Tinnitus in children: an uncommon symptom?
Tinnitus in children is regarded as an uncommon problem rarely noted by general paediatricians. Its reported prevalence varies from 12% to 36% in children with normal hearing thresholds and up to 66% in children with hearing loss and approximately 3-10% of children have been reported troubled by tinnitus. Some children do not spontaneously complain of it, but may demonstrate behavioural problems at school and home. A careful history, in conjunction with clinical findings, should guide the appropriate management approach. Even very young children are able to provide insights into what troubles them allowing children's thoughts and fears regarding this symptom to be addressed. We review the available literature on the nature and impact of tinnitus and as guidelines for this do not exist, suggest a pragmatic approach to the management of tinnitus in children. Children with troublesome tinnitus, however, should be referred on to a paediatric audiology department for further investigation and management.


Exosomal lncRNA CHL1-AS1 Derived from Peritoneal Macrophages Promotes the Progression of Endometriosis via the miR-610/MDM2 Axis.
Exosomes secreted by peritoneal macrophages (pMφ) are deeply involved in the development of endometriosis (EMs). Exosomes can mediate cell-to-cell communication by transferring biological molecules. This study aimed to explore the effect and mechanism of exosomal long non-coding RNA (lncRNA) CHL1-AS1 derived from pMφ on EMs. Exosomes (exo) from pMφ were isolated, identified, and co-cultured with ectopic endometrial stromal cells (eESCs) to investigate the biological functions of pMφ-exo. qRT-PCR was used to detect the expression of lncRNA CHL1-AS1 in pMφ-exo from EMs and control patients and verify the transportation of lncRNA CHL1-AS1 from pMφ to eESCs. The effects of exosomal lncRNA CHL1-AS1 on eESC proliferation, migration, invasion, and apoptosis were also detected. The relationships among lncRNA CHL1-AS1, miR-610, and MDM2 (mouse double minute 2) were verified by dual-luciferase reporter assay. The in vivo experiments were conducted to verify the effects of exosomal lncRNA on EMs using a xenograft model of EMs. Exosomes from pMφ were successfully isolated. EMs-pMφ-exo promoted eESC proliferation, migration, and invasion and inhibited their apoptosis. lncRNA CHL1-AS1 was upregulated in EMs-pMφ-exo and transported from pMφ to eESCs via exosomes. lncRNA CHL1-AS1 was found to act as a competing endogenous RNA of miR‑610 to promote the expression of MDM2. EMs-pMφ-exo shuttled lncRNA CHL1-AS1 to promote eESC proliferation, migration, and invasion and inhibit apoptosis by downregulating miR-610 and upregulating MDM2. Furthermore, exosomal lncRNA CHL1-AS1 promoted EMs lesions growth by increasing MDM2 in vivo. The results demonstrate that exosomal lncRNA CHL1-AS1 promotes the proliferation, migration, and invasion of eESCs and inhibits their apoptosis by downregulating miR-610 and upregulating MDM2, which might be a potential therapeutic target for EMs.


Novel therapies for graft versus host disease with a focus on cell therapies.
Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.


The disorder-specific psychological impairment in complex PTSD: A flawed working model for restoration of trust.
This article methodically gathers concepts and findings from related disciplines to propose that there is a fundamental, disorder-specific psychological impairment, which defines Complex Posttraumatic Stress Disorder (PTSD) as etiologically different from simple PTSD. This impairment is a flawed working model for restoration of trust when one partner fears betrayal. This working model is legacy of childhood relationships with manipulative caretakers who kept the child powerless to test the trustworthiness of their reasons to break promises and to fail the child's expectations. Manipulative caretakers invert the respective roles and responsibilities for restoration of trust, which constitutes perversion of intimacy. This article describes how that fundamental flaw becomes the cause of patients' disorder, by episodically rendering them powerless to ascertain a perception of grave betrayal as true or false in later relationships. Repeated failure with experiments for certainty about others' love explains the characteristic personality traits and beliefs of persons with Complex PTSD, i.e., cynicism about the world's benevolence, self-derogation and sense of a foreshortened future. This article closes with reference to a study that investigated the efficacy of a crisis intervention designed to remediate this fundamental impairment.


ASTRO's Framework for Radiopharmaceutical Therapy Curriculum Development for Trainees.
In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021.


Analytic second derivatives for general coupled-cluster and configuration-interaction models.
Analytic second derivatives of energy for general coupled-cluster (CC) and configuration-interaction (CI) methods have been implemented using string-based many-body algorithms. Wave functions truncated at an arbitrary excitation level are considered. The presented method is applied to the calculation of CC and CI harmonic frequencies and nuclear magnetic resonance chemical shifts up to the full CI level for some selected systems. The present benchmarks underline the importance of higher excitations in high-accuracy calculations.


Documentation Burden in Nursing and Its Role in Clinician Burnout Syndrome.
The purpose of this study is to understand the relationship between documentation burden and clinician burnout syndrome in nurses working in direct patient care. The Office of the National Coordinator considers documentation burden a high priority problem. However, the presence of documentation burden in nurses working in direct patient care is not well known. Furthermore, the presence of documentation burden has not been linked to the development of clinician burnout syndrome. This paper reports that the results of a cross-sectional survey study comprised of three tools: (1) The burden of documentation for nurses and mid-wives survey, (2) the system usability scale, and (3) Maslach's burnout inventory for medical professionals. Documentation burden has a weak to moderate correlation to clinician burnout syndrome. Furthermore, poor usability of the electronic health record (EHR) is also associated with documentation burden and clinician burnout syndrome. This study suggests that there is a relationship between documentation burden and clinician burnout syndrome. The correlation of poor usability and domains of clinician burnout syndrome implies the need for more work on improving the usability of EHR for nursing documentation. Further study regarding the presence of documentation burden and its correlation to clinician burnout syndrome should focus on specific areas of nursing to understand the drivers of documentation burden variation within and across specialty domains.


Extracellular vesicles in obesity and its associated inflammation.
Obesity is characterized by low-grade, chronic inflammation, which promotes insulin resistance and diabetes. Obesity can lead to the development and progression of many autoimmune diseases, including inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, thyroid autoimmunity, and type 1 diabetes mellitus (T1DM). These diseases result from an alteration of self-tolerance by promoting pro-inflammatory immune response by lowering numbers of regulatory T cells (Tregs), increasing Th1 and Th17 immune responses, and inflammatory cytokine production. Therefore, understanding the immunological changes that lead to this low-grade inflammatory milieu becomes crucial for the development of therapies that suppress the risk of autoimmune diseases and other immunological conditions. Cells generate extracellular vesicles (EVs) to eliminate cellular waste as well as communicating the adjacent and distant cells through exchanging the components (genetic material [DNA or RNA], lipids, and proteins) between them. Immune cells and adipocytes from individuals with obesity and a high basal metabolic index (BMI) produce also release exosomes (EXOs) and microvesicles (MVs), which are collectively called EVs. These EVs play a crucial role in the development of autoimmune diseases. The current review discusses the immunological dysregulation that leads to inflammation, inflammatory diseases associated with obesity, and the role played by EXOs and MVs in the induction and progression of this devastating conditi8on.


Corneal ulcer disease in Bangladesh.
The problem of acute infectious corneal disease in Bangladesh is discussed. Environmental situations combined with socioeconomic conditions create significant blindness due to this disease in this country. Clinical differentiation into bacterial and fungal ulcers was usually impossible in the advanced stages of ulceration with which the patients presented. Serious logistical problems hinder therapy. Fungal ulcers fared worse than bacterial ulcers. Conjunctival flaps were unsuccessful in alleviating the former. Critical shortage of medication as well as corneal tissue for therapeutic transplantation added to the difficulties. Large-scale public health and educational measures are indicated for effective, long-term solution.


Social cognition, brain networks and schizophrenia.
A better understanding of the neural basis of social cognition including mindreading (or theory of mind) and empathy might help to explain some deficits in social functioning in people with schizophrenia. Our aim was to review neuroimaging and neuropsychological studies on social cognition, as they may shed light on the neural mechanisms of social cognition and its dysfunction in patients with schizophrenia. A selective literature review was undertaken. Neuroimaging and neuropsychological studies suggest convergence upon specific networks for mindreading and empathy (the temporal cortex, amygdala and the prefrontal cortex). The frontal lobe is likely to play a central role in enabling social cognition, but mindreading and empathic abilities may require relatively different weighting of subcomponents within the same frontal-temporal social cognition network. Disturbances in social cognition may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Future studies should seek to explore the heterogeneity of social dysfunction within schizophrenia.


Advances in the diagnosis and treatment of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is a low-grade B-lineage lymphoid malignancy, which is often not treated until patients become symptomatic or develop signs of rapid progression. Even in this setting, treatment is non-curative and is directed at reducing the symptoms from an increasing disease burden. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in CLL patients. Recent combination chemoimmunotherapy regimens have produced frequent complete molecular remissions, and early evidence suggests this may result in an improved long-term survival. Allogeneic hematopoietic cell transplantation is the only curative therapy for CLL but is infrequently used due to the older age of most patients, although reduced intensity conditioning regimens have reduced the toxicity of allogeneic transplantation. This review will summarize recent advances in the management of CLL, including prognostic factors, combination chemotherapy including nucleoside analogs and monoclonal antibodies, and reduced intensity allogeneic transplant conditioning regimens.


Radiation Source Localization Using a Model-Based Approach.
The procedure is practically an optimization method, during which it is assumed that the gamma dose values detected at different points above the area come from the background radiation and from a single source found in the area. Accordingly, the procedure searches within the area for a geographical coordinate for which the distance law for the spatial propagation of radiation will be true. In order to validate the procedure, we performed measurements in a test area in such a way that all parameters of the source, including its location, were well defined. However, these data were not taken into account during the processing, i.e., the search procedure did not have these data. We can estimate the radiation position without a positional parameter. The exact coordinate and the intensity of the radiating sample were only used when checking the results. We have also applied the method to the raw data of our experiments carried out in the past if we used one source for them. The results confirmed our assumptions. The method is suitable for determining the starting parameters of more complex processes that can even detect multiple sources, but assuming one source, it has proven to be a reliable analytical method on its own.


