The Impact of Cycling Specialization on Successful Aging and the Mediating Role of Loneliness.
Recent studies have provided some evidence supporting that cycling specialization (CS) may be positively related to successful aging (SA) among elderly adults. However, there is a gap regarding the examination of the role of loneliness in the relationship between CS and SA. A hypothetical model was proposed to test the relationship between CS, SA, and loneliness. For this purpose, this study randomly conducted a questionnaire survey among 395 cycling participants over the age of 60 in China. The results showed that behavior, cognition, and affect had negative effects on loneliness. Behavior, cognition, and affect were positively associated with SA. Loneliness was negatively related to SA. Furthermore, behavior, cognition, and affect had positive and indirect effects on SA through loneliness. These results offered some new insights for understanding the relationship between CS and SA, especially considering the indirect effect of loneliness. The limitations and implications of the findings were discussed.


Light-emitting diode exposure enhances sperm motility in men with and without asthenospermia: preliminary results.
To evaluate the effect of light-emitting diode (LED) on sperm motility in men with and without asthenospermia. Semen samples from 27 men were assessed and washed. An aliquot was taken from each sample as a control. The remaining amount was exposed to red LED for 2, 5 and 10 minutes. Sperm motility from the test and control tubes were re-checked at the end of each time interval. In 11 of these 27 samples, the same protocol was repeated without sperm washing. Evaluation of sperm creatine kinase (CK) activity, hypoosmotic swelling (HOS) test and aniline blue staining (ANBS) were undertaken after phototherapy in additional 15 samples. Progressive sperm motility increased significantly after LED treatment at the different time intervals whether in washed (p = 0.000) or non-washed (p = 0.003) samples. The amount of the increase in motility in washed aliquots was significantly more (p = 0.000) than in naive semen. Sperm CK activity increased, but was not significant whilst there were no changes regarding HOS and ANBS. Red LED is a promising safe tool to boost sperm motility in vitro. This may have a great implication on maximizing the possibilities and outcomes of intrauterine insemination trials.


Does return to work occur earlier after work-related sick leave episodes than after non-work-related sick leave episodes? A retrospective cohort study in Spain.
In Spain, sick pay benefits for work-related sick leave episodes are higher than for non-work-related episodes. Our aim is to assess whether time to return to work is longer for higher paid sick leave episodes than for lower paid episodes. We used data from 62,376 work-related and 76,932 non-work-related sick leave episodes occurring among 338,226 workers from 56,099 companies in Spain in 2002. All episodes were followed for up to 18 months. Episodes were classified by a physician as being work- or non-work-related according to medico-legal judgments. The median episode duration and the 25th and 75th percentiles were calculated. The probability of remaining absent from work was estimated by a non-parametric estimator of the marginal survival function. The time ratio between both types of sick leave was estimated by a log-logistic regression model, using non-work-related episodes as the reference. Median episode duration (25th-75th percentiles) was 11 (6-21) days for work-related episodes and 9 (4-29) days for non-work-related episodes. Time to return to work was longer for work-related episodes than for non-work-related episodes of less than 16 days (time ratio: 1.19 in men and 1.08 in women), while the opposite was observed for episodes of more than 15 days (0.58 in men and 0.40 in women). Sick pay benefits have a limited effect on time to return to work after a sick leave episode.


Mitochondrial DNA deletions in patients with esophagitis, Barrett's esophagus, esophageal adenocarcinoma and squamous cell carcinoma.
Esophageal cancer is the eighth most common cancer globally. Esophageal adenocarcinoma (EA) and esophageal squamous-cell carcinoma (ESCC) are the two major types of esophageal cancer with poor prognosis. The mechanisms of the progression of normal esophagus to Barrett's esophagus (BE) and EA are not fully understood. Mitochondria play a central role in generating energy, apoptosis and cell proliferation. Mutations of mitochondrial DNA (mtDNA) have been identified in many diseases including cancers. Mutations of mtDNA were investigated as a part of carcinogenesis. Our objective is to study whether the 5 kb and 7.4 kb mtDNA deletions are important in the progression of normal esophagus to BE and EA. In this study, the frequency of the 5 kb and 7.4 kb deletions in mtDNA were studied in specimens ranging from normal esophageal tissue to BE and EA and also from ESCC. Seventy six paraffin-embedded tissue samples were studied. Four couple primers were used. Seventy-six tissue samples were analyzed total. The negative control and the positive control PCR product were detected in all analyzed samples. The fusion PCR products, which represent the presence of the deletions, were not detected in any of the samples. We can say that, these deletions are not associated with progression of normal esophagus to BE and EA and they do not have an important role in detecting esophagitis, BE, EA, and ESSC.


A glucose sensor fabricated by piezoelectric inkjet printing of conducting polymers and bienzymes.
Piezoelectric inkjet printing of polymers and proteins holds great promise for fabrication of miniaturized bioelectronic devices, such as biochips and biosensors. In this study, a bienzymatic glucose biosensor prototype based on poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT-PSS), glucose oxidase (GOD), and horseradish peroxidase (HRP) was fabricated by a piezoelectric inkjet printer. An aqueous bioelectrical ink containing PEDOT-PSS, GOD, and HRP was prepared and printed on an indium-tin-oxide (ITO)-coated poly(ethylene terephthalate) (PET) film. The PEDOT-PSS/GOD/HRP sensor was covered with a cellulose acetate membrane. The use of bienzymatic sensing combined with conducting polymers via piezoelectric inkjet printing showed a synergistic effect resulting in significant amplification of the response signal. The glucose sensor reached steady-state current density within 3 s, indicating a fast response time, and exhibited a linear dose-dependent electrochemical response with high sensitivity. The overall result demonstrates that a glucose sensor with high sensitivity could be readily fabricated by a piezoelectric inkjet printing system.


Familial resemblance and shared latent familial variance in recurrent fall risk in older women.
A possible familial component to fracture risk may be mediated through a genetic liability to fall recurrently. Our analysis sample included 186 female sibling-ships (n=401) of mean age 71.9 yr (SD=5.0). Using variance component models, we estimated residual upper-limit heritabilities in fall-risk mobility phenotypes (e.g., chair-stand time, rapid step-ups, and usual-paced walking speed) and in recurrent falls. We also estimated familial and environmental (unmeasured) correlations between pairs of fall-risk mobility phenotypes. All models were adjusted for age, height, body mass index, and medical and environmental factors. Residual upper-limit heritabilities were all moderate (P<0.05), ranging from 0.27 for usual-paced walking speed to 0.58 for recurrent falls. A strong familial correlation between usual-paced walking speed and rapid step-ups of 0.65 (P<0.01) was identified. Familial correlations between usual-paced walking speed and chair-stand time (-0.02) and between chair-stand time and rapid step-ups (-0.27) were both nonsignificant (P>0.05). Environmental correlations ranged from 0.35 to 0.58 (absolute values), P<0.05 for all. There exists moderate familial resemblance in fall-risk mobility phenotypes and recurrent falls among older female siblings, which we expect is primarily genetic given that adult siblings live separate lives. All fall-risk mobility phenotypes may be coinfluenced at least to a small degree by shared latent familial or environmental factors; however, up to approximately one-half of the covariation between usual-paced walking speed and rapid step-ups may be due to a common set of genes.


Fractures of the clivus and traumatic diastasis of the central skull base in the pediatric population.
Fractures of the clivus and traumatic diastases of the clival synchondroses are rare in the pediatric population. The incidence, outcome, and biomechanics associated with these fractures have been difficult to ascertain secondary to the lack of literature pertaining to their occurrence. A Boolean search of the electronic medical record database at the Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, was performed to identify patients with fractures of the clivus that were diagnosed using CT of the head. A retrospective review of the chart and radiographic imaging was then performed to assess data regarding patient demographics, mechanism of injury, and skull and brain parenchymal injuries, as well as outcomes. Between May 2002 and November 2007, 16 patients with fractures of the clivus were identified. The mean age of these patients was 9 years (range 1-16 years). Eleven (68.8%) of the 16 patients had an associated traumatic diastasis of the central skull base. Five (31.3%) of the 16 patients died. However, of the 11 patients who survived, all had a good outcome with a Glasgow Outcome Scale score of 4 or 5 at the time of discharge. The incidence of clival fractures among patients with head injuries was 0.33%. Clival fractures occur with a similar incidence in both the pediatric and adult trauma population. Outcome is not correlated directly with the extent of clival fracture, but rather with the presenting Glasgow Coma Scale score and concomitant brain parenchymal injuries. The identification of traumatic diastases in patients with clival fractures suggests that static loading forces are a significant factor in the biomechanics producing these types of fractures.


