Effects of shock waves on oxidative stress and some trace element levels of rat liver and diaphragm muscles.
This study was designed to investigate whether the short-term extracorporeal shockwave lithotripsy (ESWL) exposure to kidney produces an oxidative stress and a change in some trace element levels in liver and diaphragm muscles of rats. Twelve male Wistar albino rats were divided randomly into two groups, each consisting of six rats. The animals in the first group did not receive any treatment and served as control group. The right-side kidneys of animals in group 2 were treated with two-thousand 18 kV shock waves while anesthetized with 50 mg kg(-1) ketamine. The localization of the right kidney was achieved after contrast medium injection through a tail vein under fluoroscopy control. The animals were killed 72 h after the ESWL treatment, and liver and diaphragm muscles were harvested for the determination of tissue oxidative stress and trace element levels. Although the malondialdehyde level increased, superoxide dismutase and glutathione peroxidase enzyme activities decreased in the livers and diaphragm muscles of ESWL-treated rats. Although glutathione level increased in liver, it decreased in diaphragm muscles of ESWL-treated animals. Fe, Mg and Mn levels decreased, and Cu and Pb levels increased in the livers of ESWL-treated animals. Fe and Cu levels increased, and Mg, Pb, Mn and Zn levels decreased in the diaphragm muscles of ESWL-treated animals. It also causes a decrease or increase in many mineral levels in liver and diaphragm muscles, which is an undesirable condition for the normal physiological function of tissues.


Unaltered vasoconstrictor responsiveness after iNOS inhibition in lungs from chronically hypoxic rats.
Previous studies suggest that inducible (i) nitric oxide synthase (NOS) expression within the pulmonary vasculature is increased in rats with chronic hypoxia (CH)-induced pulmonary hypertension. We therefore hypothesized that enhanced iNOS expression associated with CH causes attenuated pulmonary vasoconstrictor responsiveness. To test this hypothesis, we examined the effect of selective iNOS blockade with L-N6-(1-iminoethyl)lysine dihydrochloride (L-NIL) and nonselective NOS inhibition with Nomega-nitro-L-arginine (L-NNA) on vasoconstrictor responses to U-46619 in isolated saline-perfused lungs from both control and CH (4 wk at 380 mmHg) rats. We additionally measured pulmonary hemodynamic responses to L-NIL in conscious CH rats (fraction of inspired O2 = 0.12). Finally, iNOS mRNA levels were assessed in lungs from each group of rats using ribonuclease protection assays. Despite a significant increase in iNOS mRNA expression after exposure to CH, responses to U-46619 were unaltered by L-NIL but augmented by L-NNA in lungs from both control and CH rats. Pulmonary hemodynamics were similarly unaltered by L-NIL in conscious CH rats. We conclude that iNOS does not modulate pulmonary vasoconstrictor responsiveness after long-term hypoxic exposure.


Association of Calpain (CAPN) 10 (UCSNP-43, rs3792267) gene polymorphism with elevated serum androgens in young women with the most severe phenotype of polycystic ovary syndrome (PCOS).
To highlight a possible association of Calpain (CAPN 10) gene UCSNP-43 polymorphism with hormonal and metabolic traits of young women with different phenotypes of polycystic ovary syndrome (PCOS). PCOS women were genotyped for the CAPN 10 gene UCSNP-43 polymorphism. A comparison of clinical and biochemical features of women with PCOS stratified on the basis of the CAPN 10 gene UCSNP-43 variants was assessed. Anthropometric, hormonal and biochemical measurements were carried out in 668 PCOS women and 200 healthy controls. Subjects were also genotyped for the CAPN 10 gene UCSNP-43 polymorphism. The genotype frequency distributions between groups and controls were compared using the chi-square test. The association of the polymorphism with the clinical and biochemical features of the study cohort was estimated as well. No association of the frequency of CAPN 10 gene UCSNP-43 polymorphism with PCOS was detected. No association of the polymorphism with the anthropometric, biochemical and hormonal features was detected both in PCOS and control women. The polymorphism was associated with serum Δ4 androstenedione (p = 0.018), as well as with 17-OH progesterone (17-hydroxyprogesterone) among women with PCOS phenotype A (p = 0.012). CAPN 10 gene polymorphism UCSNP-43 is deprived of a metabolic contribution to cardiovascular disease (CVD). However, due to its association with androgen excess in phenotype A, CAPN 10 gene polymorphism UCSNP-43 could be used as a genetic marker for CVD in young PCOS women.


Evaluation of voltage-sensitive fluorescence dyes for monitoring neuronal activity in the embryonic central nervous system.
Using an optical imaging technique with voltage-sensitive dyes (VSDs), we investigated the functional organization and architecture of the central nervous system (CNS) during embryogenesis. In the embryonic nervous system, a merocyanine-rhodanine dye, NK2761, has proved to be the most useful absorption dye for detecting neuronal activity because of its high signal-to-noise ratio (S/N), low toxicity and small dye bleaching. In the present study, we evaluated the suitability of fluorescence VSDs for optical recording in the embryonic CNS. We screened eight styryl (hemicyanine) dyes in isolated brainstem-spinal cord preparations from 7-day-old chick embryos. Measurements of voltage-related optical signals were made using a multiple-site optical recording system. The signal size, S/N, photobleaching, effects of perfusion and recovery of neural responses after staining were compared. We also evaluated optical responses with various magnifications. Although the S/N was lower than with the absorption dye, clear optical responses were detected with several fluorescence dyes, including di-2-ANEPEQ, di-4-ANEPPS, di-3-ANEPPDHQ, di-4-AN(F)EPPTEA, di-2-AN(F)EPPTEA and di-2-ANEPPTEA. Di-2-ANEPEQ showed the largest S/N, whereas its photobleaching was faster and the recovery of neural responses after staining was slower. Di-4-ANEPPS and di-3-ANEPPDHQ also exhibited a large S/N but required a relatively long time for recovery of neural activity. Di-4-AN(F)EPPTEA, di-2-AN(F)EPPTEA and di-2-ANEPPTEA showed smaller S/Ns than di-2-ANEPEQ, di-4-ANEPPS and di-3-ANEPPDHQ; but the recovery of neural responses after staining was faster. This study demonstrates the potential utility of these styryl dyes in optical monitoring of voltage changes in the embryonic CNS.


Postoperative intermittent pneumatic compression for preventing venous thromboembolism in Chinese lung cancer patients: a randomized clinical trial.
Postoperative lung cancer patients belong to the high-risk group for venous thromboembolism (VTE). The standardized preventive measures for perioperative VTE in lung cancer are not perfect, especially for the prevention and treatment of catheter-related thrombosis (CRT) caused by carried central venous catheters (CVCs) in lung cancer surgery. This study included 460 patients with lung cancer undergoing video-assisted thoracic surgery (VATS) in our center from July 2020 to June 2021. Patients were randomized into two groups, and intraoperatively-placed CVCs would be carried to discharge. During hospitalization, the control group was treated with low-molecular-weight heparin (LMWH), and the experimental group with LMWH + intermittent pneumatic compression (IPC). Vascular ultrasound was performed at three time points which included before surgery, before discharge, and one month after discharge. The incidence of VTE between the two groups was studied by the Log-binomial regression model. CRT occurred in 71.7% of the experimental group and 79.7% of the control group. The multivariate regression showed that the risk of developing CRT in the experimental group was lower than in the control group (Adjusted RR = 0.889 [95%CI0.799-0.989], p = 0.031), with no heterogeneity in subgroups (P for Interaction > 0.05). Moreover, the fibrinogen of patients in the experimental group was lower than control group at follow-up (P = 0.019). IPC reduced the incidence of CRT during hospitalization in lung cancer patients after surgery. No. ChiCTR2000034511.


A single molecular descriptor to predict solution behavior of therapeutic antibodies.
Despite the therapeutic success of monoclonal antibodies (mAbs), early identification of developable mAb drug candidates with optimal manufacturability, stability, and delivery attributes remains elusive. Poor solution behavior, which manifests as high solution viscosity or opalescence, profoundly affects the developability of mAb drugs. Using a diverse dataset of 59 mAbs, including 43 approved products, and an array of molecular descriptors spanning colloidal, conformational, charge-based, hydrodynamic, and hydrophobic properties, we show that poor solution behavior is prevalent (>30%) in mAbs and is singularly predicted (>90%) by the diffusion interaction parameter (k D), a dilute-solution measure of colloidal self-interaction. No other descriptor, individually or in combination, was found to be as effective as k D. We also show that well-behaved mAbs, a substantial subset of which bear high positive charge and pI, present no disadvantages with respect to pharmacokinetics in humans. Here, we provide a systematic framework with quantitative thresholds for selecting well-behaved therapeutic mAbs during drug discovery.


Sequence, structure and functionality of pectin methylesterases and their use in sustainable carbohydrate bioproducts: A review.
Pectin methylesterases (PMEs) are enzymes that play a critical role in modifying pectins, a class of complex polysaccharides in plant cell walls. These enzymes catalyze the removal of methyl ester groups from pectins, resulting in a change in the degree of esterification and consequently, the physicochemical properties of the polymers. PMEs are found in various plant tissues and organs, and their activity is tightly regulated in response to developmental and environmental factors. In addition to the biochemical modification of pectins, PMEs have been implicated in various biological processes, including fruit ripening, defense against pathogens, and cell wall remodelling. This review presents updated information on PMEs, including their sources, sequences and structural diversity, biochemical properties and function in plant development. The article also explores the mechanism of PME action and the factors influencing enzyme activity. In addition, the review highlights the potential applications of PMEs in various industrial sectors related to biomass exploitation, food, and textile industries, with a focus on development of bioproducts based on eco-friendly and efficient industrial processes.


VSDMIP: virtual screening data management on an integrated platform.
A novel software (VSDMIP) for the virtual screening (VS) of chemical libraries integrated within a MySQL relational database is presented. Two main features make VSDMIP clearly distinguishable from other existing computational tools: (i) its database, which stores not only ligand information but also the results from every step in the VS process, and (ii) its modular and pluggable architecture, which allows customization of the VS stages (such as the programs used for conformer generation or docking), through the definition of a detailed workflow employing user-configurable XML files. VSDMIP, therefore, facilitates the storage and retrieval of VS results, easily adapts to the specific requirements of each method and tool used in the experiments, and allows the comparison of different VS methodologies. To validate the usefulness of VSDMIP as an automated tool for carrying out VS several experiments were run on six protein targets (acetylcholinesterase, cyclin-dependent kinase 2, coagulation factor Xa, estrogen receptor alpha, p38 MAP kinase, and neuraminidase) using nine binary (actives/inactive) test sets. The performance of several VS configurations was evaluated by means of enrichment factors and receiver operating characteristic plots.


