Seizure Onset Localization in Focal Epilepsy using intracranial-EEG data and the Schrodinger Operator's Spectrum.
Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures that vary from short attention failure to convulsions. Despite its threats and limitations, existing medications target only specific types of seizures while up to 33% of epileptic conditions are drug-resistant. The best available treatment is surgical resection or neurostimulation and both require accurate localization of the Seizure Onset Zone. Its delineation is performed by analyzing neuronal activity by epileptologists, however, it is time-consuming and error-prone. Therefore, if the said zone could be located faster and more accurately, the seizure freedom of patients would be significantly enhanced. An effort within the field is aiming at developing computer-aided methods to assist medical experts and this starts with characterizing electrical neural activity. In the present paper, a new method for characterizing the epileptic intracranial EEG is proposed. The method is based on a semi-classical signal analysis (SCSA) method. Functional connectivity measures are used to compare patterns observed when feeding these measures with the raw time-series and when feeding them with SCSA features. The obtained results are undeniably promising for further investigation and improvement of the framework.Clinical relevance- The paper contributes to the design methods and algorithms to build reliable software solutions to assist medical experts in identifying Seizure Onset Zone in focal epilepsy.


Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.
Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.


[The pathogenesis, clinical picture and diagnosis of the Mallory-Weiss syndrome].
The authors consider that predisposing factors in the development of the Mallory-Weiss syndrome include restriction of mobility of the mucous and submucous layers of the cardia in relation to one another, uncoordinated and oppositely directed contractions of differently oriented muscle layers of the lower third of the esophagus and cardial portion of the stomach, incompetence of the cardial closing apparatus. Rupture of the wall of the stomach and duodenum is associated with an immediate dramatic change of the intragastric pressure. The endoscopic method of examination is thought to be the leading one in diagnosing the Mallory-Weiss syndrome.


Herpesvirus 8 inclusions in primary effusion lymphoma: report of a unique case with T-cell phenotype.
We describe a case of primary effusion lymphoma with T-cell phenotype, mixed genotype, and intranuclear herpesvirus inclusions visible with the light microscope. Cells were studied by immunohistochemical analysis, in situ hybridization, immunoglobulin and T-cell receptor gene rearrangement, and polymerase chain reaction. Primary effusion lymphoma cells with T-cell phenotype revealed herpesvirus 8 inclusions predominantly seen in apoptotic cells, suggesting that productive viral infection is associated with cell death. Clinical features were typical of primary effusion lymphoma. Cytologic, molecular genetic, and phenotypic features demonstrated a unique variant of primary effusion lymphoma.


Effects of cell surface ganglioside sialidase inhibition on growth control and differentiation of human neuroblastoma cells.
Gangliosides on the external side of the plasma membrane are important modulators of cellular functions. In previous work we had found that in cultured human SK-N-MC neuroblastoma cells a cell surface sialidase activity specifically cleaved terminal sialic acids from gangliosides, leading to a shift from higher sialylated species to GM1 and a decrease of GM3. To further elucidate the function of the enzyme, we have now examined the consequences of ganglioside sialidase inhibition. When present in the culture medium, the ganglioside sialidase inhibitors 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NeuAc2en), heparin, and heparan sulfate caused dramatic changes in cell behavior. Thus, the inhibitors uniformly led to a complete release from contact inhibition of growth, and to the loss of the differentiation markers neuron-specific enolase and neurofilaments, and a decrease of cyclic AMP. In presence of NeuAc2en, cells that normally were spread out evenly and were firmly attached, appeared smaller, rounded, and only loosely adherent to the culture vessel. Exogenous addition of vibrio cholerae sialidase mimicked the action of the plasma membrane ganglioside sialidase by retarding cell proliferation and increasing intracellular acetylcholinesterase. That the ganglioside sialidase inhibitors in the culture medium indeed affected solely the cell surface enzyme and not also a lysosomal sialidase, was demonstrated in an experiment where the desialylation of exogenously added radioactive gangliosides was determined in absence and presence of NeuAc2en and NH4Cl, an inhibitor of lysosomal function. Taken together, our results suggest that the ganglioside sialidase on the surface of SK-N-MC cells is responsible for growth control and differentiation in this neuronal cell line.


Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59 months of age in Lilongwe, Malawi: a study protocol.
Pneumonia is the leading infectious cause of death in children under 5 years of age around the globe. In addition to preventing pneumonia, there is a critical need to provide greater access to appropriate and effective treatment. Studies in Asia have evaluated the effectiveness of 3 days of oral amoxicillin for the treatment of fast-breathing pneumonia; however, further evidence is needed to determine if 3 days of oral amoxicillin is also effective for the treatment of chest indrawing pneumonia. This is a double-blind, randomized, non-inferiority trial with the objective to assess the effectiveness of shorter duration amoxicillin dispersible tablet (DT) treatment of chest indrawing childhood pneumonia in a malaria-endemic region of Malawi. The primary objective of this study is to determine whether 3 days of treatment with oral amoxicillin DT in HIV-uninfected Malawian children two to 59 months of age with chest indrawing pneumonia is as effective as 5 days of treatment. The study will enroll 2000 children presenting to Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi. Each child will be randomized to either 3 days of amoxicillin DT followed by 2 days of placebo DT or 5 days of amoxicillin DT. Children in the study will be hospitalized for 48 h after enrollment and will have scheduled study visits at Days 2, 4, 6 and 14. Treatment failure by Day 6 is the primary outcome. We hypothesize that the rates of treatment failure will be similar in both arms and that 3 days of treatment will be non-inferior to 5 days of amoxicillin DT for chest indrawing pneumonia using a relative non-inferiority margin of 1.5. This trial was approved by the Western Institutional Review Board and Malawi College of Medicine Research and Ethics Committee. Given the paucity of data from Africa, African-based research is necessary to establish appropriate duration of treatment with amoxicillin DT for chest indrawing childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base will contribute to future iterations of World Health Organization Integrated Management of Childhood Illness guidelines. NCT02678195 : Pre-results. Date registered February 9, 2016.


Bacteriophage T4 endonucleases II and IV, oppositely affected by dCMP hydroxymethylase activity, have different roles in the degradation and in the RNA polymerase-dependent replication of T4 cytosine-containing DNA.
Bacteriophage T4 mutants defective in gene 56 (dCTPase) synthesize DNA where cytosine (Cyt) partially or completely replaces hydroxymethylcytosine (HmCyt). This Cyt-DNA is degraded in vivo by T4 endonucleases II and IV, and by the exonuclease coded or controlled by genes 46 and 47.-Our results demonstrate that T4 endonuclease II is the principal enzyme initiating degradation of T4 Cyt-DNA. The activity of endonuclease IV, but not that of endonuclease II, was stimulated in the presence of a wild-type dCMP hydroxymethylase, also when no HmCyt was incorporated into phage DNA, suggesting the possibility of direct endonuclease IV-dCMP hydroxymethylase interactions. Endonuclease II activity, on the other hand, was almost completely inhibited in the presence of very small amounts of HmCyt (3-9% of total Cyt + HmCyt) in the DNA. Possible mechanisms for this inhibition are discussed.-The E. coli RNA polymerase modified by the products of T4 genes 33 and 55 was capable of initiating DNA synthesis on a Cyt-DNA template, although it probably cannot do so on an HmCyt template. In the presence of an active endonuclease IV, Cyt-DNA synthesis was arrested 10-30 min after infection, probably due to damage to the template. Cyt-DNA synthesis dependent on the unmodified (33-55-) RNA polymerase was less sensitive to endonuclease IV action.


Hemangioendothelioma of the temporal bone with radiologic findings resembling hemangioma.
Hemangioendotheliomas are rare vascular tumors that can affect bone. They account for 0.5% to 1.0% of malignant primary bone tumors. Only four cases have been reported involving the temporal bone. A 5-year-old child with grade II hemangioendothelioma of the right temporal bone is presented, and the radiologic findings on different imaging studies are described. The patient was treated with preoperative endovascular embolization followed by wide surgical resection. The imaging patterns of this malignant tumor may be similar to those of a benign lesion.


New neural circuits for robot phonotaxis.
W. Grey Walter built robotic systems to improve understanding of biological systems. In that tradition, this paper reports ongoing work on a robot model of cricket sound localization. The main advances are the inclusion of a much larger range of neuroethological detail, and the investigation of multimodal influences on the behaviour. The former allows exploration of the functionality of identified neurons in the insect, including the possible roles of multiple sensory fibres, mutually inhibitory connections, and brain neurons with pattern-filtering properties. The latter focuses on the inclusion of an optomotor stabilization response, and how this might improve tracking, particularly under conditions of random disturbance.


Plant-derived strategies to fight against severe acute respiratory syndrome coronavirus 2.
The coronavirus disease 2019 (COVID-19) pandemic has caused an unprecedented crisis, which has been exacerbated because specific drugs and treatments have not yet been developed. In the post-pandemic era, humans and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will remain in equilibrium for a long time. Therefore, we still need to be vigilant against mutated SARS-CoV-2 variants and other emerging human viruses. Plant-derived products are increasingly important in the fight against the pandemic, but a comprehensive review is lacking. This review describes plant-based strategies centered on key biological processes, such as SARS-CoV-2 transmission, entry, replication, and immune interference. We highlight the mechanisms and effects of these plant-derived products and their feasibility and limitations for the treatment and prevention of COVID-19. The development of emerging technologies is driving plants to become production platforms for various antiviral products, improving their medicinal potential. We believe that plant-based strategies will be an important part of the solutions for future pandemics.


