Voice Discrimination in Quiet and in Background Noise by Simulated and Real Cochlear Implant Users.
Cochlear implant (CI) users demonstrate poor voice discrimination (VD) in quiet conditions based on the speaker's fundamental frequency (fo) and formant frequencies (i.e., vocal-tract length [VTL]). Our purpose was to examine the effect of background noise at levels that allow good speech recognition thresholds (SRTs) on VD via acoustic CI simulations and CI hearing. Forty-eight normal-hearing (NH) listeners who listened via noise-excited (n = 20) or sinewave (n = 28) vocoders and 10 prelingually deaf CI users (i.e., whose hearing loss began before language acquisition) participated in the study. First, the signal-to-noise ratio (SNR) that yields 70.7% correct SRT was assessed using an adaptive sentence-in-noise test. Next, the CI simulation listeners performed 12 adaptive VDs: six in quiet conditions, two with each cue (fo, VTL, fo + VTL), and six amid speech-shaped noise. The CI participants performed six VDs: one with each cue, in quiet and amid noise. SNR at VD testing was 5 dB higher than the individual's SRT in noise (SRTn +5 dB). Results showed the following: (a) Better VD was achieved via the noise-excited than the sinewave vocoder, with the noise-excited vocoder better mimicking CI VD; (b) background noise had a limited negative effect on VD, only for the CI simulation listeners; and (c) there was a significant association between SNR at testing and VTL VD only for the CI simulation listeners. For NH listeners who listen to CI simulations, noise that allows good SRT can nevertheless impede VD, probably because VD depends more on bottom-up sensory processing. Conversely, for prelingually deaf CI users, noise that allows good SRT hardly affects VD, suggesting that they rely strongly on bottom-up processing for both VD and speech recognition.


PPO fiduciary responsibility.
This article will be frustrating for you. It warns you of comprehensive legal liability--but does not give you step-by-step guidance or checklists. Why? Because there are practically no examples or specifics or checklists in the Employee Retirement Income Security Act of 1974 (ERISA), especially for fiduciary duty and the new "knowing participant" fiduciary duty which applies to PPOs. Other than a relative handful of official Prohibited Transaction Exemptions (PTEs), everything is judged on a case-by-case basis. Even Department of Labor Opinion articles are merely that--opinions written with lots of caveats and not considered legal precedents. In defense of the Department of Labor, the slightest difference in circumstance can trigger a totally opposite ruling, so their hesitancy to give simple checklists is understandable. This article also takes a conservative approach. Enforcement of ERISA fiduciary duty has been sporadic. However, this article is important to you and timely. In recent years, the Department of Labor has devoted at least 50 percent of its employee review with criminal penalties of benefits cases deemed to be fraud, waste, or abuse. It is important to remember that the Department of Labor will judge your actions with 20/20 hindsight. Thus, it is important not only to have good intentions, but also to be sure that it looks like you have taken the most prudent action when all is said and done--even if the action defies common sense or normal business practices.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of the DNA methyltransferases expression on the methylation status of apoptosis-associated genes in glioblastoma multiforme.
Disruption of apoptosis is considered as an important factor aiding tumorigenesis, and aberrant DNA methylation of apoptosis-associated genes could be an important and significant mechanism through which tumor cells avoid apoptosis. However, little is known about (1) the impact of methylation status of apoptosis-associated genes on the presence of apoptosis evasion phenotype in glioma; and (2) the molecular mechanism governing the aberrant methylation of apoptosis-associated genes in glioma. By analyzing human glioma biopsies, we first show that low level of apoptosis in tumor is correlated with aberrant methylation of the bcl-2, bax and XAF-1 genes, but not with the aberrant methylation of the bcl-w, survivin, TMS1, caspase-8 and HRK genes. Our work also indicates that the expression levels of DNA methyltransferase 1 (Dnmt1), Dnmt3b and Dnmt1/Dnmt3a coregulate the methylation status of survivin, TMS1 and caspase-8, whereas no correlation was observed between the expression level of Dnmts and the methylation status of the bcl-w, bcl-2, bax, XAF-1 and HRK genes. Thus, these results indicate that the epigenetic regulation of some apoptosis-regulated genes could dictate whether glioma harbors the apoptosis evasion phenotype, and provide some bases to the identification of the methylation machineries of apoptosis-associated genes for which the Dnmt expression acts as a limiting factor.


Standard of care.
"Standard of care" sounds like a medical term, but actually it is a universal legal concept. It is codified differently by individual state statutes and is written into each state's uniform jury instructions. The phrase increasingly appears in scientific articles discussing the management of patients with headache. But, the term usually is not defined nor is evidence presented to justify the notion that the so-called standard has any scientific basis. In a courtroom, jury instructions using this phrase can be a legal sword aimed at a defendant doctor, rather than a shield. At risk is a physician's basic right to care for a patient according to that individual's particular needs.


Antioxidant therapy in diabetic complications: what is new?
In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolysis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. Classic antioxidants, like vitamin E, failed to show beneficial effects on diabetic complications probably due to their only "symptomatic" action. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Statins increase NO bioavailability and decrease superoxide production, probably interfering with NAD(P)H activity and modulating eNOS expression. ACE inhibitors and AT-1 blockers prevent hyperglycemia-derived oxidative stress modulating angiotensin action and production. This effect is of particular interest because hyperglycemia is able to directly modulate cellular angiotensin generation. Calcium channel blockers inhibit the peroxidation of cell membrane lipids and their subsequent intracellular translocation. Thiazolinediones bind and activate the nuclear peroxisome proliferator-activated receptor gamma, a nuclear receptor of ligand-dependent transcription factors. The inhibition of this receptors lead to inhibition of the inducible nitric oxide synthase and consequently reduction of peroxynitrite generation. This preventive activity against oxidative stress generation can justify a large utilization and association of this compound for preventing complications in diabetic patients, where antioxidant defences have been shown to be defective.


Quantitative effects of a nickel-titanium palatal expander on skeletal and dental structures in the primary and mixed dentition: a preliminary study.
The present study analysed the six-month effects of a nickel-titanium (NiTi) palatal expander on the dental and palatal structures of four primary (mean age 5.8 years) and nine mixed dentition children (mean age 8.7 years), with a posterior unilateral crossbite. Standardized dental and palatal landmarks were digitized using a three-dimensional (3D) electromagnetic instrument. Collected data were analysed with geometric-mathematical models. During a six-month interval, the natural growth and development of the dental arches and hard tissue palate was negligible, as assessed in seven control children (two in the primary dentition, mean age 4.4 years; five in the mixed dentition, mean age 7.7 years). In all children the crossbite was completely corrected. Indeed, dental expansion was always more than or corresponded to the palatal expansion. A smoothing of the size-independent (shape) palatal curvature in the transverse plane was observed. No differences in maximum palatal height were noted. Symmetrical derotation of the anchorage teeth in a distal direction occurred in almost all children. The inclination of the facial axis of the clinical crown (FACC) in the anatomical transverse plane of those teeth with differences between dental and palatal expansion always showed significant modifications (vestibular inclination up to 16.7 degrees). The clinical crown height of anchorage teeth remained nearly the same in all patients. No significant modifications in mandibular arch size were observed. The increase in maxillary arch width, especially in younger children, was probably due to a combination of different effects: opening of the midpalatal suture, tipping of the alveolar process, and molar tipping.


Method and quantity of liquid formulation of phosphobacteria required for seed inoculation.
The survival of vegetative and sporulated cells of the Bacillus cultures on the seeds of the crop plants was tried in different combinations. One milliliter inoculum with 1 mL adhesive combination or sterile water showed better results followed by 1.5 mL inoculum with 0.5 mL adhesive or sterile water. The population of 5.5x10(5) cfu seed(-1) on black gram, 10.5x10(5) cfu seed(-1) on soybean and 6.5x10(5) cfu seed(-1) on maize were observed after 12 h of incubation in 1 mL sporulated inoculum mixed with 1 mL of rice gruel. The sporulated inoculum along with rice gruel favoured the adherence of the regenerated cells as rice gruel is rich in nutrient content.


Linear regression analysis of censored medical costs.
This paper deals with the problem of linear regression for medical cost data when some study subjects are not followed for the full duration of interest so that their total costs are unknown. Standard survival analysis techniques are ill-suited to this type of censoring. The familiar normal equations for the least-squares estimation are modified in several ways to properly account for the incompleteness of the data. The resulting estimators are shown to be consistent and asymptotically normal with easily estimated variance-covariance matrices. The proposed methodology can be used when the cost database contains only the total costs for those with complete follow-up. More efficient estimators are available when the cost data are recorded in multiple time intervals. A study on the medical cost for ovarian cancer is presented.


Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development.
Satellite cells are resident myogenic progenitors in postnatal skeletal muscle involved in muscle postnatal growth and adult regenerative capacity. Here, we identify and describe a population of muscle-resident stem cells, which are located in the interstitium, that express the cell stress mediator PW1 but do not express other markers of muscle stem cells such as Pax7. PW1(+)/Pax7(-) interstitial cells (PICs) are myogenic in vitro and efficiently contribute to skeletal muscle regeneration in vivo as well as generating satellite cells and PICs. Whereas Pax7 mutant satellite cells show robust myogenic potential, Pax7 mutant PICs are unable to participate in myogenesis and accumulate during postnatal growth. Furthermore, we found that PICs are not derived from a satellite cell lineage. Taken together, our findings uncover a new and anatomically identifiable population of muscle progenitors and define a key role for Pax7 in a non-satellite cell population during postnatal muscle growth.