Molecular profiles of oxyphilic and chief cell parathyroid adenoma.
Parathyroid adenomas may be composed of chief cells (conventional or water-clear), oxyphilic cells or a mixture of both cells. The molecular background is rarely studied. To molecularly characterize parathyroid adenomas of different cell type composition. Chief and oxyphilic cell adenomas were compared in a cohort of 664 sporadic cases. Extensive analyses of parathyroid tissues were performed in subgroup. Gene expressions of known parathyroid-related genes were quantified by qRT-PCR. Protein expression profiles determined by liquid chromatography - tandem mass spectrometry (LC-MS/MS) were compared between each type of parathyroid adenomas. Selected proteins were analysed by Western blot and immunohistochemistry. Patients with oxyphilic cell adenoma were found to be older at the time of operation than chief cell adenoma cases but did not differ in gender, serum calcium or tumor weight. The gene expression of CASR, VDR, FGFR1, CYP27B1, CYP24A1, PTHLH, GCM2, NDUFA13, CDKN1B, MEN1 and CNND1 did not differ between the groups. VDR protein levels were weaker in oxyphilic adenomas. The proteomic studies identified a set of novel dysregulated proteins of interest such as nuclear receptor subfamily 2 group C member 2 (TR4), LIM domain only protein 3 (LMO3) and calcium-binding protein B (S100B). LMO3 and S100B showed higher expression in oxyphilic adenoma and may be involve in parathyroid tumorgenesis through the p53 pathway. TR4 showed different subcellular localisation between adenoma and normal rim. Chief and oxyphilic cell parathyroid adenomas have partly overlapping but also distinct molecular profiles. The calmodulin-eEF2K, TR4 and p53 pathways may be involved in the tumor development.


RNA-binding proteins and their role in kidney disease.
RNA-binding proteins (RBPs) are of fundamental importance for post-transcriptional gene regulation and protein synthesis. They are required for pre-mRNA processing and for RNA transport, degradation and translation into protein, and can regulate every step in the life cycle of their RNA targets. In addition, RBP function can be modulated by RNA binding. RBPs also participate in the formation of ribonucleoprotein complexes that build up macromolecular machineries such as the ribosome and spliceosome. Although most research has focused on mRNA-binding proteins, non-coding RNAs are also regulated and sequestered by RBPs. Functional defects and changes in the expression levels of RBPs have been implicated in numerous diseases, including neurological disorders, muscular atrophy and cancers. RBPs also contribute to a wide spectrum of kidney disorders. For example, human antigen R has been reported to have a renoprotective function in acute kidney injury (AKI) but might also contribute to the development of glomerulosclerosis, tubulointerstitial fibrosis and diabetic kidney disease (DKD), loss of bicaudal C is associated with cystic kidney diseases and Y-box binding protein 1 has been implicated in the pathogenesis of AKI, DKD and glomerular disorders. Increasing data suggest that the modulation of RBPs and their interactions with RNA targets could be promising therapeutic strategies for kidney diseases.


Pyelonephritis of an ectopic right kidney pretending as acute appendicitis: An unusual case.
Acute appendicitis is a common condition presenting in emergency department. A patient presenting with pain associated with fever, and tenderness in the right iliac fossa will be suspected to have Acute Appendicitis. However a variety of other clinical conditions may have similar features and may be required to be excluded. Acute pyelonephritis in an ectopic right kidney is a rare clinical condition which may mimic Acute Appendicitis. We present a middle-age male with complaints of pain in the right lower quadrant of the abdomen with high grade fever for one week. Clinical suspicion and initial ultrasonography (USG) of abdomen supported the diagnosis of acute appendicitis. The patient was initially managed conservatively and later non-contrast computed tomography (NCCT) scan was done that revealed right ectopic kidney with acute pyelonephritis. The appendix was within normal limits on NCCT scan. Ectopic kidneys result from anomalies of ascend which can result in several complications depending upon its position. Acute appendicitis can also cause pyuria and may mimic urosepsis amounting to its close anatomical proximity to urinary bladder. An un-ascended ectopic kidney with pyelonephritis mimicking acute appendicitis is a rare occurrence. USG and CT scan are important tools in the differential diagnosis but however, USG is greatly operator dependent; CT scan provides excellent diagnostic accuracy. This case report signifies importance of NCCT abdomen in accurate diagnosis of conditions featuring as right lower abdominal pain and fever. Also emphasizing significance of NCCT prior to any surgical intervention, if any conflict of diagnosis occurs.


Single π 0 production off neutrons bound in deuteron with linearly polarized photons.
The quasifree γ → d → π 0 n ( p ) photon beam asymmetry, Σ , has been measured at photon energies, E γ , from 390 to 610 MeV, corresponding to center of mass energy from 1.271 to 1.424 GeV, for the first time. The data were collected in the A2 hall of the MAMI electron beam facility with the Crystal Ball and TAPS calorimeters covering pion center-of-mass angles from 49 ∘ to 148 ∘ . In this kinematic region, polarization observables are sensitive to contributions from the Δ ( 1232 ) and N(1440) resonances. The extracted values of Σ have been compared to predictions based on partial-wave analyses (PWAs) of the existing pion photoproduction database. Our comparison includes the SAID, MAID and Bonn-Gatchina analyses; while a revised SAID fit, including the new Σ measurements, has also been performed. In addition, isospin symmetry is examined as a way to predict π 0 n photoproduction observables, based on fits to published data in the channels π 0 p , π + n and π - p .


[Experiences of hope in clients with chronic schizophrenia].
This study was done to uncover the nature of hope experienced by clients with chronic schizophrenia. A phenomenological approach developed by Van Manen was adopted. Data was collected from intensive interviews on 7 clients with chronic schizophrenia and the expatients' biographies and arts. A phenomenological reflection was done in terms of the four life world existentials. Corporeality: Perceiving the body feeling better, proudness of self, accepting their own ill body and transcending the limitation of the body, expressing self, and staying within the boundary of a healthy body were disclosed as the body's experience of hope. Spatiality: A place with safety, freedom, peace, and sharing was the space of hope. Temporality: The essential experience of time with hope was the continuity of moving forward amid cycling and moments being filled up with something. Relationality: Connecting with someone, having someone who is dependable, understandable and exchanging interest and love were identified as the relationships of hope with others. The results of this study show that chronic schizophrenic patients always strive hard to keep hope and they really need someone who can support them.


Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases.
During embryogenesis interactions between cells and extracellular matrix play a central role in the modulation of cell motility, growth, and differentiation. Modulation of matrix structure is therefore crucial during development; extracellular matrix ligands, their receptors, extracellular proteinases, and proteinase inhibitors all participate in the construction, maintenance, and remodeling of extracellular matrix by cells. The neural cell-adhesion molecule (NCAM)-negative rat glioma cell line BT4Cn secretes substantial amounts of metalloproteinases, as compared with its NCAM-positive mother cell line BT4C. We have transfected the BT4Cn cell line with cDNAs encoding the human NCAM-B and -C isoforms. We report here that the expression of transmembrane NCAM-B, but not of glycosyl-phosphatidylinositol-linked NCAM-C, induces a down-regulation of 92-kDa gelatinase (matrix metalloproteinase 9) and interstitial collagenase (matrix metalloproteinase 1), indicating that cellular expression of the recognition molecule NCAM regulates the metabolism of the surrounding matrix.


Histochemical characteristics of diphosphate nucleoside consumption in cat and rat nervous system.
Consumption of diphosphate nucleosides is investigated by histochemical methods in rat and cat nervous system. Results show NDP-ase is effectively in histological sections from animals previously perfused with glutaraldehyde or formaldehyde. Histochemical reaction is increased in presence of Ca++, Mg++, Mn++ or imidazole and inhibited by L-DOPA and Noradrenaline in incubation medium. A comparative study of TPP-ase and NDP-ase activities to dilucidate the identity of both enzymes is described.


Enhanced ammonia nitrogen removal using consistent ammonium exchange of modified zeolite and biological regeneration in a sequencing batch reactor process.
Utilizing preferential ion exchange of the modified zeolite, the zeo-sequencing batch reactor (SBR) is recommended for a new nitrogen removal process. In this study, natural zeolite was modified by sodium chloride to enhance sorption capacity for ammoniacal nitrogen. The untreated and treated zeolite was characterized by XPS and XRD techniques. The sorption isotherm tests showed that equilibrium sorption data were better represented by the Langmuir model than by the Freundlich model. Treatment of natural zeolite by sodium chloride increased the sorption capacity for ammoniacal nitrogen removal from aqueous solutions. As a result of the continuous bioregeneration of ammonium saturated zeolite-floc in the SBR, the nitrogen removal efficiency of the zeo-SBR was relatively ideal. Scanning electron microscopy results showed that microbes were abundant in the zeo-SBR process.


Accessing emergency contraception pills from pharmacies: the experience of young women in London.
Over-the-counter provision of emergency contraception pills (ECP) has increased since deregulation of progestogen-only formulations and is now the most common public health service provided by UK pharmacists. Important questions relate to women's perceptions of their experience of receiving ECPs from pharmacists. Qualitative study: in-depth interviews with young women reporting ECP use, recruited from clinic (10); pharmacy (6) and community settings (5) in London. Key advantages of pharmacy provision were ease and speed of access and convenience. Disadvantages included a less personal service, inadequate attention to information needs and to prevention of recurrence of ECP need, and unsupportive attitudes of pharmacy staff. Suggested service improvements included increasing privacy, providing more contraceptive advice, adopting a more empathetic approach and signposting follow-up services. Pharmacies are important in the choice of settings from which ECPs can be obtained and many aspects of pharmacy provision are appreciated by young women. There is scope to further enhance pharmacists' role.