A Segmented Logistic Regression Approach to Evaluating Change in Caesarean Section Rate with Reform of Birth Planning Policy in Two Regions in China from 2012 to 2016.
This study evaluated change in caesarean section rate with reform of birth planning policy in China from one-child to two-child policy. Study data were collected from patient-level hospital records of 59,668 pregnant women who visited three major urban hospitals in Jiangsu Province and Inner Mongolia Autonomous Region of China between January 2012 and December 2016. A segmented logistic regression approach was developed to evaluate the changes in caesarean section rate in these regions with the launch of China's new partial and universal two-child policies in January 2014 and January 2016, respectively. Jiangsu Province had a significantly lower non-emergency caesarean rate (Jiangsu 8.15% vs Inner Mongolia 34.03%, p < 0.001) and a much lower percentage of minority population (Jiangsu 6.99% vs Inner Mongolia 21.76%, p < 0.001) than Inner Mongolia Autonomous Region. In Jiangsu Province, no change in caesarean section rate was detected with the two-child policies (all p-values > 0.05), although the unadjusted trend change (0.038, 95% confidence interval or CI: [0.016, 0.060], p < 0.001) in log odds after the implementation of the partial two-child policy was statistically significant. In Inner Mongolia Autonomous Region, an immediate jump in caesarean section rate was discovered by the segmented logistic regression with the implementation of both the partial (unadjusted level change 0.297, CI: [0.105, 0.489], p = 0.002) and universal two-child policies (unadjusted level change 1.945, CI: [1.277, 2.614], p < 0.001); but the rate reverted to the previous level thereafter. Ethnicity, maternal age, maternal reproduction history, insurance coverage type, infant weight, and infant gender were the significant factors associated with caesarean section rate (for odds ratios, all p-values < 0.05). However, the significance of infant gender may stem from the large sample size of the study and is not clinically meaningful. Change in caesarean section rate was not observed with the launch of two-child policy in China.


Prevalence of rare visceral aneurysms on 92,833 CAT scans (2005-2021).
Studies on the prevalence of rare visceral aneurysms are still scarce and the few studies that have focused on these aneurysms present prevalence rates in groups of patients with visceral aneurysms, but little is known about their prevalence in the general population. To assess the prevalence of rare visceral aneurysms on CAT scans performed for diagnosis and follow-up of patients with other vascular pathologies. This cross-sectional study began by accessing all reports from CAT scans performed between January 2005 and July 2021 at a private hospital of excellence located in the city of São Paulo. A software program for pre-indexed reports was used to search the Radiological Information System (RIS) database to identify reports of patients with intra-abdominal aneurysms. CAT scan reports from 92,883 patients were accessed. Of these, 2,597 (2.795%) showed intra-abdominal aneurysms, 937 (1.063%) of which were visceral, including 158 (0.171%) rare visceral aneurysms, which were more frequent among male patients and in the following segments: celiac trunk (0.098%), superior mesenteric (0.033%), left gastric (0.010%), pancreatic-duodenal (0.009%), and gastroduodenal arteries (0.005%) and the pancreatic arch (0.004%). Lower prevalence was found in other segments. Additional findings revealed concomitance of rare visceral aneurysms with other intra-abdominal aneurysms ranging from 11.11% to 66.67%. The prevalence of rare visceral aneurysms in a large population undergoing CAT scan was 0.171%, with greater involvement in male patients.


The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.
RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1 -mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to EGFR tyrosine kinase inhibitors. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.


The sites for fatty acylation, phosphorylation and intermolecular disulphide bond formation of influenza C virus CM2 protein.
The sites for fatty acylation, disulphide bond formation and phosphorylation of influenza C virus CM2 were investigated by site-specific mutagenesis. Cysteine 65 in the cytoplasmic tail was identified as the site for palmitoylation. Removal of one or more of three cysteine residues in the ectodomain showed that all of cysteines 1, 6 and 20 can participate in the formation of disulphide-linked dimers and/or tetramers, although cysteine 20 may play the most important role in tetramer formation. Furthermore, it was found that serine 78, located within the recognition motifs for mammary gland casein kinase and casein kinase I, is the predominant site for phosphorylation, although serine 103 is phosphorylated to a minor extent by proline-dependent protein kinase. The effects of acylation and phosphorylation on the formation of disulphide-linked oligomers were also studied. The results showed that, while palmitoylation has no role in oligomer formation, phosphorylation accelerates tetramer formation without influencing dimer formation. CM2 mutants defective in acylation, phosphorylation or disulphide bond formation were all transported to the cell surface, suggesting that none of these modifications is required for proper oligomerization. When proteins solubilized in detergent were analysed on sucrose gradients, however, the mutant lacking cysteines 1, 6 and 20 sedimented as monomers, raising the possibility that disulphide bond formation, although not essential for proper oligomerization, may stabilize the CM2 multimer. This was supported by the results of chemical cross-linking analysis, which showed that the triple-cysteine mutant can form multimers.


Ischaemic heart disease and prodromes of sudden cardiac death. Is it possible to identify high risk groups for sudden cardiac death?
A study was carried out to determine the incidence of sudden cardiac death in a well defined population in relation to prodromes, medical history, and previous medical consultations before sudden cardiac death. In Frederiksborg county, Denmark (population 332 000), of 1309 consecutive deaths in a six month period, 166 were due to sudden cardiac death; among men aged 50-69, 22% of all deaths were due to sudden cardiac death. The incidence per 1000 population per year by age group (less than 50, 50-69, greater than or equal to 70 years) was 0.19, 3.6, 11.4 in men and 0.12, 1.0, and 6.4 in women. The increasing incidence with age was significant. Ischaemic heart disease or hypertension had been recorded in 75% (124/166) of patients. Prodromes were reported in 54% (38/71) of patients with angina, and in 26% (25/95) without. Nineteen per cent (32/166) had neither prodromes nor overt heart disease. Forty six per cent of patients with known ischaemic heart disease and 24% without had consulted a doctor less than four weeks before death. Eight per cent had had a myocardial infarction within a year of death.


Hepatopulmonary amebiasis--a review of 40 cases.
Forty cases of hepatopulmonary amebiasis secondary to hepatic amebiasis are reported. In an endemic area of amebiasis, this entity should always be borne in mind, as the frequent reports of hepatopulmonary amebiasis gives evidence of the magnitude of the problem. Diagnosis is mainly based on a palpable tender liver and/or lower intercostal tenderness, the fluoroscopic and radiological findings, and therapeutic response to dehydroemetine.


Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers.
Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia.


Single daily dose treatment of severe refractory infections with ceftriaxone. Cost savings and possible parenteral outpatient treatment.
Ceftriaxone sodium, a new cephalosporin with a very broad spectrum of action and a very long serum half-life, was administered to 127 patients in the treatment of 133 severe infections at our institution in Lausanne, Switzerland. Eighty infections had previously been treated unsuccessfully with other antimicrobials to which the pathogens were most often resistant. Sixty-five episodes were treated with two daily injections until there was an improvement in the patient's clinical condition, while 67 infections were treated from the start by a single daily injection. The results in the two groups were similar. One hundred fifteen infections (86%) were cured or improved, ten (8%) did not respond to therapy or recurred, and eight (6%) were not evaluable. The treatment was well tolerated, even by the 18 patients who received the drug for more than four weeks. The administration of a single daily dose instead of four doses as with standard antibiotic regimens produced a saving of Sfr 84,000 (+42,000) in the 127 patients. The single daily dose also made it possible to treat 25 of the 127 severely ill patients as outpatients, with a saving of Sfr 388,500 (+195,000) with respect to the hospital costs that would have been incurred for the same time period.


Improving health literacy in community populations: a review of progress.
Governments around the world have adopted national policies and programs to improve health literacy. This paper examines progress in the development of evidence to support these policies from interventions to improve health literacy among community populations. Our review found only a limited number of studies (n=7) that met the criteria for inclusion, with many more influenced by the concept of health literacy but not using it in the design and evaluation. Those included were diverse in setting, population and intended outcomes. All included educational strategies to develop functional health literacy, and a majority designed to improve interactive or critical health literacy skills. Several papers were excluded because they described a protocol for an intervention, but not results, indicating that our review may be early in a cycle of activity in community intervention research. The review methodology may not have captured all relevant studies, but it provides a clear message that the academic interest and attractive rhetoric surrounding health literacy needs to be tested more systematically through intervention experimentation in a wide range of populations using valid and reliable measurement tools. The distinctive influence of the concept of health literacy on the purpose and methodologies of health education and communication is not reflected in many reported interventions at present. Evidence to support the implementation of national policies and programs, and the intervention tools required by community practitioners are not emerging as quickly as needed. This should be addressed as a matter of priority by research funding agencies.


