[Duplication of the PLP gene and the classical form of Pelizaeus-Merzbacher disease].
Pelizaeus-Merzbacher disease (PMD) is a rare form of sudanophilic leukodystrophy which is transmitted by recessive inheritance linked to the X chromosome. It only affects the myelin of the central nervous system (CNS) and is caused by a proteolipid protein (PLP) deficit, which is coded for in Xq21.2-q22. Presentation follows a classical or connatal pattern and is associated with nystagmus, stridor and pyramidal/extrapyramidal manifestations within the framework of a clinical picture of psychomotor retardation and regression with variable clinical course and presentation. A 37-month-old male, with sever psychomotor retardation, nystagmus and choreoathetotic movements with a stationary developmental profile. An MRI scan of the brain showed severe supratentorial hypomyelination and peripheral electrophysiological explorations (EMG and NCS) were normal. The genetic study using PCR revealed duplication in the PLP gene. This observation corresponds to a classical form of PMD, which must be taken into account when associated with: 1) Psychomotor retardation; 2) Early nystagmus; 3) Pyramidal/extrapyramidal involvement; 4) Absence of peripheral neurophysiological involvement; 5) A neuroradiological pattern of hypomyelination of the CNS.


[The prognostic value of hyperglycemia, leukocytosis and decreased glomerular filtration rate in acute coronary syndromes--pharmacological protection capabilities].
The evaluation of the risk of complications and death from cardiovascular causes is conducted in all patients with acute coronary syndromes (ACS) using a variety of methods. The assessment of the risk of cardiovascular events, including also death, the cause of which are cardiovascular diseases, is a very important and essential part of clinical evaluation. Moreover, all patients with ACS are assessed as regards the risk of complications and in-hospital mortality and the short- and long-term patient outcomes. Recently, in the prognostic assessment of ACS patients attention has been paid to hyperglycemia, leukocytosis, and decreased GFR, which might worsen the prognosis. Hyperglycemia on admission and especially its occurrence and persistence during hospitalization speak for particularly poor prognosis. Furthermore, the annual and long-term mortality rate is observed to increase with the higher HbA1c level, regardless of the glucose concentration on admission to hospital. Increased risk of the occurrence of cardiovascular events is observed with the intensity of the inflammation which is reflected, among others, in elevated number of peripheral blood leukocytes. Attention is drawn to the higher rate of complications in patients with increased baseline leukocytosis. The correlation between the increase in leukocyte count and all-cause mortality is statistically significant. A higher risk of non- fatal myocardial infarction is also observed with the increase of leukocytosis. Neutrophils, which are the main pool of white blood cells, and whose activation is observed during PCI, may play a role in these unfavorable phenomena. This activation results in increased production of oxygen free radicals by these cells, intensification of adhesion and aggregation. A number of studies point to the cardioprotective mechanism of action of statins (anti-inflammatory and anti-thrombotic) in patients with ACS. The use of leukocyte reduction filters in patients during CABG may be one of the methods limiting the impact of leukocytosis on cardiovascular events in patients with ACS. Renal failure is a strong and independent predictor of mortality in patients with ACS. Contrast-induced nephropathy is a complication following coronarography which is performed in patients with ACS for diagnostic and therapeutic purposes. Hyperglycemia also has an adverse effect on this complication. The prevention of contrast-induced nephropathy includes the use of statins prior to PCI.


Controlled synthesis and photocatalytic hydrogen evolution activities of cobalt carbides with different phase compositions.
Cobalt carbides are emerging as promising materials for various magnetic and catalytic applications. However, exploring dedicated cobalt carbides with optimal catalytic properties via adjusting phase compositions remains a significant challenge. Herein, three different cobalt carbides, CoxC (Co2C-Co3C), Co2C-Co, and Co3C, were successfully prepared using a facile one-pot green method. The phase compositions of cobalt carbides could be easily controlled by varying the cobalt-based precursors and carbon sources. More remarkably, three different cobalt carbides could serve as reduction cocatalysts decorated CdS for improved hydrogen production under visible light. Intriguingly, the obtained Co3C/CdS nanocomposite displayed the highest photocatalytic hydrogen evolution activity among the three composites and superior photocatalytic stability. This work provides a fundamental approach to tuning the photocatalytic properties of cobalt carbides for energy conversion fields.


Measurement of glucose in plasma, with use of immobilized glucose oxidase and peroxidase.
We describe a novel fluorometric technique for simple, rapid, and economical assay of glucose by use of immobilized glucose oxidase and peroxidase. A cylindrical magnetic stirrer was specially designed to hold the immobilized enzymes firmly and to allow the reaction minzymic transformation quickly. Blood plasma can be assayed directly with no pretreatment. Ascrobic acid, uric acid, and creatinine in concenctrations of 0.25, 0.25, and 0.2 g/liter, respectively, did not interfere. The linearity of the assay was extended to 4.0 g of glucose concentrations. Results by our technique and by the otoluidine or hexokinase methods agreed well. The immobilized enzymes are stable for several months and can be used for several hundred highly accurate and reproducible assays.


Distribution of somatostatin-immunoreactive cell bodies and fibers in the neocortex of Macaca fuscata.
The distribution of somatostatin-immunoreactive cell bodies and processes was studied in the cerebral cortex of the macaque monkey (Macaca fuscata), by applying an immunohistochemical technique with a monoclonal antibody raised against somatostatin tetradecapeptide. Many somatostatin-immunoreactive cell bodies and processes were observed in all regions of the cerebral cortex, i.e., frontal, parietal, temporal, insular, occipital, and cingulate cortices, and also in the underlying white matter. Three types of somatostatin-containing cell bodies were distinguished in the cerebral cortex. These cell bodies were distributed in layers II to VI of the cortex, and also in the underlying white matter. There were dense deposits of somatostatin-containing granular structure in layers I and II, and many somatostatin-containing processes in layers IV and V. The present observations demonstrate that in the primate neocortex somatostatin 14-containing neuronal systems are as highly developed as other prosomatostatin-derived peptides but differ from the latter systems in terms of cell morphology and fiber distribution.


AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease.
Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers' cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan's benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan's benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan's benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aβ (amyloid β) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aβ plaques, but not diffuse plaques or Aβ species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aβ-related cognitive and cerebrovascular deficits.


Engineering a novel, stable dimeric streptavidin with lower isoelectric point.
We have engineered a soluble, stable two-chain dimeric streptavidin (TCD) in Escherchia coli. Examination of the three-dimensional structure of streptavidin aided by empirical binding free-energy calculations helped us to select mutations at subunit interfaces that dissociate the native tetramer and stabilize the desired dimer. We chose positions W120, L124, V125 and H127 and mutated them to 120D/124D/125D/127D (TCD-1); 120D/124N/125S/127D (TCD-2); and 120D/124D/125S/127D (TCD-3). The H127D mutation creates electrostatic repulsion that disrupts the dimer-dimer interface, but leaves it very hydrophobic. Therefore, W120, L124 and V125 were mutated to hydrophilic residues to increase dimer solubility. Among the three candidates, TCD-2 gave the best result: a stable, active dimer with K(d) for biotin of approximately 1x10(-7)M after purification by gel-filtration chromatography. The experimental results confirm the possibility of rational engineering of low-pI dimeric streptavidins. Reduced-size streptavidin mutants with a net negative charge may be more suitable than antibodies or wild-type streptavidin for the targeting step in radioimmunotherapy because they should clear faster from the bloodstream and the kidney.


The western red cedar (Thuja plicata) 8-8' DIRIGENT family displays diverse expression patterns and conserved monolignol coupling specificity.
The isolation and characterization of a multigene family of the first class of dirigent proteins (namely that mainly involved in 8-8' coupling leading to (+)-pinoresinol in this case) is reported, this comprising of nine western red cedar (Thuja plicata) DIRIGENT genes (DIR1-9) of 72-99.5% identity to each other. Their corresponding cDNA clones had coding regions for 180-183 amino acids with each having a predicted molecular mass of ca. 20 kDa including the signal peptide. Real time-PCR established that the DIRIGENT isovariants were differentially expressed during growth and development of T. plicata (P < 0.05). The phylogenetic relationships and the rates and patterns of nucleotide substitution suggest that the DIRIGENT gene may have evolved via paralogous expansion at an early stage of vascular plant diversification. Thereafter, western red cedar paralogues have maintained an high homogeneity presumably via a concerted evolutionary mode. This, in turn, is assumed to be the driving force for the differential formation of 8-8'-linked pinoresinol derived (poly)lignans in the needles, stems, bark and branches, as well as for massive accumulation of 8-8'-linked plicatic acid-derived (poly)lignans in heartwood.


Quality, functionality, and microbiology of fermented fish: a review.
Fermentation is a traditional food preservation method and is widely used for improving food safety, shelf life, and organoleptic and nutritional attributes. Fermented fish are produced and consumed in different parts of the world and are an integral part of many food cultures. Furthermore, fermented fish are a source of interesting microbes and are an important industry in many countries. This review tries to update the types and manufacturing processes for fermented fish around the world. The emphasis is on this work related to fermented fish and their health benefits, as well as the contribution of microorganisms to their fermentation. A variety of different approaches have been used to determine and understand microbial composition and functionality. Moreover, some challenges and future research directions regarding fermented fish are also discussed in this review. Further research into fermented fish products is of crucial importance not only for the food industry but also for human health. However, extensive in vivo and toxicological studies are essential before the application of bioactive-rich fermented fish products for human health benefits.


Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.
In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.


