Effects of an increased habitual dietary protein intake followed by resistance training on fitness, muscle quality and body composition of seniors: A randomised controlled trial.
Resistance training and a sufficient amount of dietary protein have been suggested to build up and maintain muscle mass, strength and function into old age. As there is still no consensus on the optimum amount of protein intake in older people, this study aims to evaluate first whether it is achievable to double the recommended amount, which is 1 g/kg BW/d in German speaking countries, via food administration and secondly whether this would lead to stronger improvements when subsequently combined with resistance training. In total, 136 community-dwelling older adults (54% females, 72.9 ± 4.8 yrs) were randomly assigned to one of the three study groups: observational control (CON), recommended protein (RP + T) and high protein (HP + T) intake groups. After six weeks of observation or nutritional counselling to achieve the respective protein target levels, eight weeks of resistance training (2x/week) were applied in RP + T and HP + T groups. Parameters indicative for muscle mass, strength and function were measured at baseline (t1), before (t2) and after the training period (t3). Baseline protein intake for the different groups were 0.83 (CON), 0.97 (RP + T) and 0.78 (HP + T) g/kg BW/d and increased by 0.18 ± 0.31 (RP + T, p = 0.003) and 0.83 ± 0.33 (HP + T, p > 0.001) g/kg BW/d between t1 and t3 while CON remained unchanged. Most of the physical performance parameters improved over time, but no interaction effects between group and time could be observed. While body fat mass initially increased from t1 to t2 (0.8 ± 2.3 kg, p = 0.001), skeletal muscle mass decreased (-0.5 ± 1.9 kg, p = 0.025), a trend which was reversed from t2 to t3 only in HP + T group (body fat mass: -0.47 ± 2.12 kg, p = 0.041; muscle mass: 0.51 ± 1.57 kg, p = 0.021). The findings suggest that a substantial increase of habitual protein intake above the currently recommended levels is achievable within 17 weeks in community-dwelling older adults, whereby the extra amount of protein led to minor changes in body composition but not physical performance or muscle quality (NCT04023513).


A factor IX gene probe: its use in carrier detection, antenatal diagnosis and characterisation of the molecular basis for hemophilia B.
Of hemophilia B carriers, 67% were shown to have informative restriction fragment length polymorphisms (Taq I or Xmn I) associated with the factor IX gene. Analysis of DNA for these polymorphisms can enable the detection of the hemophilia B carrier state in females and of hemophilia B in the male fetus in the first trimester. Extensive mapping of the factor IX gene in one hemophiliac who developed antibodies to factor IX failed to detect structural abnormalities in his gene. A non-deletional basis for hemophilia B is proposed in this instance.


Tacrolimus and Mycophenolic Acid Blood Concentration and Cellular Rejection After Heart Transplantation in First Endomyocardial Biopsy.
Tacrolimus and mycophenolic acid (MPA) are the most important immunosuppressive drugs in modern heart transplantation. The pharmacokinetics of tacrolimus are best described by a 2-compartment model. MPA has very variable pharmacokinetics. The aim of this research was to compare kinetics of the immunosuppressants' blood levels in a group of patients with and without graft rejection. The study was a retrospective analysis of 39 consecutive adult orthotopic heart transplantations (OHT): 10 (9 men and 1 woman) in group R had graft rejection (ISHLT >2) in the first biopsy and 29 (22 men and 7 women) in group C were without rejection. Ischemic cardiomyopathy occurred in 2 of 7 and nonischemic cardiomyopathy in 8 of 22 (group R and group C, respectively). Patients did not differ between groups except diabetes, which occurred more often in group R. Immunosuppressive drug levels were: group R and group C, respectively, 2.13 ± 0.49 and 2.11 ± 0.72 μg/mL; P = .93 for mycophenolate mofetil (MMF) and 9.42 ± 1.76 and 9.63 ± 2.30 ng/mL; P = .75 for tacrolimus. ICU stay was 14 ± 11 vs 15 ± 15 days; P = .76. There were 2 of 6 primary graft failures, 1 of 1 neurologic complications, and 0 of 6 reoperations (P < .05) in group R and group C, respectively. One patient died from group C in 30 days. During the hospital stay the incidence of graft rejection was diagnosed in 20 patients (16men and 4 women) (ISHLT >2 in endomyocardial biopsy) in the study population. Monitoring of tacrolimus concentration in the early post--heart transplant period does not identify patients with rejection in the authors' study. Monitoring concentration of MMF does not identify patients with rejection. Further investigation is needed to evaluate factors responsible for post--heart transplant rejection in the early phase.


Mitogenic stimulation transiently increases the exchangeable mitochondrial calcium pool in rat thymocytes.
Exchangeable calcium pools were measured in rat thymocytes by 45Ca labelling and selective depletion of intracellular pools with oligomycin in the presence or absence of rotenone. The mitochondrial pool increased by 150% after 3 min of treatment with the mitogen concanavalin A, and decreased to zero 10 min after mitogen addition. No significant change in the ATP-dependent pool could be detected.


Converting soy protein isolate into biomass-based polymer electrolyte by grafting modification for high-performance supercapacitors.
Soy protein isolate (SPI) is one of the most abundant plant proteins in nature. Enormous studies have been carried out on SPI-based materials, however, the application for energy storage devices is still limited due to its fiddly film forming process and lack of electrochemical performance. Herein, we presented a SPI-based polymer electrolyte by grafting modification with the hydrophilic functional monomer acrylamide (AM). The optimized gel polymer electrolyte (GPE) exhibited an excellent ionic conductivity up to 5.10 mS cm-1, which was greatly higher than gel polymer electrolyte based on original pure SPI (1.84 mS cm-1). More significantly, supercapacitors constructed by grafting-modified SPI delivered a specific capacitance of 141.74 F g-1 at 1.0 A g-1 and exhibited high capacitance retention of 95% after 8000 charge-discharge cycles. Beyond that, redox-active polymer electrolyte based on grafting-modified SPI combining with KI enormously improved the energy density of supercapacitor up to 27.52 Wh kg-1 at a current density of 0.5 A g-1. This work provided a novel and facile strategy to obtain a high-performance SPI-based polymer electrolyte and laid an experimental foundation for the high-value application of SPI in the field of energy storage devices.


Primary hepatic pregnancy. Case report.
A case of primary hepatic pregnancy presenting as a lithopedion in the right hypochondrium is presented. The lithopedion was removed and the patient recovered uneventfully. The diagnosis of primary hepatic pregnancy is briefly discussed.


Brainstem auditory evoked potentials following meningitis in children.
The report concerns findings for brainstem auditory evoked potentials (BAEPs) recorded in 116 children, aged between a few days and 7 years, having suffered from bacterial meningitis. 26% of cases occurred between birth and 6 months, 55% between 6 months and 2 years, and 19% after 2 years of age. Hemophilus was the most common bacteria (49%), followed by Pneumococcus (22%) and Meningococcus (15%). Neurological complications were found in 30% of the meningitis cases and accounted for 85% of all complications found. 29% of BAEPs were abnormal, of which 47% revealed transmission, 32% endocochlear and 21% retrocochlear impairment. Transmission impairment mainly occurred before the age of 2 years (88%), most frequently in meningococcus meningitis cases (44%), and independently of neurological complications. Retrocochlear impairment was found in association with neurological complications in 71% of cases. Endocochlear BAEP damage was found in 9.5% of cases, half of which were bilateral and total, representing cophosis: it was found at all ages, and without any particular associated neurological complication. Hemophilus was the commonest bacterial agent in endocochlear cases overall, with Pneumococcus underlying 50% of cophosis cases. The study shows BAEP recording in association with a clinical ear examination is useful following childhood bacterial meningitis, screening for definitive endocochlear and deafness, distinguishing total from partial hearing-loss and indicating suitable treatment.


Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks.
Orexins (hypocretins) are peptides that have been shown to regulate behavioral arousal and wakefulness. Recent evidence indicates that orexin neurons are activated by stress and that orexins play a role in anxiety. The present paper describes a series of experiments that examined whether orexins are involved in the anxiety that resulted from exposing rats to an acute episode of footshocks (5 × 2 s of 1.5 mA shocks). We found that prepro-orexin (ppOX) mRNA was elevated in rats at 6 and 14 days after exposure to footshock and that ppOX mRNA levels were correlated with fear at 14 days post-shock. Systemic injections of the non-selective dual orexin receptor antagonist TCS-1102 (10 and 20 mg/kg, i.p.) were found to decrease fear and anxiety in rats 14 days after exposure to footshock. We also found that rats that exhibited a high level of immobility to a novel tone the day after the footshock episode (high responders, HR) showed significantly elevated levels of ppOX mRNA at 14 days post-shock compared to control rats. Furthermore, TCS-1102 (10 mg/kg, i.p.) was found to have anxiolytic effects that were specific for HR when tested in the elevated T-maze. This study provides evidence linking the orexin system to the anxiety produced by exposure of rats to a single episode of footshocks. It also provides preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in response to an acute episode of stress.


Long-term follow-up after repair of Ebstein's anomaly.
We studied the long-term results of vertical plication repair of Ebstein's anomaly according to Carpentier. Between 1988 and 2007, 28 patients (mean age 28.8+/-15.7 years, range 4-58 years) underwent vertical plication repair of Ebstein's anomaly. At operation the anomaly was classified according to Carpentier. In three patients (11%) a cavopulmonary shunt was added at the repair on the indication of impaired right ventricular function. There was no operative mortality. Early mortality was 3.6% (one patient). Actuarial survival and actuarial freedom from reoperation at 19 years were 96% (95% CI; 96-97%) and 72% (95% CI; 53-92%), respectively. Six patients required reoperation, with a successful re-repair in three patients. Mean duration of follow-up was 10.7+/-6.5 years. One year postoperatively, tricuspid incompetence had decreased significantly (p<0.001), as had New York Heart Association (NYHA) functional class (p<0.001). In addition, exercise tolerance had increased (70+/-19% to 92+/-9% of predicted values, p<0.05). Both tricuspid function and NYHA functional class remained essentially unchanged at the end of follow-up, indicating durable haemodynamic and functional results. This study demonstrates favourable long-term results following vertical plication repair of Ebstein's anomaly with low mortality, acceptable morbidity and good haemodynamic and functional results.