Two-Year Costs and Quality in the Comprehensive Primary Care Initiative.
The 4-year, multipayer Comprehensive Primary Care Initiative was started in October 2012 to determine whether several forms of support would produce changes in care delivery that would improve the quality and reduce the costs of care at 497 primary care practices in seven regions across the United States. Support included the provision of care-management fees, the opportunity to earn shared savings, and the provision of data feedback and learning support. We tracked changes in the delivery of care by practices participating in the initiative and used difference-in-differences regressions to compare changes over the first 2 years of the initiative in Medicare expenditures, health care utilization, claims-based measures of quality, and patient experience for Medicare fee-for-service beneficiaries attributed to initiative practices and a group of matched comparison practices. During the first 2 years, initiative practices received a median of $115,000 per clinician in care-management fees. The practices reported improvements in approaches to the delivery of primary care in areas such as management of the care of high-risk patients and enhanced access to care. Changes in average monthly Medicare expenditures per beneficiary did not differ significantly between initiative and comparison practices when care-management fees were not taken into account (-$11; 95% confidence interval [CI], -$23 to $1; P=0.07; negative values indicate less growth in spending at initiative practices) or when these fees were taken into account ($7; 95% CI, -$5 to $19; P=0.27). The only significant differences in other measures were a 3% reduction in primary care visits for initiative practices relative to comparison practices (P<0.001) and changes in two of the six domains of patient experience--discussion of decisions regarding medication with patients and the provision of support for patients taking care of their own health--both of which showed a small improvement in initiative practices relative to comparison practices (P=0.006 and P<0.001, respectively). Midway through this 4-year intervention, practices participating in the initiative have reported progress in transforming the delivery of primary care. However, at this point these practices have not yet shown savings in expenditures for Medicare Parts A and B after accounting for care-management fees, nor have they shown an appreciable improvement in the quality of care or patient experience. (Funded by the Department of Health and Human Services, Centers for Medicare and Medicaid Services; ClinicalTrials.gov number, NCT02320591.).


β-Catenin/Smad3 Interaction Regulates Transforming Growth Factor-β-Induced Epithelial to Mesenchymal Transition in the Lens.
Cataracts are the leading cause of blindness worldwide. Although surgery is a successful method to restore vision loss due to cataracts, post-surgical complications can occur, such as secondary cataracts, also known as posterior capsular opacification (PCO). PCO arises when lens epithelial cells (LEC) are left behind in the capsular bag following surgery and are induced to undergo epithelial to mesenchymal transition (EMT). Following EMT, LEC morphology and phenotype are altered leading to a loss of transparency and vision. Transforming growth factor (TGF)-β-induced signaling through both canonical, TGF-β/Smad, and non-canonical, β-catenin/Wnt and Rho/ROCK/MRTF-A, pathways have been shown to be involved in lens EMT, and thus PCO. However, the interactions between these signaling pathways in the lens have not been thoroughly explored. In the current study we use rat LEC explants as an ex vivo model, to examine the interplay between three TGF-β-mediated pathways using α-smooth muscle actin (α-SMA) as a molecular marker for EMT. We show that Smad3 inhibition via SIS3 prevents nuclear translocation of β-catenin and MRTF-A, and α-SMA expression, suggesting a key role of Smad3 in regulation of MRTF-A and β-catenin nuclear transport in LECs. Further, we demonstrate that inhibition of β-catenin/CBP interaction by ICG-001 decreased the amount of phosphorylated Smad3 upon TGF-β stimulation in addition to significantly decreasing the expression levels of TGF-β receptors, TBRII and TBRI. Overall, our findings demonstrate interdependence between the canonical and non-canonical TGF-β-mediated signaling pathways controlling EMT in the lens.


Arthroscopic subacromial decompression results in normal shoulder function after two years in less than 50% of patients.
The aim of this study was to evaluate the outcome two years after arthroscopic subacromial decompression using the Western Ontario Rotator-Cuff (WORC) index and a diagram-based questionnaire to self-assess active shoulder range of motion (ROM). Outcomes in 80 patients with impingement of the shoulder undergoing arthroscopic subacromial decompression were prospectively assessed preoperatively, at three months and at two years post-operatively using the WORC index. All patients had received non-operative treatment for at least six months before undergoing surgery. Active range of motion was measured preoperatively by the examining physician and at two years by the patient him-/herself using a diagram-based questionnaire to self-assess active shoulder ROM. A total of 75 patients (94%), of whom 31 were women, completed the study. The median age was 56 years. In all, 31 patients had additional resection of the acromioclavicular joint. WORC scores improved significantly from preoperatively (median: 1,392) to three months (median: 204) and two years post-operatively (median: 243) (p < 0.001). A clinically significant decrease in the WORC index was observed in 83% of patients, but only 45% reported near normal or normal WORC scores, and 56% presented with a reduced active ROM at two years. Arthroscopic subacromial decompression -appears effective in alleviating symptoms in patients with subacromial impingement who are resistant to conservative treatment, but can only be expected to restore normal shoulder function as measured by the WORC in less than 50% of the cases. not relevant. not relevant.


GIANT: pattern analysis of molecular interactions in 3D structures of protein-small ligand complexes.
Interpretation of binding modes of protein-small ligand complexes from 3D structure data is essential for understanding selective ligand recognition by proteins. It is often performed by visual inspection and sometimes largely depends on a priori knowledge about typical interactions such as hydrogen bonds and π-π stacking. Because it can introduce some biases due to scientists' subjective perspectives, more objective viewpoints considering a wide range of interactions are required. In this paper, we present a web server for analyzing protein-small ligand interactions on the basis of patterns of atomic contacts, or "interaction patterns" obtained from the statistical analyses of 3D structures of protein-ligand complexes in our previous study. This server can guide visual inspection by providing information about interaction patterns for each atomic contact in 3D structures. Users can visually investigate what atomic contacts in user-specified 3D structures of protein-small ligand complexes are statistically overrepresented. This server consists of two main components: "Complex Analyzer", and "Pattern Viewer". The former provides a 3D structure viewer with annotations of interacting amino acid residues, ligand atoms, and interacting pairs of these. In the annotations of interacting pairs, assignment to an interaction pattern of each contact and statistical preferences of the patterns are presented. The "Pattern Viewer" provides details of each interaction pattern. Users can see visual representations of probability density functions of interactions, and a list of protein-ligand complexes showing similar interactions. Users can interactively analyze protein-small ligand binding modes with statistically determined interaction patterns rather than relying on a priori knowledge of the users, by using our new web server named GIANT that is freely available at http://giant.hgc.jp/.


Translating Developmental Science to Address Childhood Adversity.
Demystifying child development is a defining element of pediatric care, and pediatricians have long appreciated the profound influences that families and communities have on both child development and life course trajectories. Dramatic advances in the basic sciences of development are beginning to reveal the biologic mechanisms underlying well-established associations between a spectrum of childhood adversities and less than optimal outcomes in health, education and economic productivity. Pediatricians are well positioned to translate this new knowledge into both practice and policy, but doing so will require unprecedented levels of collaboration with educators, social service providers, and policy makers. Pediatricians might recognize the negative impact of family-level adversities on child development, but developing an effective response will likely require the engagement of community partners. By developing collaborative, innovative ways to promote the safe, stable, and nurturing relationships that are biologic prerequisites for health, academic success, and economic productivity, family-centered pediatric medical homes will remain relevant in an era that increasingly values wellness and population health.


Effects of Maternal Iodine Status during Pregnancy and Lactation on Maternal Thyroid Function and Offspring Growth and Development: A Prospective Study Protocol for the Ideal Breast Milk Cohort.
Iodine is an intrinsic element of thyroid hormone, which is essential for childhood growth and development. The Ideal Breast Milk (IBM) cohort study aims to evaluate the effects of maternal iodine status during pregnancy and lactation on maternal thyroid function, offspring growth and development, and offspring thyroid function. The IBM cohort study recruited pregnant women from Seoul National University Hospital between June 2016 and August 2017, followed by enrollment of their offspring after delivery. For the maternal participants, iodine status is evaluated by urinary iodine concentration (UIC) and dietary records in the third trimester and at 3 to 4 weeks and 12 to 15 months postpartum. For the child participants, cord blood sampling and UIC measurements are performed at birth. At 3 to 4 weeks of age, UIC and breastmilk iodine concentrations are measured. At 12 to 15 months of age, growth and development are assessed and measurements of UIC, a thyroid function test, and ultrasonography are performed. A total of 198 pregnant women in their third trimester were recruited. Their mean age was 35.1±3.5 years, and 78 (39.4%) of them were pregnant with twins. Thirty-three (16.7%) of them had a previous history of thyroid disease. Korea is an iodine-replete area. In particular, lactating women in Korea are commonly exposed to excess iodine due to the traditional practice of consuming brown seaweed soup postpartum. The study of the IBM cohort is expected to contribute to developing guidelines for optimal iodine nutrition in pregnant or lactating women.


Does ingestion of cranberry juice reduce symptomatic urinary tract infections in older people in hospital? A double-blind, placebo-controlled trial.
cranberry juice is often given to older people in hospital to prevent urinary tract infection (UTI), although there is little evidence to support its use. to assess whether cranberry juice ingestion is effective in reducing UTIs in older people in hospital. randomised, placebo-controlled, double-blind trial. Medicine for the Elderly assessment and rehabilitation hospital wards. 376 older patients in hospital. participants were randomised to daily ingestion of 300 ml of cranberry juice or matching placebo beverage. The primary outcome was time to onset of first UTI. Secondary outcomes were adherence to beverage drinking, courses of antibiotics prescribed, and organisms responsible for UTIs. a total of 21/376 (5.6%) participants developed a symptomatic UTI: 14/189 in the placebo group and 7/187 in the cranberry juice group. These between-group differences were not significant, relative risk (RR) 0.51 [95% CI 0.21-1.22, P = 0.122). Although there were significantly fewer infections with Escherichia coli in the cranberry group (13 versus 4) RR 0.31 [95% CI 0.10-0.94, P = 0.027], this should be interpreted with caution as it was a secondary outcome. despite having the largest sample size of any clinical trial yet to have examined the effect of cranberry juice ingestion, the actual infection rate observed was lower than anticipated, making the study underpowered. This study has confirmed the acceptability of cranberry juice to older people. Larger trials are now required to determine whether it is effective in reducing UTIs in older hospital patients.