The methyl-branched fortifications of Mycobacterium tuberculosis.
Mycobacterium tuberculosis continues to be the predominant global infectious agent, annually killing over three million people. Recommended drug regimens have the potential to control tuberculosis, but lack of adherence to such regimens has resulted in the emergence of resistant strains. Mycobacterium tuberculosis has an unusual cell envelope, rich in unique long-chain lipids, that provides a very hydrophobic barrier to antibiotic access. Such lipids, however, can be drug targets, as exemplified by the action of the front-line drug isoniazid on mycolic acid biosynthesis. A number of these lipids are potential key virulence factors and their structures are based on very characteristic methyl-branched long-chain acids and alcohols. This review details the history, structure, and genetic aspects of the biosynthesis of these methyl-branched components, good examples of which are the phthiocerols and the mycocerosic and mycolipenic acids.


Theoretical evaluation of voltage inducement on internal membranes of biological cells exposed to electric fields.
Several reports have recently been published on effects of very short and intense electric pulses on cellular organelles; in a number of cases, the cell plasma membrane appeared to be affected less than certain organelle membranes, whereas with longer and less intense pulses the opposite is the case. The effects are the consequence of the voltages induced on the membranes, and in this article we investigate the conditions under which the induced voltage on an organelle membrane could exceed its counterpart on the cell membrane. This would provide a possible explanation of the observed effects of very short pulses. Frequency-domain analysis yields an insight into the dependence of the voltage inducement on the electric and geometric parameters characterizing the cell and its vicinity. We show that at sufficiently high field frequencies, for a range of parameter values the voltage induced on the organelle membrane can indeed exceed the voltage induced on the cell membrane. Particularly, this can occur if the organelle interior is electrically more conductive than the cytosol, or if the organelle membrane has a lower dielectric permittivity than the cell membrane, and we discuss the plausibility of these conditions. Time-domain analysis is then used to determine the courses of the voltage induced on the membranes by pulses with risetimes and durations in the nanosecond range. The particularly high resting voltage in mitochondria, to which the induced voltage superimposes, could contribute to the explanation why these organelles are the primary target of many observed effects.


Preparation and evaluation of dental resin luting agents with increasing content of bisphenol-A ethoxylated dimethacrylate.
Resin luting agents in which bisphenol-A glycidyl dimethacrylate (Bis-GMA) and/or triethylene glycol dimethacrylate (TEGDMA) are replaced with increasing amounts of bisphenol-A ethoxylated dimethacrylate are prepared. Degree of conversion (DC), diametral tensile strength (DTS), Young's modulus (YM), Knoop hardness (KHN), film thickness (FT), water sorption (W(sp) ), and solubility are evaluated. Regression analyses investigate the substitution of each monomer. The most appreciable differences are detected when TEGDMA is replaced: decreased DC, DTS, and W(sp), and increased YM, KHN, and FT. For substitution of Bis-GMA, the only significant differences are reduced W(sp) and increased YM. An ideal formulation of resin cement would make use of the three monomers.


[Microbiologic principles of antibiotic therapy].
Antibiotic therapy, in contrast to other drug treatments, is aimed at the etiology of a given disease state. The main basis of antimicrobial chemotherapy is thus identification of the causative pathogen and documentation of its susceptibility to the least toxic antibiotic. However, these requirements are frequently impossible to meet in everyday management of infections. In many situations, therefore, decision-making in antimicrobial chemotherapy must be based on a "best-guess" diagnosis regarding the causative pathogen and its susceptibility to the antibiotic. The process of decision-making in antimicrobial chemotherapy for the single most frequent infections encountered in outpatients is discussed, and the pertinent antimicrobial treatment for these infections (pharyngo-tonsillitis, otitis media, sinusitis, bronchitis and urinary tract infections) is outlined.


The Fluency Amplification Model supports the GANE principle of arousal enhancement.
The GANE (glutamate amplifies noradrenergic effects) model described by Mather et al. offers a neurophysiological basis for the arousal mechanism which is essential for empirical aesthetics and Gestalt processing. More generally, the core principle of perception can be interpreted as a continuous processing of competing arousal states, yielding selective amplification and inhibition of percepts to deduce the meaning of a scene.


The genus Promalactis Meyrick (Lepidoptera: Oecophoridae) in Cambodia, with description of eight new species.
Nine species of the genus Promalactis Meyrick, 1908 are recorded from Cambodia. Eight species are described as new: P. latiuscula Wang, sp. nov., P. curvicornuta Wang, sp. nov., P. ostacantha Wang, sp. nov., P. apicuncata Wang, sp. nov., P. granulosa Wang, sp. nov., P. argentifasciaria Wang, sp. nov., P. quadrilobata Wang, sp. nov. and P. trifasciata Wang, sp. nov. One species is newly recorded for Cambodia: P. carinata Du, Li et Wang, 2011. Photographs of adults and genitalia are provided.


[A new case of Menkes syndrome. Prenatal exclusion diagnosis in a subsequent pregnancy].
Authors report the cases of a boy with a Menkes' disease which began by a convulsive encephalopathy at the age of two months with growth failure and metaphysical abnormalities. An oldest brother died at 2 years of age in an analogous scene. The diagnosis proved to be founded by the low serum copper and coeruleo-plasmia levels and by the increased uptake of copper in the cultured skin-fibroblasts. The hair was thin and kinky; microscopical study showed pili torti and trichorrhexis nodosa. For the following pregnancy of the mother, a prenatal diagnosis by precocious amniocentesis (amniotic fluid punction) allowed to say that the boy she was expecting for was clear of the disease because of the normal uptake of copper 64 Cu in cultured amniotic fluid cells of the foetus. Authors recall that Menkes' disease is a X linked recessive disorder beginning by epileptic seizure in the early months of life. The basic biochemical lesion of copper metabolism is unknown; there are abnormalities in copper and his binding protein (metallothionein) distribution with increased level is the kidney and decreased level in brain and liver. The copper therapy does not lead to clinical improvement. There is now a prenatal diagnosis: the study of copper uptake in cultured amniotic fluid cells of male fetus. It is abnormally increased in Menkes' disease.


Factors affecting the work passion of physicians during the COVID-19 pandemic: a qualitative study in Thailand.
This qualitative study explores the factors influencing physicians' work passion during the COVID-19 pandemic in the Thai medical context. Using an appreciative inquiry (AI) approach, we conducted qualitative interviews with 30 physicians from a public hospital in Thailand to investigate the factors that influence passion for their professional work (work passion). Our analysis revealed 12 codes influencing physician work passion, which were grouped into four themes: job factors (meaningful work, challenging tasks, task accomplishment, autonomy, work-life balance); organizational factors (fairness, positive environment); relationship factors (having a role model, psychological support, collaboration, recognition and respect); and individual factors (spiritual drive). These findings contribute to developing knowledge about work passion among physicians and provide information to develop effective strategies to harness and manage work passion, thus improving clinical practice and healthcare outcomes. This qualitative study sheds light on the factors that influence physician work passion during the COVID-19 pandemic in Thailand, providing valuable information for future research and guiding the development of strategies to optimize work passion and its impact on clinical practice.


Constitutional Reforms In Pakistan: Turning Around The Picture Of Health Sector In Punjab Province.
consequences of 2011 reforms on the future roles demarcation between the federation and provinces for steering the health sector. The objective of this assessment study was to conduct an institutional appraisal of the provincial health department in Punjab to mark the achievements, problem areas and issues, as well as to formulate the recommendations in the post-devolution scenario. It was an in-depth literature review comprising papers found on PubMed/Medline, Google Scholar, reports published by the government departments, independent research works, academic papers, and documents produced by the development agencies in Pakistan, covering 18th constitutional amendment and its implications on health sector. Following 18th amendment, the Punjab Government formulated health sector strategy (2012-2017) which is being implemented in a phased approach. All districts have developed their three years rolling out plans. An integrated strategic and operational plan of MNCH, Nutrition and Family Planning is under review for approval. Punjab Health Care Commission has been established and is functional to regulate the health sector. Development agencies have in principle committed to support health sector strategy till 2017. Fair investments in improving governance, service delivery structure, human resource, health information, and medical products are expected more than ever in the post 18th amendment scenario. This is the chance for the health system of Punjab to serve the vulnerable people of the provinces, saving them from health shocks.