Establishing the kinetic competency of the cationic imine intermediate in nitroalkane oxidase.
The flavoprotein nitroalkane oxidase catalyzes the oxidation of neutral nitroalkanes to the corresponding aldehydes and ketones. Cyanide inactivates the enzyme during turnover in a concentration-dependent fashion. Mass spectrometry of the flavin from enzyme inactivated by cyanide in the presence of nitroethane or nitrohexane shows that a flavin cyanoethyl or cyanohexyl intermediate has formed. At high concentrations of cyanide, inactivation does not consume oxygen. Rapid reaction studies show that formation of the adduct with 2-(2H2)-nitroethane shows a kinetic isotope effect of 7.9. These results are consistent with cyanide reacting with a species formed after proton abstraction but before flavin oxidation. The proposed mechanism for nitroalkane oxidase involves removal of a proton from the nitroalkane, forming a carbanion which adds to the flavin N(5). Elimination of nitrite from the resulting adduct would form an electrophilic imine which can be attacked by hydroxide. The present results are consistent with cyanide trapping this electrophilic intermediate.


Precision Dosing of Targeted Therapies Is Ready for Prime Time.
Fixed dosing of oral targeted therapies is inadequate in the era of precision medicine. Personalized dosing, based on pharmacokinetic (PK) exposure, known as therapeutic drug monitoring (TDM), is rational and supported by increasing evidence. The purpose of this perspective is to discuss whether randomized studies are needed to confirm the clinical value of precision dosing in oncology. PK-based dose adjustments are routinely made for many drugs and are recommended by health authorities, for example, for patients with renal impairment or for drug-drug interaction management strategies. Personalized dosing simply extrapolates this paradigm from selected patient populations to each individual patient with suboptimal exposure, irrespective of the underlying cause. If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials. We propose a path forward to demonstrate the clinical relevance of individualized dosing of molecularly-targeted anticancer drugs.


Verapamil Increases the Bioavailability and Efficacy of Bedaquiline but Not Clofazimine in a Murine Model of Tuberculosis.
Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine, and other drugs against Mycobacterium tuberculosis, has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and clofazimine against M. tuberculosis clinical isolates, including those harboring rv0678 mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity in vivo, but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.


CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice.
Innate immune mechanisms are crucial in defense against bacterial illnesses in humans, as evidenced by abnormal antibacterial responses due to defects in TLR signaling, seen in children with MyD88 or IL-1R-associated kinase 4 deficiency. Otitis media (OM) is the most common disease of childhood, and the role of innate immune molecules in this disorder remains unclear. In a murine model of OM, we show that, in the absence of TNF, a key effector of innate immunity, this disease is prolonged after middle ear infection with nontypeable Haemophilus influenzae (NTHi). In the absence of TNF, mice fail to upregulate both TLRs and downstream genes and proteins, such as CCL3, resulting in defects in both inflammatory cell recruitment and macrophage function. Peritoneal macrophages of mice lacking TNF have a diminished ability to phagocytose and kill NTHi, and this defect is partially corrected in vitro by exogenous rTNF. Addition of rCCL3 alone or in combination with rTNF restores phagocytosis and killing by TNF-deficient macrophages to that of unstimulated wild-type macrophages. In vivo administration of rCCL3 to animals deficient in TNF fully restores the ability to control OM due to NTHi, whereas a CCL3-blocking Ab impaired the ability of wild-type mice to recover from OM. Thus, CCL3 is a potent downstream effector of TNF-mediated inflammation in vitro and in vivo. Manipulation of CCL3 and/or TNF may prove to be effective therapeutic approaches in OM or other conditions associated with defective TNF generation.


Roles of piRNAs in microcystin-leucine-arginine (MC-LR) induced reproductive toxicity in testis on male offspring.
In the present study, we evaluated the toxic effects on the testis of the male offspring of MC-LR exposure during fetal and lactational periods. Pregnant females were distributed into two experimental groups: control group and MC-LR group which were exposed to 0 and 10 μg/L of MC-LR, respectively, through drinking water separately during fetal and lactational periods. At the age of 30 days after birth, the male offspring were euthanized. The body weight, testis index, and histomorphology change were observed and the global changes of piwi-interacting RNA (piRNA) expression were evaluated. The results revealed that MC-LR was found in the testis of male offspring, body weight and testis index decreased significantly, and testicular tissue structure was damaged in the MC-LR group. In addition, the exposure to MC-LR resulted in an altered piRNA expression profile and an increase of the cell apoptosis and a decrease of the cell proliferation in the testis of the male offspring. It was reasonable to speculate that the toxic effects on reproductive system of the male offspring in MC-LR group might be mediated by piRNAs through the regulation of the target genes. As far as we are aware, this is the first report showing that MC-LR could play a role in disorder of proliferative and cell apoptosis in the testis of the male offspring by the maternal transmission effect of toxicity.


Improving survival trends in primary myelofibrosis: an international study.
Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was aimed at ascertaining whether survival prolongation has actually occurred in PMF. A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups. Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 × 10(9)/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1-risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease-specific mortality occurred across all patient subgroups, except in intermediate-2-risk or high-risk patients. Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.


Degradation of pig gastric and colonic mucins by bacteria isolated from the pig colon.
Mucin degradation was studied with one Clostridium (RS42) and two Bacteroides (RS2 and RS13) strains isolated from the pig colon mucosa. Mucins from pig colon and stomach were prepared in their subunit forms for use as growth substrates, and the loss of the individual sugars from the mucins was measured after bacterial growth. Colonic mucin was more resistant to degradation than gastric mucin. The strains differed in their competence in degrading the mucins. Carbohydrate plus sulfate removal from gastric mucin varied from 63 to 76% for RS2, 37 to 46% for RS13, and 37 to 53% for RS42. All three strains removed more fucose (67 to 87%) and less sulfate (22 to 63%) than the average carbohydrate plus sulfate loss. Under the same conditions of growth, a mixed pig fecal culture removed 78% of sulfate and 96% of each sugar. Of the two major glycoprotein types present in the subunit pig gastric mucin preparation (R. A. Stanley, S. P. Lee, and A. M. Roberton, Biochim. Biophys. Acta 760:262-269, 1983), the less highly sulfated mucin was more susceptible to RS42 degradation. The degradation of gastric mucin by RS2 was not affected by glucose or high sulfate concentrations in the growth medium. The results show that the three strains of colon bacteria are capable of significant hydrolysis of mucin carbohydrate and that the extent of degradation seen with pure cultures is determined in part by the subunit glycoprotein type(s) present in the mucin.


Dopaminergic enhancement of cognitive function.
The ascending dopamine system of the mammalian brain has been associated with motor, mnemonic and goal-directed or reward-related behaviour. The most progress in understanding the cortical mechanisms of dopaminergic modulation of function has been made with regards to short-term mnemonic (or working memory) function. Research in experimental animals strongly suggests that stimulation of dopamine D1 receptors in the prefrontal cortex can ameliorate spatial working memory related cognitive deficits, and may even enhance cognitive function in healthy animals. Research in humans has not been able to clearly replicate these findings, partly due to the lack of available agents that can safely be used. Low doses of dopamine D2 receptor agonists such as bromocriptine and pergolide may be able to enhance working memory and executive functions, but these effects may be dependent on the nature of the tasks used and the baseline performance levels of the subjects. Thus, the effects of dopaminergic cognitive enhancers may not be simple, or uniform across subjects. Systematic studies in humans carefully controlling task parameters are needed in order to specify the potential cognitive processes open to enhancement with dopaminergics. However, since the DA receptor subtypes in different brain regions appear to differentially influence similar functions, carefully defining the cognitive processes to be tested against potential therapeutics is an equally important goal. Studies in patients groups using selective dopaminergics are rather restricted, but show promise for designing large-scale clinical trials into the cognitive enhancing properties of potential therapeutic agents that act through the dopamine system.


Diabetes, diet-health behavior, and obesity.
High-quality diets play an important role in diabetes prevention. Appropriate dietary adherence can improve insulin sensitivity and glycemic control, and thus contribute to lifestyle improvement. However, previous research suggests that dietary adherence is arguably among the most difficult cornerstones of diabetes management. The objectives of this study are (1) to estimate whether and to what extent individuals diagnosed with diabetes show significant differences in diet quality [healthy eating index (HEI)] compared to healthy individuals, (2) to quantify whether and to what extent diabetics experience significantly higher outcomes of body mass index (BMI), and (3) to estimate whether and to what extent dietary supplementation impacts diabetes patient's diet quality and/or BMI outcomes. We use data from the 2007-2008 U.S. National Health and Nutrition Examination Survey (NHANES). The NHANES is the primary, randomized, and nationally representative survey used to assess the health and nutritional status in the U.S. We apply propensity score matching (PSM) to account for selection bias and endogeneity between self-reported diet and health behavir (treatment) and BMI outcomes. We control for an individual's BMI as to capture the impact of past dietary behavior in its impact on HEI. Matching results suggest that regular dietary supplement consumption is associated with significant lower BMI outcomes of almost 1 kg/m(2). The close relationship between diabetes and obesity has been at the center of the diet-health policy debate across Canada and the U.S. Knowledge about this linkage may help to improve the understanding of the factors that impact dietary choices and their overall health outcomes, which may lead to a more efficient and effective promotion of dietary guidelines, healthy food choices, and targeted consumer health and lifestyle policies.


