Differences Between the Prenatal Effects of Fluoxetine or Buspirone Alone or in Combination on Pain and Affective Behaviors in Prenatally Stressed Male and Female Rats.
The selective serotonin reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone are used to treat depression and anxiety. Previously we demonstrated that chronic stress during pregnancy (prenatal stress) in rats, used as a model of maternal depression risk, increased inflammatory pain and depressive-like behavior in the offspring; buspirone injected to pregnant dams was protective. Clinically, the addition of buspirone to fluoxetine increases the latter's efficacy in treating depression in patients. Here, we investigated the influence of repeated prenatal injections of fluoxetine, buspirone or their combination on pain- and depressive-like behaviors in prenatally stressed young male and female rats. Prenatal stress augmented depressive-like behavior and both thermal and inflammatory pain (formalin test), replicating our prior findings, and increased basal levels of corticosterone in the blood plasma. Both drugs and their combination reduced the effects of prenatal stress on thermal pain and depressive-like behavior independently of sex. The combination of fluoxetine and buspirone, compared with fluoxetine, was more antinociceptive in the hot plate test in both sexes, and when compared with buspirone, was more antinociceptive only in males. A detailed study of the time-course of formalin-induced pain showed a nuanced effect of these drugs that was sex-dependent. The combination of the two drugs was less effective in females than males during the initial acute phase of nociceptive behavior in flexing + shaking behaviors, whereas that combination was more effective than fluoxetine alone in the first acute phase of licking behavior in females. The antinociceptive effect of buspirone dominated that of the drug combination and of fluoxetine alone, especially during the interphase of the formalin test in both sexes for both flexing + shaking and licking, suggesting a more effective prenatal action of buspirone on the development of a descending serotonergic inhibitory system modulating pain in the spinal cord dorsal horn neurons. Our results indicate that inflammatory pain-like responses integrated at the spinal level in males were more vulnerable to prenatal stress than females. In licking, the antinociceptive effect of fluoxetine and drug combination in the interphase was more in males than females. The data underscore the importance of considering sexual dimorphism when using drug therapy.


5-Hydroxyindole-Based EZH2 Inhibitors Assembled via TCCA-Catalyzed Condensation and Nenitzescu Reactions.
5-Hydroxyindole derivatives have various demonstrated biological activities. Herein, we used 5-hydroxyindole as a synthetic starting point for structural alterations in a combinatorial process to synthesize 22 different compounds with EZH2 inhibitor pharmacophores. A series of 5-hydroxyindole-derived compounds were screened inhibitory activities against K562 cells. According to molecular modeling and in vitro biological activity assays, the preliminary structure-activity relationship was summarized. Compound L-04 improved both the H3K27Me3 reduction and antiproliferation parameters (IC50 = 52.6 μM). These findings revealed that compound L-04 is worthy of consideration as a lead compound to design more potent EZH2 inhibitors. During the preparation of compounds, we discovered that trichloroisocyanuric acid (TCCA) is a novel catalyst which demonstrates condensation-promoting effects. To gain insight into the reaction, in situ React IR technology was used to confirm the reactivity. Different amines were condensed in high yields with β-diketones or β-ketoesters in the presence of TCCA to afford the corresponding products in a short time (10~20 min), which displayed some advantages and provided an alternative condensation strategy.


Abnormality of circulatory reflex and aldosterone response during head-up tilting in patients with primary aldosteronism.
Abnormality of the circulatory reflexes has been reported in patients with primary aldosteronism. However, changes in blood pressure, heart rate, plasma renin activity (PRA), and plasma aldosterone concentration (PAC) after head-up tilting in primary aldosteronism have not yet been reported. Seven patients with primary aldosteronism were tilted to a 65 degree head-up position which was maintained for 30 min. Systolic blood pressure decreased significantly 5 min after tilting and remained at this level during the period of tilting. Diastolic blood pressure did not change during the tilting. Heart rate increased after 5 min of tilting and this level of heart rate was maintained for 30 min. Plasma renin activity was low and did not change during tilting. However, plasma aldosterone concentration increased significantly 20 min after tilting. Plasma cortisol concentration and plasma ACTH concentration also increased significantly. These results suggest that primary aldosteronism causes abnormalities of the circulatory reflexes. The increase of endogenous ACTH may increase plasma aldosterone concentration in patients with primary aldosteronism.


Immune monitoring of SARS-CoV-2-specific T cell and B cell responses in patients with multiple sclerosis treated with ocrelizumab.
Since the development of the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there has been significant interest in determining the effectiveness of SARS-CoV-2 vaccines in patients under immunomodulatory or immunosuppressive therapies. The aim of this study was to evaluate the impact of ocrelizumab, a monoclonal anti-CD20 antibody, on SARS-CoV-2-specific T cell and B cell responses in patients with relapsing-remitting multiple sclerosis (RRMS). To this end, peripheral blood mononuclear cells (PBMCs) were isolated from n = 23 patients with RRMS. Of these patients, n = 17 were tested before (time point t0) and one month after (time point t1) their first dose of ocrelizumab. In addition, we studied n = 9 RRMS patients that got infected with SARS-CoV-2 over the course of ocrelizumab therapy (time point t2). PBMCs were also isolated from n = 19 age- and gender-matched healthy controls (HCs) after vaccination or infection with SARS-CoV-2, respectively. Interferon-γ (IFN-γ)/interleukin-2 (IL-2) and granzyme B (GzB)/perforin (PFN) double-color enzyme-linked immunospot (ELISPOT) assays or single-color ELISPOT assays were performed to measure SARS-CoV-2 antigen-specific T cell and B cell responses. Anti-viral antibody titers were quantified in the serum by chemiluminescence immunoassay. Our data indicate a significant difference in the SARS-CoV-2 specific IFN-γ (P = 0.0119) and PFN (P = 0.0005) secreting T cell compartment in the MS cohort at t0 compared to HCs. Following the first dose of ocrelizumab treatment, a significant decrease in the number of SARS-CoV-2 spike protein-specific B cells was observed (P = 0.0012). Infection with SARS-CoV-2 in MS patients under ocrelizumab therapy did not significantly alter their existing immune response against the virus. Kaplan-Meier survival analysis suggested that the spike S1 protein-specific immunoglobulin (Ig)G response might be a key parameter for predicting the probability of (re)infection with SARS-CoV-2. Our results call for a critical discussion regarding appropriate vaccination intervals and potential biomarkers for the prediction of (re)infection with SARS-CoV-2 in patients with MS receiving ocrelizumab. DRKS00029110; URL: http://apps.who.int/trialsearch/.


Gas exchange, rumen hydrogen sinks, and nutrient digestibility and metabolism in lactating dairy cows fed 3-NOP and cracked rapeseed.
Fat in the form of cracked rapeseed and 3-nitrooxypropanol (3-NOP, market as Bovaer®) were fed alone or in combination to 4 Danish Holstein multi-cannulated dairy cows, with the objective to investigate effects on gas exchange, dry matter intake (DMI), nutrient digestion, and nutrient metabolism. The study design was a 4 × 4 Latin square with a 2 × 2 factorial treatment arrangement with 2 levels of fat supplementation; 33 g crude fat/kg of dry matter (DM) or 64 g crude fat/kg of DM for low and high fat diets, respectively, and 2 levels of 3-NOP; 0 mg/kg of DM or 80 mg/kg of DM. In total, 4 diets were formulated: low fat (LF), high fat (HF), 3-NOP and low fat (3LF), and 3-NOP and high fat (3HF). Cows were fed ad libitum and milked twice daily. The adaptation period lasted 11 d, followed by 5 d with 12 diurnal sampling times of digesta and ruminal fluid. Thereafter, gas exchange was measured for 5 d in respiration chambers. Chromic oxide and titanium dioxide were used as external flow markers to determine intestinal nutrient flow. No interactions between fat supplementation and 3-NOP were observed for methane yield (g/kg of DM), total-tract digestibility of nutrients or total volatile fatty acid (VFA) concentration in the rumen. Methane yield (g/kg of DMI) was decreased by 24% when cows were fed 3-NOP. In addition, 3-NOP increased carbon dioxide and hydrogen yield (g/kg of DM) by 6% and 3,500%, respectively; However, carbon dioxide production was decreased when expressed on a daily basis. Fat supplementation did not affect methane yield but tended to reduce methane in percent of gross energy intake. A decrease (11%) in DMI was observed, when cows were fed 3-NOP. Likely, the lower DMI mediated a lower passage rate causing the tendency to higher rumen and total-tract neutral detergent fiber digestibility, when the cows were fed 3-NOP. Total VFA concentrations in the rumen were negatively affected both by 3-NOP and fat supplementation. Furthermore, 3-NOP caused a shift in the VFA fermentation profile, with decreased acetate proportion and increased butyrate proportion, whereas propionate proportion was unaffected. Increased concentrations of the alcohols methanol, ethanol, propanol, butanol, and 2-butanol were observed in the ruminal fluid when cows were fed 3-NOP. These changes in rumen metabolites indicate partial re-direction of hydrogen into other hydrogen sinks, when methanogenesis is inhibited by 3-NOP. In conclusion, fat supplementation did not reduce methane yield, whereas 3-NOP reduced methane yield, irrespective of fat level. However, the concentration of 3-NOP and diet composition and resulting desired mitigation effect must be considered before implementation. The observed reduction in DMI with 80 mg 3-NOP/kg DM was intriguing and may indicate that a lower dose should be applied in a Northern European context; however, the mechanism behind needs further investigation.