Effect of Aspirin and ibuprofen either alone or in combination on gastric mucosa and bleeding time and on serum prostaglandin E2 and thromboxane A2 levels in the anaesthetized rats in vivo.
There is much evidence that a combination of ibuprofen (IBU) and Aspirin (ASA) can antagonize the irreversible inhibition of platelet function. This study was designed to investigate the degree of gastric damage, bleeding time (BT) and fluctuations in the serum levels of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) after oral administration of ASA (200 mg/kg) and IBU (50 mg/kg) either alone or in combination in rats in vivo. The stomach was assessed for any damage either after 6 h, 18 h or 6 days and carboxymethylcellulose (1% CMC) served as a vehicle and control. ELISA was used to measure TXA2 and PGE2 in serum. Bleeding time was assessed using tail blood. The results show that ASA and IBU either alone or in combination can cause gastric ulceration in 25-100% of the rats at 6 and 18 h. In contrast, gastric ulceration was seen in 50% of rats with a combination of ASA given before IBU only after 6 days of oral administration. BT was unaffected either by ASA or IBU when administered alone except after 18 h for IBU. In contrast, BT was significantly reduced when IBU was administered before ASA after 18 h and 6 days (P < 0.001). Serum PGE2 levels decreased significantly after ASA administered either alone or in combination with IBU for 6 h, 18 h and 6 days (P < 0.05). Serum TXA2 levels were significantly reduced after 6 h, 18 h and 6 days following ASA and IBU administration except for IBU alone which caused a significant increase in serum TXA2 6 days after its administration (P < 0.01). It can be concluded that ASA and IBU administered either alone or in combination can cause gastric ulcers in the rat stomach after 6 h and 18 h, but less severe after 6 days. IBU either alone or in combination with ASA reduced BT only after 18 h and 6 days of administration. Together, the results show that gastric ulceration correlated well with the inhibition of serum PGE2 and TXA2 levels.


Molybdate and tungstate act like vanadate on glucose metabolism in isolated hepatocytes.
In rat hepatocytes, molybdate and tungstate inactivate glycogen synthase by a mechanism independent of Ca2+ and activate glycogen phosphorylase by a Ca(2+)-dependent mechanism. On the other hand, both molybdate and tungstate increase fructose 2,6-bisphosphate levels and counteract the decrease in this metabolite induced by glucagon. These effectors do not directly modify 6-phosphofructo-2-kinase activity, even though they partially counteract the inactivation of this enzyme induced by glucagon. These effects are related to an increase on the glycolytic flux, as indicated by the increase in L-lactate and CO2 production and the decrease in glucose 6-phosphate levels in the presence of glucose. All these effects are similar to those previously reported for vanadate, although molybdate and tungstate are less effective than vanadate. These results could indicate that molybdate, tungstate and vanadate act on glucose metabolism in isolated hepatocytes by a similar mechanism of action.


Emotion socialization as a dynamic process across emotion contexts.
Emotion-related socialization behaviors that occur during parent-child interactions are dynamic. According to Eisenberg, Cumberland, and Spinrad's (1998) model, ongoing parental reactions to emotions and discussions of emotion indirectly shape children's socioemotional competence throughout childhood and adolescence. Typically developing adolescents-girls especially-are at increased risk for developing internalizing symptoms. We examined if and how emotion dynamics of mother-daughter interactions contribute to adolescent girls' internalizing symptoms. We applied grid-sequence analysis (Brinberg, Fosco, & Ram, 2017) to observational data obtained while N = 96 typically developing adolescent girls (Mage = 13.99 years) and their mothers engaged in 5 different emotionally-laden discussions. We identified patterns of expressed emotions that unfolded during each discussion and examined how interdyad differences in those patterns were associated with mothers' and daughters' internalizing symptoms. Dyads differed with respect to whether mothers or daughters tended to regulate positive emotion expressions. Interdyad differences in moment-to-moment dynamics of happy/excited and worried/sad discussions were associated with adolescent girls' social anxiety symptoms, although differences in emotion dynamics of proud, frustrated/annoyed, and grateful discussions were not. Taken together, results illustrate how methodological innovations are enabling new examination and detailed description of parent-child emotion socialization dynamics. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Detection and isolation of RNA-binding proteins by RNA-ligand screening of a cDNA expression library.
A screening assay for the detection of RNA-binding proteins was developed. It allows the rapid isolation of cDNA clones coding for proteins with sequence-specific binding affinity to a target RNA. For developing the screening protocol, constituents of the human U1 snRNP were utilized as model system. The RNA partner consisted of the U1-RNA stem-loop II and the corresponding protein consisted of the 102 amino acid N-terminal recognition motif of the U1A protein, which was fused to beta-galactosidase and expressed by the recombinant lambda phage LU1A. Following binding of the fusion protein to nitrocellulose membranes, hybridization with a 32P-labeled U1-RNA ligand was carried out to detect specific RNA-protein interaction. Parameters influencing the specificity and the detection limit of binding were systematically investigated with the aid of the model system. Processing the nitrocellulose membranes in the presence of transition metals greatly increased the signal:background ratio. A simple screening protocol involving a single-buffer system was developed. Specific RNA-protein interaction could be detected in the presence of a large excess of recombinant phages from a cDNA library. Only moderate binding affinities (Kd = 10(-8) M) were required. The suitability of the RNA-ligand screening protocol was demonstrated by the identification of new viroid-RNA binding proteins from tomato.


PREGNANCY OUTCOMES IN WOMEN WITH EXTREMELY HIGH SFLT-1/PIGF RATIO: CASE SERIES.
Preeclampsia (PE) is a multisystem disorder, usually defined as the development of hypertension and proteinuria after 20 weeks of pregnancy. The sFlt-1/PlGF ratio has been widely studied as a diagnostic and prognostic marker of preeclampsia and other manifestations of placental dysfunction. A sFlt-1/PlGF ratio greater than 85 for early PE, <34 weeks of gestation suggests a high risk of PE requiring close clinical monitoring. Our main aim was to evaluate the maternal and perinatal outcomes of pregnancies with an extremely high sFlt-1/PlGF ratio. The analysis included data on placental growth factor and soluble fms-like tyrosine kinase serum levels, measured during 2017-2020 in 128 pregnant women. Here we present 8 cases of women with a numerical ratio greater than 850. In all 100% of cases, the signs of obstetric angiogenic catastrophe requiring imminent delivery developed soon. We observed a trend for worsening perinatal outcomes in women with an extremely high sFlt-1/PlGF of ≥850.


Assessment of the systolic function and contractility of the hypertensive left ventricle.
Sustained hypertension is a stimulus for development of cardiac hypertrophy, which may be either concentric or eccentric. For a given rise of aortic pressure, left ventricle (LV) wall stress (afterload) may remain normal or reduced in the former and become enhanced in the latter condition, and the LV systolic function may vary in a direction opposite to that of wall stress. It is unknown whether there are also differences in contractile properties that may have a role in the shift from normal systolic function. To clarify this we evaluated the velocity of LV fiber shortening and the fractional fiber shortening in normotensive and hypertensive subjects with normal heart size (group 1), or concentric LV (group 2) or eccentric LV (group 3) hypertrophy during baseline and after an acute hemodynamic overload induced by a cold pressor test (CPT). We found that the functional pattern in the two conditions was similar to normal in group 1, significantly enhanced during baseline and CPT in group 2, and was depressed during baseline and more so during CPT in group 3. These findings suggest that the contractile properties of the two types of hypertrophy are different, supported by the slope of the force-length line defined by the end systolic stress-end systolic volume relation in the baseline and during the hemodynamic overload imposed by the CPT. This line was steeper than normal in group 2 and less steep than normal in group 3. It remains to be defined whether the two types of hypertrophy are a separate disorder or represent a different stage of the same disease.


Antifungal susceptibility, species distribution and risk factors associated with mortality of invasive candidiasis in children in Turkey: A six-year retrospective, single-centre study.
Invasive candidiasis (IC) is a life-threatening fungal infection with high morbidity and mortality. In this study, we aimed to investigate the Candida species distribution and antifungal drug susceptibility and to identify the risk factors associated with IC mortality in children. We conducted a retrospective, single-centre study of paediatric IC in patients from a tertiary care hospital in Turkey between January 2013 and February 2019. A total of 56 Candida isolates underwent antifungal susceptibility testing performed by Sensititre YeastOne YO10 panel, and the demographic and clinical data of 65 patients were examined during the study period. The most commonly isolated species was Candida albicans in 30 patients (46%), followed by C. parapsilosis in 25 patients (38%) and C. tropicalis in three patients (5%). According to the antifungal drug susceptibility testing, C. albicans was fully susceptible to fluconazole and the other antifungal agents (100%). None of the isolates displayed resistance to anidulafungin, micafungin, flucytosine, posaconazole, voriconazole or itraconazole. There were low rates of resistance to fluconazole (1.8%), caspofungin (1.8%) and micafungin (1.8%). In addition, 5.3% of the Candida isolates were susceptible in a dose-dependent manner to itraconazole, 3.6% were susceptible to voriconazole and fluconazole and 1.8% were susceptible to anidulafungin. The mortality rate of IC was 15.4%. Thrombocytopenia after IC treatment was significantly associated with mortality in the multivariate analysis. These results, which help determine the species distribution, antifungal susceptibility patterns and risk factors for mortality, could make a significant contribution to the management of these challenging infections, including choosing appropriate empirical antifungal therapy.


