Anterior and posterior association cortex contributions to the somatosensory P300.
A P300 (P3)-evoked response is generated in a variety of mammalian species upon detection of significant environmental events. The P3 component has been proposed to index a neural system involved in attention and memory capacity. We investigated the contribution of anterior and posterior association cortex to somatosensory P3 generation. Somatosensory event-related potentials (ERPs) were recorded in controls (n = 10) and patients with unilateral lesions in temporal-parietal junction (n = 8), lateral parietal cortex (n = 8), or dorsolateral frontal cortex (n = 10). Subjects pressed a button to mechanical taps of the fifth finger (targets; p = 0.12), randomly interposed in sequences of taps to the second (standards; p = 0.76) and the third or fourth finger (tactile novels; p = 0.06). Occasional shock stimuli were delivered to the wrist (shock novels; p = 0.06). The scalp-recorded P3 was differentially affected by anterior and posterior association cortex lesions. Subjects with temporal-parietal lesions showed markedly reduced P3s to all types of stimuli at all scalp locations. The reductions were largest at the parietal electrode site over the lesioned hemisphere. Parietal patients had normal P3s for all stimulus types except for contralateral shock novels, which generated reduced P3s. Frontal lesions had reductions of the novelty P3 over frontal sites with minimal changes in the target P3. The data support the existence of multiple intracranial P3 sources. The data further indicate that association cortex in the temporal-parietal junction is critical for generating the scalp-recorded target and novelty P3s, whereas dorsolateral frontal cortex contributes preferentially to novelty P3 generation. The N2 component was reduced by parietal and frontal lesions in patients who had intact target P3s, suggesting that different neural systems underlie N2 and P3 generation.


A critical role of Sp1- and Ets-related transcription factors in maintaining CTL-specific expression of the mouse perforin gene.
This study was designed to determine the potential cis-elements involved in transcriptional regulation of the mouse perforin gene. DNase I hypersensitive site (DHS) mapping revealed that the perforin locus contained six DHS within 7.0 kb of the 5' upstream sequence (-7.0 kb) and two DHS in intron 2. The six 5' upstream and one intronic DHS were detected in only perforin-expressing lymphocytes. Chloramphenicol acetyltransferase (CAT) activities directed by 5' upstream promoter were detected preferentially in perforin-expressing cell lines. A construct termed PFP5a containing -795 bp exhibited the highest CAT activity, and PFP9a20 containing only -73 bp also produced significantly high CAT activity in CTLL-R8 cells. The proximal region in PFP9a20 contained two potential Sp1 binding sites (GC box and GT box) and one Ets binding site (EBS). Electrophoretic mobility shift assay showed that each of the cis-elements bound specific protein factors. When single-point mutation was introduced to each GC box, EBS, and GT box in PFP9a20, at least 3-fold less CAT activity was observed in CTLL-R8 cells. To confirm the importance of the three cis-acting elements in the perforin gene expression, point mutation was introduced again to each proximal GC box, EBS, and GT box of PFP5a. The point mutations resulted in a 2.5- to 3-fold reduction of CAT activity. The results suggest that a combination of the three proximal cis-acting elements may constitute a minimal region responsible for CTL-specific expression of perforin.


KDOQI US Commentary on the 2018 KDIGO Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C.
The first KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection was published in 2008. The ensuing decade bore witness to remarkable advances in the treatment of HCV infection following the approval of direct-acting antiviral (DAA) agents that deliver cure rates routinely >95%. In this context, the KDIGO organization correctly recognized the need for an updated HCV guideline that would be relevant to the treatment of HCV-infected patients with kidney disease in the DAA era. The current NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) commentary provides an in-depth review and perspective on the 2018 KDIGO guideline. Of note, the KDIGO work group made significant updates to guideline chapters 2 and 4 as a direct result of the availability of DAAs. The intent of this commentary is to provide useful interpretation for nephrologists and other practitioners caring for HCV-infected patients with chronic kidney disease, including dialysis patients and kidney transplant recipients. The availability of DAA agents that are safe and highly effective has created new opportunities, such as the transplantation of kidneys from HCV-infected kidney donors. The ability to treat HCV infection in patients with kidney disease will have a significant impact on the care of our patients and should favorably influence long-term outcomes as well.