Photoinduced electron transfer in photorobust coumarins linked with electron donors affording long lifetimes of triplet charge-separated states.
Electron donor (D) substituted 3-ethoxycarbonylcoumarin (CM) derivatives [D-CM: D = 4-diphenylaminophenyl (DPA), 4-diethylaminophenyl (DEA), 4-dimethylaminophenyl (DMA), and 2-methyl-4-dimethylaminophenyl (MeDMA)] are synthesized and characterized. Photoinduced electron transfer (ET) from the D moiety to the acceptor (CM) and back electron transfer (BET) are investigated by femtosecond and nanosecond laser flash photolysis measurements. Femtosecond laser excitation at 355 nm of a deaerated acetonitrile (MeCN) solution of D-CM shows generation of the singlet charge-separated (CS) state [(1)(D(.+)-CM(.-))] by ET from D to the singlet excited state of the CM moiety ((1)CM*), and this is followed by rapid decay within 3 ns to afford the triplet excited state (D-(3)CM*). Nanosecond laser excitation of a deaerated MeCN solution of D-CM results in formation of the triplet CS state by ET from D to (3)CM*. The quantum yield of formation of the triplet CS state [(3)(DPA(.+)-CM(.-))] in the presence of iodobenzene (PhI) in deaerated MeCN increases with increasing concentration of PhI to reach 27 % at 0.5 M PhI. The triplet CS state decays by bimolecular BET because of the long CS lifetime by unimolecular BET. Formation of the long-lived triplet CS state was confirmed by electron spin resonance (ESR) measurements. The photorobust nature of DPA-CM is demonstrated by multiple laser pulse excitation (>1000 times) at 355 nm. The photoinduced ET and BET rate constants of a series of D-CM are thoroughly analyzed in light of the Marcus theory of electron transfer.


The impact of Hepatitis C virus infection on kidney transplantation outcomes: A systematic review of 18 observational studies: The impact of HCV on renal transplantation.
Hepatitis C virus (HCV) infection occursin 0% to 51% of dialysis patients, and manyHCV-positive patients are urged to undergo kidney transplantation. However, the outcome of renal transplantation in HCV-positive recipients is unknown. Our review aimed to address the outcomesof renal transplantation recipients (RTRs)following kidney transplantation. We selected studies that used the adjusted relative risk (aRR) and 95% CI of all-cause mortality and graft loss in HCV-positive compared with HCV-negative RTRs as study endpoints. Cox proportional hazard analysis was usedin all studies to calculate the independent effects of HCV infection on RTR outcomes. Sixteen retrospective cohort studies and 2 clinical trials were selected for our review. Sixteen studies were related to patient survival, and 12 examined graft survival. The combined hazard ratio in HCV-infected recipients was 1.69-fold (1.33-1.97, p < 0.0001) and 1.56 times (1.22-2.004, p < 0.0001) greaterthan that of HCV-negative recipients for mortality and graft loss, respectively. Although HCV-infected RTRs have worseoutcomes than HCV-negative RTRs,kidney transplantation is the preferred treatment for patients with HCV infection and end-stage renal disease.


Multiply antibiotic-resistant Streptococcus pneumoniae recovered from Spanish hospitals (1988-1994): novel major clones of serotypes 14, 19F and 15F.
We analysed a collection of 95 multiply antibiotic-resistant pneumococci, recovered since 1988 from 14 Spanish hospitals, that have MICs > or = 0.25 microgram benzylpenicillin ml-1. The majority of the isolates were of serogroups 14, 23, 6, 19 and 15, which are currently the serogroups mainly associated with multiresistance in Spain. All of the serogroup 23 isolates were members of the major Spanish serotype 23F multiresistant clone. Similarly, most of the serogroup 6 isolates were members of the major multiresistant serotype 6B clone, or variants of this clone. Eighteen of the 24 isolates of serogroup 19 were members of a highly penicillin-resistant clone that appears to be a serotype 19F variant of the major Spanish serotype 23F multiresistant clone. Eighteen of the 25 isolates of serotype 14 were members of a previously uncharacterized highly penicillin-resistant clone. Thirteen of the 16 isolates of serogroup 15 were members of a single previously unreported clone of serotype 15F that had moderate levels of resistance to penicillin. Approximately 65% of the multiresistant pneumococci that are currently circulating in Spain were members of the three new clones of serotype 14, 15F and 19F that we describe here, or the previously described serotype 6B and 23F clones. The other 35% of isolates were minor variants of the major clones, unrelated minor clones, and unique isolates, many of which appeared to have arisen by horizontal gene transfer events.


Automated distinction of shearing and distortion artefacts in structured illumination microscopy.
Any motion during an image acquisition leads to an artefact in the final image. Structured illumination microscopy (SIM) combines several raw images into one high-resolution image and is thus particularly prone to these motion artefacts. Their unpredictable shape cannot easily be distinguished from real high-resolution content. We previously implemented a motion detection specifically for SIM, which had two shortcomings which are solved here. First, the brightness dependency of the motion signal is removed. Second, the empirical threshold of the calculated motion signal was not a threshold at a maximum allowed artefact. Here we investigate which artefacts are still acceptable and which linear movement creates them. Thus, the motion signal is linked with the maximal strength of the expected artefact. A signal-to-noise analysis including classification successfully distinguishes between artefact-free imaging, shearing and distortion artefacts in biological specimens. A shearing, as in wide-field microscopy, is the dominant reconstruction artefact, while distortions arise not until surprisingly fast movements.


Evaluating spatiotemporal interactions between shapes.
Spatiotemporal interactions between stimuli can alter the perceived curvature along the outline of a shape (Habak, Wilkinson, Zakher, & Wilson, 2004; Habak, Wilkinson, & Wilson, 2006). To better understand these interactions, we used a forward and backward masking paradigm with radial frequency (RF) contours while measuring RF detection thresholds. In Experiment 1, we presented a mask alongside a target contour and altered the stimulus onset asynchrony between this target-mask pair and a temporal mask. We found that a temporal mask increased thresholds when it preceded the target-mask stimulus by 130-180 ms but decreased thresholds when it followed the target-stimulus mask by 180 ms. Furthermore, Experiment 2 demonstrated that the effects of temporal and spatial masks are approximately additive. We discuss these findings in relation to theories of transient and sustained channels in vision.


A20 controls intestinal homeostasis through cell-specific activities.
The transcription factor NF-κB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-κB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.


Chronological progression of body dissatisfaction and drive for thinness in females 12 to 17 years of age.
The purpose of this secondary study of cross-sectional data was to examine patterns of scores on the Eating Disorders Inventory in a healthy sample of female adolescents thought to have a high potential for risk. Data were obtained as part of a consultation to identify risk of developing eating disorders. The screening and subsequent group level analysis was carried out with 44 female dancers 12 to 17 years of age enrolled in grades 7 to 12 in a Magnet school. This secondary analysis examined three components of the Eating Disorder Inventory (EDI-3): body dissatisfaction, drive for thinness, and bulimia for the purpose of comparing group findings across ages and grades. Some level of body dissatisfaction was widespread in the population, body dissatisfaction increased beginning notably at age 14 and increased sharply at age 15, with further increases until age 16. The correlation between body dissatisfaction and drive for thinness was shown to be statistically significant (r = 0.83, p < 0.001). Awareness that body dissatisfaction and drive for thinness increase at ages 15 and 16 means disordered eating may begin at this time. If body dissatisfaction and drive for thinness begins early in life and markedly increases at ages 14 and 15, eating disorder prevention must begin in childhood and continue into adolescence.


Opportunistic gastritis in graft-versus-host disease.
Two patients underwent bone marrow transplantation and subsequently developed graft-versus-host disease. Barium examination showed a gross nodular pattern in the stomach in one patient, an appearance not previously described. Both patients developed characteristic changes in the small bowel and in one the colon was also affected. The dramatic rise in the patient's cytomegaloviral titers (CMV) and the presence of viral inclusion bodies in gastric cells suggest that the changes in the stomach may be due to a CMV gastritis.


Methodological and conceptual problems in the study of mortality in psychiatry.
The study of mortality has a long tradition in Psychiatry. The specificity required to define risks associated with particular disorders and to monitor the effects of changing patterns of treatment necessitates rigorous attention to methodology. The strengths and limitations of particular study designs and how these must be considered when interpreting results are reviewed. Sampling of the study population involves deciding whether to define a group retrospectively or prospectively, the type of psychiatric population to be utilized (eg inpatients or outpatients), and whether cases are to be chosen randomly as to diagnosis or with selection for certain profiles. Ascertainment of death is critical in mortality studies. Once the index population is defined, cases lost to final ascertainment significantly weaken the study. Cause of death as determined by coroner's verdict is readily obtained but of questionable accuracy. Results may be influenced by the method of psychiatric assessment and diagnosis, especially whether case record or interview data is used, and whether multiple or only single diagnoses are determined. With computerization improved statistical analysis are now possible. There is no perfect mortality study design. Any particular design involves a trade-off of advantages and disadvantages.