Connectome-Based Biomarkers Predict Subclinical Depression and Identify Abnormal Brain Connections With the Lateral Habenula and Thalamus.
Subclinical depression (SD) has been considered as the precursor to major depressive disorder. Accurate prediction of SD and identification of its etiological origin are urgent. Bursts within the lateral habenula (LHb) drive depression in rats, but whether dysfunctional LHb is associated with SD in human is unknown. Here we develop connectome-based biomarkers which predict SD and identify dysfunctional brain regions and connections. T1 weighted images and resting-state functional MRI (fMRI) data were collected from 34 subjects with SD and 40 healthy controls (HCs). After the brain is parcellated into 48 brain regions (246 subregions) using the human Brainnetome Atlas, the functional network of each participant is constructed by calculating the correlation coefficient for the time series of fMRI signals of each pair of subregions. Initial candidates of abnormal connections are identified by the two-sample t-test and input into Support Vector Machine models as features. A total of 24 anatomical-region-based models, 231 sliding-window-based models, and 100 random-selection-based models are built. The performance of these models is estimated through leave-one-out cross-validation and evaluated by measures of accuracy, sensitivity, confusion matrix, receiver operating characteristic curve, and the area under the curve (AUC). After confirming the region with the highest accuracy, subregions within the thalamus and connections associated with subregions of LHb are compared. It is found that five prediction models using connections of the thalamus, posterior superior temporal sulcus, cingulate gyrus, superior parietal lobule, and superior frontal gyrus achieve an accuracy >0.9 and an AUC >0.93. Among 90 abnormal connections associated with the thalamus, the subregion of the right posterior parietal thalamus where LHb is located has the most connections (n = 18), the left subregion only has 3 connections. In SD group, 10 subregions in the thalamus have significantly different node degrees with those in the HC group, while 8 subregions have lower degrees ( p < 0.01), including the one with LHb. These results implicate abnormal brain connections associated with the thalamus and LHb to be associated with SD. Integration of these connections by machine learning can provide connectome-based biomarkers to accurately diagnose SD.


Study of the factors causing medical disputes in a Third-Level Grade A Hospital in Shanghai.
By analyzing cases of medical disputes occurred in one of top hospitals in Shanghai from 2012 to 2014, the paper tries to determine the causes and cures of the disputes based on relevant national and international experience. A cluster sample of medical disputes occurred in the hospital from 2012 to 2014 was selected, to which logistic regression analysis was applied in order to determine the factors causing medical disputes. Inadequate experience in dealing with unexpected incidents (P = 0.002), violation of routine procedures for diagnosis and treatment (P = 0.004), and therapeutic effects (P = 0.007) were found to be statistically significant. Medical disputes in the hospital would be substantially reduced by taking such measures as strengthening trainings on how to deal with unexpected incidents for medical staff, standardizing procedures for clinical practices, and improving the therapeutic effects of various diseases.


A general model for aerobic yeast growth: batch growth.
A general model for aerobic yeast growth in batch culture is presented. It is based on the concept that the aerobic metabolism of all yeasts is determined by the relative sizes of the transport rate of sugar into the cell and the transport rate of respiratory intermediates into the mitochondrion. If the rate of sugar uptake rate exceeds the rate of transport of respiratory intermediates into the mitochondrion (as in Saccharomyces cerevisiae, S. uvarum, and S. pombe), the metabolism exhibits the features of ethanol excretion and limited specific oxygen uptake rate. If the rate of transport of respiratory intermediates into the mitochondrion is of the same order as the transport of sugar into the cell (as in Candida utilis), the metabolism is characterized by little or no ethanol excretion and a much higher specific oxygen uptake rate. Batch data from an extensive range of yeast and carbon sources is used to illustrate the use of this model. The ability of this model to fit such an extensive range of experimental data suggests that it can be used as a generalized model for aerobic yeast growth.


A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion.
SLC30A8 encodes the β-cell-specific zinc transporter-8 (ZnT-8) expressed in insulin secretory granules. The single-nucleotide polymorphism rs13266634 of SLC30A8 is associated with susceptibility to post-transplantation diabetes mellitus (PTDM). We tested the hypothesis that the polymorphic residue at position 325 of ZnT-8 determines the susceptibility to cyclosporin A (CsA) suppression of insulin secretion. INS (insulinoma)-1E cells expressing the W325 variant showed enhanced glucose-stimulated insulin secretion (GSIS) and were less sensitive to CsA suppression of GSIS. A reduced number of insulin granule fusion events accompanied the decrease in insulin secretion in CsA-treated cells expressing ZnT-8 R325; however, ZnT-8 W325-expressing cells exhibited resistance to the dampening of insulin granule fusion by CsA, and transported zinc ions into secretory vesicles more efficiently. Both tacrolimus and rapamycin caused similar suppression of GSIS in cells expressing ZnT-8 R325. However, cells expressing ZnT-8 W325 were resistant to tacrolimus, but not to rapamycin. The Down's syndrome candidate region-1 (DSCR1), an endogenous calcineurin inhibitor, overexpression and subsequent calcineurin inhibition significantly reduced GSIS in cells expressing the R325 but not the W325 variant, suggesting that differing susceptibility to CsA may be due to different interactions with calcineurin. These data suggest that the ZnT-8 W325 variant is protective against CsA-induced suppression of insulin secretion. Tolerance of ZnT-8 W325 to calcineurin activity may account for its protective effect in PTDM.


Synaptically released zinc gates long-term potentiation in fear conditioning pathways.
The functional role of releasable Zn2+ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn2+ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn2+ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn2+ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn2+, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.


Improving quality measures in colonoscopy and its therapeutic intervention.
Colonoscopy with polypectomy has been shown to reduce the risk of colon cancer. The critical element in the quality of colonoscopy in terms of polyp detection and removal continues to be the performance of the endoscopist, independent of patient-related factors. Improved results in terms of polyp detection and complete removal have implications regarding the development of screening and surveillance intervals and the reduction of interval cancers after negative colonoscopy. Advances in colonoscopy techniques such as high-definition colonoscopy, hood-assisted colonoscopy and dye-based chromoendoscopy have improved the detection of small and flat-type colorectal polyps. Virtual chromoendoscopy has not proven to improve polyp detection but may be useful to predict polyp pathology. The majority of polyps can be removed endoscopically. Available polypectomy techniques include cold forceps polypectomy, cold snare polypectomy, conventional polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection. The preferred choice depends on the polyp size and characteristics. Other useful techniques include colonoscopic hemostasis for acute colonic diverticular bleeding, endoscopic decompression using colonoscopic stenting, and transanal tube placement for colorectal obstruction. Here we review the current knowledge concerning the improvement of quality measures in colonoscopy and colonoscopy-related therapeutic interventions.


Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno-associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy. These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.


[Supra-systolic elevation of the intra-cavernous pressure secondary to stimulation of the glans penis].
The role of the perineal muscles in human penile erections is still controversial. The authors investigated surface electromyographic activity of the ischiocavernous muscles together with intracavernous pressure recordings during pressure stimulations of the glans penis. Successive glans stimulations were associated with ischiocavernous muscle contractions and increases in intracavernous pressure reaching two- to fourfold the systolic blood pressure. High correlation coefficients were found between electromyographic and intracavernous pressure amplitudes. Voluntary contractions were accompanied by intracavernous pressure peaks of similar durations, and areas delineated by integrated electromyographic and intracavernous pressure curves showed very high correlation coefficients. Anaesthesia of the dorsal nerve resulted in dramatic reductions of muscle activity and intracavernous pressures in response to glans stimulation. These results suggest that the activity of the muscles in response to pressure stimulation of the glans penis is important to augment rigidity during vaginal penetration and intercourse due to their ability to increase intracavernous pressures.


The emotional distress of children with cancer in China: an item response analysis of C-Ped-PROMIS Anxiety and Depression short forms.
The pediatric patient-reported outcomes measurement information system (PROMIS) was developed to provide self-reported item banks and short forms for children and adolescents (aged 8-17 years) experiencing a chronic illness to assess their quality of life and symptoms. The pediatric PROMIS short forms have been translated into Chinese and applied in children with cancer in China. This study aimed to describe psychometric properties of the Anxiety and Depression measures. A total of 232 children and adolescents with cancer were recruited in hospital-based inpatient and outpatient clinics. Eight Chinese versions of pediatric PROMIS (C-Ped-PROMIS) measures were administered. Categorical confirmatory factor analysis (CCFA) were conducted to evaluate scale dimensionality and item local dependence of the C-Ped-PROMIS Anxiety and Depression items. Multiple indicator multiple cause models were used to analyze differential item functioning (DIF), item response theory parameters were calculated, and test information against T scores was reported for each measure. The results of the CCFA confirmed that both C-Ped-PROMIS Anxiety and Depression scales appropriately measure the theoretical constructs as designed. No significant DIF was found for the items of the two scales according to age and gender. Both scales have high test reliability as long as their T scores are not on the low or high extremes. The pediatric PROMIS Anxiety and Depression measures were developed to provide efficient and flexible assessment of emotional distress domains. Our results provide evidence that the two C-Ped-PROMIS measures can be readily applied to measure anxious and depressive symptoms in Chinese children with cancer.


NOTCH1 intracellular domain immunohistochemistry as a diagnostic tool to distinguish T-lymphoblastic lymphoma from thymoma.
Distinction between lymphocyte-rich thymoma and T-lymphoblastic lymphoma/leukemia (T-LBL) can be problematic because of a predominance of precursor T cells in both, particularly if the epithelial component in a thymoma is undersampled. Because of very different clinical implications, accurate diagnosis is critical. The NOTCH1 signaling pathway is frequently activated in T-LBL and plays a central role in the pathogenesis of this disease. Antibodies to NOTCH1 intracellular domain (N1ICD), recognizing the active form of NOTCH1, have been developed. We hypothesized that detection of N1ICD would be useful in distinguishing T-LBL from thymoma and investigated a series of formalin-fixed, paraffin-embedded tissues for immunoreactivity with an N1ICD antibody using automated immunohistochemistry. Slides were scored using a 25% nuclear reactivity threshold for positivity. Hyperplastic tonsil showed positivity in few scattered interfollicular lymphoid cells, suprabasilar epithelial cells, and endothelial cells. Thymocytes from non-neoplastic thymus were largely negative for N1ICD. All thymomas tested (n=23) were negative for N1ICD, although epithelial cells and a small minority of thymocytes may be positive, requiring careful interpretation. All T-LBL cases (n=16) were scored positive for N1ICD: 8 (50%) of these showed diffuse and mostly strong immunoreactivity, whereas the remaining 8 (50%) had less extensive positivity, but with consistently >25% nuclear staining. In conclusion, normal thymocytes do not express significant levels of N1ICD. In keeping with this pattern, thymomas are negative for N1ICD, whereas a high percentage of T-LBL expresses N1ICD. Thus, N1ICD immunohistochemistry appears to be a useful method in distinguishing T-LBL from thymoma.


