[Economic evaluation in oral care. Methods and examples in restorative dentistry].
This article briefly outlines the principles of economic evaluation in dentistry. It discusses the different types of analyses, such as cost-effectiveness analysis, cost-benefit analysis and cost-utility analysis. Furthermore, it makes clear when these analyses are most appropriate for use. Having a basic understanding of the most common analyses can be helpful to make choices between different interventions. Increasing demand for dental interventions and limited budgets necessitate the allocation of scarce resources efficiently. By identifying, measuring, valuing and comparing costs and outcome of interventions, economic evaluation can also help patients and carers in choosing between interventions. The article gives some examples in restorative dentistry to explain the relevance of economic evaluation.


Prevalence of low back pain in adolescents with idiopathic scoliosis: a systematic review.
Adolescent idiopathic scoliosis is the most common spinal deformity occurring in adolescents and its established prevalence varies from 2 to 3%. Adolescent idiopathic scoliosis has been identified as a potential risk factor for the development of low back pain in adolescents. The purpose of this study was to systematically review studies of the prevalence of low back pain in adolescents with idiopathic scoliosis in order to establish the quality of the evidence and determine whether the prevalence estimates could be statistically pooled. Systematic electronic searches were undertaken in PubMed, CINAHL, and CENTRAL without any restrictions. Studies were eligible for inclusion if they reported the prevalence of low back pain in adolescents with idiopathic scoliosis. Studies were excluded if they detailed the prevalence of pain in post-surgical subjects or were published in languages other than English or French. Data were reported qualitatively, since there was insufficient evidence for statistical pooling. The electronic search strategies yielded 1811 unique studies. Only two studies fulfilled the eligibility criteria. The prevalence of low back pain in adolescents with idiopathic scoliosis ranged from 34.7 to 42.0%. However, these prevalence estimates should be viewed cautiously as the included studies were at high risk of bias. The results of this systematic review indicate that adolescents with idiopathic scoliosis frequently experience low back pain. However, there was insufficient evidence to confidently estimate low back pain prevalence in adolescents with idiopathic scoliosis and further studies are needed in this area.


Massive colchicine overdose: a report on the toxicity.
A case of an overdose of colchicine for suicidal purposes is presented. The main complications observed involved the hematopoietic, the gastrointestinal, the respiratory and the central nervous system. Heinz bodies were noticed in the red blood cells, a finding which had not been previously documented in patients with colchicine overdose. Despite intensive management the patient died on the thirteenth hospital day of central nervous system complications.


Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis.
During REM sleep the CNS is intensely active, but the skeletal motor system is paradoxically forced into a state of muscle paralysis. The mechanisms that trigger REM sleep paralysis are a matter of intense debate. Two competing theories argue that it is caused by either active inhibition or reduced excitation of somatic motoneuron activity. Here, we identify the transmitter and receptor mechanisms that function to silence skeletal muscles during REM sleep. We used behavioral, electrophysiological, receptor pharmacology and neuroanatomical approaches to determine how trigeminal motoneurons and masseter muscles are switched off during REM sleep in rats. We show that a powerful GABA and glycine drive triggers REM paralysis by switching off motoneuron activity. This drive inhibits motoneurons by targeting both metabotropic GABA(B) and ionotropic GABA(A)/glycine receptors. REM paralysis is only reversed when motoneurons are cut off from GABA(B), GABA(A) and glycine receptor-mediated inhibition. Neither metabotropic nor ionotropic receptor mechanisms alone are sufficient for generating REM paralysis. These results demonstrate that multiple receptor mechanisms trigger REM sleep paralysis. Breakdown in normal REM inhibition may underlie common sleep motor pathologies such as REM sleep behavior disorder.


Feeding dysfunction in NICU patients with cramped synchronized movements.
Patients admitted to the neonatal intensive care unit (NICU) have higher association for neurodevelopment deficits, specifically cerebral palsy (CP). We identified patients with risk for CP using abnormal Pretchl's General Movement Assessment (GMA) and sub-category of cramped synchronized movements (CSM) and reported their feeding outcomes at discharge. Over 75 % of these patients required either nasogastric (NGT) or gastrostomy tube (GT) at discharge. Of these, 57 % weaned off their NGT or GT at home and 43 % of patients still needed a GT one year after discharge. Of those that could not wean off their NGT or GT, these patients had longer hospital stay, took lower percentage by mouth, and an older post-menstrual age at discharge. We did not find a difference in NGT or GT use between patients with IVH, ELBW, nor between their birthweight or gestation age at birth. This study provides further clinical characteristics in NICU patients who have higher risk of CP, and supports the need for skilled feeding therapy and resources both during and after NICU admission.


Basic fibroblast growth factor promotes macaque follicle development in vitro.
Fertility preservation is an important type of frontier scientific research in the field of reproductive health. The culture of ovarian cortices to i) initiate primordial follicle growth and ii) procure developing follicles for later oocyte maturation is a promising fertility preservation strategy, especially for older women or cancer patients. At present, this goal remains largely unsubstantiated in primates because of the difficulty in attaining relatively large follicles via ovarian cortex culture. To overcome this hurdle, we cultured macaque monkey ovarian cortices with FSH, kit ligand (KL), basic fibroblast growth factor (bFGF), and/or epidermal growth factor (EGF). The various factors and factor combinations promoted primordial follicle development to different extents. Notably, both bFF (bFGF, 100 ng/ml and FSH, 50 ng/ml) and KF (KL, 100 ng/ml and FSH, 50 ng/ml) contributed to the activation of primordial follicles at day 12 (D12) of culture, whereas at D18, the proportions of developing follicles were significantly higher in the bFF and KF groups relative to the other treatment groups, particularly in the bFF group. Estradiol and progesterone production were also highest in the bFF group, and primary follicle diameters were the largest. Up until D24, the bFF group still exhibited the highest proportion of developing follicles. In conclusion, the bFGF-FSH combination promotes nonhuman primate primordial follicle development in vitro, with the optimal experimental window within 18 days. These results provide evidence for the future success of human ovarian cortex culture and the eventual acquisition of mature human follicles or oocytes for fertility restoration.


Seasonal changes in microbial community composition in river water studied using 454-pyrosequencing.
The aims of this study were to determine the microbial community in five rivers in the proximity of a city in the Czech Republic using 454-pyrosequencing, as well as to assess seasonal variability over the course of 1 year and to identify the factors influencing the structure of bacterial communities. Samples from five rivers around the city of Brno were obtained during four seasons and analysed using 454 pyrosequencing of the 16S rRNA gene. The core composition of bacterial communities consisted of Actinobacteria, Bacteroidetes, Proteobacteria, Firmicutes, Fusobacteria, TM7 and others. Our approach enabled us to more closely study the correlation between the abundance of different families and environmental factors. Overall, Actinobacteria negatively correlated with phosphorus, sulphate, dissolved particle and chloride levels. In contrast, Proteobacteria positively correlated with sulphate, dissolved particle, chloride, dissolved oxygen and nitrite levels. Future work should focus on the dynamics of bacterial communities present in river water and their relation to the overall stability of the water ecosystem.


When costly migration helps to improve cooperation.
Motion is a typical reaction among animals and humans trying to reach better conditions in a changing world. This aspect has been studied intensively in social dilemmas where competing players' individual and collective interests are in conflict. Starting from the traditional public goods game model, where players are locally fixed and unconditional cooperators or defectors are present, we introduce two additional strategies through which agents can change their positions of dependence on the local cooperation level. More importantly, these so-called sophisticated players should bear an extra cost to maintain their permanent capacity to evaluate their neighborhood and react accordingly. Hence, four strategies compete, and the most successful one can be imitated by its neighbors. Crucially, the introduction of costly movement has a highly biased consequence on the competing main strategies. In the majority of parameter space, it is harmful to defectors and provides a significantly higher cooperation level when the population is rare. At an intermediate population density, which would be otherwise optimal for a system of immobile players, the presence of mobile actors could be detrimental if the interaction pattern changes slightly, thereby blocking the optimal percolation of information flow. In this parameter space, sophisticated cooperators can also show the co-called Moor effect by first avoiding the harmful vicinity of defectors; they subsequently transform into an immobile cooperator state. Hence, paradoxically, the additional cost of movement could be advantageous to reach a higher general income, especially for a rare population when subgroups would be isolated otherwise.


Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II. substrate-enzyme interactions and dynamics.
Molecular dynamics simulations of protein tyrosine phosphatase 1B (PTP1B) complexed with the phosphorylated peptide substrate DADEpYL and the free substrate have been conducted to investigate 1) the physical forces involved in substrate-protein interactions, 2) the importance of enzyme and substrate flexibility for binding, 3) the electrostatic properties of the enzyme, and 4) the contribution from solvation. The simulations were performed for 1 ns, using explicit water molecules. The last 700 ps of the trajectories was used for analysis determining enthalpic and entropic contributions to substrate binding. Based on essential dynamics analysis of the PTP1B/DADEpYL trajectory, it is shown that internal motions in the binding pocket occur in a subspace of only a few degrees of freedom. In particular, relatively large flexibilities are observed along several eigenvectors in the segments: Arg(24)-Ser(28), Pro(38)-Arg(47), and Glu(115)-Gly(117). These motions are correlated to the C- and N-terminal motions of the substrate. Relatively small fluctuations are observed in the region of the consensus active site motif (H/V)CX(5)R(S/T) and in the region of the WPD loop, which contains the general acid for catalysis. Analysis of the individual enzyme-substrate interaction energies revealed that mainly electrostatic forces contribute to binding. Indeed, calculation of the electrostatic field of the enzyme reveals that only the field surrounding the binding pocket is positive, while the remaining protein surface is characterized by a predominantly negative electrostatic field. This positive electrostatic field attracts negatively charged substrates and could explain the experimentally observed preference of PTP1B for negatively charged substrates like the DADEpYL peptide.


