Constitutive CD40L expression on B cells prematurely terminates germinal center response and leads to augmented plasma cell production in T cell areas.
CD40/CD40L engagement is essential to T cell-dependent B cell proliferation and differentiation. However, the precise role of CD40 signaling through cognate T-B interaction in the generation of germinal center and memory B cells is still incompletely understood. To address this issue, a B cell-specific CD40L transgene (CD40LBTg) was introduced into mice with B cell-restricted MHC class II deficiency. Using this mouse model, we show that constitutive CD40L expression on B cells alone could not induce germinal center differentiation of MHC class II-deficient B cells after immunization with T cell-dependent Ag. Thus, some other MHC class II-dependent T cell-derived signals are essential for the generation of germinal center B cells in response to T cell-dependent Ag. In fact, CD40LBTg mice generated a complex Ag-specific IgG1 response, which was greatly enhanced in early, but reduced in late, primary response compared with control mice. We also found that the frequency of Ag-specific germinal center B cells in CD40LBTg mice was abruptly reduced 1 wk after immunization. As a result, the numbers of Ag-specific IgG1 long-lived plasma cells and memory B cells were reduced. By histology, large numbers of Ag-specific plasma cells were found in T cell areas adjacent to Ag-specific germinal centers of CD40LBTg mice, temporarily during the second week of primary response. These results indicate that CD40L expression on B cells prematurely terminated their ongoing germinal center response and produced plasma cells. Our results support the notion that CD40 signaling is an active termination signal for germinal center reaction.


Thermoregulation during exercise in the heat: strategies for maintaining health and performance.
As a result of the inefficiency of metabolic transfer, >75% of the energy that is generated by skeletal muscle substrate oxidation is liberated as heat. During exercise, several powerful physiological mechanisms of heat loss are activated to prevent an excessive rise in body core temperature. However, a hot and humid environment can significantly add to the challenge that physical exercise imposes on the human thermoregulatory system, as heat exchange between body and environment is substantially impaired under these conditions. This can lead to serious performance decrements and an increased risk of developing heat illness. Fortunately, there are a number of strategies that athletes can use to prevent and/or reduce the dangers that are associated with exercise in the heat. In this regard, heat acclimatisation and nutritional intervention seem to be most effective. During heat acclimatisation, the temperature thresholds for both cutaneous vasodilation and the onset of sweating are lowered, which, in combination with plasma volume expansion, improve cardiovascular stability. Effective nutritional interventions include the optimisation of hydration status by the use of fluid replacement beverages. The latter should contain moderate amounts of glucose and sodium, which improve both water absorption and retention.


A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells.
Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.


Overlapping binding sites for importin β1 and suppressor of fused (SuFu) on glioma-associated oncogene homologue 1 (Gli1) regulate its nuclear localization.
A key factor in oncogenesis is the transport into the nucleus of oncogenic signalling molecules, such as Gli1 (glioma-associated oncogene homologue 1), the central transcriptional activator in the Hedgehog signalling pathway. Little is known, however, how factors such as Gli are transported into the nucleus and how this may be regulated by interaction with other cellular factors, such as the negative regulator suppressor of fused (SuFu). In the present study we show for the first time that nuclear entry of Gli1 is regulated by a unique mechanism through mutually exclusive binding by its nuclear import factor Impβ1 (importin β1) and SuFu. Using quantitative live mammalian cell imaging, we show that nuclear accumulation of GFP-Gli1 fusion proteins, but not of a control protein, is specifically inhibited by co-expression of SuFu. Using a direct binding assay, we show that Impβ1 exhibits a high nanomolar affinity to Gli1, with specific knockdown of Impβ1 expression being able to inhibit Gli1 nuclear accumulation, thus implicating Impβ1 as the nuclear transporter for Gli1 for the first time. SuFu also binds to Gli1 with a high nanomolar affinity, intriguingly being able to compete with Impβ1 for binding to Gli1, through the fact that the sites for SuFu and Impβ1 binding overlap at the Gli1 N-terminus. The results indicate for the first time that the relative intracellular concentrations of SuFu and Impβ1 are likely to determine the localization of Gli1, with implications for its action in cancer, as well as in developmental systems.


Soybean and green tea polyphenols improve immune function and redox status in very old ovariectomized mice.
In previous work we have observed that ovariectomy in rodents, a good model of mimicking human ovarian hormone loss, causes premature aging of the immune system. The prooxidative and inflammatory state that underlies the aging process is the base of that premature immunosenescence. It has been found that nutritional interventions with polyphenolic antioxidants constitute a good alternative to rejuvenate age-affected immune functions. In this study, we administered a diet supplemented with polyphenols (coming from soybean isoflavones and green tea) to sham-operated and ovariectomized mature mice for 15 weeks, until they reached a very old age. We have studied the effect of this supplementation on a broad range of parameters of immune function (in macrophages and lymphocytes) and oxidative stress (enzymatic and nonenzymatic antioxidant defences, oxidant compounds, and lipid peroxidation damage) in peritoneal leukocytes. The results showed that ovariectomy accelerates the age-related impairment of immune functions in very old mice as well as the oxidative and proinflammatory imbalance, and that the administration of soybean isoflavones and green tea improve the immune and redox state in these animals. Because the immune system is a good marker of health and a predictor of longevity, we suggest that an adequate nutritional treatment with polyphenols could be a highly recommended tool to fight against the detrimental effects of the lack of female sex hormones, through an improvement of the immune cell functions and redox state.


Japanese Care Location and Medical Procedures for People with Dementia in the Last Month of Life.
Dementia-related societies worldwide have called for palliative end-of-life care for those suffering dementia; meanwhile, the Japanese dementia plan was revised on January 2015 to introduce into its objectives the support for end-of-life care via increased social and health care collaboration. The study focus was the use of medical procedures in the last month of life among dementia patients in different care locations in Japan. This study was conducted using a retrospective study design. Data from the Survey of Institutions and Establishments for Long-Term Care, which is a nationally representative cross-sectional survey of the public long-term care insurance services, were used. The 6,148 patients who received end-of-life care in their own home, nursing homes, or hospitals in September 2007, 2010, and 2013 were included for analysis. The primary disease of each patient was based on the ICD-10 code; a diagnosis of dementia included F00 (Alzheimer's), F01 (vascular), F02 (other), and F03 (unspecified). Of 6,148 patients, 886 (14.4%) had dementia as a primary disease; most received care in the last month of life in nursing homes (48.0%) or hospitals (44.8%) rather than in their own home (7.2%). Patients were less likely to undergo pain management when their primary disease was dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.21-0.91). Education and policy efforts are required to provide palliative end-of-life care to people with dementia at home. The national dementia plan should also explore possible approaches regarding pain management for dying people who have dementia.


Twelve chromatically opponent ganglion cell types in turtle retina.
The turtle retina has been extensively used for the study of chromatic processing mechanisms. Color opponency has been previously investigated with trichromatic paradigms, but behavioral studies show that the turtle has an ultraviolet (UV) channel and a tetrachromatic visual system. Our laboratory has been working in the characterization of neuronal responses in the retina of vertebrates using stimuli in the UV-visible range of the electromagnetic spectrum. In the present investigation, we recorded color-opponent responses from turtle amacrine and ganglion cells to UV and visible stimuli and extended our previous results that UV color-opponency is present at the level of the inner nuclear layer. We recorded from 181 neurons, 36 of which were spectrally opponent. Among these, there were 10 amacrine (5%), and 26 ganglion cells (15%). Morphological identification of color-opponent neurons was possible for two ganglion cell classes (G17 and G22) and two amacrine cell classes (A22 and A23b). There was a variety of cell response types and a potential for complex processing of chromatic stimuli, with intensity- and wavelength-dependent response components. Ten types of color opponency were found in ganglion cells and by adding previous results from our laboratory, 12 types of opponent responses have been found. The majority of the ganglion cells were R+UVBG- and RG+UVB-color-opponents but there were other less frequent types of chromatic opponency. This study confirms the participation of a UV channel in the processing of color opponency in the turtle inner retina and shows that the turtle visual system has the retinal mechanisms to allow many possible chromatic combinations.


Four decades of surgery for bronchogenic carcinoma in one centre.
Since the authors' initial experience in the surgical management of bronchogenic carcinoma in 1956, more than 40 years have passed. The purpose of this report was to review the authors' data and compare the results by decade (1956-1966; 1967-1976; 1977-1986; and 1987-1996) in order to assess the changing patterns in bronchogenic carcinoma. A total of 1,597 thoracotomies have been performed. Between the first and last decades of the study, patients' mean age increased from 57 to 63 yrs, the ratio of males to females decreased from 19:1 to 3:1 and the proportion of adenocarcinoma cases increased from 10 to 34%. The operative mortality decreased from 10% in 1967- 1976 to 4% in 1987-1996 and the overall 5-yr survival improved from 27 to 36% during the same period. The rate of lobectomy progressively increased from 32% in 1956-1966 to 61% in 1987-1996, whereas that of pneumonectomy and exploratory thoracotomy decreased from 42 to 28% and from 20 to 4%, respectively. Changing patterns of patient characteristics, histology and type of surgery were associated with a constant improvement in the overall 5-yr survival. This improvement was particularly evident among patients with advanced-stage carcinoma.


