evaluation stages from September 2014 to August 2015. We followed cross-cultural adaptation guideline to produce Indonesian version of the questionnaire. The final translated questionnaire was checked by assessing the correlation of SF-36 and 6-minutes walking test (6MWT) and NT pro-BNP result. Indonesian version of SF-36 showed positive correlation between 6MWT result and physical functioning (PF) (r=0.363; p=0.001) and negative correlation between NT pro-BNP score with general health (GH) (r=-0.269; p=0.020) and mental health (MH) (r=-0.271; p=0.019). The internal consistency of Indonesian version of SF-36 questionnaire, which measured by Cronbach's alpha, was good with value of >0.70. Repeatability between day 1 and day 8 was good, with strong positive correlation (r=0.626; p=0.003). the Indonesian version of SF-36 could be used as a general questionnaire to assess quality of life in patients with permanent pacemaker.


A review of the evidence linking child stunting to economic outcomes.
To understand the full impact of stunting in childhood it is important to consider the long-run effects of undernutrition on the outcomes of adults who were affected in early life. Focusing on the costs of stunting provides a means of evaluating the economic case for investing in childhood nutrition. We review the literature on the association between stunting and undernutrition in childhood and economic outcomes in adulthood. At the national level, we also evaluate the evidence linking stunting to economic growth. Throughout, we consider randomized controlled trials (RCTs), quasi-experimental approaches and observational studies. Long-run evaluations of two randomized nutrition interventions indicate substantial returns to the programmes (a 25% and 46% increase in wages for those affected as children, respectively). Cost-benefit analyses of nutrition interventions using calibrated return estimates report a median return of 17.9:1 per child. Assessing the wage premium associated with adult height, we find that a 1-cm increase in stature is associated with a 4% increase in wages for men and a 6% increase in wages for women in our preferred set of studies which attempt to address unobserved confounding and measurement error. In contrast, the evidence on the association between economic growth and stunting is mixed. Countries with high rates of stunting, such as those in South Asia and sub-Saharan Africa, should scale up policies and programmes aiming to reduce child undernutrition as cost-beneficial investments that expand the economic opportunities of their children, better allowing them and their countries to reach their full potential. However, economic growth as a policy will only be effective at reducing the prevalence of stunting when increases in national income are directed at improving the diets of children, addressing gender inequalities and strengthening the status of women, improving sanitation and reducing poverty and inequities.


Pathogenesis and morphogenesis of microcirculatory disorders in myocardial infarction. Clinical and ultrastructural examination.
Major advances in the understanding of myocardial infarction (MI) have been made on animal models of ischemia and infarction. We performed ultrastructural examinations of the hearts of 36 patients who died during the acute phase of MI. Tissue for investigation was obtained by express necropsy immediately after death at the clinic. All components of the microcirculatory system of the heart were damaged during the acute phase of MI. Coronary thrombosis led to arteriolar spasm and intravascular blood coagulation in the vicinity of the damaged artery. Microvessels reduction in ischemic, necrotic, and near-infarct zones was caused by endothelial cell injury and rheological disturbances. Thrombocytes played a decisive role in thrombus formation and arteriolar constriction. Leukocytes nearly always impaired the microhemodynamics in ischemic zones due to their size and rigidity. Microcirculatory disorders seemed to precede myocardial cell injury and death.


Circulatory consequences of reduced endogenous nitric oxide production during small-volume resuscitation.
Hypertonic small-volume resuscitation transiently restores the cardiovascular function during various circulatory disturbances. Nitric oxide (NO) is an important mediator of flow-induced peripheral and central hemodynamic changes, and therefore, we hypothesized that a decreased endogenous NO production could influence the consequences and the effectiveness of hypertonic fluid therapy. The main goal of this study was to outline and compare the circulatory effects small volume hypertonic saline-dextran (HSD, 7.5% NaCl-10% dextran; 4 ml/kg iv) infusion with (n=7) or without (n=7) artificially diminished NO production in normovolemic anesthetized dogs. HSD administration significantly increased cardiac index (CI), coronary flow (CF) and myocardial contractility, and elevated plasma nitrite/nitrate (NOx) and endothelin-1 (ET-1) levels. However, the late (2 h) postinfusion period was characterized by significantly decreased myocardial NO synthase (NOS) and enhanced myeloperoxidase activities. Pre-treatment with the non-selective NOS inhibitor N-nitro-L-arginine (NNA, 4 mg/kg) immediately increased cardiac contractility, and the HSD-induced CI and CF elevations and the positive inotropy were absent. Additionally, plasma ET-1 levels increased and NOx levels were significantly decreased. In conclusion, our results demonstrate that HSD infusion leads to preponderant vasoconstriction when endogenous NO synthesis is diminished, and this could explain the loss of effectiveness of HSD resuscitation in NO-deficient states.