Olivocerebellar projections in control and staggerer mutant mice. An autoradiographic study.
Olivocerebellar projections were studied in normal and in staggerer mutant mice by means of autoradiographic methods following [3H]leucine injections in the inferior olivary complex. In normal mice, a sagittal banding pattern of labeled climbing fibers was apparent in the contralateral cerebellar cortex, thus confirming previous observations in rodents. In staggerer mice, olivocerebellar projections also displayed a clear sagittal zonation, thus indicating that this organization may be achieved in the mutant, in spite of pronounced abnormalities of the cerebellar cortex.


Clinical decision support with automated text processing for cervical cancer screening.
To develop a computerized clinical decision support system (CDSS) for cervical cancer screening that can interpret free-text Papanicolaou (Pap) reports. The CDSS was constituted by two rulebases: the free-text rulebase for interpreting Pap reports and a guideline rulebase. The free-text rulebase was developed by analyzing a corpus of 49 293 Pap reports. The guideline rulebase was constructed using national cervical cancer screening guidelines. The CDSS accesses the electronic medical record (EMR) system to generate patient-specific recommendations. For evaluation, the screening recommendations made by the CDSS for 74 patients were reviewed by a physician. Evaluation revealed that the CDSS outputs the optimal screening recommendations for 73 out of 74 test patients and it identified two cases for gynecology referral that were missed by the physician. The CDSS aided the physician to amend recommendations in six cases. The failure case was because human papillomavirus (HPV) testing was sometimes performed separately from the Pap test and these results were reported by a laboratory system that was not queried by the CDSS. Subsequently, the CDSS was upgraded to look up the HPV results missed earlier and it generated the optimal recommendations for all 74 test cases. Single institution and single expert study. An accurate CDSS system could be constructed for cervical cancer screening given the standardized reporting of Pap tests and the availability of explicit guidelines. Overall, the study demonstrates that free text in the EMR can be effectively utilized through natural language processing to develop clinical decision support tools.


Ginsenosides Rb3 and Rd reduce polyps formation while reinstate the dysbiotic gut microbiota and the intestinal microenvironment in ApcMin/+ mice.
Studies showed that manipulation of gut microbiota (GM) composition through the treatment of prebiotics could be a novel preventive measure against colorectal cancer (CRC) development. In this study, for the first time, we assessed the non-toxic doses of the triterpene saponins (ginsenoside-Rb3 and ginsenoside-Rd) - as prebiotics - that effectively reinstated the dysbiotic-gut microbial composition and intestinal microenvironment in an ApcMin/+ mice model. Rb3 and Rd effectively reduced the size and the number of the polyps that accompanied with the downregulation of oncogenic signaling molecules (iNOS, STAT3/pSTAT3, Src/pSrc). Both the compounds improved the gut epithelium by promoting goblet and Paneth cells population and reinstating the E-cadherin and N-Cadherin expression. Mucosal immunity remodeled with increased in anti-inflammatory cytokines and reduced in pro-inflammatory cytokines in treated mice. All these changes were correlating with the promoted growth of beneficial bacteria such as Bifidobacterium spp., Lactobacillus spp., Bacteroides acidifaciens, and Bacteroides xylanisolvens. Whereas, the abundance of cancer cachexia associated bacteria, such as Dysgonomonas spp. and Helicobacter spp., was profoundly lower in Rb3/Rd-treated mice. In conclusion, ginsenosides Rb3 and Rd exerted anti-cancer effects by holistically reinstating mucosal architecture, improving mucosal immunity, promoting beneficial bacteria, and down-regulating cancer-cachexia associated bacteria.


Quantitative end-tidal carbon dioxide monitoring in the delivery room: a randomized controlled trial.
To investigate the utility of continuous quantitative end-tidal CO2 (Etco2) monitoring for managing assisted ventilation in the delivery room (DR). This is a prospective randomized controlled trial. Infants who received positive pressure ventilation (PPV) were randomized to a control versus a monitored arm. In the monitored arm, the resuscitating team adjusted PPV based on Etco2 values. In the control arm, the team provided PPV based on clinical assessment. Etco2 levels after resuscitation and admission Pco2 levels were compared between groups. Fifty infants were enrolled, and 48 subjects had primary outcome data. Of those, 7 infants were intubated in the DR, 41 infants received PPV via mask until respiratory support could be maintained on continuous positive airway pressure alone. The median Etco2 levels at the end of resuscitation were 44 mm Hg (16-66 mm Hg) in the control arm and 43 mm Hg (29-59 mm Hg) in the monitored arm. The proportion of Etco2 levels outside of the prespecified range was 52.6% (control) and 33.3% (monitored) (P = .236). The median admission Pco2 levels were 57 mm Hg (36-110 mm Hg) in the control arm and 55 mm Hg (40-93 mm Hg) in the monitored arm. The proportion of admission Pco2 levels outside of the prespecified range was 33.3% (control) versus 37.5% (monitored) (P = .763). Etco2 monitoring in the DR did not reduce the proportion of admission Pco2 levels outside of the prespecified range in a population of infants supported mostly with noninvasive ventilation.


Stability indicating LC method for the determination of pipamperone.
A high performance liquid chromatographic method for the determination of pipamperone in the presence of one related impurity and its degradation products is described. The method is based on the use of an amide functionalized bonded phase column (LC-ABZ+ Plus) and a mobile phase of acetonitrile-tetrahydrofuran-sodium phosphate monobasic (0.05 M, pH 6.5) (16:11:73, v/v/v). All peaks are eluted in <8 min. The method was demonstrated to be precise, accurate and specific. Degradation study showed that the drug is stable in acidic medium while it degrades under basic and oxidative conditions. The results indicated that the proposed method could be used in a stability assay.


A novel assay revealed that ribonucleotide reductase is functionally important for interstrand DNA crosslink repair.
Cells have evolved complex biochemical pathways for DNA interstrand crosslink (ICL) removal. Despite the chemotherapeutic importance of ICL repair, there have been few attempts to identify which mechanistic DNA repair inhibitor actually inhibits ICL repair. To identify such compounds, a new and robust ICL repair assay was developed using a novel plasmid that contains synthetic ICLs between a CMV promoter region that drives transcription and a luciferase reporter gene, and an SV40 origin of replication and the large T antigen (LgT) gene that enables self-replication in mammalian cells. In a screen against compounds that are classified as inhibitors of DNA repair or synthesis, the reporter generation was exquisitely sensitive to ribonucleotide reductase (RNR) inhibitors such as gemcitabine and clofarabine, but not to inhibitors of PARP, ATR, ATM, Chk1, and others. The effect was observed also by siRNA downregulation of RNR. Moreover, the reporter generation was also particularly sensitive to 3-AP, a non-nucleoside RNR inhibitor, but not significantly sensitive to DNA replication stressors, suggesting that the involvement of RNR in ICL repair is independent of incorporation of a nucleotide RNR inhibitor into DNA to induce replication stress. The reporter generation from a modified version of the plasmid that lacks the LgT-SV40ori motif was also adversely affected by RNR inhibitors, further indicating a role for RNR in ICL repair that is independent of DNA replication. Intriguingly, unhooking of cisplatin-ICL from nuclear DNA was significantly inhibited by low doses of gemcitabine, suggesting an unidentified functional role for RNR in the process of ICL unhooking. The assay approach could identify other molecules essential for ICLR in quantitative and flexible manner.


Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model.
The heterogeneity of liver cancer, in particular hepatocellular carcinoma (HCC), portrays the requirement of multiple targets for both its treatment and prevention. Multifaceted agents, minimally or non-toxic for normal hepatocytes, are required to address the molecular diversity of HCC, including the resistance of putative liver cancer stem cells to chemotherapy. We designed and synthesized two fatty acid ethers of isopropylamino propanol, C16:0-AIP-1 and C18:1-AIP-2 (jointly named AIPs), and evaluated their anti-proliferative effects on the human HCC cell line Huh7 and the murine hepatoma cell line BNL 1MEA.7R.1, both in vitro and in an in vivo allograft mouse model. We found that AIP-1 and AIP-2 inhibited proliferation and caused cell death in both Huh7 and BNL 1MEA.7R.1 cells. Importantly, AIP-1 and AIP-2 were found to block the activation of putative liver cancer stem cells as manifested by suppression of clonal 'carcinosphere' development in growth factor-free and anchorage-free medium. The AIPs exhibited a relatively low toxicity against normal human or rat hepatocytes in primary cultures. In addition, we found that the AIPs utilized multifaceted pathways that mediate both autophagy and apoptosis in HCC, including the inhibition of AKTs and CAMK-1. In immune-competent mice, the AIPs significantly reduced BNL 1MEA.7R.1 cell-driven tumor allograft development, with a higher efficiency than sorafenib. A combination of AIP-1 + AIP-2 was most effective in reducing the tumor allograft incidence. AIPs represent a novel class of simple fatty acid derivatives that are effective against liver tumors via diverse pathways. They show a low toxicity towards normal hepatocytes. The addition of AIPs may represent a new avenue towards the management of chronic liver injury and, ultimately, the prevention and treatment of HCC.


Diabetes and outcomes after left ventricular assist device placement.
Patients with diabetes have poorer outcomes after surgery in general. In this study, we assess the impact of diabetes on outcomes after left ventricular assist devices (LVAD) placement. Data on 222 patients (57 diabetics) who underwent Novacor LVAD placement between 1996 and 2003 were compared for outcomes among patients who did and did not have diabetes. Significant differences between the diabetics versus nondiabetics included age (56 +/- 8 versus 49 +/- 1 years, P < .01), ischemic heart failure etiology (61% versus 44%, P = .04), history of hypertension (56% versus 30%, P < .01), thoracotomy (42% versus 30%, P = .08), stroke (14% versus 5%, P = .03), and body weight (86 +/- 16 kg versus 80 +/- 17 kg, P = .03), respectively. Eighty-four patients died on LVAD support, 28 of whom were diabetic. Thirty, 180, and 365-day survival for diabetic versus nondiabetic patients was: 76.6%, 45.6%, and 30.4% for diabetics and 86.7%, 62.4%, and 47.1% for nondiabetics (P = .02 for 180 and 365-day morality). After controlling for other variables, patients with diabetes were at a higher risk of mortality (OR 1.76, 95%CI 1.05-2.94). No significant difference in survival was noted between insulin-dependent versus non-insulin-dependent diabetics. Patients with diabetes are at a higher risk of mortality after LVAD implantation.