Metal-Chelating Polymers (MCPs) with Zwitterionic Pendant Groups Complexed to Trastuzumab Exhibit Decreased Liver Accumulation Compared to Polyanionic MCP Immunoconjugates.
Metal-chelating polymers (MCPs) can amplify the radioactivity delivered to cancer cells by monoclonal antibodies or their Fab fragments. We focus on trastuzumab (tmAb), which is used to target cancer cells that overexpress human epidermal growth factor receptor 2 (HER2). We report the synthesis and characterization of a biotin (Bi) end-capped MCP, Bi-PAm(DET-DTPA)36, a polyacrylamide with diethylenetriaminepentaacetic acid (DTPA) groups attached as monoamides to the polymer backbone by diethylenetriamine (DET) pendant groups. We compared its behavior in vivo and in vitro to a similar MCP with ethylenediamine (EDA) pendant groups (Bi-PAm(EDA-DTPA)40). These polymers were complexed to a streptavidin-modified Fab fragment of tmAb, then labeled with (111)In to specifically deliver multiple copies of (111)In to HER2+ cancer cells. Upon decay, (111)In emits γ-rays that can be used in single-photon emission computed tomography radioimaging, as well as Auger electrons that cause lethal double strand breakage of DNA. Our previous studies in Balb/c mice showed that radioimmunoconjugates (RICs) containing the Bi-PAm(EDA-DTPA)40 polymer had extremely short blood circulation time and high liver uptake and were, thus, unsuitable for in vivo studies. The polymer Bi-PAm(EDA-DTPA)40 carries negative charges on each pendant group at neutral pH and a net charge of (-1) on each pendant group when saturated with stable In(3+). To test our hypothesis that charge associated with the polymer repeat unit is a key factor affecting its biodistribution profile, we examined the biodistribution of RICs containing Bi-PAm(DET-DTPA)36. While this polymer is also negatively charged at neutral pH, it becomes a zwitterionic MCP upon saturation of the DTPA groups with stable In(3+) ions. In both nontumor bearing Balb/c mice and athymic mice implanted with HER2+ SKOV-3 human ovarian cancer tumors, we show that the zwitterionic MCP has improved biodistribution, higher blood levels of radioactivity, lower levels of normal tissue uptake, and higher tumor uptake. Surface plasmon resonance experiments employing the extracellular domain of HER2 show that the MCP immunoconjugates retain high affinity antigen recognition, with dissociation constants in the low nM range. In vitro studies with SKOV-3 cells for both MCP immunoconjugates show a combination of specific binding that can be completed in the presence of excess tmAb IgG and nonspecific binding (NSB) that persists in the presence of tmAb IgG. We conclude that zwitterionic MCPs represent a much better choice than polymers with charges along the backbone for in vivo delivery of RICs to HER2+ cancer cells.


Breakdown of wave diffusion in 2D due to loops.
The validity of the diffusion approximation for the intensity of multiply scattered waves is tested with numerical simulations in a strongly scattering 2D medium of finite extent. We show that the diffusion equation underestimates the intensity and attribute this to both the neglect of recurrent scattering paths and interference within diffusion theory. We present a theory to quantify this discrepancy based on counting all possible scattering paths between point scatterers. Interference phenomena, due to loop paths, are incorporated in a way similar to coherent backscattering.


Fatty acid oxidation and signaling in apoptosis.
It is well established that fatty acid metabolites of cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are implicated in essential aspects of cellular signaling including the induction of programmed cell death. Here we review the roles of enzymatic and non-enzymatic products of polyunsaturated fatty acids in controlling cell growth and apoptosis. Also, the spontaneous oxidation of polyunsaturated fatty acids yields reactive aldehydes and other products of lipid peroxidation that are potentially toxic to cells and may also signal apoptosis. Significant conflicting data in terms of the role of LOX enzymes are highlighted, prompting a re-evaluation of the relationship between LOX and prostate cancer cell survival. We include new data showing that LNCaP, PC3, and Du145 cells express much lower levels of 5-LOX mRNA and protein compared with normal prostate epithelial cells (NHP2) and primary prostate carcinoma cells (TP1). Although the 5-LOX activating protein inhibitor MK886 killed these cells, another 5-LOX inhibitor AA861 hardly showed any effect. These observations suggest that 5-LOX is unlikely to be a prostate cancer cell survival factor, implying that the mechanisms by which LOX inhibitors induce apoptosis are more complex than expected. This review also suggests several mechanisms involving peroxisome proliferator activated receptor activation, BCL proteins, thiol regulation, and mitochondrial and kinase signaling by which cell death may be produced in response to changes in non-esterified and non-protein bound fatty acid levels. Overall, this review provides a context within which the effects of fatty acids and fatty acid oxidation products on signal transduction pathways, particularly those involved in apoptosis, can be considered in terms of their overall importance relative to the much better studied protein or peptide signaling factors.


Inducible error-prone repair in Escherichia coli.
A hypothesis that ultraviolet-induced mutagenesis arises from the induction of an error-prone mode of postreplication repair that requires the exrA+ recA+ genotype has been tested with alkaline sucrose gradient centrifugation coupled with assays of fixation determined by loss of photoreversibility. The inhibitor of protein synthesis, chloramphenicol, added before irradiation, prevented a small amount of postreplication repair and completely eliminated mutation fixation in E. coli WP2s uvrA. However, chloramphenicol did not affect strand joining: (a) in uvrA bacteria allowed 20 min of growth between irradiation and antibiotic treatment; (b) in nonmutable uvrA exrA bacteria; and (c) in uvrA tif bacteria grown at 42 degrees for 70 min before irradiation. These observations indicate that an inducible product is involved in a fraction of postreplication repair and is responsible for induced mutagenesis.


Investigation of association of the IL12B and IL23R genes with psoriatic arthritis.
Recent reports have confirmed association of single-nucleotide polymorphisms (SNPs) mapping to the interleukin-23 receptor (IL-23R) and IL-12beta genes with psoriasis susceptibility. The aim of this study was to determine whether these variants are also associated with susceptibility to psoriatic arthritis (PsA). Two IL23R SNPs (rs7530511 and rs11209026) and 2 IL12B SNPs (rs3212227 and rs6887695) were genotyped in DNA samples from 520 white patients with PsA and 2,260 control subjects, all of whom resided in the UK. For SNP rs3212227, data on a larger group of controls (n = 4,681) were publicly available; this information was used in the analysis. Genotype counts were compared between patients with PsA and population controls, using the trend test. A haplotype comprising carriage of the common variants of both IL23R SNPs was associated with PsA susceptibility (adjusted P = 0.013 [1,000 permutations]). Both IL12B SNPs were independently associated with PsA susceptibility, and this association was strongest under a dominant model, with homozygosity for the common allele being more frequent in patients with PsA than in control subjects: for rs3212227, the odds ratio (OR) for carriage of AA versus other genotypes was 1.43 (95% confidence interval [95% CI] 1.17-1.76); for rs6887695, the OR for carriage of GG versus other genotypes was 1.43 (95% CI 1.18-1.74). Variation within IL23R and IL12B is associated with susceptibility to both psoriasis and PsA. The effect sizes observed in patients with PsA appear to be smaller than those previously reported in patients with psoriasis, suggesting that both loci are primarily associated with psoriasis susceptibility. However, this does support the idea that the genetic etiology of the psoriasis present in patients with PsA has susceptibility loci in common with those observed in patients with uncomplicated psoriasis.


The Role of Reactive Oxygen Species and Autophagy in Periodontitis and Their Potential Linkage.
Periodontitis is a chronic inflammatory disease that causes damage to periodontal tissues, which include the gingiva, periodontal ligament, and alveolar bone. The major cause of periodontal tissue destruction is an inappropriate host response to microorganisms and their products. Specifically, a homeostatic imbalance between reactive oxygen species (ROS) and antioxidant defense systems has been implicated in the pathogenesis of periodontitis. Elevated levels of ROS acting as intracellular signal transducers result in autophagy, which plays a dual role in periodontitis by promoting cell death or blocking apoptosis in infected cells. Autophagy can also regulate ROS generation and scavenging. Investigations are ongoing to elucidate the crosstalk mechanisms between ROS and autophagy. Here, we review the physiological and pathological roles of ROS and autophagy in periodontal tissues. The redox-sensitive pathways related to autophagy, such as mTORC1, Beclin 1, and the Atg12-Atg5 complex, are explored in depth to provide a comprehensive overview of the crosstalk between ROS and autophagy. Based on the current evidence, we suggest that a potential linkage between ROS and autophagy is involved in the pathogenesis of periodontitis.


Metastatic transitional cell carcinoma of the urinary bladder to the shoulder girdle.
Transitional cell carcinoma (TCC) of the bladder typically metastasizes to the pelvic lymph nodes and to visceral sites including the lungs, liver, and bones. Other sites include the brain, especially after systemic chemotherapy. To our knowledge, we report the first case of TCC metastatic to the soft tissue of the shoulder girdle and discuss common and unusual sites of metastasis in TCC.


Transcriptional regulation of the glial cell-specific JC virus by p53.
The human polyomavirus JC virus is the etiologic agent of progressive multifocal leukoencephalopathy (PML). As the JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, transcriptional regulation constitutes a major mechanism of glial tropism in PML. It has been demonstrated that SV40 or JC virus large T antigen interacts with p53 protein and regulates many viral and cellular genes. In this study we found that p53 represses the JC virus early promoter in both glial and nonglial cells. To identify the cis-regulatory elements responsible for p53-mediated repression, deletional and site-directed mutational analyses were performed. Deletion of the enhancer region diminished p53-mediated transcriptional repression. However, point mutations of several transcription factor binding sites in the basal promoter region did not produce any significant changes. In support of this observation, when the enhancer was fused to a heterologous promoter, p53 reduced the promoter activity about three fold. These results indicate that the enhancer region is important for the repression of JC virus transcription by p53. Furthermore, coexpression of JC virus T antigen with a p53 protein abolished p53-mediated repression of the JC virus early promoter in non-glial cells, but not in glial cells. This finding suggests that T antigen interacts with p53 and regulates JC virus transcription in a cell-specific manner.


Bias-Exchange Metadynamics Simulation of Membrane Permeation of 20 Amino Acids.
Thermodynamics of the permeation of amino acids from water to lipid bilayers is an important first step for understanding the mechanism of cell-permeating peptides and the thermodynamics of membrane protein structure and stability. In this work, we employed bias-exchange metadynamics simulations to simulate the membrane permeation of all 20 amino acids from water to the center of a dipalmitoylphosphatidylcholine (DPPC) membrane (consists of 256 lipids) by using both directional and torsion angles for conformational sampling. The overall accuracy for the free energy profiles obtained is supported by significant correlation coefficients (correlation coefficient at 0.5-0.6) between our results and previous experimental or computational studies. The free energy profiles indicated that (1) polar amino acids have larger free energy barriers than nonpolar amino acids; (2) negatively charged amino acids are the most difficult to enter into the membrane; and (3) conformational transitions for many amino acids during membrane crossing is the key for reduced free energy barriers. These results represent the first set of simulated free energy profiles of membrane crossing for all 20 amino acids.