The role of drug therapy in social phobia.
Social phobia is a potentially disabling condition requiring effective and well tolerated treatment. The monoamine oxidase inhibitors, benzodiazepines and, more recently, the selective serotonin reuptake inhibitors (SSRIs) have all shown promise as treatments for this disorder. Paroxetine, the most thoroughly studied SSRI, has been shown to be effective in treating the symptoms of generalized social phobia in a large-scale, placebo-controlled trial. Paroxetine and the other SSRIs show promise as a new and safe therapeutic choice for patients with social phobia.


Enhancement of biocontrol activity of yeasts by adding sodium bicarbonate or ammonium molybdate to control postharvest disease of jujube fruits.
To assess the potential of sodium bicarbonate and ammonium molybdate as additives in enhancing the biocontrol efficacy of Rhodotorula glutinis and Cryptococcus laurentii against blue mould in jujube fruits. Two yeasts at a concentration of 107 CFU ml-1, in combination with 238 mmol l-1 sodium bicarbonate or 15 mmol l-1 ammonium molybdate, showed a significant inhibition effect on blue mould of jujube fruits stored at 20 degrees C for 5 days. The colonizing ability of the yeasts in wounded sites was significantly decreased in the presence of ammonium molybdate. Combining R. glutinis or C. laurentii with sodium bicarbonate or ammonium molybdate provided a more effective control of postharvest disease than using the antagonistic yeasts or the chemicals alone. The addition of sodium bicarbonate or ammonium molybdate reduced the number of antagonists required to efficiently control disease of postharvest fruits, which could result in the reduction of costs.


Complete resection after pembrolizumab treatment followed by salvage surgery in stage IVB endometrial cancer: A case report.
There is little evidence regarding the treatment of stage IVB endometrial cancer. Therefore, chemotherapy is more likely to be chosen as the initial and first-line treatment. Pembrolizumab is a new treatment choice for unresectable endometrial cancer after first-line chemotherapy failure. Herein, we report the case of a 56-year-old patient diagnosed with stage IVB endometrial cancer. After eight cycles of first-line chemotherapy, computed tomography (CT) revealed relapse with re-enlargement of the para-aortic lymph nodes. Since the primary tumour had high microsatellite instability, we switched to pembrolizumab treatment. Pembrolizumab was effective but could not be continued due to adverse events after 10 cycles. Positron emission tomography-CT revealed active cancer in the uterus and para-aortic lymph nodes. Since pembrolizumab treatment had to be discontinued, we performed salvage surgery, which achieved complete tumour removal, and the patient has had no evidence of disease for 16 months. This is the first case of complete surgical resection after administering pembrolizumab as a second-line treatment for advanced endometrial cancer.


Influence of weak magnetic field and tartrate on the oxidation and sequestration of Sb(III) by zerovalent iron: Batch and semi-continuous flow study.
The influence of weak magnetic field (WMF) and tartrate on the oxidation and sequestration of Sb(III) by zerovalent iron (ZVI) was investigated with batch and semi-continuous reactors. The species analysis of antinomy in aqueous solution and solid precipitates implied that both Sb(III) adsorption preceding its conversion to Sb(V) in solid phase and Sb(III) oxidation to Sb(V) preceding its adsorption in aqueous phase occurred in the process of Sb(III) sequestration by ZVI. The application of WMF greatly increased the rate constants of Sbtot (total Sb) and Sb(III) disappearance during Sb(III)-tartrate and uncomplexed-Sb(III) sequestration by ZVI. The enhancing effect of WMF was primarily due to the accelerated ZVI corrosion in the presence of WMF, as evidenced by the influence of WMF on the change of solution and solid properties with reaction. However, tartrate greatly retarded Sb removal by ZVI. It was because tartrate inhibited ZVI corrosion, competed with Sb(III) and Sb(V) for the active surface sites, increased the negative surface charge of the generated iron (hydr)oxides due to its adsorption, and formed soluble complexes with Fe(III). The positive effect of WMF on Sb(III)-tartrate and uncomplexed-Sb(III) removal by ZVI was also verified with a magnetic semi-continuous reactor.


PiZZ alpha 1-antitrypsin deficiency in a 20-week fetus.
Immunoperoxidase and electron microscopic studies of the liver of a 20-week fetus with PiZZ alpha 1-antitrypsin deficiency are described. The significance of the bile duct hypoplasia observed in the liver is discussed. The abnormal morphology of the jejunal mucosa is also described.


Love Thy Neighbor: Sharing and Cooperativity in the Gut Microbiota.
To persist in the competitive gastrointestinal ecosystem, microbes often enforce selfish strategies that limit resource loss to neighboring bacteria. In contrast, a recent study in Nature by Rakoff-Nahoum et al. (2016) reveals that one commensal bacterium releases nutrients to benefit another species, which reciprocally provides growth-promoting factors to the producer.


Sleep duration and endometrial cancer risk.
Recent data indicate that night shift work is associated with increased endometrial cancer risk, perhaps through a pathway involving lower melatonin production. Melatonin is an antiestrogenic hormone, with production in a circadian pattern that is dependent on presence of dark at night. Sleep duration is positively associated with melatonin production and may be an indicator of melatonin levels in epidemiologic studies. We evaluated associations between self-reported sleep duration and endometrial cancer risk using publicly available prospective data on 48,725 participants in the Women's Health Initiative Observational Study, among whom 452 adjudicated incident cases of endometrial cancer were diagnosed over approximately 7.5 years of follow-up. Sleep duration was self-reported at baseline. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for endometrial cancer risk with adjustment for potential confounders. Most women reported sleeping ≤ 6 (33.3%) or 7 (38.5%) h each night; fewer reported sleeping 8 (23.4%) or ≥ 9 (4.8%) h each night. In adjusted analyses, there was an indication of reduced risk associated with longer sleep duration, though no statistically significant association was observed. Women who slept ≥ 9 h had a nonsignificant reduced risk of endometrial cancer compared with women who slept ≤ 6 h (HR = 0.87; 95% CI = 0.51-1.46). We found weak evidence of an association between sleep duration and endometrial cancer risk. Self-reported sleep duration may not adequately represent melatonin levels, thus further studies utilizing urinary melatonin levels are necessary to establish the mechanism by which night shift work increases endometrial cancer risk.


Glucose-induced expression of the homeotic transcription factor Prep1 is associated with histone post-translational modifications in skeletal muscle.
Chronic hyperglycaemia worsens insulin resistance in individuals with type 2 diabetes. Whether this effect is contributed by epigenetic dysregulation and which genes are involved remain unclear. Prep1 (also known as Pknox1) is a gene exerting major effects on the sensitivity of the glucose transport machinery to insulin. Here, we show that dysregulation of Prep1 expression by high glucose levels is associated with histone modifications at its 5' regulatory region. We used mouse and cell models to investigate Prep1 transcriptional regulation by glucose. Differentiated L6 skeletal muscle cells were grown in the presence of either 5.5 or 25 mmol/l glucose (normal [NG] and high glucose [HG], respectively). The HG exposure increased nuclear factor κ light chain enhancer of activated B cells (NF-κB) p65 binding and recruitment of the su(var)3-9, enhancer-of-zeste, trithorax domain-containing lysine methyltransferase 7 (SET7) histone methyltransferase and p300 acetyltransferase to the 5' region of Prep1, leading to enhanced transcription. In addition, chromatin immunoprecipitation assays revealed concomitantly increased histone H3 mono- and dimethylation and acetylation at Lys4 and Lys9/14, respectively. Skeletal muscle tissue from streptozotocin-treated diabetic mice also showed Prep1 overexpression accompanied by similarly increased recruitment of NF-κB p65 and histone modifications at the 5' region of Prep1. In these same mice, as well as in Prep1-overexpressing L6 cells, Prep1-induced recruitment of the repressor complex myocyte enhancer factor 2 (MEF2)/histone deacetylase 5 (HDAC5) at the Glut4 promoter was also increased, leading to reduced Glut4 expression. These studies indicate that HG exposure induces NF-κB recruitment and histone modification at the Prep1 5' region, thereby enhancing the transcription of Prep1 and repressing that of Glut4. Histone changes at the Prep1 gene may contribute to insulin resistance in individuals with type 2 diabetes.


The generation of immunocompetent dendritic cells from CD34+ acute myeloid or lymphoid leukemia cells.
The ability of CD34+ leukemic cells to differentiate to dendritic cells (DCs) was investigated in 18 acute myeloid leukemia (AML) and 4 lymphoid leukemia (ALL) patients. The generation of DCs was determined by the expression of DC-associated CD1a or CD83 (more than 30%) with costimulatory molecules, by CD80 antigens (>20%), and by the exhibition of allostimulatory activity. In the AML patients, allostimulatory mature DCs were generated from 3 of 9 M0 or M1, 2 of 5 M2,2 of 4 M4 or M5, and 3 of 4 ALL (L2) cases. In total, DCs were more efficiently induced from cases expressing over 75% of CD34+ among whole bone marrow mononuclear cells (8 of 12), compared with those under 75% (2 of 10; P < .05). B-cell (CD19), natural killer (NK)-cell (CD56), or T-cell (CD7) lineage markers, which were aberrantly expressed on the blasts, were rarely found on leukemic DCs at the end of the culture period, and myeloid (CD13, CD33), not lymphoid (CD10), markers were shown on ALL-derived DCs. In Philadelphia chromosome-positive ALL or AML patients with t (8;21), DCs were confirmed to be of leukemic origin by fluorescence in situ hybridization analysis.


Fluorescent fullerene nanoparticle-based lateral flow immunochromatographic assay for rapid quantitative detection of C-reactive protein.
A fluorescent fullerene nanoparticle (NP)-based lateral flow immunochromatographic assay (LFIA) was developed for the rapid and quantitative detection of C-reactive protein (CRP) in serum. The polyclonal CRP-antibody-conjugated fullerene NPs were simply prepared by 1-ethyl-3-(3-dimethyllaminopropyl)-carbodiimide hydrochloride coupling after carboxylation of fluorescent fullerene NPs. By applying the CRP-antibody-conjugated fullerene NPs to a lateral flow test strip, quantitative analysis of CRP in serum was possible at a concentration range of 0.1-10 ng/ml within 15 min. We anticipate that this novel fluorescent fullerene NP-based LFIA can be useful for the rapid and accurate sensing of biological and chemical species, contributing to the disease diagnosis and prognosis, environmental monitoring, and food safety.


From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity.
This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P=0.005 for bleomycin and P=0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms.