A murine model to evaluate the ability of in vitro clonogenic assays to predict the response to tumors in vivo.
The use of the human tumor cloning assay as a predictor of clinical response of human tumors to drugs is predicated on the hypothesis that the in vivo response of a tumor to a drug can be correlated with the in vitro response of cells derived from the tumor. To test this hypothesis, we utilized a murine tumor model in which the in vivo and in vitro responses of a tumor can be accurately and reproducibly compared. Drug activity was assessed in P388 leukemia with the standard in vivo antitumor assay (i.p. tumor/i.p. drug administration) and an in vitro assay wherein the ascites tumor cells are removed from mice, treated with a drug, and directly cloned in soft agar to measure clonogenic capacity. The response of P388 cells to analogues within four separate classes of antitumor agents, anthracyclines, anthraquinones, platinum(II) coordination complexes, and phosphinogold(I) complexes was evaluated. The clonogenic assay failed to discriminate between highly active in vivo antitumor agents and analogues with only marginal in vivo efficacy (i.e., doxorubicin and daunorubicin versus rhodomycins A and B, ametantrone versus NSC 276740, cisplatin versus transplatin, [Au(dppe)2]Cl versus [Au(depe)2]PF6. Furthermore, the in vitro clonogenic assay failed to detect carboplatin which was a highly active agent in vivo. The basis for these discrepancies was explored by a more detailed comparison of doxorubicin and rhodomycin B. In vivo or in vitro drug exposure with subsequent measurement of cell kill by the in vitro clonogenic and in vivo tumorigenic assay demonstrated that the in vitro assay overestimated the cytotoxic potency of the drugs relative to the tumorigenic assay. Treatment of tumors in vivo with doxorubicin at doses below the maximally tolerated dose in mice resulted in multiple log cell kill as measured in vitro or in vivo, whereas rhodomycin B was cytotoxic only at dose levels exceeding its maximally tolerated dose. The results indicate that a subset of tumor stem cells capable of forming colonies in soft agar are significantly more sensitive to the cytotoxic effects of anthracyclines than are in vivo tumorigenic stem cells. Cytotoxic potency as measured by an in vitro soft agar clonogenic assay is not an accurate predictor of in vivo antitumor efficacy even in a model in which ascites tumor cells are directly exposed to i.p. drug. The in vitro cytotoxicity assay is useful only as a nonselective prescreen and must be used in combination with other indicators of tumor cell selectivity and dose-limiting organ toxicity.


[Complication of renal artery embolization in kidney sarcoma].
A male patient of 47 underwent embolization of the renal artery in connection with planned nephroectomy for tumor of the left kidney. The embolizing material consisted of autohemocoagulations mixed with hemostatic sponge. Embolization was accompanied by thromboembolism of tibial arteries on the right and interlobular arteries of the right kidney with the development of multiple infarctions. The death was due to acute renal insufficiency. In this connection, the causes of complication are analysed and indications to embolization of the renal artery are discussed. Another feature of the case is the presence of a rare tumor, fibrosarcoma of the kidney of a large size with metastases into the lungs.


Potential and pitfalls of stem cell therapy in old age.
Our increasing understanding of resident stem cell populations in various tissues of the adult body provides promise for the development of cell-based therapies to treat trauma and disease. With the sharp rise in the aging population, the need for effective regenerative medicine strategies for the aged is more important then ever. Yet, the vast majority of research fuelling our understanding of the mechanisms that control stem cell behaviour, and their role in tissue regeneration, is conducted in young animals. Evidence collected in the last several years indicates that, although stem cells remain active into old age, changes in the stem cells and their microenvironments inhibit their regenerative potential. An understanding of both the cell-intrinsic stem cell changes, as well as concomitant changes to the stem cell niche and the systemic environment, are crucial for the development of regenerative medicine strategies that might be successful in aged patients.