Rapidly progressive necrotizing fasciitis caused by Staphylococcus aureus.
Necrotizing fasciitis (NF) is a rapidly progressive life-threatening infection located in the deep fascia, with secondary necrosis of the subcutaneous tissues. Staphylococcus aureus as a single etiologic agent is rare. The pathogenicity of S. aureus infections is related to various bacterial surface components and extracellular proteins. A 56-year-old man developed fever, hypotension, impaired renal and hepatic functions, disseminated intravascular coagulation, and rapidly progressive NF affecting the 4 extremities due to methicillin-susceptible S. aureus (MSSA). The initial presenting symptoms were general weakness and muscular pain over bilateral thighs and left shoulder, and gradual onset of weakness of the limbs. On the third hospital day, multiple red-purplish discoloration spread across the right lower leg and left forearm. Fasciotomy and debridement was performed on the fifth hospital day, and the diagnosis of NF was confirmed. MSSA was the only pathogen isolated from 4 sets of blood cultures taken on admission and cultures of tissues collected during surgical debridement. The disease progressed rapidly over the 4 extremities despite appropriate antibiotic treatment. He recovered after multiple extensive surgical interventions and 8 weeks of intensive medical care. Early diagnosis, intensive surgical intervention, antibiotic treatment and intensive medical care are crucial for a successful outcome in patients with septic shock and extensive NF caused by S. aureus.


Increasing dietary EPA and DHA influence estimated fatty acid desaturase activity in systemic organs which is reflected in the red blood cell in mice.
Delta-5 (D5D) and delta-6 (D6D) desaturase are key enzymes in fatty acid (FA) metabolism. Dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may alter tissue FA composition via D5D and D6D. The purpose was to determine the relationship between dietary EPA + DHA, estimated desaturase activities of various tissues and the reflection of desaturase activity in the red blood cell (RBC). Mice were fed diets with increasing percent of energy from EPA + DHA. Phospholipid FA composition of heart, muscle, spleen, lung, adipose tissues and RBC were analysed. D5D and D6D enzyme activity estimates (EAE) were calculated as the ratio of 20:4/20:3 and 20:3/18:2, respectively. D5D EAE decreased in all tissues, except muscle, with increasing dietary EPA + DHA. RBC D5D EAE positively correlated with D5D EAE in all tissues. RBC D6D EAE positively correlated with muscle and inversely correlated with adipose D6D EAE. Our findings suggest differential influence of dietary EPA + DHA upon tissue desaturase activities.


Sjogren's syndrome related autoimmune encephalopathy presenting as depression and involuntary agitation in a 15-year-old girl: a case report.
Sjogren's syndrome is an autoimmune disease that commonly involves exocrinopathy. Although studies have reported psychiatric manifestations resulting from Sjogren's syndrome, few studies have focused on such manifestations in pediatric patients. Herein, we present a case of an adolescent girl with depression and involuntary self-harm behaviors related to Sjogren's syndrome with central nervous system involvement. A 15-year-old girl, with an underlying history of epilepsy, developed depressive symptoms of a year's duration, accompanied by three seizure episodes and involuntary self-harm behaviors. The self-harm behaviors, which included head banging and arm scratching, were sudden onset, involuntary, and unable to be recalled afterwards. After admission to our ward, the patient was positive for serum antinuclear antibodies and Schirmer's test. Moreover, 24-hour electroencephalography revealed epileptiform discharges during the mood swing episodes. Positive findings for antinuclear antibodies and anti-SSA antibodies in both serum and cerebrospinal fluid, suggested central nervous system involvement in Sjogren's syndrome. After rituximab treatment, her mood became euthymic, and her involuntary self-harm behaviors ceased. Central nervous system involvement leading to psychiatric presentations has rarely been reported in adolescents with Sjogren's syndrome. When treating adolescent patients with involuntary self-harm behaviors and neurological symptoms, it is crucial to consider autoimmune encephalitis related to Sjogren's syndrome in the differential diagnosis.


Defect detection in slab surface: a novel dual Charge-coupled Device imaging-based fuzzy connectedness strategy.
To provide an accurate surface defects inspection system and make the automation of robust image segmentation method a reality in routine production line, a general approach is presented for continuous casting slab (CC-slab) surface defects extraction and delineation. The applicability of the system is not tied to CC-slab exclusively. We combined the line array CCD (Charge-coupled Device) traditional scanning imaging (LS-imaging) and area array CCD laser three-dimensional (3D) scanning imaging (AL-imaging) strategies in designing the system. Its aim is to suppress the respective imaging system's limitations. In the system, the images acquired from the two CCD sensors are carefully aligned in space and in time by maximum mutual information-based full-fledged registration schema. Subsequently, the image information is fused from these two subsystems such as the unbroken 2D information in LS-imaging and 3D depressed information in AL-imaging. Finally, on the basis of the established dual scanning imaging system the region of interest (ROI) localization by seed specification was designed, and the delineation for ROI by iterative relative fuzzy connectedness (IRFC) algorithm was utilized to get a precise inspection result. Our method takes into account the complementary advantages in the two common machine vision (MV) systems and it performs competitively with the state-of-the-art as seen from the comparison of experimental results. For the first time, a joint imaging scanning strategy is proposed for CC-slab surface defect inspection that allows a feasible way of powerful ROI delineation strategies to be applied to the MV inspection field. Multi-ROI delineation by using IRFC in this research field may further improve the results.


A critical review of the effectiveness of I/M programs for monitoring PM emissions from heavy duty vehicles.
Heavy-duty vehicles (HDV) are estimated to contribute up to 36% of particulate matter (PM) emissions in urban areas. In response, many agencies have established HDV inspection and maintenance (I/M) programs designed to target and repair vehicles with excess emissions. In this review, we conduct an international comparison of legislative context and HDV I/M program characteristics across Europe, North America, and Australia. The results of this analysis show that HDV-I/M programs vary greatly in terms of the ways in which testing is organized, for example, roadside versus periodic testing, whether the fleet is self-tested, and how nonfleet and age exemptions are handled. We also show how the I/M test criteria have changed little in the last 15 years while regulations for new heavy-duty diesel engine emissions have become increasingly stringent. In the U.S., HDV engine PM emissions limits were reduced by a factor of 26 between 1997 and 2007. Most I/M programs have continued to test according to EPA (and often with state legislative confirmation) guidance procedures having cut-points established in 1992. An analysis of data from Washington State show that only a minority of post-1997 vehicles actually exceeds the detection levels of the free-acceleration smoke-opacity test procedures, with the result that malfunctions of these vehicles may not actually be detected. From our review, it is clear that even with the potential adoption of new technologies and a more systematic and efficient framework for HDV-I/M, more research must be conducted in the efficacies of periodic versus roadside testing (and location selection), the use of evaluation methods like fail rates and opacity distributions, and finally, in development of better methods for identifying excess emissions with sensors and duty cycles.


Evaluation of the Radiation Dose-Volume Effects of Optic Nerves and Chiasm by Psychophysical, Electrophysiologic Tests, and Optical Coherence Tomography in Nasopharyngeal Carcinoma.
To evaluate the radiation dose-volume effects of optic nerves and chiasm by visual psychophysical, electrophysiologic tests, and optical coherence tomography in patients with locally advanced nasopharyngeal carcinoma. A series of visual tests including visual acuity, visual field, contrast sensitivity, visual evoked potential, and optical coherence tomography were administered to 20 patients with locally advanced (T3-T4) nasopharyngeal carcinoma who were treated with definitive chemoradiotherapy. Volume that received 55 Gy (V55), mean dose (Dmean), highest dose to 5% of the volume (D5), and maximum dose (Dmax) for optic nerves and chiasm were evaluated for each patient. Cutoff values were identified as V55: 50%, Dmean: 50 Gy, D5: 55 Gy, and Dmax: 60 Gy. The effects of radiation dose-volume on ophthalmologic tests were evaluated. Ophthalmological evaluation revealed optic neuropathy with simultaneous retinopathy in 6 eyes of 4 patients and radiation retinopathy alone in both eyes of 1 patient. Regarding radiation dose-volume effects of the optic nerve, significant detrimental effect of all parameters was observed on visual acuity. Visual field and contrast sensitivity were affected significantly with V55 ≥ 50% and Dmean ≥ 50 Gy. Visual evoked potential latency was affected significantly with Dmean ≥ 50 Gy, D5 ≥ 55 Gy, and Dmax ≥ 60 Gy. For the chiasm, significant detrimental effect of all parameters was observed on visual acuity as well. Retinal nerve fiber layer thickness and visual evoked potential amplitude were not affected by any of the dose-volume parameters neither optic nerves nor chiasm. The volume receiving the threshold dose, mean dose, and 5% of the volume receiving the maximum dose are important parameters besides maximum dose to optic nerves and chiasm. A comprehensive ophthalmological evaluation including visual field, contrast sensitivity, visual evoked potential latency, and amplitude should be performed for these patients. Visual evoked potential latency is an objective predictor of vision loss before the onset of clinical signs.