Adsorbed hollow fiber immobilized tyrosinase for the screening of enzyme inhibitors from Pueraria lobata extract.
In this study, a method based on adsorbed hollow fiber immobilized tyrosinase (TYR) was developed to screening potential TYR inhibitors from Pueraria lobate extract. Kojic acid and ranitidine were used as positive and negative control to verify the reliability of the proposed method, respectively. Several significant parameters of the screening process, including the amount of P. lobata extract, adsorption time and incubation time, were optimized. After investigating the repeatability of the developed method, seven potential active compounds in P. lobata extract were successfully detected and their chemical structures were tentatively identified by liquid chromatography - mass spectrometry analysis. Furthermore, the inhibitory activity of four identified compounds on TYR was tested in vitro, and three of them, namely, puerarin, puerarin-6″-O-xyloside and puerarin apioside were verified to have good TYR inhibitory activity with IC50 value of 478.5, 513.8, and 877.3 μM, respectively. In addition, the molecular docking results indicated that these compounds could bind to the amino acid residues in TYR catalytic pocket. These results proved that the proposed method is a feasible approach for screening of TYR inhibitors from plant extract.


[Identification and assay of nonvolatile organic by capillary column gas chromatography].
The assay of organic acids as trimethyl silyl isobutyl compounds by gas chromatography was described. The lyophilization was used instead the extraction by organic reagent of the classical methods. Our method avoids the loss of some hydroxylacids. The identification and the measurement of one organic acid need respectively 3 and 5 hours. Our method is currently used for the metabolic diseases diagnosis.


Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity.
Estrogen receptors (ERs) stimulate genomic effects by acting as nuclear transcription factors as well as non-genomic effects by activating distinct cytoplasmic protein kinase cascades. Non-genomic effects have been implicated in numerous cellular processes, such as proliferation, differentiation, apoptosis and vasorelaxation. To exploit non-genomic effects mediated by ERalpha for novel hormone replacement regimens, we screened a focused library of steroid receptor ligands to identify compounds exhibiting properties different from estradiol, i.e. substances that selectively stimulate non-genomic signal transduction pathways while exhibiting low genomic activities. Treatment of breast cancer cells and osteosarcoma cells with estradiol, estren, substance A and substance B led to non-genomic activation of Akt (protein kinase B) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascades mediated by Src (Rous Sarcoma Virus, non-receptor tyrosine kinase) and phosphatidylinositol-3-kinase (PI3K) stimulation. Such compounds leading to prominent Akt/ERK activation but exhibiting only weak genomic properties were applied in vasorelaxation assays, modeling physiological non-genomic ER responses. As expected from PI3K and Src activation data, substances were as effective as estradiol in mediating vasorelaxation. We assume that these pathway-selective estrogen receptor ligands may serve as potent lead structures for novel hormone replacement strategies exhibiting lesser side effects than the existing treatment paradigms.


Detection of protein-protein interactions by a combination of a novel cytoplasmic membrane targeting system of recombinant proteins and fluorescence resonance energy transfer.
A novel protein molecular targeting system was created using a cytoplasmic face of a plasma membrane-targeting system in Saccharomyces cerevisiae. The technique involves a molecular display for the creation of a novel reaction site and interaction sites in the field of biotechnology. In a model system, a fluorescent protein was targeted as a reporter to the cytoplasmic face of the plasma membrane. The C-terminal transmembrane domain (CTM) of Ras2p and Snc2p was examined as the portions with anchoring ability to the cytoplasmic face of the plasma membrane. We found that the CTM of Snc2p targeted the enhanced cyan fluorescent protein (ECFP)-protein A fusion protein on the cytoplasmic face of the plasma membrane more strongly than that of Ras2p. To develop it for use as a detection system for protein-protein interactions, the Fc fragment of IgG (Fc) was genetically fused with the enhanced yellow fluorescent protein (EYFP) and expressed in the cytoplasm of the ECFP-protein A-anchored cell. A microscopic analysis showed that fluorescence resonance energy transfer (FRET) between ECFP-protein A and EYFP-Fc occurred, and the change in fluorescence was observed on the cytoplasmic face of the plasma membrane. The detection of protein-protein interactions at the cytoplasmic face of a plasma membrane using FRET combined with a cytoplasmic face-targeting system for proteins provides a novel method for examining the molecular interactions of cytoplasmic proteins, in addition to conventional methods, such as the two-hybrid method in the nuclei.


Predicting the frequencies of drug side effects.
A central issue in drug risk-benefit assessment is identifying frequencies of side effects in humans. Currently, frequencies are experimentally determined in randomised controlled clinical trials. We present a machine learning framework for computationally predicting frequencies of drug side effects. Our matrix decomposition algorithm learns latent signatures of drugs and side effects that are both reproducible and biologically interpretable. We show the usefulness of our approach on 759 structurally and therapeutically diverse drugs and 994 side effects from all human physiological systems. Our approach can be applied to any drug for which a small number of side effect frequencies have been identified, in order to predict the frequencies of further, yet unidentified, side effects. We show that our model is informative of the biology underlying drug activity: individual components of the drug signatures are related to the distinct anatomical categories of the drugs and to the specific drug routes of administration.


Holistic expression of miR-17-92 cluster in obesity, kidney diseases, cardiovascular diseases, and diabetes.
miR-17-92 cluster encodes six micro RNAs (miRNAs) and plays a crucial role in the regulation of various cellular processes. Aberrant expression of this cluster may result in the onset of several diseases. Initially, the role of miR-17-92 cluster in tumorigenesis was discovered but recent research has also uncovered its role in other diseases. Members of the cluster may serve as potential biomarkers in the prognosis, diagnosis, and treatment of several diseases and their complications. In this article, we have reviewed the recent research carried out on the expression pattern of miR-17-92 cluster in non-communicable diseases i.e., obesity, cardiovascular diseases (CVD), kidney diseases (KD) and diabetes mellitus (DM). We examined miR-17-92 role in pathological processes and their potential importance as biomarkers. Each member of the cluster miR-17-92 was upregulated in obesity. miR-18a, miR-19b-3p, miR20a, and miR92a were significantly upregulated in CVD. An equal fraction of the cluster was dysregulated (upregulated and downregulated) in diabetes; however, miR-17-92 was downregulated in most studies on CKD.


Prescription n-3 fatty acids, but not eicosapentaenoic acid alone, improve reference memory-related learning ability by increasing brain-derived neurotrophic factor levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.
Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr(cp)/NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline.


Characteristics of Cases with Poor Transcranial Motor-evoked Potentials Baseline Waveform Derivation in Spine Surgery: A Prospective Multicenter Study of the Monitoring Committee of the Japanese Society for Spine Surgery and Related Research.
Prospective multicenter study. The purpose of the study is to examine cases with poor baseline waveform derivation for all muscles in multichannel monitoring of transcranial motor-evoked potentials (Tc-MEPs) in spine surgery. Intraoperative neuromonitoring (IONM) is useful for identifying neurologic deterioration during spinal surgery. Tc-MEPs are widely used for IONM, but some cases have poor waveform derivation, even in multichannel Tc-MEP monitoring. The subjects were 3625 patients (mean age 60.1 years, range 4-95; 1886 females, 1739 males) who underwent Tc-MEP monitoring during spinal surgery at 16 spine centers between April 2017 and March 2020. Baseline Tc-MEPs were recorded from the deltoid, abductor pollicis brevis, adductor longus, quadriceps femoris, hamstrings, tibialis anterior, gastrocnemius, and abductor hallucis (AH) muscles after surgical exposure of the spine. The 3625 cases included cervical, thoracic, and lumbar lesions (50%, 33% and 17%, respectively) and had preoperative motor status of no motor deficit, and motor deficit with manual muscle testing (MMT) ≥3 and MMT <3 (70%, 24% and 6%, respectively). High-risk surgery was performed in 1540 cases (43%). There were 73 cases with poor baseline waveform derivation (2%), and this was significantly associated with higher body weight, body mass index, thoracic lesions, motor deficit of MMT <3, high-risk surgery (42/1540 [2.7%] vs. 31/2085 [1.5%], P < 0.05), and surgery for ossification of the posterior longitudinal ligament (OPLL). Intraoperative waveform derivation occurred in 25 poor derivation cases (34%) and the AH had the highest rate. The rate of poor baseline waveform derivation in spine surgery was 2% in our series. This was significantly more likely in high-risk surgery for thoracic lesions and OPLL, and in cases with preoperative severe motor deficit. In such cases, it may be preferable to use multiple modalities for IONM to derive multichannel waveforms from distal limb muscles, including the AH.Level of Evidence: 3.


Challenges in the Early Diagnosis of HIV Infection in Infants: Experience from Tamil Nadu, India.
To analyze critical steps in the testing algorithm of the National Early Infant Diagnosis (EID) program in India. A retrospective analysis of data on cases enrolled in the EID program during 2010-2012 from Tamil Nadu was undertaken. 2745 dried blood spots were tested; 9% of these tested positive. Median age of infants at the time of testing was 4 months. Second specimen for confirmation was received from 67% of cases with a turn-around time of 10-270 days. Even with high levels of uptake into the program, huge delays and loss-to-follow-up observed between the first and second sampling, suggests need for revision of the current testing algorithm.


Replacing Wheat Flour with Debittered and Fermented Lupin: Effects on Bread's Physical and Nutritional Features.
In this study the breadmaking potential of lupin flour from L. mutabilis after being debittered (DLF) and solid state fermented (FLF) was evaluated in lupin-wheat breads. Different levels of substitution (10, 15, 20%) were tested on dough rheology and the technological and nutritional (composition and in vitro digestibility indexes) properties of breads, as well as acceptability. Lupin weakened the dough during mixing, having shorter development time and stability, especially FLF. Less relevant was the effect of lupin flours along heating-cooling of the doughs recorded with the Mixolab. DLF and FLF significantly affected technological properties of the lupin-wheat breads at higher substitution (> 10%), particularly reducing bread volume, crust luminosity, crumb cohesiveness and resilience. Detrimental effects observed at the highest substitutions (20%) were diminished when using FLF, although breads received lower score due to the acidic taste detected by panelists. Both lupin flours provided lupin-wheat breads with rather similar composition, rising the average content of proteins, fat and dietary fiber by 0.8, 2.4, 6.5 %, respectively, compared to wheat breads. Likewise, lupin-wheat breads had significantly lower hydrolytic and glycemic indexes. Overall, debittered and fermented lupin could be used for enriching wheat breads, although better technological properties were observed with FLF.


