The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection.
Apoptosis is a form of cell death by which the body maintains the homeostasis of the internal environment. Apoptosis is an initiative cell death process that is controlled by genes and is mainly divided into endogenous pathways (mitochondrial pathway), exogenous pathways (death receptor pathway), and apoptotic pathways induced by endoplasmic reticulum (ER) stress. The homeostasis imbalance in ER results in ER stress. Under specific conditions, ER stress can be beneficial to the body; however, if ER protein homeostasis is not restored, the prolonged activation of the unfolded protein response may initiate apoptotic cell death via the up-regulation of the C/EBP homologous protein (CHOP). CHOP plays an important role in ER stress-induced apoptosis and this review focuses on its multifunctional roles in that process, as well as its role in apoptosis during microbial infection. We summarize the upstream and downstream pathways of CHOP in ER stress induced apoptosis. We also focus on the newest discoveries in the functions of CHOP-induced apoptosis during microbial infection, including DNA and RNA viruses and some species of bacteria. Understanding how CHOP functions during microbial infection will assist with the development of antimicrobial therapies.


Data-driven identification of temporal glucose patterns in a large cohort of nondiabetic patients with COVID-19 using time-series clustering.
Hyperglycemia has emerged as an important clinical manifestation of coronavirus disease 2019 (COVID-19) in diabetic and nondiabetic patients. Whether these glycemic changes are specific to a subgroup of patients and persist following COVID-19 resolution remains to be elucidated. This work aimed to characterize longitudinal random blood glucose in a large cohort of nondiabetic patients diagnosed with COVID-19. De-identified electronic medical records of 7502 patients diagnosed with COVID-19 without prior diagnosis of diabetes between January 1, 2020, and November 18, 2020, were accessed through the TriNetX Research Network. Glucose measurements, diagnostic codes, medication codes, laboratory values, vital signs, and demographics were extracted before, during, and after COVID-19 diagnosis. Unsupervised time-series clustering algorithms were trained to identify distinct clusters of glucose trajectories. Cluster associations were tested for demographic variables, COVID-19 severity, glucose-altering medications, glucose values, and new-onset diabetes diagnoses. Time-series clustering identified a low-complexity model with 3 clusters and a high-complexity model with 19 clusters as the best-performing models. In both models, cluster membership differed significantly by death status, COVID-19 severity, and glucose levels. Clusters membership in the 19 cluster model also differed significantly by age, sex, and new-onset diabetes mellitus. This work identified distinct longitudinal blood glucose changes associated with subclinical glucose dysfunction in the low-complexity model and increased new-onset diabetes incidence in the high-complexity model. Together, these findings highlight the utility of data-driven techniques to elucidate longitudinal glycemic dysfunction in patients with COVID-19 and provide clinical evidence for further evaluation of the role of COVID-19 in diabetes pathogenesis.


[Functional treatment of extensor tendon injury of the hand].
We have treated 73 patients with 107 injuries of the extensor tendon. We started with an elastic dynamic splinting means = 9 (2-27) days after operation. The duration of functional treatment was means = 40 (13-103) days. Infections were only seen in severe cases (12.3%), and there was no rupture of the sutured tendon. Good or excellent functions were found in 92% of the patients. To sum up, primary extensor tendon repair will provide superior functional results at all levels of injury by postoperative dynamic splinting.


THE GENETIC INTERPRETATION OF INBREEDING DEPRESSION AND OUTBREEDING DEPRESSION.
Inbreeding with close relatives and outbreeding with members of distant populations can both result in deleterious shifts in the means of fitness-related characters, most likely for very different reasons. Such processes often occur simultaneously and have important implications for the evolution of mating systems, dispersal strategies, and speciation. They are also relevant to the design of breeding strategies for captive populations of endangered species. A general expression is presented for the expected phenotype of an individual under the joint influence of inbreeding and crossbreeding. This expression is a simple function of the inbreeding coefficient, of source and hybridity indices of crossbreeding, and of specific forms of gene action. Application of the model may be of use in identifying the mechanistic bases for a number of evolutionary phenomena such as the shift from outbreeding enhancement to outbreeding depression that occurs with population divergence.


Comorbidity in lipoprotein apheresis: Their role in the era of new lipid-lowering therapies.
Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention. Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA. Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia. Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues.


Interleukin 2-induced expression of proliferating cell nuclear antigen is regulated by transcriptional and post-transcriptional mechanisms.
Proliferating cell nuclear antigen (PCNA) is an auxiliary protein required for leading strand DNA synthesis by polymerase delta. Steady-state levels of PCNA RNA increase during interleukin 2 stimulated G1 activation of cloned T cells (L2 cells) and correlate with expression of the PCNA protein. We demonstrate that the initial (G1) rapid rise in PCNA RNA levels is predominantly related to increased transcription. The slower rate of increase in PCNA RNA at the initial G1-S transition is related to transcription as well as increased stability of the PCNA message and partially requires protein synthesis. These data provide a foundation for further investigation of the mechanisms of increased stability and transcription of PCNA.


Effects of phospholipase A2, 12-lipoxygenase, and cyclooxygenase inhibitors in the feline pulmonary bed.
The effects of phosphonofluoridic acid, methyl-5,8,11,14-eicosatetraenyl ester (MAFP), a phospholipase A2 inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), the calcium channel opener BAY K 8644, and the thromboxane A2 mimic U-46619 were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and BAY K 8644 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure that were reproducible with respect to time. Infusion of MAFP into the perfused lobar artery at doses of 100 to 300 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II; however, the phospholipase A2 inhibitor did not alter vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. The combination of the higher dose of the phospholipase A2 inhibitor MAFP with the phospholipase C inhibitor U-73122 significantly affected vasoconstrictor responses to ANG II, NE, and 5-HT but not to BAY K 8644. In a separate series of animals, the effects of a lipoxygenase inhibitor, baicalein, were investigated. Infusion of baicalein into the perfused lobar artery at doses of 100 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II but not the vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. In a final series of experiments, the effects of a cyclooxygenase inhibitor, meclofenamate, were investigated, and intravenous injection of the meclofenamate at a dose of 2.5 mg/kg did not significantly affect vasoconstrictor responses to ANG II, 5-HT, BAY K 8644, NE, or U-46619. These data provide support for the hypothesis that pulmonary vasopressor responses to ANG II are mediated, in part, by the activation of phospholipase A2, phospholipase C, and the lipoxygenase pathway in the pulmonary vascular bed of the cat.


Gene expression profiling of the bone marrow mononuclear cells from patients with myelodysplastic syndrome.
The gene expression pattern of bone marrow mononuclear cells (BMNCs) from 10 patients with myelodysplastic syndrome (MDS) was studied by two-color cDNA microarray techniques. To confirm the microarray results, a semiquantitative RT-PCR was performed to analyze gene expression in fifty additional MDS patients. Ninety-five genes were shown to be abnormally expressed in at least five MDS patients compared to normal controls, involving cell growth and differentiation regulation, cell cycle control, signaling and redox; such as thrombospondin 1, phosphatase and tensin homolog, MAD, DNA-damage-inducible transcript 3 (DDIT3), ets variant gene 1 (ETV1), and G1 to S phase transition 1. CD36 was also revealed up-regulated in 4 cases. MDS patients in early and advanced stages could be clustered into two distinct groups by hierarchical clustering, wherein a case with isolated thrombocytopenia and other RA patients were clustered into two subgroups. Consistent expression patterns of 3/5 (60%) genes were confirmed by semiquantitative RT-PCR. Further analysis showed the different transcript levels of RNAHP, DDIT3 in patients with MDS in different stages, AML, and normal controls. Meanwhile, the different significance of RNAHP and ETV1 expression was revealed between RA and untypical anaplastic anemia, iron deficiency anemia, and megaloblastic anemia patients. We propose that the technology of microarray may reveal the intrinsic molecular features and the expression levels of RNAHP, DDIT3, and ETV1 may provide useful markers for the diagnosis of MDS.


Identification of the date-rape drug GHB and its precursor GBL by Raman spectroscopy.
Gamma hydroxybutyric acid (GHB), also known as 'liquid ecstasy', has recently become associated with drug-facilitated sexual assaults, known colloquially as 'date rape', due to the ability of the drug to cause loss of consciousness. The drug is commonly found 'spiked' into alcoholic beverages, as alcohol increases its sedative effects. Gamma hydroxybutyric acid and the corresponding lactone gamma-butyrolactone (GBL) will reach an equilibrium in solution which favours the lactone in basic conditions and GHB in acidic conditions (less than pH 4). Therefore, we have studied both GHB and GBL, as a mildly acidic beverage 'spiked' with GHB will contain both GHB and GBL. We report the analysis of GHB as a sodium salt and GBL, its precursor, using bench-top and portable Raman spectroscopy. It has been demonstrated that we are able to detect GHB and GBL in a variety of containers including colourless and amber glass vials, plastic vials and polythene bags. We have also demonstrated the ability to detect both GBL and GHB in a range of liquid matrices simulating 'spiked' beverages.


Identification of a functional core in the RNA component of RNase MRP of budding yeasts.
RNase MRP is an endonuclease participating in ribosomal RNA processing. It consists of one RNA and at least nine protein subunits. Using oligonucleotide-directed mutagenesis, we analyzed the functional role of five of the hairpins in the secondary structure of the RNA subunit of Saccharomyces cerevisiae RNase MRP. Deletion of an entire hairpin was either lethal or resulted in very poor growth. However, peripheral portions constituting up to 70% of a hairpin could be deleted without effects on cell growth rate or processing of rRNA. To determine whether these hairpins perform redundant functions, we analyzed mutants combining four or five benign hairpin deletions. Simultaneous removal of four of these hairpin segments had no detectable effect. Removing five created a temperature- and cold-sensitive enzyme, but these deficiencies could be partially overcome by a mutation in one of the RNase MRP protein subunits, or by increasing the copy number of several of the protein subunit genes. These observations suggest that the peripheral elements of the RNA hairpins contain no structures or sequences required for substrate recognition, catalysis or binding of protein subunits. Thus, the functionally essential elements of the RNase MRP RNA appear to be concentrated in the core of the subunit.


Drug interference in laboratory testing.
Characteristic problems in the interpretation data when a drug or its metabolite interferes with a laboratory procedure are reviewed. Various mechanisms of interference (physical, chemical, pharmacological and drug-drug interaction) are discussed. The role of a computerized drug-test interference file in assisting in the predication as well as interpretation of apparent test results is described.