The Self-administered Eczema Area and Severity Index in children with moderate to severe atopic dermatitis: better estimation of AD body surface area than severity.
The Self-Administered Eczema Area and Severity Index (SA-EASI) is one of the few patient based atopic dermatitis (AD) disease activity scores and was found to be highly correlated with the EASI. Correlation with other frequently used scoring methods has not been investigated. The aim of this study was to evaluate the relation of the SA-EASI with two physician-based disease activity scores (objective SCORAD and SASSAD score) and with a serum marker for AD (Thymus and Activation-Regulated Cytokine [TARC]) in children with AD. Sixty children with moderate to severe AD were included. The SA-EASI was completed by caregivers, and the objective SCORAD and SASSAD scores were measured successively on the same day by a trained investigator. Blood for serum TARC measurement was drawn. The correlation between the SA-EASI and the objective SCORAD was high (ρ = 0.61, p = <0.001), mainly based on high correlation between the body surface area (BSA) measurements of both scores (ρ = 0.50, p = <0.001). The correlation with the SASSAD score (only severity measurement) was 0.43 (p = <0.001). The correlation with serum TARC levels was 0.46; p = <0.001, mainly based on the BSA score of the SA-EASI (ρ = 0.42, p = <0.001). Parents may have more difficulty in scoring severity of AD than scoring BSA involved. Educating parents in severity scoring of AD may improve agreement of the SA-EASI and the objective SCORAD, TARC, and SASSAD score. Additional use of the SA-EASI in routine clinical practice or in trials may then facilitate more frequent but still accurate assessment of AD.


HIV and infant feeding: to breastfeed or not to breastfeed: the dilemma of competing risks. Part 1.
The discovery of the human immunodeficiency virus (HIV) in breastmilk in 1985, and subsequent research, supports the hypothesis that breastfeeding provides a route of transmission to the nursing baby. Various routes of infection and relative rates of transmission have been studied in many parts of the world, leading to the blanket guideline that babies of HIV-infected mothers should not be breastfed, if a safe alternative can be provided. However, due to the limits inherent in various studies and various testing methods, the exact frequency of breastmilk transmission of HIV during the course of lactation remains unknown, and the conclusions drawn are thus conflicting and confusing. Replacement feeding of young babies with non-human milks and other foods may be hazardous in poverty-stricken populations in Africa and elsewhere, and still more research suggests that there are several properties in human milk that may provide specific protection to the baby of an infected mother. The possibility of providing the mother's own treated expressed breastmilk to the baby at risk of HIV infection via breastfeeding is an alternative which has yet to be fully explored and ways that this could be accomplished are examined. Those of us working with mothers and babies need more information before we can assist mothers living with HIV to make truly informed decisions about the safest way to feed their babies. Topics requiring urgent further attention are outlined.


Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients.
Whether anti-seizure medication (ASM) increases the risk for cancer has been debated for decades. While for some ASM, a carcinoma-promoting effect has been suspected, carcinoma-protective effects have been shown for other ASM. However, the issue remains unresolved as data from preclinical and clinical studies have been inconsistent and contradictory. We collected anonymous patient data from practice neurologists throughout Germany between 2009 and 2018 using the IMS Disease Analyzer database (QuintilesIMS, Frankfurt, Germany). People with epilepsy (PWE) with an initial cancer diagnosis and antiepileptic therapy prior to the index date were 1:1 matched with a control group of PWE without cancer according to age, gender, index year, Charlson Comorbidity Index, and treating physician. For both groups, the risk to develop cancer under treatment with different ASMs was analyzed using three different models (ever use vs. never use (I), effect per one (II) and per five therapy years (III). A total of 3152 PWE were included (each group, n = 1,576; age = 67.3 ± 14.0 years). The risk to develop cancer was not significantly elevated for any ASM. Carbamazepine was associated with a decreased cancer risk (OR Model I: 0.699, p < .0001, OR Model II: 0.952, p = .4878, OR Model III: 0.758, p < .0004). Our findings suggest that ASM use does not increase the risk of cancer in epilepsy patients.


SARS-CoV-2 Induced Neurological Manifestations Entangles Cytokine Storm that Implicates for Therapeutic Strategies.
The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can present neurological symptoms and induce neurological complications. The involvement in both the central and peripheral nervous systems in COVID-19 patients has been associated with direct invasion of the virus and the induction of cytokine storm. This review discussed the pathways for the virus invasion into the nervous system and characterized the SARS-CoV-2 induced cytokine storm. In addition, the mechanisms underlying the immune responses and cytokine storm induction after SARS-CoV-2 infection were also discussed. Although some neurological symptoms are mild and disappear after recovery from infection, some severe neurological complications contribute to the mortality of COVID-19 patients. Therefore, the insight into the cause of SARS-CoV-2 induced cytokine storm in context with neurological complications will formulate the novel management of the disease and also further identify new therapeutic targets for COVID-19.


Primary prevention of diabetes mellitus.
Diabetes mellitus is one of the chronic noncommunicable diseases that have increased markedly in this century. The discovery of insulin and other drugs for lowering hyperglycemia have certainly reduced mortality from acute complications of diabetes and improved the quality of life of many diabetic patients. Recent advances in research into the etiology and natural history of diabetes have increased our knowledge about different types of diabetes to such an extent that primary prevention of diabetes mellitus is becoming a reality. Until now, few studies have attempted to test measures for primary prevention of diabetes. Therefore, the data supporting the possibility for primary prevention are largely indirect and need to be tested in preventive trials or in community-based prevention programs. We believe, however, that the time is right to start action in populations in which the prevalence of diabetes is known to have clearly increased recently. We summarize the evidence that can be used as the scientific basis of primary prevention of diabetes mellitus.


Inference for sparse linear regression based on the leave-one-covariate-out solution path.
We propose a new measure of variable importance in high-dimensional regression based on the change in the LASSO solution path when one covariate is left out. The proposed procedure provides a novel way to calculate variable importance and conduct variable screening. In addition, our procedure allows for the construction of p-values for testing whether each coe cient is equal to zero as well as for testing hypotheses involving multiple regression coefficients simultaneously; bootstrap techniques are used to construct the null distribution. For low-dimensional linear models, our method can achieve higher power than the t-test. Extensive simulations are provided to show the effectiveness of our method. In the high-dimensional setting, our proposed solution path based test achieves greater power than some other recently developed high-dimensional inference methods. We extend our method to logistic regression and demonstrate in simulation that our leave-one-covariate-out solution path tests can provide accurate p-values.


Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy.
Neurodegenerative disorders are often characterized by the aggregation and accumulation of misfolded proteins (e.g. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis). Aggregated proteins are very toxic to cells in culture and both in vitro and in vivo there is overwhelming evidence that these aberrant proteins are key players in neurodegeneration. Protein quality control is a cellular defense mechanism against misfolded proteins that prevents aggregate formation under physiological conditions. The presence of accumulated aggregates of misfolded proteins in many neurodegenerative disorders, suggests that protein quality control failed to restore homeostasis in these pathological conditions. In fact, evidence from observations in cellular disease models, mouse models, as well as from post mortem patient material indicates activation of the quality control machinery in response to the pathological process. In addition, interference with protein quality control by genetic or chemical manipulation often results in aggregate formation and neurodegeneration. This stresses the importance of proper quality control in neurodegenerative disorders and indicates that it may provide a target for therapeutic intervention. In this review we will focus on the protein quality control systems in the endoplasmic reticulum (ER) and address the involvement of ER quality control in neurodegenerative disease as well as its potential as therapeutic target.


Extra-anatomic arterial reconstruction with ligation of common iliac arteries and embolization of the aneurysm for the treatment of abdominal aortic aneurysms in high-risk patients.
The mortality of an unrepaired abdominal aortic aneurysm (AAA) generally exceeds the mortality associated with surgical repair. However, as our longevity increases, more frequently we see patients whose risk of surgical repair approximates the risk of rupture. We present an extra-anatomic bypass graft with complete aneurysm exclusion by iliac ligation and coil embolization of the aneurysm as an alternative for these high-risk patients. An extra-anatomic bypass graft, followed by bilateral iliac artery ligation (retroperitoneal approach) and complete coil embolization of the AAA, was performed in eight patients (mean age, 77 years) found to be at prohibitive operative risk because of multiple comorbidities (American Society of Anesthesiologists class IV). Most patients (5 of 8) were symptomatic on presentation with a mean AAA diameter of 7 cm (range, 6.7-9.5 cm). We repair approximately 30 infrarenal aneurysms per year electively at our institution. All patients tolerated the surgical procedures. The average hospital stay was 8 days. All but two aneurysms demonstrated complete thrombosis by 48 hours. After 48 months there was no incidence of graft thrombosis, peripheral ischemia, visceral ischemia or thrombus infection. There was one perioperative death from aspiration pneumonia. Seventy-five percent (6 of 8) of patients have survived at least 1 year without surgical complications. No patient has had a ruptured aneurysm. Combining an extra-anatomic bypass graft and complete exclusion of the AAA by ligation of the common iliac arteries and a coil embolization is an effective, less invasive treatment option for patients with AAA and prohibitive operative risk. We emphasize the need for complete embolization documented by decreased aneurysm size.