Expanding and contracting optic-flow patterns and vection.
When stationary observers view an optic-flow pattern, visually induced self-motion perception (vection) and a form of motion sickness known as simulator sickness (SS), can result. Previous results suggest that an expanding flow pattern leads to more SS than a contracting pattern. Sensory conflict, a possible cause of SS, may be more salient when an expanding optic-flow pattern is viewed. An experiment was conducted to test if a more salient sensory conflict accompanying expanding flow patterns might inhibit vection. Participants (n = 15) viewed a pattern of blue squares, either steadily expanded or contracted, on a large rear-projection screen. Vection onset and magnitude were measured for 30 s with a computer-interfaced slide device. Vection onset was significantly faster, and vection magnitude stronger, when a contracting pattern was viewed. We propose that our extensive experience with forward self-motion may form a neural expectancy (exposure-history) about the sensory inputs which typically accompany expanding flow. However, since backward self-motion is less common, there may be a weaker exposure-history for contracting flow, and as a result these patterns generate less salient sensory conflict and subsequently less vection.


Quantitative studies on the mixed lymphocyte interaction in rats. II. Relationship of the proliferative response to the immunologic status of the donors.
The influence of the immunologic status of the cell donors on the proliferative behavior of rat lymphocytes in the mixed lymphocyte interaction has been studied. Mixed cultures of cells from various parental and F(1) combinations having morphologically distinguishable sex chromosomes exhibited unidirectional proliferative reactivity. The mitotic figures were predominately of parental origin. Lymphocytes from donors made tolerant at birth to homologous transplantation isoantigens were specifically unreactive against cells bearing antigens of the tolerance inducing strain, but not to indifferent third party homologous lymphocytes. Cells from animals that had been surgically thymectomized at birth exhibited a markedly and sometimes totally diminished reactivity against homologous lymphocytes. Presensitization of the cell donors resulted in a curtailment of proliferative reactivity in cultures with cells bearing the immunizing antigens. This may reflect the destructive properties that lymphocytes from sensitized animals are known to possess. The results of these experiments show that the proliferative activity of lymphocytes in the mixed lymphocyte interaction accurately reflects the immunologic status of the cell donors, and these findings provide further support for the premise that the mixed lymphocyte interaction represents a primary immunologic response by cells in culture against homologous cells bearing histocompatibility antigens.


The potential utility of urinary biomarkers for risk prediction in combat casualties: a prospective observational cohort study.
Traditional risk scoring prediction models for trauma use either anatomically based estimations of injury or presenting vital signs. Markers of organ dysfunction may provide additional prognostic capability to these models. The objective of this study was to evaluate if urinary biomarkers are associated with poor outcomes, including death and the need for renal replacement therapy. We conducted a prospective, observational study in United States Military personnel with traumatic injury admitted to the intensive care unit at a combat support hospital in Afghanistan. Eighty nine patients with urine samples drawn at admission to the intensive care unit were studied. Twelve patients subsequently died or needed renal replacement therapy. Median admission levels of urinary cystatin C (CyC), interleukin 18 (IL-18), L-type fatty acid binding protein (LFABP) and neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher in patients that developed the combined outcome of death or need for renal replacement therapy. Median admission levels of kidney injury molecule-1 were not associated with the combined outcome. The area under the receiver operating characteristic curves for the combined outcome were 0.815, 0.682, 0.842 and 0.820 for CyC, IL-18, LFABP and NGAL, respectively. Multivariable regression adjusted for injury severity score, revealed CyC (OR 1.97, 95 % confidence interval 1.26-3.10, p = 0.003), LFABP (OR 1.92, 95 % confidence interval 1.24-2.99, p = 0.004) and NGAL (OR 1.80, 95 % confidence interval 1.21-2.66, p = 0.004) to be significantly associated with the composite outcome. Urinary biomarker levels at the time of admission are associated with death or need for renal replacement therapy. Larger multicenter studies will be required to determine how urinary biomarkers can best be used in future prediction models.


Domain structure of the Moloney murine leukemia virus reverse transcriptase: mutational analysis and separate expression of the DNA polymerase and RNase H activities.
The reverse transcriptase of Moloney murine leukemia virus, like that of all retroviruses, exhibits a DNA polymerase activity capable of synthesis on RNA or DNA templates and an RNase H activity with specificity for RNA in the form of an RNA.DNA hybrid. We have generated a library of linker insertion mutants of the Moloney murine leukemia virus enzyme expressed in bacteria and assayed these mutants for both enzymatic activities. Those mutations affecting the DNA polymerase activity were clustered in the 5'-proximal two-thirds of the gene, and those affecting RNase H were in the remaining 3' one-third. Based on these maps, plasmids were made that expressed each one of the domains separately; assays of the proteins encoded by these plasmids showed that each domain exhibited only the expected activity.


[Sorption of microorganisms by fiber materials].
Candida guilliermondii and Escherichia coli cells were adsorbed on glass and basalt fibres with a similar specific surface, but with a different charge. The quantity of adsorbed microorganisms did not depend on the type and charge of a fibre surface. However, cells were adsorbed faster and more firmly on positively charged and uncharged fibres than on negatively charged fibres.


Walk2Bactive: A randomised controlled trial of a physical activity-focused behavioural intervention beyond pulmonary rehabilitation in chronic obstructive pulmonary disease.
The aim of this study was to investigate the impact of a physical activity (PA)-focused behavioural intervention during and after pulmonary rehabilitation (PR) on PA levels (primary aim), health-related outcomes and self-efficacy (secondary aims) of patients with COPD. Thirty-two patients were randomly assigned to an experimental group (EG) or control group (CG). The EG received a PA-focused behavioural intervention during PR (3 months) and follow-up support (3 months). The CG received PR (3 months). Daily PA was collected: number of steps; time spent in moderate-to-vigorous PA (MVPA), total PA and sedentary activities (SA). Secondary outcomes comprised exercise capacity, muscle strength, health-related quality of life (HRQOL) and self-efficacy. Measures were collected at baseline, 3 and 6 months. Compared with the CG, the EG improved the number of steps (p = 0.006) and time spent in MVPA (p = 0.007), total PA (p = 0.014) and SA (p = 0.018) at 3 months. Differences were maintained after follow-up support (0.025 ≤ p ≤ 0.040), except for SA (p = 0.781). Exercise capacity, muscle strength and HRQOL were increased at 3 and 6 months (p ≤ 0.002) with no between-group differences (0.148 ≤ p ≤ 0.987). No changes were observed in self-efficacy (p = 0.899). A PA-focused behavioural intervention during and after PR may improve patients' PA levels. Further research is warranted to assess the sustainability of the findings.


Ckikungunya virus infection and relationship to rainfall, the relationship study from southern Thailand.
There are several important mosquito borne infectious disease in the tropical countries. Chikungunya virus infection is an important arbovirus in this group. We hereby used a standard medicogeographical analysis to assess the correlation between prevalence of Chikungunya virus infection and rainfall in the endemic area of Thailand, the Southern region. In this work, the correlation was poor but significant. The result is concordant with a similar report from the retrospective analysis from the local center of disease control. Several other factors can affect the pattern of Chikungunya virus infection in the studied endemic area.


Correlation dimension analysis of heart rate variability in patients with dilated cardiomyopathy.
A correlation dimension analysis of heart rate variability (HRV) was applied to a group of 55 patients with dilated cardiomyopathy (DCM) and 55 healthy subjects as controls. The 24-h RR time series for each subject was divided into segments of 10,000 beats to determine the correlation dimension (CD) per segment. A study of the influence of the time delay (lag) in the calculation of CD was performed. Good discrimination between both groups (p<0.005) was obtained with lag values of 5 or greater. CD values of DCM patients (8.4+/-1.9) were significantly lower than CD values for controls (9.5+/-1.9). An analysis of CD values of HRV showed that for healthy people, CD night values (10.6+/-1.8) were significant greater than CD day values (9.2+/-1.9), revealing a circadian rhythm. In DCM patients, this circadian rhythm was lost and there were no differences between CD values in day (8.8+/-2.4) and night (8.9+/-2.1).


Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans.
Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress and disease but remain ill-defined. Although nonmobilized peripheral blood (PB) is routinely sampled for clinical management, the diagnosis and monitoring potential of PB HSPCs remain untapped, as no healthy PB HSPC baseline has been reported. Here we comprehensively delineate human extramedullary HSPC compartments comparing spleen, PB, and mobilized PB to BM using single-cell RNA-sequencing and/or functional assays. We uncovered HSPC features shared by extramedullary tissues and others unique to PB. First, in contrast to actively dividing BM HSPCs, we found no evidence of substantial ongoing hematopoiesis in extramedullary tissues at steady state but report increased splenic HSPC proliferative output during stress erythropoiesis. Second, extramedullary hematopoietic stem cells/multipotent progenitors (HSCs/MPPs) from spleen, PB, and mobilized PB share a common transcriptional signature and increased abundance of lineage-primed subsets compared with BM. Third, healthy PB HSPCs display a unique bias toward erythroid-megakaryocytic differentiation. At the HSC/MPP level, this is functionally imparted by a subset of phenotypic CD71+ HSCs/MPPs, exclusively producing erythrocytes and megakaryocytes, highly abundant in PB but rare in other adult tissues. Finally, the unique erythroid-megakaryocytic-skewing of PB is perturbed with age in essential thrombocythemia and β-thalassemia. Collectively, we identify extramedullary lineage-primed HSPC reservoirs that are nonproliferative in situ and report involvement of splenic HSPCs during demand-adapted hematopoiesis. Our data also establish aberrant composition and function of circulating HSPCs as potential clinical indicators of BM dysfunction.