Inclusive State Legislation and Reduced Risk of Past-Year Suicide Attempts Among Lesbian, Gay, Bisexual, and Questioning Adolescents in the United States.
This study examines the relationship between state legislation relevant to equality for sexual minorities and past-year suicide attempts among lesbian, gay, bisexual, and questioning (LGBQ) adolescents in the United States. Data were aggregated from 24 states that participated in the 2017 Youth Risk Behavior Surveillance System (N = 70,599). We utilized multilevel logistic regression to determine whether observed positive associations between sexual minority identity and past-year suicide attempts differ as a function of 2016 State Equality Index (SEI), an objective measure of state laws and policies affecting equality for sexual minorities. LGBQ adolescents were significantly more likely to report having made a suicide attempt in the past year than heterosexual youth (adjusted odds ratio [AOR]: 3.82; 95% confidence interval [CI]: 3.29-4.44). The 2016 SEI moderated the positive association between sexual minority identity and suicide attempts, with odds of past-year suicide attempts significantly reduced in states with more inclusive legislation (AOR: 0.91; CI: 0.85-0.97). Among sexual minority subgroups, significant effect modifications were found for bisexual (AOR: 0.88; CI: 0.77-0.99) and questioning (AOR: 0.87; CI: 0.78-0.96) - but not gay or lesbian (AOR: 1.10; CI: 0.97-1.24) - adolescents. The effect modification was strongest for bisexual males (AOR: 0.68; CI: 0.47-0.99). State legislation relevant to equality for sexual minorities differentially affected associations between sexual minority identity and suicide attempts, such that past-year suicide attempts were substantially lower in states with more inclusive legislation. Inclusive state legislation may exert a protective effect on risk for suicide attempts among sexual minority youth.


Lubriglide Sequential Ureteral Dilators®: A Safe and Effective Method of Ureteral Dilation.
During ureteroscopy (URS), ureteral dilation may be required to increase the likelihood of accessing the ureter to complete the procedure. Thus, we sought to assess the safety and efficacy of using Lubriglide sequential ureteral dilators® (Boston Scientific) to promote primary URS, without need for prestenting. Retrospective review was performed of a consecutive series of patients undergoing primary URS by a single surgeon (N.L.M.) from 2011 to 2013. The primary outcomes were to characterize the use, safety, and efficacy of sequential ureteral dilators to promote stone treatment during URS. A total of 316 nonprestented cases of primary URS were attempted over the study period. Use of sequential ureteral dilators to promote ureteral access was performed in 109 (34.5%) cases and was effective to allow completion of the procedure in 102 (93.6%) cases. No intraoperative complications occurred while performing sequential ureteral dilation. Fourteen patients (4.3%) required ureteral stent placement for passive ureteral dilation, with definitive stone treatment at a later date. Postoperative radiographic follow-up was available for 272 (86.1%) cases, and no ureteral strictures were detected in the ureteral dilation group. On multivariate analysis, both a history of prior extracorporeal shockwave lithotripsy [odds ratio (OR) 0.45, confidence interval (CI) 0.25, 0.81, p = 0.008] and prior URS (OR 0.42, CI 0.25, 0.70, p = 0.001) were inversely associated with need to perform ureteral dilation. Approximately 1/3 of nonprestented patients may require ureteral dilation for effective completion of primary URS. Use of sequential ureteral dilators may significantly decrease the need for prestenting and a secondary procedure to complete stone treatment. Thus, we conclude that sequential ureteral dilators represent a safe and effective method to perform ureteral dilation to promote ureteral access and allow for effective stone treatment in one setting.


Microbial-Assisted Wheat Iron Biofortification Using Endophytic Bacillus altitudinis WR10.
Microbial-assisted biofortification attracted much attention recently due to its sustainable and eco-friendly nature for improving nutrient content in wheat. An endophytic strain Bacillus altitudinis WR10, which showed sophistical regulation of iron (Fe) homeostasis in wheat seedlings, inspired us to test its potential for enhancing Fe biofortification in wheat grain. In this study, assays in vitro indicated that WR10 has versatile plant growth-promoting (PGP) traits and bioinformatic analysis predicted its non-pathogenicity. Two inoculation methods, namely, seed soaking and soil spraying, with 107 cfu/ml WR10 cells were applied once before sowing of wheat (Triticum aestivum L. cv. Zhoumai 36) in the field. After wheat maturation, evaluation of yield and nutrients showed a significant increase in the mean number of kernels per spike (KPS) and the content of total nitrogen (N), potassium (K), and Fe in grains. At the grain filling stage, the abundance of Bacillus spp. and the content of N, K, and Fe in the root, the stem, and the leaf were also increased in nearly all tissues, except Fe in the stem and the leaf. Further correlation analysis revealed a positive relationship between the total abundance of Bacillus spp. and the content of N, K, and Fe in grains. Seed staining confirmed the enhanced accumulation of Fe, especially in the embryo and the endosperm. Finally, using a hydroponic coculture model, qPCR quantification indicated effective colonization, internalization, translocation, and replication of strain WR10 in wheat within 48 h. Collectively, strain WR10 assisted successful Fe biofortification in wheat in the field, laying a foundation for further large-scale investigation of its applicability and effectiveness.


[Clinical value of routine contrast esophagram in the diagnosis of anastomotic leakage for three-incision esophagectomy with cervical anastomosis].
Objective: To examine the clinical value of routine contrast esophagram (RCE) for the diagnosis of anastomotic leakage (AL) after three-incision esophagectomy with cervical anastomosis. Methods: Clinical data of 1 022 patients with esophageal cancer who underwent McKeown three-incision esophagectomy with cervical anastomosis from January 2015 to December 2019 at Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Hospital and Institute were analyzed retrospectively. There were 876 males and 146 females, aging(M(IQR)) 48(16) years (range: 36 to 84 years). There were 253 patients (24.8%) with neoadjuvant therapy, and 817 patients (79.9%) with minimally invasive esophagectomy. According to the diagnosis and treatment habits of the attending surgeons, 333 patients were included in the RCE group, and RCE was performed on the 7th day postoperative, while 689 patients were included in the non-RCE group, and RCE was performed when the patients had suspicious symptoms. Taking clinical symptoms, RCE, CT, endoscopy and other methods as reference to the diagnosis of AL, the sensitivity and specificity were used to analyze and evaluate the efficacy of RCE for the diagnosis of AL. The data were compared by U test or χ² test between groups. Results: The incidence rate of AL after three-incision esophagectomy was 7.34% (75/1 022), including 30 cases in the RCE group and 45 cases in the non-RCE group (9.0%(30/333) vs. 6.5%(45/689), χ²=2.027, P=0.155). The diagnostic time of AL was 9(5) days postoperative (range: 4 to 30 days). Among them, 23 cases showed cervical leakages, 50 cases showed intro-thoracic leakages, and 2 cases both cervical and intro-thoracic leakages. The diagnostic time of patients with intro-thoracic leakages was longer than that of cervical leakages (10(4) days vs. 6(3) days, Z=-2.517, P=0.012). Among the 333 patients in the RCE group, 16 cases of RCE indicated leakages including 11 cases of true positive and 5 cases determined to be false positive, while 317 cases indicated no abnormalities including 19 cases developed leakages. The sensitivity and specificity of RCE to detect AL were 36.7%(11/30) and 98.3%(298/333), respectively. The Youden-index was 0.35, and the diagnostic accuracy was 92.8%(309/333). The positive and negative predictive value were 11/16 and 94.0%(298/317), respectively. Conclusions: Routine contrast esophagram after three-incision esophagectomy with cervical anastomosis has low sensitivity and high specificity in the diagnosis of AL. The diagnostic time of AL is the 9th day after surgery. It is necessary to prolong the observation time clinically, and combine RCE with CT, endoscopy and other inspection methods for diagnosis.


Differential visceral nociceptive, behavioural and neurochemical responses to an immune challenge in the stress-sensitive Wistar Kyoto rat strain.
A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.


Generation of Aptamers from A Primer-Free Randomized ssDNA Library Using Magnetic-Assisted Rapid Aptamer Selection.
Aptamers are oligonucleotides that can bind to specific target molecules. Most aptamers are generated using random libraries in the standard systematic evolution of ligands by exponential enrichment (SELEX). Each random library contains oligonucleotides with a randomized central region and two fixed primer regions at both ends. The fixed primer regions are necessary for amplifying target-bound sequences by PCR. However, these extra-sequences may cause non-specific bindings, which potentially interfere with good binding for random sequences. The Magnetic-Assisted Rapid Aptamer Selection (MARAS) is a newly developed protocol for generating single-strand DNA aptamers. No repeat selection cycle is required in the protocol. This study proposes and demonstrates a method to isolate aptamers for C-reactive proteins (CRP) from a randomized ssDNA library containing no fixed sequences at 5' and 3' termini using the MARAS platform. Furthermore, the isolated primer-free aptamer was sequenced and binding affinity for CRP was analyzed. The specificity of the obtained aptamer was validated using blind serum samples. The result was consistent with monoclonal antibody-based nephelometry analysis, which indicated that a primer-free aptamer has high specificity toward targets. MARAS is a feasible platform for efficiently generating primer-free aptamers for clinical diagnoses.


Uterus didelphys with blind hemivagina and ipsilateral renal agenesis (Herlyn-Werner-Wunderlich syndrome) suspected on the presence of hydrocolpos on prenatal sonography.
We report the case of a female neonate with ipsilateral renal agenesis and uterus didelphys with blind hemivagina, also known as Herlyn-Werner-Wunderlich (HWW) syndrome. Prenatal sonography revealed the absence of the left kidney and a retrovesical cystic lesion suspected as hydrometrocolpos. Postnatal evaluation confirmed that the cystic lesion was a hydrocolpos associated with double uterus and blind hemivagina (HWW syndrome). HWW syndrome can be suspected prenatally if a retrovesical cystic lesion is detected in a female fetus with unilateral absence of kidney.


Co-existing spinal canal tumours and CADASIL - a diagnostic challenge.
We would like to present a case of a 51-year-old patient with two rare co-existing diseases. The patient was suffering from two tumours in the lumbar region of the spinal canal, which caused development of hydrocephalus. Diffuse white matter hyperintensities (WMH) were observed in our patient's brain imaging. She was also suffering from headaches and she had two mild strokes. We performed some further diagnostic procedures and found out that the patient was suffering from CADASIL. CADASIL was confirmed by both ultrastructural analysis and genetic testing.