The Effectiveness of Specific Exercise Approach or Modifiable Heel Lift in the Treatment of Functional Leg Length Discrepancy in Early Post-surgery Inpatients after Total Hip Arthroplasty: A Randomized Controlled Trial with a PROBE design.
This study investigated the effectiveness of a specific exercise approach (SEA) or modifiable heel lift (MHL) to improve functional leg length discrepancy (LLD) after total hip arthroplasty (THA). The study was a randomized controlled trial with a PROBE (prospective, randomized, open, blinded-endpoint) design trial. Patients (n=33) with both functional and perceived LLDs, 1 week after THA, were randomized to the SEA, MHL, or control groups. Patients in the SEA group performed 2 weeks of exercises to improve hip contracture and lumbar scoliosis. Patients in the MHL group used an insole-type heel lift to correct functional LLD. The control group received normal postoperative care, comprising standard rehabilitation after THA. The primary outcomes were functional LLD, measured by a block test, and patient-perceived LLD at 3 weeks after the surgery. Secondary outcomes included the visual analog scale (VAS) for pain, the Timed Up and Go (TUG) test, and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 3 weeks after the surgery. The functional LLDs (mean ± SD) for the SEA (3.3 ± 3.1 mm) and MHL (2.2 ± 2.1 mm) groups were significantly smaller than for the control group (6.4 ± 4.0 mm). The degree of patient-perceived LLD differed significantly between the SEA and the control groups (p=.005). SEA and MHL use, during early post-operative recovery, can produce relevant changes in functional LLD after THA.


Stopped-flow studies of the kinetics of single-stranded DNA binding and wrapping around the Escherichia coli SSB tetramer.
We have examined the kinetic mechanism for binding of the homotetrameric Escherichia coliSSB protein to single-stranded oligodeoxynucleotides [(dT)(70) and (dT)(35)] under conditions that favor the formation of a fully wrapped ssDNA complex in which all four subunits interact with DNA. Under these conditions, a so-called (SSB)(65) complex is formed in which either one molecule of (dT)(70) or two molecules of (dT)(35) bind per tetramer. Stopped-flow studies monitoring quenching of the intrinsic SSB Trp fluorescence were used to examine the initial binding step. To examine the kinetics of ssDNA wrapping, we used a single-stranded oligodeoxythymidylate, (dT)(66), that was labeled on its 3'-end with a fluorescent donor (Cy3) and on its 5'-end with a fluorescent acceptor (Cy5). Formation of the fully wrapped structure was accompanied by extensive fluorescence resonance energy transfer (FRET) from Cy3 to Cy5 since the two ends of (dT)(66) are in close proximity in the fully wrapped complex. Our results indicate that initial ssDNA binding to the tetramer is very rapid, with a bimolecular rate constant, k(1,app), of nearly 10(9) M(-1) s(-1) in the limit of low salt concentration (<0.2 M NaCl, pH 8.1, 25.0 degrees C), whereas the rate of dissociation is very low at all salt concentrations that were examined (20 mM to 2 M NaCl or NaBr). However, the rate of initial binding and the rate of formation of the fully wrapped complex are identical, indicating that the rate of wrapping of the ssDNA around the SSB tetramer is very rapid, with a lower limit rate of 700 s(-1). The implications of this rapid binding and wrapping reaction are discussed.


Jasmonates regulate apical hook development by repressing brassinosteroid biosynthesis and signaling.
An apical hook is a special structure formed during skotomorphogenesis in dicotyledonous plant species. It is critical for protecting the shoot apical meristem from mechanical damage during seed germination and hypocotyl elongation in soil. Brassinosteroid (BR) and jasmonate (JA) phytohormones antagonistically regulate apical hook formation. However, the interrelationship between BRs and JAs in this process has not been well elucidated. Here, we reveal that JAs repress BRs to regulate apical hook development in Arabidopsis (Arabidopsis thaliana). Exogenous application of methyl jasmonate (MeJA) repressed the expression of the rate-limiting BR biosynthetic gene DWARF4 (DWF4) in a process relying on 3 key JA-dependent transcription factors, MYC2, MYC3, and MYC4. We demonstrated that MYC2 interacts with the critical BR-activated transcription factor BRASSINAZOLE RESISTANT 1 (BZR1), disrupting the association of BZR1 with its partner transcription factors, such as those of the PHYTOCHROME INTERACTING FACTOR (PIF) family and downregulating the expression of their target genes, such as WAVY ROOT GROWTH 2 (WAG2), encoding a protein kinase essential for apical hook development. Our results indicate that JAs not only repress the expression of BR biosynthetic gene DWF4 but, more importantly, attenuate BR signaling by inhibiting the transcriptional activation of BZR1 by MYC2 during apical hook development.


The Islamic Perspective of Spiritual Intervention Effectiveness on Bio-Psychological Health Displayed by Gene Expression in Breast Cancer Patients.
During the last two decades, there have been spiritual/religious interventions in cancer patients to prevent or treat a range of physical problems, including managing chronic pain, coping with the disease, boosting hope and mental health. Although societies are of different faiths and belief systems, what they all share is spirituality. Upon this we put forward the hypothesis of changes in gene receptor expressions as a result of spiritual intervention for the first time in the world. In this study, the spiritual intervention was conducted on 57 volunteer females with early breast cancer involvement. Blood samples were collected prior to and after the spiritual intervention to analyze the changes in dopamine gene receptor expressions as the main site of effect. In order to administer the spiritual intervention backed by Quran, Islam and international standards, issues, with emphasis on peace, human growth and perfection, accepting God as an eternal source of power and kindness to build trust and reduce stress, were selected. They included prayer, patience, reliance, self-sacrifice and forgiveness, altruism and kindness, remission and repentance, thankfulness, zikr (mantra), meditation, and death concept. Obtained results from peripheral blood mononuclear cell samples analyzed by real time-PCR showed significant reduction in dopamine gene receptor (DRD1-5) expressions in comparison with those of pre-test scores and the control group. Spiritual intervention based on Islamic principals can bring back mental health, increase hope and quality of life and eventually change dopamine gene receptor expressions resulting in reduction of cell proliferation, thus better prevention and management in breast cancer patients compared to other forms of treatment.


Enzymatic activity of a subtilisin homolog, Tk-SP, from Thermococcus kodakarensis in detergents and its ability to degrade the abnormal prion protein.
Tk-SP is a member of subtilisin-like serine proteases from a hyperthermophilic archaeon Thermococcus kodakarensis. It has been known that the hyper-stable protease, Tk-SP, could exhibit enzymatic activity even at high temperature and in the presence of chemical denaturants. In this work, the enzymatic activity of Tk-SP was measured in the presence of detergents and EDTA. In addition, we focused to demonstrate that Tk-SP could degrade the abnormal prion protein (PrPSc), a protease-resistant isoform of normal prion protein (PrPC). Tk-SP was observed to maintain its proteolytic activity with nonionic surfactants and EDTA at 80°C. We optimized the condition in which Tk-SP functions efficiently, and demonstrated that the enzyme is highly stable in the presence of 0.05% (w/v) nonionic surfactants and 0.01% (w/v) EDTA, retaining up to 80% of its activity. Additionally, we also found that Tk-SP can degrade PrPSc to a level undetectable by western-blot analysis. Our results indicate that Tk-SP has a great potential for technological applications, such as thermo-stable detergent additives. In addition, it is also suggested that Tk-SP-containing detergents can be developed to decrease the secondary infection risks of transmissible spongiform encephalopathies (TSE).


Development of a monoclonal antibody-based sandwich ELISA for peanut allergen Ara h 1 in food.
We have established a highly sensitive sandwich enzyme-linked immunosorbent assay (ELISA) based on two monoclonal antibodies (mAb) to measure the content of the major peanut allergen Ara h 1 in foods. Two mAbs were selected out of 12 murine hybridoma cells secreting Ara h 1-specific antibody. Using mAb 6 as the capture antibody and HRP-labelled mAb 4 as the detection antibody, the limit of detection (LOD) the assay was 0.34 ng/mL. Cross-reaction analysis showed that this method was strongly specific and had no cross-reactions with Ara h 2, pea protein or soy protein. Sample analysis showed that this ELISA was a useful tool to monitor peanut allergens in food products by measuring Ara h 1 content.


Modafinil for the treatment of pain-associated fatigue: review and case report.
Fatigue is a symptom that is frequently found in chronic pain patients with low back pain and/or neck pain. At the present time, no specific psychopharmacological treatment for this problem has been identified. Modafinil is a wakefulness-promoting agent that the FDA has approved for the treatment of excessive daytime sleepiness associated with narcolepsy. There have been reports on the use of modafinil for the treatment of fatigue in various neurological syndromes. This literature is reviewed. As such, modafinil treatment was initiated for a patient with severe fatigue associated with chronic low back pain and neck pain. There was dramatic improvement in fatigue and associated function. This case is described. It is the first such case report in the literature. The significance of this finding to the treatment of pain-associated fatigue is discussed.


Hypopharyngeal or esophageal perforation in neonates.
In spite of the many manipulations that are done in the upper airways of neonates, esophageal perforations are rare. But they may be life-threatening if not recognized and treated immediately. Along with a case history we present clinical and radiologic symptoms of a right sided pneumothorax and the feeding tube in the posterior phrenic recess. The principles of treatment are conservative with antibiotics and intravenous gavage feeding. Only with complications intensive radiography with contrast agents and surgery become necessary.


Synergistic Cytotoxicity from Drugs and Cytokines In Vitro as an Approach to Classify Drugs According to Their Potential to Cause Idiosyncratic Hepatotoxicity: A Proof-of-Concept Study.
Idiosyncratic drug-induced liver injury (IDILI) typically occurs in a small fraction of patients and has resulted in removal of otherwise efficacious drugs from the market. Current preclinical testing methods are ineffective in predicting which drug candidates have IDILI liability. Recent results suggest that immune mediators such as tumor necrosis factor-α (TNF) and interferon-γ (IFN) interact with drugs that cause IDILI to kill hepatocytes. This proof-of-concept study was designed to test the hypothesis that drugs can be classified according to their ability to cause IDILI in humans using classification modeling with covariates derived from concentration-response relationships that describe cytotoxic interaction with cytokines. Human hepatoma (HepG2) cells were treated with drugs associated with IDILI or with drugs lacking IDILI liability and cotreated with TNF and/or IFN. Detailed concentration-response relationships were determined for calculation of parameters such as the maximal cytotoxic effect, slope, and EC50 for use as covariates for classification modeling using logistic regression. These parameters were incorporated into multiple classification models to identify combinations of covariates that most accurately classified the drugs according to their association with human IDILI. Of 14 drugs associated with IDILI, almost all synergized with TNF to kill HepG2 cells and were successfully classified by statistical modeling. IFN enhanced the toxicity mediated by some IDILI-associated drugs in the presence of TNF. In contrast, of 10 drugs with little or no IDILI liability, none synergized with inflammatory cytokines to kill HepG2 cells and were classified accordingly. The resulting optimal model classified the drugs with extraordinary selectivity and specificity.