Cryosurgical modification of retrograde atrioventricular conduction. Implications for the surgical treatment of atrioventricular nodal reentry tachycardia.
Paroxysmal supraventricular tachycardia resulting from atrioventricular nodal reentry is a common arrhythmia that usually responds to medical therapy. When atrioventricular nodal reentry tachycardia is refractory to medical therapy, cryoablation or endocardial catheter ablation of the His bundle has been employed to protect the ventricles from the tachycardia. However, these techniques necessitate implantation of a permanent ventricular pacemaker. A cryosurgical procedure that ablates the anatomic-electrophysiologic substrate for atrioventricular nodal reentry tachycardia while preserving antegrade atrioventricular conduction has been described. The purpose of the present study was to determine the effects of this procedure on retrograde atrioventricular conduction and on the ventricular echo phenomenon in particular. Thirty adult mongrel dogs underwent either the cryosurgical procedure (n = 20) or a sham operation (n = 10). The animals were studied either immediately postoperatively (acute cryosurgery group and control group, n = 10 for each group) or 14 weeks postoperatively (chronic cryosurgery group, n = 10). Decremental ventricular pacing and programmed premature ventricular pacing protocols were used to determine the retrograde atrioventricular nodal conduction time, Wenckebach point, atrioventricular nodal refractory periods, and ventricular echo reflection time. No electrophysiologic alterations were noted in the sham-operated group. In the acute cryosurgery group, the retrograde Wenckebach point, atrioventricular nodal conduction time, functional refractory period of the atrioventricular node, effective refractory period of the atrioventricular node, and ventricular echo reflection time were all significantly prolonged. In the chronic cryosurgery group, no significant change in ventriculoatrial conduction was noted, but the ventricular echo phenomenon was eliminated in all but one animal. These data further document that this cryosurgical procedure is capable of ablating the anatomic-electrophysiologic substrate necessary for atrioventricular nodal reentry tachycardia while preserving atrioventricular conduction.


A nationwide, multicenter retrospective study on the effectiveness and safety of eribulin in Korean breast cancer patients (REMARK).
Approval of eribulin for metastatic breast cancer was based on data primarily from Western patients, and there is a paucity of data on the effectiveness and safety of eribulin for Asian patients. To determine the effectiveness and safety of eribulin in Korean women with breast cancer in a real-world setting, we conducted a nationwide, multicenter, retrospective study. Patients with locally advanced or metastatic breast cancer who were treated with eribulin in 14 centers throughout Korea were included in this study. Eribulin was generally administered at a dose of 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) by intravenous infusion for 2-5 min, or as a diluted solution, on Days 1 and 8 of every 21-day cycle. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included median PFS, overall survival (OS), time-to-treatment failure (TTF), tumor response rate, and incidence of hematologic treatment-emergent adverse events (TEAEs). The safety and full analysis populations included 398 and 360 (38 had no efficacy data) patients, respectively. The PFS rate at 6 months was 37.8%. Median PFS, OS, and TTF were 134, 631, and 120 days, respectively. Objective response rate, clinical benefit rate, and disease control rate were 18.1%, 50.6%, and 49.4%, respectively. Hematologic TEAEs were reported in 65.1% of patients; neutropenia (56.8%) and anemia (11.3%) were most common. Real-world effectiveness and safety of eribulin in Korean breast cancer patients were consistent with previous reports; no new safety concerns were identified.


The Effects of Bariatric Surgery on Pharmacokinetics of Drugs: a Review of Current Evidence.
Obesity constitutes a major public health concern and has been recognized as an epidemic. To date, bariatric surgery remains the most effective way for substantial long-lasting weight loss in severe obesity. The purpose of this review is to summarize how the pharmacokinetics of drugs are affected by the most common types of bariatric surgery, i.e., Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Limited data are available regarding the changes in pharmacokinetics of drugs after bariatric surgery. The lack of existing guidelines may lead patients to experience drug toxicity or therapeutic undertreatment. Pharmacokinetic parameters that need to be taken into consideration postoperatively include gastric motility, gastric volume, pH, surface area, bile secretions, carrier proteins, and first-pass metabolism. For drugs with a narrow therapeutic index, other factors need to be monitored closely, including plasma drug levels, patients' clinical outcomes, and laboratory markers. Patients should be followed up frequently and treated in accordance with their response to the drug therapy. Bariatric surgery may affect the pharmacokinetics of various drugs, due to the resultant anatomical changes and the substantial weight loss. Therefore, there is a need to identify those potential changes and adjust patients' medication doses in order to achieve higher efficacy and avoid toxicity.


[Efficacy and tolerability of the combined therapy with mesipol and baclosan in chronic recurrent vertebrogenic pain syndrome].
An article highlights the pathogenetic aspects of treatment of reflex pain syndromes in the degenerative-dystrophic spinal lesions. Attention is focused on a rational combination of medications that may shorten the duration of analgesic and anti-inflammatory therapy to prevent the development of side-effects caused by non-steroid anti-inflammatory medications. The results of own research of analgesic efficacy and tolerability of treatment in 50 patients with chronic skeletal-muscle pain syndromes in the state of exacerbation assigned to the combination of a non-steroid anti-inflammatory medication mesipol (meloxicam) with a central myorelaxant baclosan (baclofen) are discussed. It was found the positive effect of therapy not only on pain syndrome but on comorbid symptoms as well.


Celestial Versus Terrestrial Travel-An Analysis of Spaceflight Fatalities and Comparison to Other Modes of Transportation.
With the advent of commercial human spaceflight, it is important to analyze the historical safety of humans traveling to, in, and from space. We break down the fatality rates of human spaceflight and compare them to those of several terrestrial transportation modes. We created a database of human space travel, containing the vehicles, launches, and the total time and distance traveled. For the 4 fatal space missions and 18 fatalities, we determined the fatality rates, calculated by several methods, including rates per trip, person, and distance traveled, stratified by the mission segment affected. Two of the 326 launches did not reach space, and 8 others were suborbital. There have been 1285 person-launches to space; the total time in space is estimated to be 55,939 person-days; and the total distance traveled is approximately 23.5 billion person-miles. One fatal trip occurred on the way to orbit and the other 3 during the return. There has yet to be a fatality in orbit, and there have been none on any space flight since 2003. The per-trip and per-person fatality rates are 1.2% and 1.4%, respectively, but the per mile rate is much lower, depending on the flight segment.


The pro-apoptotic K-Ras 4A proto-oncoprotein does not affect tumorigenesis in the ApcMin/+ mouse small intestine.
Alterations in gene splicing occur in human sporadic colorectal cancer (CRC) and may contribute to tumour progression. The K-ras proto-oncogene encodes two splice variants, K-ras 4A and 4B, and K-ras activating mutations which jointly affect both isoforms are prevalent in CRC. Past studies have established that splicing of both the K-ras oncogene and proto-oncogene is altered in CRC in favour of K-ras 4B. The present study addressed whether the K-Ras 4A proto-oncoprotein can suppress tumour development in the absence of its oncogenic allele, utilising the ApcMin/+ (Min) mouse that spontaneously develops intestinal tumours that do not harbour K-ras activating mutations, and the K-rastmDelta4A/tmDelta4A mouse that can express the K-ras 4B splice variant only. By this means tumorigenesis in the small intestine was compared between ApcMin/+, K-ras+/+ and ApcMin/+, K-rastmDelta4A/tmDelta4A mice that can, and cannot, express the K-ras 4A proto-oncoprotein respectively. The relative levels of expression of the K-ras splice variants in normal small intestine and small intestinal tumours were quantified by real-time RT-qPCR analysis. Inbred (C57BL/6) ApcMin/+, K-ras+/+ and ApcMin/+, K-rastmDelta4A/tmDelta4A mice were generated and the genotypes confirmed by PCR analysis. Survival of stocks was compared by the Mantel-Haenszel test, and tumour number and area compared by Student's t-test in outwardly healthy mice at approximately 106 and 152 days of age. DNA sequencing of codons 12, 13 and 61 was performed to confirm the intestinal tumours did not harbour a K-ras activating mutation. The K-ras 4A transcript accounted for about 50% of K-ras expressed in the small intestine of both wild-type and Min mice. Tumours in the small intestine of Min mice showed increased levels of K-ras 4B transcript expression, but no appreciable change in K-ras 4A transcript levels. No K-ras activating mutations were detected in 27 intestinal tumours derived from Min and compound mutant Min mice. K-Ras 4A deficiency did not affect mouse survival, or tumour number, size or histopathology. The K-Ras 4A proto-oncoprotein does not exhibit tumour suppressor activity in the small intestine, even though the K-ras 4A/4B ratio is reduced in adenomas lacking K-ras activating mutations.


A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice.
Triclosan (TCS) is a high-volume chemical used as an antimicrobial ingredient in more than 2000 consumer products, such as toothpaste, cosmetics, kitchenware, and toys. We report that brief exposure to TCS, at relatively low doses, causes low-grade colonic inflammation, increases colitis, and exacerbates colitis-associated colon cancer in mice. Exposure to TCS alters gut microbiota in mice, and its proinflammatory effect is attenuated in germ-free mice. In addition, TCS treatment increases activation of Toll-like receptor 4 (TLR4) signaling in vivo and fails to promote colitis in Tlr4-/- mice. Together, our results demonstrate that this widely used antimicrobial ingredient could have adverse effects on colonic inflammation and associated colon tumorigenesis through modulation of the gut microbiota and TLR4 signaling. Together, these results highlight the need to reassess the effects of TCS on human health and potentially update policies regulating the use of this widely used antimicrobial.