Evaluation of the consistency of neonatal skin injury assessment using clinical images and the metric and graduated colour tool.
To evaluate consistency in the assessment of neonatal skin injuries. Injury images collected during a multicentre period prevalence study (n = 297) were screened for optimal quality before 60 images, stratified for size and colour, were randomly selected for assessment by three neonatal and two adult specialists. The principal investigator's assessments were the baseline for comparison and consistency. Injury characteristics and assessments were reported as descriptive statistics. Comparison of injury assessments for colour and stage were calculated using Chi-square, with p-value of <0.05 considered significant. Neonatal specialists assessed injury elements more confidently than adult specialists reporting 59-60 (98-100%) injuries visible compared to 51-53 (85-93%) respectively. Neonatal specialists attributed mechanical force to 93% of the skin injuries compared to 70% by adult specialists. Consistency of colour assessment was achieved more often with neonatal specialists (n = 50, 85%), compared to adult specialists (n = 41, 73%). Neonatal specialists' consistency for injury staging (n = 107, 60%) was higher compared to adult specialists who were uncertain (n = 8,16%) and less consistent (n = 47, 44%). When comparing specialists as a group, consistency with baseline assessment was significantly different between neonatal and adult specialists for colour (p < 0.010) and injury stage (p < 0.009). Field of expertise (neonatal versus adult) differences were noted likely related to experience and understanding of empirical differences between neonatal and adult skin structure and maturity. These results highlight the need for specialist neonatal skin injury and wound training for clinicians involved in assessment, treatment and best practices for neonates.


Seroprevalence and risk factors associated with bovine herpesvirus 1 (BHV-1) infection in dairy cattle in southern and central Ethiopia.
Bovine herpesvirus 1 (BHV-1) is an important pathogen of cattle with a worldwide distribution. It occurs as a subclinical, mild or severe disease. The clinical signs may vary widely with respiratory, genital, ocular and encephalomyelitis form. This cross-sectional study was carried out between May 2019 and March 2020 with the aim to estimate the seroprevalence of bovine herpesvirus 1 (BHV-1) and to identify related potential risk factors in dairy cattle in central and southern Ethiopia. A total of 954 serum samples were obtained from randomly selected dairy cattle in 98 herds. The samples were collected from animals over 6 months old and tested using a BHV-1 antibody blocking enzyme linked immunosorbent assay (b-ELISA). The study showed that the animal- and herd-level seroprevalence of BHV-1 was 30.0 % (95 % CI: 21.7, 39.9) and 75.5 % (95 % CI: 65.9, 83.1), respectively. Multiple logistic regression model demonstrated that adult animals (> 2.5 years) (OR = 2.4, 95 % CI: 1.1, 5.5) had higher seroprevalence of BHV-1 compared to their counterparts (p < 0.05). Cattle in farms using artificial insemination (AI), and both AI and bulls had a 3.9 (95 % CI: 1.2, 13.3) and 5.1 (95 % CI: 1.8, 14.8) odds of being seropositive, respectively, compared to farms using bulls only. Arrangement of animals in a tail-to-tail fashion appeared to be protective against BHV-1 infection (p < 0.05). However, source of the animal was not associated with BHV-1 serostatus (p > 0.05). The animal- and herd-level prevalence recorded in our study confirms that BHV-1 infection is widespread and remains endemic in dairy cattle of central and southern Ethiopia.


Do smokers with alcohol problems have more difficulty quitting?
This review compares nicotine dependence and the ability to stop smoking in smokers with no alcohol problems to smokers with current, past or lifetime (i.e., either current or past) alcohol problems. We searched computerized databases, meeting abstracts and made requests to listserves and grantees for comparisons of the above categories. We could not use meta-analyses and, thus, used consistency across studies to make conclusions. We located 17 articles on nicotine dependence, 12 on the ability to quit on a given attempt, 7 on lifetime quitting and 2 on quit attempts. Smokers with current and past alcohol problems were more nicotine dependent than smokers with no alcohol problems. Surprisingly, smokers with past problems were as able to quit on a given attempt as smokers with no problems. We hypothesize this may be because such smokers learned skills in resolving their alcohol problems that neutralized their increased nicotine dependence. Smokers with current or past alcohol problems appear to be less likely to quit in their lifetime. Given their equal ability to quit on a given attempt, this could be due to fewer quit attempts; however, whether this is actually so is unclear. Our results that smokers with past alcohol problems can quit as easily as those without alcohol problems suggest that smokers with past alcohol problems may respond to minimal treatments for smoking cessation.


Implicit solvent simulation models for biomembranes.
Fully atomic simulation strategies are infeasible for the study of many processes of interest to membrane biology, biophysics and biochemistry. We review various coarse-grained simulation methodologies with special emphasis on methods and models that do not require the explicit simulation of water. Examples from our own research demonstrate that such models have potential for simulating a variety of biologically relevant phenomena at the membrane surface.


Nitric oxide synthase regulates coelomocytes apoptosis through the NF-κB signaling pathway in the sea cucumber Apostichopus japonicus.
Nitric oxide synthase (NOS) was initially discovered to participate in the generation of nitric oxide as a defense mechanism against pathogenic infections. In recent years, it has been found that NOS plays a pivotal role in regulating apoptosis and inflammation in mammals. However, the mechanisms underlying NOS-mediated apoptosis in invertebrates remain largely unclear. In this study, we found that the Apostichopus japonicus NOS (AjNOS) expression levels were upregulated by 2.20-fold and 3.46-fold after being challenged with Vibrio splendidus at concentrations of 107 CFU mL-1 and 108 CFU mL-1 for 12 h compared to the control group, respectively. Under these conditions, the rates of coelomocytes apoptosis were increased from 14.7% to 32.7% and 45.4%, respectively. Treatment with NOS inhibitor (l-NAME) resulted in a reduction of coelomocytes apoptosis rates from 32.6% to 26.5% in V. splendidus (107 CFU mL-1) groups and from 42.3% to 33.3% in V. splendidus (108 CFU mL-1) groups, respectively. NOS has been reported to regulate apoptosis through IκBα phosphorylation. Simultaneously, exposure to V. splendidus in conjunction with l-NAME resulted in down-regulation of AjIκBα phosphorylation levels compared to the group infected solely with V. splendidus. Furthermore, immunofluorescence analysis revealed that treatment with l-NAME or interference of AjNOS using siRNA inhibited translocation of AjNF-κB/p65 (RelA) into the nucleus. Previous studies have shown that NF-κB can down-regulate expression levels of Bcl-2 family members, which is an important pathway for regulating apoptosis. In the present study, treatment with l-NAME was found to promote anti-apoptotic AjBcl-2 mRNA increase to 1.41-fold and protein expression increase to 1.86-fold at 12 h post V. splendidus challenge. However, these effects were suppressed by PMA (an NF-κB activator). Overall, our findings demonstrate that AjNOS regulates coelomocytes apoptosis induced by V. splendidus through activation of the AjNF-κB signaling pathway and down-regulation of AjBcl-2 in A. japonicus.


Ferroptosis of tumour neutrophils causes immune suppression in cancer.
Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3-5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.


Traveling wave solutions of a coupled Schrödinger-Korteweg-de Vries equation by the generalized coupled trial equation method.
The coupled Schrödinger-Korteweg-de Vries equation is a critical system of in nonlinear evolution equations. It describes various processes in dusty plasma, such as Langmuir waves, dust-acoustic waves, and electromagnetic waves. This paper uses the generalized coupled trial equation method to solve the equation. By the complete discrimination system for polynomial, a series of exact traveling wave solutions are obtained, including discontinuous periodic solutions, solitary wave solutions, and Jacobian elliptical function solutions. In addition, to determine the existence of the solutions and understand their properties, we draw three-dimensional images of the modules of the solutions with Mathematica. We obtain more comprehensive and accurate solutions than previous studies, and the results give the system more profound physical significance.


Kaiy as traditional therapy for pain: is it helpful or a myth?
Two cases of traditional kaiy (Arabic for cauterisation) therapy for pain are reported. This technique is unknown in western countries and should be banned following a review of the topic. Many patients in developing countries use alternative, complementary or traditional therapies before seeking medical advice. This may be due to social or religious beliefs. Kaiy is one such traditional therapy which should be discouraged. Two cases are reported, the first with aural pain and the second with thyroid pain (with malignancy later diagnosed). In these days of modern health care, the practice of kaiy is not science-based and is associated with considerable health risks. Health authorities in the relevant societies should move towards banning this undesirable practice; they should also use multi-media health education to advise of its dangerous outcomes, and enlist the help of community religious leaders to change public opinion and belief.


Orbital floor repair with lyophilized porcine dermis.
Various implants have been used to repair defects in orbital walls. Few are fully biocompatible. The indications for repair of a defect of the orbital floor are reviewed, and the suitability in selected cases of placement of lyophilized porcine dermis (xenograft) is discussed.


Nuchal translucency and major congenital heart defects in fetuses with normal karyotype: a meta-analysis.
To pool published data regarding the sensitivity and specificity of nuchal translucency (NT) in the diagnosis of major congenital heart defects (CHDs) in fetuses with normal karyotype. MEDLINE and Scopus searches using combinations of the terms 'nuchal' and 'cardiac*' were complemented by perusal of references of the retrieved articles and an additional automated search using the 'search for related articles' function on PubMed. Only fetuses with normal karyotype and major CHDs were analyzed. Weighted estimates were made and summary receiver-operating characteristics curves were constructed. The analysis included 20 studies (205 232 fetuses; 537 cases with major CHDs). The pooled sensitivity and specificity of NT > 95(th) centile for diagnosis of major CHDs was 44.4% (95% CI, 39.5-49.5) and 94.5% (95% CI, 94.4-94.6), respectively. The pooled sensitivity and specificity of NT > 99(th) centile was 19.5% (95% CI, 15.9-23.5) and 99.1% (95% CI, 99.1-99.2), respectively. For the subgroup of studies in which NT was measured by Fetal Medicine Foundation-certified operators, the pooled sensitivity and specificity of NT > 95(th) centile was 45.6% (95% CI, 39.6-51.7) and 94.7% (95% CI, 94.6-94.9), respectively. The corresponding estimates for NT > 99(th) centile were 21.0% (95%CI, 16.5-26.1) and 99.2% (95% CI, 99.2-99.3). The pooled positive likelihood ratio for NT > 99(th) centile was 30.5 (95% CI, 24.3-38.6). There was high across-studies heterogeneity for most estimates. Approximately 44% of chromosomally normal fetuses with CHDs have NT > 95(th) centile and 20% have NT > 99(th) centile. However, there is high heterogeneity across studies, which largely remains even in subgroup analyses of studies of apparently similar design, potentially indicating the presence of some residual unidentified bias.