Pre-application of dentin bonding agent prevents discoloration caused by mineral trioxide aggregate.
To evaluate tooth discoloration by newly developed calcium silicate-based materials, and to examine the pre-application of dentin bonding agent (DBA) for preventing discoloration caused by mineral trioxide aggregate (MTA). The roots of 50 premolars were randomly divided into five groups (n = 10) and cavities were prepared from resected root surfaces. MTA was placed in the cavities of teeth belonging to the ProRoot MTA (MTA) and RetroMTA (RMTA) groups. For teeth belonging to the ProRoot + DBA (MTA-B) and RetroMTA + DBA (RMTA-B) groups, DBA was first applied to the cavities prior to the addition of MTA. Teeth in the control group were restored with composite resin only (i.e., without MTA). After 12 weeks, MTA was removed from the MTA and RMTA groups and bleaching agents were applied for 3 additional weeks. Color assessments were recorded at baseline, and 1, 4, and 12 weeks, as well as after bleaching. A one-way ANOVA was performed to assess the differences between the two types of MTAs and color changes following DBA pre-application in each MTA group. A p-value of < 0.05 was considered indicative of statistical significance. Following 12 weeks of MTA treatment, there was a significant difference between the discoloration in the MTA and RMTA groups (p < 0.05). However, no significant difference was observed between the RMTA and RMTA-B groups (p > 0.05). Following bleaching, the color changes (ΔE values) of the MTA group were not significantly different from those of the MTA-B group (p > 0.05). The difference of ΔE between the RMTA group after internal bleaching and the RMTA-B group was also not significant (p > 0.05). RetroMTA caused significantly less discoloration than ProRoot MTA. Pre-application of DBA reduced discoloration caused by ProRoot MTA. MTA discoloration was improved equally well between DBA pre-application and post-bleaching.


A highly sensitive detection platform based on surface-enhanced Raman scattering for Escherichia coli enumeration.
A very sensitive and highly specific heterogeneous immunoassay system, based on surface-enhanced Raman scattering (SERS) and gold nanoparticles, was developed for the detection of bacteria and other pathogens. Two different types of gold nanoparticles (citrate-stabilized gold nanosphere and hexadecyltrimethylammonium bromide (CTAB)-stabilized gold nanorod particles) were examined and this immunoassay was applied for the detection of Escherichia coli. Raman labels were constructed by using these spherical and rod-shaped gold nanoparticles which were first coated with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and subsequently with a molecular recognizer. The working curve was obtained by plotting the intensity of the SERS signal of the symmetric NO(2) stretching of DTNB at 1,333 cm(-1) versus the concentration of the E. coli. The analytical performance of gold particles was evaluated via a sandwich immunoassay, and linear calibration graphs were obtained in the E. coli concentration range of 10(1)-10(5) cfu/mL with a 60-s accumulation time. The sensitivity of the Raman label fabricated with gold nanorods was more than three times higher than spherical gold nanoparticles. The selectivity of the developed sensor was examined with Enterobacter aerogenes and Enterobacter dissolvens, which did not produce any significant response. The usefulness of the developed immunoassay to detect E. coli in real water samples was also demonstrated.


Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Reversion from suppression to nonsuppression in SUQ5 [psi+] strains of yeast: the classificaion of mutations.
Reversion from the suppressed to nonsuppressed phenotype in strains of geno;type SUQ5 [psi+] ade2-1 his5-2 lys1-1 can1-100 ura3-1 has been induced by treatment with ethyl methanesulphonate, nitrosoguanidine or UV (254 nm) light. Spontaneously occurring revertants have also been selected by two different methods. Reversion has been shown to occur through a variety of nuclear mutations and through mutation of [psi+] to [psi-]. Nuclear mutations included back-mutation of SUQ5, antisuppressor mutations that were recessive, semi-dominant or dominant, and dominant or recessive mutations of genes required for the maintenance of the [psi+] factor. Complementation tests by which the various kinds of mutations could be distinguished from one another were designed. The spectra of spontaneously occurring and induced mutations have been described.


[Mitochondrial uncoupling proteins: regulation and physiological role].
Uncoupling proteins (UCPs), members of mitochondrial carrier family, are present in mitochondrial inner membrane and mediate free fatty acid-activated, purine-nucleotide-inhibited H+ re-uptake. UCPs can modulate the tightness of coupling between mitochondrial respiration and ATP synthesis. A physiological function of the first described UCP, UCP1 or termogenin, present in mitochondria of mammalian brown adipose tissues is well established. UCP1 plays a role in nonshivering thermogenesis in mammals. The widespread presence of UCPs in eukaryotes, in non-thermogenic tissues of animals, plants and in unicellular organisms implies that these proteins may elicit other functions than thermogenesis. However, the physiological functions of UCP1 homologues are still under debate. They can regulate energy metabolism through modulation of the electrochemical proton gradient and production of ROS. Functional activation of UCPs is proposed to decrease ROS production. Moreover, products of lipid peroxidation can activate UCPs and promote feedback down-regulation of mitochondrial ROS production.


Maternal obesity and pregnancy.
Obesity is a global health problem that is increasing in prevalence. The World Health Organization characterizes obesity as a pandemic issue, with a higher prevalence in females than males. Thus, many pregnant patients are seen with high body mass index (BMI). Obesity during pregnancy is considered a high-risk state because it is associated with many complications. Compared with normal-weight patients, obese patients have a higher prevalence of infertility. Once they conceive, they have higher rate of early miscarriage and congenital anomalies, including neural tube defects. Besides the coexistence of preexisting diabetes mellitus and chronic hypertension, obese women are more likely to have pregnancy-induced hypertension, gestational diabetes, thromboembolism, macrosomia, and spontaneous intrauterine demises in the latter half of pregnancy. Obese women also require instrument or Cesarean section delivery more often than average-weight women. Following Cesarean section delivery, obese women have a higher incidence of wound infection and disruption. Irrespective of the delivery mode, children born to obese mothers have a higher incidence of macrosomia and associated shoulder dystocia, which can be highly unpredictable. In addition to being large at birth, children born to obese mothers are also more susceptible to obesity in adolescence and adulthood. Prevention is the best way to prevent this problem. As pregnancy is the worst time to lose weight, women with a high BMI should be encouraged to lose weight prior to conceiving. During preconception counseling, they should be educated about the complications associated with high a BMI. Obese women should also be screened for hypertension and diabetes mellitus. In early pregnancy, besides being watchful about the higher association of miscarriage, obese women should be screened with ultrasound for congenital anomalies around 18 to 22 weeks. The ultrasound should be repeated close to term to check on the estimated fetal weight to rule out macrosomia. Obese pregnant women are screened for gestational diabetes around 24 to 28 weeks. During the second half of pregnancy, one needs to closely watch for signs and symptoms of pregnancy-induced hypertension. Once in labor, an early anesthesia consultation is highly recommended irrespective of delivery mode. When Cesarean section is performed, many obstetricians prefer an incision above the pannus to avoid skin infection. However, the incision should be decided upon the discretion of the surgeon. Peripartum, special attention is given to avoid thromboembolism by using compression stockings and early ambulation.


Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.
Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis, especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.


A randomised controlled feasibility trial for an educational school-based mental health intervention: study protocol.
With the burden of mental illness estimated to be costing the English economy alone around £22.5 billion a year 1, coupled with growing evidence that many mental disorders have their origins in adolescence, there is increasing pressure for schools to address the emotional well-being of their students, alongside the stigma and discrimination of mental illness. A number of prior educational interventions have been developed and evaluated for this purpose, but inconsistency of findings, reporting standards, and methodologies have led the majority of reviewers to conclude that the evidence for the efficacy of these programmes remains inconclusive. A cluster randomised controlled trial design has been employed to enable a feasibility study of 'SchoolSpace', an intervention in 7 UK secondary schools addressing stigma of mental illness, mental health literacy, and promotion of mental health. A central aspect of the intervention involves students in the experimental condition interacting with a young person with lived experience of mental illness, a stigma reducing technique designed to facilitate students' engagement in the project. The primary outcome is the level of stigma related to mental illness. Secondary outcomes include mental health literacy, resilience to mental illness, and emotional well-being. Outcomes will be measured pre and post intervention, as well as at 6 month follow-up. The proposed intervention presents the potential for increased engagement due to its combination of education and contact with a young person with lived experience of mental illness. Contact as a technique to reduce discrimination has been evaluated previously in research with adults, but has been employed in only a minority of research trials investigating the impact on youth. Prior to this study, the effect of contact on mental health literacy, resilience, and emotional well-being has not been evaluated to the authors' knowledge. If efficacious the intervention could provide a reliable and cost-effective method to reduce stigma in young people, whilst increasing mental health literacy, and emotional well-being. ISRCTN: ISRCTN07406026.


Adaptation of an Evidence-Based Arthritis Program for Breast Cancer Survivors on Aromatase Inhibitor Therapy Who Experience Joint Pain.
Adding aromatase inhibitors (AIs) to adjuvant treatment of postmenopausal women with hormone-receptor-positive breast cancer significantly reduces cancer recurrence. A common side effect of AIs is noninflammatory joint pain and stiffness (arthralgia) similar to arthritis symptoms. An evidence-based walking program developed by the Arthritis Foundation - Walk With Ease (WWE) - reduces arthritis-related joint symptoms. We hypothesized that WWE may also reduce AI-associated arthralgia. However, the potential for different barriers and facilitators to physical activity for these 2 patient populations suggested a need to adapt WWE before testing it with breast cancer survivors. We conducted qualitative research with 46 breast cancer survivors to explore program modification and inform the development of materials for an adapted program (Walk With Ease-Breast Cancer). Our process parallels the National Cancer Institute's Research-Tested Intervention Programs (RTIPs) guidelines for adapting evidence-based programs for cancer populations. Findings resulted in a customized 8-page brochure to supplement existing WWE materials.


Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes.
Ni-catalyzed cross-electrophile coupling reactions have emerged as appealing methods to construct organic molecules without the use of stoichiometric organometallic reagents. The mechanisms are complex: plausible pathways, such as "radical chain" and "sequential reduction" mechanisms, are dependent on the sequence of the activation of electrophiles. A combination of kinetic, spectroscopic, and organometallic studies reveals that a Ni-catalyzed, reductive 1,2-dicarbofunctionalization of alkenes proceeds through a "sequential reduction" pathway. The reduction of Ni by Zn is the turnover-limiting step, consistent with Ni(II) intermediates as the catalyst resting-state. Zn is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a result, commonly proposed Ni(0) intermediates are absent under these conditions. (Phen)Ni(I)-Br selectively activates aryl bromides via two-electron oxidation addition, whereas alkyl bromides are activated by (phen)Ni(I)-Ar through single-electron activation to afford radicals. These findings could provide insight into achieving selectivity between different electrophiles.


C-type natriuretic peptide inhibits thrombin- and angiotensin II-stimulated endothelin release via cyclic guanosine 3',5'-monophosphate.
We examined the inhibitory effect of porcine C-type natriuretic peptide (CNP) on endothelin-1 secretion stimulated by thrombin and angiotensin II (Ang II) in cultured porcine endothelial cells. The results were compared with the effects of atrial (ANP) and brain (BNP) natriuretic peptides. Thrombin and Ang II produced a concentration-dependent stimulation of immunoreactive endothelin-1 secretion, and porcine CNP-22 potently inhibited this stimulated secretion in a concentration-dependent manner. CNP-22 had a stronger inhibitory effect than either porcine ANP(1-28) or porcine BNP-26. In addition, CNP potently increased the cellular level of cyclic guanosine 3',5'-monophosphate (GMP), with the inhibition of immunoreactive endothelin-1 secretion in response to thrombin and Ang II being paralleled by the increase in the cyclic GMP level. The increase of cyclic GMP produced by CNP was also greater than that due to porcine ANP(1-28) or porcine BNP-26. The immunoreactive endothelin-1 in the culture medium had two components on high-performance liquid chromatography; the major one corresponded to endothelin-1 (1-21) and the minor one to big endothelin-1 (porcine 1-39). Treatment with CNP did not affect this profile. Our results suggest that CNP probably inhibits the endothelin-1 secretion stimulated by thrombin and Ang II through a cyclic GMP-dependent process. The increase of cyclic GMP levels and the inhibition of immunoreactive endothelin-1 secretion produced by CNP appear to be greater than those produced by ANP or BNP.


Influence of thermal processing conditions on acrylamide generation and browning in a potato model system.
Fried potato products such as French fries and chips may contain substantial amounts of acrylamide. Numerous efforts are undertaken to minimize the acrylamide content of these products while sensory properties such as color and flavor have to be respected as well. An optimization of the frying process can be achieved if the basic kinetic data of the browning and acrylamide formation are known. Therefore, heating experiments with potato powder were performed under controlled conditions (moisture, temperature, and time). Browning and acrylamide content both increased with heating time at all temperatures and moisture contents tested. The moisture content had a strong influence on the activation energy of browning and acrylamide formation. The activation energy strongly increased at moisture contents below 20%. At higher moisture contents, it was very similar for both parameters. At low moisture contents, the activation energy of acrylamide formation was larger as compared to the one for browning. This explains why the end of the frying process is very critical. Therefore, a lower temperature toward the end of frying reduces the acrylamide content of the product while color development is still good.


Widened subarachnoid space in pre-discharge cranial ultrasound: evidence of cerebral atrophy in immature infants?
The authors examined the incidence of widened subarachnoid spaces (SAS) among 75 infants with birthweights less than or equal to 1250g, and their significance in developmental outcome. Nine of 30 infants with gestations less than or equal to 27 weeks had widened SAS in their pre-discharge ultrasound scans. Three of the nine, including two with periventricular leukomalacia (PVL), had late-onset ventricular enlargement, unrelated to intraventricular haemorrhage (IVH): all three were developmentally impaired. The other six infants without ventricular enlargement developed normally, including one with IVH. Five of the remaining 21 infants with gestations less than or equal to 27 weeks and without widened SAS were developmentally impaired. Widened SAS was not associated with a significantly increased risk of developmental impairment; ventricular enlargement and PVL were the only significant factors. The authors conclude that an isolated finding of widened SAS is not predictive of impairment in immature infants.


Systemic Metabolomic Changes in Blood Samples of Lung Cancer Patients Identified by Gas Chromatography Time-of-Flight Mass Spectrometry.
Lung cancer is a leading cause of cancer deaths worldwide. Metabolic alterations in tumor cells coupled with systemic indicators of the host response to tumor development have the potential to yield blood profiles with clinical utility for diagnosis and monitoring of treatment. We report results from two separate studies using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) to profile metabolites in human blood samples that significantly differ from non-small cell lung cancer (NSCLC) adenocarcinoma and other lung cancer cases. Metabolomic analysis of blood samples from the two studies yielded a total of 437 metabolites, of which 148 were identified as known compounds and 289 identified as unknown compounds. Differential analysis identified 15 known metabolites in one study and 18 in a second study that were statistically different (p-values <0.05). Levels of maltose, palmitic acid, glycerol, ethanolamine, glutamic acid, and lactic acid were increased in cancer samples while amino acids tryptophan, lysine and histidine decreased. Many of the metabolites were found to be significantly different in both studies, suggesting that metabolomics appears to be robust enough to find systemic changes from lung cancer, thus showing the potential of this type of analysis for lung cancer detection.


Characterizing functional regional homogeneity (ReHo) as a B-SNIP psychosis biomarker using traditional and machine learning approaches.
Recently, a biologically-driven psychosis classification (B-SNIP Biotypes) was derived using brain-based cognitive and electrophysiological markers. Here, we characterized a local functional-connectivity measure, regional homogeneity (ReHo), as a biomarker across Biotypes and conventional DSM diagnoses. Whole-brain ReHo measures of resting-state functional MRI were examined in psychosis patients and healthy controls organized by Biotype and by DSM-IV-TR diagnosis (n = 737). Group-level ANOVA and individual-level prediction models using support vector machines (SVM) were employed to evaluate the discriminative characteristics in comparisons of 1) DSM diagnostic groups, 2) Biotypes, to controls, and 3) within-proband subgroups with each other. Probands grouped by Biotype versus controls showed a unique abnormality pattern: Biotype-1 displayed bidirectional ReHo differences in more widespread areas, with higher ReHo in para-hippocampus, fusiform, inferior temporal, cerebellum, thalamus and caudate, plus lower ReHo in the postcentral gyrus, middle temporal, cuneus, and middle occipital cortex; Biotype-2 and Biotype-3 showed lesser and unidirectional ReHo changes. Among diagnostic groups, only schizophrenia showed higher ReHo versus control values in the inferior/middle temporal area and fusiform gyrus. For within-patient comparisons, Biotype-1 showed characteristic ReHo when compared to Biotype-2 and Biotype-3. SVM results more accurately identified Biotypes than DSM diagnoses. We characterized patterns of ReHo abnormalities across both Biotypes and DSM sub-groups. Both group-level statistical and machine-learning methods were more sensitive in capturing ReHo deficits in Biotypes than DSM. Overall ReHo is a robust psychosis biomarker.


Penicillin resistance compromises Nod1-dependent proinflammatory activity and virulence fitness of neisseria meningitidis.
Neisseria meningitidis is a life-threatening human bacterial pathogen responsible for pneumonia, sepsis, and meningitis. Meningococcal strains with reduced susceptibility to penicillin G (Pen(I)) carry a mutated penicillin-binding protein (PBP2) resulting in a modified peptidoglycan structure. Despite their antibiotic resistance, Pen(I) strains have failed to expand clonally. We analyzed the biological consequences of PBP2 alteration among clinical meningococcal strains and found that peptidoglycan modifications of the Pen(I) strain resulted in diminished in vitro Nod1-dependent proinflammatory activity. In an influenza virus-meningococcal sequential mouse model mimicking human disease, wild-type meningococci induced a Nod1-dependent inflammatory response, colonizing the lungs and surviving in the blood. In contrast, isogenic Pen(I) strains were attenuated for such response and were out-competed by meningococci sensitive to penicillin G. Our results suggest that antibiotic resistance imposes a cost to the success of the pathogen and may potentially explain the lack of clonal expansion of Pen(I) strains.


Estimating treatment effects in randomised controlled trials with non-compliance: a simulation study.
Randomised controlled trials (RCTs) are often considered as the gold standard for assessing new health interventions. Patients are randomly assigned to receive an intervention or control. The effect of the intervention can be estimated by comparing outcomes between groups, whose prognostic factors are expected to balance by randomisation. However, patients' non-compliance with their assigned treatment will undermine randomisation and potentially bias the estimate of treatment effect. Through simulation, we aim to compare common approaches in analysing non-compliant data under different non-compliant scenarios. Based on a real study, we simulated hypothetical trials by varying three non-compliant factors: the type, randomness and degree of non-compliance. We compared the intention-to-treat (ITT), as-treated (AT), per-protocol (PP), instrumental variable (IV) and complier average casual effect (CACE) analyses to estimate large (50% improvement over the control), moderate (25% improvement) and null (same as the control) treatment effects. Different approaches were compared by the bias of estimate, mean square error (MSE) and 95% coverage of the true value. For a large or moderate treatment effect, the ITT estimate was considerably biased in all scenarios. The AT, PP, IV and CACE estimates were unbiased when non-compliant behaviours were random. The IV estimate was unbiased when non-compliant behaviours were symmetrically dependent on patients' conditions. The PP estimate was mostly unbiased when patients in the control group did not have access to the intervention. When the intervention was not different from the control, the ITT was less biased than the other approaches. Similar results were found when comparing the MSE and 95% coverage. The standard ITT analysis under non-compliance is biased when the intervention has a moderate or large effect. Alternative analyses can provide unbiased or less biased estimates. Based on the results, we make some suggestions on choosing optimal approaches for analysing specific non-compliant scenarios.