Cobalt doping of FePS3 promotes intrinsic active sites for the efficient hydrogen evolution reaction.
Exploring Earth-abundant electrocatalysts to achieve the efficient hydrogen evolution reaction (HER) is important for the development of clean and renewable hydrogen energy. Herein, we focus on a representative transition metal phosphosulfide electrocatalyst FePS3. Enlightened by our theoretical calculations that Co dopants improve H affinity on P sites and electrical conductivity, we prepared a series of Fe1-xCoxPS3 (x = 0, 0.05, 0.1, 0.15, 0.2, 0.25) compounds and characterized them by XRD, ICP, XPS, Raman, SEM, TEM, EDS, and resistivity and electrochemical measurement. It is found that the overpotential can be reduced by 166 mV, and the Tafel slope drops from 170 mV dec-1 to 80 mV dec-1. This work provides new insights to optimize the electrocatalytic hydrogen evolution activity of related transition metal phosphosulfides.


Occupational pesticide exposure among Yemeni women.
Limited research on the nature and extent of pesticide exposure among women in developing countries is available. The aim of this study was to describe potential pesticide exposure among women living in Yemen that occurs through agricultural work. In this cross-sectional study, 410 women who had a daughter enrolled in high school during 2011-2012 were surveyed regarding pesticide exposure. Of the 410 women who responded to the survey, 171 women reported working on farms during their lifetime. Of these 171 women, 147 reported working on a farm prior to marriage and 108 reported working on a farm after marriage. Among the women who reported working on a farm before marriage, 47% had worked on farms where pesticides were used. Among those women who reported working on farms after marriage, 69% of women worked on farms where pesticides were used. Among women who reported working on a farm before marriage where pesticides were used, 45% reported not using any protective equipment. This proportion was 33% among women who worked on a farm after marriage. Among the 28 commercial pesticides that were listed within the questionnaire, the banned compound dimethoate was the most commonly reported pesticide to be used on farms. The findings suggest that improving safe pesticide management practices among farmers and enforcing effective banning of the most toxic pesticides is needed to reduce pesticide exposure among Yemeni women.


Design and synthesis of paclitaxel conjugated with an ErbB2-recognizing peptide, EC-1.
The selective delivery of therapeutic agents to receptors overexpressed in cancer cells without harming the rest of the body is a major challenge in clinical oncology today. In this study, we report the design and synthesis of paclitaxel (PTX) conjugated with an erbB2-recognizing peptide (EC-1). The cyclic peptide EC-1 specifically binds to the extracellular domain of ErbB2 and selectively inhibits proliferation of breast cancer cells overexpressing ErbB2. PTX is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer, yet patients have to suffer some side effects caused by its systemic toxicity. The aim of our conjugate is to specifically deliver antitumor agent PTX to breast cancer cells that overexpress oncogenic ErbB2 with the purpose to reduce toxicity and enhance selective killing of cancer cells. In this study, a concise and efficient synthetic route for the preparation of the PTX-EC-1 conjugate has been developed in 6% overall yield. This synthetic approach provides a general method for conjugating a highly functionalized and disulfide-bridge containing cyclopeptide to Taxol or other antitumor agents.


The roles of consistency and exclusivity in perceiving body ownership and agency.
Previous rubber/virtual hand illusion studies have established important constraints for the illusion that an artificial effector becomes part of one's own body (perceived ownership), and that its actions are being caused by oneself (perceived agency). We can take these observed constraints to establish two of three Wegner's (Trends Cogn Sci 7:65-69; Wegner, Trends in Cognitive Sciences 7:65-69, 2003) criteria for the perception of personal agency: priority and consistency, but not Wegner's third criterion-exclusivity. In this study we tested with virtual hand illusion, whether exclusivity (participant is certain who was controlling the virtual effector) can also be established. We manipulated two factors: exclusivity and consistency. Our results show that on both ownership and agency judgments, consistency and exclusivity produced main effects, and the two effects interacted in an underadditive fashion. Taken together, these findings provide support for our suggestion to extend Wegner's agency theory to explain perceived body ownership, which in turn provides an integrative framework for interpreting constraints on ownership and agency illusions.


The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia.
In type 2 diabetics, the progression of atherosclerosis is more rapid than the general population and 80% of these patients will die of an atherosclerotic event. Since in these patients hyperglycemia per se confers increased risk for cardiovascular disease (CVD), the presence of even borderline-high-risk LDL-C signals the need for more aggressive LDL-lowering therapy. Most of the lipid lowering agents, currently in use in the treatment of dyslipidemia in type 2 diabetics, have a host of side effects. In contrast, dietary tocotrienols are Vitamin E and have effective lipid lowering property in addition to their potent antioxidant activity. In this study, we have investigated the therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients. Based on known tocotrienol rich fraction (TRF)-mediated decrease on elevated blood glucose and glycated hemoglobin A(1C) (HbA(1C)) in diabetic rats, we have also investigated the effect of TRF on these parameters. A randomized, double blind, placebo-controlled design involving 19 type 2 diabetic subjects with hyperlipidemia was used. After 60 days of TRF treatment, subjects showed an average decline of 23, 30, and 42% in serum total lipids, TC, and LDL-C, respectively. The goal in type 2 diabetics is to reduce LDL-C levels < or = 100mg/dl. In the present investigation tocotrienols mediated a reduction of LDL-C from an average of 179 mg/dl to 104 mg/dl. However, hypoglycemic effect of TRF was not observed in these patients because they were glycemically stable and their glucose and HbA(1) levels were close to normal values. In conclusion, daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.


Intraoperative hypotension in ambulatory surgery centers.
To measure the incidence of intraoperative hypotension (IOH) during surgery in ambulatory surgery centers (ASCs) and describe associated characteristics of patients and procedures. Retrospective analysis. 20 ASCs. 16,750 patients having non-emergent, non-cardiac surgery; ASA physical status 2 through 4. None. We assessed incidence of IOH using the definition from the Centers for Medicare & Medicaid Services (CMS) Merit-based Incentive Payment System (MIPS)-mean arterial pressure (MAP) < 65 mmHg for at least 15 cumulative minutes-and three secondary definitions: minutes of MAP <65 mmHg, area under MAP of 65 mmHg, and time-weighted average MAP <65 mmHg. 30.9% of ASC cases had a MAP <65 mmHg for at least 15 min. The incidence of IOH varied significantly, and was higher among younger adults (age 18-39; 36.2%), females (35.2%), and patients with ASA physical status 2 (32.8%). IOH increased with increasing surgery length, even when time-weighted, and was higher among low complexity (30.6%) than moderate complexity (28.8%) procedures, and highest among high complexity procedures (44.1%). There was substantial occurrence of IOH in ASCs, similar to that described in academic hospital settings in previous literature. We hypothesize that this may reflect clinician preference not to intervene in perceived healthy patients or assumptions about ability to tolerate lower blood pressures on behalf of these patients. Future research will determine whether IOH in ACSs is associated with adverse outcomes to the same extent as described in more complex hospital-based surgeries.


[Quality of advanced practice nurse counseling in home care settings (APN-BQ): psychometric testing of the instrument].
Patient centred and individually-tailored counselling of older people with a chronic condition who live at home is a useful intervention to support their independence. The paper presents the development and psychometric testing of the APN-BQ Instrument, to measure patient-centeredness. To measure the quality of an in-home counselling intervention, a 23-item questionnaire was developed and tested with 206 people 80 years and older. Principal component analysis with Varimax Rotation was conducted (n = 206). Analysis revealed a four factor (fs = 0.91) model scoring in 19 items. All factors loaded > 0.45. Cronbach's alpha was 0.86. The utility and acceptance of the instrument was confirmed by the high response rate (100 %) and the fact that participants answered 98.8 % of all questions. The APN-BQ has shown to be a reliable Instrument with good content and construct validity. It is a tool for APNs to measure structure, process, and outcome quality of a patient-centred and individually-tailored counselling program, including the degree of patient participation, and patient empowerment.


Modeling the doubly excited state with time-dependent Hartree-Fock and density functional theories.
Multielectron excited states have become a hot topic in many cutting-edge research fields, such as the photophysics of polyenes and in the possibility of multiexciton generation in quantum dots for the purpose of increasing solar cell efficiency. However, obtaining multielectron excited states has been a major obstacle as it is often done with multiconfigurational methods, which involve formidable computational cost for large systems. Although they are computationally much cheaper than multiconfigurational wave function based methods, linear response adiabatic time-dependent Hartree-Fock (TDHF) and density functional theory (TDDFT) are generally considered incapable of obtaining multielectron excited states. We have developed a real-time TDHF and adiabatic TDDFT approach that is beyond the perturbative regime. We show that TDHF/TDDFT is able to simultaneously excite two electrons from the ground state to the doubly excited state and that the real-time TDHF/TDDFT implicitly includes double excitation within a superposition state. We also present a multireference linear response theory to show that the real-time electron density response corresponds to a superposition of perturbative linear responses of the S(0) and S(2) states. As a result, the energy of the two-electron doubly excited state can be obtained with several different approaches. This is done within the adiabatic approximation of TDDFT, a realm in which the doubly excited state has been deemed missing. We report results on simple two-electron systems, including the energies and dipole moments for the two-electron excited states of H(2) and HeH(+). These results are compared to those obtained with the full configuration interaction method.