The benefits of paid employment among persons with common mental health problems: evidence for the selection and causation mechanism.
Objectives The aims of this study were to (i) investigate the impact of paid employment on self-rated health, self-esteem, mastery, and happiness among previously unemployed persons with common mental health problems, and (ii) determine whether there are educational inequalities in these effects. Methods A quasi-experimental study was performed with a two-year follow-up period among unemployed persons with mental health problems. Eligible participants were identified at the social services departments of five cities in The Netherlands when being diagnosed with a common mental disorder, primarily depression and anxiety disorders, in the past 12 months by a physician (N=749). Employment status (defined as paid employment for ≥12 hours/week), mental health [Short Form 12 (SF-12)], physical health (SF-12), self-esteem, mastery, and happiness were measured at baseline, after 12 months and 24 months. The repeated-measurement longitudinal data were analyzed using a hybrid method, combining fixed and random effects. The regression coefficient was decomposed into between- and within-individual associations, respectively. Results The between-individuals associations showed that persons working ≥12 hours per week reported better mental health (b=26.7, SE 5.1), mastery (b=2.7, SE 0.6), self-esteem (b=5.7, SE 1.1), physical health (b=14.6, SE 5.6) and happiness (OR 7.7, 95% CI 2.3-26.4). The within-individual associations showed that entering paid employment for ≥12 hours per week resulted in better mental health (b=16.3, SE 3.4), mastery (b=1.7, SE 0.4), self-esteem (b=3.4, SE 0.7), physical health (b=9.8, SE 2.9), and happiness (OR 3.1, 95% CI 1.4-6.9). Among intermediate- and high-educated persons, entering paid employment had significantly larger effect on mental health than among low-educated persons. Conclusions This study provides evidence that entering paid employment has a positive impact on self-reported health; thus work should be considered as an important part of health promotion programs among unemployed persons.


Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters.
Within the mammalian central nervous system, the efficient removal of L-glutamate from the extracellular space by excitatory amino acid transporters (EAATs) has been postulated to contribute to signal termination, the recycling of transmitter, and the maintenance of L-glutamate at concentrations below those that are excitotoxic. The development of potent and selective inhibitors of the EAATs has contributed greatly to the understanding of the functional roles of these transporters. In the present study, we use a library of conformationally constrained glutamate analogs to address two key issues: the differentiation of substrates from nontransportable inhibitors and the comparison of the pharmacological profile of synaptosomal uptake with those of the individual EAAT clones. We demonstrate that the process of transporter-mediated heteroexchange can be exploited in synaptosomes to rapidly distinguish transportable from nontransportable inhibitors. Using this approach, we demonstrate that 2,4-methanopyrrolidine-2,4-dicarboxylate, cis-1-aminocyclobutane-1,3-dicarboxylate, and L-trans-2, 4-pyrrolidine dicarboxylate act as substrates for the rat forebrain synaptosomal glutamate uptake system. In contrast, L-anti-endo-3, 4-methanopyrrolidine-3,4-dicarboxylate, L-trans-2,3-pyrrolidine dicarboxylate, and dihydrokainate proved to be competitive inhibitors of D-[(3)H]aspartate uptake that exhibited little or no activity as substrates. When these same compounds were characterized for substrate activity by recording currents in voltage-clamped Xenopus laevis oocytes expressing the human transporter clones EAAT1, EAAT2, or EAAT3, it was found that the pharmacological profile of the synaptosomal system exhibited the greatest similarity with the EAAT2 subtype, a transporter believed to be expressed primarily on glial cells.


Geniposide alleviated hydrogen peroxide-induced apoptosis of human hepatocytes via altering DNA methylation.
Geniposide (GP) is the homology of medicine and food with bioactive effects of antioxidation and resistance to apoptosis in the liver. It's of great significance to explore the biosafety exposure limits and action mechanisms of GP. This study detected the global DNA methylation microenvironment and the regulation of specific genes in GP against cellular apoptosis induced by hydrogen peroxide (H2O2) of human hepatocyte L-02 cells. The half inhibitory concentration (IC50) of GP on normal L-02 cells was 57.7 mg/mL. GP exerted new epigenetic activity, increased DNMT1, decreased TET1 and TET2 expression, and reversed the demethylation effect to some extent, thereby increasing the overall genomic DNA methylation level at the concentration of 900 μg/mL. GP pretreatment could also adjust the level of P53, Bcl-2 and AKT altered by H2O2, reducing their specific DNA methylation levels in the promoter regions of AKT and Bcl-2 to inhibit apoptosis. Taken together, GP regulates the global DNA methylation level and controls the expression changes of P53, Bcl-2 and AKT, jointly inhibiting the occurrence of apoptosis in human hepatocytes and providing the newly theoretical references for its safety evaluation.