Plasma miR-145, miR-20a, miR-21 and miR-223 as novel biomarkers for screening early-stage non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the world. Late diagnosis is one of the most significant reasons for the high mortality rate of lung cancer. The identification of microRNAs (miRNAs) has opened a new field for molecular diagnosis of cancer. The purpose of the present study was to investigate whether plasma miRNAs may be used as biomarkers for early-stage NSCLC. A total of 232 participants, including 149 NSCLC patients and 83 healthy controls, were recruited between July 2012 and May 2014. We measured the levels of 10 miRNAs (miR-30d, miR-383, miR-20a, miR-145, miR-221, miR-25, miR-223, miR-21, miR-126 and miR-210) in plasma samples of 40 individuals (20 patients and 20 matched healthy controls) at the point of identification of disease, and 129 NSCLC patients and 83 healthy controls at the validation stage using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristics (ROC) curves were generated for each possible combination of the miRNAs. We observed that the expression of plasma miR-145, miR-20a, miR-21 and miR-223 was significantly increased in the early-stage NSCLC samples compared with controls. miRNAs have significant diagnostic value for early-stage NSCLC. Combined ROC analyses using these four miRNAs revealed an elevated area under the ROC curve (AUC) of 0.897, with a sensitivity and specificity of 81.8 and 90.1%, respectively. This AUC helped in distinguishing early-stage NSCLC. Furthermore, the levels of the four plasma miRNAs were significantly decreased following surgery (P<0.05). Altered expression of miR-145, miR-20a, miR-21 and miR-223 in plasma are of tumor origin, and the four miRNAs may represent potential novel non-invasive biomarkers for early-stage NSCLC.


Evaluating Motivation for the Use of an Electronic Health Record Simulation Game.
Experiential learning via simulation offers a variety of benefits including reduced risks, repetitive exposure, and mastery of complex processes. How to motivate people to engage in and enjoy playing games is an important concept in the creation of serious games focused on learning new skills. This study sought to determine the motivators that increase users' pleasurable experience when playing an electronic health record simulation game. To examine how intrinsic and extrinsic motivation affected both engagement and enjoyment, we surveyed students of health professions at one university. Results indicate that while both forms of motivation are significant in increasing engagement and enjoyment, extrinsic motivation such as badges, points, and scoreboards were much more important than internal motivations for our participants. These findings have implications for the development of an electronic health record simulation game.


Generally overlooked fundamentals of bacterial genetics and ecology.
Several important aspects of the antimicrobial resistance problem have not been treated extensively in previous monographs on this subject. This section very briefly updates information on these topics and suggests how this information is of value in assessing the contributions of human and agricultural use of antimicrobial agents on the problem of increasing antimicrobial resistance. The overall themes are (1) that propagation of resistance is an ecological problem, and thus (2) that ameliorating this problem requires recognition of long-established information on the commensal microbiota of mammals, as well as that of recent molecular understanding of the genetic agents involved in the movement of resistance genes.


Highly Durable and Active Pt-Based Nanoscale Design for Fuel-Cell Oxygen-Reduction Electrocatalysts.
Fuel cells are one of the promising energy-conversion devices due to their high efficiency and zero emission. Although recent advances in electrocatalysts have been achieved using various material designs such as alloys, core@shell structures, and shape control, many issues still remain to be resolved. Especially, material design issues for high durability and high activity are recently accentuated owing to severe instability of nanoparticles under fuel-cell operating conditions. To address these issues, fundamental understanding of functional links between activity and durability is timely urgent. Here, the activity and durability of nanoscale materials are summarized, focusing on the nanoparticle size effect. In addition to phenomenological observation, two major degradation origins, including atomic dissolution and particle size increase, are discussed related to the activity decrease. Based on the fundamental understanding of nanoparticle degradation, recent promising strategies for durable Pt-based nanoscale electrocatalysts are introduced and the role of each design for durability enhancement is discussed. Finally, short comments related to the future direction of nanoparticle issues are provided in terms of nanoparticle synthesis and analysis.


High molecular weight melanoidins from coffee brew.
The composition of high molecular weight (HMw) coffee melanoidin populations, obtained after ethanol precipitation, was studied. The specific extinction coefficient (K(mix)) at 280, 325, 405 nm, sugar composition, phenolic group content, nitrogen content, amino acid composition, and non-protein nitrogen (NPN) content were investigated. Results show that most HMw coffee melanoidins are soluble at high ethanol concentrations. The amino acid composition of the HMw fractions was similar, while 17% (w/w) of the nitrogen was NPN, probably originating from degraded amino acids/proteins and now part of melanoidins. A strong correlation between the melanoidin content, the NPN, and protein content was found. It was concluded that proteins are incorporated into the melanoidins and that the degree of chemical modification, for example, by phenolic groups, determines the solubility of melanoidins in ethanol. Although the existence of covalent interaction between melanoidins and polysaccharides were not proven in this study, the findings suggest that especially arabinogalactan is likely involved in melanoidin formation. Finally, phenolic groups were present in the HMw fraction of coffee, and a correlation was found with the melanoidin concentration.


Implementation and Evaluation of the Value of Improved and Sustained Information Access by Library Expertise (VISIBLE) Program.
To increase knowledge of National Library of Medicine resources by using a train-the-trainer approach. Workshops were held in spring 2016 to increase knowledge of 4 National Library of Medicine tools. Data were collected before the workshop and immediately, 3 months, and 1 year after the workshop. Knowledge questions were scored as 1 point per question; an aggregated knowledge score could range from 0 to 16 points. A paired t test assessed the change in knowledge from before to after the workshop. Four workshops were hosted, with a total of 74 attendees. The response rate for the surveys ranged from 50% to 100%. Knowledge scores changed significantly from 7.2 to 11.9 (t = 15, P < .001). One year after the workshop, more of the participants reported having informally trained others (56.8%) than reported providing 1 or more formal training session (8.1%)(P < .001). Objective measures of knowledge and information dissemination showed that the National Library of Medicine workshop was successful and resulted in both short- and long-term gains. This workshop could be repeated with other populations to further disseminate information regarding the National Library of Medicine tools, which could help improve disaster response.


Retrospective analysis of epidemiologic features and clinical course of COVID-19 patients and comparison between vaccinated and unvaccinated patients.
At our Pneumology Department, we dealt with three waves of COVID-19 pandemics. The purpose of this study is to compare patients' epidemiological and clinical characteristics across waves and to assess the effect of vaccination on clinical presentation, course, and prognosis. From March 2020 to March 2022, a retrospective cohort study was conducted to compare patient characteristics. Based on the time of hospital admission, data from 456 patients were collected and divided into three groups (IW, IIW, and IIIW). In addition, we looked at the link between vaccination and clinical presentation and hospitalization outcome. The average age and comorbidities of patients increased, as did the worsening of respiratory conditions at admission (PaO2/FiO2 median 207 in IW, 95.5 in IIW, and 99 in IIIW). Continuous positive airway pressure (CPAP) was the primary respiratory support during the first wave, but an increase in the use of high flow nasal cannula and noninvasive ventilation was later observed, resulting in a higher hospital discharge rate and a lower intubation rate. Vaccinated patients had less severe COVID-19-related respiratory failure, a better clinical course, and a higher hospital discharge rate (71.4% in V-group vs 44.7% in NV-group, p<0.001). Patients' characteristics changed over the three waves, possibly due to virus mutations. The advancement of clinical and therapeutic management knowledge has contributed to a reduction in the severity of respiratory failure. The vaccination campaign improved the clinical course and reduced mortality.


5,11-Conjugation-extended low-bandgap anthradithiophene-containing polymer exhibiting enhanced thin-film order and field-effect mobility.
Anthradithiophene was incorporated in a polymer structure by extending its conjugation from the 5,11-positions, through in situ desilylation followed by acetylenic coupling with a dibromo-monomer. The resulting polymer showed largely redshifted order in a thin film as well as order in thin film, forming lamellar structures out of the substrate plane. As a result, it exhibits field-effect hole mobilities, on the order of 0.1 cm(2) V(-1) s(-1), a ten to hundred-fold improvement as compared to previous acene-containing polymers.


High-resolution computed tomography evaluation of peripheral airways in asthma patients: comparison of focal and diffuse air trapping.
Air trapping evaluated in high-resolution computed tomography (HRCT) reflects changes in small bronchi. We simultaneously evaluated focal and diffuse air trapping in asthmatic patients. (1) To evaluate air trapping and bronchial wall thickness in asthmatics. (2) To estimate the relationship between air trapping and bronchial wall thickness, pulmonary function tests (PFTs), age, gender and asthma severity. (3) To compare air trapping between subgroups of asthmatic patients with normal FEV(1) % pred. and FEV(1)/FVC % and controls. (4) To compare air trapping and bronchial wall thickness between aspirin-induced asthmatics (AIA) and aspirin-tolerant asthmatics (ATA). Both groups (asthmatics and controls) included 30 patients. All patients underwent HRCT and PFTs. Focal (p < 0.0001) and diffuse (p = 0.0004) air trappings and bronchial wall thickness (T: p < 0.0001; T/D: p < 0.0001; WA%: p < 0.0001) were significantly greater in asthmatics. Focal and diffuse air trappings were inversely correlated (p = 0.021). Diffuse air trapping correlated with bronchial wall thickness: T/D (p = 0.047), T (p = 0.037), and WA% (p = 0.048). There was a significant difference in the extent of focal air trapping between a subgroup of asthmatics with normal FEV(1) % pred. and FEV(1)/FVC % and controls (p < 0.0001). There were no significant differences in focal (p = 0.095) and diffuse air trapping (p = 0.186) and bronchial wall thickness (T: p = 0.086; T/D: p = 0.428; WA%: p = 0.428) between AIA and ATA patients. Both focal and diffuse air trappings provide valuable diagnostic information and therefore deserve to be estimated. The lack of significant differences in air trapping and bronchial wall thickness between AIA and ATA patients needs further investigation.