Comparison between fibroblast wound healing and cell random migration assays in vitro.
Cell migration plays a key role in many biological processes, including cancer growth and invasion, embryogenesis, angiogenesis, inflammatory response, and tissue repair. In this work, we compare two well-established experimental approaches for the investigation of cell motility in vitro: the cell random migration (CRM) and the wound healing (WH) assay. In the former, extensive tracking of individual live cells trajectories by time-lapse microscopy and elaborate data processing are used to calculate two intrinsic motility parameters of the cell population under investigation, i.e. the diffusion coefficient and the persistence time. In the WH assay, a scratch is made in a confluent cell monolayer and the closure time of the exposed area is taken as an easy-to-measure, empirical estimate of cell migration. To compare WH and CRM we applied the two assays to investigate the motility of skin fibroblasts isolated from wild type and transgenic mice (TgPED) overexpressing the protein PED/PEA-15, which is highly expressed in patients with type 2 diabetes. Our main result is that the cell motility parameters derived from CRM can be also estimated from a time-resolved analysis of the WH assay, thus showing that the latter is also amenable to a quantitative analysis for the characterization of cell migration. To our knowledge this is the first quantitative comparison of these two widely used techniques.


Inconsistent reporting of minimally invasive surgery errors.
Minimally invasive surgery (MIS) is a complex task requiring dexterity and high level cognitive function. Unlike surgical 'never events', potentially important (and frequent) manual or cognitive slips ('technical errors') are underresearched. Little is known about the occurrence of routine errors in MIS, their relationship to patient outcome, and whether they are reported accurately and/or consistently. An electronic survey was sent to all members of the Association of Surgeons of Great Britain and Ireland, gathering demographic information, experience and reporting of MIS errors, and a rating of factors affecting error prevalence. Of 249 responses, 203 completed more than 80% of the questions regarding the surgery they had performed in the preceding 12 months. Of these, 47% reported a significant error in their own performance and 75% were aware of a colleague experiencing error. Technical skill, knowledge, situational awareness and decision making were all identified as particularly important for avoiding errors in MIS. Reporting of errors was variable: 15% did not necessarily report an intraoperative error to a patient while 50% did not consistently report at an institutional level. Critically, 12% of surgeons were unaware of the procedure for reporting a technical error and 59% felt guidance is needed. Overall, 40% believed a confidential reporting system would increase their likelihood of reporting an error. These data indicate inconsistent reporting of operative errors, and highlight the need to better understand how and why technical errors occur in MIS. A confidential 'no blame' reporting system might help improve patient outcomes and avoid a closed culture that can undermine public confidence.


Profiling of EBV-Encoded microRNAs in EBV-Associated Hemophagocytic Lymphohistiocytosis.
Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening complication of EBV infection. MicroRNAs (miRNAs) were small non-coding RNA, and EBV could encode miRNAs that are involved in the progression of infection. However, the profiles of EBV-miRNAs in EBV-HLH were unknown. Here, we aimed to profile the expression of EBV-miRNAs in children with EBV-HLH by analyzing 44 known EBV-miRNAs, encoded within the BamHI fragment H rightward open reading frame 1 (BHRF1) and the BamHI-A region rightward transcript (BART), in plasma and cellular targets by real-time quantitative PCR. The study included 15 children with EBV-HLH, 15 children with infectious mononucleosis (IM), and 15 healthy controls. CD8(+) T cells were found to be the cellular target of EBV infection in EBV-HLH, while CD19(+) B cells were infected with EBV in IM. We also found the greater levels of several miRNAs encoded by BART in EBV-HLH, compared to those in IM and healthy controls, whereas the levels of BHRF1 miRNAs were lower than those in IM. The profile and pattern of EBV-miRNAs in EBV-HLH indicated that EBV could display type II latency in EBV-HLH. Importantly, the level of plasma miR-BART16-1 continued decreasing during the whole chemotherapy, suggesting that plasma miR-BART16-1 could be a potential biomarker for monitoring EBV-HLH progression. The pathogenesis of EBV-HLH might be attributed to the abundance of EBV-miRNAs in EBV-HLH. These findings help elucidate the roles of EBV miRNAs in EBV-HLH, enabling the understanding of the basis of this disease and providing clues for its treatment.


Prussian Blue/Chitosan Micromotors with Intrinsic Enzyme-like Activity for (bio)-Sensing Assays.
Prussian Blue (PB)/chitosan enzyme mimetic tubular micromotors are used here for on-the-fly (bio)-sensing assays. The micromotors are easily prepared by direct deposition of chitosan into the pores of a membrane template and in situ PB synthesis during hydrogel deposition. Under judicious pH control, PB micromotors display enzyme mimetic capabilities with three key functions on board: the autonomous oxygen bubble propulsion (with PB acting as a catalase mimic for hydrogen peroxide decomposition), 3,3',5,5'-tetramethylbenzidine (TMB) oxidation (with PB acting as a peroxidase mimic for analyte detection), and as a magnetic material (to simplify the (bio)-sensing steps). In connection with chitosan capabilities, these unique enzyme mimetic micromotors are further functionalized with acetylthiocholinesterase enzyme (ATChE) to be explored in fast inhibition assays (20 min) for the colorimetric determination of the nerve agent neostigmine, with excellent analytical performance in terms of quantification limit (0.30 μM) and concentration linear range (up to 500 μM), without compromising efficient micromotor propulsion. The new concept illustrated holds considerable potential for a myriad of (bio)-sensing applications, including forensics, where this conceptual approach remains to be explored. Micromotor-based tests to be used in crime scenes are also envisioned due to the reliable neostigmine determination in unpretreated samples.


Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.
Increases in p53 protein levels after DNA damage have largely been attributed to an increase in the half-life of p53 protein. Here we demonstrate that increased translation of p53 mRNA is also a critical step in the induction of p53 protein in irradiated cells. Ribosomal protein L26 (RPL26) and nucleolin were found to bind to the 5' untranslated region (UTR) of p53 mRNA and to control p53 translation and induction after DNA damage. RPL26 preferentially binds to the 5'UTR after DNA damage, and its overexpression enhances association of p53 mRNA with heavier polysomes, increases the rate of p53 translation, induces G1 cell-cycle arrest, and augments irradiation-induced apoptosis. Opposite effects were seen when RPL26 expression was inhibited. In contrast, nucleolin overexpression suppresses p53 translation and induction after DNA damage, whereas nucleolin downregulation promotes p53 expression. These findings demonstrate the importance of increased translation of p53 in DNA-damage responses and suggest critical roles for RPL26 and nucleolin in affecting p53 induction.


The general fertility rate in women with psychotic disorders.
This study determined the general fertility rate and age-specific fertility rates for women with psychotic disorders. This historical matched-cohort study of patient records from a primary care database (the General Practice Research Database) was carried out for women of childbearing age (15-44 years) with psychotic disorders. The women with psychotic disorders (N=7,936) had a lower overall general fertility rate than the normal comparison subjects (N=23,023), although fertility was only significantly lower in the women aged 25 and above. This lower fertility rate was less marked in women with affective psychoses. There was no evidence that treatment with neuroleptics influenced the fertility rate in women with non-affective psychoses. This study found markedly lower fertility rates in women with psychotic disorders than in matched normal comparison subjects, particularly in women with non-affective disorders. Knowledge of fertility rates in women with psychotic disorders is fundamental for clinicians and researchers, since it has implications for family planning services, prevention of obstetric complications, child-care support, and hypotheses about the etiology of these disorders.


After vs. priming effects of anodal transcranial direct current stimulation on upper extremity motor recovery in patients with subacute stroke.
Transcranial direct current stimulation (tDCS) of the motor cortex seems to be effective in improving motor performance in patients with chronic stroke, while some recent findings have reported conflicting results for the subacute phase. We aimed to verify whether upper extremity motor rehabilitation could be enhanced by treatment with tDCS administered before a rehabilitative session. Hand dexterity and force in 16 individuals with subacute stroke were assessed before (T0) and after anodal stimulation (T1) and after a successive session of motor rehabilitation (T2) in a double-blind, randomized, sham-controlled, crossover trial. To confirm the value of the device as a specific effector, behavioral tests were also administered. Anodal and sham stimulation plus rehabilitation significantly improved manual dexterity (repeated-measure Anova: A-tDCS: p = 0.005; S-tDCS: p = 0.042). Post hoc analysis revealed a significant stimulation effect only for A-tDCS (p = 0.013 between T0 and T1) and not for S-tDCS, whereas the rehabilitation effect (between T1 and T2) was not significant in either group. Hand force and behavioral features were unchanged. Anodal brain stimulation improves hand dexterity but does not increase the effectiveness of the rehabilitation directly. These results suggest the presence of aftereffects, not priming effects, of A-tDCS superimposed onto motor learning phenomena.


Nociceptive responses in the neostriatum and globus pallidus of the anesthetized rat.
1. Extracellular recordings were made from neurons in the neostriatum (caudate nucleus-putamen, CPu) and globus pallidus (GP) of anesthetized rats. Few cells (3%) were classified as low-threshold-mechanoreceptive (LTM) neurons. The majority (97%) of somatosensory CPu and GP neurons responded differentially or exclusively to noxious mechanical stimulation of the skin. Nociceptive neurons were classified into the following three groups on the basis of their response properties to noxious mechanical stimulation: wide-dynamic-range (WDR) neurons (21%); nociceptive-specific (NS) neurons (67%); and inhibited (INH) neurons (13%). 2. No differences in the response properties or in the proportions of WDR, NS, and INH neurons were found in the CPu compared with the GP. Nociceptive neurons were located most often along the CPu-GP border. Additionally, neurons of similar functional classification were often clustered within 200-400 microns of each other along a single microelectrode track. 3. The receptive fields of nociceptive CPu and GP neurons were often large and bilateral; some receptive fields encompassed the entire body. The trigeminal region, especially the perioral area, was included in the receptive fields of nociceptive neurons more often (62 of 63 cells) than any other part of the body. However, no preference for any particular division of the trigeminal nerve was observed in the receptive fields. Some neurons had receptive fields that were discontinuous. 4. Noxious pinching of the skin significantly increased the spontaneous neuronal discharge of WDR and NS neurons by an average of 482 and 221%, respectively. There were no significant differences between the discharge adaptation rates of WDR and NS neurons. Afterdischarge activity was observed in some WDR and NS neurons. INH neurons decreased their resting activity levels by an average of 43% after a noxious pinch. 5. The von Frey stimulus threshold of WDR neurons (11.0 g/mm2) was significantly lower than that of NS neurons (33.6 g/mm2) and INH neurons (32.6 g/mm2). Mean stimulus thresholds of WDR, NS, and INH neurons determined by using calibrated forceps were 1.6, 4.8, and 2.2 g/mm2, respectively. 6. Individual stimulus-response functions of nociceptive neurons were best fit by a negatively accelerating (logarithmic) curves. However, WDR neurons had significantly steeper slopes than NS neurons. 7. The results demonstrate that a large proportion of somatosensory neurons within the neostriatum and globus pallidus (especially along the CPu-GP border) receive nociceptive information. These data are discussed in relation to several putative afferent nociceptive pathways projecting to the CPu and GP.(ABSTRACT TRUNCATED AT 400 WORDS)