Greater Outflow Facility Increase After Targeted Trabecular Bypass in Angiographically Determined Low-low Regions.
To investigate the impact of trabecular bypass surgery targeted to angiographically determined high- vs. low-aqueous humor outflow areas on outflow facility (C) and intraocular pressure (IOP). Ex vivo comparative study. Postmortem ex vivo porcine and human eyes. Porcine (n = 14) and human (n = 13) whole globes were acquired. In both species, anterior segments were dissected, mounted onto a perfusion chamber, and perfused using Dulbecco's phosphate buffered solution containing glucose in a constant flow paradigm to achieve a stable baseline. Fluorescein was perfused into the anterior chamber and used to identify baseline segmental high- and low-flow regions of the conventional outflow pathways. The anterior segments were divided into 2 groups, and a 5 mm needle goniotomy was performed in either a high- or low-flow area. Subsequently, C and IOP were quantitatively reassessed and compared between surgery in baseline "high-flow" and "low-flow" region eyes followed by indocyanine green angiography. Outflow facility. In all eyes, high- and low-flow segments could be identified. Performing a 5-mm goniotomy increased outflow facility to a variable extent depending on baseline flow status. In the porcine high-flow group, C increased from 0.31 ± 0.09 to 0.39 ± 0.09 μL/mmHg/min (P = 0.12). In the porcine low-flow group, C increased from 0.29 ± 0.03 to 0.56 ± 0.10 μL/mmHg/min (P < 0.001). In the human high-flow group, C increased from 0.38 ± 0.20 to 0.41 ± 0.20 μL/mmHg/min (P = 0.02). In the human low-flow group, C increased from 0.25 ± 0.11 to 0.32 ± 0.11 μL/mmHg/min (<0.001). There was statistically significant greater increase in C for eyes where surgery was targeted to baseline low-flow regions in both porcine (0.07 ± 0.09 vs. 0.27 ± 0.13, P = 0.007 μL/mmHg/min, high vs low flow) and human eyes (0.03 ± 0.03 vs. 0.07 ± 0.02, P = 0.03 μL/mmHg/min, high vs. low flow). Targeting surgery to low-flow areas of the trabecular meshwork yields higher overall facility increase and IOP reduction compared to surgery in high-flow areas. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Brain surgery in combination with tyrosine kinase inhibitor and whole brain radiotherapy for epidermal growth factor receptor-mutant non-small-cell lung cancer with brain metastases.
The role of brain surgery (BS) on the survival of patients with non-small-cell lung cancer (NSCLC) and brain metastases (BM), particularly those with epidermal growth factor receptor (EGFR) mutations under tyrosine kinase inhibitors (TKIs) is yet to be defined. We aimed to investigate whether BS could improve the survival of patients in addition to the combination of TKIs and whole brain radiotherapy (WBRT). A cohort of 1394 NSCLC patients between 2011 and 2016 was retrospectively studied. One hundred patients with BM receiving TKI + RT were enrolled. Forty patients (40%) received TKI + BS + RT, and 60 patients (60%) received TKI + RT. Survival time was calculated from the date of BM diagnoses to the date of death or last follow-up. With a median follow-up of 25.6 months (95% CI, 18.6-35.7), the median survival after BM was 18.2 months (95% CI, 10.8 to 27.4) in the TKI + BS + RT group and 11.8 months (95% CI, 5.2 to18) in the TKI + RT group. Cox proportional hazards regression model for the patients with the largest BM over 1 cm showed that TKI + BS + RT group was associated with improved survival relative to TKI + RT group (HR, 0.49; 95% CI, 0.29 to 0.83; P = 0.008). BS adds significant survival benefits in addition to TKIs and WBRT, especially for patients with EGFR-mutant NSCLC and the largest BM over 1 cm.


A survey of Fusarium toxins in Austrian feed stuffs.
During the last decade observations have been made concerning the occurrence of the fusariotoxins zearalenone and deoxynivalenol in Austria. Feed samples were tested in a large-scaled examination. They usually consisted of cereals (barley, oat, wheat, rye and corn), mixed feed (meal or pellets) and corn or corn cob silage.


Fast and biphasic 8-nitroguanine production from guanine and peroxynitrite.
Guanine (Gua), among purines, is a preferred oxidation/nitration target because of its low one-electron redox potential. The reactive oxygen/nitrogen species peroxynitrite (ONOO-), produced in vivo by the reaction between nitric oxide (•NO) and superoxide radical (O2•‒), is responsible for several oxidative modifications in biomolecules, including nitration, nitrosation, oxidation, and peroxidation. In particular, the nitration of Gua, although detected, as well as its reaction kinetics have been seldom investigated. Thus, we studied the concentration- and temperature-dependent formation of 8-nitroguanine (8-NitroGua) in phosphate buffer (pH 7.40) using stopped-flow spectrophotometry. Traces showed a biexponential behavior, with best-fit rate constants: kfast = 4.4 s-1 and kslow = 0.41 s-1 (30 °C, 400 μM both Gua and ONOO-). kfast increased linearly with the concentration of both reactants whereas kslow was concentration-independent. Linear regression analysis of kfast as a function of Gua and ONOO- concentration yielded values of 2.5-6.3 × 103 M-1s-1 and 1.5-3.5 s-1 for the second-order (slope) and first-order (ordinate) rate constants, respectively (30 °C). Since ONOO- is a short-lived species, its decay kinetics was also taken into account for this analysis. The 8-NitroGua product was stable for at least 4 h, so no spontaneous denitration was observed. Stopped-flow assays using antioxidants and free-radical scavengers suggested a mixed direct/indirect reaction mechanism for 8-NitroGua formation. Gua nitration by ONOO- was also observed in the presence of physiologically relevant CO2 concentrations. The reaction product identity, its yield (∼4.2%, with 400 μM ONOO- and 200 μM Gua), and the reaction mechanism were unequivocally determined by HPLC-MS/MS experiments. In conclusion, 8-NitroGua production at physiologic pH reached significant levels in a few hundred milliseconds, suggesting that the process might be kinetically relevant in vivo and can likely cause permanent nitrative damage to DNA bases.


STRATUSOCT and multifocal ERG in unilateral acute idiopathic maculopathy.
Unilateral acute idiopathic maculopathy (UAIM) is a rare entity, in which an inflammatory process involves the macular retinal pigment epithelium (RPE) and outer retina. It represents a wide spectrum of ocular findings not consistently present in all patients, which may lead to difficulties in the recognition of the condition. This observational case report presents the third-generation optical coherence tomography (StratusOCT) and multifocal electroretinogram (mfERG) findings in a 31-year-old woman with UAIM in the acute phase as well as two months later, and discusses the role of StratusOCT in the diagnosis. In the acute phase, StratusOCT demonstrated abnormal heterogeneous hyperreflectivity and thickening at the level of the outer retina and RPE in the foveal region. Two months after the initial presentation, StratusOCT examination showed a subfoveal area of homogeneous hyperreflectivity that extended from the RPE to the outer retinal layers with posterior shadowing, and sparse points of hyperreflectivity at several different levels of the neurosensory retina, including its superficial layers. The foveal retinal thickness during the acute phase was thicken compared with that after resolution. Seven days after the initial evaluation, mfERG showed severely reduced N1-P1 amplitudes with normal latencies in the region corresponding to the affected area of the papillomacular bundle and fovea. Two months later, mfERG results were normal. StratusOCT provided valuable information, allowing for the exclusion of other disorders that might mimic UAIM. mfERG findings were consistent with transient outer retinal dysfunction as the cause of visual loss. We are unaware of previous reports of UAIM studied by these methods and could find no reference to them in a computerized search using MEDLINE.


Optic tract syndrome. A review of 21 patients.
Twenty-one patients with lesions compromising the optic tract were reviewed. The involvement of the optic tract may be diagnosed in the presence of highly incongruous hemianopia, an afferent pupillary defect, and characteristic atrophy of the optic discs. Behr's pupil, hemianopic pupillary reaction (Wernicke's sign), and associated major neurologic deficits were encountered rarely.


Chromatic pupillometry for the characterization of the pupillary light reflex in Octodon degus.
The common degu (Octodon degus) is an emerging model in biomedical science research due to its longevity and propensity to develop human-like conditions. However, there is a lack of standardized techniques for this non-traditional laboratory animal. In an effort to characterize the model, we developed a chromatic pupillometry setup and analysis protocol to characterize the pupillary light reflex (PLR) in our animals. The PLR is a biomarker to detect early signs for central nervous system deterioration. Chromatic pupillometry is a non-invasive and anesthesia-free method that can evaluate different aspects of the PLR, including the response of intrinsically photosensitive retinal ganglion cells (ipRGCs), the disfunction of which has been linked to various disorders. We studied the PLR of 12 degus between 6 and 48 months of age to characterize responses to LEDs of 390, 450, 500, 525 and 605 nm, and used 5 with overall better responses to establish a benchmark for healthy PLR (PLR+) and deteriorated PLR (PLR-). Degu pupils contracted up to 65% of their horizontal resting size before reaching saturation. The highest sensitivity was found at 500 nm, with similar sensitivities at lower tested intensities for 390 nm, coinciding with the medium wavelength and short wavelength cones of the degu. We also tested the post-illumination pupillary response (PIPR), which is driven exclusively by ipRGCs. PIPR was largest in response to 450 nm light, with the pupil preserving 48% of its maximum constriction 9 s after the stimulus, in contrast with 24% preserved in response to 525 nm, response driven mainly by cones. PLR- animals showed maximum constriction between 40% and 50% smaller than PLR+, and their PIPR almost disappeared, pointing to a disfunction of the iPRGCs rather than the retinal photoreceptors. Our method thus allows us to non-invasively estimate the condition of experimental animals before attempting other procedures.