Multiframe Joint Enhancement for Early Interlaced Videos.
Early interlaced videos usually contain multiple and interlacing and complex compression artifacts, which significantly reduce the visual quality. Although the high-definition reconstruction technology for early videos has made great progress in recent years, related research on deinterlacing is still lacking. Traditional methods mainly focus on simple interlacing mechanism, and cannot deal with the complex artifacts in real-world early videos. Recent interlaced video reconstruction deep deinterlacing models only focus on single frame, while neglecting important temporal information. Therefore, this paper proposes a multiframe deinterlacing network joint enhancement network for early interlaced videos that consists of three modules, i.e., spatial vertical interpolation module, temporal alignment and fusion module, and final refinement module. The proposed method can effectively remove the complex artifacts in early videos by using temporal redundancy of multi-fields. Experimental results demonstrate that the proposed method can recover high quality results for both synthetic dataset and real-world early interlaced videos. At the same time, the method also won the first place in the MSU Deinterlacer Benchmark. The code is available at: https://github.com/anymyb/MFDIN.


Using Caenorhabditis elegans for Studying Trans- and Multi-Generational Effects of Toxicants.
Information about toxicities of chemicals are essential in their application and waste management. For chemicals at low concentrations, the long-term effects are very important in judging their consequences in the environment and on human health. In demonstrating long-term influences, effects of chemicals over generations in recent studies provide new insight. Here, we describe protocols for studying effects of chemicals over multiple generations using free-living nematode Caenorhabditis elegans. Two aspects are presented: (1) trans-generational (TG) and (2) multi-generational effect studies, the latter of which is separated to multi-generational exposure (MGE) and multi-generational residual (MGR) effect studies. The TG effect study is robust with a simple purpose to determine whether chemical exposure to parents can result in any residual consequences on offspring. After the effects are measured on parents, sodium hypochlorite solutions are used to kill the parents and keep the offspring so as to facilitate effect measurement on the offspring. The TG effect study is used to determine whether the offspring are affected when their parent is exposed to the pollutants. The MGE and MGR effect study is systematical used to determine whether continuous generational exposure can result in adaptive responses in offspring over generations. Careful pick-up and transfer are used to distinguish generations to facilitate effect measurement on each generation. We also combined protocols to measure locomotion behavior, reproduction, lifespan, biochemical and gene expression changes. Some example experiments are also presented to illustrate the trans- and multi-generational effect studies.


Morphological correlates of intrinsic electrical excitability in neurons of the deep cerebellar nuclei.
To what degree does neuronal morphology determine or correlate with intrinsic electrical properties within a particular class of neuron? This question has been examined using microelectrode recordings and subsequent neurobiotin filling and reconstruction of neurons in the deep cerebellar nuclei (DCN) of brain slices from young rats (P13-16). The neurons reconstructed from these recordings were mostly large and multipolar (17/21 cells) and were likely to represent glutamatergic projection neurons. Within this class, there was considerable variation in intrinsic electrical properties and cellular morphology. Remarkably, in a correlation matrix of 18 electrophysiological and 6 morphological measures, only one morphological characteristic was predictive of intrinsic excitability: neurons with more spines had a significantly slower basal firing rate. To address the possibility that neurons with fewer spines represented a slowly maturing subgroup, recordings and reconstructions were also made from neurons at a younger age (P6-9). While P6-9 neurons were morphologically indistinguishable from P13 to 16 neurons, they were considerably less excitable: P6-9 neurons had a lower spontaneous spiking rate, larger fast AHPs, higher resting membrane potentials, and smaller rebound depolarizations. Thus while the large projection neurons of the DCN are morphologically mature by P6-9, they continue to mature electrophysiologically through P13-16 in a way that renders them more responsive to the burst-and-pause pattern that characterizes Purkinje cell inhibitory synaptic drive.


Pain attenuation through mindfulness is associated with decreased cognitive control and increased sensory processing in the brain.
Pain can be modulated by several cognitive techniques, typically involving increased cognitive control and decreased sensory processing. Recently, it has been demonstrated that pain can also be attenuated by mindfulness. Here, we investigate the underlying brain mechanisms by which the state of mindfulness reduces pain. Mindfulness practitioners and controls received unpleasant electric stimuli in the functional magnetic resonance imaging scanner during a mindfulness and a control condition. Mindfulness practitioners, but not controls, were able to reduce pain unpleasantness by 22% and anticipatory anxiety by 29% during a mindful state. In the brain, this reduction was associated with decreased activation in the lateral prefrontal cortex and increased activation in the right posterior insula during stimulation and increased rostral anterior cingulate cortex activation during the anticipation of pain. These findings reveal a unique mechanism of pain modulation, comprising increased sensory processing and decreased cognitive control, and are in sharp contrast to established pain modulation mechanisms.


Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Asian Patients With Atrial Fibrillation.
There are limited real-world data comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with nonvalvular atrial fibrillation. We aimed to compare the effectiveness and safety between NOACs and warfarin users in the Korean atrial fibrillation population, with particular focus on high-risk patients. Using the Korean National Health Insurance Service database, we analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH) events, and all-cause death in NOAC users (n=11 611 total, n=5681 taking rivaroxaban, n=3741 taking dabigatran, and n=2189 taking apixaban) compared with propensity score-matched warfarin users (n=23 222) among patients with high-risk atrial fibrillation (CHA2DS2-VASc score ≥2) between 2014 and 2015. NOAC treatment was associated with similar risk of ischemic stroke and lower risk of ICH and all-cause mortality compared with warfarin. All 3 NOACs were associated with a similar risk of ischemic stroke and a lower risk of ICH compared with warfarin. Dabigatran and apixaban were associated with a lower risk of total mortality and the composite net clinical outcome (ischemic stroke, ICH, and all-cause death) compared with warfarin, whereas this was nonsignificant for rivaroxaban. Among previously oral anticoagulant-naive patients (n=23 262), dabigatran and apixaban were superior to warfarin for ICH prevention, whereas rivaroxaban and warfarin were associated with similar risk of ICH. In real-world practice among a high-risk Asian atrial fibrillation population, all 3 NOACs demonstrated similar risk of ischemic stroke and lower risk of ICH compared with warfarin. All-cause mortality was significantly lower only with dabigatran and apixaban.


Postoperative alkaline reflux gastritis.
1. The syndrome of reflux gastritis is produced by the actions of bile and upper intestinal and pancreatic secretions alone or in combination on an altered gastric mucosa. 2. The triad of epigastric pain unrelieved by antacids, bilious vomiting, and weight loss, particularly after a gastric operation should make one suspect this syndrome. Anemia due to loss of blood and dysphagia occur less frequently. 3. The definitive diagnosis is made by endoscopy. Barium studies are of less value. Acid secretory studies are not diagnostic and are of academic interest. 4. Medical treatment utilizes antacids and cholestyramine alone or together. Good, long-lasting results with these are infrequent. Despite these results, medical treatment should be tried first. 5. Surgical treatment consists of diversion of the biliary and upper intestinal secretions from the stomach and doing a vagotomy with or without a distal gastric resection to prevent a marginal ulcer from developing. 6. The two most popular operations are a Roux-en-Y diversion or interposed peristaltic jejunal limb. The simplicity of the former has made this more popular with most American surgeons. 7. The results of surgery are good to excellent in 75 to 95 per cent of cases. Relief of symptoms, improvement in histologic and secretory studies, and weight gain should be anticipated. 8. Less than optimal results are reported when the surgical diversion has not been total, gastric stasis persists, or other postgastrectomy sequelae accompany reflux gastritis.


Understanding the Patterns of Health Information Dissemination on Social Media during the Zika Outbreak.
Social media are important platforms for risk communication during public health crises. Effective dissemination of accurate, relevant, and up-to-date health information is important for the public to raise awareness and develop risk management strategies. This study investigates Zika virus-related information circulated on Twitter, identifying the patterns of dissemination of popular tweets and tweets from public health authorities such as the CDC. We leveraged a large corpus of Twitter data covering the entire year of 2016. We analyzed the data using quantitative and qualitative content analyses, followed by machine learning to scale the manual content analyses to the corpus. The results revealed possible discrepancies between what the general public was most interested in, or concerned about, and what public health authorities provided during the Zika outbreak. We provide implications for public health authorities to improve risk communication through better alignment with the general public's information needs during public health crises.