[Interdisciplinary connections of neurosurgery in the past, present and future].
Giving examples derived from history, the development and the present level of neurosurgery as an expression of the close interdisciplinary co-operation are dealt with. Neurosurgery has shown to be useful in our days and will continue to do so the future as a link between the great number of medical and non-medical disciplines; it has integrative functions, the roots of which frequently reach back to the beginnings of the disciplines, and these functions call for a constant further maintenance of the interests of the people concerned reaching far beyond their own fields. In this way, the neurosurgeon can avoid to become only a marginal figure in the sense of the surgical assistant of other medical disciplines. Being conscious of the history of one's own field often gives surprisingly important information about one's future development and permits an analysis of one's daily work.


[Information system of heat-disorders and prevention].
In Japan several services for providing information on heat-disorders and its prevention are available. For the information on patients of heat-disorders, National Institute for Environmental Studies (NIES) and Fire and Disaster Management Agency(FDMA) have systems for providing the information of the patients transported by ambulance cars from heat-disorders. NIES deals the data from major cities and FDMA deals the data of all Japan by prefecture. For the information on preventing heat-disorders, Japan Meteorological Agency (JMA) and NIES have systems for providing the weather information. JMA alarms when the daily maximum temperature reached or will reach to extremely high (> or = 35 degrees C) and NIES provides the WBGT(wet-bulb globe temperature) forecast for coming three days for all around Japan.


Accuracy of staging rectal tumors with contrast-enhanced transrectal MR imaging.
Our objective was to evaluate the accuracy of contrast-enhanced transrectal MR imaging in staging rectal adenoma and carcinoma by correlating with histopathologic findings. Thirty-five patients underwent transrectal MR imaging on a 1.5-T superconducting unit using unenhanced T1-weighted and T2-weighted spin-echo and turbo spin-echo sequences, a dynamic gadopentetate dimeglumine-enhanced turbo fast low-angle shot sequence, and enhanced T1-weighted spin-echo sequences. For all patients, histopathologic correlation was available from biopsy (n = 15) or surgical resection (n = 20). Two radiologists unaware of each other's interpretations of the scans interpreted each case from which we evaluated qualitative and quantitative data. Rectal adenomas (n = 15) were identified when imaging revealed an intact muscularis mucosae, a homogeneous internal structure, and high contrast enhancement of the lesion. Carcinomas staged as T1 by TNM criteria (n = 6) were best revealed by dynamic turbo fast low-angle shot sequences, in which an intact muscularis propria could be seen. Visualization of enhancing tumor tissue in the muscularis propria indicated T2 carcinoma (n = 5). All T3 (n = 5) and T4 (n = 4) carcinomas were correctly staged with dynamic and static MR imaging. The stage revealed by MR imaging correlated well with histologic staging results in 89% (observer 1) and 86% (observer 2) of interpretations. However, when interpreting MR imaging, observers tended to overstage and never understaged. Transrectal surface-coil MR imaging provided reliable information in staging patients before surgery and in evaluating rectal adenoma and carcinoma.


Family homeostasis and the physician.
Physical illness, including psychosomatic disorders, often play an unexpected role in maintaining emotional balances within the family. The outbreak of such disorders, conversely, can be utilized by the physician as a barometer of family emotional difficulties.


Implantable loop recorder allows an etiologic diagnosis in one-third of patients. Results of the Spanish reveal registry.
The implantable loop recorder (ILR) is a useful tool for diagnosing paroxysmal conditions potentially related to arrhythmias. Most investigations have focused on selected clinical studies or high-volume centers. The aim of this study was to evaluate the indications and outcomes of the ILR in real clinical practice. This was a prospective, multicenter registry of patients undergoing ILR implantation for clinical indications (April 2006-December 2008). Clinical characteristics (symptoms, arrhythmias, treatments) were recorded in a database. Follow-up data at 1 year or after the occurrence of the first episode were also recorded. Total enrollment: 743 patients (male, 413, 55.6%; 64.9 ± 16 years); 228 (30.7%) had structural heart disease (SHD), and 183 (24.6%), bundle branch block (BBB). Recurrent syncope (76.4%) was the most common indication for implantation. Complete follow-up was obtained for 680 patients (91.5%). Three hundred and twenty-five patients (48%) presented 414 events, with a final diagnosis in 230 patients (70.8% of patients with events; 33.1% of patients with follow-up). Syncope secondary to bradyarrhythmia was the most frequent diagnosis. Similar rates of final diagnoses were noted in subgroups of SHD, BBB and normal heart. Regarding the cause of implantation, higher event rates were registered among patients with recurrent syncope. One-third of patients obtained a final diagnosis with the ILR, independent of the baseline characteristics. Only the cause of implantation provided different rates of final diagnosis.


Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.
Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.


[Radiologic diagnosis of opportunistic pulmonary infections].
Advances in the area of tumour therapy and transplantation medicine as well as increasing numbers of immunodeficiency syndromes have resulted into growing importance of opportunistic infections. The radiological diagnosis and differential diagnosis become more difficult due to the broad spectrum of possible pathogenic organisms, pulmonary complications as part of the underlying disease and finally through possible side effects of therapy. An assignment of these changes to certain radiographic patterns seems useful. However, very few infections present with a characteristic pattern. In the majority of cases the radiography by itself cannot lead to the correct diagnosis. Here, more than in other areas, additional information and wide experience are of great importance to the radiologist.


Non-papillary carcinoma in situ of the urinary bladder. An electron microscopic study.
A case of non-papillary carcinoma in situ of the urinary bladder was presented with ultrastructural descriptions. Dysplastic urothelial cells had a large nucleus with prominent nucleoli and increased euchromatin. The nuclei had a wavy outline with irregular invaginations. Cytoplasmic organella were immature and fairly good amount of glycogen particles existed in the cytoplasm. Among the dysplastic cells, there are two types of epithelium, one which has irregular pleomorphic cytoplasmic processes and the other which has relatively smooth cell borders. Both types had few poorly developed desmosome-like cell attachments and wide intercellular space. This study revealed that decreased numbers of desmosome-like attachments and wide intercellular space with or without cytoplasmic processes of non-papillary transitional cell carcinoma of the urinary bladder might be a morphologic expression of loss of cohesiveness in this type of carcinoma.


LOX-1 plays an important role in ischemia-induced angiogenesis of limbs.
LOX-1, lectin-like oxidized low-density lipoprotein (LDL) receptor-1, is a single transmembrane receptor mainly expressed on endothelial cells. LOX-1 mediates the uptake of oxidized LDL, an early step in atherosclerosis; however, little is known about whether LOX-1 is involved in angiogenesis during tissue ischemia. Therefore, we examined the role of LOX-1 in ischemia-induced angiogenesis in the hindlimbs of LOX-1 knockout (KO) mice. Angiogenesis was evaluated in a surgically induced hindlimb ischemia model using laser Doppler blood flowmetry (LDBF) and histological capillary density (CD) and arteriole density (AD). After right hindlimb ischemia, the ischemic/nonischemic hindlimb blood flow ratio was persistently lower in LOX-1 KO mice than in wild-type (WT) mice. CD and AD were significantly smaller in LOX-1 KO mice than in WT mice on postoperative day 14. Immunohistochemical analysis revealed that the number of macrophages infiltrating ischemic tissues was significantly smaller in LOX-1 KO mice than in WT mice. The number of infiltrated macrophages expressing VEGF was also significantly smaller in LOX-1 KO mice than in WT mice. Western blot analysis and ROS production assay revealed that LOX- KO mice show significant decrease in Nox2 expression, ROS production and HIF-1α expression, the phosphorylation of p38 MAPK and NF-κB p65 subunit as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and LOX-1 itself in ischemic muscles, which is supposed to be required for macrophage infiltration expressing angiogenic factor VEGF. Reduction of VEGF expression successively suppressed the phosphorylation of Akt and eNOS, which accelerated angiogenesis, in the ischemic leg of LOX-1 KO mice. Our findings indicate that LOX-1 plays an important role in ischemia-induced angiogenesis by 1) Nox2-ROS-NF-κB activation, 2) upregulated expression of adhesion molecules: VCAM-1 and LOX-1 and 3) promoting macrophage infiltration, which expresses angiogenic factor VEGF.


[Study of dynamic counterrolling of the eye--quantitative analysis of effects by visual and vestibular systems].
Dynamic counterrolling of the eye is induced when the head is tilted to one side: it includes cyclorotatory nystagmus, which is affected by visual and vestibular systems. Both of these two ocular movements were measured quantitatively through a video recording system, and the role of visual and vestibular systems in visual stabilization was analyzed. The relationship between the optokinetic and vestibulo-ocular systems was variable in relation to the velocity of head tilting. The optokinetic system contributed more in slow head tilting. As the velocity of head tilting increased, the suppression by the optokinetic system was decreased and eventually the vestibulo-ocular system became more dominant. This suggests that the role of visual and vestibular systems in head tilting is similar to that in head rotation. Visual and vestibular systems seem to work together mutually with some individual variation in stabilizing vision with sensory control in the higher level of the visual cortex.