A rust-inducible gene from flax (fis1) is involved in proline catabolism.
A gene fis1 from flax (Linum usitatissimum), which is induced in mesophyll cells at the site of rust (Melampsora lini) infection, is also expressed in vascular tissue, particularly in floral structures of healthy plants. This paper reports that the promoter controlling this expression is contained within 282 bp 5' to the coding region and that fis1 gene induction is specifically by the rust pathogen and not by other fungal pathogens or by wounding. The fis1 gene has 73% homology with an Arabidopsis gene which encodes delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDH) which is a part of the proline degradation pathway. Transgenic flax plants that either over-express fis1 or show reduced fis1 expression due to RNA-mediated gene silencing have an unaltered morphology. However, plants with reduced fis1 expression have markedly increased sensitivity to exogenous proline and show alteration in epidermal cell morphology, callose deposition and the production of hydrogen peroxide during proline-induced death. These lines, which show a biologically significant level of fis1 suppression, have an unaltered reaction to either virulent or avirulent rust infections, as do fis1 over-expression lines. These data indicate that the fis1 gene plays a role in proline metabolism and most likely encodes for a P5CDH enzyme. However, the precise role of fis1 and P5C catabolism in the development of rust disease remains unclear.


RNA-binding protein RBM8A (Y14) and MAGOH localize to centrosome in human A549 cells.
RBM8A (Y14) is carrying RNA-binding motif and forms the tight heterodimer with MAGOH. The heterodimer is known to be a member of exon junction complex on exporting mRNA and is required for mRNA metabolisms such as splicing, mRNA export and nonsense-mediated mRNA decay. Almost all RBM8A-MAGOH complexes localize in nucleoplasm and shuttle between nuclei and cytoplasm for RNA metabolism. Recently, the abnormality of G2/M transition and aberrant centrosome regulation in RBM8A- or MAGOH-deficient cells has been reported. These results prompt us to the reevaluation of the localization of RBM8A-MAGOH in human cells. Interestingly, our immunostaining experiments showed the localization of these proteins in centrosome in addition to nuclei. Furthermore, the transiently expressed eYFP-tagged RBM8A and Flag-tagged MAGOH also co-localized with centrosome signals. In addition, the proximity ligation in situ assay was performed to detect the complex formation in centrosome. Our experiments clearly showed that Myc-tagged RBM8A and Flag-tagged MAGOH formed a complex in centrosome. GFP-tagged PLK1 also co-localized with Myc-RBM8A. Our results show that RBM8A-MAGOH complex is required for M-phase progression via direct localization to centrosome rather than indirect effect.


Distribution and genetic diversity of porcine hokovirus in wild boars.
Porcine hokovirus (PHoV), a newly discovered member of the family Parvoviridae and the proposed genus Hokovirus, is considered phylogenetically distinct from other parvoviruses. Here, we report a comprehensive spatio-temporal study of PHoV infection in Romanian wild boars. The prevalence of PHoV differed significantly in samples from 2006/2007 (22.76%) and 2010/2011 (50.54%), and also increased with age. Sequence analysis of PHoVs from 2006/2007 showed a close relationship to PHoVs from pigs from England and wild boars from Germany, while the PHoVs from 2010/2011 were mostly similar to isolates from Hong Kong. The most variable regions were detected in the NS1 gene and proved to be suitable for analysis of the genetic diversity of the virus. It was observed that PHoVs from older wild boar samples differed from those collected recently. These results suggested that porcine hokovirus could be a newly emerging virus of both domestic and wild pigs with yet unknown implications.


Micropipette holders: vented types are preferable to closed types.
Due to the large coefficient of volume expansion of water with temperature, the use of closed micropipette holders results in significant pipette motion and pressure ejection of electrolytes or marker dyes as the temperature of the pipette goes up upon insertion in the CNS or spinal cord of warm blooded preparations.


A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis.
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). It was reported that anti-histone autoantibody was detected in PBC, suggesting that bacterial histone-like DNA-binding protein (HLP) may be involved in the pathogenesis of PBC. To identify bacterial species in PBC to confirm this possibility, serum reactivity to bacterial cells was studied by ELISA. The IgM class Streptococcus intermedius titers were significantly higher in PBC than chronic hepatitis due to hepatitis C virus (CH-C) and healthy subjects. Among the streptococci, S. intermedius was selected for further study. The antigenic peptide of S. intermedius of HLP was synthesized to examine the serum reactivity to Si-HLP. IgM class anti-Si-HLP peptide titers were significantly higher in PBC. Immunoreactivity to anti-Si-HLP was detected in the cytoplasm of biliary epithelial cells and inflammatory cells in the portal area in PBC patients' livers. Streptococci, especially S. intermedius, might play a key role in the pathogenesis of PBC, possibly involving HLP.


Histidine kinases as targets for new antimicrobial agents.
The emergence and spread of hospital acquired multi drug resistant bacteria present a need for new antibiotics with innovative mode of action. Advances in molecular microbiology and genomics have led to the identification of numerous bacterial genes coding for proteins that could potentially serve as targets for antibacterial compounds. Histidine kinase promoted two-component systems are extremely common in bacteria and play an important role in essential signal transduction for adapting to bacterial stress. Since signal transduction in mammals occurs by a different mechanism, inhibition of histidine kinases could be a potential target for antimicrobial agents. This review will summarize our current knowledge of the structure and function of histidine kinase and the development of antibiotics with a new mode of action: targeting histidine kinase promoted signal transduction and its subsequent regulation of gene expression system.


Renal cortex guanylate cyclase. Preferential enrichment in glomerular membranes.
1. The localisation and some of the properties of rabbit kidney cortex guanylate cyclase (GTP pyrophosphatase lyase (cyclizing) EC 126.96.36.199) have been studied. Upon fractionation of dissociated renal cortex, guanylate cyclase activity was preferentially enriched in fractions of pure glomeruli, where its specific activity was 44.5 times that measured in tubular fragments. Most, if not all, of the glomerular activity was found to be firmly membrane-bound, whereas the guanylate cyclase activity of the tubules was mainly soluble. Therefore, particulate guanylate cyclase activity could serve as marker enzyme for kidney glomeruli. 2. All hormones or hormone-like agents tested were without effect on kidney guanylate cyclase activity. Triton X-100 stimulated both glomerular and tubular activity. 3. Considering the high cyclic GMP forming capacity of kidney glomeruli, part of the cyclic GMP found in urine might be synthetized locally in these structures.


[A case of staphylococcal spondylodiscitis after spinal injury. Post-traumatic spondylodiscitis?].
The authors report the case of a patient who had a D9-D10 staphylococcic spondylodiscitis three month after a fracture of the first lumbar vertebra, which they consider to be posttraumatic despite the fact that it is localised in a different area. They insist on the insufficiency of the literature existing on such cases and on the various pathogenic hypotheses to be applied by the practitionner.


Dehydroepiandrosterone sulfate treatment for atrichia pubis.
To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for atrichia pubis in female adolescents. Two XY female adolescents with 17-hydroxylase deficiency and 2 XX females with panhypopituitarism presenting with atrichia pubis were treated with a daily dosage of DHEAS 10 mg/m2 body surface in addition to their regular substitution therapy. The dosage was increased according to clinical response. Pubic hair stages, growth and serum DHEAS were evaluated and in 1 case also serum IGFs and IGFBPs. A dosage of 10 mg/m2 for 1 year led to serum DHEAS levels at the lower limit of the normal range. 15 mg/m2 was needed to achieve pubic hair stage 4-5 and axillary hair in patients with 17-hydroxylase deficiency. In panhypopituitarism, pubic hair developed at a slower pace and reached stage 4 on a dosage of 25-30 mg/m2. Baseline serum IGF-I SDS was -0.67 and did not change on the initial dosage of DHEAS, in combination with submaximal estrogen substitution (10 microg ethinyl estradiol). On the combination of 15 mg/m2 DHEAS and full estrogen substitution, IGF-I SDS increased to an average of -0.15. IGFBP-3 SDS increased from 1.4 to a mean of 2.6 in the first year, and went back to 1.4 in the second year. IGFBP-6 SDS was low at baseline (-2.5) and rose to -1.9 and -1.7 IGF-II and IGFBP-1 showed an irregular pattern. Oral administration of DHEAS in a dosage of 15 mg/m2 o.d. is an efficacious treatment for atrichia pubis. For females with a panhypopituitarism a higher dosage appears needed. Given this and other biological actions of DHEAS, substitution therapy with DHEAS or DHEA to females with adrenal androgen deficiency appears rational.


Comparison of Intraoperative and Discharge Residual Lesion Severity in Congenital Heart Surgery.
While the predischarge technical performance score (DC-TPS) is significantly associated with outcomes after congenital cardiac surgery, the utility of the intraoperative TPS (IO-TPS) remains unknown. This was a single-center retrospective review of consecutive patients who underwent congenital cardiac surgery from January 2011 to December 2019. Intraoperative and predischarge echocardiograms were used to assign IO-TPS and DC-TPS, respectively, for each index operation (class 1, no residua; class 2, minor residua; class 3, major residua). Anatomic modules identifying the principal residual lesion were assigned to all class 2/3 patients. Overall and module-specific TPS comparisons were made. Multivariable regression models with IO-TPS and DC-TPS as separate predictors of postoperative outcomes were compared. Of 6201 patients, overall agreement between IO-TPS and DC-TPS was observed in 4251 patients (68.6%); scores were likelier to be worse at discharge (P < .001). Paired comparative analyses revealed that among patients with at least class 2 atrioventricular and semilunar valve residua, IO-TPS was likelier to worsen than improve (both P < .001). Class 3 patients had a higher risk of in-hospital/early mortality (IO-TPS: odds ratio, 7.5; 95% CI, 2.4-23; DC-TPS: odds ratio, 6.6; 95% CI, 3.0-15), postdischarge/late mortality (IO-TPS: hazard ratio [HR], 3.1, 95% CI, 1.3-7.1; DC-TPS: HR, 2.3; 95% CI, 1.2-4.4), and late unplanned reintervention (IO-TPS: HR, 2.8; 95% CI, 1.9-4.0; DC-TPS: HR, 3.4; 95% CI, 2.8-4.2) vs class 1 (all P < .05). IO- and DC-TPS models were equivalent fits for predicting early and late mortality; the latter was a marginally better fit for late reintervention. IO-TPS and DC-TPS are both important adjuncts for quality improvement in congenital cardiac surgery.