PAIR Comparison between Two Within-Group Conditions of Resting-State fMRI Improves Classification Accuracy.
Classification approaches have been increasingly applied to differentiate patients and normal controls using resting-state functional magnetic resonance imaging data (RS-fMRI). Although most previous classification studies have reported promising accuracy within individual datasets, achieving high levels of accuracy with multiple datasets remains challenging for two main reasons: high dimensionality, and high variability across subjects. We used two independent RS-fMRI datasets (n = 31, 46, respectively) both with eyes closed (EC) and eyes open (EO) conditions. For each dataset, we first reduced the number of features to a small number of brain regions with paired t-tests, using the amplitude of low frequency fluctuation (ALFF) as a metric. Second, we employed a new method for feature extraction, named the PAIR method, examining EC and EO as paired conditions rather than independent conditions. Specifically, for each dataset, we obtained EC minus EO (EC-EO) maps of ALFF from half of subjects (n = 15 for dataset-1, n = 23 for dataset-2) and obtained EO-EC maps from the other half (n = 16 for dataset-1, n = 23 for dataset-2). A support vector machine (SVM) method was used for classification of EC RS-fMRI mapping and EO mapping. The mean classification accuracy of the PAIR method was 91.40% for dataset-1, and 92.75% for dataset-2 in the conventional frequency band of 0.01-0.08 Hz. For cross-dataset validation, we applied the classifier from dataset-1 directly to dataset-2, and vice versa. The mean accuracy of cross-dataset validation was 94.93% for dataset-1 to dataset-2 and 90.32% for dataset-2 to dataset-1 in the 0.01-0.08 Hz range. For the UNPAIR method, classification accuracy was substantially lower (mean 69.89% for dataset-1 and 82.97% for dataset-2), and was much lower for cross-dataset validation (64.69% for dataset-1 to dataset-2 and 64.98% for dataset-2 to dataset-1) in the 0.01-0.08 Hz range. In conclusion, for within-group design studies (e.g., paired conditions or follow-up studies), we recommend the PAIR method for feature extraction. In addition, dimensionality reduction with strong prior knowledge of specific brain regions should also be considered for feature selection in neuroimaging studies.


Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.
Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN-sensitive NMDARs are essential for LTP induction.


Mismatched decoding in the brain.
"How is information decoded in the brain?" is one of the most difficult and important questions in neuroscience. We have developed a general framework for investigating to what extent the decoding process in the brain can be simplified. First, we hierarchically constructed simplified probabilistic models of neural responses that ignore more than Kth-order correlations using the maximum entropy principle. We then computed how much information is lost when information is decoded using these simplified probabilistic models (i.e., "mismatched decoders"). To evaluate the information obtained by mismatched decoders, we introduced an information theoretic quantity, I*, which was derived by extending the mutual information in terms of communication rate across a channel. We showed that I* provides consistent results with the minimum mean-square error as well as the mutual information, and demonstrated that a previously proposed measure quantifying the importance of correlations in decoding substantially deviates from I* when many cells are analyzed. We then applied this proposed framework to spike data for vertebrate retina using short natural scene movies of 100 ms duration as a set of stimuli and computing the information contained in neural activities. Although significant correlations were observed in population activities of ganglion cells, information loss was negligibly small even if all orders of correlation were ignored in decoding. We also found that, if we inappropriately assumed stationarity for long durations in the information analysis of dynamically changing stimuli, such as natural scene movies, correlations appear to carry a large proportion of total information regardless of their actual importance.


Early Results of Rheumatic Mitral Valve Repair.
Mitral valve repair (MVr) in rheumatic heart disease (RHD) remains challenging. The present authors' surgical experience of MVr in 56 patients with RHD operated in between January 2011 and September 2014 is reported. Among the patients (mean age 32 ± 11 years), 11 were in NYHA functional class II, 32 in class III, and seven in class IV. An adequate or oversized autologous pericardial patch was sutured to extend the coaptating edge of both the anterior leaflet (in 18 patients) and the posterior leaflet (in 30 patients). Neochordae were implanted as needed (n = 43), and leaflet thinning (n = 13), commissurotomy (n = 15) and chordal splitting (n = 9) were also performed. A rigid annuloplasty ring was implanted in 32 patients, and in 24 patients a complete flexible annuloplasty ring made from pericardium, 4 mm Gore-Tex tube graft or a Dacron patch was constructed. Repair was not attempted in 16 patients, with replacement using a mechanical bileaflet prosthesis being considered the only option. Intraoperative post-repair transesophageal echocardiography demonstrated competency, with trivial mitral regurgitation (MR) up to grade I in all patients and a minimum coaptation depth ≥5 mm. There were no intraoperative or in-hospital deaths. Clinical and echocardiographic evaluations were performed up to six weeks after surgery, at which time 51 patients were in NYHA classes I-II and five were in class III. Residual mild MR up to grade I was identified in six patients. No recurrence of MR was observed in any of the patients, and no patients were reoperated on. The lack of adequate access to anticoagulation medication and monitoring, in addition to religious/cultural bias to the type of prosthetic valve used in low-income countries, necessitates an increase in the numbers of rheumatic MVr.


More than just a substrate for mites: Moss-dominated biological soil crust protected population of the oribatid mite, Oppia nitens against cadmium toxicity in soil.
Metal-impacted sites often need aggressive ecorestoration strategies to restore a functional plant-soil system. The use of biological soil crusts for soil stabilization, moisture retention and C and N input in disturbed and contaminated soils is becoming a more common ecorestoration practice. Biological soil crusts comprise cyanobacteria, fungi, lichens, and bryophytes (mostly moss). Moss-dominated BSCs provide significant N mineralization rate in most terrestrial ecosystems. Oribatid mites or moss mites dominate moss-dominated BSCs and provide essential ecosystem services such as decomposition and nutrient cycling. We hypothesized that moss-dominated BSCs would create a high-quality habitat niche for O. nitens to resist Cd-induced toxicity. Adult mites were exposed to Cd for 28 days in soil with or without BSCs that were aged for eight months. Cadmium toxicity to mites in soil without BSCs was 1.7 and 5.4times greater than in soil with BSCs, respectively for the mites reproduction and instantaneous population growth rate (PGRi). The moss-dominated BSC did not reduce Cd bioavailability in the mites but increased the mite's resilience to Cd toxicity, likely mediated by the trophic transfer of calcium from the BSC to the mites. Our work identifies a second mechanistic avenue by which BSCs are useful for ecorestoration, i.e., the improvement of soil invertebrate physiology to resist metal stress.


A Study of Urodynamic Parameters at Different Bladder Filling Stages for Predicting Upper Urinary Tract Dilatation.
To identify more accurate predictors of upper urinary tract dilatation (UUTD) in neurogenic bladder (NB) children, we studied the relationship among urodynamic parameters at different bladder filling stages, detrusor leak point pressure (DLPP) and UUTD. A total of 158 children (3-16 years) with NB were included and then divided into 2 groups according to whether their NB diagnosis was complicated with UUTD: the UUTD group (39 patients) and those without UUTD group (control group, 119 patients). The bladder filling phase was divided into 3 equal parts: the early, middle, and end filling stages. The bladder compliance (BC) and detrusor pressure (△Pdet) at each phase and DLPP at the end filling stage were recorded. A BC<8 mL/cm H2O both in the middle and end stages is more specific than a BC<9 mL/cm H2O in the end stage (72%, 73%, vs. 66%), and △Pdet >8 cm H2O in the early stage, 20 cm H2O in the middle stage and 25 cm H2O in the end stage are more sensitive than △Pdet >40 cm H2O in the end stage (82%, 85%, 85%, vs. 49%). A DLPP cutoff value of 20 cm H2O showed higher sensitivity for predicting UUTD than 40 cm H2O. Low BC and a high △Pdet in the middle and end filling stages are more accurate factors than classic indicators for predicting UUTD. In addition, a DLPP value of >20 cm H2O in the end bladder filling stage shows high sensitivity.


Modification of phospholipids fatty acid composition in reuber H35 hepatoma cells: effect on HMG-CoA reductase activity.
There is controversy about the effect of saturated and polyunsaturated fats on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the main regulatory enzyme of cholesterogenic pathway. Results from dietary studies are difficult to interpret because diets normally contain a mixture of fatty acids. Therefore, we have used Reuber H35 hepatoma cells whose phospholipids were enriched in different individual fatty acids and have studied their effects on the cellular reductase activity. Lauric, myristic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids were supplemented to the culture medium coupled to bovine serum albumin. The four fatty acids were incorporated into phospholipids from cells grown in media containing whole serum or lipoprotein-poor serum (LPPS). Reductase activity of cells cultivated in a medium with LPPS was three to four times higher than those cultivated in medium with whole serum. Saturated fatty acids increased reductase activity of cells grown in medium with whole serum, whereas n-3 polyunsaturated fatty acids (PUFA) decreased it. However, both saturated and polyunsaturated fatty acids increased reductase activity when serum lipoproteins were removed. In conclusion, this is one of the first reports demonstrating that saturated and n-3 PUFA only show differential effects on HMG-CoA reductase activity in the presence of lipoproteins.