Mistaken identity: severe vomiting, bradycardia and hypotension after eating a wild herb.
A 53-year-old woman presented with severe vomiting 3.5 hours after eating a boiled wild herb thought to be Hosta montana. She was alert, and did not complain of diplopia or numbness of her limbs. Her vital signs were temperature of 35.9°C, blood pressure of 84/33 mmHg, and heart rate of 59 beats/minute. There was no arrhythmia or conduction block on electrocardiogram. Her blood pressure and heart rate were decreased to 75/44 mmHg and 51 beats/minute at the minimum, respectively. Complete blood count and serum chemistry were normal. The herb was correctly identified when the patient's husband brought in the herb for identification.


Percentages of oleic acid and arachidonic acid are inversely related in phospholipids of human sera.
Many health effects of oils rich in oleic acid (18:1 n9) seem to be opposite those of arachidonic acid (20:4 n6), i.e. concerning cardiovascular risk. In recent study in rats we observed that percentages of oleic acid and arachidonic acid were inversely related in total serum lipids. In the present work we investigate whether an inverse relationship between this couple of fatty acids also exists in the phospholipid fraction of human sera. The study group consisted of 11 men and 35 women. Mean age was 23.8 ± 2.5 years (mean ± SD), and the body mass index was 23.5 ± 3.2 kg/m2. After fasting overnight, blood was drawn and the concentration of fatty acids in serum phospholipids was determined, using gas chromatography. We studied the association between percentages of oleic acid and arachidonic acid using bivariate correlations (Pearson), and multiple linear regressions. We found an inverse relationship (r = -0.563, p < 0.001; n = 46) between % oleic acid and % arachidonic acid in the serum phosholipid fraction of the 46 fasting subjects. By multiple linear regression, and % 20:4 n6 as the dependent variable, the inverse association with % 18:1 n9 persisted when controlling for sex, age, body mass index, and percentages of the other fatty acids measured (t = -17.6, p < 0.001). Per cent 20:4 n6 seemed to correlate negatively (r = -0.289, p = 0.05) with the (18:1 n9)/(18:0) ratio, estimating Delta9 desaturase activity, and % oleic acid correlated negatively (r = -0.321, p = 0.029) with the (20:4)/(18:2) ratio, estimating desaturases/elongase activities. In a group of healthy human subjects, percentages of oleic acid and arachidonic acid were inversely related, and the inverse association persisted when controlling for possible confounding variables. The findings might contribute to explain positive health effects of foods rich in oleic acid.


Uniform trichromacy in Alouatta caraya and Alouatta seniculus: behavioural and genetic colour vision evaluation.
Primate colour vision depends on a matrix of photoreceptors, a neuronal post receptoral structure and a combination of genes that culminate in different sensitivity through the visual spectrum. Along with a common cone opsin gene for short wavelengths (sws1), Neotropical primates (Platyrrhini) have only one cone opsin gene for medium-long wavelengths (mws/lws) per X chromosome while Paleotropical primates (Catarrhini), including humans, have two active genes. Therefore, while female platyrrhines may be trichromats, males are always dichromats. The genus Alouatta is inferred to be an exception to this rule, as electrophysiological, behavioural and molecular analyses indicated a potential for male trichromacy in this genus. However, it is very important to ascertain by a combination of genetic and behavioural analyses whether this potential translates in terms of colour discrimination capability. We evaluated two howler monkeys (Alouatta spp.), one male A. caraya and one female A. seniculus, using a combination of genetic analysis of the opsin gene sequences and a behavioral colour discrimination test not previously used in this genus. Both individuals completed the behavioural test with performances typical of trichromatic colour vision and the genetic analysis of the sws1, mws, and lws opsin genes revealed three different opsin sequences in both subjects. These results are consistent with uniform trichromacy in both male and female, with presumed spectral sensitivity peaks similar to Catarrhini, at ~ 430 nm, 532 nm, and 563 nm for S-, M- and L-cones, respectively.


An integrated transcriptional switch at the β-selection checkpoint determines T cell survival, development and leukaemogenesis.
In T cell development, a pivotal decision-making stage, termed β-selection, integrates a TCRβ checkpoint to coordinate survival, proliferation and differentiation to an αβ T cell. Here, we review how transcriptional regulation coordinates fate determination in early T cell development to enable β-selection. Errors in this transcription control can trigger T cell acute lymphoblastic leukaemia. We describe how the β-selection checkpoint goes awry in leukaemic transformation.


Do shallow soil, low water availability, or their combination increase the competition between grasses with different root systems in karst soil?
Uneven soil depth and low water availability are the key limiting factors to vegetation restoration and reconstruction in limestone soils such as in vulnerable karst regions. Belowground competition will possibly increase under limited soil resources. Here, we investigate whether low resource availability (including shallow soil, low water availability, and shallow soil and low water availability combined) stimulates the competition between grasses with different root systems in karst soil, by assessing their growth response, biomass allocation, and morphological plasticity. In a full three-way factorial blocked design of soil depth by water availability by neighbor identity, we grew Festuca arundinacea (deep-rooted) and Lolium perenne (shallow-rooted) under normal versus shallow soil depth, high versus low water availability, and in monoculture (conspecific neighbor) versus mixture (neighbor of the other species). The key results were as follows: (1) total biomass and aboveground biomass in either of the species decreased with reduction of resources but were not affected by planting patterns (monoculture or mixture) even at low resource levels. (2) For F. arundinacea, root biomass, root mass fraction, total root length, and root volume were higher in mixture than in monoculture at high resource level (consistent with resource use complementarity), but lower in mixture than in monoculture at low resource levels (consistent with interspecific competition). In contrast for L. perenne, either at high or low resource level, these root traits had mostly similar values at both planting patterns. These results suggest that deep-rooted and shallow-rooted plant species can coexist in karst regions under current climatic regimes. Declining resources, due to shallow soil, a decrease in precipitation, or combined shallow soil and karst drought, increased the root competition between plants of deep-rooted and shallow-rooted species. The root systems of deep-rooted plants may be too small to get sufficient water and nutrients from dry, shallow soil, while shallow-rooted plants will maintain a dominant position with their already adaptive strategy in respect of root biomass allocation and root growth.


Reemergence of dengue in Mauritius.
Dengue reemerged in Mauritius in 2009 after an absence of >30 years, and >200 cases were confirmed serologically. Molecular studies showed that the outbreak was caused by dengue virus type 2. Phylogenetic analysis of the envelope gene identified 2 clades of the virus. No case of hemorrhagic fever was recorded.


In Vivo Quantification of Cardiac-Pulsatility-Induced Motion Before and After Double-Branched Endovascular Aortic Arch Repair.
The Relay®Branch stent-graft (Terumo Aortic, Sunrise, FL, USA) offers a custom-made endovascular solution for complex aortic arch pathologies. In this technical note, a modified electrocardiography (ECG)-gated computed tomography (CT)-based algorithm was applied to quantify cardiac-pulsatility-induced changes of the aortic arch geometry and motion before and after double-branched endovascular repair (bTEVAR) of an aortic arch aneurysm. This software algorithm has the potential to provide novel and clinically relevant insights in the influence of bTEVAR on aortic anatomy, arterial compliance, and stent-graft dynamics.


Mean dose rate in ultra-high dose rate electron irradiation is a significant predictor for O2consumption and H2O2yield.
Objective. The objective of this study was to investigate the impact of mean and instantaneous dose rates on the production of reactive oxygen species (ROS) during ultra-high dose rate (UHDR) radiotherapy. The study aimed to determine whether either dose rate type plays a role in driving the FLASH effect, a phenomenon where UHDR radiotherapy reduces damage to normal tissues while maintaining tumor control.Approach. Assays of hydrogen peroxide (H2O2) production and oxygen consumption (ΔpO2) were conducted using UHDR electron irradiation. Aqueous solutions of 4% albumin were utilized as the experimental medium. The study compared the effects of varying mean dose rates and instantaneous dose rates on ROS yields. Instantaneous dose rate was varied by changing the source-to-surface distance (SSD), resulting in instantaneous dose rates ranging from 102to 106Gy s-1. Mean dose rate was manipulated by altering the pulse frequency of the linear accelerator (linac) and by changing the SSD, ranging from 0.14 to 1500 Gy s-1.Main results. The study found that both ΔH2O2and ΔpO2decreased as the mean dose rate increased. Multivariate analysis indicated that instantaneous dose rates also contributed to this effect. The variation in ΔpO2was dependent on the initial oxygen concentration in the solution. Based on the analysis of dose rate variation, the study estimated that 7.51 moles of H2O2were produced for every mole of O2consumed.Significance. The results highlight the significance of mean dose rate as a predictor of ROS production during UHDR radiotherapy. As the mean dose rate increased, there was a decrease in oxygen consumption and in H2O2production. These findings have implications for understanding the FLASH effect and its potential optimization. The study sheds light on the role of dose rate parameters and their impact on radiochemical outcomes, contributing to the advancement of UHDR radiotherapy techniques.


Association Between Single Nucleotide Polymorphisms in the Vitamin D Receptor and Incidence of Dry Eye Disease in Chinese Han Population.
BACKGROUND Dry eye disease (DED) is a chronic dysfunction of the ocular surface and has become an important public problem. Vitamin D receptor (VDR) gene polymorphism has been found to be associated with different kinds of diseases. The relationship between single nucleotide polymorphisms (SNPs) in the VDR gene should be studied. MATERIAL AND METHODS In the present case-control study, we investigated the association of VDR gene polymorphism with DED risk. Clinical data including age, gender, body mass index (BMI, kg/m²), smoking history, diabetes, and blood pressure were recorded. Serum 25-hydroxy vitamin D (25[OH]D) was chosen as the main parameter that reflected the level of vitamin D. We identified SNPs of VDR gene Apa-1, Bsm-1, Fok-1, and Taq-1 in both DED cases and healthy controls. RESULTS A total of 124 DED cases and 135 healthy controls were included in this study. It was reported that aa in Apa-1 (OR=2.803, 95% CI, 1.350-5.820) and tt in Taq-1 (OR=0.362, 95% CI, 0.141-0.930) were associated with increased the risk of DED. Analysis of the allele frequencies of VDR gene polymorphisms among DED patients and healthy controls showed that allele differences in Apa-1 were significantly associated with higher risk. CONCLUSIONS SNPs of VDR gene (Apa-1 and Taq-1) were associated with the risk of DED. No significant association of Bsm-1 and Fok-1 in VDR gene demonstrated significant effect in the incidence of DED. Thus, we found that several SNPs of VDR gene could provide significant pathogenic effects in the risk of DED.