Clinical features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis.
To compare distinctive clinical features of presumed tuberculous serpiginouslike choroiditis (Tb-SLC) with classic serpiginous choroiditis (SC) in patients living in a region that is nonendemic for tuberculosis. Retrospective comparative analysis of clinical features of 5 patients with recurrent Tb-SLC and 5 with SC. All patients with recurrent Tb-SLC primarily emigrated from areas highly endemic for tuberculosis and had been unsuccessfully treated with steroids/immunosuppressive agents. Results of uveitis investigations were negative except for positive tuberculin skin test results. These patients received oral tuberculostatic drugs, without recurrences (follow-up, 6-91 months). The ocular involvement in Tb-SLC was mostly unilateral, with multiple irregular serpiginoid lesions involving the posterior pole and periphery but usually sparing the juxtapapillary area. All 5 cases had inflammatory cells in the vitreous. Patients with SC were from areas nonendemic for tuberculosis, had negative uveitis workup findings (including tuberculin skin test results), and were successfully managed with steroids/immunosuppressive agents (follow-up, 6-72 months) with no recurrence. Ocular involvement in SC was usually bilateral, rarely multifocal, and primarily involved the posterior pole, especially around the optic disc and extending contiguously to the macula. No patient with SC presented with vitritis. In areas nonendemic for tuberculosis, SC can be clinically differentiated from Tb-SLC. Patients with Tb-SLC come from highly endemic regions, show significant vitritis, and often present with multifocal lesions in the posterior pole and periphery. Cases of SC, in contrast, reveal minimal or no vitritis and frequently show bilateral involvement with larger solitary lesions extending primarily from the juxtapapillary area and sparing the periphery.


A critical review and analysis of the context, current burden, and application of policy to improve cancer equity in Ghana.
Cancer causes a major disease burden worldwide. This is increasingly being realised in low and middle-income countries, which account disproportionately for preventable cancer deaths. Despite the World Health Organization calling for governments to develop policies to address this and alleviate cancer inequality, numerous challenges in executing effective cancer policies remain, which require consideration of the country-specific context. As this has not yet been considered in Ghana, the aim of this review was to bring together and critique the social-environmental, health policy and system factors to identifying opportunities for future health policies to reduce cancer burden in the Ghanian context. A critical policy-focused review was conducted to bring together and critique the current health systems context relating to cancer in Ghana, considering the unmet policy need, health system and social factors contributing to the burden and policy advances related to cancer. The findings highlight the changing burden of cancer in Ghana and the contextual factors within the socio-ecosystem that contribute to this. Policies around expanding access to and coverage of services, as well as the harmonization with medical pluralism have potential to improve outcomes and increase equity but their implementation and robust data to monitor their impact pose significant barriers.


Validation of D value by different SCD culture medium manufacturer and/or different SCD culture medium constituent.
Variation in decimal reduction (D) time/value for attaining sterility assurance was reported in terms of difference between lot to lot and/or manufacturer to manufacturer of soybean casein digest (SCD) culture medium. The D value variation phenomenon itself due to SCD culture medium was reported by Graham et al; however, it was not sufficiently clarified what constituent(s) of SCD culture medium would mainly contribute to the variation of D value. If it is not well clarified, the reproducible sterility assurance cannot be successfully attained. The authors studied individually the constituent of SCD broth (SCDB), SCD agar (SCDA) and SCD broth plus 1.5% agar (SCDB/A). As a result, the culture medium constituent causing D value variation among SCD culture medium was determined as the difference of calcium (Ca) amount as well as the presence and the absence of K2HPO4 in SCD culture medium. Additionally, it was clarified D value differed significantly between SCDB and SCDA. D value using the former was around 1 min lower than that using the latter. This phenomenon can be explained from the formation of insoluble CaHPO4 in SCDB culture medium, resulting in insufficiency of usable Ca to B. stearothermophilus in SCDB culture medium.


Ehrlichiosis in a recent kidney transplant recipient: The repellent that did not repel! A case report and literature review of ehrlichiosis in solid organ transplant patients.
Ehrlichiosis has been infrequently reported in immunosuppressed patients such as solid organ transplants (SOT). We report a case of Ehrlichia chaffeensis infection in an immunosuppressed woman four months after deceased donor kidney transplantation. The diagnosis was confirmed by PCR testing in serum, and the patient responded promptly to treatment with doxycycline. To supplement our Case Report, a literature review encompassing 1995 to present was also performed using PubMed as the search vehicle. Search terms that were utilized include: ehrlichiosis, HME, E chaffeensis, kidney transplant(ation), renal transplant(ation), solid organ transplant(ation), and immunosuppression. The diagnosis of ehrlichiosis can be challenging in SOT patients since ehrlichiosis is not a classic opportunistic infection in SOT. Transplant physicians must have a high clinical suspicion for the diagnosis in patients with an acute febrile illness accompanied by headache, worsening cytopenias, and transaminitis who live in endemic areas, especially if they have tick exposure.


A case of rectal cancer in a patient with neurofibromatosis type 1.
A rectal cancer was found in a 67-year-old man with a history of neurofibromatosis type 1. A low anterior resection was performed, and he received concurrent chemoradiation for 6 months. Twelve months after the surgery, a tumor was found at the anastomotic site by positron emission tomography-computed tomography and colonoscopy and was mistaken as anastomotic site recurrence. The tumor was confirmed as an inflammatory myofibroblastic tumor through transanal excision.


Diabetes and disenrollment in a health maintenance organization setting: a 4-year longitudinal study with a matched cohort.
The increasing enrollment of Medicare beneficiaries in health maintenance organizations (HMOs) in recent years has caused concern about whether HMOs and their providers have created an unfavorable environment for members who are chronically ill. This study was designed to examine whether there are any differences in disenrollment rates among enrollees with diabetes and enrollees without diabetes. This was a 4-year longitudinal follow-up study with a matched cohort. Medicare beneficiaries (aged > or =65 years) with diabetes identified through pharmacy records in 1994 were matched with a comparison group according to age, sex, comorbidities, and type of provider groups in an HMO in California. The overall distribution of the characteristics of members in the diabetic and matched nondiabetic group is almost identical. The matched-pair chi2 tests indicated that there were no statistical differences in disenrollment rates between diabetic and nondiabetic members during all three follow-up periods (P = 0.16-0.85). We found that the HMO members with diabetes did not disenroll from the HMO at a higher rate than those without diabetes. The findings should alleviate some of the concern that HMOs and their contracted providers have created an unattractive environment for members who have chronic diseases such as diabetes.


Toxic substances in rivers and streams.
Many of the toxic substances entering freshwaters today are those which were present several decades ago, but others have become significant recently. The effects of toxicants in flowing waters are modified by unidirectional transport and dispersion which afford the potential for a degree of 'self-purification'. The chemical quality of the receiving water also affects toxicity. Biological factors also contribute to the ultimate effect of pollutants. The potential for accumulation of toxic substances within tissues increases the significance of certain pollutants which may be present in water even though ambient concentrations are very low. The biota of flowing waters may be restored, following catastrophic entry of pollutants, by drift from unaffected regions upstream. The range of potential toxic substances is very extensive and includes inorganic poisons, organic poisons, heavy metals, pesticides and PCBs. Metals, pesticides and PCBs have the greatest potential for bioaccumulation. Few generalisations can be made regarding the effects of toxic substances on the biota. Each species tends to respond to different toxicants in different ways and even at different stages in its life-history. Toxicity tests conducted under controlled laboratory conditions sometimes produce conflicting results: it is not then to be unexpected that field observations should sometimes vary widely. Determinations of toxicity in laboratory tests must be applied with caution to field conditions and it is not wise to extrapolate findings to other species or environments.


Metabolic determinants of lupus pathogenesis.
The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4+ T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues.


Incorrect base insertion and prematurely terminated transcripts during T7 RNA polymerase transcription elongation past benzo[a]pyrenediol epoxide-modified DNA.
DNA replication and transcription are affected adversely by the presence of bulky adducts that are generated by the covalent binding of a variety of metabolically activated environmental pollutants to cellular DNA. When these lesions are not cleared by cellular repair enzymes prior to replication, mutations and ultimately tumor initiation can occur. Transcription and DNA repair appear to be intimately connected, since certain adducts are more efficiently removed from the transcribed strands of active loci than from non-transcribed strands and other quiescent domains in the genome. The mechanism by which RNA polymerases deal with bulky adducts during DNA transcription is therefore of great interest. The availability of site-specifically modified and stereochemically defined oligodeoxyribonucleotides derived from the covalent reaction of 7r, 8t-dihydroxy-9, 10t-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) with guanine residues prompted us to study the efficiencies of transcription past these lesions using bacteriophage T7 RNA polymerase. We show here that T7 RNA polymerase can bypass such lesions in a DNA template, providing that a cytosine residue is incorporated opposite anti-BPDE-modified guanine. However, when an incorrect base (most frequently a purine) is inserted opposite the modified site, the RNA polymerase stalls, and the complex dissociates, resulting in a truncated transcript. The ability of the T7 RNA polymerase to discriminate between a correct and an incorrect inserted base and, accordingly, to continue or terminate transcription, might constitute an important mechanism that ensures the fidelity of transcription past a modified base present on the transcribed strand of the DNA template.