Clinical assessment of the neonatal Dinamap 847 during anesthesia in neonates and infants.
Direct measurements of systolic, diastolic, and mean arterial blood pressure and electrocardiogram-derived heart rates were compared with indirect arterial blood pressure measurements using the Dinamap 847XT noninvasive monitor. A total of 260 paired comparisons from 16 patients were analyzed. A regression analysis of paired data over a wide range of blood pressure values gave the following results: for heart rate r = 0.97, for systolic arterial pressure r = 0.84, for mean arterial pressure r = 0.73, and for diastolic arterial pressure r = 0.52. The 95% confidence limits for systolic, mean, and diastolic arterial pressure were +/- 16 mm Hg, +/- 18 mm Hg, and +/- 21 mm Hg, respectively. The Dinamap monitor was found to be an accurate trend recorder of heart rate and blood pressure during anesthesia in neonates and small infants.


Iminodiacetic acid-modified magnetic poly(2-hydroxyethyl methacrylate)-based microspheres for phosphopeptide enrichment.
Magnetic non-porous hydrophilic poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) microspheres prepared by the dispersion polymerization and modified with iminodiacetic acid (IDA) were employed for the IMAC separation of phosphopeptides. Fe(3+) and Ga(3+) ions immobilized on IDA-modified magnetic microspheres were used for the enrichment of phosphopeptides from the proteolytic digests of two model proteins differing in their physico-chemical properties and phosphate group content: porcine pepsin A and bovine α-casein. The optimum conditions for phosphopeptide adsorption and desorption in both cases were investigated and compared. The phosphopeptides separated from the proteolytic digests were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The ability of the prepared Fe(3+)- and Ga(3+)-IDA-modified magnetic microspheres to capture phosphopeptides from complex mixtures was shown on an example of bovine milk proteolytic digest.


Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis.
Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics-in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-β. GNbAC1 as a new MSRV-Env-antagonist mAb could be a specific and causal treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.


Quality of life analysis of patients treated with cetuximab or cisplatin for locoregionally advanced squamous cell carcinoma of head and neck in the United States.
To compare quality of life of patients treated with cetuximab with or without radiation therapy (±RT) vs. cisplatin±RT for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) in the real-world setting. In this retrospective observational study, electronic medical records and Patient Care Monitor (PCM) survey data from the Vector Oncology Data Warehouse were utilized from adult patients in the United States who received initial treatment with cetuximab±RT or cisplatin±RT for locoregionally advanced SCCHN between January 1, 2007 and January 1, 2017. Quality of life was assessed using PCM index scores and individual PCM items. Cetuximab±RT and cisplatin±RT cohorts were balanced using propensity score weighting. Linear mixed models were used to assess the impact of baseline demographic and clinical characteristics on PCM endpoints. Of 531 patients with locoregionally advanced SCCHN, 187 received cetuximab±RT, and 344 received cisplatin±RT. Before propensity score weighting, the cetuximab±RT cohort was older (mean [SD] age of 63.9 [9.6] years vs. 57.4 [8.6] years), and more likely to be white (82.4% vs. 72.4%) compared to the cisplatin±RT cohort. After propensity score weighting, the two cohort subsamples (cetuximab±RT, N = 60; cisplatin±RT, N = 177) with PCM data showed no significant differences in General Physical Symptoms, Treatment Side Effects, Impaired Ambulation, or Impaired Performance index scores. Patients in the cetuximab±RT cohort had higher Acute Distress index (p = 0.023), Despair index (p = 0.011), and rash (p = 0.003) scores but lower numbness/tingling scores (p = 0.022) than patients in the cisplatin±RT cohort. Significant group differences were observed in this comparative analysis, as the cetuximab±RT cohort had significantly higher Acute Distress index, Despair index, and rash scores compared with the cisplatin±RT cohort but lower numbness/tingling scores. These patterns of symptoms appear consistent with previously reported symptoms associated with the treatment of SCCHN.


[COVID-19, families and institutions put to the test in paediatric psychiatry].
The lockdown provoked by the COVID-19 pandemic has resulted in a reorganisation of the provision of care. The staff of the child psychiatry unit in Coulommiers has had to redesign the care provision in the light ofthe current constraints and requirements. New tools and methods have appeared, along with a new symptomatology which has had to be understood in its context. The health crisis has also affected the patients. Some have disappeared from view while others show signs of anxiety and panic attacks. Caregivers have managed to adapt in order to guarantee the necessary continuity of care.


Use of anti-seminoma monoclonal antibody to confirm the diagnosis of mediastinal seminoma. A case report.
Chest x-ray in a 20-year-old man showed a large anterior mediastinal mass and a needle aspirate was diagnosed by light microscopy (LM) as non-Hodgkin's lymphoma. Treatment with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) was ineffective and a tissue biopsy was performed. LM showed large, non-cohesive cells with abundant cytoplasm and rounded nuclei. Differential diagnoses included malignant lymphoma, seminoma, thymoma, anaplastic carcinoma, malignant melanoma and paraganglioma. Electron microscopy was not conclusive and immunoperoxidase staining was carried out. The malignant cells were negative for common leukocyte antigen, Leu M1, alpha-fetoprotein, chorionic gonadotrophin, cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, S-100 protein and neuron-specific enolase but positive for placental alkaline phosphatase. In addition, there was strong positivity with a monoclonal antibody (mAb) which was recently shown to react with testicular seminomas. This case illustrates the value of this mAb in confirming the diagnosis of mediastinal seminoma.


Ifosfamide and mesna at high doses for the treatment of cancer of the cervix: a GETLAC study.
This study was carried out to assess the efficacy of high-dose ifosfamide/mesna (HDIFM) in the treatment of advanced or recurrent cancer of the cervix. In all, 18/21 evaluable patients with advanced or inoperable cervical cancer were included. The mean age was 42 years (range, 31-58 years); and the International Federation of Gynecology and Obstetrics (FIGO) stage was III in 10 patients and IV in 11. The Karnofsky performance status ranged between 70 and 90, with a median of 77. Ten patients had previously been treated with surgery, radium and cobalt (8) or cobalt alone (2). Therapy consisted of 3.5 g/m2, ifosfamide (IFO) given in an 8-h i.v. infusion on days 1-5 and mesna at 20% of the IFO dose, given i.v. at 0, 2, 4, 6 and 8 h, followed by mesna at 40% of the IFO dose by the oral route at 10 and 12 h on days 1-5. For evaluation purposes, patients received at least two cycles. Toxicity was registered in 137 cycles and was mild to moderate. Three complete (16.6%) and six partial (33.3%) responses were observed (50%), but 66% of them occurred in areas that had not previously been irradiated. The median duration of response was 14 months and the overall median survival was 15+ months (18+ months for responders). The Karnofsky scale after treatment ranged from 90 to 100. The results of this study indicate that HDIFM is well tolerated, giving a high percentage of remission (50%) and significantly improving the quality of life.


Garcinia mangostana hydrogel patch: bactericidal activity and clinical safety for acne vulgaris treatment.
Garcinia mangostana, simply known as mangosteen, has long been used by Thai traditional medicine because of its reported antibacterial and anti-inflammatory activities for the treatment of skin infections. In this study, mangosteen pericarps were developed into a hydrogel patch to eradicate acne-inducing bacteria. The G. mangostana extract was investigated for bactericidal activity. A hydrogel patch containing the extract was examined for mechanical properties, antibacterial activity, in vitro release, skin permeation, and a phase I clinical study of skin irritation and allergic testing by a closed patch test. The G. mangostana hydrogel patch made from carrageenan and locust bean gum powders was yellow in color, smooth, durable, and flexible. This G. mangostana hydrogel patch was effective against Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus. The active ingredient, α-mangostin, was released and permeated from the G. mangostana hydrogel patch within the first 30 min at 33.16 ± 0.81% and 32.96± 0.97%, respectively. The G. mangostana hydrogel patch showed no irritation in 30 healthy volunteers. However, two volunteers had delayed allergic contact dermatitis to 0.5% (w/w) G. mangostana hydrogel patch. This hydrogel patch containing G. mangostana ethanolic extract is not recommended for patients who have any reaction to mangosteen but has utility as an anti-acne facial mask.


The effect of a Tropaeolum speciosum oil supplement on the nervonic acid content of sphingomyelin in rat tissues.
The lipids of Tropaeolum speciosum (T. speciosum) are a rich source of naturally occurring nervonic acid (24:1n-9). We report that adding a T. speciosum oil supplement to a semi-purified diet significantly increased the amount of 24:1n-9 in liver and heart, but not brain, sphingomyelin (SM) of young rats. The bioavailability of 24:1n-9 from the lipids of T. speciosum was similar to that of 24:1n-9 ethyl ester in this rat bioassay.


Cases from the aerospace medicine residents' teaching file: atrial fibrillation.
An Army aviator in training develops recurrent episodes of tachycardia diagnosed as atrial fibrillation. The presentation, diagnosis, treatment, and aeromedical issues surrounding atrial fibrillation are discussed.


Functional Genomic Complexity Defines Intratumor Heterogeneity and Tumor Aggressiveness in Liver Cancer.
Chronic inflammation and chromosome aneuploidy are major traits of primary liver cancer (PLC), which represent the second most common cause of cancer-related death worldwide. Increased cancer fitness and aggressiveness of PLC may be achieved by enhancing tumoral genomic complexity that alters tumor biology. Here, we developed a scoring method, namely functional genomic complexity (FGC), to determine the degree of molecular heterogeneity among 580 liver tumors with diverse ethnicities and etiologies by assessing integrated genomic and transcriptomic data. We found that tumors with higher FGC scores are associated with chromosome instability and TP53 mutations, and a worse prognosis, while tumors with lower FGC scores have elevated infiltrating lymphocytes and a better prognosis. These results indicate that FGC scores may serve as a surrogate to define genomic heterogeneity of PLC linked to chromosomal instability and evasion of immune surveillance. Our findings demonstrate an ability to define genomic heterogeneity and corresponding tumor biology of liver cancer based only on bulk genomic and transcriptomic data. Our data also provide a rationale for applying this approach to survey liver tumor immunity and to stratify patients for immune-based therapy.


pH-sensitive microfiltration membrane prepared from polyethersulfone grafted with poly(itaconic acid) synthesized by simultaneous irradiation in homogeneous phase.
Poly(itaconic acid) (PIA) was grafted onto polyethersulfone (PES) by homogeneously phased γ-ray irradiation. Kinetic polymerization observed was studied by analyzing the effect of irradiation dosages and monomer concentrations. Then, a pH-sensitive microfiltration (MF) membrane was prepared from these PES-g-PIA polymers with different degrees of grafting under phase inversion method. Finally, the contact angles, morphologies, pore sizes, deionized water permeability and filtration performance for aqueous polyethylene glycols solution of the MF membranes were studied. The results show that grafting PIA groups onto PES molecular chains endowed the MF membranes with effective pH-sensitive properties.