Chediak-Higashi Syndrome: a rare disorder of lysosomes and lysosome related organelles.
Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects including recurrent bacterial infections, impaired chemotaxis and abnormal natural killer (NK) cell function. Patients with this syndrome exhibit other symptoms such as an associated lymphoproliferative syndrome, bleeding tendencies, partial albinism and peripheral neuropathies. The classic diagnostic feature of CHS is the presence of huge lysosomes and cytoplasmic granules within cells. Similar defects are found in other mammals, the most well studied being the beige mouse and Aleutian mink. A positional cloning approach resulted in the identification of the Beige gene on chromosome 13 in mice and the CHS1/LYST gene on chromosome 1 in humans. The protein encoded by this gene is 3801 amino acids and is highly conserved throughout evolution. The identification of CHS1/Beige has defined a family of genes containing a common BEACH motif. The function of these proteins in vesicular trafficking remains unknown.


Association Between Aqueous Flare and Epiretinal Membrane in Retinitis Pigmentosa.
Epiretinal membrane (ERM) is a frequent macular complication in patients with retinitis pigmentosa (RP). The etiology of ERM formation in RP is largely unknown. The purpose of this study was to investigate the association between aqueous flare, a surrogate index of intraocular inflammation, and ERM secondary to RP. We retrospectively studied a total of 206 eyes of 117 patients who were diagnosed with typical RP. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. Spectral-domain optical coherence tomography images and fundus photographs taken on the same day of the aqueous flare measurements were analyzed for ERM detection. The mean values of aqueous flare, age, and frequency of male sex were significantly higher in the RP patients with ERM compared with the RP patients without ERM (P < 0.0001, P = 0.007, and P = 0.004, respectively). After adjustment for age and sex, the eyes in the highest quartile of aqueous flare had significantly higher odds of having ERM than those in the lowest quartile (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.04-6.93), and the linear trend across flare levels was significant (P = 0.005). In addition, each 1-log-transformed increase in flare values was associated with an elevation of the likelihood of having ERM (OR, 2.59; 95% CI, 1.33-5.06). Our analysis demonstrated that elevated aqueous flare is associated with ERM secondary to RP, suggesting that inflammation may be implicated in the pathogenesis of ERM formation in RP.


[High level of efficacy and safety of antiviral vaccines and unsubstantiated critique].
To counterbalance the unsubstantial declarations of some vaccinologists that vaccines and vaccination are not only useless, but also injurious to the health, this work represents the evidence that vaccines and vaccination not only reduce the morbidity of viral infection, but also allow some viral diseases to be eradicated and eliminated. The work also adduces the data about reducing economic impact of viral infections with the help of vaccination, as well as the data, which clearly show that serious reactions to vaccination are thousands of times less frequent than reactions and complications caused by infectious diseases.


Cytochrome P450 (CYP450,2D6*A), N-Acetyltransferase-2 (NAT2*7, A) and Multidrug Resistance 1 (MDR1 3435 T) Alleles Collectively Increase Risk of Ulcerative Colitis.
Discovering the association between genetic variations of metabolizing enzymes with idiopathic diseases such as ulcerative colitis (UC) may not only be an auxiliary agent in diagnosis but also could be an effective pharmacotherapy for inflammatory bowel disease (IBD). The aim of the present case-control study was to determine the association of cytochrome P450 2D6 (CYP2D6 *4), N-acteyltransferase-2 (NAT2*7) and multidrug resistance 1 (MDR1) 3435 C/T genotypes with UC susceptibility and thiopurine methyltransferase (TPMT) enzyme activity. TPMT activity was measured by high performance liquid chromatography (HPLC) and genotypes for the 3 mentioned polymorphisms were determined in 215 unrelated UC patients and 212 unrelated healthy controls by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) in a Kurdish population from Iran. CYP2D6*4 A allele, NAT2*7 A and MDR1 3435 C/T alleles act synergistically to increase the risk of UC by 3.49 times. The frequency of the A allele of CYP2D6*4 was significantly higher in UC patients (12.6%) compared to control subjects (8.5%, P = 0.046) that significantly increased the risk of UC by 1.56-fold (P = 0.047). The frequencies of NAT2*7 genotypes and alleles were similar in both studied groups. The most important outcome of this study is that for the first time we demonstrated the simultaneous presence of TMDR1, A CYP2D6*4 and A NAT2*7 alleles robustly increased the risk of developing UC by 3.49-fold. The current study suggests that CYP2D6*4 and MDR1 3435 C/T gene polymorphisms may be risk factors for UC susceptibility.