Caregiver Perceptions about their Decision to Pursue Tracheostomy for Children with Medical Complexity.
To describe the perceptions of caregivers of children with medical complexity (CMC) about their decision to pursue tracheostomy for their children, in particular the satisfaction with their decision. In this qualitative study conducted in western North Carolina between 2013 and 2014, we interviewed 56 caregivers of 41 CMC who had received tracheostomies in the past 5 years. Three of the CMC were deceased at the time of the interview; 8 were decannulated. In-depth interviews (35 English, 6 Spanish) were conducted, audio-recorded, and transcribed verbatim. We used ATLAS.ti software to manage data and identified themes related to caregiver perceptions about tracheostomy decision. We found that caregivers often chose tracheostomy because extending the lives of their children and being able to care for them at home were important. Caregivers reported the many benefits of tracheostomy including improvement in respiratory symptoms, physical and developmental health, quality of life, and means to provide medical care quickly when needed. There were negative effects of tracheostomy such as mucous plugs, excessive secretions, accidental decannulation necessitating emergency tracheostomy tube change, and the increased infection risk. Providing medical care for CMC with tracheostomy at home was difficult, but improved over time. Caregivers were generally satisfied with their decision to pursue tracheostomy for their CMC. Decisional satisfaction with tracheostomy for CMC is high. In counseling caregivers about tracheostomy, clinicians should present both the benefits and risks. Future studies should quantify the outcomes described in this study.


Where is community during COVID-19? The experiences of families living in housing insecurity.
This article explores the understanding of community to families living in insecure housing in one Australian state during the COVID-19 pandemic. Five female-headed families were interviewed during the pandemic and asked to identify what community meant to them. All participants were referred by an agency caring for families experiencing homelessness or housing insecurity. Community was defined using Bourdieu's concept of social capital, allowing for both bonding and bridging relationships to be explored. Bonding relationships refer to close emotional ties with family and friends, while bridging ties establish networks that provide individuals with access to resources. Two themes emerged that shed light on how community is understood during times of crisis: The first suggests that for families experiencing housing insecurity, particularly women escaping family violence, their links with community were primarily maintained by welfare and church agencies. These organisations provided bridging social capital during the pandemic that allowed the women and their children to cope with the isolation and to maximise opportunities. The second themes point to traditional notions of community as family and geographical space. Here the findings are mixed. Resources provided by government, and mediated through the welfare agency, allowed these families to create a safe and comfortable space. However, for First Nations women, the lockdown meant that it was difficult to maintain community obligations, while children who appeared to identify community with attendance at school found the lockdown confusing because of the disruption to their normal social space.


Feasibility evaluation of long-term use of beta-blockers and calcium antagonists in patients with Brugada syndrome.
Beta-blockers (BBs) and calcium antagonists (CAs) are reported to aggravate ST-segment elevation in some patients with Brugada syndrome (BrS). The feasibility of their long-term use in BrS still remains unknown. We investigated the safety of long-term use of BB and CA in BrS patients. Of the 360 consecutive BrS patients, 29 [5: a history of ventricular fibrillation (VF), 17: syncope, 7: asymptomatic] took BB and/or CA (BB: 22, CA: 8) for more than 1 year for the treatment of co-morbidities such as atrial tachyarrhythmia, vasospastic angina, and neurally mediated syncope. The electrocardiographic changes and clinical outcome after the treatment were evaluated. Eleven patients showed type 1 electrocardiogram (ECG) at baseline. BBs and CAs were used within normal dosage range in all patients. After starting a BB and/or CA, type 1 ECG was still observed in 9 patients. There were no significant differences in the ECG parameters such as the amplitude of J-point, QRS duration, and corrected QT intervals before and after starting BB and/or CA. During follow-up of 89 ± 65 months after initiation of the drugs, 1 patient experienced a VF recurrence without significant changes of ECG parameters 2 years after BB therapy was started. Long-term intake of BB or CA within normal dosage range was not associated with the aggravation of ECG parameters and clinical outcome in patients with BrS. The use of BBs and CAs is acceptable under careful observation.


Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel.
CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere) both in vitro and in vivo. In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time points by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated with CV787 and taxane. In vivo, using the PSA+ LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1.


An experimental study of the effects of bacteria on asphaltene adsorption and wettability alteration of dolomite and quartz.
The adsorption of asphaltene on the rock surface and the changes in its wettability are very relevant issues in flow assurance and oil recovery studies, and for carbonate reservoirs, they are even more important. During microbial enhanced oil recovery (MEOR) processes, wettability alteration is considered a crucial mechanism leading to improved oil recovery. Therefore, it is essential to understand the mechanisms of surface wettability changes by bacteria and biosurfactants and find new and reliable methods to prevent asphaltene adsorption. Hence, the main aim of this research was to investigate the effect of a mixture of thiobacillus thiooxidans and thiobacillus ferooxidans microorganisms with an optimum effective temperature of around 30 °C (referred to as mesophilic bacteria), as well as a mixture of two moderate thermophiles Sulfobacillus thermosulfidooxidans for operating temperatures around 50 °C (referred to as moderately thermophilic bacteria) on the adsorption of asphaltene samples isolated from two different crude oils onto main reservoir minerals (i.e., quartz and dolomite). The results indicated that after two weeks of mineral aging in moderate thermophilic bacteria, the adsorption of asphaltene on both minerals increased between 180 and 290%. Fourier-transform infrared spectroscopy (FTIR) analysis for quartz and dolomite samples demonstrated that after aging in bacterial solution, bonds related to the adsorption of bacterial cells and biosurfactant production appear, which are the main factors of change in wettability. Alteration in wettability towards hydrophilicity expands hydrogen bonds on the surface, thus improving asphaltene adsorption due to polar interaction. Asphaltene 1 changed the contact angle of dolomite from 53.85° to 90.51° and asphaltene 2 from 53.85° to 100.41°. However, both strains of bacteria caused a strong water-wetting effect on the dolomite rock samples. The influence of moderate thermophilic bacteria on surface wettability is more significant than that of mesophilic bacteria, which may be caused by the high protein content of these bacteria, which expands hydrogen bonding with the surface. Adsorption of asphaltenes on dolomite rocks previously aged with bacteria showed that the wetted rock samples retained their water-wet state. This study highlights the dual impact of the used microorganisms. On one hand, they significantly reduce contact angles and shift wettability towards a strongly water-wet condition, a crucial positive factor for MEOR. On the other hand, these microorganisms can elevate the adsorption of asphaltenes on reservoir rock minerals, posing a potential challenge in the form of formation damage, particularly in low-permeability reservoirs.


Tryptophan Pathway Abnormalities in a Murine Model of Hereditary Glaucoma.
It has been shown that a possible pathogenetic mechanism of neurodegeneration in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma.


Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria.
Magnetic resonance imaging studies in patients with phenylketonuria (PKU) revealed white matter alterations that correlated to most recent blood phenylalanine (Phe) concentrations as well as to brain Phe concentrations measured by magnetic resonance spectroscopy. The clinical significance of these changes is unknown. Magnetic resonance imaging data thus have no impact on therapeutic recommendations for adolescents and adults with PKU. Kinetic investigations of patients by magnetic resonance spectroscopy showed differences in brain Phe concentrations despite similar blood Phe levels. These were influenced by interindividual variations of blood-brain barrier Phe transport constants and by variations of the individual brain Phe consumption rate. Blood-brain barrier Phe transport characteristics as well as brain Phe consumption rates thus seem to be causative factors for the individual outcome in PKU.


Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events.
Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.


Liver x receptors stimulate lipogenesis in bovine mammary epithelial cell culture but do not appear to be involved in diet-induced milk fat depression in cows.
Abstract Milk fat synthesis of ruminants can be inhibited by intermediates of ruminal fatty acid biohydrogenation including trans-10, cis-12 conjugated linoleic acid (CLA). These biohydrogenation intermediates signal a coordinated downregulation of genes involved in mammary FA synthesis, transport, and esterification. We have previously reported decreased mammary expression of sterol response element-binding protein 1 (SREBP1), SREBP1-activating proteins, and thyroid hormone-responsive spot 14 (S14) in the cow during diet-induced milk fat depression (MFD), and treatment with trans-10, cis-12 CLA. Liver x receptors (LXR) and retinoid x receptors (RXR) regulate lipogenesis and are known to bind polyunsaturated FA and LXR agonist increases lipid synthesis in mammary epithelial cell culture. The current studies investigated if biohydrogenation products of rumen origin inhibit mammary lipogenesis through LXR and/or RXR. Expression of LXRs was not different in lactating compared to nonlactating bovine mammary tissue, and expression of LXRs, RXRα, and selected LXR and RXR target genes was not changed in mammary tissue during diet-induced or CLA-induced MFD in the cow. In bovine mammary epithelial cell culture, LXR agonist stimulated lipogenesis and expression of LXRß, ATP-binding cassette 1 (ABCA1), SREBP1c, and S14, but LXR activation did not overcome CLA inhibition of lipogenesis and downregulation of LXRß, SREBP1c, and S14 expression. Lastly, expression of the LXR-regulated carbohydrate-responsive element-binding protein (ChREBP) was higher in lactating than nonlactating tissue and was decreased during CLA-induced MFD. We conclude that changes in mammary LXR expression in dairy cows are not involved in MFD and that trans-10, cis-12 CLA inhibition of lipogenesis and diet-induced MFD appears independent of direct LXR signaling.