The crystal structure of the C-terminal fragment of striated-muscle alpha-tropomyosin reveals a key troponin T recognition site.
Contraction in striated and cardiac muscles is regulated by the motions of a Ca(2+)-sensitive tropomyosin/troponin switch. In contrast, troponin is absent in other muscle types and in nonmuscle cells, and actomyosin regulation is myosin-linked. Here we report an unusual crystal structure at 2.7 A of the C-terminal 31 residues of rat striated-muscle alpha-tropomyosin (preceded by a fragment of the GCN4 leucine zipper). The C-terminal 22 residues (263-284) of the structure do not form a two-stranded alpha-helical coiled coil as does the rest of the molecule, but here the alpha-helices splay apart and are stabilized by the formation of a tail-to-tail dimer with a symmetry-related molecule. The site of splaying involves a small group of destabilizing core residues that is present only in striated muscle tropomyosin isoforms. These results reveal a specific recognition site for troponin T and clarify the physical basis for the unique regulatory mechanism of striated muscles.


Effects of Azadirachta indica and Melia azedarach (Meliaceae) extracts from leaves on Trypanosoma cruzi growth and ultrastructure.
The chloroformic extracts from dried fresh leaves ofAzadirachta indica A. Juss. and Melia azedarach L. (Meliaceae) showed marked inhibitory activity on epimastigotes growth of Trypanosoma cruzi, evidenced by 96-wells microtiter plate bioassay and radioactive thymidine incorporation experiment. Each chloroformic extract was separated using silica gel and alumina column. In transmission electron microscopy the bioactive chromatographic fractions caused ultrastructural changes in epimastigotes such as vacuolization probably induced by degeneration of the kinetoplast-mitochondrion complex, organelle degeneration, and cell division disruption. In spectral analysis these bioactive fractions seemed to be composed mainly of fatty acid mixtures.


Effects of vasopressin administration during hysteroscopic surgery.
A study was performed to assess the effect of dilute vasopressin on intraoperative bleeding and intravasation of the medium during resectoscopic hysteroscopic surgery. Dilute vasopressin or placebo was injected into the cervical stroma at the commencement of resectoscopic endometrial ablation and/or submucous myomectomy in a prospective, computer-generated, double-blind, placebo study. The operator estimated the intraoperative bleeding. The inflow volume and outflow recovered volume of sorbitol, used as a distending medium, were recorded. Pressures were kept constant with a pump. Operating time was also recorded. In 64 women the mean inflow volume was 5,584 mL (range, 500-27,000), and the mean deficit (intravasation) was 311 mL (range, 0-2,100). The mean surgical time was 37.1 minutes (range, 11-120). The deficit volume was related to the duration of surgery (P = .001) and to total inflow volume (P = .001). Increased operating time and volume infused also increase intravasation. Multivariate analysis showed that patients receiving vasopressin had a 0.36 risk of intravasation (confidence limit, 0.14-0.91) as compared with the placebo. Vasopressin injected intracervically, in conjunction with resectoscopic intrauterine surgery, reduces but does not eliminate intravasation of the medium. It also decreases intraoperative bleeding.


Hishot display--a new combinatorial display for obtaining target-recognizing peptides.
Display technologies are procedures used for isolating target-recognizing peptides without using immunized animals. In this study, we describe a new display method, named Hishot display, that uses Escherichia coli and an expression plasmid to isolate target-recognizing peptides. This display method is based on the formation, in bacteria, of complexes between a polyhistidine (His)-tagged peptide including random sequences and the peptide-encoding mRNA including an RNA aptamer against the His-tag. When this system was tested using a sequence encoding His-tagged green fluorescent protein that included an RNA aptamer against the His-tag, the collection of mRNA encoding the protein was dependent on the RNA aptamer. Using this display method and a synthetic library of surrogate single-chain variable fragments consisting of VpreB and Ig heavy-chain variable domains, it was possible to isolate clones that could specifically recognize a particular target (intelectin-1 or tumor necrosis factor-α). These clones were obtained as soluble proteins produced by E. coli, and the purified peptide clones recognizing intelectin-1 could be used as detectors for sandwich enzyme-linked immunosorbent assays. The Hishot display will be a useful method to add to the repertoire of display technologies.


Pollen production in olive cultivars and its interannual variability.
Olive (Olea europaea subsp. europaea var. europaea) is the most extensively cultivated fruit crop worldwide. It is considered a wind-pollinated and strictly outcrossing crop. Thus, elevated pollen production is crucial to guarantee optimum fruit set and yield. Despite these facts, the variability of pollen production within the cultivated olive has been scarcely studied. This study is aimed to characterize this feature by analysing a representative set of worldwide olive cultivars. We evaluated the average pollen grains per anther in 57 principal cultivars over three consecutive years. We applied a standard generalized linear model (GLM) approach to study the influence of cultivar, year and previous year fruit load on the amount of pollen per anther. Additionally, the K-means method was used for cluster analysis to group cultivars based on their pollen production capacity. Pollen production per anther was highly variable among olive cultivars. The cultivar significantly accounted for 51.3% of the variance in pollen production and the year for 0.3%. The interaction between both factors explained 8.4% of the variance, indicating that not all cultivars were equally stable in producing pollen across the years. The previous year fruit load and its interaction with the year were significant, but barely accounted for 1.5% of the variance. Olive cultivars were classified into four clusters according to their capacity to produce pollen. Interestingly, the fourth cluster was composed of male-sterile cultivars, which presumably share this character by inheritance. Pollen production per anther varied extensively within the cultivated olive. This variation was mainly driven by the cultivar and its interaction with the year. The differential capacity of olive cultivars to produce pollen should be considered not only for designing new orchards but also gardens where this species is used as ornamental.


The impact of gene expression profile testing on confidence in chemotherapy decisions and prognostic expectations.
Little is known about whether gene expression profile (GEP) testing and specific recurrence scores (e.g., medium risk) improve women's confidence in their chemotherapy decision or perceived recurrence risk. We evaluate the relationship between these outcomes and GEP testing. We surveyed women eligible for GEP testing (stage I or II, Gr1-2, ER+, HER2-) identified through the Surveillance, Epidemiology, and End Results (SEER) Registry of Washington or Kaiser Permanente Northern California from 2012 to 2016, approximately 0-4 years from diagnosis (N = 904, RR = 45.4%). Confidence in chemotherapy was measured as confident (Very, completely) versus Not Confident (Somewhat, A little, Not At All); perceived risk recurrence was recorded numerically (0-100%). Women reported their GEP test receipt (Yes, No, Unknown) and risk recurrence score (High, Intermediate, Low, Unknown). In our analytic sample (N = 833), we propensity score weighted the three test receipt cohorts and used propensity weighted multivariable regressions to examine associations between the outcomes and the three test receipt cohorts, with receipt stratified by score. 29.5% reported an unknown GEP test receipt; 86% being confident. Compared to no test receipt, an intermediate score (aOR 0.34; 95% CI 0.20-0.58), unknown score (aOR 0.09; 95% CI 0.05-0.18), and unknown test receipt (aOR 0.37; 95% CI 0.24-0.57) were less likely to report confidence. Most women greatly overestimated their recurrence risk regardless of their test receipt or score. GEP testing was not associated with greater confidence in chemotherapy decisions. Better communication about GEP testing and the implications for recurrence risk may improve women's decisional confidence.


The effect of the endothelial cell cortex on atomic force microscopy measurements.
We examined whether the presence of the cell cortex might explain, in part, why previous studies using atomic force microscopy (AFM) to measure cell modulus (E) gave higher values with sharp tips than for larger spherical tips. We confirmed these AFM findings in human umbilical vein endothelial cells (HUVEC) and Schlemm's canal (SC) endothelial cells with AFM indentation ≤ 400 nm, two cell types with prominent cortices (312 ± 65 nm in HUVEC and 371 ± 91 nm in SC cells). With spherical tips, E (kPa) was 0.71 ± 0.16 in HUVEC and 0.94 ± 0.06 in SC cells. Much higher values of E were measured using sharp tips: 3.23 ± 0.54 in HUVEC and 6.67 ± 1.07 in SC cells. Previous explanations for this difference such as strain hardening or a substrate effect were shown to be inconsistent with our measurements. Finite element modeling studies showed that a stiff cell cortex could explain the results. In both cell types, Latrunculin-A greatly reduced E for sharp and rounded tips, and also reduced the ratio of the values measured with a sharp tip as compared to a rounded tip. Our results suggest that the cell cortex increases the apparent endothelial cell modulus considerably when measured using a sharp AFM tip.


Outcomes of Kidney Transplantation from Circulatory Death Donors With Increased Terminal Creatinine Levels in Serum.
To alleviate chronic renal graft shortages in Japan, donation after circulatory death (DCD) is an increasingly used organ resource. Organs from DCD donors with progressively increased terminal creatinine (t-Cr) levels are frequently used, but the effects of this condition on kidney transplantation (KTx) remain unclear. Between 1996 and 2013, 99 KTx from DCD donors were conducted in our department. Recipients were grouped according to the t-Cr (in mg/dL) of donors: group 1, t-Cr less than < 1.5; group 2, 1.5 ≤ t-Cr < 3.0; and group 3, t-Cr ≥ 3.0. We analyzed the long-term outcomes of KTx from DCD donors retrospectively in terms of donors' terminal renal function. The respective mean donor t-Cr in groups 1, 2, and 3 were 0.73 ± 0.28, 2.02 ± 0.40, and 6.69 ± 3.68. The respective death-censored graft survival rates (%) in groups 1, 2, and 3 were 90.2, 96.2, and 86.7 at 1 year and 70.3, 86.2, and 73.4 at 10 years after transplantation. Group 1 exhibited lower incidence of delayed graft function than either group 2 or group 3 (80.5% vs 100% and 93.3%). Nevertheless, no significant difference was found between groups for several measures: Cr levels 1 month after KTx and lowest Cr levels throughout the observation period, prevalence of biopsy-proven acute rejection, and graft survival. Cox proportional hazard regression showed that donor age, cerebrovascular event, terminal urine output, and history of hypertension were significantly associated with graft survival. Results suggest that, under certain conditions, kidneys from DCD donors with progressively increased t-Cr can be used safely with promising long-term outcomes.