Cross-reactivity between antigens of Anisakis simplex s.l. and other ascarid nematodes.
A study of the cross-reactivity among somatic and excretory-secretory antigens of the third stage larvae of Anisakis simplex s.l. and somatic antigens of other ascarid nematodes (Ascaris lumbricoides, A. suum, Toxocara canis, Anisakis physeteris, Hysterothylacium aduncum and H. fabri) was carried out by immunoblotting. It was revealed a high degree of cross-reactivity among ascarids in the 30 and > 212 kDa range by using sera against somatic and excretory-secretory antigens of A. simplex s.l. It has been revealed also specific components of the Anisakis genus (< 7.2, 9, 19 and 25 kDa) that will be interesting in diagnosis.


Concurrent cetuximab with stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: a single institution matched case-control study.
Locally recurrent head and neck squamous cell carcinoma can be treated with curative intent by surgical salvage or reirradiation with or without chemotherapy. We have previously demonstrated the feasibility and safety of stereotactic body reirradiation at our institution; however, efficacy has been unsatisfactory. Based on the successful combination of cetuximab with radiotherapy in locally-advanced squamous cell carcinoma of the head and neck, we compared stereotactic body radiotherapy alone with combination therapy, using concomitant cetuximab with stereotactic body radiotherapy, to enhance clinical efficacy while minimizing toxicity. In a retrospective-matched cohort study, we compared 2 groups of patients treated over a 6-year period with stereotactic body radiation therapy alone (n=35) or with weekly cetuximab infusion during stereotactic body radiotherapy (n=35), and evaluated clinical response, local control, overall survival, and toxicity. Cox proportional hazard models were used to assess independent prognostic factors. The median follow-ups for patients alive at last contact were 21.3 months and 24.8 months for stereotactic body radiotherapy only (n=13) and stereotactic body radiotherapy plus cetuximab (n=22), respectively. Our results indicate that cetuximab conferred an overall survival advantage (24.5 vs. 14.8 months) when compared with the stereotactic body radiotherapy alone arm, without a significant increase in grade 3/4 toxicities. This survival advantage was also observed in the subgroup that had received cetuximab therapy during their prior therapeutic regimen. Our results suggest an overall survival benefit of concomitant cetuximab with stereotactic body radiotherapy in locally recurrent head and neck squamous cell carcinoma, and suggest a role in this setting. Concomitant cetuximab with stereotactic body radiotherapy is a reasonable approach for unresectable recurrent squamous cell carcinoma of the head and neck, and should be tested in prospective randomized trials to validate its clinical efficacy.


Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study.
The cardioprotective effects of fumarate have been linked to its metabolism to succinate through both oxidative and reductive pathways. To date, the relative contribution of these pathways is a subject of controversy. To address this question, we designed a protocol with 13C substrates and took advantage of 13C isotopomer analysis by gas chromatography-mass spectrometry. Rat hearts were perfused with 11 mM glucose, 1 mM lactate, 0.2 mM pyruvate, 0.2 mM [1-13C]octanoate, and 0.04 or 0.4 mM [U-13C4]fumarate. On reoxygenation after 40 min of severe hypoxia, hearts perfused with 0.4 mM fumarate showed a better recovery of contractile function and released less lactate dehydrogenase (an index of cellular necrosis) than those perfused with 0.04 mM fumarate. The 13C data showed that, in hypoxic hearts, fumarate conversion to succinate occurred only through reduction, although it accounted for only 16% of total succinate release. Most of the succinate was formed through the oxidation of alpha-ketoglutarate or its precursors (50 +/- 5%) and by another yet-unidentified pathway (34 +/- 4%). These data show that, in a model of hypoxia-reoxygenation, the cardioprotective effects of fumarate were associated with its predominant metabolism to succinate through the reductive pathway.