Disseminated syringomas of the upper extremities. Case history and immunohistochemical and ultrastructural study.
A case of disseminated syringomas with unusual distribution and high age of onset is reported. The 66-year-old male patient presented with multiple lesions confined to dorsum of both hands and flexor side of both forearms. Morphological and immunohistochemical studies using keratin, S-100, carcinoembryonic antigen, and epithelial membrane antigen antibodies were performed both at light microscopical and ultrastructural level. These investigations revealed the presence of keratin filament containing colloid bodies near syringomatous epithelia. Reactivity for carcinoembryonic antigen could be demonstrated on the membranes of intracytoplasmic vesicles as well as within luminal debris. Absence of S-100 and epithelial membrane antigen in the tumor and ultrastructural features indicate ductal origin of syringoma.


Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors worldwide, with a high malignant degree and poor prognosis. The present study aims to investigate the relationship between pyruvate kinase M2 (PKM2) expression and the prognosis of patients with ESCC. The expression of PKM2 in 86 cases of esophageal carcinoma tissues was tested using immunohistochemistry. The relationship between PKM2 expression and clinical pathological parameters, and their effects on the prognosis of patients with ESCC were analyzed. The expression levels of PKM2 in both cytoplasm and nucleus of ESCC tissues were significantly higher than those in paracancerous tissues (P=6.73×10(-9) and 4.32×10(-6), respectively). The Kaplan-Meier analysis showed that nuclear PKM2 expression was closely related to the survival of patients with ESCC (P=0.005). Patients with high PKM2 expression in the nucleus had significantly shorter survival times than those with low PKM2 expression in the nucleus (hazard ratio for death, 2.358; 95% confidence interval, 1.156-4.812; P=0.018). No other significant difference was found between PMK2 expression and clinico-pathological features of ESCC patients (all P>0.05). In conclusion, high PKM2 expression in the nucleus is essential in the pathogenic process of ESCC and may be used to predict the prognosis of patients with ESCC.


Effects of coenzyme Q10 in a propofol infusion syndrome model of rabbits.
Coenzyme Q (CoQ) might be the main site of interaction with propofol on the mitochondrial respiratory chain in the propofol infusion syndrome (PRIS) because of the structural similarity between coenzyme Q10 (CoQ10) and propofol. To investigate the effects of CoQ10 on survival and organ injury in a PRIS model in rabbits. Sixteen male New Zealand white rabbits were divided into 4 groups: (1) propofol infusion group, (2) propofol infusion and CoQ10, 100 mg/kg was administered intravenously, (3) sevoflurane inhalation was administered, and (4) sevoflurane inhalation and CoQ10, 100 mg/kg intravenously, was administered. Arterial blood gas and biochemical analyses were repeated every 2 h and every 12 h, respectively. Animals that were alive on the 24th hour after anesthesia induction were euthanized. The organ damages were investigated under light and transmission electron microscopy (TEM). The propofol infusion group had the highest troponin T levels when compared with the other three groups at the 12th hour. The propofol + CoQ10 group had lower troponin T levels when compared with the propofol and sevoflurane groups (P < 0.05). Administration of CoQ10 decreased total liver injury scores and total organ injury scores both in the propofol and sevoflurane groups. The propofol and sevoflurane organ toxicities were attenuated with CoQ10 in liver, gallbladder, urinary bladder, and spleen. The addition of CoQ10 to propofol and sevoflurane anesthesia prevented the propofol-associated increase in troponin T levels at the 12th hour of infusion and decreased anesthetic-induced total liver and organ injury scores.


Anthrax Toxin-Expressing Bacillus cereus Isolated from an Anthrax-Like Eschar.
Bacillus cereus isolates have been described harboring Bacillus anthracis toxin genes, most notably B. cereus G9241, and capable of causing severe and fatal pneumonias. This report describes the characterization of a B. cereus isolate, BcFL2013, associated with a naturally occurring cutaneous lesion resembling an anthrax eschar. Similar to G9241, BcFL2013 is positive for the B. anthracis pXO1 toxin genes, has a multi-locus sequence type of 78, and a pagA sequence type of 9. Whole genome sequencing confirms the similarity to G9241. In addition to the chromosome having an average nucleotide identity of 99.98% when compared to G9241, BcFL2013 harbors three plasmids with varying homology to the G9241 plasmids (pBCXO1, pBC210 and pBFH_1). This is also the first report to include serologic testing of patient specimens associated with this type of B. cereus infection which resulted in the detection of anthrax lethal factor toxemia, a quantifiable serum antibody response to protective antigen (PA), and lethal toxin neutralization activity.


Farnesylation of Batten disease CLN3 protein.
The carboxyl terminal of the predicted amino acid sequence of the Batten disease CLN3 gene protein is CQLS. This motif is expected to be a site for farnesylation at the cysteine residue. In order to determine whether this is indeed farnesylated we have carried out the in-vitro prenylation of tetrapeptides CVLS, CAIL and CQLS using a farnesyl transferase preparation from bovine brain. The data shows that the CQLS is a good acceptor of a farnesyl group similar to CVLS while it is a poor acceptor of a geranylgeranyl group unlike CAIL, which is a good acceptor of a geranylgeranyl group. This suggests that the CLN3 gene product may be a farnesylated protein.


Brønsted Acid-Initiated Formal [1,3]-Rearrangement Dictated by β-Substituted Ene-Aldimines.
The rearrangement of ene-aldimines is a useful reaction for affording homoallylic amines. Despite their utilities in synthetic chemistry, the rearrangement for accessing homoallylic amines substituted at the 2-position remains elusive. In this study, the Brønsted acid-initiated formal [1,3]-rearrangement of ene-aldimines was developed to synthesize 2,4,4-substituted homoallylic amines that were otherwise inaccessible previously. Our study reveals an intermolecular pathway in which the rearrangement proceeds via a protonation-mediated 2-azaallenium cation.


Invasive candidal enterocolitis followed shortly by fatal cerebral hemorrhage in immunocompromised patients.
Two immunocompromised adult patients (male, 43 years of age; female, 50 years of age) are described who developed unusual and similarly unique complications. After chemotherapy, both presented with abdominal pain and severe bloody diarrhea. Initial blood cultures were negative, and abdominal CT showed pneumatosis and thickening of colonic wall. Colonoscopy showed severe right-sided colitis. Relentless bloody diarrhea necessitated emergency right hemicolectomy in both cases. Pathologic examination of the specimens showed extensive and severe hematogenous Candida enterocolitis. Both patients died of acute cerebral hemorrhage within 3 days of hemicolectomy. Autopsy, performed on 1 of the 2 cases, showed diffuse severe cerebritis and cerebral hemorrhage secondary to hematogenous invasive candidiasis. This sequence of events is not documented in the English literature on candidal enterocolitis, which is reviewed.


Group B streptococcus in a general hospital.
Eighty-six percent of 707 beta-hemolytic streptococci isolated in a general hospital and excluded by presumptive tests from groups A and D were identified serologically as group B. More than 70% of the group B isolates were from urine cultures, the female genital gract, or newborn infants. Types III and II were the most common group B serotypes from most sources. However, types Ia, Ib, and Ic were more commonly isolated from the respiratory tract than from other sites, and type III was responsible for most serious neonatal infections. All group B streptococci were sensitive in vitro to comparable levels of penicillin G, ampicillin, and cephalothin and were highly resistant to kanamycin. Seventy-two percent were resistant to tetracycline but only 1%-2% to erythromycin, clindamycin, and chloramphenicol. Despite consistent sensitivity to penicillin G, the minimal inhibitory concentrations were significantly higher for group B than for group A streptococci.


Bias induced spin transitions of spin crossover molecules: the role of charging effect.
The spin transition of spin crossover molecules induced by bias voltages from low spin to high spin was observed recently and several mechanisms were suggested to understand it. However, these mechanisms fail to explain the dependence of spin transitions on the bias polarity in experiments and thus may still be questionable. Based on a first-principles study, we propose that the bias-induced spin transition is triggered by a charging effect, namely, the filling of the lowest unoccupied molecular orbital of spin crossover molecules. Our proposal is substantiated by three steps: (1) the spin transition from low spin to high spin can be achieved by charging the isolated spin crossover molecules with one extra electron; (2) in molecular junctions, the charging of spin crossover molecules can be realized by electron transfer from electrodes to molecules under finite bias; (3) more importantly, the electron transfer is dependent on the bias polarity due to asymmetrical couplings of the sandwiched molecule with two electrodes. This mechanism satisfactorily explains the bias-polarity dependent spin transitions in experiments [Miyamachi et al., Nat. Commun., 2012, 3, 938; Gopakumar et al., Angew. Chem. Int. Ed., 2012, 51, 6262].


Primary activation of cytosolic phosphoenolpyruvate carboxykinase gene in fetal rat liver and the biogenesis of its mRNA.
The primary appearance of phosphoenolpyruvate (P-pyruvate) carboxykinase RNA transcripts in fetal liver was induced by a number of different stimulii . This may occur as rapidly as an hour after injection in utero of N6,O2'-dibutyryl-adenosine 3',5'-monophosphate (Bt2cAMP) to fetuses, suggesting that all stimulii predominantly affect activation of the P-pyruvate carboxykinase gene. Bt2cAMP treatment induces the appearance of the enzyme RNA transcripts, predominantly of the mature type in the cytoplasm. However, insulin deficiency by streptozotocin treatment causes the appearance of large-size as well as mature mRNA in the nucleus, in addition to the appearance of P-pyruvate carboxykinase mRNA in the cytoplasm. Insulin treatment of such diabetic fetuses, prior to causing the disappearance of P-pyruvate carboxykinase mRNA, reduces nuclear transcripts but increases the abundance of mature cytoplasmic enzyme mRNA. Bt2cAMP treatment of insulin-deficient fetuses causes an additive effect, increasing the abundance of not only the mature but the large P-pyruvate carboxykinase RNA transcripts as well. The results are best interpreted as insulin acting both to inhibit transcription of and accelerate post-transcriptional processes affecting P-pyruvate carboxykinase RNA.