Frequency of HLA-DPB1 disparities detected by reference strand-mediated conformation analysis in HLA-A, -B, and -DRB1 matched siblings.
The role of HLA-DPB1 as transplantation antigen is controversial. The frequency and relevance of HLA-DPB1 mismatch in hematopoietic stem cell transplantation are unknown. To ascertain the rate of HLA-DBP1 mismatch in siblings that had been matched for HLA-A, -B, and -DRB1, reference strand mediated conformation analysis (RSCA) a high resolution HLA typing method was used. Locus-specific primers were used to amplify the HLA-DPB1 locus. The PCR product was then hybridized with two fluorescein-labeled references and the duplexes were analyzed after electrophoresis in a short polyacrylamide gel. Among the 113 pairs of individuals tested, six HLA-DPB1 mismatches were identified, which corresponds to a frequency of 5.31 % (95% confidence interval 3.20%-7.42 %).


The effect of five-year storage prior to bonding on enamel/composite bond strength.
The purpose of this study was to examine the effect of pre-bonding storage durations on the shear strength of light-cured composite bonded to enamel. Thirty whole extracted human molars--12 with a storage time of five years, 12 with a storage time of three or fewer months, and six with a storage time of 24 hours or less--were mounted in improved dental stone in copper tubing. The molars were faced 90 degrees to the horizontal with a milling device to produce 120 surfaces, 48 each for two groups, and 24 for one group. Composite buttons 2.3 mm in diameter were bonded to the enamel using the acid-etch light-curing system. The samples were tested in shear utilizing a cross-head speed of 0.5 cm/min with a 500-kg load cell. The results showed that: there was no significant difference, at the 0.05 confidence level, in composite/enamel bond strength between teeth stored for 24 hours, three months, and five years prior to bonding; the lingual surface developed the highest composite/enamel bond strength in all three groups; and enamel fracture occurred 29% of the time on de-bonding.


The use of thiols by ribonucleotide reductase.
Ribonucleotide reductase (RNR) catalyzes the rate-limiting de novo synthesis of 2'-deoxyribonucleotides from the corresponding ribonucleotides and thereby provides balanced deoxyribonucleotide pools required for error-free DNA replication and repair. The essential role of RNR in DNA synthesis and the use of DNA as genetic material has made it an important target for the development of anticancer and antiviral agents. The most well known feature of the universal RNR reaction in all kingdoms of life is the involvement of protein free radicals. Redox-active cysteines, thiyl radicals, and thiol redox proteins of the thioredoxin superfamily play major roles in the catalytic mechanism. The involvement of cysteine residues in catalysis is common to all three classes of RNR. Taking account of the recent progress in this field of research, this review focuses on the use of thiols in the redox mechanism of RNR enzymes.


Successful treatment of IBL-like T-cell lymphoma with cyclosporin A: two case reports with special reference to serum cytokine levels.
The prognosis of immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is grave, and its effective treatments have not been established. We applied oral cyclosporin A (CsA) treatment to two cases of IBL-like T-cell lymphoma, and succeeded in achieving complete remissions. CsA is known to have a suppressive effect on the immune system, most notably T-cells, but it also has a direct cytotoxic/apoptosis-inducing effect on lymphocytes. Its combined effects on neoplastic T-cells might have played an important role in achieving remission. In both cases, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) were elevated and decreased or returned to normal after achieving remissions. Considering that both cytokines represent monokines, it seems that a macrophage system is also involved in the pathogenesis of this disorder. Our two cases indicate that administration of CsA may be an effective therapy for IBL-like T-cell lymphoma.


Pityriasis versicolor in the aged: a clinical investigation and epidemiological survey in 190 elderly hospitalized patients.
190 subjects over 60 yrs of age, hospitalized for long stays were checked for scaling and hyperpigmented patches of P. versicolor. 20 patients (10.5%) showed no clinical lesions; 170 patients (89.5%) showed scaling and/or hyperpigmented patches of which 13 patients (6.8%) on direct microscopic exam showed hyphae and yeasts of M. furfur, 64 (33.6%) only globular forms of P. orbiculare and 113 cases (59.4%) showed no fungal elements. Wood's light examination showed that 38 subjects (20%) were 6 positive for M. furfur and 23 for P. orbiculare while in the other 9 no fungal elements were observed on microscopic exam. Whereas 48/132 patients negative to Wood's light were positive for yeasts on microscopic exam (false negative). This study indicates that P. versicolor is not rare in the elderly and that Wood's light examination is not diagnostic. There was no relationship between P. versicolor and underlying illness.


Functional MR Imaging Techniques in Oncology in the Era of Personalized Medicine.
DW and DCE MR imaging contribute significantly to diagnosis, treatment planning, response assessment, and prognosis in personalized cancer medicine. Nevertheless, the need for further standardization of these techniques needs to be addressed. Whole-body DW MR imaging is an exciting field; however, future studies need to investigate in more depth the biologic significance of the findings depicted, their prognostic relevance, and cost-effectiveness in comparison with MDCT and PET/CT. New MR imaging probes, such as targeted or activatable contrast agents and dynamic nuclear hyperpolarization, show great promise to further improve the care of patients with cancer in the near future.


Competencies for the Nurse Practitioner Working with Adult Urology Patients.
The role of the nurse practitioner (NP) has expanded into specialty domains. This document proposes 24 competencies specific to the urology NP, which are also consistent with the recommendations of National Organization of Nurse Practitioner Faculties (NONPF) and compliment the American Urologic Association (AUA) 2014 white paper on the incorporation of advanced practice providers in urology practices. It describes three levels of practice and experience progression for the urology NP working with adult patients, independent of specific clinical setting. These urology-specific competencies supplement and complement the core competencies and population-focused competencies of generalist nurse practitioners.


[Certain problems of pathogenesis and clinical course of chronic venous insufficiency in the lower limbs after deep burns].
Based on the examination of 66 patients with chronic venous insufficiency of the lower limbs following deep burns, the authors found that its occurrence mainly results from thromboses of profound veins of the lower extremities during the period of existence of burn wounds and mechnic obstruction of venous outflow, produced by extensive scars. In associated lesions of venous and lymph systems secondary postburn elephantiasis may develop.


VDR activation attenuates osteoblastic ferroptosis and senescence by stimulating the Nrf2/GPX4 pathway in age-related osteoporosis.
Ferroptosis plays an essential role in the pathology of osteoporosis. This study investigated whether vitamin D receptor (VDR) activation could protect against age-related osteoporosis through an anti-ferroptosis mechanism. d-galactose (D-gal)-induced mice and VDR-knockout mice were used in the in-vivo study. The VDR activator (1,25(OH)2D3) attenuated senescence and ferroptosis in the D-gal-induced bone, as illustrated by downregulated senescence-associated secretory phenotype genes, improved mitochondrial morphology, elevated glutathione, and decreased lipid peroxidation markers (malondialdehyde and 4-hydroxynonenal). The pre-osteoblast MC3T3-E1 cells and primary rat osteoblasts were applied in the in-vitro studies. 1,25(OH)2D3 or ferroptosis inhibitor (ferrostatin-1) treatment downregulated the cellular senescence markers in D-gal-induced osteoblasts. Mechanistically, 1,25(OH)2D3 activated the VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, resulting in the downregulation of lipid peroxidation. Nrf2 knockdown or addition of GPX4 inhibitor (RSL-3) blocked the protective effect of 1,25(OH)2D3 against D-gal-induced ferroptosis and senescence. VDR knockdown impeded the 1,25(OH)2D3-induced activation of Nrf2/GPX4 pathway in osteoblasts. Proteomics and immunofluorescence analysis confirmed that ferroptosis and suppression of the Nrf2/GPX4 pathway occurred in VDR-knockout mice. Our data demonstrated that ferroptosis played an essential role in age-related osteoporosis. The VDR activation attenuated osteoblast ferroptosis via stimulating the Nrf2/GPX4 signaling pathway.


Right precordial leads and lead aVR at exercise electrocardiography: does it change test results?
A recent study on exercise testing (ET) suggested that ST-segment changes in the right precordial leads (RPL) may increase its sensitivity substantially. However, this study looked at a highly selected population of patients who all underwent thallium-201 scintigraphy and coronary angiography. The present study evaluated the clinical utility of ST-segment changes in the RPL and lead aVR in an unselected population of patients undergoing ET. A total of 906 consecutive patients who received ET were included in the study. ET was done using the Bruce Protocol with a 12-lead electrocardiogram (ECG) substituting V(4)R and V(6)R for V(1) and V(6). Leads V(1) and V(6) were selected for omission as these two leads hardly ever manifest changes in isolation. Substituting two leads would obviate the need for a more complex recording system, thus improving clinical utility. On the basis of horizontal/downsloping ST-segment depression (STD) of 1.0 mm or more (the usually accepted criterion for a positive ET), 159 (17.5%) patients had a positive ET. In those patients with a negative ET (545 patients), 4 patients (0.7%) manifested STD and 5 patients (0.9%) manifested ST-segment elevation (STE) in leads V(4)R and/or V(6)R, respectively. Of note, 44.7% of the positive ET group had STE in lead aVR. The use of ST-segment changes in RPL during exercise stress testing does not appreciably change the test results of a standard ET. If one was to consider an additional marker, STE in aVR may be more useful, as it shows a stronger correlation with positive tests and does not require the recording of additional leads.