Tunable elastomer-based virtually imaged phased array.
Virtually imaged phased arrays (VIPAs) offer a high potential for wafer-level integration and superior optical properties compared to conventional gratings. We introduce an elastomer-based tunable VIPA enabling fine tuning of the dispersion characteristics. It consists of a poly-dimethylsiloxane (PDMS) layer sandwiched between silver bottom and top coatings, which form the VIPA's high reflective and semi-transparent mirror, respectively. The latter also acts as an electrode for Joule heating, such that the optical PDMS resonator cavity tuning is carried out via a combination of thermal expansion and the thermo-optic effect. Analogous to the free spectral range (FSR), based on a VIPA specific dispersion law, we introduce a new characteristic VIPA performance measure, namely the free angular range (FAR). We report a tuning span of one FAR achieved by a 7.2K temperature increase of a 170μm PDMS VIPA. Both resonance quality and tunability are analyzed in numerical simulations and experiments.


3'-Hydroxypterostilbene Potently Suppresses Tumor Growth via Inhibiting the Activation of the JAK2/STAT3 Pathway in Ovarian Clear Cell Carcinoma.
Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with higher interleukin-6 (IL-6) levels, and suppression of the Janus kinase 2/Signal transducer and activator of transription 3 (JAK2/STAT3) pathway may contribute to the suppression of this cancer. This study aims to compare the anti-cancer effect of pterostilbene (PSB) and 2'- and 3'-hydroxypterostilbene (2HPSB and 3HPSB, respectively) on the JAK2/STAT3 pathway. In vitro experiments with the OCCC cell line TOV21G and a xenograft nude mouse model are used to achieve the study aims. The results showed that 3HPSB has the greatest anti-proliferative and pro-apoptotic effects of the three compounds studied. Activation of the JAK2/STAT3 pathway and the nuclear translocation of STAT3 are effectively inhibited by 3HPSB and PSB. Both 3HPSB and PSB can effectively suppress tumor growth, which is mediated by the inhibition of JAK2/STAT3 phosphorylation. This is the first study to compare the efficacy of PSB, 3HPSB, and the newly identified compound 2HPSB regarding ovarian cancer. Moreover, targeting JAK2/STAT3 is shown to be a potentially effective strategy for OCCC treatment. This study is expected to provide new insights into the potential of the abovementioned phytochemicals for development as adjuvants for cancer treatment in the future.


Pea DNA helicase 45 promotes salinity stress tolerance in IR64 rice with improved yield.
The helicases provide duplex unwinding function in an ATP-dependent manner and thereby play important role in almost all the nucleic acids transaction. Since stress reduces the protein synthesis by affecting the cellular gene expression machinery, so it is evident that molecules involved in nucleic acid processing including translation factors/helicases are likely to be affected. Earlier pea DNA helicase 45 (PDH45), a homolog of translation initiation factor 4A (eIF4A) was reported to play important role in salinity stress tolerance in tobacco and Bangladeshi rice variety Binnatoa. We report here the overexpression of PDH45 gene in the indica rice variety IR64, via Agrobacterium-mediated transformation. Molecular analysis of the transgenics revealed stable integration of the transgene in the T1 generation. Enhanced tolerance to salinity was observed in the plants transformed with PDH45 gene. Better physiological and yield performances including endogenous nutrient contents (N, P, K, Na) of the transgenics under salt treatment were observed as compared with wild type (WT), vector control and antisense transgenics. All these results indicated that the overexpression of PDH45 in the IR64 rice transgenics enable them to perform better with enhanced salinity stress tolerance and improved physiological traits. Based on the homology of PDH45 protein with eIF4A protein we suggest that it may act at the translational level to enhance or stabilize protein synthesis under stress conditions.