Exploration of bladder cancer-associated methylated miRNAs by methylated DNA immunoprecipitation sequencing.
The current study aimed to explore the association between two epigenomic components, miRNA and DNA methylation, in bladder cancer (BC). Eight paired samples of tumor tissue and matched adjacent normal tissues from BC patients were subjected to methylated DNA immunoprecipitation sequencing and sRNA-Seq for differentially methylated miRNA genes and differential miRNA analysis. The miRNAs regulated by DNA methylation were screened and their functions involved in BC were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) as well as a miRNA-mRNA interaction network. The methylation levels of 212 genes were different between tumors and normal tissues with specific enrichment at transcription initiation and termination sites. Among these genes, 154 were hypermethylated and 58 were hypomethylated. GO and KEGG pathway enrichment analysis indicated that differentially methylated miRNA genes were mainly enriched in tumor-associated GO terms and signaling pathways. Pairwise statistical analysis of MeDIP-Seq and sRNA-Seq data showed that there are 154 and 165 candidate methylation-regulated genes in tumors and normal tissues, respectively. Notably, an interaction network indicated that the miRNAs regulated by methylation regulated a broad range of mRNAs associated with cancer development and progression. In particular, the most differentially expressed miRNAs were validated by qRT-PCR, such that miR-145-5p was downregulated and miR-182-5p was upregulated in patients with bladder cancer. A large number of miRNA genes were modified by methylation in BC. Identification of changes in the expression of these miRNAs provides a great deal of important information for BC diagnosis.


Left ventricular shape variation in asymptomatic populations: the Multi-Ethnic Study of Atherosclerosis.
Although left ventricular cardiac geometric indices such as size and sphericity characterize adverse remodeling and have prognostic value in symptomatic patients, little is known of shape distributions in subclinical populations. We sought to quantify shape variation across a large number of asymptomatic volunteers, and examine differences among sub-cohorts. An atlas was constructed comprising 1,991 cardiovascular magnetic resonance (CMR) cases contributed from the Multi-Ethnic Study of Atherosclerosis baseline examination. A mathematical model describing regional wall motion and shape was used to establish a coordinate map registered to the cardiac anatomy. The model was automatically customized to left ventricular contours and anatomical landmarks, corrected for breath-hold mis-registration between image slices. Mathematical techniques were used to characterize global shape distributions, after removal of translations, rotations, and scale due to height. Differences were quantified among ethnicity, sex, smoking, hypertension and diabetes sub-cohorts. The atlas construction process yielded accurate representations of global shape (errors between manual and automatic surface points in 244 validation cases were less than the image pixel size). After correction for height, the dominant shape component was associated with heart size, explaining 32% of the total shape variance at end-diastole and 29% at end-systole. After size, the second dominant shape component was sphericity at end-diastole (13%), and concentricity at end-systole (10%). The resulting shape components distinguished differences due to ethnicity and risk factors with greater statistical power than traditional mass and volume indices. We have quantified the dominant components of global shape variation in the adult asymptomatic population. The data and results are available at cardiacatlas.org. Shape distributions were principally explained by size, sphericity and concentricity, which are known correlates of adverse outcomes. Atlas-based global shape analysis provides a powerful method for quantifying left ventricular shape differences in asymptomatic populations. ClinicalTrials.gov NCT00005487.


[Radical cystectomy for the treatment of infiltrating bladder carcinoma. Analysis of 15 years].
Radical cystectomy continues to be the procedure of choice in the treatment of invasive bladder cancer and it is currently an exceptional procedure as monotherapy. The development of surgical techniques for urinary diversion, with less complications, has led to a significant improvement of the overall results achieved with this procedure. We performed a retrospective study of 143 cystectomy procedures that had been performed over a period of 15 years in patients with this tumor type. We evaluated the operative mortality, the morbidity resulting from the procedure, and patient nutritional status and its relation to the appearance of complications. Similarly, we analyzed the different therapeutic strategies we utilized throughout the course of our urological evolution, clearly differentiated into three periods during which we associated radical cystectomy with radiotherapy pre- and post-surgery, neoadjuvant or adjuvant chemotherapy (monotherapy with CDDP or multiple therapy with M-VAC). The operative mortality rate was 0.94% and the incidence of early complications varied according to the different periods, 62% and 32%. Late complications were observed to be 24%. The overall 5-year survival rate was 39% for cystectomy + radiotherapy, 59% when we utilized cisplatin as adjuvant therapy, and 70% (2 years) when we utilized M-VAC neoadjuvant chemotherapy. We believe that distant metastasis was the most common cause of late failures of total cystectomy for infiltrating bladder tumor. Similarly, we believe that the reduced incidence of early complications reported in recent years can be ascribed to the enhanced surgical techniques, better nutritional status of the patient undergoing this procedure, antibiotic therapy, perioperative care, and overall better management and understanding of this disease entity; i. e., the use of a combined therapeutic approach.


Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.
The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs.


Lung transplantation.
First performed in 1963, lung transplantation is approaching the half-century mark. With more than 32,000 procedures having been performed worldwide, lung transplantation has become the standard of care for select patients with advanced lung diseases of various nonmalignant etiologies. Indications for transplantation have broadened over the years, and selection criteria have become less restrictive. A relatively scarce donor pool limits wider application of this therapy, but this is being addressed in part through relaxation of donor selection criteria, donor management protocols that preserve and optimize lung function, and development of ex vivo perfusion techniques to "recondition" suboptimal organs. Bilateral lung transplantation has become the procedure of choice for most indications, although its preferential use in patients with idiopathic pulmonary fibrosis remains controversial. Post-transplantation survival has steadily improved, but significant constraints on long-term survival persist as evidenced by a median survival rate that currently stands at 5.7 years. This has brought into focus the question of whether and for whom transplantation actually confers a survival advantage, a question that in the absence of randomized trials can only be answered with statistical modeling. Primary graft dysfunction, infection, and bronchiolitis obliterans syndrome are common complications encountered by the lung transplant recipient and are major impediments to long-term survival. This review provides an overview of the current status of lung transplantation, highlighting both the many advances that have taken place and the challenges that remain.


Nonuniformity of inner and outer systolic wall thickening in conscious dogs.
Transmural differences in systolic wall thickening were analyzed in 13 conscious dogs by implanting sonomicrometers to continuously measure total wall thickness (WT) and outer WT approximately half the distance through the myocardium at a closely adjacent location. Inner WT was derived by subtraction of outer WT from total WT. Outer wall measurements spanned, on average, the outer 44 +/- 10% (+/- SD) of the wall; derived inner wall measurements spanned the remaining 56 +/- 10%. At rest the fractional contribution (FC) of the outer wall to total systolic wall thickening was 29 +/- 9%, which was significantly less than the FC of the inner wall, 71 +/- 9%. These data are in good agreement with simplified modeling of a cross section of the left ventricle as two concentric rings that predicts that the FC of inner and outer halves of the wall should be approximately 67 and 33%, respectively. During treadmill exercise, the extent of both inner and outer thickening increased significantly (30 and 29%, respectively) but the relative FC of the inner and outer wall remained the same. The data indicate that systolic wall thickening is nonuniform and that this nonuniformity remains constant during the increased inotropic and chronotropic stimulation associated with exercise.


Soybean peptide lunasin suppresses in vitro and in vivo 7,12-dimethylbenz[a]anthracene-induced tumorigenesis.
Lunasin is a novel peptide identified in soybean and other seeds. This study evaluated the anti-tumorigenic effects of lunasin on 7,12-dimethylbenz(a)anthracene (DMBA) and 3-methylcholanthrene-treated (MCA) fibroblast NIH/3T3 cells. Lunasin significantly inhibited cell proliferation and cancerous foci formation in these 2 chemical carcinogens-treated cells. An in vivo SENCAR mouse model induced with DMBA was used to study the mammary cancer preventive properties of dietary lunasin contained in soy protein. Tumor incidence was 67% and 50%, and the tumor generation was 1.88 ± 0.48 and 1.17 ± 0.17, respectively, for the mice fed control diet and experimental diet obtained after AIN-93G supplementation with lunasin-enriched soy protein concentrate (containing 0.23% lunasin). However, no effects were observed in mice fed AIN-93G supplemented with soy protein concentrate (containing 0.15% lunasin). The data provided illustrate the anticancer potential of lunasin both in vitro and in vivo and supports the recommendation of soy protein as a dietary component that may aid in the prevention of mammary cancer.


Solitary rectal ulcer syndrome--clinical, endoscopic, and histological spectrum.
Nineteen patients with solitary rectal ulcer syndrome are presented. The diagnosis was established on sigmoidoscopic and histopathological grounds; the clinical, endoscopic, and histological states were assessed at presentation and on last follow-up. Most of the patients suffered from rectal bleeding, abdominal and anorectal pains, constipation, and straining at defecation. Thirteen patients had macroscopic ulcerations on presentation and six patients did not. These six patients did not develop ulcer during the follow-up period. Four patients entered clinical and endoscopic remission with no histological improvement. Three of them managed conservatively and one underwent suturing of the ulcer and internal anal sphincter dilatation. They remained in remission for a mean follow-up of 1 yr.


Encoding by synchronization in the primate striatum.
Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.