Primary hypothyroidism, pituitary insufficiency and pregnancy. A case report.
A 23-year-old woman presented with primary hypothyroidism and inability to lactate following uneventful childbirth. Endocrine evaluation revealed that she had autoimmune hypothyroidism and deficiencies of ACTH and prolactin. Despite partial hypopituitarism, she again conceived spontaneously, had an uneventful pregnancy and delivery but failed to lactate. Radiologic evaluation of the hypophysis, including CAT scan, was normal, and antibodies to anterior pituitary cells were not detected. The etiology of the pituitary insufficiency might have been autoimmune hypophysitis , a recently described entity in which anterior pituitary, along with the other endocrine glands, is destroyed by an autoimmune process. The clinical course suggested that women with pituitary insufficiency, although rare, are able to conceive and carry the pregnancy to term. Our patient illustrates that prolactin insufficiency does not preclude a successful outcome of pregnancy but can result in no lactation.


Prevalence and determinants of metabolic syndrome and elevated Framingham risk score in epithelial ovarian cancer survivors: a controlled observational study.
Bilateral oophorectomy has been associated with increased risk of metabolic syndrome (MetS) and coronary heart disease; however, the risk in women oophorectomized for epithelial ovarian cancer has not been studied previously. Among 287 epithelial ovarian cancer survivors (EOCSs) alive in 2004 and treated with bilateral oophorectomy between 1979 and 2003 at the Norwegian Radium Hospital, 189/287 (66%) participated and 165/189 (87%) provided demographic and health history data and fasting serum samples. Controls were women from the general population. Metabolic syndrome was defined according to the International Diabetes Federation and 2005 Adult Treatment Program III criteria. Framingham risk score assessing the 10-year risk of coronary heart disease was calculated. We found that to be an EOCS was significantly associated with increased risk of MetS (odds ratio, 1.7; 95% confidence interval, 1.1-2.8) but not with Framingham risk score of more than 10% (odds ratio, 0.4; 95% confidence interval, 0.2-1.1) compared with controls. Older age and higher body mass index were also significantly associated with increased risk of MetS, whereas less education and not living with a partner were associated with an increased level in the Framingham risk score. The association between EOCSs and increased risk of MetS may imply that EOCSs can be at higher risk of type 2 diabetes and cardiovascular disease. In view of the increasing number of EOCSs, these novel findings should be given therapeutic considerations when such patients are followed up by health care professionals.


Monitoring the Genotoxic and Cytotoxic Potential and the Presence of Pesticides and Hydrocarbons in Water of the Sinos River Basin, Southern Brazil.
The Sinos River is one of the most polluted rivers in Brazil. The purpose of this work was to monitor the presence of some pesticides and hydrocarbons as well as the genotoxic and cytotoxic potential on HEp-2 cells from water samples collected at seven sites in the Sinos River Basin (SRB), southern Brazil. Nine samples were taken from the three main rivers in the SRB and used as a solution to dilute the HEp-2 cell culture medium after microfiltration. Twenty-four pesticides and 19 hydrocarbons were measured. Cytotoxicity was assessed by methyl thiazolyl tetrazolium (MTT) and neutral red (NR) assays, in which cells were exposed to different concentrations of the water samples for 24 h. Genotoxicity of the microfiltrated raw water samples was assessed by comet assay after 6 and 24 h of exposure. Among the chemicals analyzed, only the 2,4-D, dichloromethane, tetrachloroethene, chloroform, bromodichloromethane, styrene, and toluene were detected, but they were all lower than the limit established by Brazilian regulations. Twenty samples from a total of 60 had a cytotoxic effect in the MTT assay and 30 in the NR assay. The comet assay indicated the presence of genotoxic substances in the water at the seven locations monitored. Temporal and spatial variation was observed in the cytotoxicity and genotoxicity assays. Results indicated that the water in all stretches of the SRB is contaminated and it can cause harmful effects to humans and to the aquatic biota. This HEp-2 cell-line approach can be an additional tool for environmental monitoring.


Potential association between coronary artery disease and the inflammatory biomarker YKL-40 in asymptomatic patients with type 2 diabetes mellitus.
Inflammation plays an important role in coronary artery disease from the initiation of endothelial dysfunction to plaque formation to final rupture of the plaque. In this study, we investigated the potential pathophysiological and clinical relevance of novel cytokines secreted from various cells including adipocytes, endothelial cells, and inflammatory cells, in predicting coronary artery disease (CAD) in asymptomatic subjects with type 2 diabetes mellitus. We enrolled a total of 70 asymptomatic type 2 diabetic patients without a documented history of cardiovascular disease, and determined serum levels of chemerin, omentin-1, YKL-40, and sCD26. We performed coronary computed tomographic angiography (cCTA) in all subjects, and defined coronary artery stenosis ≥ 50 % as significant CAD in this study. Subjects were classified into two groups: patients with suspected coronary artery stenosis on cCTA (group I, n = 41) and patients without any evidence of stenosis on cCTA (group II, n = 29). Group I showed significantly higher YLK-40 levels and lower HDL-C levels than group II (p = 0.038, 0.036, respectively). Levels of chemerin, omentin-1, and sCD26 were not significantly different between the two groups. Serum YKL-40 levels were positively correlated with systolic/diastolic BP, fasting/postprandial triglyceride levels, and Framingham risk score. Furthermore, YKL-40 levels showed moderate correlation with the degree of coronary artery stenosis and the coronary artery calcium score determined from cCTA. In multivariate logistic analysis, after adjusting for age, gender, smoking history, hypertension, and LDL-cholesterol, YLK-40 levels showed only borderline significance. YKL-40, which is secreted primarily from inflammatory cells, was associated with several CVD risk factors and was elevated in type 2 diabetic patients with suspected coronary artery stensosis on cCTA. These results suggest the possibility that the inflammatory biomarker YKL-40 might be associated with coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.


Applications of molecular genetics technology for prenatal diagnosis of genetic disease.
Information about the studies currently available and guidelines for identifying genetics resources, both clinical and laboratory, for provision of these services is provided. Rapid progress in the field of molecular genetics has provided increased opportunities for carrier and presymptomatic testing and prenatal diagnosis of numerous genetic diseases. The development of these diverse diagnostic services creates new challenges for clinical laboratory professionals who are likely to receive requests for these studies. Crucial decisions must be made in family identification for testing and in posttesting genetic counseling. Specific case examples are presented to illustrate the potential benefits and limitations of these studies. The molecular techniques currently available provide families with highly accurate information about their genetic risks.


Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations.
The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80). At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. UMIN C000002789, Post-results.


PARP1-cGAS-NF-κB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease.
Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas cardiomyopathy. In the present study, we investigated the role of extracellular vesicles (Ev) in shaping the macrophage (Mφ) response in progressive Chagas disease (CD). We purified T. cruzi Ev (TcEv) from axenic parasite cultures, and T. cruzi-induced Ev (TEv) from the supernatants of infected cells and plasma of acutely and chronically infected wild-type and Parp1-/- mice. Cultured (Raw 264.7) and bone-marrow Mφ responded to TcEV and TEv with a profound increase in the expression and release of TNF-α, IL-6, and IL-1β cytokines. TEv produced by both immune (Mφ) and non-immune (muscle) cells were proinflammatory. Chemical inhibition or genetic deletion of PARP1 (a DNA repair enzyme) significantly depressed the TEv-induced transcriptional and translational activation of proinflammatory Mφ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory Mφ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NFκB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NFκB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-α+ Mφ in the myocardium of CD wild-type mice. In comparison, chronically infected Parp1-/- mice exhibited low-to-moderate tissue inflammation, >80% decline in myocardial infiltration of TNF-α+ Mφ, and no change in immunoregulatory IL-10+ Mφ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-κB pathway of proinflammatory Mφ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the Mφ activation and controlling the chronic inflammation in CD.


Modulation of specific beta cell gene (re)expression during in vitro expansion of human pancreatic islet cells.
The need for transplantable beta cells with a stable phenotype has given rise to several strategies including the expansion of existing pancreatic islets and/or growth of new ones. In vitro studies of beta cell proliferation on extracellular matrices plus growth factors have highlighted a possible cell expansion technique; however, the technique was accompanied with loss of insulin secretion. Herein we showed that human islet cell proliferation was marked by a decreased expression of specific differentiation markers, particularly insulin, insulin promoting factor-1 (IPF-1), and glucokinase. After a 6-day expansion period, we tried to reexpress the beta cell differentiation markers with compounds known for their differentiation and/or insulin-secreting properties. Sodium butyrate was a potent factor of IPF-1, insulin, and glucokinase gene reexpression; it also clearly induced secretion of gastrin, a known neogenic factor. Other compounds, namely TGF-beta, calcitriol, GLP-1, and activin A, efficiently enhanced the glucose sensor machinery, particularly Glut-1 and glucokinase, thus triggering glucose responsiveness. Our results indicate that specific beta cell gene expression may be induced after expansion and dedifferentiation. This rekindles interest in human beta cell expansion. The possible stabilization of specialized genes needed by beta cells to fulfill their role as nutrient sensors and metabolic regulators may also be of interest to ensure graft maintenance and efficiency.


High-intensity vapor lamp for biological research.
A vapor arc light source has been adapted to the study of the lethal action on bacteria of near-ultraviolet (UV) and visible light. Its use makes possible much shorter exposure times than could be obtained from previously available sources. The output of radiant energy is sufficient to provide a fairly detailed action spectrum for lethality in the long-UV and visible region without the addition of exogenous sensitizers. Populations of cells of Escherichia coli WP2 were inactivated through five log(10) cycles with light at 460 nm. Significant inactivation also was obtained with light at 550 and 650 nm.