Effects of a Delphi consensus acupuncture treatment protocol on the levels of stress and vascular tone in women undergoing in-vitro fertilization: a randomized clinical trial protocol.
The variability of published acupuncture protocols for patients undergoing In-Vitro Fertilization (IVF) complicates the interpretation of data and hinders our understanding of acupuncture's impact. In 2012, an acupuncture treatment protocol developed by a Delphi consensus process was published to describe the parameters of best practice acupuncture for Assisted Reproductive Technology and future research. However, there has been no clinical trial utilizing this protocol to assess the effects of acupuncture. This study aims to assess the implementation of Dephi consensus acupuncture protocol and to examine the impact of acupuncture on stress and uterine and ovarian blood flow among women between ages 21-42 years seeking IVF. This study is a one site prospective, two-arm randomized controlled non-blind clinical trial conducted in a medical school-affiliated fertility center . Participants will be randomized 1:1 into either the acupuncture group or the standard of care (no acupuncture) group using computer generated tables. Both groups will have 3 regular clinical visits as their standard IVF care during an approximately 2 to 3 weeks window. Women who are randomized into the acupuncture group would receive three sessions based on the Delphi consensus acupuncture protocol in addition to the standard care. The first treatment will be administered between days 6 to 8 of the stimulated IVF cycle. The second session will be performed on the day of embryo transfer at least 1 h prior to the transfer. The third session will be performed within 48 h post-embryo transfer. Participants will be followed for their pregnancy test and pregnancy outcome when applicable. The outcomes stress and blood flow will be measured by a validated perceived stress scale and vasoactive molecules, respectively. Although recruitment and scheduling could be challenging at times, the Delphi consensus acupuncture protocol was implemented as planned and well-accepted by the patients. Because of the time-specified sessions around patients' IVF cycle, it is highly recommended to have on-site study acupuncturist(s) to accommodate the schedule. ClinicalTrials NCT02591186 registered on October 7, 2015.


Oxidized omega-3 fatty acids inhibit pro-inflammatory responses in glomerular endothelial cells.
Omega-3 fatty acids have beneficial effects in chronic inflammatory diseases that are characterized by accumulation of leukocytes and leukocyte-mediated tissue injury. Accumulation of leukocytes occurs, in part, due to pro-inflammatory responses in endothelial cells, such as increase in expression of leukocyte adhesion receptors and chemokines, such as MCP-1 and IL-8. omega-3 fatty acids, such as EPA, are highly polyunsaturated and readily undergo auto-oxidation. We studied the effect of oxidized EPA and unoxidized (native) EPA on leukocyte-glomerular endothelial cell interactions using adhesion assays, ELISA assays and transmigration assays. We used electrophoresis mobility shift assays to determine the effect of oxidized and unoxidized EPA on cytokine-induced nuclear factor-kappaB (NF-kappaB) activation. Oxidized EPA but not unoxidized EPA dose-dependently inhibits cytokine-induced leukocyte adhesion receptors on glomerular endothelial cells, which correlates with inhibition of leukocyte-glomerular endothelial cell interactions. Oxidized EPA but not unoxidized EPA inhibits cytokine-induced glomerular endothelial and mesangial cell expression of MCP-1, and to a lesser extent IL-8. Transmigration assays show that oxidized EPA but not unoxidized EPA inhibits leukocyte transmigration across glomerular endothelial cells. Oxidized EPA but not unoxidized EPA potently inhibited cytokine-induced activation of NF-kappaB in glomerular endothelial and mesangial cells. These studies show that the beneficial effects of fish oil in chronic inflammatory diseases, including IgA nephropathy, may result from the inhibitory effects of oxidized omega-3 fatty acids on pro-inflammatory events in endothelial cells via inhibition of NF-kappaB activation.


Lateral Segregation of Photosystem I in Cyanobacterial Thylakoids.
Photosystem I (PSI) is the dominant photosystem in cyanobacteria and it plays a pivotal role in cyanobacterial metabolism. Despite its biological importance, the native organization of PSI in cyanobacterial thylakoid membranes is poorly understood. Here, we use atomic force microscopy (AFM) to show that ordered, extensive macromolecular arrays of PSI complexes are present in thylakoids from Thermosynechococcus elongatus, Synechococcus sp PCC 7002, and Synechocystis sp PCC 6803. Hyperspectral confocal fluorescence microscopy and three-dimensional structured illumination microscopy of Synechocystis sp PCC 6803 cells visualize PSI domains within the context of the complete thylakoid system. Crystallographic and AFM data were used to build a structural model of a membrane landscape comprising 96 PSI trimers and 27,648 chlorophyll a molecules. Rather than facilitating intertrimer energy transfer, the close associations between PSI primarily maximize packing efficiency; short-range interactions with Complex I and cytochrome b6f are excluded from these regions of the membrane, so PSI turnover is sustained by long-distance diffusion of the electron donors at the membrane surface. Elsewhere, PSI-photosystem II contact zones provide sites for docking phycobilisomes and the formation of megacomplexes. PSI-enriched domains in cyanobacteria might foreshadow the partitioning of PSI into stromal lamellae in plants, similarly sustained by long-distance diffusion of electron carriers.