Microbacterium kitamiense sp. nov., a new polysaccharide-producing bacterium isolated from the wastewater of a sugar-beet factory.
Two strictly aerobic, heterotrophic and mesophilic new organisms, strains Kitami A1 and Kitami C2T, were isolated from the wastewater of a sugar-beet factory in Kitami City, Hokkaido, Japan. In batch cultures, these organisms produced both insoluble and soluble exopolysaccharides (EPSs) utilizing sucrose as the sole carbon source. The G + C contents of the strains Kitami C2T and Kitami A1 were 69.2 mol%. Both strains had anteiso-C15:0 acid, anteiso-C17:0 acid and iso-C16:0 as major components. The major isoprenoid quinones from these strains included menaquinone-11 and menaquinone-12. Physiological and biochemical characterization, phylogenetic analysis and DNA-DNA relatedness indicated that these two organisms are new species of the genus Microbacterium, for which the name Microbacterium kitamiense is proposed. The type strain of M. kitamiense is strain Kitami C2T (= JCM 10270T).


Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective.
The functional optimization of neural ensembles is central to human higher cognitive functions. When the functions through which neural activity is tuned fail to develop or break down, symptoms and cognitive impairments arise. This review considers ways in which disturbances in the balance of excitation and inhibition might develop and be expressed in cortical networks in association with schizophrenia. This presentation is framed within a developmental perspective that begins with disturbances in glutamate synaptic development in utero. It considers developmental correlates and consequences, including compensatory mechanisms that increase intrinsic excitability or reduce inhibitory tone. It also considers the possibility that these homeostatic increases in excitability have potential negative functional and structural consequences. These negative functional consequences of disinhibition may include reduced working memory-related cortical activity associated with the downslope of the "inverted-U" input-output curve, impaired spatial tuning of neural activity and impaired sparse coding of information, and deficits in the temporal tuning of neural activity and its implication for neural codes. The review concludes by considering the functional significance of noisy activity for neural network function. The presentation draws on computational neuroscience and pharmacologic and genetic studies in animals and humans, particularly those involving N-methyl-D-aspartate glutamate receptor antagonists, to illustrate principles of network regulation that give rise to features of neural dysfunction associated with schizophrenia. While this presentation focuses on schizophrenia, the general principles outlined in the review may have broad implications for considering disturbances in the regulation of neural ensembles in psychiatric disorders.


Psychosis and systemic lupus erythematosus: a review of the literature and case reports.
In a review of the literature of the last 60 years concerning the association between psychosis and systemic lupus erythematosus, reports of 227 cases of this association were found. The average incidence of psychosis in the various series of systemic lupus erythematosus that were reviewed was 22 per cent. In only 25 per cent of the cases in which the information was given was the psychosis associated with steroid therapy. The psychiatric manifestations are variable and may be associated with a neurological disorder. Psychosis may antedate by many years other features of lupus. The psychosis due to lupus may respond to steroid therapy. Since systemic lupus erythematosus sometimes may be an important differential diagnosis of functional psychosis, appropriate diagnostic studies should be carried out in psychotic patients who have an accelerated sedimentation rate or positive serological test for syphilis without apparent reason.


Five points to check when comparing visual perception in humans and machines.
With the rise of machines to human-level performance in complex recognition tasks, a growing amount of work is directed toward comparing information processing in humans and machines. These studies are an exciting chance to learn about one system by studying the other. Here, we propose ideas on how to design, conduct, and interpret experiments such that they adequately support the investigation of mechanisms when comparing human and machine perception. We demonstrate and apply these ideas through three case studies. The first case study shows how human bias can affect the interpretation of results and that several analytic tools can help to overcome this human reference point. In the second case study, we highlight the difference between necessary and sufficient mechanisms in visual reasoning tasks. Thereby, we show that contrary to previous suggestions, feedback mechanisms might not be necessary for the tasks in question. The third case study highlights the importance of aligning experimental conditions. We find that a previously observed difference in object recognition does not hold when adapting the experiment to make conditions more equitable between humans and machines. In presenting a checklist for comparative studies of visual reasoning in humans and machines, we hope to highlight how to overcome potential pitfalls in design and inference.


Glycine-rich cell wall proteins act as specific antigen targets in autoimmune and food allergic disorders.
Our objective was to investigate the presence of a B and T cell immune response directed against the glycine-rich cell wall protein (GRP) in patients with different autoimmune disorders and with food allergy. GRP is an ubiquitous food protein that has high homology with cytokeratins and other self proteins [Epstein-Barr virus nuclear antigen-1 (EBNA-I), heterogeneous nuclear ribonucleoprotein, fibrillar collagen] which are common targets in autoimmune disorders. A peptide (GGYGDGGAHGGGYGG) derived from GRP was used to screen human sera in direct and competitive ELISA assay. Anti-GRP-specific IgG were analyzed for their ability to cross-react with autoantigens. The intracellular cytokine profiles of the peptide-specific T cell clones obtained from representative patients have been studied. BALB/c mice were immunized with the peptide coupled to the carrier protein keyhole limpet hemocyanin (KLH). Serum IgG antibodies directed against the GRP peptide were detected in several autoimmune disorders and in food allergic patients, and were able to cross-react with autoantigens including keratin, collagen and EBNA-I. Twenty-five T cell clones showed a specific proliferative response to the GRP peptide and were of the T(h)0 phenotype. Eight of the 10 BALB/c mice immunized with the peptide coupled to KLH developed an autoimmune response. Our data suggest that phylogenetically highly conserved epitopes in plants, viruses and humans may be responsible for an autoimmune response in susceptible individuals. They also indicate that the antigen spreading of a particular sequence among apparently divergent proteins may participate to initiate or amplify an immune response.


Unique synergistic formulation of curcumin, epicatechin gallate and resveratrol, tricurin, suppresses HPV E6, eliminates HPV+ cancer cells, and inhibits tumor progression.
Curcumin (from curry) (C) is highly potent against cervical cancer cells (CCC), but poor bioavailability has limited its clinical use. Similar natural polyphenols resveratrol (from grapes) (R), and epicatechin gallate (from green tea) (E) also display activity against CCC. By treating CCC (HeLa) with C, E, or R, or combinations of these compounds, we computed combination indices and observed a strong synergism among C, E, and R at the unique molar ratio 4:1:12.5. This combination, named as TriCurin, rapidly down regulated HPV18 E6 and NF-kB expression while concomitantly inducing the tumor suppressor protein p53 in HeLa cells. In the mouse c-Ha-ras and HPV16 E6, E7-expressing TC-1 CCC, both C and TriCurin elicited suppression of E6, induction of both p53 and acetyl-p53 (activated p53), and activation of caspase-3, but the TriCurin-evoked changes were several-fold greater than that produced by curcumin (4.7-fold for E6 inhibition, and 2-fold, 6-fold, and 1.7-fold for the induction of p53, acetyl-p53, and active caspase-3, respectively). Consequently, TriCurin was more potent in killing TC-1 and HeLa cells. Intralesional TriCurin treatment of tumors generated in mice by subcutaneously implanting the TC-1 CCC caused an 80-90% decrease in tumor growth. The ability of C to eliminate HeLa cells was significantly stabilized when delivered as TriCurin than when delivered alone. Topical application of TriCurin dispersed in a cream base afforded efficient transfer of C across the skin. Subcutaneous TriCurin injection yielded no adverse effect in tumor-naïve healthy mice. Thus, TriCurin is a safe and promising therapeutic agent against HPV-associated disease.


Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production.
Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli.


Alcohol withdrawal-induced hippocampal neurotoxicity in vitro and seizures in vivo are both reduced by memantine.
The ethanol withdrawal (EWD) syndrome is typically treated using benzodiazepines such as diazepam. However there is concern that benzodiazepines may not prevent neurotoxicity associated with EWD. Antagonists of glutamate/N-Methyl-D-Aspartate receptors (NMDARs) such as MK801 have been shown to be effective against both EWD-induced neurotoxicity in vitro and seizures in vivo. However, most of these agents have adverse side effects. An exception is the moderate affinity NMDAR channel blocker memantine, used in Alzheimer's dementia. The present studies examined the ability of memantine to protect against EWD-related toxicity in vitro and seizures in vivo. Organotypic hippocampal slice cultures from neonatal rat pups were treated starting at 15 days in vitro with 100 mM ethanol for 10 days followed by a 24-hour EWD period. During the 24-hour EWD period cultures were treated with memantine (15 or 30 microM). MK801 (10 microM) was utilized as a positive control. For the in vivo studies, the ability of memantine (2, 5, 10, and 15 mg/kg) to reduce convulsions was analyzed in Swiss-Webster mice using the handling induced convulsion test paradigm. In vitro studies demonstrated that memantine is effective at blocking EWD-induced neurotoxicity. In vivo experiments showed that memantine also significantly reduced convulsions induced by EWD in mice. Memantine may be of therapeutic value during alcohol detoxification by virtue of its having neuroprotective effects in addition to anti-seizure activity. The potential role of memantine in treatment of alcoholism is deserving of further study.