Effect of a nasal dilatator on nasal patency during normal and forced nasal breathing.
A nasal dilatator contains two elastic strips, which provide the dilatator with a spring action. The aimed function of the nasal dilatator is to slightly open the nares and hereby facilitate nasal breathing. The aim of this study was to evaluate the effect of a nasal dilatator by measuring nasal airway resistance during normal breathing and nasal forced expiratory and inspiratory flows and volumes with and without use of the nasal dilatator. Nasal resistance was measured with a whole body plethysmograph; maximal expiratory and inspiratory flow-volume curves were obtained with a pneumotachometer. These measurements were performed in ten healthy volunteers. No significant difference was found between nasal resistance with and without the nasal dilatator. However, values for forced inspiratory volume in 1 s (FIV 1) with the nasal dilatator, proved to be significantly higher (p=0.045,paired t-test) than values obtained without the nasal dilatator; mean improvement was 0.26 L (sd = 0.36). No significant improvement in peak inspiratory flow (PIF) was found, as was the case for the other flows and volumes. It is concluded that the nasal dilatator causes no appreciable improvement of nasal patency during normal breathing. In view of the fact that FIV 1 values increased significantly, we believe that the nasal dilatator prevents collapse of the external nares during forced inspiration. A beneficial effect during exercise when ventilation is increased is however doubtful because in that situation most volunteers switch to oronasal breathing already at submaximal exercise.


Mismatch Repair-Proficient Colorectal Cancer: Finding the Right TiME to Respond.
New approaches are required for addressing the important and unmet need to expand the benefits of checkpoint blockade to patients with mismatch repair proficient colorectal cancer. Systematic profiling of the tumor immune microenvironment provides insights into potential mechanisms of resistance, predictive biomarkers, and novel combinatorial strategies for overcoming resistance.See related article by Llosa et al., p. 5250.


Evaluation of Diagnostic Accuracy of Eight Commercial Assays for the Detection of Measles Virus-Specific IgM Antibodies.
The World Health Organization (WHO) has targeted measles for global eradication through mass immunization. For effective monitoring of eradication targets, high-quality surveillance is needed. The detection of IgM antibodies, specific to the measles virus, with the use of commercial enzyme-linked immunosorbent assays (ELISA or EIA) is broadly used within the WHO global measles and rubella laboratory network for laboratory confirmation, and in particular, ELISA kits manufactured by Siemens (Enzygnost kits) have been primarily used. Spurred by the discontinuation of these kits, this study aims to report on the clinical sensitivity and specificity of comparable commercial ELISA kits and one automated chemiluminescent immunoassay (CLIA) method. A panel of 239 serum samples was assembled that included sera from confirmed measles cases (n = 50) and probable post-MMR vaccine response (n = 2). Measles-negative sera (n = 187) were collected from individuals presenting with other fever and rash illnesses. A total of 7 ELISA kits (Euroimmun native antigens and recombinant nucleoprotein, IBL, Clin-Tech Microimmune, NovaTec NovaLisa, Serion, and Siemens Enzygnost) and one CLIA method (DiaSorin LIAISON XL) were evaluated. The ELISA kits included two IgM capture methods and five indirect methods. Calculated sensitivities and specificities ranged from 75.0% to 98.1% and 86.6% to 99.5%, respectively. The parvovirus B19 IgM positive sera were noted to cause false-positive results, particularly for the ELISA kits from Serion and NovaLisa; specificities for this subset of samples ranged from 51.4% to 100.0%. The capture IgM ELISA methods provided the best combination of sensitivity and specificity.


Retrotransposons as pathogenicity factors of the plant pathogenic fungus Botrytis cinerea.
Retrotransposons are genetic elements inducing mutations in all domains of life. Despite their detrimental effect, retrotransposons can become temporarily active during epigenetic reprogramming and cellular stress response, which may accelerate host genome evolution. In fungal pathogens, a positive role has been attributed to retrotransposons when shaping genome architecture and expression of genes encoding pathogenicity factors; thus, retrotransposons are known to influence pathogenicity. We uncover a hitherto unknown role of fungal retrotransposons as being pathogenicity factors, themselves. The aggressive fungal plant pathogen, Botrytis cinerea, is known to deliver some long-terminal repeat (LTR) deriving regulatory trans-species small RNAs (BcsRNAs) into plant cells to suppress host gene expression for infection. We find that naturally occurring, less aggressive B. cinerea strains possess considerably lower copy numbers of LTR retrotransposons and had lost retrotransposon BcsRNA production. Using a transgenic proof-of-concept approach, we reconstitute retrotransposon expression in a BcsRNA-lacking B. cinerea strain, which results in enhanced aggressiveness in a retrotransposon and BcsRNA expression-dependent manner. Moreover, retrotransposon expression in B. cinerea leads to suppression of plant defence-related genes during infection. We propose that retrotransposons are pathogenicity factors that manipulate host plant gene expression by encoding trans-species BcsRNAs. Taken together, the novelty that retrotransposons are pathogenicity factors will have a broad impact on studies of host-microbe interactions and pathology.


Adalimumab for juvenile idiopathic arthritis-associated uveitis.
To assess the long-term outcomes and complications of patients with uveitis from juvenile idiopathic arthritis (JIA) treated with adalimumab. Prospective interventional case series. All patients who underwent treatment with adalimumab for JIA and anterior uveitis were prospectively included in the study. The anterior chamber inflammation was evaluated according to the Standardization of Uveitis Nomenclature criteria. Twenty-one patients (16 females, five males, 38 eyes) were included in the study. Mean age of patients at referral was 11.1 ± 3.8 (5-17) years. Before initiation of treatment, mean duration of arthritis was 7.0 ± 5.5 (median, 6) months, mean duration of uveitis was 7.0 ± 4.4 (median, 7) months. Oligoarticular arthritis was present in 15 cases (71 %), polyarticular arthritis in six cases (28 %). After a mean follow-up of 18.2 ± 7.7 (9-41) months, resolution of anterior chamber inflammation was obtained in 29/38 eyes (76 %). The anterior uveitis flare rate during the 12 months prior to enrollment was 1.6 ± 0.4/year, and was reduced during adalimumab treatment to 0.7 ± 0.3/year (p<0.001). A significant decrease of the number of relapses/month was present after onset of treatment with adalimumab (0.18 ± 0.2 before versus 0.02 ± 0.1 after treatment onset, p<0.001). No significant correlation was found between relapse number and age, sex, type of JIA and doses of previous steroid treatment (p>0.05). Adalimumab showed to be effective and relatively safe for treatment of JIA-associated uveitis.


Transmorph: a unifying computational framework for modular single-cell RNA-seq data integration.
Data integration of single-cell RNA-seq (scRNA-seq) data describes the task of embedding datasets gathered from different sources or experiments into a common representation so that cells with similar types or states are embedded close to one another independently from their dataset of origin. Data integration is a crucial step in most scRNA-seq data analysis pipelines involving multiple batches. It improves data visualization, batch effect reduction, clustering, label transfer, and cell type inference. Many data integration tools have been proposed during the last decade, but a surge in the number of these methods has made it difficult to pick one for a given use case. Furthermore, these tools are provided as rigid pieces of software, making it hard to adapt them to various specific scenarios. In order to address both of these issues at once, we introduce the transmorph framework. It allows the user to engineer powerful data integration pipelines and is supported by a rich software ecosystem. We demonstrate transmorph usefulness by solving a variety of practical challenges on scRNA-seq datasets including joint datasets embedding, gene space integration, and transfer of cycle phase annotations. transmorph is provided as an open source python package.


Workers' emotional exhaustion and mental well-being over the COVID-19 pandemic: a Dynamic Structural Equation Modeling (DSEM) approach.
The COVID-19 pandemic has presented significant challenges to the workforce, particularly concerning emotional and mental well-being. Given the prolonged periods of work-related stress, unexpected organizational changes, and uncertainties about work faced during the pandemic, it becomes imperative to study occupational health constructs under a dynamic methodological perspective, to understand their stable and unstable characteristics better. In this study, drawing on the Dynamic Structural Equation Modeling (DSEM) framework, we used a combination of multilevel AR(1) models, Residual-DSEM (RDSEM), multilevel bivariate VAR(1) models, and multilevel location-scale models to investigate the autoregression, trend, and (residual) cross-lagged relationships between emotional exhaustion (EmEx) and mental well-being (MWB) over the COVID-19 pandemic. Data were collected weekly on 533 workers from Germany (91.18%) and Italy (8.82%) who completed a self-reported battery (total number of observations = 3,946). Consistent with our hypotheses, results were as follows: (a) regarding autoregression, the autoregressive component for both EmEx and MWB was positive and significant, as well as it was their associated between-level variability; (b) regarding trend, over time EmEx significantly increased, while MWB significantly declined, furthermore both changes had a significant between-level variability; (c) regarding the longitudinal bivariate (cross-lagged) relationships, EmEx and MWB negatively and significantly affected each other from week to week, furthermore both cross-lagged relationships showed to have significant between-level variance. Overall, our study pointed attention to the vicious cycle between EmEx and MWB, even after controlling for their autoregressive component and trend, and supported the utility of DSEM in occupational health psychology studies.


Selective inhibitors of protein methyltransferases.
Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. PMTs are divided into two categories: protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs). There has been a steadily growing interest in these enzymes as potential therapeutic targets and therefore discovery of PMT inhibitors has also been pursued increasingly over the past decade. Here, we present a perspective on selective, small-molecule inhibitors of PMTs with an emphasis on their discovery, characterization, and applicability as chemical tools for deciphering the target PMTs' physiological functions and involvement in human diseases. We highlight the current state of PMT inhibitors and discuss future directions and opportunities for PMT inhibitor discovery.