Titrimetric method for determination of O-desulfated heparin in physiological samples using protamine-sensitive membrane electrode as endpoint detector.
O-Desulfated heparin (ODSH) is a promising new anti-inflammatory agent for the prevention of reperfusion injury following myocardial infarction or stroke. This partially desulfated heparin derivative has less anticoagulant activity than unfractionated heparin but retains the inherent anti-inflammatory properties of heparin. Thus, ODSH could be administered at the high doses needed to achieve desired anti-inflammatory function without risk of hemorrhage. However, given the very low anticoagulant activity of this species, traditional methods for heparin determination in clinical samples might not be well suited for ODSH measurements. In this article, a novel titrimetric method for detection of ODSH in buffer and plasma is described using a protamine-sensitive polymer membrane electrode as the detector. Titrations of ODSH with the heparin antagonist protamine yield sharp endpoints with sensitivity to ODSH in the micrograms per milliliter range for plasma samples. The stoichiometry for protamine interaction with ODSH is determined to average 1.39 microg protamine/microg ODSH in plasma. This technology is further applied to a toxicokinetic study of ODSH in an animal model, demonstrating the ability to detect the changes in ODSH concentrations in biological samples.


Mass Casualty Incident Primary Triage Methods in China.
To evaluate the technical characteristics and application of mass casualty incident (MCI) primary triage (PT) methods applied in China. Chinese literature was searched by Chinese Academic Journal Network Publishing Database (founded in June 2014). The English literature was searched by PubMed (MEDLINE) (1950 to June 2014). We also searched Official Websites of Chinese Central Government's (http://www.gov.cn/), National Health and Family Planning Commission of China (http://www.nhfpc.gov.cn/), and China Earthquake Information (http://www.csi.ac.cn/). We included studies associated with mass casualty events related to China, the PT applied in China, guidelines and standards, and application and development of the carding PT method in China. From 3976 potentially relevant articles, 22 met the inclusion criteria, 20 Chinese, and 2 English. These articles included 13 case reports, 3 retrospective analyses of MCI, two methods introductions, three national or sectoral criteria, and one simulated field testing and validation. There were a total of 19 kinds of MCI PT methods that have been reported in China from 1950 to 2014. In addition, there were 15 kinds of PT methods reported in the literature from the instance of the application. The national and sectoral current triage criteria are developed mainly for earthquake relief. Classification is not clear. Vague criteria (especially between moderate and severe injuries) operability are not practical. There are no triage methods and research for children and special populations. There is no data and evidence supported triage method. We should revise our existing classification and criteria so it is clearer and easier to be grasped in order to build a real, practical, and efficient PT method.


Physicochemical principles of controlled release solid dispersion containing a poorly water-soluble drug.
The aim of this study was to investigate the physicochemical properties of polyethylene oxide (PEO)-based controlled release solid dispersions (CR-SDs) containing aceclofenac, Gelucire 44/14, poloxamer 407 and pH modifier (Na2CO3). The immediate release solid dispersions containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while the CR-SDs with PEO showed controlled release. A bigger droplet size and a higher surface charge for the CR-SDs were observed compared with the immediate release solid dispersions. The pH modifier played an important role in modulating the release rate of the drug through changes in the drug crystallinity and the hydrogen-bonding interaction, as well as the microenvironmental pH. Near-infrared images revealed a modulation of the PEO concentration to preserve the pH modifier within the system for controlled release of the drug. The dissolution process of PEO-based solid dispersions containing a water-insoluble drug was governed by the changing net effect of the microenvironmental pH, the surface charge, the particle size and the release rate of the pH modifier, as well as the function of PEO in controlling drug release.


Cerebellar anatomy as applied to cerebellar microsurgical resections.
To define the anatomy of dentate nucleus and cerebellar peduncles, demonstrating the surgical application of anatomic landmarks in cerebellar resections. Twenty cerebellar hemispheres were studied. The majority of dentate nucleus and cerebellar peduncles had demonstrated constant relationship to other cerebellar structures, which provided landmarks for surgical approaching. The lateral border is separated from the midline by 19.5 mm in both hemispheres. The posterior border of the cortex is separated 23.3 mm from the posterior segment of the dentate nucleus; the lateral one is separated 26 mm from the lateral border of the nucleus; and the posterior segment of the dentate nucleus is separated 25.4 mm from the posterolateral angle formed by the junction of lateral and posterior borders of cerebellar hemisphere. Microsurgical anatomy has provided important landmarks that could be applied to cerebellar surgical resections.


Chemical and functional properties of mutastein, an inhibitor of insoluble glucan synthesis by Streptococcus sobrinus.
Mutastein, a potent inhibitor of insoluble glucan synthesis by Streptococcus sobrinus, is a protein with a molecular weight of approximately 2 x 10(6). Amino acid and ELISA analyses suggested that mutastein is a mixture of heterogenous polymers of alpha-casein contained in the culture medium of the producing strain, Aspergillus terreus M3328. Mutastein strongly inhibited the primer-dependent insoluble glucan synthase of S. sobrinus B13. The primer-independent soluble glucan synthase was not affected by mutastein while primer-dependent soluble glucan synthase was slightly activated.


Characterization of vulvar skin of healthy Thai women: influence of sites, age and menopause.
Although the physiological characteristics of vulvar skin have been characterized in Caucasians, little is known about the vulvar skin of Asian women. This study assessed the moisture content, transepidermal water loss (TEWL) and pH of vulvar skin of 99 healthy Asian women residing in Bangkok, aged 20-69 years, during their non-menstrual period, including 39 post-menopausal women. Skin pH was acidic at all sites, and the pH of the vulvar areas was significantly higher than the control sites (inner thigh, inner forearm). Skin moisture was slightly, but significantly, lower around the vulvar area and the thigh than around the forearm. TEWL was significantly higher in vulvar areas than control sites. Ageing and menopause did not cause notable alterations in most properties of vulvar skin. In conclusion, the vulvar skin of Asian women has similar properties to that of Caucasians.


Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review.
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated neurological disorder that (among other severe neuropsychiatric symptoms) affects cognition. This study aimed to summarize current knowledge regarding the rates, nature, and predictors of neuropsychological dysfunction in patients recovering from anti-NMDAR encephalitis. A systematic review of studies describing neuropsychological outcomes following anti-NMDAR encephalitis was conducted. Electronic databases Medline, PsycINFO, EMBASE, and CINAHL were searched from inception to September 2016. Results were summarized using descriptive statistics and a series of chi-square analyses. Of 4030 identified studies, 44 were included. These reported neuropsychological outcomes for 109 treated patients (83.5% female, Mage = 22.5 years, range = 2-67) recovering from anti-NMDAR encephalitis. High rates of neuropsychological dysfunction were identified, with diverse impairments of variable severity documented in >75% of patients at assessments conducted during acute, subacute, and longer term recovery periods. Despite this, cognitive outcomes were ultimately considered favorable in most cases (74.3%). This estimate does not account for the potential impact of relapses. The frequency of impairments in overall intellectual functioning, language, attention, working memory, and visuospatial functions were significantly higher within the acute recovery period than in later phases of convalescence. However, rates of impaired processing speed, episodic memory, and aspects of executive functioning were consistent across time points. Adverse neuropsychological outcomes occurred at significantly higher frequency in patients where immunotherapy was delayed, χ2(1, N = 66) = 10.84, p < .003. Neuropsychological deficits are prevalent at all points of recovery from anti-NMDAR encephalitis, although improvement in cognitive outcomes can be expected as patients recover. Some cognitive deficits may be less likely than others to resolve. Close neuropsychological monitoring is warranted in this population. Longitudinal studies of neuropsychological functioning of patients with anti-NMDAR encephalitis are needed to accurately inform prognosis.


In Vitro Metabolism Evaluation of the Ergot Alkaloid Dihydroergotamine: Application of Microsomal and Biomimetic Oxidative Model.
Dihydroergotamine is a semisynthetic natural product derived from ergotamine, an ergot alkaloid. It is used to treat migraines, a neurological disease characterized by recurrent moderate to severe headaches. In this work, the in vitro metabolism of dihydroergotamine was evaluated in a biomimetic phase I reaction, aiming to verify all possible formed metabolites. Dihydroergotamine was submitted to an in vitro metabolism assay using rat liver microsomes, and the metabolites were analyzed by HPLC-MS/MS. The biomimetic reactions were performed with Jacobsen catalyst for scaling up production of oxidized metabolites. Two hydroxylated metabolites were isolated and characterized by MS/MS and 1H NMR analysis.


Pharmacokinetics in rats and efficacy in murine ovarian cancer model for solid lipid nanoparticles loading docetaxel.
Docetaxel was used extensively in ovarian cancer treatment in the combination with platinum compound. However, the serious side effect of clinically available formulation limits its further application. The aim of this work was to evaluate the pharmacokinetic behavior, acute toxicity and in vivo antitumor efficacy in murine ovarian cancer model of docetaxel loaded solid lipid nanoparticles (DSN). The particle size of DSN was 97.4 +/- 6.4 nm, and the encapsulation efficiency and loading capacity were 91.1 +/- 1.5% and 3.52 +/- 0.05%, respectively. The release behavior of docetaxel from DSN showed that only 45% of docetaxel was released within 24 h. The pharmacokinetics and biodistribution showed that the half-life (t1/2) and mean residence time (MRT) of docetaxel in DSN treated rats were significantly elongated because of the redistribution of docetaxel from reticulo-endothelial system (RES) to circulation system. Compared with Taxotere, DSN showed more potent in vivo anti-ovarian cancer activity with higher maximum tolerated dose (MTD). Our results suggested for the first time that solid lipid nanoparticles could be a potential candidate to enhance the efficacy of anti-ovarian cancer of docetaxel with low toxicity. The systematical study on pharmacokinetics, biodistribution, in vivo anti-tumor activity and MTD of DSN could improve the understanding of increased antitumor activity of DSN in vivo.


NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo.
Protein kinase B (PKBalpha/Akt1) a PI3K-dependent serine-threonine kinase, promotes T cell viability in response to many stimuli and regulates homeostasis and autoimmune disease in vivo. To dissect the mechanisms by which PKB inhibits apoptosis, we have examined the pathways downstream of PKB that promote survival after cytokine withdrawal vs Fas-mediated death. Our studies show that PKB-mediated survival after cytokine withdrawal is independent of protein synthesis and the induction of NF-kappaB. In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor. Using gene-deficient and transgenic mouse models, we establish that NF-kappaB1, and not c-Rel, is the critical signaling molecule downstream of the PI3K-PTEN-PKB signaling axis that regulates lymphocyte homeostasis.