Monozygotic twins discordant for Aicardi syndrome.
Aicardi syndrome is a developmental disorder characterised by agenesis of the corpus callosum, retinal lacunae, seizures, and developmental delay. It is believed to be X linked with lethality in males. We report a set of monozygotic female twins one of whom is healthy and intellectually normal while the other has the classical Aicardi phenotype with profound retardation. Family history is negative. Both had normal karyotypes. Monozygosity was established by blood grouping, chromosomal heteromorphisms, and DNA analysis using six hypervariable probes (five autosomal and one X linked) and three X linked RFLP probes. We tested the hypothesis that preferential inactivation of a different X chromosome had occurred in each girl. Methylation sensitive RFLP analysis of DNA from EBV transformed B lymphocytes and cultured skin fibroblasts using MspI/HpaII digestion and probing with M27 beta showed a very similar pattern of X inactivation in both twins with no evidence of preferential expression of one particular X chromosome. We conclude that the abnormalities in the affected twin are probably the consequence of a postzygotic mutation in early embryonic development.


Integration of a precolumn fluorogenic reaction, separation, and detection of reduced glutathione.
Reduced glutathione (GSH) has been determined by fluorescence detection after derivatization together with a variety of separations. The reactions between GSH and fluorescent reagents usually are carried out during the sample pretreatment and require minutes to hours for complete reactions. For continuous monitoring of GSH, it would be very convenient to have an integrated microdevice that could perform online precolumn derivatization, separation, and detection. Heretofore, thiol-specific fluorogenic reagents require fairly long reaction times, preventing effective online precolumn derivatization. We demonstrate here that the fluorogenic, thiol-specific reagent, ThioGlo-1, reacts rapidly enough for efficient precolumn derivatization. The second order rate constant for the reaction of GSH and reagent (pH 7.5, room temperature) is 2.1 x 10(4) M(-1)s(-1). The microchip integrates this precolumn derivatization, continuous flow gated sampling, separation, and detection on a single device. We have validated this device for monitoring GSH concentration continuously by studying the kinetics of glutathione reductase (EC 188.8.131.52), an enzyme that catalyzes the reduction of oxidized glutathione (GSSG) to GSH in the presence of beta-NADPH (beta-nicotinamide adenine dinucleotide phosphate, reduced form) as a reducing cofactor. During the experiment, GSH being generated in the enzymatic reaction was labeled with ThioGlo-1 as it passed through a mixing channel on the microfluidic chip. Derivatization reaction products were introduced into the analysis channel every 10 s using flow gated injections of 0.1 s. Baseline separation of the internal standard, ThioGlo-1, and the fluorescently labeled GSH was successfully achieved within 4.5 s in a 9 mm separation channel. Relative standard deviations of the peak area, peak height, and full width at half-maximum (fwhm) for the internal standard were 2.5%, 2.0%, and 1.0%, respectively, with migration time reproducibility for the internal standard of less than 0.1% RSD in any experiment. The GSH concentration and mass detection limit were 4.2 nM and approximately 10(-18) mol, respectively. The Michaelis constants (K(m)) for GSSG and beta-NADPH were found to be 40 +/- 11 and 4.4 +/- 0.6 muM, respectively, comparable with those obtained from UV/vis spectrophotometric measurements. These results show that this system is capable of integrating derivatization, injection, separation, and detection for continuous GSH determinations.


Seasonal changes in migratory and predatory activity of two species of gadoid preying on inshore northern shrimp Pandalus borealis.
The interaction between two species of gadoid and a shrimp stock was studied in a 40 km long two-armed fjord in north-west Iceland. On the basis of acoustic and trawl surveys in 2005 and 2006, immature cod Gadus morhua and haddock Melanogrammus aeglefinus were found to migrate to the inner part of the fjord in late summer, concurrent with rising temperatures. At the same time, the local northern shrimp Pandalus borealis stock retreated into the north-east arm of the fjord. Vertical distribution of acoustic targets indicated that a significant and temporally variable fraction of the gadoids was inaccessible to the trawl. Shrimp was a significant part of the diet of immature G. morhua, except in June 2006 when euphausiids comprised most of the diet of both G. morhua and M. aeglefinus. Shrimp was only a minor part of the diet of M. aeglefinus. An on-off relationship was observed in the catches of gadoids and shrimp. In hauls with large catches of gadoids, few shrimp were found and vice versa, indicating avoidance reaction at this spatial scale. The cooling in winter may have driven the gadoids to the outer parts of the fjord, which in turn may have aided in the dispersal of the shrimp stock in the following months.


Expression and native structure of cytosolic class II small heat-shock proteins.
Higher plants synthesize small heat-shock proteins (smHSPs) from five related gene families. The class I and II families encode cytosolic smHSPs. We characterized the class II smHSPs of pea (Pisum sativum) and compared them with class I smHSPs. Antibodies against recombinant HSP17.7, a class II smHSP, recognized four heat-inducible 17- to 18-kD polypeptides and did not cross-react with class I smHSPs. On sucrose gradients the class II smHSPs sedimented primarily at 8 Svedberg units, indicating that they are components of large complexes similar in size to class I smHSP complexes. However, the class I and II complexes were readily distinguishable by nondenaturing polyacrylamide gel electrophoresis and isoelectric focusing. Nondenaturing immune precipitations using anti-HSP17.7 or anti-HSP18.1 (a class I smHSP) antiserum provide further evidence that the class I and II smHSPs exist in different complexes, composed primarily of smHSPs. Recombinant HSP17.7 and HSP18.1 formed complexes of sizes similar to those formed in vivo. When these two smHSPs were mixed, denatured with urea, and then dialyzed, the distinct class I and II complexes again formed, each containing only HSP18.1 or HSP17.7. Thus, cytosolic smHSPs from two related gene families expressed simultaneously form distinct complexes in vivo, suggesting that they have subtly different functions.


Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View.
Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.


Stimulus-specific deactivation of chemotactic factor-induced cyclic AMP response and superoxide generation by human neutrophils.
The responses of isolated human peripheral neutrophils to either simultaneous or sequential additions of two chemotactic factors were studied. Simultaneous additions of formyl-methionyl-leucyl-phenylalanine (10-100 nM) and the fifth component of complement, C5a (1-10 microliters/ml), evoked partially additive responses of membrane depolarization as measured by the fluorescent dye 3,3'-dipropyl-thiocarbocyanine, a transient elevation of intracellular cyclic AMP (cAMP), and superoxide (O2-) generation as assessed by ferricytochrome c reduction. Preincubation of the cells with either formyl-methionyl-leucyl-phenylalanine or C5a alone caused dose-dependent inhibition of the depolarization, the cAMP increase, and O2- release induced by a subsequent exposure to an optimal dose of the same stimulus, i.e., deactivation occurred. In contrast, when cells were treated with one chemotactic factor and then exposed to the other stimulus, the cells exhibited a normal response of peak depolarization, the rise in cAMP, and O2-0 production i.e., cross-deactivation failed to occur. The results imply that deactivation of these phenomena is stimulus specific. Further, these observations are consistent with the hypothesis that cross-deactivation of chemotaxis is mediated by one or more processes that are irrelevant to O2- generation, and that occur distal to the depolarization and cAMP steps in the sequence of neutrophil activation: possibly microtubule polymerization and orientation.


Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity.
During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase Cgamma2, which is brought into close proximity of Btk by SLP-65. However, this model was recently challenged by the identification of a role for Btk as a tumor suppressor in the absence of SLP-65 and by the finding that Btk function is partially independent of its kinase activity. To investigate if enzymatic activity is critical for the tumor suppressor function of Btk, we crossed transgenic mice expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65 double-deficient background. We found that K430R-Btk expression rescued the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65 double-deficient mice. Moreover, K430R-Btk could functionally replace wild-type Btk as a tumor suppressor in SLP-65- mice: at 6 months of age, the observed pre-B-cell lymphoma frequencies were approximately 15% for SLP-65- mice, 44% for Btk/SLP-65-deficient mice, and 14% for K430R-Btk transgenic mice on the Btk/SLP-65-deficient background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity.