A Useful Blood Flow Restriction Training Risk Stratification for Exercise and Rehabilitation.
Blood flow restriction training (BFRT) is a modality with growing interest in the last decade and has been recognized as a critical tool in rehabilitation medicine, athletic and clinical populations. Besides its potential for positive benefits, BFRT has the capability to induce adverse responses. BFRT may evoke increased blood pressure, abnormal cardiovascular responses and impact vascular health. Furthermore, some important concerns with the use of BFRT exists for individuals with established cardiovascular disease (e.g., hypertension, diabetes mellitus, and chronic kidney disease patients). In addition, considering the potential risks of thrombosis promoted by BFRT in medically compromised populations, BFRT use warrants caution for patients that already display impaired blood coagulability, loss of antithrombotic mechanisms in the vessel wall, and stasis caused by immobility (e.g., COVID-19 patients, diabetes mellitus, hypertension, chronic kidney disease, cardiovascular disease, orthopedic post-surgery, anabolic steroid and ergogenic substance users, rheumatoid arthritis, and pregnant/postpartum women). To avoid untoward outcomes and ensure that BFRT is properly used, efficacy endpoints such as a questionnaire for risk stratification involving a review of the patient's medical history, signs, and symptoms indicative of underlying pathology is strongly advised. Here we present a model for BFRT pre-participation screening to theoretically reduce risk by excluding people with comorbidities or medically complex histories that could unnecessarily heighten intra- and/or post-exercise occurrence of adverse events. We propose this risk stratification tool as a framework to allow clinicians to use their knowledge, skills and expertise to assess and manage any risks related to the delivery of an appropriate BFRT exercise program. The questionnaires for risk stratification are adapted to guide clinicians for the referral, assessment, and suggestion of other modalities/approaches if/when necessary. Finally, the risk stratification might serve as a guideline for clinical protocols and future randomized controlled trial studies.


Age estimation based on pulp cavity to tooth volume ratio using postmortem computed tomography images.
Pulp cavity size is known to decrease with age and can therefore serve as an indicator for age estimation. Here, we evaluated whether reconstructed images of multidetector-row computed tomography (MDCT) acquired before forensic autopsy are useful for estimating age at death. Images of 136 mandibular first premolars obtained from bodies of known age at death were analyzed, and the volume of the regions corresponding to pulp cavity and that of the whole tooth were determined using a voxel counting function. The pulp cavity was clearly distinguishable from dental hard tissue on the reconstructed images when using a cutoff value of 1400 Hounsfield units. Regression analysis adjusted for sex showed that estimated age correlated significantly with the pulp cavity to tooth volume ratio (r = 0.76). MDCT is gaining more widespread use in forensic medicine, and analyzing dental images to obtain parameters for age prediction is a practical approach for postmortem identification.


A REEVALUATION OF THE ORIGIN OF PENTADACTYLY.
The hypothesis suggested by Coates that pentadactyly arose twice is based on the presumed affinities between Tulerpeton, embolomeres, and amniotes. Flaws were found in the coding of some characters that supported this clade and, once corrected, the matrix fails to support the proposed phylogeny. Furthermore, interpretation of the phylogeny of Coates is difficult because no amniotes and no lissamphibians were included in this analysis. A reappraisal of the affinities of Tulerpeton using a matrix composed of a greater range of taxa suggests that it is a stem-tetrapod, that pentadactyly arose only once, and that the first tetrapod was already pentadactyl.


Living donor kidney transplantation: how far should we go?
The aim of this review was to describe the work that the Başkent University Faculty of Medicine has done to increase kidney donors' number in Turkey and also to discuss the major effects that donor-organ shortage is currently having worldwide. From 1975 through 2003, our transplantation team at Hacettepe University Hospital and later at the Başkent University Transplantation Center (BUTC) performed 1451 kidney transplantations. Cadaver donation rates prior to and after the establishment of the National Coordination Center (NCC) were calculated and compared. Also, patient and graft survival rates for various groupings of transplantation types were compared. All statistical analysis was done using the log-rank test. Of all the renal transplantations completed in Turkey from 1975 to January 2004, 20% were performed by our team in our center. For the years 1990 through 2003, the 1-, 3-, and 5-year patient survival rates in the first-degree-living-related kidney transplantation group were 96%, 93%, and 91%, respectively, and the corresponding graft survival rates were 93%, 84%, and 81%. In the second-degree living-related group, the 1-, 3-, and 5-year patient survival rates were 94%, 90%, and 87%, respectively, and the corresponding graft survival rates were 93%, 86%, and 84%. For living-unrelated transplantations, the 1-, 3- and 5-year patient survival rates were 93%, 90%, and 83%, respectively, and the corresponding graft survival rates were 83%, 78%, and 76%. In the cadaver-kidney transplantation group, the 1-, 3- and 5-year patient survival rates were 85%, 78%, and 70%, respectively, and the corresponding graft survival rates were 82%, 64%, and 53%. During this same period, the 1-, 3-, and 5-year graft survival rates for our cadaver donors and living donors older than 55 years of age were 80%, 52%, 46% and 88%, 69%, 61%, respectively. Vigorous efforts by our group at Başkent University and by other transplant surgeons across the nation have increased the numbers of transplantations performed each year. As well, since the NCC was established in 2001, the number of cadaver-kidney transplantations has more than doubled. The initial results with this new nationwide organ-sharing system are promising, and there is every indication that this approach will continue to raise the number of transplant operations performed across Turkey each year. We suggest that Turkish citizens should consider changing our national policies on organ donation. Opt-out policies can increase the pool of cadaver-organ transplants. In addition, to increasing cadaver donation, we feel that living-related donation restricted to first- and second-degree relatives and acceptable non-blood-related donors (such as spouses) is the best path to expanding kidney transplantation worldwide.


Astrocyte: An Innovative Approach for Alzheimer's Disease Therapy.
Alzheimer's disease (AD) is a devastating neurological illness with a heavy economic impact. Further comorbidities in combination with the social impact of this disorder increase the urgency of a clearer comprehension of its etiopathogenesis, allowing the execution of novel therapeutic strategies. Despite astrocytes have been widely described as active participant in the regulation of cerebral circuits, available data are still poor. Even less information is available about their precise role in the pathogenesis of illness. Moreover, the scant knowledge about the astrocyte-neuron interplay in health and disease still impedes pioneering discoveries. The focus of this review is to look for new and innovative pharmacological approaches against AD. In order to perform this, we used the following keywords in PubMed search engine: astrocytes, therapy, Alzheimer's disease, and glia in different combinations. With this review, we collected data available in literature describing how also astrocytes besides neurons might be new potential targets for drug discovery. Different approaches currently being studied include modulation of glutamate transporters expression, astroglial genetic manipulation, free radicals inhibition, up-regulation of neurotrophins, and regulation of astrogliosis and neuroinflammation. Since several studies already demonstrated that astrocytes are definitely involved in AD pathogenesis, these cells can represent a promising new therapeutic target.


Synthesis and reactivity of W3Te74+ clusters and chalcogen exchange in the M3Q7 (M = Mo, W; Q = S, Se, Te) cluster family.
Heating WTe(2), Te, and Br(2) at 390 degrees C followed by extraction with KCN gives [W(3)Te(7)(CN)(6)](2-). Crystal structures of double salts Cs(3.5)K{[W(3)Te(7)(CN)(6)]Br}Br(1.5).4.5H(2)O (1), Cs(2)K(4){[W(3)Te(7)(CN)(6)](2)Cl}Cl.5H(2)O (2), and (Ph(4)P)(3){[W(3)Te(7)(CN)(6)]Br}.H(2)O (3) reveal short Te(2)...X (X = Cl, Br) contacts. Reaction of polymeric Mo(3)Se(7)Br(4) with KNCSe melt gives [Mo(3)Se(7)(CN)(6)](2-). Reactions of polymeric Mo(3)S(7)Br(4) and Mo(3)Te(7)I(4) with KNCSe melt (200-220 degrees C) all give as final product [Mo(3)Se(7)(CN)(6)](2)(-) via intermediate formation of [Mo(3)S(4)Se(3)(CN)(6)](2-)/[Mo(3)SSe(6)(CN)(6)](2-) and of [Mo(3)Te(4)Se(3)(CN)(6)](2-), respectively, as was shown by ESI-MS. (NH(4))(1.5)K(3){[Mo(3)Se(7)(CN)(6)]I}I(1.5).4.5H(2)O (4) was isolated and structurally characterized. Reactions of W(3)Q(7)Br(4) (Q = S, Se) with KNCSe lead to [W(3)Q(4)(CN)(9)](5-). Heating W(3)Te(7)Br(4) in KCNSe melt gives a complicated mixture of W(3)Q(7) and W(3)Q(4) derivatives, as was shown by ESI-MS, from which E(3)[W(3)(mu(3)-Te)(mu-TeSe)(3)(CN)(6)]Br.6H(2)O (5) and K(5)[W(3)(mu(3)-Te)(mu-Se)(3)(CN)(9)] (6) were isolated. X-ray analysis of 5 reveals the presence of a new TeSe(2-) ligand. The complexes were characterized by IR, Raman, electronic, and (77)Se and (125)Te NMR spectra and by ESI mass spectrometry.


Establishment of a Single Temperature Incubation Approach for Environmental Monitoring Samples with Focus on Mold Recoveries.
A robust environmental monitoring program is essential to properly estimate and identify microorganisms in cleanrooms, ensuring that microbial contamination remains acceptably low, and a good state of control is maintained in the manufacturing areas. The incubation conditions are important to support optimal microbial recoveries, considering that there is no single culture medium, temperature and incubation time that can recover all microorganisms. Particularly molds are quite sensitive microorganisms, and some species may have very specific nutritional and environmental needs. In this study, a two-phase approach was used to identify a single incubation-temperature approach that could recover most of the cleanroom microbial flora with focus on molds. Phase 1 included a growth promotion study performed in the laboratory using pharmacopeial and in-house strains, comparing different media (SDA and TSA) at single or dual incubation-temperature approaches for 5 or 6 days. Phase 2 was based on an in situ study where sampling was performed in different areas of a pharmaceutical facility, comparing the recoveries at different incubation conditions. In addition, extension studies of phase 1 and phase 2 were performed to get a better understanding of growth requirements for in-house molds. The results show that an incubation on Tryptone Soy Agar (TSA) at 25-30° for 3-4 days was able to recover most tested microorganisms in phase 1 and a large variety of microorganisms in phase 2, indicating that the single incubation-temperature is an optimal approach for the recovery of microorganisms in cleanrooms. Exceptions were noted for one strain of the species Cutibacterium acnes, a microaerophilic bacterium for which anaerobiosis and higher temperatures were needed, and two mold strains (Sistotrema brinkmannii and Stereum hirsutum), indicating that those molds required a specific media (Sabouraud Dextrose Agar, SDA) for their proliferation. The results showed that TSA incubated at single or dual incubation-temperature approach cannot compensate for the absence of SDA for some environmental molds that may be atypical in cleanrooms. Therefore, in addition to TSA, certain monitoring with SDA at e.g., cleanroom entrance points may be beneficial to recover molds with very specific nutritional requirements.