Acute kidney injury and other factors associated with mortality in hiv-infected patients.
HIV-related mortality is still high, especially in developed countries. The aim of this study is to investigate factors associated to death in HIV-infected patients. This is a cross-sectional study with all HIV adult patients admitted to a tertiary infectious diseases hospital in Fortaleza, Northeast Brazil, from January 2013 to December 2014. Patients were divided into two groups: survivors and non-survivors. Demo-graphical, clinical and laboratory data were compared and a logistic regression was performed in order to investigate risk factors for death. P values ≤0.05 were considered statistically significant. A total of 200 patients with mean age of 39 years were including in the study, 69.5% males. Fifteen patients (7.5%) died. Non-survivors presented a higher percentage of males (93.3 vs. 67.3%, p = 0.037). Non-survivors presented AKI (73.3 vs. 10.3%, p < 0.001), liver dysfunction (33.3 vs. 11.5, p = 0.031), dyspnea (73.3 vs. 33.0%, p = 0.002) and disorientation (33.3 vs. 12.4%, p = 0.025) more frequently. Non-survivors also had higher levels of urea (73.8 ± 52.7vs. 36.1 ± 29.1 mg/dL, p < 0.001), creatinine (1.98 ± 1.65 vs. 1.05 ± 1.07 mg/dL, p < 0.001), aspartate aminotransferase (130.8 vs. 84.8 U/L, p = 0.03), alanine aminotransferase (115.6 vs. 85.4 U/L, p = 0.045) and lactate dehydrogenase (LDH) (1208 vs. 608 U/L, p = 0.012), as well as lower levels of bicarbonate (18.0 ± 4.7 vs. 21.6 ± 4.6 mEq/L, p = 0.016) and PCO2 (27.8 ± 7.7 vs. 33.0 ± 9.3 mmHg, p = 0.05). In multivariate analysis, disorientation (p = 0.035, OR = 5.523, 95%CI = 1.130 - 26.998), dyspnoea (p = 0.046, OR = 4.064, 95%CI = 1.028 - 16.073), AKI (p < 0.001, OR = 18.045, 95%CI = 4.308 - 75.596) and disseminated histoplasmosis (p = 0.016, OR = 12.696, 95%CI = 1.618 - 99.646) and LDH > 1000 U/L (p = 0.038, OR = 4.854, 95%CI = 1.093 - 21.739) were risk factors for death.]CONCLUSION: AKI and disseminated histoplasmosis (DH) were the main risk factors for death in the studied population. Neurologic and respiratory impairment as well as higher levels of LDH also increased mortality in HIV-infected patients.


Predicting physical-chemical properties of compounds from molecular structures by recursive neural networks.
In this paper, we report on the potential of a recently developed neural network for structures applied to the prediction of physical chemical properties of compounds. The proposed recursive neural network (RecNN) model is able to directly take as input a structured representation of the molecule and to model a direct and adaptive relationship between the molecular structure and target property. Therefore, it combines in a learning system the flexibility and general advantages of a neural network model with the representational power of a structured domain. As a result, a completely new approach to quantitative structure-activity relationship/quantitative structure-property relationship (QSPR/QSAR) analysis is obtained. An original representation of the molecular structures has been developed accounting for both the occurrence of specific atoms/groups and the topological relationships among them. Gibbs free energy of solvation in water, Delta(solv)G degrees , has been chosen as a benchmark for the model. The different approaches proposed in the literature for the prediction of this property have been reconsidered from a general perspective. The advantages of RecNN as a suitable tool for the automatization of fundamental parts of the QSPR/QSAR analysis have been highlighted. The RecNN model has been applied to the analysis of the Delta(solv)G degrees in water of 138 monofunctional acyclic organic compounds and tested on an external data set of 33 compounds. As a result of the statistical analysis, we obtained, for the predictive accuracy estimated on the test set, correlation coefficient R = 0.9985, standard deviation S = 0.68 kJ mol(-1), and mean absolute error MAE = 0.46 kJ mol(-1). The inherent ability of RecNN to abstract chemical knowledge through the adaptive learning process has been investigated by principal components analysis of the internal representations computed by the network. It has been found that the model recognizes the chemical compounds on the basis of a nontrivial combination of their chemical structure and target property.


A cost-effectiveness analysis of over-the-counter statins.
To estimate the costs and benefits of over-the-counter (OTC) statins under the 2013 American College of Cardiology/American Heart Association guidelines. A 10-year cost-effectiveness model using a health system perspective was developed to analyze the impact of making an OTC statin drug available. We calibrated the model by using nationally representative survey data on statin use and cardiovascular risk, data from clinical studies on the safety and efficacy of statins, and data from a study on consumer decisions to use an OTC statin. We estimated that OTC statins would result in 252,359 fewer major coronary events, 41,133 fewer strokes, and 135,299 fewer coronary revascularization procedures over 10 years, as well as reduce coronary heart disease- and stroke-related deaths by 68,534 over the same time frame. These averted events would save more than $10.8 billion in healthcare costs while the costs of drug therapy would increase by $28.3 billion. Increased statin utilization is estimated to cause 3864 more cases of rhabdomyolysis-a very rare but severe side effect of statins. The estimated incremental cost-effectiveness ratio (ICER) of OTC statins was $5667 per quality-adjusted life-year, and the 95% CI of the ICER was $1384 to $12,701. With proper labeling and consumer education, it is highly likely that OTC statins would be cost-effective, as they significantly improve population health without large increases in healthcare costs.


Acute renal failure secondary to angiotensin II receptor blockade in a patient with bilateral renal artery stenosis.
A 54-year-old man with diabetes mellitus, peripheral vascular disease, and hypertension was admitted to the hospital for an acute exacerbation of chronic heart failure. Therapy with intravenous furosemide and oral losartan 100 mg twice/day was begun. Ten days later, the patient's blood urea nitrogen and serum creatinine levels rose and peaked at 110 and 6.0 mg/dl, respectively. His serum potassium level increased to 5.7 mg/dl, urine output dropped to 400 ml over 24 hours, and mental status changes occurred. Magnetic resonance angiography revealed bilateral renal artery stenosis. After losartan was discontinued and hemodialysis was performed for 3 consecutive days, the patient's renal function returned to his baseline level. Reports in the medical literature reinforce the importance of recognizing that angiotensin-converting enzyme inhibitors should be used with caution in patients with bilateral renal artery stenosis. However, the literature is not as definitive about using of angiotensin II receptor blockers (ARBs) in these patients. Our patient's experience suggests that ARBs should be used with caution in patients with bilateral renal artery stenosis. Clinicians should be aware that renal failure might occur when using ARBs in these patients.


Ventilation parallels plasma potassium during incremental and continuous variable intensity exercise.
The aim of the present investigation was to examine the relationship between plasma potassium (K+) and ventilation (VE) during incremental and prolonged continuous exercise which varied between low and moderate intensity. Seven well-trained male cyclists who had a mean maximal aerobic power (VO2max) of 69.4 +/- 2.9 ml/kg/min were recruited to participate as subjects. The graded incremental exercise bout was composed of 3 min stages set to elicit 40, 50, 60, 70, 80 and 90% VO2max. The continuous variable intensity exercise consisted of 30 min of cycling at 45% VO2max and then 6 x 16 min periods which consisted of cycling for 8 min at 75% VO2max and 8 min at 45% VO2max. During prolonged continuous exercise, VE and plasma K+ changed in a coordinated manner between the low and moderate intensity exercise bouts with the responses during the moderate intensity intervals being significantly greater (p < 0.05) than the responses during the low intensity intervals. During the incremental exercise test, a strong positive relationship between VE and plasma K+ concentration was found for each subject. However, a positive relationship and slope was also found when the VE/K+ ratio was correlated with exercise intensity (r = 0.90-0.99). This indicates that with increasing exercise intensity, the rise in VE becomes increasingly greater than the rise in plasma K+. These findings suggest that the plasma K+ concentration contributes to but may not be the sole determinant of ventilatory regulation during exercise.


Blood component use in orthotopic liver transplantation.
Blood component use during orthotopic liver transplantation (OLT) was evaluated after an initial 23-month experience with 37 consecutive transplant procedures. Blood component support of OLTs in 24 adult and 13 pediatric patients was reviewed. Adult procedures required intraoperatively a mean of 24.5 units of red cells (RBCs), 38.7 units of fresh-frozen plasma (FFP), 26.1 random-donor platelets (RDP), and 12.2 units of cryoprecipitate (Cryo); pediatric procedures required 4.8 units of RBCs, 5.8 of FFP, 3.9 of RDP, and 1.2 of Cryo. RBC salvage constituted 17 percent of the RBCs transfused intraoperatively. Intraoperative support in adult and pediatric OLT patients accounted for the majority of the total components required for the entire hospital stay. OLT blood component use constituted 1.3, 7.0, 3.6, and 8.1 percent of hospital-wide use of RBC, FFP, RDP, and Cryo, respectively, during the period of the study.


DFT studies on the mechanism of allylative dearomatization catalyzed by palladium.
The reaction mechanism of the Pd-catalyzed benzyl/allyl coupling of benzyl chloride with allyltributylstannan, resulting in the dearomatization of the benzyl group, was studied using density functional theory calculations at the B3LYP level. The calculations indicate that the intermediate (eta(3)-benzyl)(eta(1)-allyl)Pd(PH(3)) is responsible for the formation of the kinetically favored dearomatic product. Reductive elimination of the dearomatic product from the intermediate occurs by coupling the C-3 terminus of the eta(1)-allyl ligand and the para-carbon of the eta(3)-benzyl ligand in (eta(3)-benzyl)(eta(1)-allyl)Pd(PH(3)). For comparison, various C-C coupling reaction pathways have also been examined.