Post-operative visual outcomes based on morphological staging of idiopathic epiretinal membranes on OCT.
To evaluate the recently described optical coherence tomography (OCT) based classification of epiretinal membrane (ERM) and its usefulness in predicting the functional outcome. A retrospective observational review of OCT scans of patients with the diagnosis of idiopathic ERM was carried out from January 2016 to June 2021. All consecutive images diagnosed with any stage of idiopathic ERM and fulfilled the eligibility criteria were included in the analysis. ERM was identified on OCT scans as a thin hyperreflective layer over the inner layers of retina. OCT scans of patients with ERM who underwent vitrectomy, were independently staged as per the new classification by two independent retinal surgeons to form a consensus on stage. Best corrected visual acuity (BCVA) in logMAR scale and central subfield thickness (CST) on pre- and post-operative spectral domain OCT scans were the variables noted for all patients at the time of diagnosis and at 6 and 12mo follow up visit after undergoing intervention. Partial correlation coefficient was computed between BCVA (logMAR) and CST by ERM stage adjusting by baseline measures. Clinical charts of 74 patients with idiopathic ERM were assessed. Clinically significant improvement in BCVA overtime was observed with significant difference in median visual acuity of patients with Stage II-IV ERM with P<0.001. The median CST of all patients with stage II-IV ERM showed similar consistent improvement with P<0.001 from baseline to 12th month. Our results showed not only gain in visual acuity but also shift from baseline to anatomical normalization of CST in stage II. We found a decrease in CST with difference of 166 µm and 151 µm in stage III and stage IV respectively. Our results remained consistent with the hypothesis of improved visual outcomes with all stages of ERM with adjusted moderate linear correlation between visual acuity and CST in stage II-IV (r>0.3). Equally significant visual outcomes of patients with ERM staged II-IV and therefore can be counselled for improved visual acuity after surgical removal of ERM with improvement up to 5 lines on Snellen's chart from the baseline.


EGF ligand fused to truncated Pseudomonas aeruginosa exotoxin A specifically targets and inhibits EGFR‑positive cancer cells.
Cancer cells have been known to overexpress the epidermal growth factor receptor (EGFR) and hence relevant multiple‑targeted therapies have been developed, with a recent clinical application of the antibody‑mediated inhibition of the EGFR. However, this strategy is not useful in cancer cells with mutations in KRAS; a GTPase downstream of EGFR which constitutively activates the pathway without EGF stimulation. Furthermore, mutations in EGFR also reduce the binding of monoclonal antibodies and thereby render them ineffective. In the present study, we designed a chimeric EGF protein fused to the truncated N‑terminal domain fragment of Pseudomonas aeruginosa exotoxin A (EGF‑ETA), which has ADP‑ribosylation activity and induces apoptosis. The EGF‑ETA protein was expressed in E. coli as a His‑tagged fusion. Our results showed that EGF‑ETA significantly inhibited the proliferation of EGFR‑positive A431 epidermoid carcinoma (IC50 27 ng/ml) and HN5 head and neck squamous cell carcinoma (IC50 36 ng/ml) cells. However, its effect on cancer cells with little or no EGFR expression was limited (A549‑IC50 1,000 ng/ml; MCF‑7‑IC50 >10,000 ng/ml). Compared to cetuximab, EGF‑ETA was highly potent in its killing capacity of HN5 cancer cells at 1,000 ng/ml, while cetuximab had little effect at 1,000 ng/ml. Furthermore, EGF‑ETA was just as potent in HCT116 (KRAS G13D) and SW480 (KRAS G12V) colon cancer cell lines harbouring KRAS hyperactivating mutations when compared to KRAS wild‑type HT29 colon cancer cells. Finally, co‑incubation of EGF‑ETA with an anti‑EGF antibody abrogated its effect on the EGFR‑positive A431 cells. Our results show that the chimeric EGF‑ETA toxin is extremely effective against EGFR‑positive cancers and raises the potential to further develop this chimera for use in targeting EGFR‑positive tumours resistant to monoclonal antibodies.


Catalytic asymmetric synthesis of 3-aryl phthalides enabled by arylation-lactonization of 2-formylbenzoates.
The catalytic asymmetric synthesis of 3-aryl phthalides is reported through a sequential asymmetric arylation-lactonization reaction. The reaction is enabled by a boron-zinc exchange to generate reactive arylating agents, which react with 2-formylbenzoates in the presence of a chiral amino naphthol ligand. The enantiodetermining step is the arylation of the aldehyde, which then undergoes a lactonization event to yield the corresponding phthalides in good yields and enantioselectivities.


Speckle Reduction in OCT using Massively-Parallel Detection and Frequency-Domain Ranging.
Speckle noise significantly limits the information content provided by coherent optical imaging methods such as optical coherence tomography and its recent derivative, optical frequency-domain imaging (OFDI). In this paper, we demonstrate a novel OFDI system that simultaneously acquires hundreds of angularly resolved images, which can be compounded to reduce speckle noise. The system comprises an InGaAs line-scan camera and an interferometer, configured so that the elements of the detector array simultaneously capture light spanning a backscattering angular range of 32 degrees. On successive read-outs of the array, the wavelength of the laser source was stepped through a range of 130 nm centered at 1295 nm to concurrently generate 400 angle-resolved OFDI images. A theory of angle-resolved OFDI and the design equations of the system are presented. Incoherent averaging of the angle-resolved data is shown to yield substantial speckle reduction (as high as an 8 dB SNR improvement) in images of a tissue phantom and esophageal tissue ex vivo.


Tumor necrosis factor alpha neutralization attenuates immune checkpoint inhibitor-induced activation of intermediate monocytes in synovial fluid mononuclear cells from patients with inflammatory arthritis.
During treatment with immune checkpoint inhibitors (ICI) such as the anti-PD-1 antibody pembrolizumab, half of patients with pre-existing inflammatory arthritis experience disease flares. The underlying immunological mechanisms have not been characterized. Here, we investigate the effect of pembrolizumab on cells involved in inflammation and destruction in the synovial joint and how immunosuppressive treatments affect the pembrolizumab-induced immune reactions. We included synovial fluid mononuclear cells (SFMCs, n = 28) and peripheral blood mononuclear cells (PBMCs, n = 6) from patients with rheumatoid arthritis and peripheral spondyloarthritis and PBMCs from healthy controls (n = 6). Fibroblast-like synovial cells (FLSs) were grown from SFMCs. The in vitro effect of pembrolizumab was tested in SFMCs cultured for 48 h, FLS-PBMC co-cultures and in SFMCs cultured for 21 days (inflammatory osteoclastogenesis). Cells and supernatants were analyzed by ELISA, flow cytometry, and pro-inflammatory multiplex assay. Finally, the effect of the disease-modifying anti-rheumatic drugs (DMARDs) adalimumab (TNFα inhibitor), tocilizumab (IL-6R inhibitor), tofacitinib (JAK1/JAK3 inhibitor), and baricitinib (JAK1/JAK2 inhibitor) on pembrolizumab-induced immune reactions was tested. Pembrolizumab significantly increased monocyte chemoattractant protein-1 (MCP-1) production by arthritis SFMCs (P = 0.0031) but not by PBMCs from patients or healthy controls (P = 0.77 and P = 0.43). Pembrolizumab did not alter MMP-3 production in FLS-PBMC co-cultures (P = 0.76) or TRAP secretion in the inflammatory osteoclastogenesis model (P = 0.28). In SFMCs, pembrolizumab further increased the production of TNFα (P = 0.0110), IFNγ (P = 0.0125), IL-12p70 (P = 0.0014), IL-10 (P = 0.0100), IL-13 (P = 0.0044), IL-2 (P = 0.0066), and IL-4 (P = 0.0008) but did not change the production of IL-6 (P = 0.1938) and IL-1 (P = 0.1022). The SFMCs treated with pembrolizumab showed an increased frequency of intermediate monocytes (P = 0.044), and the MCP-1 production increased only within the intermediate monocyte subset (P = 0.028). Lastly, adalimumab, baricitinib, and tofacitinib treatment were able to attenuate the pembrolizumab-induced MCP-1 production (P = 0.0004, P = 0.033, and P = 0.025, respectively), while this was not seen with tocilizumab treatment (P = 0.75). Pembrolizumab specifically activated intermediate monocytes and induced the production of several cytokines including TNFα but not IL-6. These findings indicate that flares in patients with pre-existing inflammatory arthritis involve monocyte activation and could be managed with TNFα neutralization.


Gambling and Substance Use: Co-occurrence among Adults in a Recent General Population Study in the United States.
This study is an up-to-date examination of gambling behaviors as well as gambling problems and their relationships to substance use and abuse. Further, the co-occurrence between problem gambling and substance abuse is studied using a large-scale, representative sample of adults aged 18 years and older in the United States. This random-digit-dial national survey was carried out in 2011-2013 with completed interviews from 2,963 respondents. Of the four gambling and substance use behaviors considered, past year gambling was the most prevalent (76.9%), followed by alcohol use (67.6%), tobacco use (28.7%) and marijuana use (11.2%). Problem gambling and the three substance abuse measures were highly related. Current problem gambling (3+ DIS criteria) was predicted by being male, being black, having low socioeconomic status and by alcohol abuse/dependence, tobacco dependence, and marijuana abuse/dependence. Thus, problem gambling is linked to other problem behaviors, especially substance abuse. Consequently, effective treatment approaches should screen and intervene for both problem gambling as well as co-occurring substance abuse.


Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior.
Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.