[Analysis of the densitometric method of hand bone radiograms and assessment of early changes of bone structure in the children with Gaucher s disease on enzyme replacement therapy (ERT)].
In the study of changes of bone structure eighteen children with Gaucher s disease (ERT) at the 4 to 19.8 years, used was densitometric in vivo method of hand bone radiograms. On the basis of the radiogram assessed was the bone age of patient also optical bone density and dimension in the second metacarpal bone. Differential diagnostics was produced based on standardized cortical thickness and optical bone density, according to the norm of Polish population (1989, 2004). The analysis of hand bone radiograms in children with Gaucher's (ERT) shows that 55.5% of patients had normal skeletal status, 38.8% indicated osteopenia traits, one patient had osteoporotic traits.


A Comparison of Rollback Ratio between Bicruciate Substituting Total Knee Arthroplasty and Oxford Unicompartmental Knee Arthroplasty.
The purpose of this study was to compare the rollback ratio in bicruciate substituting (BCS) total knee arthroplasty (TKA) and bicruciate-retaining Oxford unicompartmental knee arthroplasty (UKA). In this study, 64 subjects (64 knees) undergoing BCS-TKA (Journey II: Smith and Nephew) and 50 subjects (50 knees) undergoing Oxford UKA (Zimmer-Biomet holdings, Inc., IN) were included. Approximately 6 months after surgery, and when the subjects had recovered their knee range of motion, following the Laidlow's method, lateral radiographic imaging of the knee was performed with active full knee flexion. The most posterior tibiofemoral contact point was measured for the evaluation of femoral rollback (rollback ratio). Flexion angle was also measured using the same radiograph and the correlation of rollback and flexion angle was analyzed. As a control, radiographs of the asymptomatic contralateral knees of subjects undergoing Oxford UKA were evaluated (50 knees). The rollback ratios of the BCS-TKA, Oxford UKA, and control knees were 37.9 ± 4.9, 35.7 ± 4.2, and 35.3 ± 4.8% respectively. No significant difference in rollback ratio was observed among the three groups. The flexion angles of the BCS-TKA, Oxford UKA, and control knees were 123.8 ± 8.4, 125.4 ± 7.5, and 127 ± 10.3 degrees, respectively. No significant difference in knee flexion angle was observed among the three groups. Significant correlation between rollback ratio and knee flexion angle was observed (p = 0.002; Pearson's correlation coefficient = - 0.384). BCS-TKA showed no significant difference in rollback ratio when compared with control knees and Oxford UKA knees. The BCS-TKA design is likely to reproduce native anterior cruciate ligament and posterior cruciate ligament function, and native knee rollback.


Long lasting nitrate leaching after bark beetle attack in the highlands of the Bavarian Forest National Park.
During the past decade bark beetle (Ips typographus) attacks killed nearly all of the Norway spruce [Picea abies (L.) Karst.] stands in the unmanaged zone in the highlands of the Bavarian Forest National Park. This study was conducted to predict if and how long the catastrophic event might cause elevated nitrate NO3(-) concentration in seepage water, and if the presence of ground vegetation may reduce NO3(-) leaching. A chronosequence approach was used to investigate NO3(-) leaching before and after the death of trees. Additionally, the impact of ground vegetation coverage on NO3(-) leaching was determined. Flux weighted yearly NO3(-) concentrations were significantly elevated in the first 5 yr after the dieback compared with intact stands (27 micromol(c) L(-1)), with highest concentrations in the fifth year after the dieback (579 micromol(c) L(-1)). Lowest NO3(-) concentrations were observed 17 yr after the dieback (10 micromol(c) L(-1)). Suction cups in places without ground vegetation showed significantly higher NO3(-) concentrations of 163 to 727 micromol(c) L(-1) (Year 2-5 after the dieback) than suction cups without vegetation. However, net uptake of N by ground vegetation observed during the first 7 yr after the dieback was low on a plot scale. Compared with other severe disturbances in forests, NO3(-) concentrations were elevated for a longer period. Due to high rates of precipitation, NO3(-) dilution occurred and concentrations remained mostly below the European critical level for drinking water. Part of the observed heterogeneity in NO3(-) concentrations could be attributed to different patterns of ground vegetation coverage.


Relationship between Structure and Fluctuations of Lipid Nonlamellar Phases Deposited at the Solid-Liquid Interface.
The structure and dynamics of nanostructure films formed by mixtures of soy phosphatidylcholine and glycerol dioleate at the silicon-aqueous interface were studied by grazing incidence neutron spin echo spectroscopy (GINSES), specular and off-specular neutron reflectometry, and small-angle X-ray diffraction. Reverse hexagonal (HII) and micellar cubic phase (Fd3m) layers at the solid-liquid interface have been identified with neutron reflectometry measurements. A preferred orientation of the liquid crystalline (LC) domains was observed only for the anisotropic HII phase. The size of the LC domains was found to be about 1 micrometer as estimated from the width of the diffraction peaks. GINSES revealed that the cubic phase forms rather rigid films. In comparison, the HII film was more flexible, appearing as a modified undulation spectrum of the cylinders due to the interaction with the substrate.


Immunohistochemical detection of the BRAF V600E mutant protein in colorectal neoplasms.
Reliable assessment of the BRAF mutation status is becoming increasingly important in the clinical management of colorectal carcinomas (CRC). The aim of this study was to investigate the use of a recently developed mutation-specific antibody (VE1; SpringBio, Pleasanton, CA) to detect the BRAF V600E protein in paraffin tissue. We analyzed by immunohistochemistry (IHC) 117 cases that had been evaluated for BRAF mutation using a MALDI-TOF mass spectrometry-based assay. Immunohistochemical staining was evaluated without the knowledge of the genetic data and was considered positive when there was distinct homogenous cytoplasmic staining in the tumor cells. The analyzed cases included 4 polyps, 63 primary CRC, and 50 metastatic CRC. Forty-five of the 46 (97.8%) cases that were positive by IHC had a BRAF V600E mutation by genetic analysis; the 1 discordant case was notably of signet ring cell type. Similarly, 66 of the 67 (98.5%) cases that were negative by IHC were also negative by genetic analysis. Four cases that showed weak cytoplasmic staining and/or nuclear staining in the tumor cells were considered to be IHC equivocal; by genetic analysis, 2 of the 4 were positive and 2 were negative. The overall sensitivity and specificity of IHC for the detection of a BRAF V600E mutant tumor was 93.7% and 95.6%, respectively. Our results support the use of VE1 IHC for identification of colorectal neoplasms harboring the BRAF V600E mutation. Difficulties in immunohistochemical interpretation may arise in a small number of cases and in those cases molecular testing is required.


An integrated approach to the characterization of immune repertoires using AIMS: An Automated Immune Molecule Separator.
The adaptive immune system employs an array of receptors designed to respond with high specificity to pathogens or molecular aberrations faced by the host organism. Binding of these receptors to molecular fragments-collectively referred to as antigens-initiates immune responses. These antigenic targets are recognized in their native state on the surfaces of pathogens by antibodies, whereas T cell receptors (TCR) recognize processed antigens as short peptides, presented on major histocompatibility complex (MHC) molecules. Recent research has led to a wealth of immune repertoire data that are key to interrogating the nature of these molecular interactions. However, existing tools for the analysis of these large datasets typically focus on molecular sets of a single type, forcing researchers to separately analyze strongly coupled sequences of interacting molecules. Here, we introduce a software package for the integrated analysis of immune repertoire data, capable of identifying distinct biophysical differences in isolated TCR, MHC, peptide, antibody, and antigen sequence data. This integrated analytical approach allows for direct comparisons across immune repertoire subsets and provides a starting point for the identification of key interaction hotspots in complementary receptor-antigen pairs. The software (AIMS-Automated Immune Molecule Separator) is freely available as an open access package in GUI or command-line form.


Plasma free metanephrine, normetanephrine, and 3-methoxytyramine for the diagnosis of pheochromocytoma/paraganglioma.
Pheochromocytomas (PHEO) and paragangliomas (PGL) are derived from paraganglia of the sympathetic and parasympathetic nervous system. Most of the sympathetic PHEO/PGL secrete either catecholamine or their metabolites, metanephrines, whereas parasympathetic PHEO/PGL are nonsecretory. We assessed the utility of plasma free 3-methoxytyramine (3MT), normetanephrine (NM), and metanephrine (MN) for the diagnosis of PHEO/PGL. Sixty-five patients referred to endocrine/ENT clinics were enrolled. Twelve patients with von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1) and multiple endocrine neoplasia type 2 (MEN2) syndromes were excluded. Remaining 53 patients (39 patients with adrenal, abdominal, cervical and thoracic PHEO/PGL and 14 patients with head and neck PGL (HNPGL) were taken for this study. Sixty-five age- and sex-matched subjects were taken as controls. Plasma levels 3MT, NM, and MN were measured using high-performance liquid chromatography. Receivers operating characteristics was plotted and cut-off levels were established. When compared with controls, there was a 36-, 8.7- and 9.5-fold increase in levels of NM, 3MT and MN in the patients with PHEO/PGL and 7.2- and 2.7-fold increase in 3MT and NM, in the patients with HNPGL, respectively. In malignant PHEO/PGL, there was a 99-, 16- and 20-fold increase and in benign PHEO/PGL, there was 19-, 6.8- and 6.4-fold increase in levels of NM, 3MT, and MN, respectively. NM in combination with MN was high in 97% of the patients with PHEO/PGL. All three metabolites in combination were high in 83% of patients with HNPGL. In malignant PHEO/PGL, 50% subjects had increased levels of both NM and 3MT. Measurement of plasma-free NM along with 3MT and MN provides a better tool for the diagnosis of PHEO/PGL as well as HNPGL. Further, NM in combination with 3MT can be used for the diagnosis of malignant PHEO/PGL.


Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification.
Channelopathies are a diverse set of disorders associated with defects in ion channel (and transporter) function. Although the vast majority of channelopathies are linked with inherited mutations that alter ion channel biophysical properties, another group of similar disorders has emerged that alter ion channel synthesis, membrane trafficking, and/or posttranslational modifications. In fact, some electrical and episodic disorders have now been identified that are not defects in the ion channel but instead reflect dysfunction in an ion channel (or transporter) regulatory protein. This review focuses on alternative paradigms for physiological disorders associated with protein biosynthesis, folding, trafficking, and membrane retention. Furthermore, the review highlights the role of aberrant posttranslational modifications in acquired channelopathies.