Factors associated with early tibial tuberosity fracture after tibial plateau leveling osteotomy.
To determine factors contributing to tibial tuberosity fracture (TTF) after tibial plateau leveling osteotomy (TPLO). Retrospective case-control study. Dogs (n = 2490) with cranial cruciate ligament rupture that underwent 3000 TPLO surgeries. Radiographs of 3000 stifles from dogs that underwent TPLO were reviewed for evidence of TTF. Two ratios were generated: (1) the height of the tuberosity over the width of the tibia at the most distal extent of the osteotomy (TW) and (2) the width of the narrowest point of the tuberosity over TW. Twenty-three (0.77%) cases of fracture were identified. Factors that correlated with increased odds of fracture were placement of antirotational pins distal to the insertion of the patellar ligament (PL), tuberosities with the narrowest point below the insertion of PL, placement of multiple pins distal to the PL, and bilateral simultaneous TPLO. Tuberosities that fractured were significantly taller and narrower than those that did not fracture. Rotation past the "safe point" and presence of a gap at the osteotomy were not correlated with fracture. Placement of multiple pins, pin placement distal to the insertion of the PL, location of the narrowest point of the tibial tuberosity distal to the insertion of the PL, and simultaneous bilateral TPLO were all associated with TTF in this study CLINICAL SIGNIFICANCE: Preoperative planning and postoperative assessment of TPLO should take into consideration the predisposing factors identified in this study to prevent TTF.


Complete Decongestive Therapy Is an Option for the Treatment of Rosacea Lymphedema (Morbihan Disease): Two Cases.
Morbihan disease, also known as rosacea lymphedema, is a rare persistent form of lymphedema that is associated with the disease rosacea. Even though acne rosacea responds well to standard medical treatment, the lymphedema component of the disease is resistant to both medical and surgical therapy. Complete decongestive therapy (CDT) can be considered as a conservative alternative option for treatment of rosacea lymphedema. To date, there is no report on the use of CDT in treating facial lymphedema secondary to acne rosacea. We present 2 cases of women with a diagnosis of Morbihan disease and chronic facial lymphedema that remained resistant to drug treatment for many years before CDT was offered. The treatment program included 4 components: manual lymphatic drainage, compression bandaging, exercises to enhance lymphatic drainage, and patient education. Following 10 to 15 sessions of CDT, the first patient's facial edema had almost completely resolved. The second patient's response to treatment was assessed as moderate. To the best of our knowledge, these 2 cases of Morbihan disease treated with CDT are the first of their kind to be presented in the literature. As the treatment options for Morbihan disease remain inadequate, we believe that CDT should be considered as a treatment option in those patients who do not benefit from or refuse drug treatment, before moving on to more invasive procedures. Prospective studies should be designed to demonstrate the efficacy of CDT and provide management details.


Antioxidant-Rich Fraction of Urtica dioica Mediated Rescue of Striatal Mito-Oxidative Damage in MPTP-Induced Behavioral, Cellular, and Neurochemical Alterations in Rats.
Parkinson's disease (PD) having a complex and multi-factorial neuropathology includes mainly the degeneration of the dopaminergic nigrostriatal pathway, which is a cumulative effect of depleted endogenous antioxidant enzymes, increased oxidative DNA damage, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. The present study was designed to investigate the neuroprotective effect of a potent antioxidant from Urtica dioica in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. MPTP was administered intranigrally for the induction of PD in male Wistar rats. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and different biochemical, cellular, and neurochemical parameters were measured. Intranigrally repeated administration of MPTP showed significant impairment of motor co-ordination and marked increase of mito-oxidative damage and neuroinflammation in rats. Intranigral MPTP significantly decreases the dopamine and its metabolites with impairment of dopaminergic cell density in rat brain. However, post-treatment with the potent antioxidant fraction of Urtica dioica Linn. (UD) (20, 40, 80 mg/kg) improved the motor function, mito-oxidative defense alteration significantly and dose dependently in MPTP-treated rats. In addition, the potent antioxidant fraction of UD attenuated the pro-inflammatory cytokines (TNF-α and IL-β) and restored the level of dopamine and its metabolites in MPTP-induced PD in rats. Moreover, minocycline (30 mg/kg) with lower dose of UD (20 mg/kg) had significantly potentiated the protective effect of minocycline as compared to its effect with other individual drug-treated groups. In conclusion, Urtica dioica protected the dopaminergic neurons probably by reducing mito-oxidative damage, neuroinflammation, and cellular alteration along with enhanced neurotrophic potential. The above results revealed that the antioxidant rich fraction of UD contain flavonoids and phenolic compounds, which have a promising approach in therapeutics of PD.


Weight and mortality following heart failure hospitalization among diabetic patients.
Type 2 diabetes is an important risk factor for heart failure and is common among patients with heart failure. The impact of weight on prognosis after hospitalization for acute heart failure among patients with diabetes is unknown. The objective of this study was to examine all-cause mortality in relation to weight status among patients with type 2 diabetes hospitalized for decompensated heart failure. The Worcester Heart Failure Study included adults admitted with acute heart failure to all metropolitan Worcester medical centers in 1995 and 2000. The weight status of 1644 patients with diabetes (history of type 2 diabetes in medical record or admission serum glucose ≥200 mg/dL) was categorized using body mass index calculated from height and weight at admission. Survival status was ascertained at 1 and 5 years after hospital admission. Sixty-five percent of patients were overweight or obese and 3% were underweight. Underweight patients had 50% higher odds of all-cause mortality within 5 years of hospitalization for acute heart failure than normal weight patients. Class I and II obesity were associated with 20% and 40% lower odds of dying. Overweight and Class III obesity were not associated with mortality. Results were similar for mortality within 1 year of hospitalization for acute heart failure. The mechanisms underlying the association between weight status and mortality are not fully understood. Additional research is needed to explore the effects of body composition, recent weight changes, and prognosis after hospitalization for heart failure among patients with diabetes.


Individual differences in valence bias: fMRI evidence of the initial negativity hypothesis.
Facial expressions offer an ecologically valid model for examining individual differences in affective decision-making. They convey an emotional signal from a social agent and provide important predictive information about one's environment (presence of potential rewards or threats). Although some expressions provide clear predictive information (angry, happy), others (surprised) are ambiguous in that they predict both positive and negative outcomes. Thus, surprised faces can delineate an individual's valence bias, or the tendency to interpret ambiguity as positive or negative. Our initial negativity hypothesis suggests that the initial response to ambiguity is negative, and that positivity relies on emotion regulation. We tested this hypothesis by comparing brain activity during explicit emotion regulation (reappraisal) and while freely viewing facial expressions, and measuring the relationship between brain activity and valence bias. Brain regions recruited during reappraisal showed greater activity for surprise in individuals with an increasingly positive valence bias. Additionally, we linked amygdala activity with an initial negativity, revealing a pattern similarity in individuals with negative bias between viewing surprised faces and maintaining negativity. Finally, these individuals failed to show normal habituation to clear negativity. These results support the initial negativity hypothesis, and are consistent with emotion research in both children and adult populations.


A Novel Computerized Cognitive Stress Test to Detect Mild Cognitive Impairment.
The Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) is a novel and increasingly employed instrument that has outperformed widely used cognitive measures as an early correlate of elevated brain amyloid and neurodegeneration in prodromal Alzheimer's Disease (AD). The LASSI-L has distinguished those with amnestic mild cognitive impairment (aMCI) and high amyloid load from aMCI attributable to other non-AD conditions. The authors designed and implemented a web-based brief computerized version of the instrument, the LASSI-BC, to improve standardized administration, facilitate scoring accuracy, real-time data entry, and increase the accessibility of the measure. The psychometric properties and clinical utility of the brief computerized version of the LASSI-L was evaluated, together with its ability to differentiate older adults who are cognitively normal (CN) from those with amnestic Mild Cognitive Impairment (aMCI). After undergoing a comprehensive uniform clinical and neuropsychological evaluation using traditional measures, older adults were classified as cognitively normal or diagnosed with aMCI. All participants were administered the LASSI-BC, a computerized version of the LASSI-L. Test-retest and discriminant validity was assessed for each LASSI-BC subscale. LASSI-BC subscales demonstrated high test-retest reliability, and discriminant validity was attained. The LASSI-BC, a brief computerized version of the LASSI-L is a valid and useful cognitive tool for the detection of aMCI among older adults.


IgA antibodies to Toxoplasma gondii in human tears.
To investigate whether mucosal immune responses directed against the ubiquitous parasite Toxoplasma gondii can be detected in tears of healthy humans. Nonstimulated tears and blood were obtained from 62 healthy humans (mean age, 35 +/- 10 [SD] years). Serum anti-T. gondii immunoglobulin titers were determined by Sabin-Feldman (SF) dye test. Western blot analysis was used to compare the anti-T. gondii repertoire in tears and serum, and antibody avidity was determined by urea elution. Diluted tear and serum samples were incubated with the intact parasite to determine whether the antibodies found in tears and serum are capable of binding to surface exposed antigens of T. gondii. Eighty-one percent of the individuals tested had an anti-T. gondii IgA response in their tears, whereas only 23% had evidence of systemic immunity against the parasite. There was no apparent relation between chronic infection and presence of anti-T. gondii IgA in tears. Characteristically, the antigens recognized by the IgA antibodies in tears were often limited to at least one of four antigens with molecular weights of 74, 70, 49, and 34 kDa. The avidity of the anti-T. gondii IgA antibodies in tears was similar to the avidity of serum IgG antibodies. IgA antibodies directed against the 49- and 74-kDa antigens recognized epitopes exposed on the surface of the parasite. A major finding of this study is that tears of many individuals, chronically infected or not, contain IgA antibodies against T. gondii. It is not known whether these frequently observed antibody responses are the result of common mucosal immune responses against T. gondii or represent the natural antibody repertoire.