Primary afferent stimulation acts through a 193 base pair promoter region to upregulate preproenkephalin expression in dorsal horn of transgenic mice.
The expression of the principal opioid peptide gene, preproenkephalin A, is exquisitely regulated by primary afferent inputs to the spinal and medullary dorsal horns. This regulated expression in response to neural synaptic activity has been referred to as trans-synaptic regulation. To define which DNA regions could mediate this trans-synaptic regulation, transgenic 'HEC' mice whose genomes include 193 bp of the human preproenkephalin A promoter fused to a chloramphenicol acetyltransferase (CAT) reporter gene were studied. Mice received unilateral electrical stimulation of the trigeminal ganglion or adjuvant injection into the hindpaw, stimuli known to regulate dorsal horn proenkephalin expression in vivo. CAT activity conferred by this promoter displayed trans-synaptic upregulation with both stimuli. Although the level of the upregulation was 2- to 3-fold higher than the change in the wild type gene, several features of this induction paralleled aspects of the behavior of the wild-type gene: the rapidity of responses to trigeminal ganglion stimulation, the stimulation intensity dependence of responses to trigeminal ganglion stimulation and the time course of upregulation noted following adjuvant injection. Regulatory proteins binding to this restricted promoter region are thus likely to mediate aspects of dorsal horn enkephalin regulation by pain and other somatic stimuli.


Characterization of a highly divergent Sugarcane mosaic virus from Canna indica L. by deep sequencing.
Cannas are popular ornamental plants and widely planted for the beautiful foliage and flower. Viral disease is a major threaten to canna horticulture industry. In the city of Beijing, mosaic disease in canna was frequently observed, but the associated causal agent and its biological characterization is still unknown. After small RNA deep sequencing, 36,776 contigs were assembled and 16 of them shared high sequence identities with the different proteins of Sugarcane mosaic virus (SCMV) of the size ranging from 86 to 1911 nt. The complete genome of SCMV isolate (canna) was reconstructed by sequencing all cDNA clones obtained from RT-PCR and 5'\3' RACE amplifications. SCMV-canna isolate showed to have a full RNA genome of 9579 nt in length and to share 78% nt and 85% aa sequence identities with SCMV isolates from other hosts. The phylogenetic tree constructed based on the full genome sequence of SCMV isolates allocated separately the canna-isolate in a distinct clade, indicating a new strain. Recombination analyses demonstrated that SCMV-canna isolate was a recombinant originating from a sugarcane-infecting isolate (major parent, acc. no. AJ310103) and a maize-infecting isolate (minor parent, acc. no. AJ297628). Pathogenicity test showed SCMV-canna could cause typical symptoms of mosaic and necrosis in some tested plants with varying levels of severity but was less virulent than the isolate SCMV-BJ. Field survey showed that the virus was widely distributed. This study identified SCMV as the major agent causing the prevalent mosaic symptom in canna plants in Beijing and its genomic and biological characterizations were further explored. All these data enriched the knowledge of the viruses infecting canna and would be helpful in effective disease management in canna.


A Survey to Assess Perceived Differences in Referral Pathways to Board-Certified Pediatric Dermatologists.
This study surveyed all U.S. board-certified pediatric dermatologists to determine referral pathways to the specialty; we obtained a 48% (108/226) response rate. Significantly higher self-referral rates were found in private practice than in academic settings, and higher referral rates from specialist and generalist physicians were observed in academic practice. The substantial differences found in this preliminary study indicate that triage inefficiency may be occurring, and further study to investigate the causes for referral differences and their effect on clinical outcomes is needed.


Control of managed pressure drilling systems using nonlinear predictive generalized minimum variance approach based on a Volterra model.
This paper proposes a nonlinear predictive generalized minimum variance (NPGMV) control scheme for automatic control of the managed pressure drilling (MPD) systems in the presence of disturbances. Since the exact model of the system is not usually available in practice, the hydraulic flow model of MPD is described by an autoregressive second-order Volterra model. The conventional least-squares method is applied to input-output data, thereby identifying the Volterra model. Bottom-hole pressure regulation and kick handling are achieved through the control scheme. To deal with a reservoir kick, the proposed method switches to flow control mode automatically, and prevents the reservoir fluid influx into the well surface. The proposed method also has the capability to keep the bottom-hole pressure above the reservoir pressure during a formidable scenario such as pipe connection. In addition, the robustness of the controller in the face of heave disturbance and uncertainty is investigated. To show the effectiveness of the proposed method, the comparison study of several scenarios with a switching PI controller is provided and demonstrates the NPGMV control outperforms other approaches with respect to steady-state performance.


Louisiana (LA) Health: design and methods for a childhood obesity prevention program in rural schools.
There is a worldwide epidemic of obesity with far-reaching consequences for the health of our nation. Prevention of obesity, especially in children, has been deemed by public health policy makers to be one of the most important objectives for our country. This prevention project, called Louisiana (LA) Health, will test whether modification of environmental and behavioral factors can prevent inappropriate weight gain in children from rural parishes of Louisiana who are enrolled in the fourth to sixth grades during Year 1. The primary aim of the LA Health project is to test the efficacy of two school-based approaches for obesity prevention: primary prevention alone and a combination of primary and secondary prevention which will be compared to a no-intervention control group using a cluster randomization research design, with 17 school clusters randomly assigned to the three treatment arms. The study will span 3 years and will provide critical tests of strategies that: 1) modify the child's environment as a primary prevention strategy and 2) provide health behavior modification via classroom instruction and internet counseling as a secondary prevention strategy. The study will also recruit a similar sample of students to measure changes in body weight relative to height, gender, and age over the same three-year period.


Gamma-aminobutyric acid is present in a spatially discrete subpopulation of hair cells in the crista ampullaris of the toadfish Opsanus tau.
Although gamma-aminobutyric acid (GABA) and glutamate are known to be present in the vestibular sensory epithelia of a variety of species, the functional relationship between these two transmitters is not clear. The present study addresses the three-dimensional spatial distribution of GABA and glutamate immunoreactivity in the vestibular labyrinth of the oyster toadfish by using whole end organs labeled by immunofluorescence with monoclonal anti-GABA and/or antiglutamate antibodies and visualized as whole mounts by multiphoton confocal microscopy. We find glutamate-immunoreactive hair cells present throughout the sensory epithelium. In contrast, prominent GABA immunoreactivity is restricted to a small population of hair cells located in the central region of the crista. Double immunofluorescence reveals two distinct staining patterns in GABA-labeled hair cells. Most ( approximately 80%) GABA-labeled cells show trace levels of glutamate, appropriate for the metabolic/synthetic role of cytoplasmic glutamate. The remainder of the GABA-stained cells contain substantial levels of both GABA and glutamate, suggesting transmitter colocalization. In the toadfish utricle, glutamatergic hair cells are present throughout the macula. GABA-immunoreactive hair cells follow the arc of the striola, and most GABA-labeled receptor cells coexpress glutamate. The localization of GABA was explored in other species as well. In the pigeon, GABAergic hair cells are present throughout the crista ampullaris. Our findings demonstrate that multiple, neurochemically distinct types of hair cells are present in vestibular sensory epithelia. These observations, together with the excitatory activity generally associated with 8th nerve afferent fibers, strongly suggest that GABA serves an important, specific, and complex role in determining primary afferent response dynamics.


Forsythiae Fructuse water extract attenuates liver fibrosis via TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways.
Forsythiae Fructuse water extract (FSE) is a water-soluble component extracted from the traditional Chinese medicine Forsythiae Fructuse (The fruit of Forsythia suspensa (Thunb.) Vahl) usually used to treat inflammatory diseases. However, little is known about the therapeutic effect of FSE on liver fibrosis. The purpose of our study was to investigate the therapeutic effect of FSE on liver fibrosis and reveal the underlying mechanism. Liver fibrosis model was established by subcutaneous injection of olive oil containing 40% CCl4. Rat liver tissue morphologic pathology was investigated by using HE staining, Masson staining and Sirius red staining. Several biochemical markers including liver (ALT, AST, AKP, γ-GT), fibrosis (HA, LN, PC III, Col IV) and inflammation (IL-6, IL-1β, TNF-α) were determined by using Elisa kits. Immunohistochemistry was used to observe the distribution of α-SMA and COL1 in liver tissue. Effects of FSE on inflammatory pathway (TLR4/MyD88/NF-κB) and fibrotic pathway (TGF-β/smads) were detected by western blot and qPCR. The results showed that hepatic histopathological injury, abnormal liver function, fibrosis and inflammation induced by CCl4 were improved by FSE (2.5, 5 g/kg). Immunohistochemistry and western blot results indicated that the expression of α-SMA and COL1 in liver tissue was inhibited by FSE (2.5, 5 g/kg). Western blot and qPCR results further proved that FSE (2.5, 5 g/kg) inhibited the transduction of TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways. FSE can inhibit the expression of inflammatory factors and fibrotic cytokines, reduce liver injury, and inhibit the development of liver fibrosis through TLR4/MyD88/NF-κB and TGF-β/smads signaling pathways.


The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms.
Inter-individual variations in the genes encoding xenobiotic-metabolizing enzymes have been reported to alter susceptibility to various diseases involving hematological disorders. The purpose of this case-control study was to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing BCR-ABL1 negative myeloproliferative neoplasms (MPN). PCR-RFLP was used for genotyping single nucleotide polymorphisms (SNP) in CYP2D6 and GSTP1 in 139 patients with MPN and 126 controls. There was a significantly increased risk for developing BCR-ABL1 negative MPN for the group bearing the CYP2D6*4 variant allele (X2: 4.487; OR 1.738; 95% CI 1.040-2.904; p = 0.034). The platelet count was higher in CYP2D6*4 allele carriers (p = 0.047). There was no association between the GSTP1 Ile105Val polymorphism and the risk of developing MPNs. MPN patients bearing the GSTP1 Ile105Val variant allele had a higher prevalence of bleeding complications (X2: 7.510; OR 4.635; 95% CI 1.466-14.650; p = 0.006). Our study provides new data that the CYP2D6*4 polymorphism may be associated with an increased risk to develop MPNs while the GSTP1 Ile105Val polymorphism does not show such an association. To our knowledge, the current study is the first to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing MPNs in the Turkish population. Further studies with more patients and controls are needed to support our data.