Pregnancy outcome after a first trimester sonogram demonstrating fetal cardiac activity.
We conducted a prospective study to assess pregnancy outcome after a first trimester sonogram demonstrating a singleton intrauterine gestation with fetal cardiac activity. In each of the 556 cases, data recorded included indication for the sonogram, results of the sonogram, and pregnancy outcome. Sonographic abnormalities were found more frequently in patients scanned because of symptoms (14.0%) than among patients scanned for routine indications (6.0%) (P < 0.05, chi-squared). Among 556 patients with known outcomes, the overall loss rate was 9.4%. A trend was seen toward a higher loss rate in patients with abnormal than normal sonograms (15.2% versus 8.8%). The loss rate after a normal scan was similar in symptomatic (10.6%) and asymptomatic patients (9.1%) and declined progressively with gestational age from 17.0% at 6 to 7.9 weeks to 4.3% at 12 to 13 weeks (P < 0.01, chi-squared). These results can be used to convey prognostic information to patients after a normal first trimester sonogram demonstrating fetal cardiac activity. The likelihood of a good pregnancy outcome can be stated as a function of gestational age, and a symptomatic patient can be reassured after a normal scan that her prognosis is similar to that of an asymptomatic patient with a normal sonogram.


The Combination of Neural Tracking and Alpha Power Lateralization for Auditory Attention Detection.
Purpose The acoustic source that is attended to by the listener in a mixture can be identified with a certain accuracy on the basis of their neural response recorded during listening, and various phenomena may be used to detect attention. For example, neural tracking (NT) and alpha power lateralization (APL) may be utilized in order to obtain information concerning attention. However, these methods of auditory attention detection (AAD) are typically tested in different experimental setups, which makes it impossible to compare their accuracy. The aim of this study is to compare the accuracy of AAD based on NT, APL, and their combination for a dichotic natural speech listening task. Method Thirteen adult listeners were presented with dichotic speech stimuli and instructed to attend to one of them. Electroencephalogram of the subjects was continuously recorded during the experiment using a set of 32 active electrodes. The accuracy of AAD was evaluated for trial lengths of 50, 25, and 12.5 s. AAD was tested for various parameters of NT- and APL-based modules. Results The obtained results suggest that NT of natural running speech provides similar accuracy to APL. The statistically significant improvement of the accuracy of AAD using a combined method has been observed not only for the longest duration of test samples (50 s, p = .005) but also for shorter ones (25 s, p = .011). Conclusions It seems that the combination of standard NT and APL significantly increases the effectiveness of accurate identification of the traced signal perceived by a listener under dichotic conditions. It has been demonstrated that, under certain conditions, the combination of NT and APL may provide a benefit for AAD in cocktail party scenarios.


Impaired germ cell development in the testes of immature rats with neonatal hypothyroidism.
The induction of neonatal hypothyroidism from day 1 to day 25 postpartum using 6-propyl-2-thiouracil (PTU) resulted in a 45% and 77% reduction of testis weight on days 20 and 30, respectively, and an increase in Sertoli cell number. The present study evaluated the effect of neonatal hypothyroidism on the developing germ cell population during the first 30 days postnatally. Qualitative and quantitative studies using the optical disector method were undertaken on the testes of control and hypothyroid rats, on days 10, 20, and 30 after birth. Germ cell development was obviously impaired in the hypothyroid rats, as shown by decreased primary spermatocyte and round spermatid numbers in day 20 and day 30 testes, and the persistence of gonocytes on days 10 and 20. These reductions obviously accounted for the reduced testis weight, absolute volume, and diameter of the seminiferous cords/tubules, especially on days 20 and 30. The failure to establish a seminiferous tubule lumen in hypothyroid rats probably reflects decreased fluid production and a functional immaturity of the Sertoli cells. The delay in germ cell maturation and increased degeneration may be because of the immature state of the Sertoli cell or result from the low follicle-stimulating hormone and thyroxine levels known to occur in the hypothyroid rats.


[Chief factors in the system of women's physical dimensions].
The investigation has been performed in 670 young (18--20 years-old) Estonian women. They are healthy students from Tartu University having a normal menstrual cycle, or with some slight deviations in it. In every woman 56 body dimensions, including the external obstetric pelvic ones, are analysed. The measurement technique in general corresponds to the classical techniques suggested by V. V. Bunak (1941) and R. Martin (1928). The linear correlation matrix of the body dimensions statistically significant positive correlations have been revealed between all the signs studied, the body mass and length possessing, the highest correlations. When the influence of the body mass and length is eliminated, the usual correlative correlation system is destroyed. Instead of the previous system, where all the signs are statistically positively significantly connected, the only connections remain that include 46% of negative connections and 30% of statistically significant, but very weak connections (the critical value r-0,088). The factor matrix is calculated on the base of the correlation matrix by means of the main components method. For its rotation the so called method of varimax is used. Three, five and seven factors are rotated (the parts of the initial signs in the total variance are 56, 65, 72%, respectively). The factor analysis also supports the main role of the body mass and length. When the number of the factors and described by them the part of the total variance increases, only some peculiar factors connected with subsystems are added. The factor analysis demonstrates that, besides the body mass and length, there are no other equally important body dimensions which could be used for description of the woman's body structure.


Microwave spectrum sensing based on photonic time stretch and compressive sampling.
An approach to realizing microwave spectrum sensing based on photonic time stretch and compressive sampling is proposed. The time stretch system is used to slow down the input high-speed signal and the compressive sampling based on random demodulation can further decrease the sampling rate. A spectrally sparse signal in a wide bandwidth can be captured with a sampling rate far lower than the Nyquist rate thanks to both time stretch and compressive sampling. It is demonstrated that a system with a time stretch factor 5 and a compression factor 8 can be used to capture a signal with multiple tones in a 50 GHz bandwidth, which means a sampling rate 40 times lower than the Nyquist rate. In addition, the time stretch of the microwave signal largely decreases the data rate of random data sequence and therefore the speed of the mixer in the random demodulator.


Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions.
Fibromyalgia is a complex and heterogeneous clinical syndrome, mainly characterized by the presence of widespread pain, possibly associated with a variety of other symptoms. Fibromyalgia can have an extremely negative impact on the psychological, physical and social lives of people affected, sometimes causing patients to experience dramatically impaired quality of life. Nowadays, the diagnosis of fibromyalgia is still clinical, thus favoring diagnostic uncertainties and making its clear identification challenging to establish, especially in primary care centers. These difficulties lead patients to undergo innumerable clinical visits, investigations and specialist consultations, thus increasing their stress, frustration and even dissatisfaction. Unfortunately, research over the last 25 years regarding a specific biomarker for the diagnosis of fibromyalgia has been fruitless. The discovery of a reliable biomarker for fibromyalgia syndrome would be a critical step towards the early identification of this condition, not only reducing patient healthcare utilization and diagnostic test execution but also providing early intervention with guideline-based treatments. This narrative article reviews different metabolite alterations proposed as possible biomarkers for fibromyalgia, focusing on their associations with clinical evidence of pain, and highlights some new, promising areas of research in this context. Nevertheless, none of the analyzed metabolites emerge as sufficiently reliable to be validated as a diagnostic biomarker. Given the complexity of this syndrome, in the future, a panel of biomarkers, including subtype-specific biomarkers, could be considered as an interesting alternative research area.


Synovial sarcoma mimicking benign peripheral nerve sheath tumor.
To assess the radiographic and clinicopathologic features of synovial sarcoma of the nerve that were clinically or radiologically interpreted as benign peripheral nerve sheath tumor. Five patients with synovial sarcoma arising from the peripheral nerve and interpreted clinically and radiologically as peripheral nerve sheath tumors were identified. Clinicopathologic and imaging features were evaluated. There were three females and two males, ranging in age from 28 to 50 (mean 35.8) years. Most patients (4/5) complained of a mass, discomfort or pain. MR images demonstrated a heterogeneous, enhancing, soft tissue mass contiguous with the neurovascular bundle. On histologic examination, most tumors were monophasic synovial sarcoma (4/5). At the time of surgery, all tumors were noted to arise along or within a peripheral nerve. All patients were alive with no evidence of disease with median follow-up of 44 (range 32-237) months. For comparison, approximately 775 benign peripheral nerve sheath tumors of the extremities were identified during the same time period. Primary synovial sarcoma of the nerve can mimic peripheral nerve sheath tumors clinically and on imaging and should be included in the differential diagnosis for tumors arising from peripheral nerves.


Peaceful awareness in patients with advanced cancer.
Previous studies have shown that prognostic awareness may be harmful to mental health yet beneficial for end of life care planning. The effects of prognostic awareness coupled with a sense of inner peace are unknown. In the multisite, longitudinal Coping with Cancer Study, 280 patients with advanced cancer were interviewed at baseline. Patients defining themselves as "terminally ill" and/or "at peace" most days were paired with others on sociodemographic, mental health and advance care planning. Primary caregivers of deceased patients were interviewed 6 months postloss and compared on their physical and mental health and their perceptions of patients' end-of-life care and death. Overall, 17.5% of patients reported being both peaceful and aware. Peacefully aware patients had lower rates of psychological distress and higher rates of advance care planning (e.g., completing do-not-resuscitate [DNR] orders, advance care planning discussions with physicians) than those who were not peacefully aware. Additionally, peacefully aware patients had the highest overall quality of death as reported by their caretakers in a postmortem evaluation. Surviving caregivers of peacefully aware patients were more physically and mentally healthy 6 months postloss than caregivers of patients who were "aware" but not peaceful. Patients with advanced cancer who are peacefully aware have better mental health and quality of death outcomes, and their surviving caregivers have better bereavement outcomes. Peaceful awareness is associated with modifiable aspects of medical care (e.g., discussions about terminal treatment preferences).


Nap and melatonin-induced changes in hippocampal activation and their role in verbal memory consolidation.
Overnight sleep contributes to memory consolidation; even a short nap improves memory performance. Such improvement has been linked to hippocampal activity during sleep. Melatonin has been shown to affect the human hippocampus and to induce 'sleep like' changes in brain activation. We therefore conducted and compared two functional magnetic resonance imaging studies: the first study assessed the effect of a 2-hr mid-day nap versus an equal amount of wakefulness on a verbal memory task (unrelated word pair association); the second assessed the effect of melatonin versus placebo (both conditions without nap) on a similar task. We report that following a nap relative to wakefulness, successful retrieval-related activation in the parahippocampus is decreased. A smaller decrease is seen in wakefulness with melatonin but not placebo. In parallel, an improvement in verbal memory recall was found after a nap compared with wakefulness but not with melatonin during wakefulness compared with placebo. Our findings demonstrate effects of melatonin that resemble those of sleep on verbal memory processing in the hippocampus thus suggesting that melatonin, like sleep, can initiate offline plastic changes underlying memory consolidation; they also suggest that concomitant rest without interferences is necessary for enhanced performance.


Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in "Low-Intermediate Risk" Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy.
To characterize long-term MD Anderson Dysphagia Inventory (MDADI) results after primary intensity modulated radiation therapy (IMRT) for oropharyngeal carcinoma (OPC) among patients with "low-intermediate risk" OPC who would be eligible for current trials (eg, ECOG 3311, NRG HN002, CRUK PATHOS). A retrospective pooled analysis combined data from 3 single-institution clinical trials for advanced-stage head and neck carcinoma. Inclusion criteria were clinical stage III/IV OPC (T1-2/N1-2b, T3/N0-2b) treated with definitive split-field IMRT and prospectively collected MDADI at baseline and at least 1 posttreatment interval available in trial databases. Patients were sampled to represent likely human papillomavirus (HPV)-associated disease (HPV+/p16+ or <10 pack-years if HPV/p16 unknown). The MDADI composite scores were collected at baseline and 6, 12, and 24 months after treatment. Pairwise tests were Bonferroni corrected for multiple comparisons. Forty-six patients were included. All received bilateral neck irradiation with a median dose of 70 Gy and systemic therapy (57% concurrent, 43% induction only). Overall the mean baseline MDADI composite score was 90.1, dropping to 74.6 at 6 months (P<.0001) and rising to 78.5 (P<.0001) and 83.1 (P=.002) by 12 and 24 months relative to baseline, respectively, representing a clinically meaningful drop in MDADI scores at 6 months that partially recovers by 24 months (6 vs 24 months, P=.05). Poor MDADI scores (composite <60) were reported in 4%, 11%, 15%, and 9% of patients at baseline and 6, 12, and 24 months, respectively. Fifteen percent of patients had a persistently depressed composite score by at least 20 points at the 24-month interval. "Low-intermediate risk" patients with OPC treated with laryngeal/esophageal inlet dose-optimized split-field IMRT are highly likely to report recovery of acceptable swallowing function in long-term follow-up. Only 15% report poor swallowing function and/or persistently depressed MDADI at 12 months or more after IMRT. These data serve as a benchmark future trial design and endpoint interpretation.


[Wavelet packet extraction and entropy analysis of telemetry EEG from the prelimbic cortex of medial prefrontal cortex in morphine-induced CPP rats].
The purpose of the present study is to analyze the relationship between the telemetry electroencephalogram (EEG) changes of the prelimbic (PL) cortex and the drug-seeking behavior of morphine-induced conditioned place preference (CPP) rats by using the wavelet packet extraction and entropy measurement. The recording electrode was stereotactically implanted into the PL cortex of rats. The animals were then divided randomly into operation-only control and morphine-induced CPP groups, respectively. A CPP video system in combination with an EEG wireless telemetry device was used for recording EEG of PL cortex when the rats shuttled between black-white or white-black chambers. The telemetry recorded EEGs were analyzed by wavelet packet extraction, Welch power spectrum estimate, normalized amplitude and Shannon entropy algorithm. The results showed that, compared with operation-only control group, the left PL cortex's EEG of morphine-induced CPP group during black-white chamber shuttling exhibited the following changes: (1) the amplitude of average EEG for each frequency bands extracted by wavelet packet was reduced; (2) the Welch power intensity was increased significantly in 10-50 Hz EEG band (P < 0.01 or P < 0.05); (3) Shannon entropy was increased in β, γ₁, and γ₂waves of the EEG (P < 0.01 or P < 0.05); and (4) the average information entropy was reduced (P < 0.01). The results suggest that above mentioned EEG changes in morphine-induced CPP group rat may be related to animals' drug-seeking motivation and behavior launching.


Fast Gas Chromatography with Tandem Mass Spectrometry Analysis of Selected Persistent Organic Pollutants and Organophosphorus and Synthetic Pyrethroid Pesticides in Indian Prawn (Fenneropenaeus indicus) in Compliance with the EU-MRLs.
A fast GC with tandem MS method was developed and validated for multiresidue determination of 95 chemical contaminants (24 synthetic pyrethroids, 17 organochlorines, 17 organophosphorus compounds, 18 polycyclic aromatic hydrocarbons, and 19 polychlorinated biphenyls) in Indian prawns (Fenneropenaeus indicus) as per the European Union maximum residual limit requirements. Chromatographic separation and MS determination were achieved within a short run time of 18 min, without compromising sensitivity and specificity. Our findings revealed a 2.5× reduction in the run time compared with conventional GC methods. Sample preparation involved a QuEChERS-based extraction of 10 g sample with 10 mL acidified acetonitrile (1% acetic acid) and phase separation with 6 g anhydrous magnesium sulfate and 1.5 g sodium acetate. The extract was cleaned in two steps, first by dispersive cleanup with primary secondary amine and then by C18 SPE cartridge. The regression coefficients of linearity (r2) for the concentration range of 5-50 ng/mL were >0.99 for all the compounds. Recoveries at 5 and 10 ng/g levels were within the acceptable range of 70-120%. The repeatability (RSDr) and within-laboratory reproducibility (RSDwR) precisions were ≤20%. The method was successfully applied for analysis of the real world samples for incurred residues.


The role of anti-cyclic citrullinated peptide antibodies in predicting rheumatoid arthritis.
The study presents the results of predicting role of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis, compared to rheumatoid factor. 32 patients with rheumatoid arthritis were identified from a retrospective chart review. The results of our study show that presence of the rheumatoid factor has less diagnostic and prognostic significance than the anti-cyclic citrullinated peptide, and suggests its superiority in predicting an erosive disease course.


Babe Ruth: with vision like that, how could he hit the ball?
Unfortunately, it is unlikely that a definitive answer will be known. We believe that it is most likely that Ruth was not amblyopic. This seems possible only if Dr. Kara had missed some amblyogenic factor such as strabismus or a significant refractive error. Our favored solution is that Ruth's unilateral vision loss was a complication of his cancer, and that Dr. Kara's examination occurred before the optic nerve damage became detectable. Of course, this is in disagreement with the ophthalmologist who examined his eyes.


Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease.
It is well established that diabetes is the major cause of chronic kidney disease worldwide. Both hyperglycemia, and more recently, advanced glycation endproducts, have been shown to play critical roles in the development of kidney disease. Moreover, the renin-angiotensin system along with growth factors and cytokines have also been shown to contribute to the onset and progression of diabetic kidney disease; however, the role of lipids in this context is poorly characterized. The current study aimed to compare the effect of 20 weeks of streptozotocin-induced diabetes or western diet feeding on kidney disease in two different mouse strains, C57BL/6 mice and hyperlipidemic apolipoprotein (apo) E knockout (KO) mice. Mice were fed a chow diet (control), a western diet (21% fat, 0.15% cholesterol) or were induced with streptozotocin-diabetes (55 mg/kg/day for 5 days) then fed a chow diet and followed for 20 weeks. The induction of diabetes was associated with a 3-fold elevation in glycated hemoglobin and an increase in kidney to body weight ratio regardless of strain (p < 0.0001). ApoE deficiency significantly increased plasma cholesterol and triglyceride levels and feeding of a western diet exacerbated these effects. Despite this, urinary albumin excretion (UAE) was elevated in diabetic mice to a similar extent in both strains (p < 0.0001) but no effect was seen with a western diet in either strain. Diabetes was also associated with extracellular matrix accumulation in both strains, and western diet feeding to a lesser extent in apoE KO mice. Consistent with this, an increase in renal mRNA expression of the fibrotic marker, fibronectin, was observed in diabetic C57BL/6 mice (p < 0.0001). In summary, these studies demonstrate disparate effects of diabetes and hyperlipidemia on kidney injury, with features of the diabetic milieu other than lipids suggested to play a more prominent role in driving renal pathology.


3-[(1-Benzyl-1H-1,2,3-triazol-5-yl)meth-yl]-6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridine.
There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C(22)H(17)BrN(6). The dihedral angles between the imidazo[4,5-b]pyridine mean plane and the phenyl rings are 20.4 (2) and 24.0 (2)° in the two mol-ecules. The orientation of triazoles compared to the imidazo[4,5-b]pyridine system is almost the same in both mol-ecules, with dihedral angles of 64.2 (2) and 65.1 (2)°. However, the main difference between the two mol-ecules lies in the arrangement of the phenyl groups compared to imidazo[4,5-b]pyridine in each mol-ecule. Indeed, in the first mol-ecule the dihedral angle between the plane of the phenyl ring and that of the imidazo[4,5-b]pyridine system is 67.7 (2)°, while in the second mol-ecule the plane of the phenyl ring is almost perpendicular to that of the imidazo[4,5-b]pyridine system with a dihedral angle of 86.0 (2)°.


Adult spinal V2a interneurons show increased excitability and serotonin-dependent bistability.
In mice, most studies of the organization of the spinal central pattern generator (CPG) for locomotion, and its component neuron classes, have been performed on neonatal [postnatal day (P)2-P4] animals. While the neonatal spinal cord can generate a basic locomotor pattern, it is often argued that the CPG network is in an immature form whose detailed properties mature with postnatal development. Here, we compare intrinsic properties and serotonergic modulation of the V2a class of excitatory spinal interneurons in behaviorally mature (older than P43) mice to those in neonatal mice. Using perforated patch recordings from genetically tagged V2a interneurons, we revealed an age-dependent increase in excitability. The input resistance increased, the rheobase values decreased, and the relation between injected current and firing frequency (F/I plot) showed higher excitability in the adult neurons, with almost all neurons firing tonically during a current step. The adult action potential (AP) properties became narrower and taller, and the AP threshold hyperpolarized. While in neonates the AP afterhyperpolarization was monophasic, most adult V2a interneurons showed a biphasic afterhyperpolarization. Serotonin increased excitability and depolarized most neonatal and adult V2a interneurons. However, in ∼30% of adult V2a interneurons, serotonin additionally elicited spontaneous intrinsic membrane potential bistability, resulting in alternations between hyperpolarized and depolarized states with a dramatically decreased membrane input resistance and facilitation of evoked plateau potentials. This was never seen in younger animals. Our findings indicate a significant postnatal development of the properties of locomotor-related V2a interneurons, which could alter their interpretation of synaptic inputs in the locomotor CPG.


[Pulmonary arterial hypertension: achievements and realities of modern treatment, a look into the future].
The paper summarizes the most important aspects of modern treatment of patients with pulmonary arterial hypertension (PAH): the goals of therapy are indicated, the issues of risk stratification of PAH progression/mortality, the place of combination specific therapy and switching strategies are considered, as well as new promising approaches to therapy; features of the course of the new coronavirus infection COVID-19 in this category of patients are discussed.