Effects of Methylsulfonylmethane (MSM) on exercise-induced oxidative stress, muscle damage, and pain following a half-marathon: a double-blind, randomized, placebo-controlled trial.
Oxidative stress and muscle damage occur during exhaustive bouts of exercise, and many runners report pain and soreness as major influences on changes or breaks in training regimens, creating a barrier to training persistence. Methylsulfonylmethane (MSM) is a sulfur-based nutritional supplement that is purported to have pain and inflammation-reducing effects. To investigate the effects of MSM in attenuating damage associated with physical exertion, this randomized, double-blind, placebo-controlled study evaluated the effects of MSM supplementation on exercise-induced pain, oxidative stress and muscle damage. Twenty-two healthy females (n = 17) and males (n = 5) (age 33.7 ± 6.9 yrs.) were recruited from the 2014 Portland Half-Marathon registrant pool. Participants were randomized to take either MSM (OptiMSM®) (n = 11), or a placebo (n = 11) at 3 g/day for 21 days prior to the race and for two days after (23 total). Participants provided blood samples for measurement of markers of oxidative stress, and completed VAS surveys for pain approximately one month prior to the race (T0), and at 15 min (T1), 90 min (T2), 1 Day (T3), and 2 days (T4) after race finish. The primary outcome measure 8-hydroxy-2-deoxyguanine (8-OHdG) measured oxidative stress. Secondary outcomes included malondialdehyde (MDA) for oxidative stress, creatine kinase (CK) and lactate dehydrogenase (LDH) as measures of muscle damage, and muscle (MP) and joint pain (JP) recorded using a 100 mm Visual Analogue Scale (VAS). Data were analyzed using repeated and multivariate ANOVAs, and simple contrasts compared post-race time points to baseline, presented as mean (SD) or mean change (95% CI) where appropriate. Running a half-marathon induced significant increases in all outcome measures (p < 0.001). From baseline, 8-OHdG increased significantly at T1 by 1.53 ng/mL (0.86-2.20 ng/mL CI, p < 0.001) and T2 by 1.19 ng/mL (0.37-2.01 ng/mL CI, p < 0.01), and fell below baseline levels at T3 by -0.46 ng/mL (-1.18-0.26 CI, p > 0.05) and T4 by -0.57 ng/mL (-1.27-0.13 CI, p > 0.05). MDA increased significantly at T1 by 7.3 μM (3.9-10.7 CI, p < 0.001). Muscle damage markers CK and LDH saw significant increases from baseline at all time-points (p < 0.01). Muscle and joint pain increased significantly from baseline at T1, T2, and T3 (p < 0.01) and returned to baseline levels at T4. Time-by-treatment results did not reach statistical significance for any outcome measure, however, the MSM group saw clinically significant (Δ > 10 mm) reductions in both muscle and joint pain. Participation in a half-marathon was associated with increased markers of oxidative stress, muscle damage, and pain. MSM supplementation was not associated with a decrease from pre-training levels of oxidative stress or muscle damage associated with an acute bout of exercise. MSM supplementation attenuated post-exercise muscle and joint pain at clinically, but not statistically significant levels.


Palliation of radiation-related mucositis.
Oral mucositis associated with head and neck radiotherapy can substantially hinder completion of cancer therapy. Alleviation of this often severe stomatitis can provide enhanced patient comfort and facilitate appropriate care. A double-blind format was used in a pilot project to measure, against a control rinse, the effectiveness of an oral rinse consisting of hydrocortisone, nystatin, tetracycline, and diphenhydramine in controlling radiation-related mucositis. A combination of clinical evaluation and patient responses to a questionnaire was used to judge the results of the topical medications. Patients using the experimental medication developed less mucositis than did patients in the control group.


Targeting receptor tyrosine kinase on lymphatic endothelial cells for the therapy of colon cancer lymph node metastasis.
Oral treatment with the dual-receptor tyrosine kinase inhibitor AEE788 effectively reduces the number of peritumoral lymphatic vessels and the incidence of lymph node metastasis in nude mice with human HT29 colon cancer cells growing in the cecum. Whether inhibition of lymph node metastasis in colon cancer can be achieved by directly targeting lymphatic endothelial cells remains unclear. Using a microsurgical approach, we generated conditionally immortalized lymphatic endothelial cell lines from the H-2K(b)-tsA58 mouse mesentery and characterized these cells for the expression of lymphatic endothelial cell markers. Lymphatic endothelial cells were stimulated in culture with an array of tumor cell-produced cytokines, leading to the identification of redundant pathways for proliferation and survival. Treatment with AEE788 decreased the migration, proliferation, and survival of lymphatic endothelial cells, demonstrating that oral treatment with AEE788 effectively decreases the incidence of colon cancer lymphatic metastasis due, in part, to the direct inhibition of lymphatic endothelial cell signaling.


Tin protoporphyrin activates the oxidant-dependent NRF2-cytoprotective pathway and mitigates acute kidney injury.
Tin protoporphyrin (SnPP), a heme oxygenase (HO) inhibitor, can paradoxically protect against diverse forms of acute kidney injury (AKI). This study sought potential underlying mechanisms. CD-1 mice received intravenous SnPP, followed 4-18 hours later by a variety of renal biochemical, histologic, and genomic assessments. Renal resistance to ischemic-reperfusion injury (IRI) was also sought. SnPP was rapidly taken up by kidney and was confined to proximal tubules. Transient suppression of renal heme synthesis (decreased δ aminolevulinic acid synthase expression), a 2.5-fold increase in "catalytic" Fe levels and oxidant stress resulted (decreased glutathione; increased malondialdehyde, and protein carbonyl content). Nrf2 nuclear translocation (∼2x Nrf2 increase; detected by enzyme-linked immunosorbent assay, Western blotting), with corresponding activation of ∼20 Nrf2-sensitive genes (RNA-Seq) were observed. By 18 hours after SnPP injection, marked protection against IRI emerged. This represented "preconditioning", not a direct SnPP effect, given that SnPP administered at the time of IRI exerted no protective effect. The importance of transient oxidant stress in SnPP "preconditioning" was exemplified by the following: (1) oxidant stress induced by a different mechanism (myoglobin injection) recapitulated SnPP's protective action; (2) GSH treatment blunted SnPP's protective influence; (3) SnPP raised cytoprotective heavy chain ferritin (Fhc), a response enhanced by exogenous Fe injection; and (4) SnCl2, a ∼35- to 50-fold HO-1 inducer (not inhibitor) evoked neither oxidant stress nor mitigated IRI (seemingly excluding HO-1 activity in SnPP's protective effect). SnPP specifically accumulates within proximal tubule cells; transient "catalytic" Fe overload and oxidative stress result; Nrf2-cytoprotective pathways are upregulated; and these changes help protect against ischemic AKI.


Nasalance scores of Brazilian Portuguese speakers at 5 years of age.
To determine nasalance scores of Brazilian Portuguese speaking children without evident speech disorders, language delay and orofacial deformities, at age 5 years, and analyze differences between types of speech samples and genders. Twenty children were analyzed, 11 males, age ranging from 4 years and 10 months to 5 years and 11 months. The Nasometer II 6450 (KayPENTAX) was used for nasalance assessment. Speech samples were eight consonant-vowel syllables and one sequence of nine words. The significance of differences between speech samples and genders were assessed by the Tukey test and Mann-Whitney test, respectively, at a significance level of 5%. Mean nasalance scores were: /pa/= 10±4%, /pi/= 22±7%, /sa/= 11±5%, /si/= 24±11%, /ma/= 57±11%, /mi/= 73±13%, /la/= 14±9%, /li/= 25±11%, words (pipa, bis, burro, tatu, pilha, cuca, gui, fila, luz)= 20±6%. Nasalance scores of nasal syllables were significantly higher than those of oral syllables (with high or neutral vowels) and nasalance scores of oral syllables with high vowels were significantly higher than those of oral syllables with neutral vowels, for the majority of comparisons. There was no difference between genders. Normative nasalance scores for 5-year-old Brazilian children were determined. The methodology can serve as a standard for the early diagnosis of nasality deviations, such as hypernasality observed in cleft palate speech.


Cardiac tamponade and septic shock caused by viral infection in a previously healthy woman.
A previously healthy woman was admitted to hospital after 'flu-like' symptoms for 5 days followed by acute intense abdominal and lower back pain. On admission she was found to be in severe shock and was transferred to the ICU. Echocardiography revealed cardiac tamponade, and pericardiocentesis was performed immediately. Thereafter her cardiovascular state improved, but she developed hypotension with low systemic vascular resistance and required vasoactive treatment for 4 days. Nine days after admission the patient was transferred to the ward, after which she recovered rapidly and completely. The cause of her illness was extensively screened. No underlying disease was found, and all bacterial cultures remained negative. Acute virus infection was confirmed by diagnostic elevations of antibody titers to Influenza A and adenovirus. Adenovirus was also isolated from her bronchoalveolar lavage fluid.


Water-Based Synthesis of Palladium Trigonal Bipyramidal/Tetrahedral Nanocrystals with Enhanced Electrocatalytic Oxidation Activity.
Well-defined palladium trigonal bipyramidal/tetrahedral nanocrystals were synthesized by an aqueous-phase hydrothermal method. The final products were a mixture of trigonal bipyramidal and tetrahedral nanocrystals. Statistics indicated that there were more trigonal bipyramids than tetrahedra in the products. Ethylenediamine tetraacetic acid disodium salt (EDTA-2Na) was proven to be essential in controlling the final shapes of palladium nanocrystals. Some control experiments were also conducted to investigate the shape evolution and formation mechanisms. The synthesized palladium nanocrystals showed enhanced catalytic properties for ethanol and glycerol electrooxidation in alkaline medium. This work provides a new method in preparing Pd nanomaterials with well-defined shapes.