Structural insights into the catalytic mechanism of Bacillus subtilis BacF.
The nonribosomal biosynthesis of the dipeptide antibiotic bacilysin is achieved by the concerted action of multiple enzymes in the Bacillus subtilis bac operon. BacF (YwfG), encoded by the bacF gene, is a fold type I pyridoxal 5-phosphate (PLP)-dependent stereospecific transaminase. Activity assays with L-phenylalanine and 4-hydroxyphenylpyruvic acid (4HPP), a chemical analogue of tetrahydrohydroxyphenylpyruvic acid (H4HPP), revealed stereospecific substrate preferences, a finding that was consistent with previous reports on the role of this enzyme in bacilysin synthesis. The crystal structure of this dimeric enzyme was determined in its apo form as well as in substrate-bound and product-bound conformations. Two ligand-bound structures were determined by soaking BacF crystals with substrates (L-phenylalanine and 4-hydroxyphenylpyruvate). These structures reveal multiple catalytic steps: the internal aldimine with PLP and two external aldimine conformations that show the rearrangement of the external aldimine to generate product (L-tyrosine). Together, these structural snapshots provide an insight into the catalytic mechanism of this transaminase.


Incremental value of strain rate imaging to wall motion analysis for prediction of outcome in patients undergoing dobutamine stress echocardiography.
Wall motion score at dobutamine stress echocardiography is an independent predictor of mortality. We sought to determine whether quantification of DSE by strain rate imaging was incremental to wall motion score for predicting outcome. In 646 patients undergoing dobutamine stress echocardiography for the evaluation of known or suspected coronary disease, customized software was used to automatically measure peak systolic strain rate (SR(s)) and end-systolic strain (S(es)) in 18 segments. Results were expressed as the number of abnormal segments and the mean SR(s) and S(es) per patient. All-cause mortality was identified over 7 years of follow-up (mean, 5.2+/-1.5 years). Contributions of clinical, wall motion, and SR(s) and S(es) data to outcome were analyzed with Cox models, which also were used to define cut points for SR(s) and S(es). Ischemia (new or worsening wall motion abnormalities) was detected in 45%, and 39% had a previous myocardial infarction. In patients with no ischemia, annualized mortality without and with previous myocardial infarction were 2% and 3% compared with 5% in patients with ischemia. Peak wall motion score index, mean SR(s), segmental S(es), and segmental SR(s) were all predictors of mortality, but only segmental SR(s) (hazard ratio, 3.6; 95% CI, 1.7 to 7.2) was independently predictive. In sequential Cox models, the model based on clinical data (overall chi2, 12.7) was improved by peak wall motion score index (18.4, P=0.002) and further increased by either segmental SR(s) (31.8, P<0.001) or mean SR(s) (25.7, P=0.009). Segmental analysis by SR(s), derived from automated strain rate imaging analysis of dobutamine stress echocardiography response, offers prognostic information that is independent and incremental to standard wall motion score index.


Stroke in Africa: profile, progress, prospects and priorities.
Stroke is a leading cause of disability, dementia and death worldwide. Approximately 70% of deaths from stroke and 87% of stroke-related disability occur in low-income and middle-income countries. At the turn of the century, the most common diseases in Africa were communicable diseases, whereas non-communicable diseases, including stroke, were considered rare, particularly in sub-Saharan Africa. However, evidence indicates that, today, Africa could have up to 2-3-fold greater rates of stroke incidence and higher stroke prevalence than western Europe and the USA. In Africa, data published within the past decade show that stroke has an annual incidence rate of up to 316 per 100,000, a prevalence of up to 1,460 per 100,000 and a 3-year fatality rate greater than 80%. Moreover, many Africans have a stroke within the fourth to sixth decades of life, with serious implications for the individual, their family and society. This age profile is particularly important as strokes in younger people tend to result in a greater loss of self-worth and socioeconomic productivity than in older individuals. Emerging insights from research into stroke epidemiology, genetics, prevention, care and outcomes offer great prospects for tackling the growing burden of stroke on the continent. In this article, we review the unique profile of stroke in Africa and summarize current knowledge on stroke epidemiology, genetics, prevention, acute care, rehabilitation, outcomes, cost of care and awareness. We also discuss knowledge gaps, emerging priorities and future directions of stroke medicine for the more than 1 billion people who live in Africa.


Does the Canadian Occupational Performance Measure (COPM) Capture the Complex Experiences of Cancer Survivors? A Mixed Methods Approach.
Occupational therapy practitioners are uniquely positioned to address the needs of cancer survivors. This study aimed to understand the complex needs of survivors using The Canadian Occupational Performance Measure and in-depth interviewing. A convergent, mixed methods approach was utilized with a purposive sample of 30 cancer survivors. The results indicate that while the COPM can be a practical tool to address basic occupational performance problems, the in-depth interviews exposed these challenges are intricately connected to identity, relationships, and roles. Implications for occupational therapy practitioners include a critical approach to evaluation and interventions to capture the complex needs of survivors.


Congenital atresia of unilateral pulmonary veins associated with a single ventricle: a rare case report and literature review.
Congenital atresia or extreme hypoplasia of individual pulmonary veins is a rare condition that is usually asymptomatic if it only involves 1 or 2 segments of the lungs. It may be fatal if it occurs in combination with other complex cardiac defects. The patients often present with recurrent pulmonary infections, hemoptysis, or cyanosis in the latter case. A definitive diagnosis can be made by cardiac catheterization with selective pulmonary wedge angiography. The treatment of this condition is a challenge and is controversial, and the prognosis is usually poor. We describe the case of a male infant who suffered from shortness of breath and cyanosis since birth. On echocardiography and cardiac catheterization, he was found to have a complex congenital heart disease with a single ventricle (right ventricle morphology), mitral atresia, large atrial septal defect, and atresia of the right pulmonary veins; severe pulmonary hypertension was also observed. He underwent pulmonary artery banding at the age of 2.5 months, but he died because of a pulmonary infection at the age of 6 months. In this report, we present this rare case and review the previous literature.


Methane emission and sulfide levels increase in tropical seagrass sediments during temperature stress: A mesocosm experiment.
Climate change-induced ocean warming is expected to greatly affect carbon dynamics and sequestration in vegetated shallow waters, especially in the upper subtidal where water temperatures may fluctuate considerably and can reach high levels at low tides. This might alter the greenhouse gas balance and significantly reduce the carbon sink potential of tropical seagrass meadows. In order to assess such consequences, we simulated temperature stress during low tide exposures by subjecting seagrass plants (Thalassia hemprichii) and associated sediments to elevated midday temperature spikes (31, 35, 37, 40, and 45°C) for seven consecutive days in an outdoor mesocosm setup. During the experiment, methane release from the sediment surface was estimated using gas chromatography. Sulfide concentration in the sediment pore water was determined spectrophotometrically, and the plant's photosynthetic capacity as electron transport rate (ETR), and maximum quantum yield (Fv/Fm) was assessed using pulse amplitude modulated (PAM) fluorometry. The highest temperature treatments (40 and 45°C) had a clear positive effect on methane emission and the level of sulfide in the sediment and, at the same time, clear negative effects on the photosynthetic performance of seagrass plants. The effects observed by temperature stress were immediate (within hours) and seen in all response variables, including ETR, Fv/Fm, methane emission, and sulfide levels. In addition, both the methane emission and the size of the sulfide pool were already negatively correlated with changes in the photosynthetic rate (ETR) during the first day, and with time, the correlations became stronger. These findings show that increased temperature will reduce primary productivity and increase methane and sulfide levels. Future increases in the frequency and severity of extreme temperature events could hence reduce the climate mitigation capacity of tropical seagrass meadows by reducing CO2 sequestration, increase damage from sulfide toxicity, and induce the release of larger amounts of methane.