A quantitative analysis of the relationship between habitual energy expenditure, fitness and the metabolic cardiovascular syndrome.
Previous epidemiological studies have suggested an association between low levels of physical activity, fitness and the metabolic cardiovascular syndrome. However, many studies have used subjective non-quantitative questionnaire-based methods for assessing physical activity which do not distinguish between the different dimensions of this complex exposure, and in which measurement error in the exposure has not been estimated. These deficiencies in the measurement of this exposure complicate the interpretation of the results of epidemiological studies, and consequently make it difficult to design appropriate interventions and to estimate the expected benefit which would result from intervention. In particular, it is unclear whether public health advice should be to increase total energy expenditure, or to attempt to raise fitness by recommending periods of vigorous activity. To separate the effects of fitness and total energy expenditure in the aetiology of the metabolic cardiovascular syndrome, we measured the physical activity level (PAL), defined as total energy expenditure: BMR, and fitness (maximum O2 consumption (VO2max per kg), measured in a sub-maximal test) in a cross-sectional population-based study of 162 adults aged 30-40 years. Heart-rate monitoring with individual calibration was used to measure total energy expenditure using the HRFlex method (Ceesay et al. 1989) which has been validated previously against doubly-labelled water and whole-body calorimetry. The relationship between a single measure of PAL, VO2max per kg and the usual or habitual level for each exposure was measured in a sub-study of twenty-two subjects who undertook four repeated measures over the course of 1 year. This study design allows the reliability coefficient to be computed, which is used to adjust the observed associations for measurement error in the exposure. Twelve men (16.4%) and sixteen women (18.0%) were defined as having one or more features of the metabolic cardiovascular syndrome. The univariate odds ratio for each increasing quartile for PAL was 0.64 (95% CI 0.43-0.94) and was 0.49 (95% CI 0.32-0.74) for VO2max per kg, suggesting that the association with the metabolic cardiovascular syndrome was stronger for fitness than for PAL. However, after adjustment for obesity and sex, and correction for exposure measurement error, the odds ratio per quartile for PAL was 0.32 (95% CI 0.13-0.83) and 0.44 (95% CI 0.24-0.78) for VO2max per kg. Thus, although univariate analysis would suggest that fitness has a stronger association with the metabolic cardiovascular syndrome than PAL, this conclusion is reversed once confounding and the differences in measurement error are considered. We conclude from the present study that the metabolic cardiovascular syndrome is strongly associated with reduced habitual energy expenditure. The method employed to assess the exposure in the present study demonstrates the utility of assessing a known dimension of physical activity using a physiologically-based and objective measure with repeated estimation to adjust for measurement error. Such quantitative epidemiological data provide the basis for planning and evaluating the expected benefit of population-level interventions.


Nephron-sparing surgery.
The curative management of renal cell carcinoma remains surgical. Recent advances in imaging and increased use of cross-sectional imaging modalities have led to an increased detection of incidental renal cell carcinomas. There is little debate regarding the role of nephron-sparing surgery (NSS) when absolutely indicated. Radical nephrectomy is still considered by many as the treatment of choice for localized renal cell carcinoma in the setting of a normal contralateral kidney. However, there is growing evidence that in the correct patient, the use of NSS in this setting is justified. Therefore, the indications of NSS have evolved in the past decade. Recent data indicate that radical nephrectomy and NSS provide effective and equivalent curative treatment for most renal cell carcinomas, especially those 4 cm or smaller. These data, along with new, refined surgical techniques, new studies regarding the biology of renal cell carcinoma and true incidence of occult multifocality, and earlier diagnosis make NSS an attractive consideration for the practicing urologist.


The Role of Cross-Links in Posterior Spinal Fusion for Cerebral Palsy-Related Scoliosis.
Retrospective review of a multicenter, prospective database. Our aim was to compare complication rates and maintenance of radiographic correction at 2 years after posterior spinal fusion (PSF) with or without cross-links in patients with cerebral palsy (CP)-related scoliosis. Cross-links are frequently used in PSF to correct scoliosis in patients with CP because they are thought to increase the stiffness and torsional rigidity of the construct. We reviewed the records of patients with CP who underwent primary PSF with or without cross-links between August 2008 and April 2015. Inclusion criteria were minimum follow-up of 2 years, availability of complications data (implant failure, surgical site infection, revision), and pre- and postoperative measurements of the major curve (measured using the Cobb method). The 256 patients included in this analysis had a mean age of 14.1 ± 2.7 years. Ninety-four patients had cross-links (57% using one cross-link; 43% using two cross-links) and 162 patients did not have cross-links. P < 0.05 was considered statistically significant. The two groups did not differ significantly with regard to sex, age at surgery, preoperative menarche status, Gross Motor Function Classification System level, major curve magnitude, pelvic obliquity, kyphosis, and lordosis angles. There were no significant differences between groups in the correction achieved or the maintenance of correction at 2 years for the major curve, pelvic obliquity, kyphosis, or lordosis (all P > 0.05). Complication rates were similar between the cross-link group (16%, N = 15) and the non-cross-link group (14%, N = 22). At 2 years after PSF to treat CP-related scoliosis, patients had no significant differences in the degree of correction achieved, the maintenance of correction, or the rate of complications between those whose fusion constructs used cross-links and those whose constructs did not. 3.


Polymerase Chain Reaction Assays Reverted to Positive in 25 Discharged Patients With COVID-19.
We report the observation that 14.5% of COVID-19 patients had positive RT-PCR testing again after discharge. We describe correlations between laboratory parameters and treatment duration (P = .002) and time to virus recrudescence (P = .008), suggesting the need for additional measures to confirm illness resolution in COVID-19 patients.


A new species of Syndicus s. str. from Sumatra (Coleoptera, Staphylinidae, Scydmaeninae).
To date, only one species of the nominotypical subgenus of Syndicus Motschulsky was known to occur in Sumatra. A second species, Syndicus (s. str.) minimus sp. n., is described, based on males and females collected in Aceh, North and West Sumatra provinces. The new species is remarkably small-bodied and has conspicuously punctate elytra. An updated checklist of species in the nominotypical subgenus of Syndicus is given.


Physical cues of cell culture materials lead the direction of differentiation lineages of pluripotent stem cells.
Both human pluripotent stem cells (hPSCs) from embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have the potential ability to differentiate into many different cell types originating from all three germ layers. This review discusses physical cues from natural and synthetic biomaterials that guide the differentiation of hESCs and hiPSCs into several different lineages. We place special focus on how the hPSC differentiation fate is affected by (a) the elasticity of biomaterials used for hPSC culture, (b) the topography of biomaterials used for hPSC culture, and (c) the mechanical forces associated with biomaterials (stretching and electrical stimulation via biomaterials) used for hPSC culture.


The Effect of Occlusal Loading on Gingival Microleakage of Bulk Fill Composites Compared with a Conventional Composite.
Bulk fill composites have been introduced over the recent years in order to accelerate the process of tooth restoration by inserting composite in bulk up to 4mm thickness. Occlusal loading may influence the gingival microleakage of this composite. This in vitro study aims to evaluate the effect of occlusal loading on the gingival microleakage of bulk fill composites compared with a conventional composite. In this experimental study, box only class II cavities with gingival margins placed 1mm below the cemento-enamel junction were prepared on the mesial and distal surfaces of 36 maxillary premolars (72 cavities). The samples were divided into three groups and restored as follows: Group 1 (Tetric N-Ceram, incremental filling), Group 2 (X-tra fill, bulk filling), Group 3 (Tetric N-Ceram Bulk Fill, bulk filling). All restorations were thermocycled for 2000 cycles (5-50̊C) and then half of the samples were subjected to 200,000 cycles of loading. All the specimens were immersed in 0.5% basic fuchsin for 48 hours, then, sectioned, and evaluated for microleakage with a stereomicroscope. Data were analyzed using Kruskal-Wallis and Mann-Whitney U-tests. p< 0.05 was considered significant. There were no significant differences among the gingival microleakage of three composites in both unloaded and loaded groups. In addition, no statistically significant difference was found between the microleakage of unloaded and loaded groups in all materials. Occlusal loading did not affect the gingival microleakage of bulk fill composites, and the microleakage of class II cavities restored with the bulk filling technique was similar to that of restored with the incremental technique.


Analysis of hair from alopecia congenita.
Two patients with alopecia congenita had short vellus hairs of the scalp but some apparently normal-sized hairs in other areas. Both fibrous and matrix proteins were detected in the scalp hairs by polyacrylamide gel electrophoresis (PAGE), and x-ray diffraction analysis revealed a normal alpha pattern. Amino acid analysis showed a decreased cystine content suggesting a quantitative or qualitative change in the matrix component. Scanning electron microscopic examination revealed pits and bulges in the cuticle cells which may be related to wearing a wig. The data suggest a defect in the development of the follicle rather than an abnormality in a component of the hair.


[Role of dogs in the spread of Lamblia (Giardia) intestinalis infection].
Above 3,300 cases of human lambliasis have been annually notified in Perm since 2004 as shown by the data of the Board of the Federal Service for Surveillance on Consumer Rights Protection. Serological studies show that 22.29% of the Perm dogs have antibodies against Lamblia intestinalis antigens. Social (domestic and working) dogs have been found to be vectors of Lamblia in the urban population. Excretion of Giardia sp. cysts has been recorded in 0.28% of the domestic dogs. Overall, dogs are of no epidemiological value in spreading human lambliasis.


Urinary recovery of lactulose compared to D-xylose absorption kinetics in HIV patients with diarrhea and weight loss.
Using a kinetic model of D-xylose absorption, we have previously shown that there is severely impaired absorption of D-xylose in HIV patients with diarrhea and weight loss. The absorptive defect is characterized by an increased rate constant for nonabsorptive loss of D-xylose, Ko, and a decreased absorptive rate constant, Ka, and is unrelated to histology or the presence of pathogens. It is not known if there is also abnormal paracellular transport in these patients. We have extended our observations in these patients by including a measurement of paracellular transport, lactulose absorption. Nine HIV patients with chronic diarrhea, weight loss, and no detectable intestinal pathogens, two healthy volunteers, and three non-HIV patients with chronic diarrhea (two functional and one with scleroderma) were enrolled. Of the nine HIV patients, six had diminished bioavailability of D-xylose, F (range: 19-52%, normal >70%), and elevated rate constant for nonabsorptive loss, Ko (range: 0.54-1.35/hr, normal <0.353/min). Four of the six also had decreased Ka (range: 0.09-0.36/hr, normal >0.634/min). Only one of these six had increased lactulose recovery (3.51%, normal <0.5%). Two of three patients with normal kinetic parameters of D-xylose absorption had increased lactulose urinary recovery (1.92%, 2.61%). In conclusion, lactulose absorption is increased in some patients with HIV-related diarrhea who have normal D-xylose absorption, suggesting a paracellular mechanism for diarrhea in some patients with AIDS enteropathy.