Carcinomatous meningitis due to gastric adenocarcinoma: A rare presentation of relapse.
While solid tumors are less commonly associated with meningeal involvement; lung, breast and melanoma are the ones most often reported. A few case reports have included gastric carcinoma but these are rare and most often associated with systemic disease at the time of diagnosis. Here we report a unique presentation of gastric carcinoma relapse with leptomeningeal carcinomatosis. An 81-year-old female was diagnosed with gastric cancer approximately one year before presentation. Following neoadjuvant chemotherapy, she had gastrectomy. Her periodic surveillance was stable. Thereafter she presented with a one week history of progressive fatigue lightheadedness, syncope. During hospitalization her mental status deteriorated. A repeat computed axial tomography scan of the head showed no changes to suggest an etiology. A lumbar puncture was performed and cerebral spinal fluid (CSF) cytopathology confirmed gastric signet cell adenocarcinoma. Encephalopathy was likely caused by increased intracranial pressure from communicating hydrocephalus. Leptomeningeal carcinomatosis is associated with short life expectancy. Therapeutic lumbar punctures and best supportive care or systemic therapy can be applied with guarded prognosis. Survival, however, may improve with cytologic negative conversion of the CSF if patient performance status allows treatment.


Enhancement of photon number reflected by the relativistic flying mirror.
Laser light reflection by a relativistically moving electron density modulation (flying mirror) in a wake wave generated in a plasma by a high intensity laser pulse is investigated experimentally. A counterpropagating laser pulse is reflected and upshifted in frequency with a multiplication factor of 37-66, corresponding to the extreme ultraviolet wavelength. The demonstrated flying mirror reflectivity (from 3 x 10(-6) to 2 x 10(-5), and from 1.3 x 10(-4) to 0.6 x 10(-3), for the photon number and pulse energy, respectively) is close to the theoretical estimate for the parameters of the experiment.


[Effects of interferon on immunoglobulin production in normal subjects and in patients with selective IgA deficiency. An "in vitro" study].
The ability of Interferon (IFN) alpha, beta and gamma to induce IgA production from IgA deficient patients lymphocytes was tested "in vitro". In affected patients IgG and IgM production was similar to the normal cases but no effect on IgA production was observed. In normal cases variable concentration of alpha- beta- and gamma-IFN resulted in different immunoglobulin production. In IgA selective deficiency a low number of SmIgA bearing cells and defective transformation in IgA-plasma cells was noted as possible primary defect.


Esophageal Atresia and Respiratory Morbidity.
Respiratory diseases are common in children with esophageal atresia (EA), leading to increased morbidity and mortality in the first year. The primary study objective was to identify the factors associated with readmissions for respiratory causes in the first year in EA children. A population-based study. We included all children born between 2008 and 2016 with available data and analyzed factors at birth and 1 year follow-up. Factors with a P value <.10 in univariate analyses were retained in logistic regression models. Among 1460 patients born with EA, 97 (7%) were deceased before the age of 1 year, and follow-up data were available for 1287 patients, who constituted our study population. EAs were Ladd classification type III or IV in 89%, preterm birth was observed in 38%, and associated malformations were observed in 52%. Collectively, 61% were readmitted after initial discharge in the first year, 31% for a respiratory cause. Among these, respiratory infections occurred in 64%, and 35% received a respiratory treatment. In logistic regression models, factors associated with readmission for a respiratory cause were recurrence of tracheoesophageal fistula, aortopexy, antireflux surgery, and tube feeding; factors associated with respiratory treatment were male sex and laryngeal cleft. Respiratory morbidity in the first year after EA repair is frequent, accounting for >50% of readmissions. Identifying high risk groups of EA patients (ie, those with chronic aspiration, anomalies of the respiratory tract, and need for tube feeding) may guide follow-up strategies.


Paths to the discovery of antivenom serotherapy in France.
The current study presents a descriptive chronological survey of the articles published by Césaire Auguste Phisalix and Albert Calmette on snake poison, with the aim of shedding a light on the areas of research and reasoning followed by these scientists, leading up to their simultaneous discovery of antivenom serotherapy in 1894. The path taken by Phisalix is revealed in 15 articles that demonstrate the motivation of a naturalist and the way he confronted the puzzle of immunity against snake venom. In the case of Calmette, two articles preceded the discovery; microbiology was his theoretical base and the Pasteurian spirit of solving health problems his driving force. These two researchers followed distinct paths, mobilized by different motivations, but produced one single result. It is incontestable that the discovery of antivenom serotherapy was the work of two groups of researchers who deserve equal recognition, but who, in fact, did not receive it. Following the discovery both Calmette and Phisalix returned to their previous motivations. Calmette put the discovery into practice and began to produce antivenom serum in Lille. He came to be generally considered as the sole discoverer of antivenom serotherapy and was the recipient of a number of prestigious prizes. Phisalix, on the other hand, received little recognition and returned to his original interests, devoting himself to research on natural immunity. In Brazil, the discovery of antivenom serum therapy had a profound impact on the work of Vital Brazil Mineiro da Campanha, a researcher known worldwide for his scientific discoveries and for the evidence of the specificity of antivenom serums.


Retargeting vesicular stomatitis virus glycoprotein pseudotyped lentiviral vectors with enhanced stability by in situ synthesized polymer shell.
The ability to introduce transgenes with precise specificity to the desired target cells or tissues is key to a more facile application of genetic therapy. Here, we describe a novel method using nanotechnology to generate lentiviral vectors with altered recognition of host cell receptor specificity. Briefly, the infectivity of the vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vectors was shielded by a thin polymer shell synthesized in situ onto the viral envelope, and new binding ability was conferred to the shielded virus by introducing acrylamide-tailored cyclic arginine-glycine-aspartic acid (cRGD) peptide to the polymer shell. We termed the resulting virus "targeting nanovirus." The targeting nanovirus had similar titer with VSV-G pseudotypes and specifically transduced Hela cells with high transduction efficiency. In addition, the encapsulation of the VSV-G pseudotyped lentivirus by the polymer shell did not change the pathway that VSV-G pseudotypes enter and fuse with cells, as well as later events such as reverse transcription and gene expression. Furthermore, the targeting nanovirus possessed enhanced stability in the presence of human serum, indicating protection of the virus by the polymer shell from human serum complement inactivation. This novel use of nanotechnology demonstrates proof of concept for an approach that could be more generally applied for redirecting viral vectors for laboratory and clinical purposes.


Pelvic pain: a pathway for care developed for both men and women by the British Pain Society.
This paper aims to explain the key points and highlight some of the controversies in the development of the British Pain Society's pelvic pain patient pathway map. Many clinicians lack experience and confidence with this group of patients, and this issue is highlighted. Additionally, the difficulties of classification and definitions in this area are discussed in detail. These are historical causes of disagreement among specialists which can lead to confused clinical care. This group of patients have multiple issues that cross many professional boundaries; they are best managed by the co-ordinated involvement of multiple teams. Patients suffer from significant distress and disability that often needs specialist assessment and intervention (interdisciplinary). This suggests that an integrated approach is required across the historic boundaries of primary and secondary care. A variety of interventions, including opioids and neuromodulation are recommended in the pathway and the controversies surrounding these inclusions are aired in detail.


Rapid Unambiguous Structure Elucidation of Streptnatamide A, a New Cyclic Peptide Isolated from A Marine-derived Streptomyces sp.
Cyclic peptides have been excellent source of drug leads. With the advances in discovery platforms, the pharmaceutical industry has a growing interest in cyclic peptides and has pushed several into clinical trials. However, structural complexity of cyclic peptides brings extreme challenges for structure elucidation efforts. Isotopic fine structure analysis, Nuclear magnetic resonance (NMR), and detailed tandem mass spectrometry rapidly provided peptide sequence for streptnatamide A, a cyclic peptide isolated from a marine-derived Streptomyces sp. Marfey's analysis determined the stereochemistry of all amino acids, enabling the unambiguous structure determination of this compound. A non-ribosomal peptide synthetase biosynthetic gene cluster (stp) was tentatively identified and annotated for streptnatamide A based on the in silico analysis of whole genome sequencing data. These analytical tools will be powerful tools to overcome the challenges for cyclic peptide structure elucidation and accelerate the development of bioactive cyclic peptides.


Percutaneous absorption of organic sunscreens.
The increased awareness of protection against skin cancer has led to a rise in the use of topically applied chemical sunscreen agents. There is a concern about the systemic absorption of organic filters in sunscreen formulations. The present study briefly reviews theoretical models for the prediction of the percutaneous penetration of the organic molecules and the accepted methods for the in vitro and in vivo evaluations of the penetration. The influence of the vehicle and the formulation viscosity on the penetration of sunscreens are examined. The development of novel methods for the minimization of sunscreen absorption is also discussed.


Short-term adenosine monophosphate-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside treatment increases the sirtuin 1 protein expression in skeletal muscle.
Adenosine monophosphate-activated protein kinase (AMPK) has been proposed to stimulate mitochondrial biogenesis and fat and glucose metabolism in skeletal muscle. Nicotinamide adenine dinucleotide-dependent histone deacetylase sirtuin 1 (SIRT1) is also thought to play a pivotal role for such metabolic adaptations. The purpose of the present study was to examine the effect of AMPK activation with the administration of AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) to rats on skeletal muscle SIRT1 protein expression as well as peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) and glucose transporter 4 (GLUT4) protein expression and hexokinase activity. The AICAR promoted the phosphorylation of AMPK α-subunit (Thr¹⁷²) and acetyl-coenzyme A carboxylase (Ser⁷⁹) without any change of total AMPK α-subunit or acetyl-coenzyme A carboxylase protein levels in both the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles. The SIRT1 protein expression increased at 24 hours after administration of AICAR in the EDL muscle but not in the soleus muscle. The PGC-1α protein expression increased in both the soleus and EDL muscles and GLUT4 did in the EDL muscle at 24 hours after an administration of AICAR. The hexokinase activity increased at 18 and 24 hours in the soleus and at 12, 18, and 24 hours in the EDL after an AICAR treatment. These results suggest that short-term AICAR treatment to rats promotes skeletal muscle AMPK phosphorylation and then coincidently increases the SIRT1 protein expression. In addition, such treatment also enhances the PGC-1α and GLUT4 protein contents and hexokinase activity in skeletal muscle.