Mineral concentrations in milk from cows fed seaweed (Saccharina latissima) under different basal protein supplementation.
Sixteen multiparous Holstein cows in four blocks of 4 × 4 Latin square over 4-week experimental periods were used to study the effects of seaweed (Saccharina latissima) supplement (with/without) and protein source (rapeseed meal (RSM)/wheat distiller's grain (WDG)) on milk mineral concentrations. Dietary treatments did not affect milk production and basic composition. Feeding seaweed slightly decreased milk Ca and Cu concentrations; whilst increased (by 3.3-fold) milk iodine (I) concentration, due to a higher dietary I supply. Substitution of WDG with RSM increased feed-to-milk transfer of Ca, Na, and Se and decreased that of Mg, P, Fe, and Mn; but only reduced milk Mn and I concentrations (the latter by 27 % as a potential result of increased glucosinolate intake). Seaweed supplement can improve milk I content when cows' I supply/availability is limited, but care should be taken to avoid excess milk I contents that may pose nutritional risks for young children.


Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats.
Low-grade inflammation may play a role in the pathogenesis of irritable bowel syndrome (IBS). Although corticosteroids are potent inhibitors of inflammatory processes, only one study with corticosteroids in patients with postinfectious IBS exists, which suggests that prednisolone is not an effective treatment for IBS symptoms. To evaluate whether dexamethasone treatment prevents protease-activated receptor-2 (PAR-2) activation-induced visceral hyperalgesia and increased permeability in rats, and to determine whether the effects involve colonic mast cells. Abdominal contractions provoked by rectal distension were recorded in rats equipped with intramuscular electrodes. Changes in visceral hypersensitivity provoked by intracolonic administration of PAR-2-activating peptide (SLIGRL; H-serine-leucine-isoleucine-glycine-arginine-leucine-OH), changes in colonic mucosal rat mast cell protease-II (RMCP-II) content, mast cell count and PAR-2 expression were measured after a 4-day treatment with dexamethasone (1 mg/day/rat intraperitoneally) or its vehicle (water). The effect of mast cell stabiliser (doxantrazole, 1 mg/kg intraperitoneally, 2 h before and 6 h after intracolonic infusion of SLIGRL) on SLIGRL-induced visceral hyperalgesia was also assessed. The effects of SLIGRL and a mast cell degranulator (compound 48/80) on the permeability of colonic strips from vehicle- or dexamethasone-treated rats were investigated in Ussing chambers. 4 days of dexamethasone as well as doxantrazole diminished the SLIGRL-induced hyperalgesia for all volumes of distension. This effect of dexamethasone was accompanied by a reduced responsiveness of colonic permeability to compound 48/80, and decreased RMCP-II content and mast cell number. Dexamethasone treatment did not influence colonic mucosal PAR-2 expression and permeability responsiveness to SLIGRL. Dexamethasone treatment improves PAR-2 agonist-induced visceral hypersensitivity but does not prevent PAR-2 agonist-induced increase in colonic permeability in rats. This effect is coupled with a reduction of colonic mast cell number and RMCP-II contents.


Remyelination modulators in multiple sclerosis patients.
Multiple Sclerosis (MS) is a complex autoimmune neuro-inflammatory disorder characterized by persistent MS plaques in the central nervous system. Resolution of MS plaques is dependent on the remyelination competence of surviving oligodendrocytes and surrounding environment. Here, we assessed myelination modulators in a 100 MS patients against 77 healthy controls. Plasma fractions were used for the assessment of insulin growth factor binding protein1 (IGFBP1), brain-derived neurotrophic factor (BDNF), and lipocalin2 (LCN2) using a Luminex multiplex assay, whereas neurofilament light chain (NF-L) was assessed with an enzyme-linked immunosorbent assay. Circulating levels of IGFBP1, LCN2 and NF-L were significantly higher in MS patients (p<0.01). Whereas BDNF levels were significantly lower in MS patients (p=0.014). MS Female patients had significantly higher levels of IGFBP1 compared to male MS patients (p=0.006). MS patients treated with fingolimod had higher LCN2 levels compared to those on natalizumab (r=0.25, p=0.03). Higher NF-L levels associated with clinically isolated syndrome's (CIS) conversion into MS (p=0.002). We conclude that low BDNF and high LCN2 and NF-L levels are associated with MS pathogenesis, and high IGFBP1level is a biomarker for female MS only, suggesting different MS progression pathways between the sexes. LCN2 is a candidate predictor of response to natalizumab treatment, and NF-L is a candidate predictor of CIS conversion into MS.


Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.
With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.


Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder.
Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 × 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.


Factors Associated with Amputation after Popliteal Vascular Injuries.
Popliteal artery trauma has the highest rate of limb loss of all peripheral vascular injuries. The objectives of this study were to evaluate outcomes after popliteal vascular injury and to identify predictors of amputation. Retrospective data over a 14-year period were collected for patients with popliteal artery with or without vein injuries. Patient demographics, mechanism of injury, Injury Severity Score (ISS), Mangled Extremity Severity Score (MESS), and physiologic parameters were extracted. Time to operative intervention, operative time, type of vascular repair, need for concomitant orthopedic procedures, and outcomes including amputation rate, and in-hospital mortality were recorded. Fifty-one patients were found to have popliteal artery injuries, with a median age of 25 (range 10-70 years). The median ISS was 9, and the mean extremity Abbreviated Injury Severity score was 3. The mechanism of injury was blunt for 43% and penetrating for 57%. Fasciotomies were performed in 74% of patients and 64% of patients underwent combined orthopedic and vascular procedures. Overall, 66% of these patients had their vascular procedure performed first. Ten patients required amputation: 1 immediate and 9 after attempted limb salvage (20%). We found that those patients requiring amputation had a higher incidence of blunt trauma (80% vs. 35%, P = 0.014) and higher MESS score (7.1 vs. 4.7, P = 0.02). There was no difference in the incidence of amputation for those who underwent orthopedic fixation before vascular repair (P = 0.68). Popliteal vascular injuries continue to be associated with a high risk of amputation. Those patients undergoing attempted limb salvage should be revascularized expediently, but selected patients may undergo orthopedic stabilization before vascular repair without increased risk of limb loss.


The impact of acute kidney injury on short-term survival in an Eastern European population with stroke.
Stroke is one of the leading causes of death and of serious disability with significant impact on patients' long-term survival. The short-term evolution following stroke can associate acute kidney injury (AKI) as a possible complication, frequently overlooked and underestimated in clinical trials. We aimed to describe in an East European cohort (i) the incidence of AKI and its risk factors; (ii) the 30-day mortality and its risk factors and (iii) the relationship between mortality, pre-existent renal function and subsequent AKI. A total of 1090 consecutive cases hospitalized-during a 12-month period-with a CT-confirmed diagnosis of stroke, from a distinct administrative region were included. Demographic details, comorbidities, laboratory and outcome data were retrieved from the electronic hospital database. All patients included in the study were followed for 30 days or until death. The mean age of this population was 66.1 +/- 11.5 years, 49.3% were males, mean glomerular filtration rate (GFR) 68.9 +/- 22.6 ml/min/1.73 m(2). The 30-day mortality rate was 17.2%. One hundred and fifty-eight patients presented with haemorrhagic stroke and 932 patients had ischaemic stroke. Stroke mortality was-14% for ischaemic stroke and almost twice as high for haemorrhagic stroke-36.3%. One hundred fifty-eight (14.5%) patients were classified as developing AKI. The AKI patients were older, had a higher baseline serum creatinine, lower GFR, higher serum glucose, higher prevalence of chronic heart failure and ischaemic heart disease, were more likely to have suffered a haemorrhagic stroke, and had a significantly higher 30-day mortality rate (43.1 vs 12.8%) (P < 0.05 for all). Independent predictors for AKI development in the logistic regression analysis were age, GFR, presence of comorbidities (ischaemic heart disease and chronic heart failure) and type of stroke (Cox and Snell R(2) 0.244; Nagelkerke R(2) 0.431; P < 0.05). In our study, we demonstrated that the occurrence of AKI is not a rare finding in stroke patients. This is the first study to report the incidence of AKI in a distinct geographic population base, in patients with stroke. Baseline renal function emerged as both a significant independent marker for short-term survival after an acute stroke (even after adjustment for baseline comorbidities) and as a risk factor for subsequent AKI.


Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer.
Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.


In silico screening and molecular dynamics simulation of deleterious PAH mutations responsible for phenylketonuria genetic disorder.
Phenylketonuria (PKU) is a genetic disorder that if left untreated can lead to behavioral problems, epilepsy, and even mental retardation. PKU results from mutations within the phenylalanine-4-hydroxylase (PAH) gene that encodes for the PAH protein. The study of all PAH causing mutations is improbable using experimental techniques. In this study, a collection of in silico resources, sorting intolerant from tolerant, Polyphen-2, PhD-SNP, and MutPred were used to identify possible pathogenetic and deleterious PAH non-synonymous single nucleotide polymorphisms (nsSNPs). We identified two variants of PAH, I65N and L311P, to be the most deleterious and disease causing nsSNPs. Molecular dynamics (MD) simulations were carried out to characterize these point mutations on the atomic level. MD simulations revealed increased flexibility and a decrease in the hydrogen bond network for both mutants compared to the native protein. Free energy calculations using the MM/GBSA approach found that BH4 , a drug-based therapy for PKU patients, had a higher binding affinity for I65N and L311P mutants compared to the wildtype protein. We also identify important residues in the BH4 binding pocket that may be of interest for the rational drug design of other PAH drug-based therapies. Lastly, free energy calculations also determined that the I65N mutation may impair the dimerization of the N-terminal regulatory domain of PAH.