Construction of low-ethanol-wine yeasts through partial deletion of the Saccharomyces cerevisiae PDC2 gene.
We propose an alternative GMO based strategy to obtain Saccharomyces cerevisiae mutant strains with a slight reduction in their ability to produce ethanol, but with a moderate impact on the yeast metabolism. Through homologous recombination, two truncated Pdc2p proteins Pdc2pΔ344 and Pdc2pΔ519 were obtained and transformed into haploid and diploid lab yeast strains. In the pdc2Δ344 mutants the DNA-binding and transactivation site of the protein remain intact, whereas in pdc2Δ519 only the DNA-binding site is conserved. Compared to the control, the diploid BY4743pdc2Δ519 mutant strain reduced up to 7.4% the total ethanol content in lab scale-vinifications. The residual sugar and volatile acidity was not significantly affected by this ethanol reduction. Remarkably, we got a much higher ethanol reduction of 10 and 15% when the pdc2Δ519 mutation was tested in a native and a commercial wine yeast strain against their respective controls. Our results demonstrate that the insertion of the pdc2Δ519 mutation in wine yeast strains can reduce the ethanol concentration up to 1.89% (v/v) without affecting the fermentation performance. In contrast to non-GMO based strategies, our approach permits the insertion of the pdc2Δ519 mutation in any locally selected wine strain, making possible to produce quality wines with regional characteristics and lower alcohol content. Thus, we consider our work a valuable contribution to the problem of high ethanol concentration in wine.


Theoretical approaches to the engagement with patients in case-management programmes and assertive outreach teams: A systematic review of the literature.
WHAT IS KNOWN ON THE SUBJECT?: It is generally accepted that all interventions carried out by mental health nurses involve engagement with the patient; this engagement is a process that is gradually constructed and is not immediate. In Spain during last decade, nurses working in assertive outreach teams have gradually replaced the traditional institutional setting in favour of environments that are more familiar to the patient. In contrast, when patients and nurses interact outside institutional settings, a new approach and skillset is required in order to adapt to the new environment. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: We have systematically identified and assessed the available evidence on how nurses work in assertive outreach team programmes. The therapeutic link is not just assistance; it is actually a construct, which is established between nurse and patient, with the aim of favouring, fostering and strengthening the therapeutic relationship. Only a few studies have discussed the nurse-patient therapeutic link in assertive outreach services. However, it seems important that nurses use a standardized language, that is, a language promoted as a model of correct use and used for functions of greater prestige, especially in public administration and teaching, to integrate it into the theoretical framework. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: With the synthesis that we present, we hope that it promote a more consistent use of the engagement concept in research on this topic. In turn, this will enhance staff support and training and will foster evidence-based practice. The conceptualization of nursing language and its use by professionals helps to improve practice and the lack of a theoretical framework with a nurse perspective. It is necessary to establish a consensus between mental health nurses around the engagement' meaning in the programmes of assertive outreach teams. ABSTRACT: Introduction During last decade in Spain, nurses working in assertive outreach programmes have replaced the traditional institutional setting in favour of the patient's own environment. Engagement with patients requires a different skillset when the axis of the nurse-patient interaction is the patient's own environment. The engagement alone could be associated with the innate concept of patient's care and the helping relationship. However, in the individualized care models, the engagement seems to be an instrument with its own characteristics for the purpose of providing mental health care. Aim/Question To systematically identify and assess the empirical evidence on the relationships and engagement between patients with mental illness (schizophrenia, psychotic disorders, schizoaffective disorders, mood disorders and disorders of adult personality) and nursing mental health nurses. Method Systematic literature review based on PRISMA guidance. Results We identified and reviewed seven primary research studies. Following the analytic processes, three themes emerged: existence of different engagement levels, training needs and skills in the creation and consolidation of the engagement, and engagement as process. Discussion The engagement of nurse and patient is understood as a process that incorporates different stages. Whilst it is established, the engagement is subject to positive and negative influences. For the creation of the engagement and its maintenance specialized skills, knowledge and personal attributes (resilience, psychosocial skills, compressive knowledge of mental health illnesses, capacity to build effective relationships, adaptability and problem-solving) are necessary, but the main focus is on context where it develops, selected by the patient himself, for example, his home. Implications for Practice Administrators may have questions about appropriate hiring practices for assertive outreach teams since certain skills are necessary to obtain un engagement process, and staff training should be considered a key issue to provide specific skills for enhancing engagement and the therapeutic relationship. Conclusion The engagement must be understood as a long-term process. For the creation of the engagement and its maintenance, specialized skills, knowledge and personal attributes are necessary.


Role of the cyclooxygenase 2-thromboxane pathway in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced decrease in mesencephalic vein blood flow in the zebrafish embryo.
Previously, we reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) evoked developmental toxicity required activation of aryl hydrocarbon receptor type 2 (AHR2), using zebrafish embryos. However, the downstream molecular targets of AHR2 activation are largely unknown and are the focus of the present investigation. TCDD induces cyclooxygenase 2 (COX2), a rate-limiting enzyme for prostaglandin synthesis in certain cells. In the present study, we investigated the role of the COX2-thromboxane pathway in causing a specific endpoint of TCDD developmental toxicity in the zebrafish embryo, namely, a decrease in regional blood flow in the dorsal midbrain. It was found that the TCDD-induced reduction in mesencephalic vein blood flow was markedly inhibited by selective COX2 inhibitors, NS-398 and SC-236, and by a general COX inhibitor, indomethacin, but not by a selective COX1 inhibitor, SC-560. Gene knock-down of COX2 by two different types of morpholino antisense oligonucleotides, but not by their negative homologs, also protected the zebrafish embryos from mesencephalic vein circulation failure caused by TCDD. This inhibitory effect of TCDD on regional blood flow in the dorsal midbrain was also blocked by selective antagonists of the thromboxane receptor (TP). Treatment of control zebrafish embryos with a TP agonist also caused a reduction in mesencephalic vein blood flow and it too was blocked by a TP antagonist, without any effect on trunk circulation. Finally, gene knock-down of thromboxane A synthase 1 (TBXS) with morpholinos but not by the morpholinos' negative homologs provided significant protection against TCDD-induced mesencephalic circulation failure. Taken together, these results point to a role of the prostanoid synthesis pathway via COX2-TBXS-TP in the local circulation failure induced by TCDD in the dorsal midbrain of the zebrafish embryo.


Reaction-diffusion approach to modeling water diffusion in glutinous rice flour particles during dynamic vapor adsorption.
Dynamic vapor sorption (DVS) method is now widely adopted to determine water diffusion properties in food materials using a sheet or bulk particles as test samples. The Fickian second law with an instant equilibrium boundary condition, although commonly used, can not accurately model the water adsorption kinetics during DVS tests. Dynamic water adsorption of glutinous rice flour was measured at 30 °C and eleven relative humidity steps, and modeled using the Fickian second law with three kinds of boundary condition. Results indicated that the boundary conditions had great impacts on the predicted values especially for the initial section in the DVS curves, and that modifying boundary conditions could not improve the fitness of the final section which characterized a continuing slight increase of water concentration. A reaction-diffusion model, which assumes two diffusible water populations and describes water transport as a competition between diffusion and reversible adsorption on solid matrix, was developed and found to be able to capture the features of water diffusion in the whole adsorption duration. Implementation of the reaction-diffusion approach to glutinous rice flour indicated that diffusion of the Langmuir water became very slow when its adsorption reached equilibrium, while the diffusion of the non-Langmuir water slowed down when water clustering occurred, at the same time the rates of the surface adsorption and bulk adsorption began to decrease. The model developed in this work would help to deepen our mechanistic understanding of water diffusion during a isothermal adsorption.


Kinetics of CO Recombination to the Heme in Geobacillus Stearothermophilus Nitric Oxide Synthase.
We report the kinetics of CO rebinding to the heme in His134Ser, Ile223Val and His134Ser/Ile223Ser mutants of Geobacillus stearothermophilus nitric oxide synthase (gsNOS). The amplitudes of the two observed kinetics phases, which are insensitive to CO concentration, depend on enzyme concentration. We suggest that two forms of gsNOS are in equilibrium under the conditions employed (6.1-27 µM gsNOS with 20 or 100% CO atmosphere). The kinetics of CO rebinding to the heme do not depend on the identity of the NO-gate residues at positions 134 and 223.


Antiepileptic Drugs in the Management of Cerebral Metastases.
Seizures represent a common and debilitating complication of central nervous system metastases. The use of prophylactic antiepileptic drugs (AEDs) in the preoperative period remains controversial, but the preponderance of evidence suggests that it is not helpful in preventing seizure and instead poses a significant risk of adverse events. Studies of postoperative seizure prophylaxis have not shown substantial benefit, but this practice remains widespread. Careful analysis of the risk of seizure based on patient-specific factors, such as tumor location and primary tumor histology, should guide the physician's decision on the initiation and cessation of prophylactic AED therapy.


Enhancement of chemotactic migration by the local anesthetic tetracaine.
The local amine anesthetic tetracaine added to a suspension of guinea pig or human neutrophilic granulocytes inhibited their random migration in Boyden chambers, but increased their chemotactic migration towards the chemotactic tripeptide f-Met-Leu-Phe, complement-activated normal guinea pig serum, and the eosinophil chemotactic factor ECF. Tetracaine not only increased the distance migrated by the leading cells, it also caused more cells to leave the upper filter surface and to migrate into the filter. The effect required the presence of the drug; cells preincubated with tetracaine and washed did not differ from control cells. It is suggested that tetracaine specifically enhanced a mechanism operative in a cell's response to a concentration gradient of a chemotactic factor.


NDGA reduces secondary damage after spinal cord injury in rats via anti-inflammatory effects.
After spinal cord injury (SCI), a series of complex pathophysiological processes follows the initial injury. Because inflammation plays a key role in this secondary pathology damage, anti-inflammatory drug treatment may reduce secondary damage and protect neurons after SCI. Though nordihydroguaiaretic acid (NDGA) can inhibit inflammatory responses, its potential roles in neuroprotection and anti- inflammation in an SCI model have not been studied. In this study, we investigated the anti-inflammatory effects of NDGA in SCI. First, histopathological alterations were evaluated with hematoxylin/eosin (HE) and Nissl staining, showing an increased number of neurons after NDGA administration. Additionally, the extent of secondary damage was assessed by TUNEL assay and measurement of astrocyte proliferation. The data showed that the numbers of apoptotic cells and the proliferative extent of astrocytes were significantly decreased by the use of NDGA. The anti-inflammatory effect of NDGA was evaluated by measuring myeloperoxidase (MPO) levels as an indicator of neutrophil activity, macrophage/microglia numbers, and expression of inflammatory cytokines including IL-1β and TNF-α. NDGA treatment significantly decreased the MPO level and the number of macrophages/microglia. In addition, NDGA also suppressed the expression of IL-1β and TNF-α after SCI. These data suggest that anti-inflammatory action by NDGA can reduce secondary damage after SCI.