Identification of the prognostic immune subtype in copy-number high endometrial cancer.
The TCGA molecular subtype of endometrial cancer (EC) is widely applied, among which the copy-number high (CNH) subtype has the poorest prognosis. However, the heterogeneity of this subtype remains elusive. In this study, we aimed to identify heterogeneous immune subtypes in CNH EC and explore their prognostic significance. We collected 60 CNH EC cases in the TCGA database and performed unsupervised cluster analysis based on the enrichment scores of immune-related gene signatures to identify immune subtypes. We described their immune characteristics and prognoses and conducted differential gene analysis and lasso regression to identify a prognostic biomarker, GZMM. For experimental validation, we performed immunohistochemical staining of GZMM in 39 p53-positive EC surgical samples. We defined two immune subtypes, immune-hot (IH) and immune-cold (IC), which differed in immune cell infiltration, cytokine and chemokine expression and prognosis. The IH subtype has significantly stronger immune activation than the IC subtype, showing a significant infiltration of immune effector cells and high expression of relevant chemokines, with better prognosis. Moreover, the immunohistochemical staining of GZMM in a cohort of 39 p53-positive EC surgical samples confirmed GZMM as a unique prognostic biomarker, with high expression in both tumor cells and lymphocytes predicting a better prognosis. Our study revealed heterogeneous immune subtypes in CNH EC and identified GZMM as a prognostic biomarker. The stratified classification strategy combining molecular and immune subtypes provides valuable insights for future clinical practice.


Massive schwannoma of the nose and paranasal sinuses.
Schwannomas, uncommon tumors of the nose and paranasal sinuses, are discovered late in their clinical course because of their obscure anatomic location. In this report, we have described the clinical findings in a massive nasal schwannoma (neurilemoma) that obstructed both nares, the left maxillary sinus, and the ethmoid sinuses, and protruded from the oropharynx and nose. The preoperative work-up included both computerized tomographic and magnetic resonance imaging studies.


Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells.
To investigate the pathogenesis of three novel de novo CACNA1C variants (p.E411D, p.V622G, and p.A272V) in causing neurodevelopmental disorders and arrhythmia. Several molecular experiments were carried out on transfected human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells to explore the effects of p.E411D, p.V622G, and p.A272V variants on electrophysiology, mitochondrial and lysosomal functions. Electrophysiological studies, RT-qPCR, western blot, apoptosis assay, mito-tracker fluorescence intensity, lyso-tracker fluorescence intensity, mitochondrial calcium concentration test, and cell viability assay were performed. Besides, reactive oxygen species (ROS) levels, ATP levels, mitochondrial copy numbers, mitochondrial complex I, II, and cytochrome c functions were measured. The p.E411D variant was found in a patient with attention deficit-hyperactive disorder (ADHD), and moderate intellectual disability (ID). This mutant demonstrated reduced calcium current density, mRNA, and protein expression, and it was localized in the nucleus, cytoplasm, lysosome, and mitochondria. It exhibited an accelerated apoptosis rate, impaired autophagy, and mitophagy. It also demonstrated compromised mitochondrial cytochrome c oxidase, complex I, and II enzymes, abnormal mitochondrial copy numbers, low ATP levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, and elevated mitochondrial calcium ions. The p.V622G variant was identified in a patient who presented with West syndrome and moderate global developmental delay. The p.A272V variant was found in a patient who presented with epilepsy and mild ID. Both mutants (p.V622G and p.A272V) exhibited reduced calcium current densities, decreased mRNA and protein expressions, and they were localized in the nucleus, cytoplasm, lysosome, and mitochondria. They exhibited accelerated apoptosis and proliferation rates, impaired autophagy, and mitophagy. They also exhibited abnormal mitochondrial cytochrome c oxidase, complex I and II enzymes, abnormal mitochondrial copy numbers, low ATP, high ROS levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, as well as elevated mitochondrial calcium ions. The p.E411D, p.V622G and p.A272V mutations of human CACNA1C reduce the expression level of CACNA1C proteins, and impair mitochondrial and lysosomal functions. These effects induced by CACNA1C variants may contribute to the pathogenesis of CACNA1C-related disorders.


Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.
The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomarkers have the potential to predict response to nCRT at an early time point, but none have currently reached the clinic. Integration of diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology, and rigorous validation using samples which represent disease heterogeneity, will allow to develop a sensitive and cost-effective molecular biomarker panel for precision medicine in rectal cancer. Here, we aim to review the recent advance in tissue- and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.


Serum reactivity against Borrelia burgdorferi OspA in patients with rheumatoid arthritis.
Lyme arthritis and rheumatoid arthritis share common clinical features and synovial histology. It is unclear whether they also share similar pathogenesis. Previous studies have shown that the severity and duration of Lyme arthritis correlate directly with serum concentrations of antibody against outer surface protein A (OspA) of the causative pathogen Borrelia burgdorferi. We tested the sera of 68 subjects with rheumatoid arthritis, 147 subjects with other autoimmune diseases, and 44 healthy subjects who had never had Lyme disease, as well as sera of 16 patients who had Lyme disease, for reactivity against the B. burgdorferi OspA protein. The sera of about a quarter of the rheumatoid arthritis patients and a 10th of the autoimmune disease and Lyme disease patients reacted against OspA antigen. Of 50 rheumatoid arthritis patients who could be evaluated for disease severity, a 28-joint count disease activity score of >2.6 was noted for 11 of 15 (73%) patients whose sera reacted against OspA antigen and 13 of 35 (37%; P < 0.05) whose sera were nonreactive. Serum reactivity against OspA antigen is associated with the pathogenesis of rheumatoid arthritis.


A prospective comparison of triple extrastimuli and left ventricular stimulation in studies of ventricular tachycardia induction.
One hundred and one patients with sustained unimorphic ventricular tachycardia underwent programmed ventricular stimulation with one of two protocols. Fifty patients underwent programmed stimulation with protocol A, which consisted of burst overdrive pacing, single, double, and triple extrastimuli at the right ventricular apex, right ventricular outflow tract, or septum, and then at the left ventricular apex. Fifty-one patients underwent programmed stimulation with protocol B, which consisted of burst overdrive pacing, single and double extrastimuli at the right ventricular apex, right ventricular outflow tract or septum, and at the left ventricular apex, followed by triple extrastimuli at these sites. The stimulation protocol was continued until sustained ventricular tachycardia or rapid, polymorphic ventricular tachycardia greater than 10 sec in duration was induced. With protocol A, clinical and nonclinical ventricular tachycardia was induced in 76% and 36% of patients, respectively; with protocol B, clinical and nonclinical ventricular tachycardia was induced in 85% and 38% of patients, respectively. Direct-current countershock for sustained polymorphic ventricular tachycardia was required in 10% of patients studied under protocol A, compared with in 2% of patients studied under protocol B. With protocol A, near-maximal yield of induced clinical (72%) and nonclinical ventricular tachycardia (30%) was attained after the use of triple extrastimuli at the first stimulation site. The yield of stimulation at a second right ventricular site and of left ventricular stimulation was only an additional 2% each. With protocol B, triple extrastimuli increased the yield of induced clinical ventricular tachycardia from 61% to 85%.(ABSTRACT TRUNCATED AT 250 WORDS)


Global prevalence of edentulism and dental caries in middle-aged and elderly persons: A systematic review and meta-analysis.
The aim of the study was to analyze data collected from studies worldwide on the prevalence of edentulism and dental caries, in community-dwellers aged ≥ 45 years. Inclusion criteria; participants aged ≥ 45 years, community-dwellers. Exclusion criteria; participants aged < 45 years, in nursing homes, data obtained from dental clinics or pre-2005. The quality assessment tool by The National Heart, Lung and Blood Institute for Observational Cohort and Cross-sectional studies was used. Meta-analysis using the random-effects model (95% confidence interval) was done with data on participants who were edentulous and/or had active dental caries and stratified by regions of the world, age and Gross National Income per capita. Limitations in the data arose from several factors such as design of the studies included differences in socioeconomic status and access to health care among different countries. Embase, MEDLINE via Pubmed and Scopus, manual searches, from January 2016, restricted to English. Experts from different countries were contacted to identify National oral health surveys (NOHS) conducted from 2010 onwards. Eighty-six papers and seventeen NOHS were selected for data extraction. Majority of the studies (n = 69) were cross-sectional and of fair quality. 1.1%-70%, 4.9% - 98% prevalence of edentulism and dental caries, respectively. 22%, 45% estimated random-effects pooled prevalence of edentulism and dental caries, respectively. Within the limitations of this study, the findings indicate that untreated dental caries and tooth loss are prevalent on a global level with wide variations among different countries, age groups and socioeconomic status. The findings demonstrate the reality of the new cohort of older adults, with higher tooth retention implying more dental caries incidence and the need for different care strategies to ensure better oral health. Large variations and difficulty in making comparisons among different countries highlight the need for more standardized, regular research.