Testing the validity of conflict drift-diffusion models for use in estimating cognitive processes: A parameter-recovery study.
Researchers and clinicians are interested in estimating individual differences in the ability to process conflicting information. Conflict processing is typically assessed by comparing behavioral measures like RTs or error rates from conflict tasks. However, these measures are hard to interpret because they can be influenced by additional processes like response caution or bias. This limitation can be circumvented by employing cognitive models to decompose behavioral data into components of underlying decision processes, providing better specificity for investigating individual differences. A new class of drift-diffusion models has been developed for conflict tasks, presenting a potential tool to improve analysis of individual differences in conflict processing. However, measures from these models have not been validated for use in experiments with limited data collection. The present study assessed the validity of these models with a parameter-recovery study to determine whether and under what circumstances the models provide valid measures of cognitive processing. Three models were tested: the dual-stage two-phase model (Hübner, Steinhauser, & Lehle, Psychological Review, 117(3), 759-784, 2010), the shrinking spotlight model (White, Ratcliff, & Starns, Cognitive Psychology, 63(4), 210-238, 2011), and the diffusion model for conflict tasks (Ulrich, Schröter, Leuthold, & Birngruber, Cogntive Psychology, 78, 148-174, 2015). The validity of the model parameters was assessed using different methods of fitting the data and different numbers of trials. The results show that each model has limitations in recovering valid parameters, but they can be mitigated by adding constraints to the model. Practical recommendations are provided for when and how each model can be used to analyze data and provide measures of processing in conflict tasks.


Aureobasidium pullulans volatilome identified by a novel, quantitative approach employing SPME-GC-MS, suppressed Botrytis cinerea and Alternaria alternata in vitro.
Volatile organic compounds (VOCs) produced by Aureobasidium pullulans were investigated for antagonistic actions against Alternaria alternata and Botrytis cinerea. Conidia germination and colony growth of these two phytopathogens were suppressed by A. pullulans VOCs. A novel experimental setup was devised to directly extract VOCs using solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) from antagonist-pathogen culture headspace. The proposed system is a robust method to quantify microbial VOCs using an internal standard. Multivariate curve resolution-alternating least squares deconvolution of SPME-GC-MS spectra identified fourteen A. pullulans VOCs. 3-Methyl-1-hexanol, acetone, 2-heptanone, ethyl butyrate, 3-methylbutyl acetate and 2-methylpropyl acetate were newly identified in A. pullulans headspace. Partial least squares discriminant analysis models with variable importance in projection and selectivity ratio identified four VOCs (ethanol, 2-methyl-1-propanol, 3-methyl-1-butanol and 2-phenylethanol), with high explanatory power for discrimination between A. pullulans and pathogen. The antifungal activity and synergistic interactions of the four VOCs were evaluated using a Box-Behnken design with response surface modelling. Ethanol and 2-phenylethanol are the key inhibitory A. pullulans VOCs against both B. cinerea and A. alternata. Our findings introduce a novel, robust, quantitative approach for microbial VOCs analyses and give insights into the potential use of A. pullulans VOCs to control B. cinerea and A. alternata.


Early markers of prolonged hospital stay in demented inpatients: a multicentre and prospective study.
Dementia is a serious, chronic, and costly public health problem. Prior studies have described dementia as increasing length of hospital stay, but so far no explanations have been proposed. To identify early markers for prolonged hospital stay in demented elderly inpatients, 178 community-dwelling or institutionalized subjects aged 75+, hospitalized through an emergency department in 9 teaching hospitals in France, were analyzed. Prolonged hospital stays were defined according a limit adjusted for Diagnosis Related Group. All patients underwent a comprehensive geriatric assessment at admission. Logistic regression multifactorial mixed model was performed. Center effect was considered as a random effect. Of the 178 stays, 52 were prolonged. Most concerned community-dwelling patients (86%). Multifactor analysis demonstrated that demographic variables had no influence on the length of stay, while diagnosis of delirium (OR 2.31; 95% CI 1.77 - 2.91), walking difficulties (OR 1.94; 95% CI 1.62 - 2.43) and report by the informal caregiver of moderate or severe burden (OR 1.52; 95% CI 1.19 - 1.86) or low social quality-of-life score (OR 1.25; 95% CI 1.03 - 1.40), according to the Zarit's Burden Inventory short scale (12 items) and the Duke's Health Profile respectively, were identified as early markers for prolonged hospital stays. At the time of the rising incidence of cognitive disorders, these results suggest that preventive approaches might be possible. In a hospital setting as well as in a community-dwelling population, more specific, specialized and coordinated care, using the expertise of multiple disciplines appears as a probable effective measure to limit prolonged hospital stay. Such approaches require (i) clear patient-oriented goal definition, (ii) understanding and appreciation of roles among various health care and social disciplines and, (iii) cooperation between partners in patient's management. However, the cost- and health-effectiveness of such approaches should be evaluated.


Identification of the Genome Segments of Bluetongue Virus Serotype 26 (Isolate KUW2010/02) that Restrict Replication in a Culicoides sonorensis Cell Line (KC Cells).
Bluetongue virus (BTV) can infect most ruminant species and is usually transmitted by adult, vector-competent biting midges (Culicoides spp.). Infection with BTV can cause severe clinical signs and can be fatal, particularly in naïve sheep and some deer species. Although 24 distinct BTV serotypes were recognized for several decades, additional 'types' have recently been identified, including BTV-25 (from Switzerland), BTV-26 (from Kuwait) and BTV-27 from France (Corsica). Although BTV-25 has failed to grow in either insect or mammalian cell cultures, BTV-26 (isolate KUW2010/02), which can be transmitted horizontally between goats in the absence of vector insects, does not replicate in a Culicoides sonorensis cell line (KC cells) but can be propagated in mammalian cells (BSR cells). The BTV genome consists of ten segments of linear dsRNA. Mono-reassortant viruses were generated by reverse-genetics, each one containing a single BTV-26 genome segment in a BTV-1 genetic-background. However, attempts to recover a mono-reassortant containing genome-segment 2 (Seg-2) of BTV-26 (encoding VP2), were unsuccessful but a triple-reassortant was successfully generated containing Seg-2, Seg-6 and Seg-7 (encoding VP5 and VP7 respectively) of BTV-26. Reassortants were recovered and most replicated well in mammalian cells (BSR cells). However, mono-reassortants containing Seg-1 or Seg-3 of BTV-26 (encoding VP1, or VP3 respectively) and the triple reassortant failed to replicate, while a mono-reassortant containing Seg-7 of BTV-26 only replicated slowly in KC cells.


NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham Study.
To determine if NIDDM and blood pressure are risk factors for poor cognitive performance and if history and duration of NIDDM and blood pressure interact such that the risk of poor performance is greater for subjects with both NIDDM and hypertension. We used a large prospective cohort sample with 187 NIDDM subjects and 1,624 nondiabetic subjects who were followed for 28-30 years. Cognitive function was assessed using eight tests of learning, memory, visual organization, verbal fluency attention, concept formation, and abstract reasoning. A composite score was also calculated. Odds ratios were used to estimate the relative risk of performing below the lower 25th percentile of z scores on these tests. NIDDM and blood pressure interacted such that diagnosis and duration of NIDDM were associated with greater risk of poor performance on tests of visual memory and on the composite score for hypertensive subjects. Duration of NIDDM was associated with increased risk for poor performance on tests of verbal memory and concept formation. Insulin-treated NIDDM subjects were at higher risk for poor cognitive performance than those NIDDM subjects treated with oral agents or diet. Blood pressure level was associated independently with a measure of verbal fluency. History and duration of NIDDM and high blood pressure are significant risk factors for poor cognitive performance. Hypertensive people with NIDDM are at greatest risk for poor performance on tests measuring visual organization and memory.


Policies and Guidelines for COVID-19 Preparedness: Experiences from the University of Washington.
The coronavirus disease 2019 (COVID-19) pandemic initially manifested in the United States in the greater Seattle area and has rapidly progressed across the nation in the past 2 months, with the United States having the highest number of cases in the world. Radiology departments play a critical role in policy and guideline development both for the department and for the institutions, specifically in planning diagnostic screening, triage, and management of patients. In addition, radiology workflows, volumes, and access must be optimized in preparation for the expected surges in the number of patients with COVID-19. In this article, the authors discuss the processes that have been implemented at the University of Washington in managing the COVID-19 pandemic as well in preparing for patient surges, which may provide important guidance for other radiology departments who are in the early stages of preparation and management.


Longer-Term Physiological and Metabolic Effects of Gastric Bypass Surgery.
Obesity is closely associated with the development of type 2 diabetes. Many strategies have been used in the past to combat these two conditions, but very few provide for stable and durable glycemic control. Bariatric surgery has emerged as a powerful tool for treating obesity and in over 70 % of cases provides a short-term cure for diabetes. While the acute metabolic effects of surgery are striking, it remains important for us to also consider the long-term effects. This review aims to summarize the chronic or long-term metabolic and physiological effects of Roux-en-Y gastric bypass (RYGB) surgery on pancreatic function, skeletal muscle and hepatic insulin sensitivity, and gastrointestinal remodeling. An increased understanding of the current state of research in these areas can provide the basis for stimulating further research that would contribute to new treatment and management strategies for obesity and diabetes.