Exercise Tolerance and the Post Exercise Diastolic Filling Pattern in Patients With the Resting Impaired Relaxation.
In patients with normal LV systolic function, cardiac output increases with exercise mediated by increased stroke volume early in exercise and an increase in heart rate later in exercise. Despite normal LV systolic function, patients who display an impaired relaxation pattern may have a reduced exercise tolerance. We hypothesized that the resting impaired relaxation pattern that persists during exercise results in reduced LV filling volume and reduced exercise tolerance. We evaluated consecutive exercise echocardiograms performed at Harper Hospital from 1998-2000 for patients with sinus rhythm, normal resting wall motion and ejection fraction (> 55%), evidence of resting impaired relaxation, and a negative exercise echocardiogram. There were 49 patients fitting the above criteria who were compared with a group of age and sex matched patients (43 patients) with a normal rest and exercise echocardiogram with normal resting transmitral Doppler. Rest and post exercise echocardiography and Doppler parameters were obtained. Patients in the impaired relaxation group demonstrated shorter exercise times as compared to the normal control group (8.8 ± 1.6 versus 9.7 ± 2.0 minutes, P < 0.001). In patients with normal resting transmitral diastolic filling, there was an increased the extent of atrial contribution to LV filling volume post exercise associated with shortening of isovolumic relaxation. Two patterns were seen in the impaired relaxation group post exercise. In 1 subgroup in which E/A ratio decreased post exercise, exercise duration was reduced (7.4 ± 1.3 minutes, P < 0.001) as compared to the subgroup with E/A increase (9.6 ± 1.2 minutes) post exercise which was similar to normal controls. Forward stepwise regression indicated that exercise time was primarily related to E/A change post exercise for all patient groups (r = 0.625, P = 0.0008). Specifically, this was true for patients with E/A reversal at rest (r = 0.584, P = 0.0028). However, for patients with normal diastolic filling at rest, the diastolic velocity integral was the major predictor (r = 0.695, P < 0.0084). We conclude that the transmitral Doppler pattern post exercise provides insight into the mechanism of reduced exercise tolerance in some patients with the resting impaired relaxation pattern. Preservation of this pattern post exercise is associated with reduced exercise tolerance.


Ultrastructural observation of Helicobacter pylori in glucose-supplemented culture media.
Helicobacter pylori in the human gut can be divided morphologically into spiral and coccoid forms. The spiral form is known to change into the coccoid form in culture in vitro. The ultrastructural changes and culturability of H. pylori were studied in medium supplemented with different concentrations of glucose. H. pylori ATCC 43504(T) was cultured in liquid medium containing 10 % heat-inactivated horse serum supplemented with glucose (at 0, 10, 100, 300 and 500 mM) for 7 days. Bacterial ultrastructure and culturability were examined daily. With extended time in culture, the spiral forms had transformed into coccoid forms in all media. The coccoid forms could be further divided into two types, A and B, by electron microscopy. The type A coccoid form had an irregular surface with few flagella and indistinct cytoplasmic membrane. The type B coccoid form had a better-maintained integral membrane structure and was the dominant form in 300 mM glucose-supplemented medium. The highest culturability was obtained using 300 mM glucose-supplemented medium. Based on observations of ultrastructural changes in relation to the culturability data, the coccoid forms could be categorized into three stages: dying, viable but non-culturable and proliferating organisms. The optimal glucose concentration for H. pylori culture in this liquid medium culture experiment was approximately 300 mM.


[Study on the relationships of childhood obesity and the duration of sleep as well as insulin resistance].
To investigate the relationships of childhood obesity and the duration of sleep as well as insulin resistance. Two hundred and sixty-nine simple obese children aged from 7 to 15 years with body mass index(BMI) over 23 and 120 normal healthy children were recruited in this study. Obese children were divided into three groups: Group A: 23 < or = BMI < 25; Group B: 25 < or = BMI < 30; Group C: BMI > or = 30. Duration of sleep was calculated according to the reported sleeping hours during working days and weekends. Oral glucose tolerance test and insulin releasing test were performed in all obese children. Seventy of the 120 healthy children received fasting plasma glucose (FBG) and fasting insulin (FINS) detection. Homeostasis model assessment-insulin resistance (HOMA-IR) and islet beta cell secreting index (HOMA-IS) were calculated. The duration of sleep was shorter in all 3 obese groups than that in the control group and the levels of FBG, FINS and HOMA-IR were higher (P < 0.05). The levels of HOMA-IS in Group B and C were higher than that in the control group (P < 0.05), while HOMA-IS did not show much difference among the 3 obese groups and between Group A and the control group (P > 0.05). Logistic analysis showed that the duration of sleep was related to childhood obese (P < 0.05). Results from multiple linear regression model analysis showed that BMI bore a relation to HOMA-IR and HOMA-IS (P < 0.05), as well as one unit increase in BMI accompanied with 0.261 and 11.054 increase in HOMA-IR and HOMA-IS, respectively. Children with shorter duration of sleep were susceptible to become obese. A significant correlation did exist between BMI and insulin resistance.


Streptococcus suis serotype 2 strains isolated in Argentina (South America) are different from those recovered in North America and present a higher risk for humans.
Streptococcus suis serotype 2 is an important swine pathogen and emerging zoonotic agent causing meningitis and septicemia/septic shock. Strains are usually virulent (Eurasia) or of intermediate/low virulence (North America). Very few data regarding human and swine isolates from South America are available. Seventeen new human S. suis cases in Argentina (16 serotype 2 strains and a serotype 5 strain) are reported. Alongside, 14 isolates from pigs are analyzed: 12 from systemic disease, one from lungs and one from tonsils of a healthy animal. All human serotype 2 strains and most swine isolates are sequence type (ST) 1, as determined by multilocus sequence typing and present a mrp+/epf+/sly+ genotype typical of virulent Eurasian ST1 strains. The remaining two strains (recovered from swine lungs and tonsils) are ST28 and possess a mrp+/epf - /sly- genotype typical of low virulence North American strains. Representative human ST1 strains as well as one swine ST28 strain were analyzed by whole-genome sequencing and compared with genomes from GenBank. ST1 strains clustered together with three strains from Vietnam and this cluster is close to another one composed of 11 strains from the United Kingdom. Close contact with pigs/pork products, a good surveillance system, and the presence of potentially virulent Eurasian-like serotype 2 strains in Argentina may be an important factor contributing to the higher number of human cases observed. In fact, Argentina is now fifth among Western countries regarding the number of reported human cases after the Netherlands, France, the UK and Poland.


Effect of nurse case management on the treatment of older women with breast cancer.
To evaluate the effect of nurse case management on the treatment of older women with breast cancer. Randomized prospective trial. Sixty surgeons practicing at 13 community and two public hospitals in southeast Texas. Three hundred thirty-five women (166 control and 169 intervention) aged 65 and older newly diagnosed with breast cancer. Women seeing surgeons randomized to the intervention group received the services of a nurse case manager for 12 months after the diagnosis of breast cancer. The primary outcome was the type and use of cancer-specific therapies received in the first 6 months after diagnosis. Secondary outcomes were patient satisfaction and arm function on the affected side 2 months after diagnosis. More women in the intervention group received breast-conserving surgery (28.6% vs 18.7%; P=.031) and radiation therapy (36.0% vs 19.0%; P=.003). Of women undergoing breast-conserving surgery, greater percentages in the case management group received adjuvant radiation (78.3% vs 44.8%; P=.001) and axillary dissection (71.4% vs 44.8%; P=.057). Women in the case management group were also more likely to receive more breast reconstruction surgery (9.3% vs 2.6%, P=.054), and women in the case management group with advanced cancer were more likely to receive chemotherapy (72.7% vs 30.0%, P=.057). Two months after surgery, higher percentages of women in the case manager group had normal arm function (93% vs 84%; P=.037) and were more likely to state that they had a real choice in their treatment (82.2% vs 69.9%, P=.020). Women with indicators of poor social support were more likely to benefit from nurse case management. Nurse case management results in more appropriate management of older women with breast cancer.


Parasympathetic cardiovascular control in human disease: a critical review of methods and results.
A variety of experimental approaches have been used to alter reflex parasympathetic cardiovascular control in normal human subjects and in patients with cardiovascular diseases. This review critically appraises several of these methods (the Valsalva maneuver, upright tilt, lower body negative pressure, pressor drug infusion, neck suction, and coronary arteriography) and summarizes the normal response patterns of healthy subjects and the abnormal response patterns of some patients with cardiovascular disease. Tests of parasympathetic function tend to be heterogeneous; they are not standardized, and, therefore, valid comparisons between results from different studies may be difficult to make. Moreover, although most of these tests are simple to perform, they may provoke surprisingly complex alterations of afferent and efferent autonomic activity. Notwithstanding these methodological difficulties, the research area of human parasympathetic cardiovascular control may have great importance, because parasympathetic reflex mechanisms are involved in diseases of major public health significance for which animal models may be imperfect or nonexistent.


Brown seaweed fucoidan: biological activity and apoptosis, growth signaling mechanism in cancer.
Seaweeds, being abundant sources of bioactive components have much interest in recent times. The complex polysaccharides from the brown, red and green seaweeds possess broad spectrum therapeutic properties. The sulfated polysaccharides are routinely used in biomedical research and have known biological activities. Fucoidan, a fucose-rich polysaccharide extracted from brown seaweed has various biological functions including anticancer effects. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, the mechanism of cell death depends on the magnitude of DNA damage following exposure to anticancer agents. Apoptosis is mainly regulated by cell growth signaling molecules. Number of research studies evidenced that fucoidan shown to induce cytotoxicity of various cancer cells, induces apoptosis, and inhibits invasion, metastasis and angiogenesis of cancer cells. There are few articles discussing on fucoidan biological activity but no specific review on cancer and its signaling mechanism. Hence, this review discusses the brown seaweed fucoidan structure and some biological function and role in apoptosis, invasion, metastasis, angiogenesis and growth signal mechanism on cancer.