Effect of Mg2+ and spermine on the kinetics of Ca2+ transport in rat-liver mitochondria.
Plots relating the initial rate of mitochondrial Ca2+ transport to the Ca2+ concentration (kinetic plots) have a hyperbolic shape in a Ca2+ concentration range of 2.5-100 muM as measured in sucrose or KCl media. In the presence of Mg2+ or a polyamine spermine, which both are competitive inhibitors of Ca2+ binding to low affinity sites at the membrane surface, the shape of the plots becomes sigmoidal. At higher concentrations of these agents linear kinetic plots are obtained as measured in a sucrose medium. In a KCl medium the sigmoidality of the kinetic plots is enhanced by an increase in the Mg2+ or spermine concentration. It is suggested that Mg2+ and spermine affect the kinetics of Ca2+ transport by interfering with Ca2+ binding to low affinity sites of the membrane surface and that the binding of Ca2+ to these sites is the first step of the mitochondrial Ca2+ transport.


Effects of Fetal Substance Exposure on Offspring Substance Use.
Prenatal exposure to alcohol and drugs is associated with physical, cognitive, and behavioral problems across the offspring's lifespan and an increased risk of alcohol and drug use in adolescent and young adult offspring. These prenatal effects continue to be evident after control for demographic background and parental alcohol and drug use. Behavior problems in childhood and adolescence associated with prenatal exposures may serve as a mediator of the prenatal exposure effects on offspring substance use.


PREVALENCE OF SCOLIOSIS IN PUBLIC ELEMENTARY SCHOOL STUDENTS.
To evaluate the prevalence of scoliosis and the risk factors in elementary school students. A cross-sectional study was carried out in 954 students in 2015. The instrument involved was a questionnaire on postural habits, socioeconomic conditions, and demographic factors. The anthropometric measurements, including height and weight, a visual inspection of the deformity of the vertebral column, the leveling of shoulders, and the Adam's test were obtained. The sample was calculated in the expected frequency of 12.3%, acceptable error rate of 2.0% and confidence level of 95.0%. To compare the proportions, the chi-square test or Fisher's exact test was applied. The association between scoliosis and risk factors was evaluated by logistic regression, being significant p <0.05. The prevalence of scoliosis was 24.3%, higher in obese patients and students who adopted a sitting position for a long period of time. Obese students showed a 1.8 times higher chance of testing positive Adam's Forward Bend Test when compared to normal-weight/lean and 2.1 times higher chance compared to overweight students. The sitting position for watching television increases the chance of testing positive Adam's test in 38.0%, when compared to the lying position. Obesity increases the risk of testing positive Adam's test in 74.0 and 98.0%, when compared, respectively, to the underweight/normal weight and overweight. There was a high prevalence of scoliosis in students from public elementary schools in Santos. The most influential factors for this deviation of the spine were obesity and the position adopted by students to watch television.


Genetic polymorphisms of IL6 gene -174G > C and -597G > A are associated with the risk of COVID-19 severity.
Coronavirus disease-2019 (COVID-19) is pro-inflammatory disorder characterized by acute respiratory distress syndrome. Interleukin-6, a cytokine secreted by macrophages, which mediates an inflammatory response, is frequently increased and associated with the severity in COVID-19 patients. The differential expression of IL6 cytokine in COVID-19 patients may be associated with the presence of single nucleotide polymorphisms (SNPs) in regulatory region of cytokine genes. The aim of this study is to investigate the role of two promoter polymorphisms of the IL6 gene (-597G > A and -174G > C) with the severity of COVID-19. The study included 242 patients, out of which 97 patients with severe symptoms and 145 patients with mild symptoms of COVID-19. Genotyping of two selected SNPs, rs1800795 (-174G > C) and rs1800797 (-597G > A) of promoter region of IL6 gene, was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In our study, individuals with GC genotypes of IL6 (-174G > C) polymorphism showed significantly higher risk of severity [adjusted odds (OR) 3.86, p <.001] but we did not observe any association of COVID-19 severity with rs1800797 (-597G > A) polymorphism. The COVID-19 severity was significantly higher in individuals having 'C' allele of IL6 (-174G > C) polymorphism (p = .014). Linkage disequilibrium between rs1800795 (-174G > C) and rs1800797 (-597G > A) showed that individuals having AC* haplotype significantly association with COVID-19 severity (p = .034). Our results suggest that 'C' allele of rs1800795 (-174G > C) polymorphism of IL6 may be the risk allele for severity of COVID-19 in North Indian population.


Biology and clinical application of CAR T cells for B cell malignancies.
Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies. We further summarize the status of CD19 CAR clinical therapy for non-Hodgkin lymphoma and B cell acute lymphoblastic leukemia, including their efficacy, toxicities (cytokine release syndrome, neurotoxicity and B cell aplasia) and current management in humans. We conclude with an overview of recent pre-clinical advances in CAR design that argues favorably for the advancement of CAR therapy to tackle other hematological malignancies as well as solid tumors.


[Which treatment for the malar bags?].
The treatment of malar bags is known to be particularly difficult; although it is not the most frequent palpebral anomaly justifying a surgical recourse, this problem cannot be ignored. It is important to distinguish their minor forms and to be able to analyze them in order to propose the best to our patients. We review the literature concerning this subject. The various surgical techniques are discussed and we present five of our cases. Even taking into account its various evolutions, the standard lower eyelid blepharoplasty can correct neither the ptosis nor the excess of orbicularis oculi muscle, which appear to be the main components of the malar bag. Publications, precisely mentioning malar bags or festoons, analyzing their physiopathology or their treatments, are few. We discuss the current data of the literature and on the results obtained in our experiment, and the surgical techniques suggested for their treatment. All the techniques suggested for the malar bags remain local or regional approaches. Results obtained with those techniques do not seem effective to us: although it has not been specifically proposed for the treatment of malar bags, the midface sub-periosteal lift, combining a skin flap lower eyelid dissection and a subperiosteal malar dissection, seems to be able to correct the lowest part of the orbicularis oculi muscle due to its concentric action and its major vertical vector of traction. This study underlines the importance of clinical analysis of the malar bags to appreciate the contribution of each element. So the surgeon will be able to choose the most adapted treatment, which is most often a midface sub-periosteal lift associated with a blepharoplasty.


1,4,8,11-Tetraazoniacyclotetradecane tetrakis(phenylphosphonate) dihydrate forms hydrogen-bonded sheets.
In the title compound, C(10)H(28)N(4)(4+).4C(6)H(6)O(3)P(-).2H(2)O, the cation lies across a centre of inversion in space group P2(1)/n. The two independent anions and the water molecule are linked by four O-H.O hydrogen bonds [H.O = 1.74-2.15 (3) A, O.O = 2.5482 (14)-3.0438 (16) A and O-H.O = 160-176 (2) degrees ] into sheets containing equal numbers of centrosymmetric R(6)(6)(16) and R(10)(10)(36) rings. The cation lies at the centre of the R(10)(10)(36) ring and is linked to it by eight N-H.O hydrogen bonds [H.O = 1.77-1.98 A, N.O = 2.6756 (15)-2.8168 (16) A and N-H.O = 151-169 degrees ].


General principles to enhance practice patterns in gastrointestinal endoscopy.
To develop general rules on how to pursue a therapeutic goal of interventional endoscopy without getting lost in abundant details. The influences of various medical interventions on the survival of a patient with gastrointestinal haemorrhage are modelled by an influence diagram. Survival is the focal point of multiple influences affecting its overall strength. Any downstream influence can represent the focal point of other preceding upstream influences. The mathematics underlying the influence diagram are similar to those of a decision tree with some notable exceptions. Its formalism allows one to consider inhibitory and additive influences and to include in the same analysis non-commensurable qualities, such as correct diagnosis, haemostasis or survival. The analysis reveals five general rules. First, the large number of factors involved in successful endoscopy render the influence of each individual factor less important. Second, a single factor that exerts its influence on many subsequent factors tends to be associated with an overall greater relevance. Third, remote influences are of lesser relevance than those directly linked to the final outcome. Fourth, factors multiplied by several consecutive probabilities lose their influence. Fifth, endoscopists need to assess the relevance of individual factors with respect to the immediate goals of endoscopy, as well as the general goals of patient well-being. The influence model of endoscopic haemostasis reveals several general principles that can be utilized as tools in endoscopy training.


Transcriptional and translational control of the message for transition protein 1, a major chromosomal protein of mammalian spermatids.
The spermatid transition proteins comprise a set of basic chromosomal proteins that appear during the period when spermatids are undergoing nuclear elongation and condensation, about midway between the end of meiosis and the release of spermatozoa from the seminiferous tubule. The transition proteins replace the histones but are themselves subsequently replaced by protamines, and they are not found in sperm nuclei. We have used a cDNA clone for the smallest transition protein (TP1, 54 amino acids) to show that its message first appears postmeiotically in late round spermatids. Thus production of TP1 is an example of haploid gene expression. The message remains translationally inactive for some 3-4 days before translation occurs in early elongating spermatids. While translationally repressed, TP1 message is nonpolysomal and has a discrete size of about 590 bases, including a 140 residue poly(A) tail. In contrast, polysome-associated message is of heterogeneous size due to variability of poly(A) lengths.


Torque control of maxillary anterior teeth with the double J retractor and palatal miniscrews during en masse retraction.
A double J retractor (DJR) and palatal miniscrews were used to retract maxillary anterior teeth after failure of buccal posterior miniscrews. The line of action passing through the center of resistance of the maxillary anterior teeth and the moment generated by the palatal miniscrews via torquing springs successfully controlled the overbite and incisor torque during space closure. The DJR and palatal miniscrews work well with labial fixed appliances to address bimaxillary protrusion.