The metabolism and antitumour activity of the enantiomers of cis- and trans-4-methylcyclophosphamide.
4-Methylcyclophosphamide, an analogue of the antitumour agent cyclophosphamide, exists in cis and trans forms, each of which comprises a pair of optical isomers. The extents of metabolism by rat liver microsomes during 20 min were compared for the four steroisomers incubated separately, and for the racemic cis and trans-derivatives in admixture, using mass spectrometry and gas chromatography respectively. In comparative antitumour tests against the ADJ/PC6 plasma cell tumour in mice, the racemic cis and trans forms of 4- and 6-methylcyclophosphamide had similar therapeutic indices. The four stereoisomers of 4-methylcyclophosphamide exhibited an approx. two-fold range in therapeutic index so that there was no marked effect on either metabolism or antitumour activity occasioned by change of configuration either at C-4 or at phosphorus.


[Plasma ghrelin levels in the late postoperative period of vertical sleeve gastrectomy].
Plasma ghrelin levels may decrease after vertical sleeve gastrectomy, probably due to the excision of a large portion of the gastric fundus. It is worth exploring the long term effects of this surgical procedure on ghrelin levels and their associations with changes in body weight. To assess ghrelin levels and changes in body weight, one and five years after a vertical sleeve gastrectomy. Plasma ghrelin was measured prior to gastric sleeve gastrectomy, immediately after surgery and BMI was controlled at one and five years of the postoperative period in 16 and 10 obese patients, respectively. Mean baseline body mass index was 40.4 ± 6 kg/m2. Ghrelin decreased in 10 patients and increased in six during the long term postoperative period. At one year, mean body mass index decreased to 25.1 ± 1.6 kg/m2. Changes in weight and ghrelin levels had no relationship whatsoever. At five years of follow up, body mass index had increased to 29.9 ± 2.5 kg/m2, again without any association with ghrelin levels. Ghrelin levels may decrease or increase after vertical sleeve gastrectomy and have no association with changes in body weight.


Regulatory affairs in biotechnology: optimal statistical designs for biomedical experiments.
One of the major issues in all applications of biotechnology is how to regulate the process through which new technological information is produced. The end products of biotechnological applications are diverse (e.g., better drugs, better interventions, better fertilizers). Such applications should be properly regulated to obtain valid scientific findings in the most efficient way possible. Some statistically optimal designs are more popularly employed than others as regulatory tools in medical, pharmaceutical and clinical trials. The statistical and practical properties (strengths and weaknesses) are presented to better appreciate their optimality. Recent developments on some related issues are also reviewed.


The VLCFA elongase gene family in Arabidopsis thaliana: phylogenetic analysis, 3D modelling and expression profiling.
As precursors of wax compounds, very long chain fatty acids participate in the limitation of non-stomatal water loss and the prevention of pathogen attacks. They also serve as energy storage in seeds and as membrane building blocks. Their biosynthesis is catalyzed by the acyl-CoA elongase, a membrane-bound enzymatic complex containing four distinct enzymes (KCS, KCR, HCD and ECR). Twenty-one 3-ketoacyl-CoA synthase (KCS) genes have been identified in Arabidopsis thaliana genome. In this paper we present an overview of the acyl-CoA elongase genes in Arabidopsis focusing on the entire KCS family. We show that the KCS family is made up of 8 distinct subclasses, according to their phylogeny, duplication history, genomic organization, protein topology and 3D modelling. The analysis of the subcellular localization in tobacco cells of the different subunits of the acyl-CoA elongase shows that all these proteins are localized in the endoplasmic reticulum demonstrating that VLCFA production occurs in this compartment. The expression patterns in Arabidopsis of the acyl-CoA elongase genes suggest several levels of regulations at the tissular or organ level but also under stress conditions suggesting a complex organization of this multigenic family.


Characterization of genetic polymorphisms in Nigerians residing in Guangzhou using massively parallel sequencing.
African populations exhibit extensive linguistic and cultural diversity but are less studied from a population genetic standpoint. Although much genetic data on admixed African individuals, such as African Americans, have been published, genetic polymorphism data, especially that based on sequence-based typing, are still insufficient in indigenous Africans. In this study, we examined the genetic diversity of 85 Nigerians residing in Guangzhou, China. Forensically relevant genetic markers, including autosomal short tandem repeats (A-STRs), X-chromosomal STRs (X-STRs), Y-chromosomal STRs (Y-STRs), and identity-informative single nucleotide polymorphisms (iiSNPs) were genotyped to uncover the genetic polymorphisms of this population. Sequence-based allelic variations were observed in 22 A-STRs, ten Y-STRs, and four X-STRs. Using massively parallel sequencing (MPS), the allele number increased from 475 length-based alleles to 683 sequence-based alleles. Compared to other populations, the overall observed heterozygosity of the 27 A-STRs was the highest in Nigerians, which reflected the higher genetic diversity of this population. The combined match probability of the 27 A-STRs was low at 9.06 × 10-38. When both A-STRs and iiSNPs were considered, the cumulative discrimination power, and combined power of exclusion for duo and trio paternity testing was 1-2.97 × 10-57, 1-2.20 × 10-10 and 1-4.61 × 10-17, respectively, which demonstrated that the STRs and SNPs analyzed here can be applied to forensic investigations. In summary, this study uncovers the genetic features of the Nigerian population and provides valuable frequency data for forensic applications.


Development of spontaneous intracranial hypotension concurrent with grade IV mobilization of the cervical and thoracic spine: a case report.
Spontaneous intracranial hypotension (SIH) has been clinically defined as the development of severe orthostatic headaches caused by an acute cerebrospinal fluid (CSF) leak. Typically, intracranial hypotension occurs as a complication of lumbar puncture, but recent reports have identified cases caused by minor trauma. We report a case of SIH secondary to a dural tear caused by a cervical and thoracic spine mobilization. A 32-year-old woman with SIH presented with severe positional headaches with associated hearing loss and C6-8 nerve root distribution weakness. CSF opening pressure was less than 5cmH(2)O and showed no abnormalities in white blood cell count. Cranial, cervical, and thoracic magnetic resonance imaging revealed epidural and subdural collections of CSF with associated meningeal enhancement. Repeated computed tomography myelograms localized the leak to multiple levels of the lower cervical and upper thoracic spine. A conservative management approach of bedrest and increased caffeine intake had no effect on the dural tear. The headache, hearing loss, and arm symptoms resolved completely after 2 epidural blood patches were performed. Practitioners performing manual therapy should be aware of this rare, yet potential complication of spinal mobilizations and manipulations.


Pontine and non-pontine pathways mediating early mossy fiber responses from sensorimotor cortex to cerebellum in the cat.
Stimulation of the cat's sensorimotor cortex evokes a short-latency mossy fiber field potential (N2) in the pars intermedia of the cerebellum. The fraction of the response carried by each of the six cerebellar peduncles was determined by comparing the field potentials before and after electrolytic lesions of individual cerebellar peduncles. The response evoked from the contralateral cerebrum is 3.5 times as large as that evoked from ipsilateral cerebrum. The size of the N2 wave from contralateral cerebral cortex is reduced to about half of the original size after electrolytic lesion of either the brachium pontis (BP) or the restiform body (RB) ipsilateral to the recording site, while only a small reduction in the size of N2 is observed after lesions of contralateral BP and RB. This indicates that inputs responsible for the generation of the N2 wave from contralateral cerebral cortex enter the cerebellum primarily through ipsilateral BP and RB. In contrast, the N2 wave from ipsilateral cerebral cortex is reduced by approximately one quarter following lesions of any one of the four RB's and BP's. Fibers in the brachium conjunctivum do not contribute to these responses. Observation on the P2 field potential, representing postsynaptic firing of granule cells, suggest that the cerebro-ponto-cerebellar and cerebro-reticulo-cerebellar mossy fiber pathways converge onto granule cells. Furthermore, these two inputs must arrive within 3 ms of each other in order to activate the granule cells. In addition, it is shown that BP lesions reducing the mossy fiber input lead to an increase in the climbing fiber input.


Unbending the Light: Changing Laws and Policies to Make Transgender Health Visible; Reflections of an Advocate.
This essay describes an instrumental advocate's development, engagement, and accomplishments in transgender health at the intersection of law and medicine. Reflecting on the evolution of insurance policy reforms in conjunction with the need to increase the availability of clinicians who can understand and respectfully treat transgender patients, the author demonstrates how visibility, tenacity, and ingenuity can create far-reaching change.


Pig heart and lung xenotransplantation: Present status.
The recent pig heart transplant in a patient at the University of Maryland Medical Center has stimulated renewed interest in the xenotransplantation of organs from genetically engineered pigs. The barriers to the use of pigs as sources of organs have largely been overcome by 2 approaches - (1) the deletion of expression of the three known pig carbohydrate xenoantigens against which humans have preformed antibodies, and (2) the transgenic introduction of human 'protective' proteins, such as complement-regulatory proteins. These gene modifications, coupled with immunosuppressive therapy based on blockade of the CD40/CD154 costimulation pathway, have resulted in survival of baboons with life-supporting pig heart grafts for almost 9 months. The initial clinical success at the University of Maryland reinforces encouraging preclinical results. It suggests that pig hearts are likely to provide an effective bridge to an allotransplant, but their utility for destination therapy remains uncertain. Because of additional complex immunobiological problems, the same approach has been less successful in preclinical lung xenograft transplantation, where survival is still measured in days or weeks. The first formal clinical trials of pig heart transplantation may include patients who do not have access to an allotransplant, those with contraindications for mechanical circulatory support, those in need of retransplantation or with a high level of panel-reactive antibodies. Infants with complex congenital heart disease, should also be considered.


Cerebrospinal fluid total protein in Guillain-Barré syndrome variants: correlations with clinical category, severity, and electrophysiology.
The discriminative value of CSF total protein (CSF-TP) in subtypes of Guillain-Barré syndrome has not been well documented in North-American patients. We reviewed 173 cases from a single institution, comprising the following clinical categories of neuropathy: 134 Sensorimotor (SM) GBS, 13 Motor (M) GBS, 8 Localized (L) GBS, and 18 Miller Fisher syndrome (MFS). We grouped the electrophysiological interpretation in primarily demyelinating, primarily axonal and normal / equivocal categories. Mean CSF-TP were substantially higher for SM and L-GBS, as well as cases classified as Acute-onset chronic inflammatory demyelinating polyneuropathy. They were lower for M-GBS and L-GBS. The most statistically significant correlation was found for elevated CSF-TP in GBS cases showing an electrophysiologic pattern classified as demyelinating (1.56 g/L) compared with axonal (0.68 g/L) or normal/ equivocal patterns (0.65 g/L). There was a correlation between CSF-TP and time interval between symptom onset and lumbar puncture. There was a weak correlation between CSF-TP and maximal overall-clinical severity grade, which was likely mostly determined by the electorphysiological pattern. Though CSF-TP is a sensitive test for GBS in the second week after onset, it may not be a reliable predictor of clinical severity. There is a robust association of CSF-TP elevation and a demyelinative electrophysiologic pattern and a suggestion that lower mean CSF-TP values can be expected in GBS-spectrum disorders thought to represent nodo-paranodopathies.