Calculated nitrogen balance in hemodialysis patients: influence of protein intake.
Optimal nutrient intake is important in the maintenance of a positive nitrogen balance in hemodialysis (HD) patients. The objectives of this study were (1) to assess the influence of two levels of protein intakes on nitrogen balance in stable adult HD patients, and (2) to identify a minimum level of protein intake that would result in a negative nitrogen balance, so that preliminary recommendations may be made in Indian patients on maintenance HD (MHD). Stable, adult, nondiabetic MHD patients were recruited after informed consent into a cross over trial with a high-protein (HP) diet [1.2 g/kg ideal body weight (IBW)/day), followed by a low-protein (LP) diet (0.6 g/kg IBW/day] after appropriate periods of equilibration; for both diets, 50% of protein was of high biological value, and calorie intake was 35 kCal/kg IBW/day. Duplicate meals and residues were weighed, homogenized, and stored at -20 degrees C for analysis of dietary N by the Kjeldahl method, used to check the consistency of the N content of the diet supplied. Pre- and post- (30-minute equilibrated) blood urea samples were drawn, and details of weights and other HD parameters were recorded. Interdialytic urine collections for urea were obtained. N input came from dietary protein calculated as 16% of the weight of biological protein; N output was calculated using blood-side urea measurements and urinary urea excretion and was the sum of urea N (UN) and nonurea N (NUN) losses (assumed to be equal to 0.031 g N/kg/day). Fifteen patients were recruited. Twelve patients completed both limbs of the study. The mean age was 30.3 +/- 12.7 years. The body mass index was 18.9 +/- 2.4. Serum albumin was 3.8 +/- 0.35 g/dL, and Kt/V (equilibrated) was 1.17 +/- 0.3 g/dL. Protein consumed was 1.06 +/- 0.18 g/kg IBW/day in the HP limb versus 0.61 +/- 0.1 g/kg IBW/day in the LP limb (P = 0.000). Energy intake was 33 +/- 6.5 vs. 32.8 +/- 6. 7 kCal/kg IBW/day, respectively (P = 0.8). The normalized protein N appearance (nPNA) was 0.88 +/- 0.2 g/kg/day in the HP limb versus 0. 78 +/- 0.2 g/kg/day in the LP limb (P = 0.02). Dietary N was 73.5 +/- 15.3 g in the HP week and 42.5 +/- 7.5 g in the LP week (P = 0. 000). The difference between this and the sum of (UN + NUN) losses over the week was 29 +/- 13.2 g versus 1.2 +/- 8.1 g, respectively (P = 0.001), showing a strong, uniformly positive nitrogen balance with HP diet and neutral to negative nitrogen balance with LP diet. The ratio of dietary protein intake (DPI) to nPNA was significantly lower (anabolic) in the HP limb (0.7 +/- 0.2 vs. 1.12 +/- 0.3, P = 0. 000). On a scatter plot of nPNA to DPI, a catabolic relationship was demonstrated below a DPI of 0.75 g/kg/day (95% CI, 0.65 to 0.85 g/kg/day). A DPI of approximately 1.1 g/kg/day produces a positive nitrogen balance and 0.6 g/kg/day a neutral to negative nitrogen balance, demonstrating protein anabolism as a function of protein intake. It is suggested that a protein intake of 0.85 g/kg/day should be considered unsafe. These conclusions apply in stable nondiabetic adult HD patients in the setting of adequate dialysis and adequate calorie intake.


[The genetic bases of the lipid metabolic disorders in atherosclerosis].
The development of dyslipoproteinemia is to a large extent genetically determined. The mutations in gene controlling receptor to lipoproteids of low density, the genes Apo B, Apo A-1, and Apo E have a dominant role in the disturbance of lipid metabolism. The development of atherosclerosis at young age is apparently associated with the mutations in gene of receptors, in the gene Apo B and some mutations in a cluster of the genes A-I--CIII--AIV.


A comparative study of mammalian and reptilian alternative pathway of complement-mediated killing of the Lyme disease spirochete (Borrelia burgdorferi).
The potential bactericidal activity of the alternative complement pathway of mammalian and reptilian sera to Borrelia burgdorferi sensu stricto (s.s.) was evaluated in vitro. Complement-mediated killing was observed when cultured spirochetes were inoculated into sera from the western fence lizard (Sceloporus occidentalis) and from the southern alligator lizard (Elgaria multicarinata), but not when they were inoculated into serum from either the deer mouse (Peromyscus maniculatus) or from humans. Spirochetes were still alive after 4 hr in lizard serum that had been preheated at 56 C for 30 min to inactivate complement. Furthermore, when lizard serum was chelated with 10 mM ethylenediaminetetraacetic acid to block all complement activation, borreliacidal activity was arrested. When lizard serum was chelated with 10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus 4 mM MgCl2 to block only classical complement pathway activation, >85% of spirochetes were immobilized within 1 hr. Differences in B. burgdorferi s.s. mortality were not observed when chelators with or without MgCl2 were added to serum from either deer mice or humans. Proteins comprising the alternative complement pathway are responsible for the borreliacidal activity observed in the blood of S. occidentalis and E. multicarinata.


[Objective histological grading of squamous and adenosquamous lung cancer].
The prognostic value of quantitative histopathological parameters was evaluated in 55 consecutively treated patients with operable lung carcinoma of squamous and adenosquamous cell type. Using a projection microscope, estimates were obtained of mean nuclear volume (vV(nuc)), mean nuclear profile area, nuclear profile density, nuclear volume fraction, and mitotic profile frequency. Patient sex, age, and clinical stage was recorded. Single-factor analyses showed a prognostic significance of clinical stage and patient age (2p < or = 0.03), whereas sex was marginally significant (2p = 0.09). Of the quantitative histopathological parameters only estimates of vV(nuc) were of prognostic significance (2p = 0.02), in that small nuclear volumes were associated with the worst prognosis. In a multivariate Cox analysis, clinical stage, age, and vV(nuc) were found to be of significant, independent prognostic value. Thus, the present study indicates that vV(nuc) is of prognostic value, independent of clinical stage. The parameter is highly reproducible and easily obtained using unbiased stereology, and may be of future importance in the management of lung cancer patients.


Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis.
Tumour necrosis factor (TNF) is known to increase the concentrations of interleukin (IL) 6 and C reactive protein (CRP) and to induce proatherogenic changes in the lipid profile and may increase the cardiovascular risk of patients with rheumatoid arthritis (RA) and other inflammatory disorders. To assess whether anti-TNF therapy modifies the cardiovascular risk profile in patients with RA. The lipoprotein spectrum and the inflammation markers CRP and IL6 were investigated in 33 patients with RA treated with human anti-TNF monoclonal antibodies (D2E7, adalimumab, Humira) and 13 patients with RA given placebo, before and after 2 weeks' treatment. In the anti-TNF treated group, the mean (SD) concentrations of HDL-cholesterol were significantly higher after 2 weeks' treatment (0.86 (0.30) mmol/l v 0.98 (0.33) mmol/l, p<0.01), whereas LDL and triglyceride levels were not significantly changed. Additionally, a significant decrease in CRP (86.1 (54.4) mg/l v 35.4 (35.0) mg/l, p<0.0001), and IL6 (88.3 (60.5) pg/ml v 42.3 (40.7) pg/ml, p<0.001) concentrations was seen in this group. No changes in lipid profile, IL6, or CRP levels were seen in the placebo group. TNF neutralisation with monoclonal anti-TNF antibodies increased HDL-cholesterol levels and decreased CRP and IL6 levels after 2 weeks. Therefore this treatment may improve the cardiovascular risk profile of patients with RA.


Pedestrian-oriented zoning moderates the relationship between racialized economic segregation and active travel to work, United States.
Pedestrian-oriented zoning, including zoning code reforms (ZCR), may be especially beneficial to racially and economically segregated communities, which may lack built environment features that support physical activity. This study examined associations between racialized economic segregation, measured by quintiles of the Index of Concentration at the Extremes, and public transit (PTW) and active travel (ATW) to work, and whether associations were moderated by pedestrian-oriented zoning provisions and ZCR, respectively. Zoning codes effective as of 2010 representing 3914 US municipalities (45.45% of US population) were evaluated for the presence of ZCR and eight pedestrian-oriented zoning provisions. These data were linked with American Community Survey 2013-2017 and NAVTEQ 2013 data on the outcomes and relevant covariates. Fractional logit regressions were computed with standard errors clustered on county. Workers from more deprived quintiles were less likely to engage in PTW and ATW (OR = 0.22-0.55, p < 0.01), and tests revealed moderation by zoning (p < 0.05). ZCR was positively associated with PTW for the three most deprived quintiles (OR = 1.53-2.38, p < 0.01), and with ATW for the two most deprived quintiles (OR = 1.42-1.69, p < 0.01) and the second most privileged quintile (OR = 1.26, p < 0.05). In the most privileged quintile, the zoning scale score was negatively associated with PTW (OR = 0.91, p < 0.001) and ATW (OR = 0.94, p < 0.01). However, in the most deprived quintiles, the zoning scale score was positively associated with PTW (Q2: OR = 1.13, p < 0.01) and ATW (Q1-Q2: OR = 1.07-1.09, p < 0.05). Pedestrian-oriented zoning can provide opportunities for ATW in the most deprived communities. Work is needed to explore zoning policy implementation in those communities.


Quantitative in vivo studies on the active Na-K transports in "tonic" muscle of the hypokalemic rat.
Central nervous system (CNS)-induced suppression on the muscle Na-pump activity was studied in soleus (SOL) muscles of hypokalemic rats. Peripheral nerve section, cervical soleus and brainstem transection, decerebration, and cortical spreading depression with 20% KCl activated the Na-pump in SOL muscles during hypokalemia. Blockage of the nerve conduction by tetrodotoxin (TTX) also activated the Na-pump in SOL muscles. The activation of Na-pump after the denervation was completely abolished by the pre-treatment of ouabain. However, the muscle cation contents were not affected by the injection of curare and atropine. The activation of Na-pump in the muscles after denervation in the curarized hypokalemic rats was completely removed by electrical stimulus of the distal nerve stump of cut sciatic nerve. alpha-Adrenoreceptor antagonists (phenoxybenzamine, phentolamine and dibenamine, and prazosin) stimulated the Na+ and K+ transports in the SOL muscles during hypokalemia while beta-adrenoreceptor antagonist (propranolol) had no effect. The denervation effect on SOL muscle cation contents was not affected with or without the presence of propranolol. It is concluded that CNS acts to inhibit the Na-pump mechanism in SOL muscles of hypokalemic rats and the inhibition is achieved by the apparent release of catecholamines onto muscle following neural activity. Thus, the CNS-induced suppression on the muscle Na-pump is prevented by denervation and by treatment with drugs that block either nerve conduction or alpha-adrenoreceptor.