Binding of the cSH3 domain of Grb2 adaptor to two distinct RXXK motifs within Gab1 docker employs differential mechanisms.
A ubiquitous component of cellular signaling machinery, Gab1 docker plays a pivotal role in routing extracellular information in the form of growth factors and cytokines to downstream targets such as transcription factors within the nucleus. Here, using isothermal titration calorimetry (ITC) in combination with macromolecular modeling (MM), we show that although Gab1 contains four distinct RXXK motifs, designated G1, G2, G3, and G4, only G1 and G2 motifs bind to the cSH3 domain of Grb2 adaptor and do so with distinct mechanisms. Thus, while the G1 motif strictly requires the PPRPPKP consensus sequence for high-affinity binding to the cSH3 domain, the G2 motif displays preference for the PXVXRXLKPXR consensus. Such sequential differences in the binding of G1 and G2 motifs arise from their ability to adopt distinct polyproline type II (PPII)- and 3(10) -helical conformations upon binding to the cSH3 domain, respectively. Collectively, our study provides detailed biophysical insights into a key protein-protein interaction involved in a diverse array of signaling cascades central to health and disease.


The Endometrial Polarity Paradox: Differential Regulation of Polarity Within Secretory-Phase Human Endometrium.
A major cause of infertility in normal and assisted reproduction cycles is failure of the endometrium to undergo appropriate changes during the secretory phase of the menstrual cycle as it acquires receptivity for an implanting blastocyst. Current dogma states that loss of epithelial polarity in the luminal epithelial cells, the point of first contact between maternal endometrium and blastocyst, may facilitate embryo implantation. Loss of polarity is likely an important change during the secretory phase to overcome mutual repulsion between otherwise polarized epithelial surfaces. Although "plasma membrane transformation" describes morphological/molecular alterations associated with loss of polarity, direct measures of polarity have not been investigated. Transepithelial resistance, a proxy measure of polarity, was downregulated in endometrial epithelial (ECC-1) cells by combined estrogen/progestin, mimicking the hormonal milieu of the secretory phase. Examination of defined polarity markers within human endometrium throughout the menstrual cycle identified downregulation of atypical protein kinase C, Stardust, Crumbs, and Scribble within the luminal-epithelial layer, with upregulation of Scribble within the stromal compartment as the menstrual cycle progressed from the estrogen-dominated proliferative to progesterone-dominated secretory phase. Epithelial (ECC-1) Scribble expression was downregulated in vitro by combined estrogen/progestin and estrogen/progestin/human chorionic gonadotropin treatment, whereas knockdown of Scribble in these cells enhanced "embryo" (trophectodermal spheroid) adhesion. In contrast, Scribble was upregulated within decidualized primary human endometrial stromal cells, with decidualization downregulated upon Scribble knockdown. These data highlight an important contribution of polarity modulation within the human endometrium, likely important for receptivity. Clinical investigations examining how polarity may be modulated in the infertile endometrium may facilitate fertility.


Effect of cooling on smooth muscle response to 5-hydroxytryptamine in human hand veins.
5-Hydroxytryptamine has been suggested to be a mediator in peripheral cold-induced vasospasm. In order to investigate the contribution of different 5-hydroxytryptamine receptor subtypes in the contractile response during cooling, segments of subcutaneous hand veins obtained from 50 patients undergoing hand surgery were examined in vitro in organ baths. The temperature in the bath was initially 37 degrees C and was either continuously lowered to 10 degrees C or kept constant at 37 degrees C, 29 degrees C. Cooling to 25 degrees C augmented the contractile response to 5-hydroxytryptamine in intact as well as in endothelium-denuded segments. The 5-hydroxytryptamine2 receptor antagonist ketanserin antagonized the contractile response to 5-hydroxytryptamine at 37 degrees C, and in addition abolished the cold-induced enhancement of the response during cooling. This points to a major role of the 5-hydroxytryptamine2 receptor in the cold-induced augmentation of the response to 5-hydroxytryptamine, which was further supported by increased contractions to the 5-hydroxytryptamine2 receptor agonist alpha-methyl-5-hydroxytryptamine during cooling. Contractile responses were also obtained by the selective 5-hydroxytryptamine1-like receptor agonist GR43175 interpreted to indicate the presence of a smaller 5-hydroxytryptamine1-like receptor population. However, the response to GR43175 was unaffected by cooling. These results warrant further investigations of the role of 5-hydroxytryptamine in cold-induced peripheral vasospasm.


Barcoded point-of-care bioassays.
Barcode technology can deliver batched information for patient healthcare. For clinical examinations, barcodes serve as reporters for labeling multiple targets, and meanwhile, facilitate improved sensitivity and specificity, thus enabling barcode as a promising alternative to traditional labels for biomarker identification and signal amplification. However, faced with the stringent claims of point-of-care (POC) bioassays, efforts are needed to advance current technologies toward rapidity, robustness, affordability, and user-friendliness. In the past decades, chemists have succeeded in delicate fabrication of the barcode libraries for encoding. Nevertheless, the decoding technologies remain poorly discussed, especially simplified decoding strategies for POC bioassays. Recent emergence of portable cartridges and miniaturized signal-recording devices has brought a promise to merge barcodes-assisted bioassay with POC testing (POCT). This review provides a comprehensive summary on barcode encoding and decoding, with emphasis on their potential use in POCT, facilitated by improved manufacturing and portable devices. Future directions of barcoded bioassays for POCT and current challenges are also presented. We anticipate that this review will be beneficial to promoting barcodes toward broad applications.


Percutaneous stenting of the internal carotid artery: the European CAST I Study. Carotid Artery Stent Trial.
To report the results of a multicenter safety trial of percutaneous carotid stenting performed by vascular surgeons. Symptomatic or asymptomatic patients > or = 65 years of age with internal carotid artery (ICA) stenoses > or = 70% and < or = 2-cm long were eligible for enrollment. The procedures were performed in an operating room with the choice of anesthesia and the percutaneous access site at the discretion of the surgeon. Only Palmaz stents were used. From January 1, 1996 to December 31, 1997, 99 patients (74 men, mean age 70 years, range 51 to 94) were enrolled in the study. More than half (57 of 99 patients) were asymptomatic. The direct cervical approach was used predominantly (97%). Three (3%) cases were converted to surgery for inability to access the artery or deploy the stent (technical success 97%). No perioperative death or myocardial infarction was reported. Six (6%) procedural complications included 1 reversible arterial spasm, 2 dissections, 1 cervical hematoma, and 2 residual stenoses. One neurological event reversed within 7 days (1% minor stroke rate) and 4 (4%) transient ischemic attacks resolved within 24 hours. One (1%) asymptomatic early occlusion occurred 2 days postoperatively. No neurological event was observed in the 1- to 24-month follow-up (mean 13 months). Two (2%) patients died of nonprocedurally related causes. No stent compression was seen, but 1 asymptomatic occlusion and 3 asymptomatic, non-flow-limiting restenoses (2 < 40%, 1 at 60%) were found within 1 year (3% restenosis rate on an intention-to-treat basis). Patency was 98% at 1 year. The results of this trial support the contention that carotid stenting of short ICA lesions can be performed with a low neurological complication rate.


Maternal body burdens of PCDD/Fs and PBDEs are associated with maternal serum levels of thyroid hormones in early pregnancy: a cross-sectional study.
Thyroid hormones (THs) regulate many biological functions in the human body and are essential for normal brain development. Epidemiological studies have observed diverging associations between halogenated persistent organic pollutant (POP) exposure and concentrations of THs in pregnant women and their infants. We investigated whether background exposure to polybrominated diphenyl ethers (PBDEs) is related to TH status in a Swedish population of pregnant women and their infants. Furthermore, we examined associations between polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) and TH status in early pregnancy as an extension of an earlier study focusing on late pregnancy TH status. Free thyroxine (T4), total triiodo-thyronine (T3) and thyroid stimulating hormone (TSH) were analysed in serum from first-time mothers (N = 220-281) in the first and third trimester, and in infants (N = 115-150) 3 weeks and 3 months after delivery. Antibodies to thyroid peroxidase (anti-TPO) (N = 260) were measured in maternal third trimester serum. Maternal body burdens of PCBs (N = 281) were estimated from serum lipid PCB concentrations in late pregnancy, and PCDD/F (N = 97) and PBDE (N = 186) body burdens were estimated from concentrations in mother's milk lipids 3 weeks after delivery. Linear regression models allowed for covariate adjustment of the associations between ln-transformed POP body burdens and concentrations of TH and anti-TPO. Maternal body burden of BDE-153 was inversely associated with first trimester total T3, otherwise no associations between PBDEs and first and second trimester THs were observed. No associations were found between maternal PBDE body burdens and infant THs. Maternal body burden of PCDD/Fs were inversely associated with first trimester total T3. No associations were observed between PCBs and first trimester THs. Third trimester anti-TPO was not associated with maternal PCBs, PCDD/Fs and PBDEs. Our results suggest that maternal PCDD/F and BDE-153 body burdens influence maternal TH status in early pregnancy, which is a critical period when maternal TH status influences fetal development.