Rectal contrast increases rectal dose during vaginal cuff brachytherapy.
To evaluate the impact of rectal dose on rectal contrast use during vaginal cuff brachytherapy (VCB). A retrospective review of gynecology patients who received some brachytherapy fractions with and without rectal contrast was carried out. Rectal contrast was instilled at the clinician's discretion to increase rectal visibility. Thirty-six pairs of CT scans in preparation for brachytherapy were analyzed. Pairs of CTs were segmented and planned using the same parameters. The rectum was always defined from 1 cm above the cylinder tip up to 1.5 cm below the last activated dwell source position. An individual plan was computed at every VCB fraction. A set of values (Dmax, D(0.1cc), D(1cc), and D(2cc)) derived from dose-volume histograms were extracted and compared according to the rectal status. Rectal volume was 26.7% larger in the fractions with rectal contrast. Such an increase in volume represented a significant increase from 7.7% to 10.4% in all parameters analyzed except Dmax dose-volume histogram. Avoiding rectal contrast is a simple way of decreasing the rectal dose parameters of VCB, which would mean a better therapeutic ratio. Results also suggest that action directed at maintaining the rectum empty might have the same effect.


Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma.
The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1). Our data also demonstrate that curcumin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for curcumin, acting as a suppressor of JAK-1 and STAT3 activation in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. Therefore, curcumin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of STAT3.


Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury.
Glutamine (Gln) is the most widely acting and abundant amino acid in the body and has anti-inflammatory properties, regulates body metabolism, and improves immune function. However, the mechanism of Gln's effect on hyperoxic lung injury in neonatal rats is unclear. Therefore, this work focused on examining Gln's function in lung injury of newborn rats mediated by hyperoxia and the underlying mechanism. We examined body mass and ratio of wet-to-dry lung tissue weights of neonatal rats. Hematoxylin and eosin (HE) staining was performed to examine histopathological alterations of lung tissues. In addition, enzyme-linked immunoassay (ELISA) was conducted to measure pro-inflammatory cytokine levels within bronchoalveolar lavage fluid (BALF). Apoptosis of lung tissues was observed using TUNEL assay. Western blotting was performed for detecting endoplasmic reticulum stress (ERS)-associated protein levels. The results showed that Gln promoted body weight gain, significantly reduced pathological damage and oxidative stress in lung tissue, and improved lung function in neonatal rats. Gln reduced pro-inflammatory cytokine release as well as inflammatory cell production in BALF and inhibited apoptosis in lung tissue cells. Furthermore, we found that Gln could downregulate ERS-associated protein levels (GRP78, Caspase-12, CHOP) and inhibit c-Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) phosphorylation. These results in an animal model of bronchopulmonary dysplasia (BPD) suggest that Gln may have a therapeutic effect on BPD by reducing lung inflammation, oxidative stress, and apoptosis and improving lung function; its mechanism of action may be related to the inhibition of the IRE1α/JNK pathway.


Long-term outcomes in patients with PET-predicted poor-responsive HER2-positive breast cancer treated with neoadjuvant bevacizumab added to trastuzumab and docetaxel: 5-year follow-up of the randomised Avataxher study.
The open-label, randomised Phase 2 AVATAXHER study (NCT01142778) demonstrated that early PET assessment identified HER2-positive breast cancer patients who responded poorly to neoadjuvant docetaxel plus trastuzumab. Adding neoadjuvant bevacizumab for PET-predicted poor-responders improved pathological complete response (pCR) rates (43.8% vs 24.0%). We investigated long-term study outcomes. Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with ≥70% change in the maximum standardised uptake value (∆SUVmax) received four further cycles of standard neoadjuvant therapy (PET responders). PET-predicted poor-responders (∆SUVmax <70%) were randomised (2:1) to neoadjuvant therapy with (Group A) or without (Group B) bevacizumab for cycles 3-6. All patients received one further cycle of trastuzumab before surgery plus adjuvant trastuzumab (11 cycles). 142 patients were randomized and treated (PET responders, n = 69; Group A, n = 48; Group B, n = 25). 5-year disease-free survival rates were 90.5% (95% CI: 80.0-95.6%) in PET responders, 90.2% (95% CI: 75.9-96.2%) in Group A, and 76.0% (95% CI: 54.2-88.4%) in Group B. However, no difference was observed between randomised arms in a sensitivity analysis. During adjuvant therapy, the incidence of Grade ≥3 (Group A: 25.6%; Group B 12.5%) and serious adverse events (Group A: 18.6%; Group B 12.5%) was higher in Group A vs Group B, but with no apparent effect on cardiac events. In patients with HER2-positive breast cancer, an intervention based on early PET assessment and improvement of pCR does not modify disease-free survival. Roche France.


Risk of Subsequent Infection Among Patients Receiving Tumor Necrosis Factor Inhibitors and Other Disease-Modifying Antirheumatic Drugs.
To describe the incidence of subsequent serious infections in patients who received systemic drug therapy after an initial serious infection. Patients with rheumatic conditions (rheumatoid arthritis [RA], psoriatic arthritis, ankylosing spondylitis) or psoriasis who experienced a serious infection between January 1, 2006 and December 31, 2011 were identified in a claims database. Patients were required to be continuously enrolled in the Truven Health Analytics MarketScan Research Database for 12 months prior to and at least 60 days after the date of discharge or the end of intravenous antibiotic therapy for the index serious infection. Subsequent serious infection incidence rates per 100 patient-years with 95% confidence intervals (95% CIs) were calculated for up to 18 months post-index, starting 60 days post-index. Cox proportional hazards models were used to adjust for baseline demographic and clinical characteristics, treatment duration, and changes during followup. Among the 21,699 patients who met the inclusion criteria, the majority (84.3%) had RA. Patients who received tumor necrosis factor (TNF) inhibitor therapy after their index infection had a lower rate of subsequent serious infections (18.1 per 100 patient-years for those treated with a TNF inhibitor alone and 17.3 per 100 patient-years for those treated with a TNF inhibitor plus a nonbiologic disease-modifying antirheumatic drug [DMARD]) compared with those treated with a nonbiologic DMARD alone (21.4 per 100 patient-years). Etanercept, either alone (adjusted hazard ratio [HR] 0.87, 95% CI 0.77-0.99) or in combination with a nonbiologic DMARD (adjusted HR 0.76, 95% CI 0.66-0.88), and infliximab (only in combination with a nonbiologic DMARD) (adjusted HR 0.80, 95% CI 0.67-0.95) were associated with a significantly lower risk of subsequent serious infections compared with a nonbiologic DMARD alone. We did not observe an increased risk of subsequent infection in patients who received TNF inhibitor treatment following a serious infection. The risk of a subsequent serious infection was lower in patients treated with both a TNF inhibitor and a nonbiologic DMARD compared with that in patients treated with a nonbiologic DMARD alone.


Negative life events, emotions and psychological difficulties as determinants of salivary cortisol in Belgian primary school children.
This paper describes whether children's life events, emotions and psychological difficulties are related to their salivary cortisol patterns and whether this is different between sexes. In 385 children (5-10 years old) participating in the ChiBS study, salivary cortisol samples were collected when waking up, 30 min and 60 min after wake up and in the evening on two consecutive weekdays. Moreover, data on children's life events, emotions and difficulties were collected. Statistical analysis was done separately for boys and girls by multilevel growth curve modelling with adjustments for age, body mass index, socio-economic status and wake up time. In boys and girls with more negative life events during the last three months, the diurnal cortisol slope was steeper (more decline). Boys with higher self-reported happiness showed lower overall, morning and evening cortisol levels. In contrast, the diurnal slope was steeper (more decline) in boys with emotional problems due to higher morning values. In girls, peer problems were associated with lower overall and morning cortisol levels. Children's salivary cortisol patterns were related to some negative life events, emotions and difficulties, although differently in boys and girls. As such, sex-differences in HPA functioning are already present in young children. Most findings support the upregulation of the cortisol response to stress, although lower morning values were found in the presence of peer problems in girls. Future studies should focus on sex differences, positive emotions and the diurnal cortisol slope.


Pangolin-inspired untethered magnetic robot for on-demand biomedical heating applications.
Untethered magnetic miniature soft robots capable of accessing hard-to-reach regions can enable safe, disruptive, and minimally invasive medical procedures. However, the soft body limits the integration of non-magnetic external stimuli sources on the robot, thereby restricting the functionalities of such robots. One such functionality is localised heat generation, which requires solid metallic materials for increased efficiency. Yet, using these materials compromises the compliance and safety of using soft robots. To overcome these competing requirements, we propose a pangolin-inspired bi-layered soft robot design. We show that the reported design achieves heating > 70 °C at large distances > 5 cm within a short period of time <30 s, allowing users to realise on-demand localised heating in tandem with shape-morphing capabilities. We demonstrate advanced robotic functionalities, such as selective cargo release, in situ demagnetisation, hyperthermia and mitigation of bleeding, on tissue phantoms and ex vivo tissues.


Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disease caused by alterations in the NOTCH3 gene. We describe the clinical, instrumental, and genetic findings in CADASIL patients who carry novel NOTCH3 gene mutations. This study broadens the spectrum of clinical manifestations and genetic alterations associated with this disease.


Endocytic and autophagic pathways crosstalk in plants.
The vacuole is the central site for both storage and metabolism in plant cells and mediates multiple cellular events during plant development and growth. Cargo proteins are usually sequestered into membrane-bound organelles and delivered into the vacuole upon membrane fusion. Two major organelles are responsible for the recognition and transport of cargos targeted to the vacuole: the single-membrane multivesicular body (MVB) or prevacuolar compartment (PVC) and the double-membrane autophagosome. Here, we will highlight recent discoveries about MVB/PVC-mediated and autophagosome-mediated protein trafficking and degradation, and will pay special attention to a possible interplay between the endocytic and autophagic pathways in regulating vacuolar degradation in plants.