Glatiramer: new preparation. No place in multiple sclerosis.
(1) Interferon beta-1a is the reference treatment for relapsing-remitting multiple sclerosis. It reduces the frequency of exacerbations and was the first interferon beta shown to delay the onset of disability. (2) Glatiramer, a peptide with certain structural similarities to myelin components, was recently approved for use in this indication. (3) Three randomised double-blind trials lasting a maximum of two years compared glatiramer with placebo. They showed that glatiramer has no impact on the progression of disability. Glatiramer increased slightly the interval between exacerbations: each patient avoided about one exacerbation after two years treatment. But the drug had no effect on the number of patients who experienced exacerbation. Glatiramer has not been compared with interferon beta in clinical trials. (4) The treatment withdrawal rates for adverse effects among patients treated with glatiramer and interferon beta are about the same, although the two drugs have different adverse effect profiles. Most patients using glatiramer have reactions at the injection site. Nearly half the patients given glatiramer have an immediate systemic reaction, and these can be serious. (5) Glatiramer therapy requires daily injections, unlike the more convenient interferon beta (which is given every three days). (6) Glatiramer is no cheaper than interferon beta. (7) In practice, the minor benefits of glatiramer are offset by its adverse effects and less convenient administration. There is currently no place for glatiramer in the treatment of multiple sclerosis.


Control of beta-catenin stability: reconstitution of the cytoplasmic steps of the wnt pathway in Xenopus egg extracts.
Regulation of beta-catenin degradation by intracellular components of the wnt pathway was reconstituted in cytoplasmic extracts of Xenopus eggs and embryos. The ubiquitin-dependent beta-catenin degradation in extracts displays a biochemical requirement for axin, GSK3, and APC. Axin dramatically accelerates while dishevelled inhibits beta-catenin turnover. Through another domain, dishevelled recruits GBP/Frat1 to the APC-axin-GSK3 complex. Our results confirm and extend models in which inhibition of GSK3 has two synergistic effects: (1) reduction of APC phosphorylation and loss of affinity for beta-catenin and (2) reduction of beta-catenin phosphorylation and consequent loss of its affinity for the SCF ubiquitin ligase complex. Dishevelled thus stabilizes beta-catenin, which can dissociate from the APC/axin complex and participate in transcriptional activation.


Tumor suppressor PALB2 maintains redox and mitochondrial homeostasis in the brain and cooperates with ATG7/autophagy to suppress neurodegeneration.
The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7/autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.


Viral and atypical bacterial detection in acute respiratory infection in children under five years.
Acute respiratory infection (ARI) is a leading cause of morbidity and mortality in children worldwide. This study aimed to determine the viral and atypical bacterial causes of different severities and clinical manifestations of ARI in preschool children from low-income families in North-East Brazil. Clinical/demographic data and nasopharyngeal aspirates (NPA) were prospectively collected from children <5 years presenting with ARI over one year to a paediatric A&E department. Disease severity was grouped according to presence of lower respiratory tract signs, need for hospital admission and need for oxygen. Clinical manifestation of ARI was based on discharge diagnosis from hospital with four conditions predominating: bronchiolitis, pneumonia, episodic viral wheeze/asthma and upper respiratory tract infection. Multiplex PCR was used to detect 17 common respiratory viral and atypical bacterial pathogens in NPA. 407 children with a median age of eight months were recruited. Pathogens were detected in 85·5% samples with co-infection being particularly common (39·5%). Respiratory Syncytial Virus (RSV; 37%), Adenoviruses (AdV; 25%), Rhinoviruses (hRV; 19%), Bocavirus (hBoV; 19%), human Meta-pneumovirus (hMPV; 10%) and Mycoplasma pneumoniae (Mpp; 10%) were most prevalent. Detection and co-infection rates were similar in all severities and clinical manifestations of ARI apart from RSV, which was associated with more severe disease and specifically more severe cases of bronchiolitis, and Mpp, which was associated with more severe cases of pneumonia. Mpp was detected in 17% of children admitted to hospital with pneumonia. This study underlines the importance of viral and atypical bacterial pathogens in ARI in pre-school children and highlights the complex epidemiology of these pathogens in this age group. Generally, viruses and atypical bacteria were detected in all severities and clinical manifestations of ARI but RSV and Mpp were associated with more severe cases of bronchiolitis and pneumonia respectively.


Design of new promoters and of a dual-bioreporter based on cross-activation by the two regulatory proteins XylR and HbpR.
The HbpR protein is the sigma54-dependent transcription activator for 2-hydroxybiphenyl degradation in Pseudomonas azelaica. The ability of HbpR and XylR, which share 35% amino acid sequence identity, to cross-activate the PhbpC and Pu promoters was investigated by determining HbpR- or XylR-mediated luciferase expression and by DNA binding assays. XylR measurably activated the PhbpC promoter in the presence of the effector m-xylene, both in Escherichia coli and Pseudomonas putida. HbpR weakly stimulated the Pu promoter in E. coli but not in P. azelaica. Poor HbpR-dependent activation from Pu was caused by a weak binding to the operator region. To create promoters efficiently activated by both regulators, the HbpR binding sites on PhbpC were gradually changed into the XylR binding sites of Pu by site-directed mutagenesis. Inducible luciferase expression from mutated promoters was tested in E. coli on a two plasmid system, and from mono copy gene fusions in P. azelaica and P. putida. Some mutants were efficiently activated by both HbpR and XylR, showing that promoters can be created which are permissive for both regulators. Others achieved a higher XylR-dependent transcription than from Pu itself. Mutants were also obtained which displayed a tenfold lower uninduced expression level by HbpR than the wild-type PhbpC, while keeping the same maximal induction level. On the basis of these results, a dual-responsive bioreporter strain of P. azelaica was created, containing both XylR and HbpR, and activating luciferase expression from the same single promoter independently with m-xylene and 2-hydroxybiphenyl.


Primary endovascular treatment of post-irradiated carotid pseudoaneurysm at the skull base with the Pipeline embolization device.
A post-irradiated carotid pseudoaneurysm at the skull base can cause life-threatening blowout syndrome. Conventional treatments include parent vessel occlusion, endovascular coiling or covered stenting. Use of the Pipeline embolization device (PED) for pseudoaneurysm exclusion at the skull base is not well described. To report the clinical and angiographic outcome after using multiple PEDs to treat recently ruptured radiation-induced carotid pseudoaneurysms at the skull base. Retrospective review of the clinical and angiographic records of patients who received PEDs as primary treatment for skull base carotid pseudoaneurysm between April 1, 2011 to March 31, 2013. Seven patients (five men, two women) with a mean age of 58 years (range 47-65) were treated in the study period. Primary treatment with the PED alone, with adjunct coil embolization in two patients, achieved immediate hemostasis in all patients, with no pseudoaneurysm rebleeding after a mean follow-up of 15.3 months (range 4-24 months). One patient had periprocedural cerebral infarction. Delayed internal carotid artery occlusion secondary to in-stent thrombosis occurred in three patients, one of whom had lacunar infarct and two remained asymptomatic. Endovascular treatment with the PED was effective in excluding skull base post-irradiated carotid pseudoaneurysms and preventing recurrent blowout. However, the risk of ischemic complications in this group of patients was high and our experience did not support the use of flow diverters as a first-line treatment for this condition.


[Indirect flourescent antibody test in toxoplasmosis. Advantage of the use of fluorescent anti-IgG conjugate (author's transl)].
The indirect fluorescent antibody (IFA) test effected with anti-human conjugate gives appreciably equivalent results to those obtained with the dye (SABIN-FELDMAN) test, but weak serum dilutions may raise non specific reactions, due to the presence of substances possessing the IgM antibody properties. Those substances are not present in the serum of children during the first months of their life. The application of an anti-IgG conjugate allows to prevent those unspecific reactions. The application of the modified IFA test for detecting the toxoplasmic infection during pregnancy and the use of the REMINGTON test for the early diagnosis of the congenital toxoplasmosis are discussed.


Targeting circulating tumor cells to prevent metastases.
Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor, enter the bloodstream or body fluids, and spread to other body parts, leading to metastasis. Their presence and characteristics have been linked to cancer progression and poor prognosis in different types of cancer. Analyzing CTCs can offer valuable information about tumors' genetic and molecular diversity, which is crucial for personalized therapy. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), play a significant role in generating and disseminating CTCs. Certain proteins, such as EpCAM, vimentin, CD44, and TGM2, are vital in regulating EMT and MET and could be potential targets for therapies to prevent metastasis and serve as detection markers. Several devices, methods, and protocols have been developed for detecting CTCs with various applications. CTCs interact with different components of the tumor microenvironment. The interactions between CTCs and tumor-associated macrophages promote local inflammation and allow the cancer cells to evade the immune system, facilitating their attachment and invasion of distant metastatic sites. Consequently, targeting and eliminating CTCs hold promise in preventing metastasis and improving patient outcomes. Various approaches are being explored to reduce the volume of CTCs. By investigating and discussing targeted therapies, new insights can be gained into their potential effectiveness in inhibiting the spread of CTCs and thereby reducing metastasis. The development of such treatments offers great potential for enhancing patient outcomes and halting disease progression.


Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas.
Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in approximately 60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.


The safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious uveitis in childhood.
To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis. Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months. Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY). In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.


Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.
Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow.


Assessing the efficacy of spray-delivered 'eco-friendly' chemicals for the control and eradication of marine fouling pests.
Despite its frequent use in terrestrial and freshwater systems, there is a lack of published experimental research examining the effectiveness of spray-delivered chemicals for the management of non-indigenous and/or unwanted pests in marine habitats. This study tested the efficacy of spraying acetic acid, hydrated lime and sodium hypochlorite for the control of marine fouling assemblages. The chemicals are considered relatively 'eco-friendly' due to their low toxicity and reduced environmental persistence compared to synthetic biocides, and they were effective in controlling a wide range of organisms. Pilot trials highlighted acetic acid as the most effective chemical at removing fouling cover, therefore it was selected for more comprehensive full-scale trials. A single spray of 5% acetic acid with an exposure time of 1 min effectively removed up to 55% of the invertebrate species present and 65% of the cover on fouled experimental plates, while one application of 10% acetic acid over 30 min removed up to 78% of species present and 95% of cover. Single-spray treatments of 5% acetic acid reduced cover of the tunicate pest species Didemnum vexillum by up to 100% depending on the exposure duration, while repeat-spraying ensured that even short exposure times (1 min) achieved approximately 99% mortality. Both 5 and 10% acetic acid solutions appeared equally effective at removing the majority of algal species. This technique could be used for controlling the introduction of unwanted species or preventing the spread of pests, and is applicable to use on a variety of natural and artificial substrata, or for the treatment of structures that can be removed from the water.


The evidence-based use of thiazide diuretics in hypertension and nephrolithiasis.
Thiazide-type diuretics are commonly used in the treatment of hypertension and nephrolithiasis. Evidence from randomized clinical trials needs to be considered in decisions about agent choice and dose. In nephrolithiasis, one of the major limitations of the literature is a paucity of data on the dose-response effect of hydrochlorothiazide (HCTZ) on urinary calcium excretion. The best available evidence for prevention of stone recurrence suggests the use of indapamide at 2.5 mg/d, chlorthalidone at 25 to 50 mg daily, or HCTZ 25 mg twice a day or 50 mg daily. In hypertension, chlorthalidone (12.5 to 30 mg daily) may be the best choice when a diuretic is used for initial therapy, with indapamide (1.5 mg daily) being a valuable alternative for older patients. When adding a thiazide to other drug classes, indapamide (2.5 mg daily) has demonstrated value in hypertensive patients who have had a stroke, and HCTZ (12.5 to 25 mg daily) has a safe track record in several patient groups. Although chlorthalidone has not been tested as add-on therapy, the authors believe it is a safe option in such cases.


Feature Selection for Optimized High-Dimensional Biomedical Data Using an Improved Shuffled Frog Leaping Algorithm.
High dimensional biomedical datasets contain thousands of features which can be used in molecular diagnosis of disease, however, such datasets contain many irrelevant or weak correlation features which influence the predictive accuracy of diagnosis. Without a feature selection algorithm, it is difficult for the existing classification techniques to accurately identify patterns in the features. The purpose of feature selection is to not only identify a feature subset from an original set of features [without reducing the predictive accuracy of classification algorithm] but also reduce the computation overhead in data mining. In this paper, we present our improved shuffled frog leaping algorithm which introduces a chaos memory weight factor, an absolute balance group strategy, and an adaptive transfer factor. Our proposed approach explores the space of possible subsets to obtain the set of features that maximizes the predictive accuracy and minimizes irrelevant features in high-dimensional biomedical data. To evaluate the effectiveness of our proposed method, we have employed the K-nearest neighbor method with a comparative analysis in which we compare our proposed approach with genetic algorithms, particle swarm optimization, and the shuffled frog leaping algorithm. Experimental results show that our improved algorithm achieves improvements in the identification of relevant subsets and in classification accuracy.


Characterization of the cutaneous exanthem in macaques infected with a Nef gene variant of SIVmac239.
The molecularly cloned viruses known as SIVmac239/R17Y and SIVmac239/YEnef cause extensive lymphocyte activation and induce an acute disease syndrome in macaque monkeys. One manifestation of this syndrome is a severe diffuse cutaneous maculopapular exanthem that is similar to the exanthem associated with HIV-1 infection. To examine the pathogenesis of this exanthem, biopsies obtained throughout the course of clinically evident rash were examined for the presence of virus by in situ hybridization and immunohistochemistry, and the cellular infiltrate was characterized with respect to cellular immunophenotype and chemokine receptor expression. The onset of rash was associated with abundant simian immunodeficiency virus nucleic acid and protein within perivascular dermal infiltrates and occasionally within intraepithelial cells. Analysis of cellular infiltrates showed that biopsies, obtained on the day of rash onset, were composed of equal numbers of CD4+ and CD8+ lymphocytes and abundant alphaEbeta7 positive cells surrounding vessels with upregulated endothelial E-selectin. Moreover, by examining virus expression in sequential skin biopsies from the same animal, the clearance of virus and the resolution of rash were associated with an increase in the percentage of cells expressing CD8, the chemokine receptor CXCR3, and GMP-17, a marker of cytotoxic granules. These results suggest that activated cytotoxic T cells are trafficking to sites of inflammation in the skin and directly or indirectly affect levels of viral replication at these sites.


[Pulmonary nodule: a bayesian approach].
A solitary pulmonary nodule is a common clinical problem. It is usually detected incidentally. The prevalence of solitary pulmonary nodule (SPN) in the lung cancer screening study varies from 8 to 50% (with a prevalence of malignant nodule from 1 to 13%). The bayesian approach can help us to identify promptly malignant nodule in order to treat them surgically and to avoid surgery for benign nodules. Therefore, it is needed to estimate the probability of cancer (Pca) in the SPN. Likelihood ratio (LR) for overall prevalence of malignancy and for different clinical and radiological information (age, smoking exposure, symptoms, cancer history, nodule size, spiculation, calcification, location, growth...) can be obtained from the literature. The odds of cancer-malignancy (odds ca) can be calculated by multiplying all of these LRs together. The Pca = odds ca/1+odds ca. Using this bayeasian approach, the probability of cancer based on an abnormal or normal fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan has been estimated. Sensitivity, specificity, positive predictive value and negative predictive value of PET scan are respectively about 90%, 83%, 92% and 90%. Moreover, the LR for malignancy are higher with an abnormal PET scan when compared to most clinical and radiological LRs. Today, the Bayesian approach of SPN must include PET scan.


[Condition and perspectives of development of vehicle-park of medical evacuation in the Armed Forces].
The article presents an observe of vehicles of medical evacuation (VME), existing in medical service of the Armed Forces of RF, intended for transporting of ill and wounded persons with delivery of emergency care in passing. Were presented perspective examples of CMV "Aybolit" and VME of middle and grand evacocapacity, pertained to elaboration. There was made a conclusion that the new generation of VME on chassis of the army all-wheel-drive vehicles, having an armor defense (complex of local defense), system of smooth transporting and loading-unloading system, permits solve questions of evacuation of ill and wounded persons from battle field more effectively.


RNA Sequencing Reveals Xyr1 as a Transcription Factor Regulating Gene Expression beyond Carbohydrate Metabolism.
Xyr1 has been demonstrated to be the main transcription activator of (hemi)cellulases in the well-known cellulase producer Trichoderma reesei. This study comprehensively investigates the genes regulated by Xyr1 through RNA sequencing to produce the transcription profiles of T. reesei Rut-C30 and its xyr1 deletion mutant (Δxyr1), cultured on lignocellulose or glucose. xyr1 deletion resulted in 467 differentially expressed genes on inducing medium. Almost all functional genes involved in (hemi)cellulose degradation and many transporters belonging to the sugar porter family in the major facilitator superfamily (MFS) were downregulated in Δxyr1. By contrast, all differentially expressed protease, lipase, chitinase, some ATP-binding cassette transporters, and heat shock protein-encoding genes were upregulated in Δxyr1. When cultured on glucose, a total of 281 genes were expressed differentially in Δxyr1, most of which were involved in energy, solute transport, lipid, amino acid, and monosaccharide as well as secondary metabolism. Electrophoretic mobility shift assays confirmed that the intracellular β-glucosidase bgl2, the putative nonenzymatic cellulose-attacking gene cip1, the MFS lactose transporter lp, the nmrA-like gene, endo T, the acid protease pepA, and the small heat shock protein hsp23 were probable Xyr1-targets. These results might help elucidate the regulation system for synthesis and secretion of (hemi)cellulases in T. reesei Rut-C30.