[Progress on sORF-encoded micropeptides].
Existing research has shown that there are a large amount of non-coding RNAs (ncRNAs) in organisms. Short open reading frames (sORFs) abundantly exist in molecular sequences inaccurately annotated as ncRNAs. Several sORFs can be transcribed and translated into evolutionarily conserved micropeptides, which were ignored in previous studies due to short sequence lengths and the limitations of research techniques. To date, sORF-encoded micropeptides with various functions have been found to play important roles in regulating vital biological activities. This article reviews the functional micropeptides which have been found in recent years, introduces the new micropeptide designated as MIAC that we have discovered and describes the related technologies for mining potential micropeptides, thereby providing insights and references for new micropeptide discovery for researchers.


Aspergchromones A and B, two new polyketides from the marine sponge-associated fungus Aspergillus sp. SCSIO XWS03F03.
Two new polyketides, aspergchromones A (1) and B (2), together with five known compounds, secalonic acid D (3), noreugenin (4), (3S)-5-hydroxymellein (5), (4S)-6-hydroxyisosclerone (6), and (-)-regiolone (7), were isolated from the ethyl acetate extract of marine sponge-derived fungus Aspergillus sp. SCSIO XWS03F03. Their structures were elucidated by means of spectroscopic techniques (1D and 2D NMR, MS, UV, and IR). The absolute configurations of the new compounds were established by ECD calculations. Compound 3 showed moderate antimicrobial activity.


Analysis of mutations in the XPD gene in a patient with brittle hair.
Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder characterized by sulfur-deficient brittle hair, growth and mental retardation, and ichthyosis. TTD is caused primarily by mutations in the xeroderma pigmentosum group D (XPD) gene, which encodes a subunit of the basal transcription factor IIH. We have identified a novel heterozygous mutation in XPD (c.1906C>T; p.R636W) resulting in mild-phenotype TTD in the proband and her mother. No identical variations were found in one hundred healthy Korean controls. In silico analysis suggested that the novel mutation was a causative mutation for TTD. This genotype-phenotype correlation provides a unique insight into the TTD inheritance pattern and could prove useful in the diagnosis of patients.


Growth of carbon nanotubes on surfaces: the effects of catalyst and substrate.
We report a study of synthesising air-stable, nearly monodispersed bimetallic colloids of Co/Pd and Fe/Mo of varying compositions as active catalysts for the growth of carbon nanotubes. Using these catalysts we have investigated the effects of catalyst and substrate on the carbon nanostructures formed in a plasma-enhanced chemical vapour deposition (PECVD) process. We will show how it is possible to assess the influence of both the catalyst and the support on the controlled growth of carbon nanotube and nanofiber arrays. The importance of the composition of the catalytic nuclei will be put into perspective with other results from the literature. Furthermore, the influence of other synthetic parameters such as the nature of the nanoparticle catalysts will also be analysed and discussed in detail.


Tetanus after application of traditional topical treatment to a severe burn.
A 2-year-old child was accompanied by his parents to the pediatric emergency room for refusal to eat, trismus and generalized contractures four days after the application of a traditional topical treatment (Cassava leaves) on lesions of a severe thermal burn. A temperature of 38̊C, a heart rate of 114 beats/min, and a blood pressure of 90/60 mm Hg were recorded. The tetanus vaccination was not up to date. The diagnosis of tetanus was immediately suggested. Antitetanus serum (immunoglobulin), an antibiotic (amoxicillin and clavulanic acid), and a myorelaxant (benzodiazepine) were administered. Local treatments were also performed. The child died within 24 hours.


Investigation of doxorubicin resistance in MCF-7 breast cancer cells using shot-gun comparative proteomics with proteolytic 18O labeling.
A shot-gun comparative proteomic investigation utilizing proteolytic 18O labeling has been carried out on a drug susceptible MCF-7 human breast cancer cell line and a related cell line that is resistant to doxorubicin. The proteolytic 18O labeling method has been further refined and optimized for application to a protein fraction stemming from the cytosol of the breast cancer cells. The comparative investigation revealed several proteins with altered expression levels in the doxorubicin resistant line. These altered proteins are considered for a possible role in doxorubicin resistance.


Skeletal muscle loss during neoadjuvant chemotherapy predicts poor prognosis in patients with breast cancer.
The skeletal muscle index (SMI), which is calculated as the ratio of skeletal muscle area at the third lumbar vertebral level divided by height squared, has been considered a prognostic factor in patients with breast cancer. However, the prognostic impact of changes in SMI during treatment remains unclear. This study aimed to evaluate the influence of SMI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). We reviewed patients with breast cancer who underwent NAC and subsequent surgery for breast cancer between 2010 and 2017. The rate of SMI change during NAC was calculated, and the association between SMI changes and prognosis was retrospectively analyzed. In total, 141 patients were evaluated. 48 (34.0%), 53 (37.6%), and 40 (28.4%) patients exhibited increased (≥ 3%), maintained (- 3% <, < 3%), and decreased (- 3% ≥) SMI during NAC, respectively. The decreased SMI group showed significantly poorer disease-free survival than the maintained and increased SMI groups (hazard ratio [HR] 8.29, p < 0.001 for the decreased vs. increased SMI groups; HR 3.49, p < 0.001 for the decreased vs. maintained SMI groups). Moreover, decreased SMI was an independent risk factor for disease-free survival in multivariate analysis (HR 3.68, p < 0.01). Skeletal muscle loss during NAC predicts poor prognosis. Our results underscore the importance of monitoring and maintaining skeletal muscle mass during NAC.


A dataset of EEG recordings from 47 participants collected during a virtual reality working memory task where attention was cued by a social avatar and non-social stick cue.
This data article describes electroencephalography (EEG) and behavioral data from 47 participants. Data was collected using a 64 channel eego™ sports mobile EEG system during a visual working memory task presented in virtual reality (VR) using Unity with an Oculus Rift S head-mounted display. In the memory task, participants had to remember the status of and details about objects presented on a table. Prior to object appearance a moving, 3D social avatar or non-social stick cue was presented which pointed to the left or right of the table. Items for encoding could appear in the valid, cued location or the invalid, un-cued location, with the cue being uninformative to the task. The cue type was presented within subjects, blocked, counterbalanced. The data (behavioral & EEG (raw and processed)), scripts and the full task are available. The data is set up to allow investigation of neural signals during attention cueing, and memory encoding, maintenance and retrieval. The main novelty of the dataset is the presentation of the social avatar and non-social stick cue in VR within subjects, thus, allowing comparison across time points, including a period of eye contact. The data is also of interest to researchers interested in the neural corelates of working memory. Further, it is of interest to researchers interested in combining VR and EEG.


GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration.
ADAMs are cell surface metalloproteases that control multiple biological processes by cleaving signaling and adhesion molecules. ADAM13 controls cranial neural crest (CNC) cell migration both by cleaving cadherin-11 to release a promigratory extracellular fragment and by controlling expression of multiple genes via its cytoplasmic domain. The latter activity is regulated by γ-secretase cleavage and the translocation of the cytoplasmic domain into the nucleus. One of the genes regulated by ADAM13, the protease calpain8, is essential for CNC migration. Although the nuclear function of ADAM13 is evolutionarily conserved, it is unclear whether the transcriptional regulation is also performed by other ADAMs and how this process may be regulated. We show that ADAM13 function to promote CNC migration is regulated by two phosphorylation events involving GSK3 and Polo-like kinase (Plk). We further show that inhibition of either kinase blocks CNC migration and that the respective phosphomimetic forms of ADAM13 can rescue these inhibitions. However, these phosphorylations are not required for ADAM13 proteolysis of its substrates, γ-secretase cleavage, or nuclear translocation of its cytoplasmic domain. Of significance, migration of the CNC can be restored in the absence of Plk phosphorylation by expression of calpain-8a, pointing to impaired nuclear activity of ADAM13.


Nitrate supplementation improves physical performance specifically in non-athletes during prolonged open-ended tests: a systematic review and meta-analysis.
Nitrate (NO3 -) is an ergogenic nutritional supplement that is widely used to improve physical performance. However, the effectiveness of NO3 - supplementation has not been systematically investigated in individuals with different physical fitness levels. The present study analysed whether different fitness levels (non-athletes v. athletes or classification of performance levels), duration of the test used to measure performance (short v. long duration) and the test protocol (time trials v. open-ended tests v. graded-exercise tests) influence the effects of NO3 - supplementation on performance. This systematic review and meta-analysis was conducted and reported according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A systematic search of electronic databases, including PubMed, Web of Science, SPORTDiscus and ProQuest, was performed in August 2017. On the basis of the search and inclusion criteria, fifty-four and fifty-three placebo-controlled studies evaluating the effects of NO3 - supplementation on performance in humans were included in the systematic review and meta-analysis, respectively. NO3 - supplementation was ergogenic in non-athletes (mean effect size (ES) 0·25; 95 % CI 0·11, 0·38), particularly in evaluations of performance using long-duration open-ended tests (ES 0·47; 95 % CI 0·23, 0·71). In contrast, NO3 - supplementation did not enhance the performance of athletes (ES 0·04; 95 % CI -0·05, 0·15). After objectively classifying the participants into different performance levels, the frequency of trials showing ergogenic effects in individuals classified at lower levels was higher than that in individuals classified at higher levels. Thus, the present study indicates that dietary NO3 - supplementation improves physical performance in non-athletes, particularly during long-duration open-ended tests.