Prevalence and etiology of urinary stones in hospitalized patients in Baghdad.
Epidemiology and pathogenesis in urinary stones diagnosed in 184 patients were studied. Mean age was 38.3 years. Male to female ratio was 2.5:1. Stones were predominantly of mixed type: calcium oxalate was the commonest compound. Anatomical distribution of urinary stones was 67.4% renal, 12.5% ureteric and 14.6% bladder. Recurrence rate following previous surgical removal was 15.0%. Bacteria were isolated from 19 (24.4%) of 78 urinary stones: 14 were urea splitting and 5 non-urea splitting. Females had a greater chance of having infected stones. All bacteria isolated were sensitive to gentamicin and nalidixic acid. All isolates were resistant to amoxicillin and erythromycin. Multiple resistance to 6 antimicrobial agents was common (58.8%).


Local Health Departments' Engagement in Activities to Address Opioid Use and Abuse: The Influence of Surveillance Systems' Use.
To examine the extent to which local health departments (LHDs) conduct activities to address opioid use and abuse. To test the hypothesis that (i) LHDs' access to data from an electronic syndromic surveillance system is associated with conducting activities to address opioid use and abuse, and (ii) among those LHDs with access to syndromic surveillance data, the use of syndromic and other surveillance data on opioid-related events is associated with LHDs' report of conducting activities to address opioid use and abuse. Logistic regression was used to analyze data from the 2018 Forces of Change Survey of a statistically representative sample of 966 LHDs, of which 591 participated in the survey. The LHDs' access to a syndromic surveillance system was significantly associated with their report of conducting activities to address opioid use and abuse. Compared with LHDs that had no surveillance systems, odds of participating in activities to address the opioid use or abuse were higher for LHDs that managed their own surveillance systems (adjusted odds ratio, AOR = 3.022, P = .03) and those who had but did not manage their own surveillance systems (AOR = 1.920, P < .01). The LHDs' use of syndromic surveillance systems (AOR = 2.98, P = .01) or other surveillance systems (AOR = 2.21, P = .03) was also associated with higher odds to participate in activities to address the opioid use or abuse (vs no such use). The LHDs are strategically well positioned to play their role in addressing this multifaceted epidemic. Access to data or information from electronic syndromic surveillance systems that use hospital emergency department data might significantly improve LHDs' engagement in conducting activities to address opioid use and abuse within their communities while building their capacity to face the next epidemic.


The pharmacology of diabetic complications.
In spite of the significant developments in antidiabetic therapy, diabetic complications, particularly seen in long-term diabetes, continue to be seriously deleterious. Various types of diabetic complications affecting different systems in the body have been reported. The clinical course of the disease is largely determined by those complications. Therefore, an important area is obviously prevention or treatment of the disabling complications associated with diabetes. Recent investigations address to the problem from different angles, since the development of diabetes-induced long-term problems is likely a multifactorial process. In this review, some of the factors which are implicated in the development of these complications such as neuropathy, retinopathy and cataract are discussed. Some of the approaches which have been used in attempts to prevent or delay those abnormalities are reported as well.


Direct visualization of organelle movement along actin filaments dissociated from characean algae.
A system has been developed in which organelle transport can be studied without the influence of an organized cellular cytoplasm. Binding and continuous unidirectional movement of organelles along isolated cellular transport cables were directly visualized by video light microscopy after the dissociation of the cytoplasm of characean algae cells in a Ca2+-free buffer containing adenosine triphosphate. Individual organelles had more than one attachment site and moved at mean rates of 11.2 or 62.1 micrometers per second along multiple parallel pathways on each cable. Electron microscopy of these cables after direct freezing demonstrated that they consist of compact bundles of actin filaments. Under these conditions, characteristics of organelle movement should reflect directly the underlying molecular processes of binding and force generation.


The epidemiology of illness and injury at the alpine venues during the Salt Lake City 2002 Winter Olympic Games.
The Emergency Medicine literature has described levels of medical care for mass gatherings in the United States, including for the Los Angeles 1984 Summer and Calgary 1988 Winter Olympic Games. However, there are limited data to describe the type and number of illness or injury that may occur during mass gatherings in an alpine winter environment. To describe the epidemiology of illness and injury seen among spectators at the alpine and snowboarding venues during the Salt Lake City 2002 Winter Olympic Games, we conducted a retrospective review of the Salt Lake City 2002 Olympic Medical Care database for all patient encounters during the operational period of the Games at the alpine and snowboarding venues. The three venues included were: Deer Valley Resort (DVR), Park City Mountain Resort (PCM), and Snowbasin Resort (SBA). Each venue had a medical clinic located on site for spectators and another for athletes. Physicians, nurses, emergency medical technicians, and therapists staffed the clinics. The database was created by Inter-mountain Health Care (IHC) in conjunction with Salt Lake City 2002 Winter Olympic staff and consisted of descriptive reports of all patient encounters from all venues including demographic, epidemiology, and outcome information. IHC maintains the database, and was the sole medical provider for the Games. Each venue had at least 6 days of competition events. Over the 19 days of the Olympiad, a total of 410,160 spectators and 3,961 competitive athletes attended the three venues. There were 841 spectators evaluated and treated at the venue clinics, and mobile medical staff treated 262 spectators. The top five spectator clinic diagnostic categories were: sprain/strain (n=108), miscellaneous trauma (n=103), respiratory (n=88), miscellaneous medical (n=69), and digestive (n=52). Fifty spectators required transport to a hospital for additional care: 27 required transfer by ground ambulance and the remainder were transported by private vehicle. The overall spectator medical utilization rate was 26.9. In conclusion, the rate and acuity of patients seen at the alpine venues during the 2002 Winter Olympic Games was low. Nevertheless, we recommend full on-site physician and nurse staffing with advanced trauma and cardiac life support available during similar events.


[Metformin-induced lactic acidosis due to acute renal failure].
Lactic acidosis is a serious but uncommon side effect of metformin use. We discuss the pathophysiological mechanisms of lactic acidosis with particular regard to the role played by the drug as a potential cause of the entity. We report on a severe case of this kind of drug toxicity in a patient with type 2 diabetes mellitus, admitted to the emergency department with acute renal failure symptoms. The diagnosis was supported by elevated serum levels of the biguanide, a procedure scarcely used in clinical practice. The management of this complication consists in drug discontinuation and hemodialysis with bicarbonate that provides symptomatic and ethiological treatment by removing both the lactate and the hypoglycemic agent from the serum. Since the symptoms of metformin-associated lactic acidosis are unspecific and its onset is subtle, a high level of suspicion is needed to establish an early diagnosis.


Prevalence of substance misuse in new patients in an outpatient psychiatry clinic using a prescription monitoring program.
To investigate the value of a prescription monitoring program in identifying prescription drug misuse among patients presenting to a resident physician outpatient psychiatry clinic at an academic medical center. Participants were 314 new patients aged 18 years or older presenting to the clinic from October 2011 to June 2012. Resident physicians completed a data collection form for each participant using information from the patient interview and from the prescription monitoring program report. Prescription drug misuse was defined as having any 1 of the following 5 criteria in the prescription monitoring program report: (1) filled prescriptions for 2 or more controlled substances, (2) obtained prescriptions from 2 or more providers, (3) obtained early refills, (4) used 3 or more pharmacies, and (5) the prescription monitoring program report conflicted with the patient's report. At least 1 indicator of prescription drug misuse was found in 41.7% of patients. Over 69% of the patients that the residents believed were misusing prescription drugs actually met 1 of the criteria for prescription drug misuse. The prescription monitoring program report changed the management only 2.2% of the time. Patients with prior benzodiazepine use (χ(2) 1 = 17.68, P < .001), prior opioid use (χ(2) 1 = 19.98, P < .001), a personality disorder (χ(2) 1 = 7.22, P < .001), and chronic pain (χ(2) 1 = 14.31, P < .001) had a higher percentage of prescription drug misuse compared to patients without these factors. Using the prescription monitoring program to screen patients with prior benzodiazepine and opioid use, with a personality disorder, and/or with chronic pain may be useful in confirming the suspicion of prescription drug misuse identified at the initial evaluation.


Prevalence, associated factors and source of support concerning supportive care needs among Japanese cancer survivors.
The current study aimed to describe cancer survivors' supportive care needs in Japan, to identify associated factors of unmet needs, and to describe the source of support that are preferred and actually used by cancer survivors. Using a web-based questionnaire, we examined unmet supportive needs and its associated factors among 628 adult Japanese cancer survivors. The questionnaire comprised 16 items representing five domains (medical-psychological, financial, social-spiritual, sexual, and physical needs). Prevalence of unmet need ranged from 5 to 18%, depending on different domains. The prevalence was high in medical-psychological and financial domains and relatively low in physical and sexual domains. Poor performance status, psychiatric morbidity and low income status were associated with unmet needs of most domains. Most cancer survivors preferred and actually sought support from their family and friends. Financial needs were preferred to be provided by non-medical professionals. Call for peer support was intense, especially for medical-psychological, social-spiritual, and sexual needs; however, peer support was not well-provided. This study illustrated characteristics of Japanese cancer survivors who are likely to have unmet needs. The study demonstrated need for expanded involvement of non-medical professionals and peer support, especially in the domains of medical-psychological, social-spiritual, financial and sexual needs.


The refinement of dose assessment of the THOR BNCT beam.
A refined dose assessment method has been used now in the THOR BNCT facility, which takes into account more delicate corrections, carefully handled calibration factors, and the spectrum- and kerma-weighted k(t) value. The refined method solved the previous problem of negative derived neutron dose in phantom at deeper positions. With the improved dose assessment, the calculated and measured gamma-ray dose rates match perfectly in a 15×15×15 cm(3) PMMA phantom.