Deep femoral to anterior tibial bypass after failed femoropopliteal reconstructions.
Deep femoral to anterior tibial artery bypass is a reconstructive technique occasionally applicable when more conventional attempts at revascularization of the distal portion of the leg have failed. Three such patients, in whom the anterior tibial was the only distal patent branch of the popliteal artery, had severe symptoms of arterial insufficiency. Deep femoral to anterior tibial bypass was done using autogenous The distal portion of the deep femoral artery was exposed through an anteromedial distal thigh approach. The three patients have been followed up for a mean of 20.3 months, and each maintains graft patency and marked symptomatic improvement.


NECTIN4 Expression in Extramammary Paget's Disease: Implication of a New Therapeutic Target.
Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the anogenital area. Most EMPD tumors remain dormant as in situ lesions, but the outcomes of patients with metastatic EMPD are poor because of the lack of effective systemic therapies. Nectin cell adhesion molecule 4 (NECTIN4) has attracted attention as a potential therapeutic target for some cancers. Urothelial cancer is one such cancer, and clinical trials of enfortumab vedotin, a drug-conjugated anti-NECTIN4 antibody, are ongoing. However, little is known regarding the role of NECTIN4 in EMPD. In this study, we conducted immunohistochemical analysis of NECTIN4 expression in 110 clinical EMPD samples and normal skin tissue. In normal skin, positive signals were observed in epidermal keratinocytes (particularly in the lower part of the epidermis), eccrine and apocrine sweat glands, inner and outer root sheaths, and matrix of the hair follicles. The most EMPD lesions exhibited strong NECTIN4 expression, and high NECTIN4 expression was significantly associated with increased tumor thickness, advanced TNM stage, and worse disease-specific survival. These results support the potential use of NECTIN4-targeted therapy for EMPD. Our report contributes to the better understanding of the pathobiology of NECTIN4 in the skin and the skin-related adverse effects of NECTIN4-targeted therapy.


Characterization of increased mucus production of HT29-MTX-E12 cells grown under Semi-Wet interface with Mechanical Stimulation.
The intestinal mucus layer plays a crucial role in human health. To study intestinal mucus function and structure in vitro, the mucus-producing intestinal cell line HT29-MTX-E12 has been commonly used. However, this cell line produces only low amounts of the intestine-specific MUC2. It has been shown previously that HT29-MTX-E12 cells cultured under Semi-Wet interface with Mechanical Stimulation (SWMS) produced higher amounts of MUC2, concomitant with a thicker mucus layer, compared to cells cultured conventionally. However, it remains unknown which underlying pathways are involved. Therefore, we aimed to further explore the cellular processes underlying the increased MUC2 production by HT29-MTX-E12 cells grown under SWMS conditions. Cells grown on Transwell membranes for 14 days under static and SWMS conditions (after cell seeding and attachment) were subjected to transcriptome analysis to investigate underlying molecular pathways at gene expression level. Caco-2 and LS174T cell lines were included as references. We characterized how SWMS conditions affected HT29-MTX-E12 cells in terms of epithelial barrier integrity, by measuring transepithelial electrical resistance, and cell metabolism, by monitoring pH and lactate production per molecule glucose of the conditioned medium. We confirmed higher MUC2 production under SWMS conditions at gene and protein level and demonstrated that this culturing method primarily stimulated cell growth. In addition, we also found evidence for a more aerobic cell metabolism under SWMS, as shown previously for similar models. In summary, we suggest different mechanisms by which MUC2 production is enhanced under SWMS and propose potential applications of this model in future studies.


Marginal zone lymphomas: factors that affect the final outcome.
A retrospective review and analysis of 275 patients with marginal zone lymphoma (MZL) was performed to determine prognostic factors. An effort was also made to establish a specific prognostic score for patients with extranodal MZL. Patients were divided into 3 groups according to the type of MZL: extranodal, nodal, and splenic. Factors analyzed included age; gender; presence of B symptoms; Zubrod performance score; clinical stage; serum β(2)-microglobulin, lactate dehydrogenase, albumin, and hemoglobin levels; and presence of autoimmune disorder. The 5-year overall survival rates of patients with extranodal, nodal, and splenic MZL were 87%, 89%, and 93%, respectively (P = .95). On multivariate analysis, splenic MZL patients had the best prognosis (hazard ratio, 0.18; P = .018). An elevated serum β(2)-microglobulin level (P = .010), B symptoms (P = .021), and male gender (P = .036) were found to be correlated with decreased recurrence-free survival (RFS) on multivariate analysis. Using these 3 variables, a 3-tier prognostic scoring system was created for patients with extranodal MZL: low-risk with no adverse factors, intermediate-risk with 1 adverse factor, and high-risk with ≥ 2 adverse factors. The 5-year RFS rates for the low-risk, intermediate-risk, and high-risk groups were 80%, 71%, and 44%, respectively (P = .01). Patients with extranodal and nodal MZL have a similar prognosis, whereas patients with splenic MZL have a better prognosis despite the increased prevalence of negative prognostic indicators. With the use of 3 readily available factors, a prognostic scoring system was identified for patients with extranodal MZL.


Sensory Modality-Independent Activation of the Brain Network for Language.
The meaning of a sentence can be understood, whether presented in written or spoken form. Therefore, it is highly probable that brain processes supporting language comprehension are at least partly independent of sensory modality. To identify where and when in the brain language processing is independent of sensory modality, we directly compared neuromagnetic brain signals of 200 human subjects (102 males) either reading or listening to sentences. We used multiset canonical correlation analysis to align individual subject data in a way that boosts those aspects of the signal that are common to all, allowing us to capture word-by-word signal variations, consistent across subjects and at a fine temporal scale. Quantifying this consistency in activation across both reading and listening tasks revealed a mostly left-hemispheric cortical network. Areas showing consistent activity patterns included not only areas previously implicated in higher-level language processing, such as left prefrontal, superior and middle temporal areas, and anterior temporal lobe, but also parts of the control network as well as subcentral and more posterior temporal-parietal areas. Activity in this supramodal sentence-processing network starts in temporal areas and rapidly spreads to the other regions involved. The findings indicate not only the involvement of a large network of brain areas in supramodal language processing but also that the linguistic information contained in the unfolding sentences modulates brain activity in a word-specific manner across subjects.SIGNIFICANCE STATEMENT The brain can extract meaning from written and spoken messages alike. This requires activity of both brain circuits capable of processing sensory modality-specific aspects of the input signals as well as coordinated brain activity to extract modality-independent meaning from the input. Using traditional methods, it is difficult to disentangle modality-specific activation from modality-independent activation. In this work, we developed and applied a multivariate methodology that allows for a direct quantification of sensory modality-independent brain activity, revealing fast activation of a wide network of brain areas, both including and extending beyond the core network for language.


Plastid translation and transcription genes in a non-photosynthetic plant: intact, missing and pseudo genes.
The non-photosynthetic, parasitic flowering plant Epifagus virginiana has recently been shown to contain a grossly reduced plastid genome that has lost many photosynthetic and chloro-respiratory genes. We have cloned and sequenced a 3.9 kb domain of plastid DNA from Epifagus to investigate the patterns of evolutionary change in such a reduced genome and to determine which genes are still present and likely to be functional. This 3.9 kb domain is colinear with a 35.4 kb region of tobacco chloroplast DNA, differing from it by a minimum of 11 large deletions varying in length from 354 bp to 11.5 kb, as well as by a number of small deletions and insertions. The nine genes retained in Epifagus encode seven tRNAs and two ribosomal proteins and are coextensive and highly conserved in sequence with homologs in photosynthetic plants. This suggests that these genes are functional in Epifagus and, together with evidence that the Epifagus plastid genome is transcribed, implies that plastid gene products play a role in processes other than photosynthesis and gene expression. Genes that are completely absent include not only photosynthetic genes, but surprisingly, genes encoding three subunits of RNA polymerase, four tRNAs and one ribosomal protein. In addition, only pseudogenes are found for two other tRNAs. Despite these defunct tRNA genes, codon and amino acid usage in Epifagus protein genes is normal. We therefore hypothesize that the expression of plastid genes in Epifagus relies on the import of nuclear encoded tRNAs and RNA polymerase from the cytoplasm.


A sensor histidine kinase from a plant-endosymbiont bacterium restores the virulence of a mammalian intracellular pathogen.
Alphaproteobacteria include organisms living in close association with plants or animals. This interaction relies partly on orthologous two-component regulatory systems (TCS), with sensor and regulator proteins modulating the expression of conserved genes related to symbiosis/virulence. We assessed the ability of the exoS+Sm gene, encoding a sensor protein from the plant endosymbiont Sinorhizobium meliloti to substitute its orthologous bvrS in the related animal/human pathogen Brucella abortus. ExoS phosphorylated the B. abortus regulator BvrR in vitro and in cultured bacteria, showing conserved biological function. Production of ExoS in a B. abortus bvrS mutant reestablished replication in host cells and the capacity to infect mice. Bacterial outer membrane properties, the production of the type IV secretion system VirB, and its transcriptional regulators VjbR and BvrR were restored as compared to parental B. abortus. These results indicate that conserved traits of orthologous TCS from bacteria living in and sensing different environments are sufficient to achieve phenotypic plasticity and support bacterial survival. The knowledge of bacterial genetic networks regulating host interactions allows for an understanding of the subtle differences between symbiosis and parasitism. Rewiring these networks could provide new alternatives to control and prevent bacterial infection.