Development of Woolly Hair and Hairlessness in a CRISPR-Engineered Mutant Mouse Model with KRT71 Mutations.
Hypotrichosis simplex (HS) and woolly hair (WH) are rare and monogenic disorders of hair loss. HS, characterized by a diffuse loss of hair, usually begins in early childhood and progresses into adulthood. WH displays strong coiled hair involving a localized area of the scalp or covering the entire side. Mutations in the keratin K71(KRT71) gene have been reported to underlie HS and WH. Here, we report the generation of a mouse model of HS and WH by the co-injection of Cas9 mRNA and sgRNA, targeting exon6 into mouse zygotes. The Krt71-knockout (KO) mice displayed the typical phenotypes, including Krt71 protein expression deletion and curly hair in their full body. Moreover, we found that mice in 3-5 weeks showed a new phenomenon of the complete shedding of hair, which was similar to nude mice. However, we discovered that the mice exhibited no immune deficiency, which was a typical feature of nude mice. To our knowledge, this novel mouse model generated by the CRISPR/Cas9 system mimicked woolly hair and could be valuable for hair disorder studies.


Lapatinib ditosylate rescues memory impairment in D-galactose/ovariectomized rats: Potential repositioning of an anti-cancer drug for the treatment of Alzheimer's disease.
Epidermal growth factor receptor (EGFR) signaling plays a substantial role in learning and memory. The upregulation of EGFR has been embroiled in the pathophysiology of Alzheimer's disease (AD). Nevertheless, most of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been extensively studied for non-CNS diseases such as cancer and rheumatoid arthritis. TKIs targeting-based research in neurodegenerative disorders sounds to be lagging behind those of other diseases. Hence, this study aims to explore the molecular signaling pathways and the efficacy of treatment with lapatinib ditosylate (LAP), as one of EGFR-TKIs that has not yet been investigated in AD, on cognitive decline induced by ovariectomy (OVX) with chronic administration of D-galactose (D-gal) in female Wistar albino rats. OVX rats were injected with 150 mg/kg/day D-gal ip for 8 weeks to induce AD. Administration of 100 mg/kg/day LAP p.o. for 3 weeks starting after the 8th week of D-gal administration improved memory and debilitated histopathological alterations. LAP decreased the expression of GFAP, p-tau, and Aβ 1-42. Besides, it reduced EGFR, HER-2, TNF-α, NOX-1, GluR-II, p38 MAPK, and p-mTOR. LAP increased nitrite, and neuronal pro-survival transduction proteins; p-PI3K, p-AKT, and p-GSK-3β levels. Taken together, these findings suggest the role of LAP in ameliorating D-gal-induced AD in OVX rats via activating the pro-survival pathway; PI3K-Akt-GSK-3β, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways. Moreover, this research offered a significant opportunity to advance awareness of the repositioning of TKI anti-cancer drugs for the treatment of AD.


Expression of human tissue-type plasminogen activator from lytic viral vectors and in established cell lines.
We have used two kinds of vectors to express a cDNA of human tissue plasminogen activator (t-PA) in mammalian cells. In one case, cDNAs inserted into vectors based on bovine papilloma virus were introduced into cultured murine cells and cell lines were established that efficiently and continuously secrete enzymatically active t-PA into the medium. Second, the t-PA gene was used to replace the sequences of the simian virus (SV40) genome that code for the viral coat proteins. Virus stocks were generated and used to infect a stable line of cultured simian cells. During the resulting lytic infection, expression of the t-PA gene is governed by the potent SV40 late promoter and enzymatically active t-PA accumulates rapidly in the medium. We have used these two vector systems to analyze the biosynthesis and transport of recombinant t-PA and to compare its properties with those of "natural" t-PA secreted by the Bowes line of human melanoma cells. t-PA secreted from all three sources is identical in specific activity (approximately 20,000 units/mg) despite differences in patterns of terminal glycosylation. Furthermore, non-glycosylated t-PA synthesized in the presence of tunicamycin was secreted efficiently and was indistinguishable in specific activity from glycosylated t-PAs.


Dual-functional semithiobambusurils.
Semithiobambusurils, which represent a new family of macrocyclic host molecules, have been prepared by a convenient, scalable synthesis. These new cavitands are double functional: they strongly bind a broad variety of anions in their interiors and metal ions at their sulfur-edged portals. The solid-state structure of semithiobambus[4]uril with HgCl2 demonstrates the ability of these compounds to form linear chains of coordination polymers with thiophillic metal ions. The crystal structure of semithiobambus[6]uril with tetraphenylphosphonium bromide exhibits the unique anion-binding properties of the host cavity and the characteristics of the binding site.


Polyarteritis nodosa presenting with frank hematuria.
Polyarteritis nodosa (PAN) is an uncommon systemic vasculitis characterized by necrotizing inflammation of small- or medium-sized arteries. The disease normally presents with non-specific symptoms. Urological symptoms at presentation are extremely rare. We report a 65-year-old man who was diagnosed with a polyarteritis nodosa having presented atypically with left testicular pain and swelling, and an intratesticular lesion. He developed painless visible hematuria while under investigation. No gross arterio-venous fistula was seen to suggest a false aneurysm. Subsequently, laboratory studies showed positive anti-neutrophil cytoplasmic antibody levels and a raised erythrocyte sedimentation rate. This was an unusual presentation of PAN diagnosed with multidisciplinary input from the urology, radiology and nephrology teams.


Smoking outcome by psychiatric history after behavioral and varenicline treatment.
Treatment outcomes were compared across smokers enrolled in the COMPASS cessation trial with (positive psychiatric history [PH+], n = 271) and without (PH-, n = 271) a diagnosis of PH based on medical record evidence of anxiety, depression, psychotic disorder, or bipolar disorder. Everyone received behavioral counseling plus varenicline and was followed for 6 months post quit date. PH+ smokers took varenicline for fewer days on average (59.4 vs. 68.5, p < or = .01) but did not differ in their use of behavioral treatment. PH+ smokers were more likely to report anxiety and depression, but side-effect intensity ratings did not differ after adjusting for multiple comparisons. Overall, all side effects were rated as moderate intensity or less. Groups had similar 30-day abstinence rates at 6 months (31.5% PH+ vs. 35.4% PH-, p = .35). In sum, having a psychiatric diagnosis in this trial did not predict worse treatment outcome or worse treatment side effects.


Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells.
Sorafenib is currently used to treat advanced and/or unresectable hepatocellular carcinoma (HCC), but the increase of the median survival was only 3 months. Moreover, sorafenib has severe side effects and patients develop resistance quickly. Epigenetic alterations such as DNA methylation play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that analysed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies, we found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis allowed identifying several enriched signaling pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis, angiogenesis and invasion, and genes belonging to pathways known to be deregulated in HCC such as RAF/MEK/ERK, JAK-STAT, PI3K/AKT/mTOR and NF-κB. Generally, we found that oncogenes tended to be hypermethylated and the tumor suppressor genes tended to be hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results for several genes found differentially methylated such as BIRC3, FOXO3, MAPK3, SMAD2 and TSC2, using both COBRA assay and direct bisulfite sequencing and we evaluated their mRNA expression. Our findings suggest that sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways in HCC cells, some of which have been previously described to be directly targeted by sorafenib.


Thermal oxidation of V2O3 nanocrystals: a template method for the fabrication of monoclinic phase VO2 nanocrystals.
We report the fabrication of VO2(M) nanocrystals by direct thermal oxidation V2O3 nanocrystals. The controlling of the thermal oxidation temperature and vacuum is essential for obtaining pure VO2(M) nanocrystals. The VO2(M) nanocrystals have nearly a spherical morphology with sizes ranging from 50 to 80 nm and well dispersed. The phase transition temperature is about 65 degrees C with relatively narrow endothermic and exothermal peaks in DSC curve. Variable temperature resistance and infrared transmission measurements demonstrate a reversible phase transition of the VO2(M) nanocrystals. Our method is facile, economical and can be easily scaled-up for mass production.


Metabolic syndrome: nature, therapeutic solutions and options.
Metabolic syndrome (MetS) defines the clustering in an individual of multiple metabolic abnormalities, based on central obesity and insulin resistance. In addition to its five components, prothrombotic and proinflammatory states are essential features. The significance of MetS lies in its close association with the risk of type 2 diabetes and cardiovascular disease (CVD). This field being an evolving one necessitated the current review. The areas covered in this review include the so far unproven concept that enhanced low-grade inflammation often leads to dysfunction of the anti-inflammatory and atheroprotective properties of apolipoprotein A-I (apoA-I) and HDL particles, which further increases the risk of diabetes and CVD. It was emphasized that lifestyle modification is essential in the prevention and management of MetS, which includes maintenance of optimal weight by caloric restriction, adherence to a diet that minimizes postprandial glucose and triglyceride fluctuations, restricting alcohol consumption, smoking cessation and engaging in regular exercise. Drug therapy should target the dyslipoproteinemia and the often associated hypertension or dysglycemia.Statins are the drugs of first choice, to be initiated in patients with MetS at high 10-year cardiovascular risk. Such treatment is inadequate if fasting serum triglycerides remain at > 150 mg/dl, when niacin should be combined. Fibrates, omega 3 fatty acids, metformin, angiotensin-converting enzyme inhibitors and pioglitazone are additional options in drug therapy. Research on MetS in subpopulations prone to impaired glucose tolerance and insulin resistance has indicated that proinflammatory state and oxidative stress are often prominently involved in MetS, to the extent that evidence of impaired function of HDL and apo A-I particles is discernible by biological evidence of functional defectiveness via outcomes studies and/or correlations with inflammatory and anti-inflammatory biomarkers. A sex difference has been clear in this development.