Obesity in Children with Leptin Receptor Gene Polymorphisms.
The study of single nucleotide polymorphisms (SNPs) of the leptin receptor gene (LEPR) based on next generation genomic sequencing (NGS) data is becoming an increasingly important aspect of diagnosis, treatment and prevention of both metabolically healthy (MHO) and metabolically unhealthy obesity (MUO) phenotypes. 35 obese children 6-18 years old were examined by the NGS method with bioinformatic analysis. The main group (n = 18) was formed by children with MUO, according to the recommendations of the expert group of the National Heart, Lung, and Blood Institute. The control group (n = 17) was represented by children with MHO. Statistical methods were used: analysis of variance, Wald's sequential analysis, Spearman's correlation analysis, analysis of nominal data and multiple discriminant analysis. 10 types of non-synonymous SNPs (rs3790435, rs1137100, rs2186248, rs70940803, rs79639154, rs1359482195, rs1137101, rs1805094, rs13306520, rs13306522) of the LEPR gene in obese children have been identified. Multiple discriminant analysis demonstrated that the following LEPR SNPs are of greatest importance in the development of MUO: rs3790435, rs13306522, rs13306520. Analysis of nominal data revealed significant differences in the groups for Copy number variation (CNV) rs3790435 of the LEPR gene. Wald's analysis allowed us to identify 6 important predictors of MUO (І ≥ 0.5): 2 CNV rs3790435 (Relative Risk, RR = 2, Prognostic coefficient, PC = +2.76); male gender of the child (RR = 1.3, PC = +1.35); rs3790435 (RR = 1.9, PC = +2.76); hyperleptinemia more than 40.56 ng/ml (RR = 2, PC = +3); CNV rs1359482195 ≥ 3 (RR = 1.9, PC = +5.8); SNP of the LEPR gene ≥4 (RR = 3.8, PC = +5.8). Children with the genotype rs3790435 gene LEPR had signs of MUO more often.


Fronto-facial advancement and bipartition in Crouzon-Pfeiffer and Apert syndromes: Impact of fronto-facial surgery upon orbital and airway parameters in FGFR2 syndromes.
A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon-Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon-Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes.


Patient-controlled analgesia-related medication errors in the postoperative period: causes and prevention.
Patient-controlled analgesia (PCA) is a common and effective means of managing postoperative pain. Unfortunately, the complex processes and equipment associated with the setup, programming and administration of intravenous or epidural PCA have allowed it to become a significant source of preventable medication errors. These errors can be classified into two major categories: human (operator) errors and equipment errors (malfunctions). Such errors are potentially harmful to patients, time-consuming for hospital staff and costly for healthcare providers. The objective of this article is to describe PCA medication errors and examine systems and modalities that may help reduce the incidence of system-related errors. Data from the US FDA's Manufacturer and User Facility Device Experience (MAUDE) database indicate that 6.5% of intravenous PCA-related events were due to operator error. Most (81%) of these errors were due to pump misprogramming, of which almost half were associated with patient harm; 76.4% of adverse events were attributed to device malfunction (e.g. due to frayed wires or a crack in the drug cartridge), although only 0.5% of these were associated with harm to patients. In a report based on data from MEDMARX, a voluntary database that captures reports on medication errors, 7.9% of the PCA-related errors captured over a 5-year period were described as causing harm to patients. Technological advances, such as improved PCA pump designs based on ergonomic and cognitive engineering principles, the use of barcode technology and other 'smart pump' safety features, and new postoperative pain management modalities, may play a significant role in reducing the future incidence and severity of PCA medication errors.


Extensive sampling of polar bears (Ursus maritimus) in the Northwest Passage (Canadian Arctic Archipelago) reveals population differentiation across multiple spatial and temporal scales.
As global warming accelerates the melting of Arctic sea ice, polar bears (Ursus maritimus) must adapt to a rapidly changing landscape. This process will necessarily alter the species distribution together with population dynamics and structure. Detailed knowledge of these changes is crucial to delineating conservation priorities. Here, we sampled 361 polar bears from across the center of the Canadian Arctic Archipelago spanning the Gulf of Boothia (GB) and M'Clintock Channel (MC). We use DNA microsatellites and mitochondrial control region sequences to quantify genetic differentiation, estimate gene flow, and infer population history. Two populations, roughly coincident with GB and MC, are significantly differentiated at both nuclear (F ST = 0.01) and mitochondrial (ΦST = 0.47; F ST = 0.29) loci, allowing Bayesian clustering analyses to assign individuals to either group. Our data imply that the causes of the mitochondrial and nuclear genetic patterns differ. Analysis of mtDNA reveals the matrilineal structure dates at least to the Holocene, and is common to individuals throughout the species' range. These mtDNA differences probably reflect both genetic drift and historical colonization dynamics. In contrast, the differentiation inferred from microsatellites is only on the scale of hundreds of years, possibly reflecting contemporary impediments to gene flow. Taken together, our data suggest that gene flow is insufficient to homogenize the GB and MC populations and support the designation of GB and MC as separate polar bear conservation units. Our study also provide a striking example of how nuclear DNA and mtDNA capture different aspects of a species demographic history.


Isolation of 45 exon-like fragments from 8p22-->p21.3, a region that is commonly deleted in hepatocellular, colorectal, and non-small cell lung carcinomas.
The loss of heterozygosity that is frequently observed at chromosome 8p22-->p21.3 in hepatocellular carcinomas (HCC), colorectal cancers (CRC), prostate cancers (PRC). and non-small cell lung cancers (NSCLC), suggests the presence there of one or more tumor suppressor genes associated with development and/or progression of these types of carcinomas. We have constructed a cosmid contig map of the target region by means of Southern hybridization and have isolated 45 exon-like fragments by exon amplification, using cosmid clones derived from three yeast artificial chromosomes (YACs). The map and the exon-like fragments reported here will be useful resources for isolation of the putative tumor suppressor gene(s) as well as other novel genes located in the 8p22-->p21.3 region.


Investigation of the frequency of COVID-19 in patients treated with intravesical BCG.
In this retrospective study, we aimed to investigate the frequency of COVID-19 in patients with and without BCG application due to bladder tumors. The presence of COVID-19 was investigated in 167 patients with BCG and 167 without bladder cancer. All patients were compatible with COVID-19 infection. Patients with RT-PCR positive for SARS-CoV-2 and/or Chest CT positive for viral pneumonia between March and May 2020 were included in the study. A total of 334 patients were included in the study. The mean age of the 167 patients in the study group was 71.1±14.2 1 (min. 38.0- max. 98.0 years), 141 (84.4%) were male. The mean age of the 167 patients in the control group was 70.5±13.8 years (min. 41.0- max. 96.0 years), and 149 were male (p> 0.05). COVID-19 was detected in 5 patients in the BCG group and in 4 patients in the control group (P> 0.05). Intravesical BCG administration does not decrease the frequency of COVID-19 infection.


Retinal nerve fiber layer thickness in multiple sclerosis with and without optic neuritis: a four-year follow-up study from Oman.
Multiple sclerosis (MS) is an autoimmune disease that attacks the central nervous system, with optic neuritis (ON) being a common early manifestation. Retinal nerve fiber layer (RNFL) thickness may be a biomarker of neuroaxonal damage in MS patients. We sought to evaluate changes in RNFL thickness over 4 years in Omani MS patients with or without ON in comparison to a healthy control group. This retrospective case-control study involved 27 MS patients and 25 healthy controls. Optical coherence tomography was performed upon first diagnosis and at a four-year follow-up. Differences in mean RNFL thickness were calculated. A total of 51 eyes from the MS group and 50 eyes from the control group were evaluated. There was a significant reduction in mean RNFL thickness among MS patients with ON at follow-up (81.21 versus 72.14 μm; P = .003), whereas no significant RNFL thinning was observed among MS patients without ON. However, there was a significant reduction in RNFL thickness among MS patients compared to healthy controls (76.79 versus 93.72 μm; P = .009), regardless of ON presence/absence. Axonal damage was seen in the optic nerves of Omani MS patients. Moreover, there was a significant reduction in RNFL thickness among MS patients with ON as the disease progressed; however, while there was evidence of RNFL thinning in MS patients without ON, this difference lacked statistical significance. Evaluation of RNFL thickness may represent a useful biomarker for monitoring disease progression in MS and its association with ON.


Bounding Analysis of Drinking Water Health Risks from a Spill of Hydraulic Fracturing Flowback Water.
A bounding risk assessment is presented that evaluates possible human health risk from a hypothetical scenario involving a 10,000-gallon release of flowback water from horizontal fracturing of Marcellus Shale. The water is assumed to be spilled on the ground, infiltrates into groundwater that is a source of drinking water, and an adult and child located downgradient drink the groundwater. Key uncertainties in estimating risk are given explicit quantitative treatment using Monte Carlo analysis. Chemicals that contribute significantly to estimated health risks are identified, as are key uncertainties and variables to which risk estimates are sensitive. The results show that hypothetical exposure via drinking water impacted by chemicals in Marcellus Shale flowback water, assumed to be spilled onto the ground surface, results in predicted bounds between 10-10 and 10-6 (for both adult and child receptors) for excess lifetime cancer risk. Cumulative hazard indices (HICUMULATIVE ) resulting from these hypothetical exposures have predicted bounds (5th to 95th percentile) between 0.02 and 35 for assumed adult receptors and 0.1 and 146 for assumed child receptors. Predicted health risks are dominated by noncancer endpoints related to ingestion of barium and lithium in impacted groundwater. Hazard indices above unity are largely related to exposure to lithium. Salinity taste thresholds are likely to be exceeded before drinking water exposures result in adverse health effects. The findings provide focus for policy discussions concerning flowback water risk management. They also indicate ways to improve the ability to estimate health risks from drinking water impacted by a flowback water spill (i.e., reducing uncertainty).


Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity.
Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.


Polymorphic TP53BP1 and TP53 gene interactions associated with risk of squamous cell carcinoma of the head and neck.
Tumor protein 53-binding protein 1 (TP53BP1) and TP53 interact during TP53-mediated transcriptional activation and during checkpoint activation in response to DNA damage. Because suboptimal repair of tobacco-induced DNA damage is associated with risk of squamous cell carcinoma of the head and neck (SCCHN), we hypothesized that potentially functional polymorphisms in TP53BP1 and TP53 may contribute jointly to SCCHN risk. In a case-control study, DNA samples from age- and sex-matched SCCHN patients (n=818) and cancer-free controls (n=821) were genotyped for the presence of three variants of TP53BP1 (T-885G, Glu(353)Asp, and Gln(1136)Lys) and three variants of TP53 (Arg(72)Pro, PIN3, and MspI). Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Although none of these six genetic variants alone was associated with SCCHN risk, the combined TP53BP1 genotypes were associated with a significant, dose response-dependent decrease in SCCHN risk among carriers of TP53Pro(72)Pro, TP53PIN3del/del, and TP53Msp1AA genotypes (trend test: P=0.024, 0.016, and 0.016, respectively). Furthermore, TP53BP1 variant haplotype GGC carriers who were also TP53 variant homozygotes had a significantly lower risk of SCCHN than did TP53BP1 haplotype TCA carriers (adjusted OR, 0.48; 95% CI, 0.25-0.94 for TP53Pro(72)Pro; adjusted OR, 0.17; 95% CI, 0.04-0.69 for TP53PIN3del/de; and adjusted OR, 0.16; 95% CI, 0.04-0.65 for TP53Msp1AA). There was statistical evidence of interaction between TP53BP1 and TP53 diplotypes (P=0.017). Our data suggest that TP53BP1 variants may have protective effects on SCCHN risk but such effects were confined to TP53 variant allele/haplotype carriers.


Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD/Shi/Kbe mice by anti-MHC class I Kd monoclonal antibody.
The immune mechanisms directly responsible for beta-cell destruction in insulin-dependent diabetes are undefined. We studied the role of MHC class I-restricted T lymphocytes in the development of diabetes in cyclophosphamide (CY)-treated male and untreated female NOD mice (H-2Kd,Db). After administration of CY to 10-wk-old male NOD/Shi/Kbe mice, 37 of 64 (58%) phosphate-buffered saline-injected control mice and 13 of 22 (59%) anti-Kb and 12 of 27 (44%) anti-Db monoclonal antibody (MoAb)-injected mice became diabetic by 14 wk of age, whereas only 3 of 38 (8%) anti-Kd and 2 of 13 (15%) anti-Lyt-2 MoAb-injected mice did. In untreated female NOD/Shi/Kbe mice, 30 of 46 (65%) mice developed spontaneous diabetes by 30 wk of age, whereas none of 9 anti-Kd MoAb-injected mice became diabetic. Immunohistochemical studies showed that islet-infiltrating cells in CY-treated control mice were composed mainly of both L3T4+ and Lyt-2+ T lymphocytes, whereas many L3T4+ and very few Lyt-2+ lymphocytes infiltrated within the islets in anti-Kd MoAb-injected mice. Administration of anti-Lyt-2 MoAb induced the absence of Lyt-2+ T lymphocytes in the islet and spleen. However, anti-Kd MoAb did not change the number of spleen cells or the T-lymphocyte subset and response to concanavalin A. These results suggest that MHC class I Kd-restricted Lyt-2+ T lymphocytes play an important role as direct effector cells in destruction of beta-cells in NOD/Shi/Kbe mice.


Effect of a Nutritional and Behavioral Intervention on Energy-Reduced Mediterranean Diet Adherence Among Patients With Metabolic Syndrome: Interim Analysis of the PREDIMED-Plus Randomized Clinical Trial.
High-quality dietary patterns may help prevent chronic disease, but limited data exist from randomized trials about the effects of nutritional and behavioral interventions on dietary changes. To assess the effect of a nutritional and physical activity education program on dietary quality. Preliminary exploratory interim analysis of an ongoing randomized trial. In 23 research centers in Spain, 6874 men and women aged 55 to 75 years with metabolic syndrome and no cardiovascular disease were enrolled in the trial between September 2013 and December 2016, with final data collection in March 2019. Participants were randomized to an intervention group that encouraged an energy-reduced Mediterranean diet, promoted physical activity, and provided behavioral support (n = 3406) or to a control group that encouraged an energy-unrestricted Mediterranean diet (n = 3468). All participants received allotments of extra-virgin olive oil (1 L/mo) and nuts (125 g/mo) for free. The primary outcome was 12-month change in adherence based on the energy-reduced Mediterranean diet (er-MedDiet) score (range, 0-17; higher scores indicate greater adherence; minimal clinically important difference, 1 point). Among 6874 randomized participants (mean [SD] age, 65.0 [4.9] years; 3406 [52%] men), 6583 (96%) completed the 12-month follow-up and were included in the main analysis. The mean (SD) er-MedDiet score was 8.5 (2.6) at baseline and 13.2 (2.7) at 12 months in the intervention group (increase, 4.7 [95% CI, 4.6-4.8]) and 8.6 (2.7) at baseline and 11.1 (2.8) at 12 months in the control group (increase, 2.5 [95% CI, 2.3-2.6]) (between-group difference, 2.2 [95% CI, 2.1-2.4]; P < .001). In this preliminary analysis of an ongoing trial, an intervention that encouraged an energy-reduced Mediterranean diet and physical activity, compared with advice to follow an energy-unrestricted Mediterranean diet, resulted in a significantly greater increase in diet adherence after 12 months. Further evaluation of long-term cardiovascular effects is needed. isrctn.com Identifier: ISRCTN89898870.


Baseline neurological evaluations in a hyperbaric trial of post-concussive syndrome.
Standard neurologic examinations may not detect abnormalities in U.S. military service members with persistent post-concussive symptoms following mild traumatic brain injury. The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) enrolled 71 participants September 2012-May 2014. Participants received: comprehensive neurological and oculomotor exam; balance testing (Berg Balance Scale-BBS; Romberg Test-RT, Sharpened Romberg Test-SRT); olfactory function (Brief Smell Identification Test-BSIT). Two trained neurologists conducted the examinations at a central facility in Colorado Springs. Median age was 32 years (range 21-53), 99% male, 82% Caucasian, 49% PTSD, 28% most recent qualifying injury three months to one year prior to enrollment, 32% blast injuries only, and 73% multiple injuries. Some participants presented with abnormal facial sensation (15%), abnormal tandem gait (13%), and tremor (11%). 54% had abnormal near point of convergence (abnormal range 13-80 cm). 86% scored ≥ 55 on the BBS, with no participant scoring ⟨ 50. 49% scored ⟨ 30 seconds on the best trial of the SRT. RT was abnormal in 10%. 15% of participants scored ≤ 9 (out of 12) on BSIT, about twice what is expected in a normal population. The neurological examination found abnormalities across a range of testing, with convergence insufficiency and SRT having the most sensitivity. ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.


Mineralization of organics in hazardous waste sulfuric acid by natural manganese oxide ore and a combined MnO2/activated carbon treatment to produce qualified manganese sulfate.
To effectively dispose and utilize the hazardous waste H2SO4 generated from alkylation, an environmentally friendly and feasible technology for the simultaneous oxidative degradation of organics and consumption of H2SO4 was developed. Pyrolusite, a natural manganese oxide ore, was used for the oxidative degradation and mineralization of the organics, and reduction leaching of Mn from the pyrolusite occurred simultaneously. The total organic carbon (TOC) removal and Mn leaching efficiency were 46% and 16.44%, respectively. In addition, pyrites was applied as a reductant to extract Mn from the pyrolusite, and an Mn leaching efficiency of 98.31% was obtained under the optimized conditions of 4/1 liquid/solid ratio, 350 rpm stirring speed, 1.5 mol L-1 H2SO4 concentration, and 95 °C for 1 h in the first oxidative degradation stage and a molar ratio of FeS2/MnO2 of 0.55/1 for 4 h in the reduction leaching stage. Subsequently, a combined treatment of MnO2/activated carbon was developed for further oxidation and adsorption of the organics in the solution, with the TOC removal of 84.11%. The resulting purified MnSO4 solution was concentrated to produce qualified MnSO4∙H2O, which met the requirements of an industrial product. This technology showed application potential in highly-efficient removal of hazardous organic contaminates.