[A cross-correlational analysis of the background neuronal pulse trains in surviving slices of the guinea pig neocortex].
Cross-correlation analysis of interdependence of the background spike activity was carried out for pairs of adjacent neurons simultaneously recorded in the incubated slices of the neocortex of guinea-pig. Statistical correlation of spike discharges was detected in 16 out of 26 recorded pairs of the neurons. Significant correlation was observed mainly in the range of +/- 100 ms from the null point. Cross-correlation had symmetric or asymmetric maxima up to 150 ms long and negative shifts up to 200 ms long. More complex positive-negative types of cross-correlations were also obtained. The data were compared to those known from other authors for the intact brain. The contribution of intrinsic intracortical interactions and extrinsic afferent influences in these correlations of activity is discussed.


Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies.
Several chronic inflammatory diseases are associated with cardiovascular disease, but the risk in ANCA-associated vasculitis is poorly quantified. The aim of the present study was to review the evidence for an increased cardiovascular risk, including ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease, in patients with ANCA-associated vasculitis. A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses. The databases PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies comparing vasculitis patients with at least one control group. Summary estimates were derived with a random-effects model and reported as relative risks. One thousand three hundred and seventy-five studies were identified. Seven studies were included, comprising almost 14 000 ANCA-associated vasculitis patients vs general population controls in six studies and chronic kidney disease patients in one study. ANCA-associated vasculitis carried a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI: 1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents. We did not find studies that addressed the risk for peripheral arterial disease separately. No heterogeneity was seen in the estimates. This meta-analysis of observational studies supports an increase in cardiovascular risk in patients with ANCA-associated vasculitis of ∼65%, similar to that found in other chronic inflammatory diseases. Hence, there is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis.


Pilocytic astrocytoma of neurohypophysis.
A case of pilocytic astrocytoma of neurohypophysis is presented. The clinical, pathological and MRI features of a rare tumor of the neurohypophysis are described. A 5-year-old girl presented with a 3 month history of lethargy, imbalance and visual disturbances. A MRI revealed a large suprasellar mass. Histopathological examination demonstrated a pilocytic astrocytoma. Its astrocytic nature was confirmed by positive immunostaining for GFAP and the findings of an electron microscopy.


The Hog1 mitogen-activated protein kinase is essential in the oxidative stress response and chlamydospore formation in Candida albicans.
Candida albicans mutants with mutations in mitogen-activated protein (MAP) kinase HOG1 displayed an increased sensitivity to agents producing reactive oxygen species, such as oxidants (menadione, hydrogen peroxide, or potassium superoxide), and UV light. Consistent with this finding, C. albicans Hog1 was activated not only in response to an increase in external osmolarity, as happens with its Saccharomyces cerevisiae homologue, but also in response to hydrogen peroxide. The Hog1-mediated response to oxidative stress was different from that of transcription factor Cap1, the homologue of S. cerevisiae Yap1, as shown by the different sensitivities to oxidants and the kinetics of cell death of cap1Delta, hog1, and hog1 cap1Delta mutants. Deletion of CAP1 did not influence the level of Hog1 phosphorylation, and deletion of HOG1 did not affect Cap1 nuclear localization. Moreover, we show that the HOG1 gene plays a role in chlamydospore formation, another oxygen-related morphogenetic event, as demonstrated by the fact that hog1 cells were unable to generate these thick-walled structures in several media through a mechanism different from that of the EFG1 regulator. This is the first demonstration of the role of the Hog1-mediated MAP kinase pathway in resistance to oxidative stress in pathogenic fungi, and it allows us to propose a molecular model for the oxidative stress response in C. albicans.


Enhanced peroxydisulfate electrochemiluminescence for dopamine biosensing based on Au nanoparticle decorated reduced graphene oxide.
This work reports a novel strategy to amplify the electrochemiluminescence (ECL) signal of peroxydisulfate solution based on the Au nanoparticle decorated reduced graphene oxide (Au NP-RGO), and further an ECL biosensor for sensitive and selective detection of dopamine (DA) was constructed. Due to the synergistic amplification of Au NPs and RGO, the ECL signal of peroxydisulfate solution on the Au NP-RGO modified electrode was about 5-fold enhanced compared to that of the bare electrode with the ECL onset potential positively shifted from -1.2 V to -0.9 V. More interestingly, the ECL intensity of peroxydisulfate solution increased with the increase of DA concentration, based on which an ECL biosensor for DA determination was fabricated. The as-prepared solid-state ECL DA sensor showed a wide linear response of 0.02-40 μM with a detection limit of 6.7 nM (S/N = 3). Moreover, we expect this work would open up a new field in the application of peroxydisulfate solution ECL for highly sensitive bioassays.


Exploiting Long Noncoding RNAs as Pharmacological Targets to Modulate Epigenetic Diseases.
Long non-coding RNAs (lncRNAs) constitute the largest class of non-coding transcripts in the human genome. Results from next-generation sequencing and bioinformatics advances indicate that the human genome contains more non-coding RNA genes than protein-coding genes. Validated functions of lncRNAs suggest that they are master regulators of gene expression and often exert their influences via epigenetic mechanisms by modulating chromatin structure. Specific lncRNAs can regulate transcription in gene clusters. Since the functions of protein-coding genes in clusters are often tied to specific pathways, lncRNAs constitute attractive pharmacological targets. Here we review the current knowledge of lncRNA functions in human cells and their roles in disease processes. We also present forward-looking perspectives on how they might be manipulated pharmacologically for the treatment of a variety of human diseases, in which regulation of gene expression by epigenetic mechanisms plays a major role.


BACON: A tool for reverse inference in brain activation and alteration.
Over the past decades, powerful MRI-based methods have been developed, which yield both voxel-based maps of the brain activity and anatomical variation related to different conditions. With regard to functional or structural MRI data, forward inferences try to determine which areas are involved given a mental function or a brain disorder. A major drawback of forward inference is its lack of specificity, as it suggests the involvement of brain areas that are not specific for the process/condition under investigation. Therefore, a different approach is needed to determine to what extent a given pattern of cerebral activation or alteration is specifically associated with a mental function or brain pathology. In this study, we present a new tool called BACON (Bayes fACtor mOdeliNg) for performing reverse inference both with functional and structural neuroimaging data. BACON implements the Bayes' factor and uses the activation likelihood estimation derived-maps to obtain posterior probability distributions on the evidence of specificity with regard to a particular mental function or brain pathology.


Contrast mechanisms on nanoscale subsurface imaging in ultrasonic AFM: scattering of ultrasonic waves and contact stiffness of the tip-sample.
Ultrasonic atomic force microscopy (AFM) and its associated derivatives are nondestructive techniques that can elucidate subsurface nanoscale structures and properties. Despite the usefulness of these techniques, the physical contrast mechanisms responsible for the reported subsurface features observed in ultrasonic AFM are not well defined. In this study, we present a comprehensive model combining ultrasonic wave scattering and tip-sample contact stiffness to better reproduce the experimentally measured phase variations over subsurface features in two model systems. These model systems represent the two extreme sample types typically imaged by ultrasonic AFM, one being a hard material and the other a soft polymeric material. The theoretical analysis presented and associated comparisons with experimental results suggest that the image contrast depends on the combination of two contrast mechanisms: the perturbation of the scattered ultrasonic waves and the local variation of the contact stiffness at the tip-sample contact. The results of this study open up a new door for the depth estimation of buried nanoscale features into hard (engineering structures) and soft (polymers and biological structures) materials, and eventually lead to non-invasive, high-resolution 3D nano-tomography by ultrasonic AFM.


Epidermal thickness and skin appendage involvement in vulvar intraepithelial neoplasia.
Colposcopically directed biopsies obtained from 165 women with vulvar intraepithelial neoplasia (VIN) were studied to determine both the thickness of the dysplastic epithelium and the depth of involved and noninvolved skin appendages and ultimately to provide a morphometric basis for laser therapy for the condition. Multiple measurements per section were made, and the mean epithelial thickness was calculated for each biopsy. The mean (+/- SD) thickness of the epithelium for all grades of VIN was 0.52 +/- 0.23 mm, with the lesions ranging in thickness from 0.10 to 1.90 mm. The thickness of the involved epithelium varied little, regardless of the location of the lesions. The study indicated that VIN frequently is a multifocal disease most commonly affecting the central vulvar structures, with the posterior half of the vulva the area affected most often. The difference in thickness between the various grades of VIN was not of practical clinical significance from a therapeutic point of view. The measurements suggest that laser vaporization to a depth of 1.0 mm, including the zone of thermal necrosis, should be sufficient to destroy most epidermal lesions without skin appendage involvement. If the initial biopsy showed involvement of adjacent hair follicles or sebaceous glands, deeper tissue destruction would be necessary to theoretically achieve greater than 90% elimination of the disease.


Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand?
Heart disease remains a leading cause of mortality and a major worldwide healthcare burden. Recent advances in stem cell biology have made it feasible to derive large quantities of cardiomyocytes for disease modeling, drug development, and regenerative medicine. The discoveries of reprogramming and transdifferentiation as novel biological processes have significantly contributed to this paradigm. This review surveys the means by which reprogramming and transdifferentiation can be employed to generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and induced cardiomyocytes (iCMs). The application of these patient-specific cardiomyocytes for both in vitro disease modeling and in vivo therapies for various cardiovascular diseases will also be discussed. We propose that, with additional refinement, human disease-specific cardiomyocytes will allow us to significantly advance the understanding of cardiovascular disease mechanisms and accelerate the development of novel therapeutic options.