Implementing and Evaluating Environmental and Policy Interventions for Promoting Physical Activity in Rural Schools.
Schools are an important setting for improving behaviors associated with obesity, including physical activity. However, within schools there is often a tension between spending time on activities promoting academic achievement and those promoting physical activity. A community-based intervention provided administrators and teachers with a training on evidence-based public health and then collaborated with them to identify and implement environmental (walking track) and local school policy interventions (brain breaks). The evaluation included conducting in-depth interviews and SOPLAY observations to assess the facilitators and barriers and impact of the dissemination of environmental and policy changes. Individual, organizational, intervention, and contextual factors influenced dissemination. Teachers reported that brain breaks increased student focus and engagement with classroom material and decreased student behavioral problems. Students decreased sedentary behavior and increased vigorous behavior. Of the 4 schools, 2 increased walking. Active dissemination of environmental and policy interventions by engaging school administrators and teachers in planning and implementation shows potential for increasing physical activity in rural school settings.


[Suicide by Ethiopian immigrants in Israel].
49 Ethiopian immigrants to Israel committed suicide between Jan. 1983 and Sept. 1992. First and second degree relatives and friends of 32 of the suicides were interviewed using a questionnaire ("psychological autopsy"). In 12 cases detailed reports of welfare services and also 7 summaries from mental health institutions were analyzed. Except in 1989, the suicide rate of Ethiopian Jews was considerably higher than that of the general population of Israel (19-46 vs 6-8/100,000). The profile of a high suicide risk in an Ethiopian immigrant was that of a married man up to 40 years old, usually with a marital conflict, who appears depressed but does not communicate suicidal intent, and who frequently visits his general physician. This profile differs considerably from that of immigrants from other countries and of Israelis in general. The social message of the Ethiopian suicide conveys feelings of indignation. 3 cases are presented.


[Analgesia and renal insufficiency].
Chronic kidney disease (CKD) prevalence increases with population aging and makes drugs prescription more difficult. Only a few studies have reported drug dosing adjustment in CKD patients, even in the important field of pain management. We propose an algorithm based on the current literature that helps in selecting right analgesic according to the degree of renal failure. Drug dosing adjustment of the most usually used analgesics (acetaminophen, nonsteroidal anti-inflammatory drugs and opioids) is discussed.


Cobalt-based paramagnetic probe to study RNA-protein interactions by NMR.
Paramagnetic resonance enhancement (PRE) is an NMR technique that allows studying three-dimensional structures of RNA-protein complexes in solution. RNA strands are typically spin labeled using nitroxide reagents, which provide minimal perturbation to the native structure. The current work describes an alternative approach, which is based on a Co2+-based probe that can be covalently attached to RNA in the vicinity of the protein's binding site using 'click' chemistry. Similar to nitroxide spin labels, the transition metal based probe is capable of attenuating NMR signal intensities from protein residues localized <40Å away. The extent of attenuation is related to the probe's distance, thus allowing for construction of the protein's contact surface map. This new paradigm has been applied to study binding of HIV-1 nucleocapsid protein 7, NCp7, to a model RNA pentanucleotide.


Photocontrol of the collagen triple helix: synthesis and conformational characterization of bis-cysteinyl collagenous peptides with an azobenzene clamp.
For the photomodulation of the collagen triple helix with an azobenzene clamp, we investigated various collagenous peptides consisting of ideal (Gly-Pro-Hyp) repeats and containing cysteine residues in various positions for a side chain-to-side chain crosslink with a suitable chromophore derivative. Comparative conformational analysis of these cysteine peptides indicated an undecarepeat peptide with two cysteine residues located in the central portion in i and i+7 positions and flanked by (Gly-Pro-Hyp) repeat sequences as the most promising for the cross-bridging experiments. In aqueous alcoholic solution the azobenzene-undecarepeat peptide formed a stable triple helix in equilibrium with the monomeric species as a trans-azobenzene isomer, whereas photoisomerization to the cis isomer leads to unfolding of at least part of the triple helix. Furthermore, the residual supercoiled structure acts like an intermolecular knot, thus making refolding upon cis-to-trans isomerization a concentration-independent fast event. Consequently, these photoswitchable collagenous systems should be well suited for time-resolved studies of folding/unfolding of the collagen triple helix under variable thermodynamic equilibria.


Expression of normal and cystic fibrosis phenotypes by continuous airway epithelial cell lines.
Continuous epithelial cell lines from individuals with cystic fibrosis (CF) and normal controls are required to understand the genetic and cellular defects in CF. We used retroviruses to transduce SV40 large T antigen into nasal epithelial cells. Transformed continuous cell lines were isolated that expressed epithelial markers, cytokeratin, and tight junctions. Northern blot analysis shows that all of the cell lines express the putative CF gene mRNA. Studies of transepithelial electrolyte transport show that CF and normal cell lines develop a transepithelial electrical resistance. Normal but not CF cell lines secreted Cl- in response to agonists that increase cellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) (isoproterenol, forskolin, and a membrane-permeant analogue of cAMP) or in response to a tumor-promoting phorbol ester that activates protein kinase C. In contrast, the Ca2(+)-elevating agonist bradykinin and the Ca2+ ionophore A23187 stimulated secretion in both normal and CF cell lines. The continuous cell lines we have produced maintain their proper phenotypes and will serve as useful tools in understanding the pathophysiology of CF.


Energy charge and mitotic activity in regenerating rat liver during parenteral nutrition.
The relationship among parenteral nutrition, hepatic energy charge, and mitotic activity was investigated in partially hepatectomized rats fed diets based on glucose, ketone bodies, and saline (starvation). Male Sprague-Dawley rats underwent 70% hepatectomy and jugular vein catheterization for parenteral feeding. All rats were infused with saline for 6 hours, then randomly assigned to one of three parenteral infusions. Rats received either 0.9% saline only (group A rats), 25% glucose + 4% amino acid (group B rats), or 18% monoacetoacetin + 7% glucose + 4% amino acid (group C rats). Three rats receiving saline infusion were killed at 2, 4, and 6 hours after surgery, and three rats from each diet group were killed at 2- to 4-hour intervals from 10 through 32 hours. Hepatic energy charge and mitotic index were measured at each time point. Energy charge was similar for each treatment until 18 hours but was depressed from 6 through 16 hours and began to increase between 16 and 18 hours. Energy charge at 22 hours for group B rats was significantly higher than energy charge for group A and C rats. This difference was maintained through 32 hours. Mitosis started between 24 and 26 hours for all treatments, and group A and C rats exhibited a much higher mitotic index than did group B rats. Adenosine triphosphate was the main driving force for changes in energy charge. The data showed that energy charge and mitotic index were inversely related. It is speculated that high energy charge may negatively influence activity of enzymes inasmuch as activity of these enzymes is altered by phosphorylation-dephosphorylation.


Macrolides and gastrointestinal motility.
Erythromycin was the first macrolide used clinically, and it is still the most widely prescribed in spite of reports of gastrointestinal side-effects. Erythromycin was given iv or orally to fasted and fed dogs with sensors implanted on the gastrointestinal tract for the measurement of motility. There was a large increase in stomach and upper small bowel contractile activity, accompanied by nausea and vomiting, while the distal small bowel appeared inhibited. Similar effects were seen in man. By contrast, two 16-membered macrolides, spiramycin and josamycin, did not produce such side-effects when given either orally or intravenously to dogs.


Specular Reflection Separation With Color-Lines Constraint.
According to dichromatic reflection model, the previous methods of specular reflection separation in image processing often separate specular reflection from a single image using patch-based priors. Due to lack of global information, these methods often cannot completely separate the specular component of an image and are incline to degrade image textures. In this paper, we derive a global color-lines constraint from dichromatic reflection model to effectively recover specular and diffuse reflection. Our key observation is from that each image pixel lies along a color line in normalized RGB space and the different color lines representing distinct diffuse chromaticities intersect at one point, namely, the illumination chromaticity. For pixels along the same color line, they spread over the entire image and their distances to the illumination chromaticity reflect the amount of specular reflection components. With global (non-local) information from these color lines, our method can effectively separate specular and diffuse reflection components in a pixelwise way for a single image, and it is suitable for real-time applications. Our experimental results on synthetic and real images show that our method performs better than the state-of-the-art methods to separate specular reflection.


Gauging the Auditory Dimensions of Dysarthric Impairment: Reliability and Construct Validity of the Bogenhausen Dysarthria Scales (BoDyS).
Standardized clinical assessment of dysarthria is essential for management and research. We present a new, fully standardized dysarthria assessment, the Bogenhausen Dysarthria Scales (BoDyS). The measurement model of the BoDyS is based on auditory evaluations of connected speech using 9 scales (traits) assessed by 4 elicitation methods. Analyses of the BoDyS' reliability and construct validity were performed to test this model, with the aim of gauging the auditory dimensions of speech impairment in dysarthria. Interrater agreement was examined in 70 persons with dysarthria. Construct validity was examined in 190 persons with dysarthria using a multitrait-multimethod design with confirmatory factor analysis. Interrater agreement of < 1 on a 5-point scale was found in 91% of cases across listener pairs and scales. Average reliability was .85. Inspection of the multitrait-multimethod matrix pointed at a high convergent and discriminant validity. Modeling of the BoDyS trait and method factors using confirmatory factor analysis yielded high goodness of fit. Model coefficients confirmed high discriminant and convergent validity and revealed meaningful relationships between scales and methods. The 9 auditory scales of the BoDyS provide a reliable and valid profile of dysarthric impairment. They permit standardized measurement of clinically relevant dimensions of dysarthric speech.