Gene organization of the mating type regions in the ectomycorrhizal fungus Laccaria bicolor reveals distinct evolution between the two mating type loci.
In natural conditions, basidiomycete ectomycorrhizal fungi such as Laccaria bicolor are typically in the dikaryotic state when forming symbioses with trees, meaning that two genetically different individuals have to fuse or 'mate'. Nevertheless, nothing is known about the molecular mechanisms of mating in these ecologically important fungi. Here, advantage was taken of the first sequenced genome of the ectomycorrhizal fungus, Laccaria bicolor, to determine the genes that govern the establishment of cell-type identity and orchestrate mating. The L. bicolor mating type loci were identified through genomic screening. The evolutionary history of the genomic regions that contained them was determined by genome-wide comparison of L. bicolor sequences with those of known tetrapolar and bipolar basidiomycete species, and by phylogenetic reconstruction of gene family history. It is shown that the genes of the two mating type loci, A and B, are conserved across the Agaricales, but they are contained in regions of the genome with different evolutionary histories. The A locus is in a region where the gene order is under strong selection across the Agaricales. By contrast, the B locus is in a region where the gene order is likely under a low selection pressure but where gene duplication, translocation and transposon insertion are frequent.


Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor.
Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.


Disease related single point mutations alter the global dynamics of a tetratricopeptide (TPR) α-solenoid domain.
Tetratricopeptide repeat (TPR) proteins belong to the class of α-solenoid proteins, in which repetitive units of α-helical hairpin motifs stack to form superhelical, often highly flexible structures. TPR domains occur in a wide variety of proteins, and perform key functional roles including protein folding, protein trafficking, cell cycle control and post-translational modification. Here, we look at the TPR domain of the enzyme O-linked GlcNAc-transferase (OGT), which catalyses O-GlcNAcylation of a broad range of substrate proteins. A number of single-point mutations in the TPR domain of human OGT have been associated with the disease Intellectual Disability (ID). By extended steered and equilibrium atomistic simulations, we show that the OGT-TPR domain acts as an elastic nanospring, and that each of the ID-related local mutations substantially affect the global dynamics of the TPR domain. Since the nanospring character of the OGT-TPR domain is key to its function in binding and releasing OGT substrates, these changes of its biomechanics likely lead to defective substrate interaction. We find that neutral mutations in the human population, selected by analysis of the gnomAD database, do not incur these changes. Our findings may not only help to explain the ID phenotype of the mutants, but also aid the design of TPR proteins with tailored biomechanical properties.


Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh.
Diarrhea and malnutrition are common in young children in developing countries and a reciprocal relationship has been postulated with diarrhea leading to malnutrition and malnutrition predisposing to diarrhea. To investigate the importance of malnutrition as a determining factor in diarrheal illnesses, data were analyzed from a longitudinal community-based study done in rural Bangladesh. Children classified by nutritional status according to a variety of anthropometric indicators were prospectively evaluated for incidence, duration, and etiology of diarrhea. Children with low weight for length had longer durations of diarrhea than better nourished children; however, children of differing nutritional status had similar diarrheal incidences. The duration of diarrhea, including that associated with enterotoxigenic Escherichia coli and Shigella, increased progressively as nutritional status indicators worsened. These results suggest that nutritional interventions alone are unlikely to reduce the high incidence of diarrhea, but that efforts to improve nutritional status may have a beneficial effect on the duration of diarrhea and its unfavorable nutritional consequences.


Epithelial-mesenchymal interactions in the developing kidney lead to expression of tenascin in the mesenchyme.
Tenascin, a mesenchymal extracellular matrix glycoprotein, has been implicated in epithelial-mesenchymal interactions during fetal development (Chiquet-Ehrismann, R., E. J. Mackie, C. A. Pearson, T. Sakakura, 1986, Cell, 47:131-139). We have now investigated the expression of tenascin during embryonic development of the mouse kidney. In this system, mesenchymal cells convert into epithelial cells as a result of a tissue interaction. By immunofluorescence, tenascin could not be found in the mesenchyme until kidney tubule epithelial began to form. It then became detectable around condensates and s-shaped bodies, the early stages of tubulogenesis. In an in vitro culture system, tenascin expression by the mesenchyme is tightly coupled to the de novo formation of epithelial, and does not occur if tubulogenesis is suppressed. The results strongly suggest that the formation of the new epithelium stimulates the expression of tenascin in the nearby mesenchyme. During postnatal development, the expression of tenascin decreases and the spatial distribution changes. In kidneys from adult mice, no tenascin can be found in the cortex, but interspersed patches of staining are visible in the medullary stroma. The results strongly support the view that tenascin is involved in epithelial-mesenchymal interactions. It could therefore be crucial for embryonic development.


A sling of a normal right inferior vena cava around the abdominal aorta.
Variations in the anatomy of inferior vena cava (IVC) may have important clinical implications. In-depth knowledge of its embryology and variations are of fundamental importance to prevent any potential medical complications related to anatomic variations of the IVC. In this article, we described a previously unreported, to the best of our knowledge, a variation of IVC. In the case we presented, the IVC was seen almost completely encircling the abdominal aorta. We decided to call this anatomic variation as "a sling of a normal right IVC around the abdominal aorta". Cross-sectional imaging is a prompt and highly reliable method to evaluate IVC anatomy and may have significant clinical importance to prevent any potential complications related to IVC during surgery or interventional radiology procedures.


Metal overlayer on metal carbide substrate: unique bimetallic properties for catalysis and electrocatalysis.
Transition metal carbides often display electronic and catalytic properties that are similar to Pt-group metals. In this tutorial review, we describe the feasibility of replacing the Pt-group metal component in bimetallic systems with metal carbides. By supporting a metal monolayer on a carbide substrate, these bimetallic surfaces exhibit similar catalytic and electrocatalytic activity to the corresponding Pt-based bimetallic systems while demonstrating the advantages of lower cost and higher thermal stability. Another promising aspect is that the carbide substrates often promote the formation of small, flat metal particles with novel catalytic properties. We review the synthesis, characterization, and utilization of carbide-supported metal surfaces in heterogeneous catalysis and electrocatalysis. An overview is given for both theoretical and experimental investigations, and trends are drawn from the literature. We also discuss opportunities for future research on carbide-supported metal surfaces.


Comparison of various methods for monitoring hybridoma cell proliferation.
The design of a strategy for the control of large scale cultures of hybridoma cells requires the use of convenient indicators to monitor properly the evolution of the biomass. In order to select appropriate indicators, we have measured in parallel, in bulk cultures of mouse hybridoma cells, the evolution of several metabolic parameters together with those of cell density and viability. We observed that flow cytometry analysis gives an early indication of the proliferative capacity of the cell population. Determination of metabolic rates (i.e. glucose, glutamine, amino acid, consumption, lactic acid or ammonium production) adequately indicates the current metabolic status of the cells. Indeed, a sharp decrease in these metabolic rates occurs rapidly following nutrient deficiency. Finally, measurements of lactate dehydrogenase (LDH) and DNA fragments released into the culture supernatants accurately reflect the kinetics of cell death.


Stabilizing Au2+ in a mixed-valence 3D halide perovskite.
Although Cu2+ is ubiquitous, the relativistic destabilization of the 5d orbitals makes the isoelectronic Au2+ exceedingly rare, typically stabilized only through Au-Au bonding or by using redox non-innocent ligands. Here we report the perovskite Cs4AuIIAuIII2Cl12, an extended solid with mononuclear Au2+ sites, which is stable to ambient conditions and characterized by single-crystal X-ray diffraction. The 2+ oxidation state of Au was assigned using 197Au Mössbauer spectroscopy, electron paramagnetic resonance, and magnetic susceptibility measurements, with comparison to paramagnetic and diamagnetic analogues with Cu2+ and Pd2+, respectively, as well as to density functional theory calculations. This gold perovskite offers an opportunity to study the optical and electronic transport of the uncommon Au2+/3+ mixed-valence state and the characteristics of the elusive Au2+ ion coordinated to simple ligands. Compared with the perovskite Cs2AuIAuIIICl6, which has been studied since the 1920s, Cs4AuIIAuIII2Cl12 exhibits a 0.7 eV reduction in optical absorption onset and a 103-fold increase in electronic conductivity.


Outcome of COVID19 in Patients With Osteogenesis Imperfecta: A Retrospective Multicenter Study in Saudi Arabia.
Although genetic diseases are rare, children with such conditions who get infected with COVID-19 tend to have a severe illness requiring hospitalization. Osteogenesis imperfecta (OI) is a rare genetic disorder of collagen resulting in fractures and skeletal deformities. Kyphoscoliosis, restrictive lung disease, and pneumonia worsen the prognosis of patients with OI. The use of bisphosphonate improves bone mineral density (BMD) and reduces fractures in OI. There is no literature describing the impact of COVID-19 in patients with OI. A retrospective multi-center study was performed in three hospitals in Jeddah and Riyadh, Saudi Arabia, from March 1st, 2020, until August 31st, 2021, aiming to evaluate the outcome of COVID-19 in patients with OI. Demographics, vaccination status, underlying kyphoscoliosis, functional status, use of bisphosphonate, BMD, and COVID-19 severity, and course were recorded for all patients. Twelve cases of confirmed COVID-19 were identified among 146 patients with OI. 9 (75%) of patients were less than 18 years, 6 (50%) were male, 5 (41%) had kyphoscoliosis, and 5 (41%) were wheelchair-bound. 6 (50%) received bisphosphonate, and 7(58%) had normal BMD. All patients had mild disease and did not require hospitalization. None of OI the patients with COVID-19 were fully vaccinated before the infection, and some were ineligible for vaccination. Patients with OI and COVID-19 in our study recovered without complications, unlike patients with other genetic diseases. Young age and mild illness contributed to the favorable outcome. Half of the patients received bisphosphonate and had normal BMD.