Three-Dimensional Right Ventricular Strain Versus Volume Quantification in Heart Transplant Recipients in Relation to Pulmonary Artery Pressure.
Residual pulmonary hypertension challenges the right ventricular function and worsens the prognosis in heart transplant recipients. The complex geometry of the right ventricle complicates estimation of its function with conventional transthoracic echocardiography. We evaluated right ventricular function in heart transplant recipients with the use of 3-dimensional echocardiography in relation to systolic pulmonary artery pressure. We performed 32 studies in 26 heart transplant patients, with 6 patients having 2 studies at different time points with different pressures and thus included. Right atrial volume, tricuspid annular plane systolic excursion, peak systolic annular velocity, fractional area change, and 2-dimensional speckle tracking longitudinal strain were obtained by 2-dimensional and tissue Doppler imaging. Three-dimensional right ventricular volumes, ejection fraction, and 3-dimensional right ventricular strain were obtained from the 3-dimensional data set by echocardiographers. Systolic pulmonary artery pressure was obtained during right heart catheterization. Overall mean systolic pulmonary artery pressure was 26 ± 7 mm Hg (range, 14-44 mmHg). Three-dimensional end-diastolic (r = 0.75; P < .001) and end-systolic volumes (r = 0.55; P = .001)correlated well with systolic pulmonary artery pressure. Right ventricular ejection fraction and right atrium volume also significantly correlated with systolic pulmonary artery pressure (r = 0.49 and P = .01 for both). However, right ventricular 2- and 3-dimensional strain, tricuspid annular plane systolic excursion, and tricuspid annular velocity did not. The effects of pulmonary hemodynamic burden on right ventricular function are better estimated by a 3-dimensional volume evaluation than with 3-dimensional longitudinal strain and other 2-dimensional and tissue Doppler measurements. These results suggest that the peculiar anatomy of the right ventricle necessitates 3-dimensional volume quantification in heart transplant recipients in relation to residual pulmonary hypertension.


Antiangiogenic Pterocarpan and Flavonoid Constituents of Erythrina lysistemon.
The roots of Erythrina lysistemon, growing in Egypt, yielded 24 flavonoid compounds, including 17 pterocarpans, two isoflavanones, one flavanone, two isoflavans, one 2-arylbenzofuran, and an isoflava-3-ene. Nine pterocarpans have not been reported previously (7-9, 11-14, 19, and 20), and 11 are reported here for the first time from this species. Structures were established using HRESIMS, NMR, and circular dichroism techniques. Selected compounds were tested for their ability to block the growth of human retinal endothelial cells and antiangiogenic activity in vitro. The isoflavonoids 5 and 6, and the pterocarpans 1, 2, 4, 20, and 22 demonstrated selective antiproliferative activities on endothelial cells compared to a nonendothelial cell type, with concentration-dependent antiangiogenic effects in vitro against HRECs, a cell type relevant to neovascular eye diseases.


Prevalence of hypothyroidism in patients with hyponatremia: A retrospective cross-sectional study.
Hypothyroidism has been suggested to be an uncommon cause of hyponatremia. However, little is known about the prevalence of hypothyroidism in patients with different levels of hyponatremia. The objective of this study was to investigate the prevalence of hypothyroidism among patients with hyponatremia of varying severity while taking into consideration potential confounders associated with thyroid function. All data on thyrotropin (TSH), free thyroxine (T4), and serum sodium (Na) levels were retrospectively collected from medical records at two Japanese tertiary hospitals. The main outcome measure was overt hypothyroidism, defined as TSH > 10.0 μIU/mL and free T4 < 1.01 ng/dL. Of 71,817 patients, 964 patients (1.3%) had overt hypothyroidism. The prevalence of overt hypothyroidism in each category of hyponatremia (Na ≥136, 130-135, and ≤129 mEq/L) was 1.2% (787/65,051), 2.4% (124/5,254) and 3.5% (53/1,512), respectively. A significant increase in prevalence was observed as the severity of hyponatremia increased (P < 0.001 for trend). Multivariate logistic regression with adjustment for age, sex, kidney function, and serum albumin level showed that the odds ratios for overt hypothyroidism increased with increasing severity of hyponatremia when compared with Na ≥ 136 mEq/L (130-135 mEq/L: 1.43, 95% confidence interval [CI], 1.15 to 1.78, P = 0.001; ≤129 mEq/L: 1.87, 95% CI, 1.32 to 2.63, P < 0.001; P< 0.001 for trend). The prevalence of overt hypothyroidism was significantly higher as the severity of hyponatremia progressed, even after adjusting for potential confounders. Hypothyroidism should be differentiated in patients with hyponatremia.


Posterior Cord Syndrome and Trace Elements Deficiency as an Uncommon Presentation of Common Variable Immunodeficiency.
Diarrhea is one of the most common symptoms in common variable immunodeficiency, but neurologic manifestations are rare. We presented a 50-year-old woman with recurrent diarrhea and severe weight loss that developed a posterior cord syndrome. Endoscopy found a duodenal villous blunting, intraepithelial lymphocytosis, and lack of plasma cells and magnetic resonance imaging of the spine was normal. Laboratory assays confirmed common variable immunodeficiency syndrome and showed low levels of trace elements (copper and zinc). Treatment was initiated with parenteral replacement of trace elements and intravenous human immunoglobulin and the patient improved clinically. In conclusion, physicians must be aware that gastrointestinal and neurologic disorders may be related to each other and remember to request trace elements laboratory assessment.


Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney.
The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target.


Medullary allotransplant in acute myeloblastic leukemia in a child.
Although acute myeloblastic leukemia (AML) is more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), significant progresses have been achieved over the last 20 years with an improvement in the long-term survival up to 50-60%. This may be attributed to the intensification of chemotherapy, including the increased use of stem-cell transplantation (HSCT) in well-defined subgroups. Allo-HSCT represents an extremely effective alternative in pediatric AML treatment panel, but its efficiency is limited both by the toxic effects and by the difficulty of finding a matched HLA donor.


Inhibition of diacylglycerol acyltransferase by prenylated flavonoids isolated from the stem bark of Maackia amurensis.
A new prenylated flavanone, erythraddison Z (1), together with eight known flavonoids (2-9), was isolated from the stem bark of Maackia amurensis. Their structures were elucidated on the basis of spectroscopic methods, including 1D and 2D NMR (COSY, HMQC, and HMBC) techniques. All the isolates, with the exception of 3, 6 and 7, strongly inhibited diacylglycerol acyltransferase activity in an in vitro assay with IC50 values ranging from 96.5 ± 0.6 to 135.1 ± 1.4 μM.


Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.
RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo.


The role of renal circadian biorhythms in lifelong LUTS.
This article delves into the intricate relationship between kidney function, diuresis, and lower urinary tract symptoms (LUTS) throughout the transitions of the human lifespan. It explores circadian regulation of urine production, maturation of renal function from birth to adulthood, and effects of aging on kidney function and LUTS. The complex connections between these factors are highlighted, offering insights into potential interventions and personalized management strategies. An international panel of seven experts engaged in online discussions, focusing on kidney function, diuresis, and LUTS throughout life. This manuscript summarizes expert insights, literature reviews, and findings presented during a webinar and subsequent discussions. Renal function undergoes significant maturation from birth to adulthood, with changes in glomerular filtration rate, diuresis, and tubular function. A circadian rhythm in urine production is established during childhood. Adolescents and young adults can experience persistent enuresis due to lifestyle factors, comorbidities, and complex physiological changes. In older adults, age-related alterations in kidney function disrupt the circadian rhythm of diuresis, contributing to nocturnal polyuria and LUTS. The interplay between kidney function, diuresis, and LUTS is crucial in understanding lifelong urinary health. Bridging the gap between pediatric and adult care is essential to address enuresis in adolescents and young adults effectively. For older adults, recognizing the impact of aging on renal function and fluid balance is vital in managing nocturia. This holistic approach provides a foundation for developing innovative interventions and personalized treatments to enhance quality of life for individuals with LUTS across all stages of life.


Myofibroblasts in hollow visceral myopathy: the origin of gastrointestinal fibrosis?
A patient with hollow visceral myopathy is reported in whom light microscopical studies of the small and large intestine showed typical features of degeneration, thinning, and fibrous replacement of smooth muscle of the gastrointestinal tract. Electron microscopy showed a striking increase in collagen with minimal fibroblast proliferation. Smooth muscle fibres had a range of ultrastructural abnormalities including myofilament disarray, electron lucency of the cytoplasm, and proliferation of the endoplasmic reticulum. Some fibres seemed to have typical ultrastructural characteristics of myofibroblasts, and others to be transition forms between typical smooth muscle cells and typical myofibroblasts. It seems likely that the fibrosis typical of this disorder has its origin in the transformation of smooth muscle fibres from a purely contractile to a myofibroblast collagen synthetic phenotype.


Detection of audiovisual speech correspondences without visual awareness.
Mounting physiological and behavioral evidence has shown that the detectability of a visual stimulus can be enhanced by a simultaneously presented sound. The mechanisms underlying these cross-sensory effects, however, remain largely unknown. Using continuous flash suppression (CFS), we rendered a complex, dynamic visual stimulus (i.e., a talking face) consciously invisible to participants. We presented the visual stimulus together with a suprathreshold auditory stimulus (i.e., a voice speaking a sentence) that either matched or mismatched the lip movements of the talking face. We compared how long it took for the talking face to overcome interocular suppression and become visible to participants in the matched and mismatched conditions. Our results showed that the detection of the face was facilitated by the presentation of a matching auditory sentence, in comparison with the presentation of a mismatching sentence. This finding indicates that the registration of audiovisual correspondences occurs at an early stage of processing, even when the visual information is blocked from conscious awareness.


Design of solid state neutral particle analyzer array for National Spherical Torus Experiment-Upgrade.
A new compact, multi-channel Solid State Neutral Particle Analyzer (SSNPA) diagnostic based on silicon photodiode array has been designed and is being fabricated for the National Spherical Torus Experiment-Upgrade (NSTX-U). The SSNPA system utilizes a set of vertically stacked photodiode arrays in current mode viewing the same plasma region with different filter thickness to obtain fast temporal resolution (∼120 kHz bandwidth) and coarse energy information in three bands of >25 keV, >45 keV, and >65 keV. The SSNPA system consists of 15 radial sightlines that intersect existing on-axis neutral beams at major radii between 90 and 130 cm, 15 tangential sightlines that intersect new off-axis neutral beams at major radii between 120 and 145 cm. These two subsystems aim at separating the response of passing and trapped fast ions. In addition, one photodiode array whose viewing area does not intersect any neutral beams is used to monitor passive signals produced by fast ions that charge exchange with background neutrals.