Information system needs in health promotion: a case study of the Safe Community programme using requirements engineering methods.
The international Safe Community programme was used as the setting for a case study to explore the need for information system support in health promotion programmes. The 14 Safe Communities active in Sweden during 2002 were invited to participate and 13 accepted. A questionnaire on computer usage and a critical incident technique instrument were distributed. Sharing of management information, creating social capital for safety promotion, and injury data recording were found to be key areas that need to be further supported by computer-based information systems. Most respondents reported having access to a personal computer workstation with standard office software. Interest in using more advanced computer applications was low, and there was considerable need for technical user support. Areas where information systems can be used to make health promotion practice more efficient were identified, and patterns of computers usage were described.


A comprehensive review of bioactive peptides obtained from animal byproducts and their applications.
Livestock generates high quantities of residues, which has become a major socioeconomic issue for the meat industry. This review focuses on the identification of bioactive peptides (BPs) in animal byproducts and meat wastes. Firstly, the main bioactivities that peptides can have will be described and the methods for their evaluation will be discussed. Secondly, the various origins of these BPs will be studied. Then, the techniques and tools for the generation of BPs will be detailed in order to discuss, in the final part, how peptides could be used and assimilated. BPs possess diverse biological activities and can be strategic candidates for substituting synthetic molecules. In silico potentiality studies are a helpful tool to understand and predict BPs released from proteins and their potential activities. However, in vitro validation is often required. Although BP use is compelled by strict regulations in relation to the field of application, they are also limited by their low bioavailability and bioaccessibility. Therefore, it is important to test peptide stability during gastrointestinal digestion. Protective strategies have been discussed since their use could improve the stability and effectiveness of BPs.


Effects of hydraulic circuit training on cardiovascular function.
The effect of hydraulic circuit training (HCT) on cardiovascular (CV) function was assessed in 32 healthy middle-aged males (X age = 42.2 +/- 2.1 yr). Maximal aerobic power (VO2max), with simultaneous measurement of stroke volume (SV) and cardiac output (CO), by impedance cardiography, was assessed pre- and post-training. Subjects were randomly assigned to a nonexercising control group, a cycle training group (cycle), or one of the two HCT groups. Training groups participated in a 9 wk program, 3 d.wk-1. Subjects assigned to HCT exercised on a 9 station circuit, completing 3 circuits.d-1. Each circuit consisted of three 20 s work intervals at each station with a 1:1 work:rest ratio. One HCT group (HCTmax) completed the maximal repetitions possible (RM) during each work interval. The other HCT group (HCTsub) exercised at 70-85% of RM. Following training VO2max (ml.kg-1 min-1) was significantly increased in all training groups (18.0, 12.5, and 11.3% for cycle, HCTsub, and HCTmax groups, respectively; P less than 0.05). The increase in VO2max observed in the cycle group was significantly greater than that recorded by the two HCT groups (P less than 0.05). For all three training groups, the increase in VO2max was associated with increases in SVmax and COmax (P less than 0.05 for both). These findings suggest that both maximal and submaximal HCT programs can elicit improvements in cardiovascular fitness.


Sense of presence and atypical social judgments in immersive virtual environments. Responses of adolescents with Autism Spectrum Disorders.
Immersive virtual environments (IVEs) are potentially powerful educational resources but their application for children with Autism Spectrum Disorder (ASD) is under researched. This study aimed to answer two research questions: (1) Do children with ASD experience IVEs in different ways to typically developing children given their cognitive, perceptual and sensory differences? and (2) Can an IVE accurately simulate ecologically valid social situations? Ten children with ASD and 14 typically developing (TD) adolescents all aged 12-16 years experienced three different IVEs. They completed self-report questionnaires on their sense of 'presence' in the IVEs and rated 'social attractiveness' of a virtual character in socially desirable and undesirable scenarios. The children with ASD reported similar levels of presence to their TD peers and no negative sensory experiences. Although TD adolescents rated the socially desirable character as more socially attractive than the undesirable character, adolescents with ASD rated the two characters as equally socially attractive. These findings suggest that children with ASD do not experience IVEs in different ways to their TD counterparts and that the IVEs are realistic enough to simulate authentic social situations. This study paints a very encouraging picture for the potential uses of IVEs in assessing and educating individuals with ASD.


Palmitoylation of superoxide dismutase 1 (SOD1) is increased for familial amyotrophic lateral sclerosis-linked SOD1 mutants.
Mutations in Cu,Zn-superoxide dismutase (mtSOD1) cause familial amyotrophic lateral sclerosis (FALS), a neurodegenerative disease resulting from motor neuron degeneration. Here, we demonstrate that wild type SOD1 (wtSOD1) undergoes palmitoylation, a reversible post-translational modification that can regulate protein structure, function, and localization. SOD1 palmitoylation was confirmed by multiple techniques, including acyl-biotin exchange, click chemistry, cysteine mutagenesis, and mass spectrometry. Mass spectrometry and cysteine mutagenesis demonstrated that cysteine residue 6 was the primary site of palmitoylation. The palmitoylation of FALS-linked mtSOD1s (A4V and G93A) was significantly increased relative to that of wtSOD1 expressed in HEK cells and a motor neuron cell line. The palmitoylation of FALS-linked mtSOD1s (G93A and G85R) was also increased relative to that of wtSOD1 when assayed from transgenic mouse spinal cords. We found that the level of SOD1 palmitoylation correlated with the level of membrane-associated SOD1, suggesting a role for palmitoylation in targeting SOD1 to membranes. We further observed that palmitoylation occurred predominantly on disulfide-reduced as opposed to disulfide-bonded SOD1, suggesting that immature SOD1 is the primarily palmitoylated species. Increases in SOD1 disulfide bonding and maturation with increased copper chaperone for SOD1 expression caused a decrease in wtSOD1 palmitoylation. Copper chaperone for SOD1 overexpression decreased A4V palmitoylation less than wtSOD1 and had little effect on G93A mtSOD1 palmitoylation. These findings suggest that SOD1 palmitoylation occurs prior to disulfide bonding during SOD1 maturation and that palmitoylation is increased when disulfide bonding is delayed or decreased as observed for several mtSOD1s.


Safe poultry meat production in the next century.
The revolutionary industrialisation of the poultry industry in the last 30 years has made the food poultry meat available for large groups of consumers. Due to its nutritional, sensory and economical characteristics, poultry meat is by far the most popular animal food product world-wide. Epidemiological reports, however, incriminate poultry meat as a source for outbreaks of human food poisoning. The organisms involved are Salmonella spp., Campylobacter spp. and, to a lesser extent, Listeria monocytogenes, Escherichia coli, Staphylococcus aureus, Yersinia enterocolitica, Clostridium perfringens and Aeromonas spp. Contamination of the end-product with pathogenic microorganisms is a reflection of the contamination of the live birds and, therefore, measures to be taken by industry to avoid contamination of the consumer-ready product should start at that level. In terms of the critical control point approach of the HACCP concept, the quantitative contribution of critical phases in the production chain towards end-product contamination should be estimated in order to take the necessary intervention or corrective steps. To guarantee the production of safe poultry meat, knowledge of the capability of microorganisms to colonise the gastrointestinal tract is needed and the use of vaccines, antimicrobials and competitive exclusion microfloras as well as the implementation of new processing technology should be encouraged.


Using bibliographic software to appraise and code data in educational systematic review research.
Bibliographic database software is often recommended as a tool that can assist researchers in managing the large numbers of references produced in early stages of a systematic review. The uses of such software in systematic review research are often represented solely in terms of bibliographic functions, while the uses that extend beyond simple bibliographic functions have not been explored. This article provides a guide on how to use extended functions of bibliographic software to systematically complete the steps of appraising search results and coding references for inclusion in or exclusion from the systematic review. The process is illustrated using an ongoing systematic review as a case description and using screenshots from the bibliographic database, EndNote®, the authors' preferred software program for the study. The case description illustrates how bibliographic software serves not only to organize and store search results, but also to appraise and code search results and to explicitly track researchers' decisions across the systematic review. Bibliographic tools can contribute to make the methods that researchers adopt for the phase following the initial literature search more transparent and systematic. The illustrative case description involves a systematic review of academic education in occupational therapy, but easily generalizes to systematic reviews in other health science professions.


K-CapsNet: K-Nearest Neighbor Based Convolution Capsule Network for Cerenkov Luminescence Tomography Reconstruction.
Cerenkov luminescence tomography (CLT) has received significant attention as a promising imaging modality that can display the three-dimensional (3D) distribution of radioactive probes. However, the reconstruction of CLT suffers from severe ill-posed problem. It is difficult for traditional model-based method to obtain satisfactory result. Recently, deep learning-based method have shown great potential for accurate and efficient CLT reconstruction. In this study, a KNN-based convolution capsule network, named K-CapsNet, is proposed for cerenkov luminescence tomography. In K-CapsNet, the surface photon intensity is encoded in capsule form. The KNN-based convolution and K-means clustering are proposed for efficient encoding. Numerical simulation experiments have been carried out to verify the performance of K-CapsNet, and the results show that it performs superior in source localization and morphological restoration compared with existing methods.