An fMRI investigation of cortical contributions to spatial and nonspatial visual working memory.
The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.


A Canadian Working Group report on fecal microbial therapy: microbial ecosystems therapeutics.
A working group from across Canada comprised of clinician and basic scientists, epidemiologists, ethicists, Health Canada regulatory authorities and representatives of major funding agencies (Canadian Institutes of Health Research and the Crohn's and Colitis Foundation of Canada) met to review the current experience with fecal microbial therapy and to identify the key areas of study required to move this field forward. The report highlights the promise of fecal microbial therapy and related synthetic stool therapy (together called 'microbial ecosystems therapeutics') for the treatment of Clostridium difficile colitis and, possibly, other disorders. It identifies pressing clinical issues that need to be addressed as well as social, ethical and regulatory barriers to the use of these important therapies.


Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.
Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia. Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity. The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given. We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.


Gross Hematuria Is More Common in Male and Older Patients with Renal Tuberculosis in China: A Single-Center 15-Year Clinical Experience.
This study aimed to investigate the clinical features of renal tuberculosis and identify the age- and gender-related differences. A total of 419 patients at the Peking University First Hospital from January 2000 to July 2015 were retrospectively reviewed. Data on demographic characteristics, clinical presentation, complications, laboratory results, radiologic imaging, surgical procedures, and pathology features were collected and compared between genders and 3 different age groups (under 40 years, 41-60, years and over 60 years). The most common local presentations were lower urinary tract symptoms (65.2%), flank pain (37.9%), and gross hematuria (26.3%). Constitutional symptoms were also observed in 38.9% of the patients. Gross hematuria was more common in male patients (32.2%) and older patients (45.5%). Flank pain was more common in female patients (43.6%). Patients younger than 40 years of age had lower frequencies of calcification of the urinary tract (22.2%) and kidney atrophy (4.2%) in CT. In the postoperative pathological reports, atrophy (35.9%) and fibrosis (38.5%) were found to be significantly more common in older patients. While gross hematuria is more prevalent in older patients and male patients, flank pain is more common in female patients. Radiological and pathological features including calcification of the urinary tract, fibrosis, and kidney atrophy are more common in older patients.


Toward improved statistical reporting in the journal of consulting and clinical psychology.
Philip Kendall's (1997) editorial encouraged authors in the Journal of Consulting and Clinical Psychology (JCCP) to report effect sizes and clinical significance. The present authors assessed the influence of that editorial--and other American Psychological Association initiatives to improve statistical practices--by examining 239 JCCP articles published from 1993 to 2001. For analysis of variance, reporting of means and standardized effect sizes increased over that period, but the rate of effect size reporting for other types of analyses surveyed remained low. Confidence interval reporting increased little, reaching 17% in 2001. By 2001, the percentage of articles considering clinical (not only statistical) significance was 40%, compared with 36% in 1996. In a follow-up survey of JCCP authors (N=62), many expressed positive attitudes toward statistical reform. Substantially improving statistical practices may require stricter editorial policies and further guidance for authors on reporting and interpreting measures.


Effects of age and task difficulty on recognition of facial affect.
Current evidence suggests that older adults are less accurate than young adults in their ability to identify facial expressions of emotion. In the present study, young and older adults' ability to correctly recognize facial affect representative of 6 different emotions (happiness, surprise, disgust, fear, anger, and sadness) was examined in 3 conditions varying in difficulty. Task difficulty was measured by varying the number of labels available in a forced choice recognition task to 2, 4, and 6. Results showed that age differences were present in the 2 more difficult conditions for fear and sadness. Older adults were impaired in recognizing facial expressions of surprise only in the 4-label condition. Current findings suggest that task difficulty moderates age differences in emotion labeling. The present study has contributed to previous research by illuminating the conditions under which age differences in the accuracy of labeling of facial affect are more likely to be observed.


A novel viral RNA species in Sindbis virus-infected cells.
Sindbis virus (SIN), the type alphavirus, has been studied extensively to identify the viral cis-acting sequences and proteins involved in RNA transcription and replication. However, very little is known about how these processes are coordinated. For example, synthesis of the genomic RNA and the subgenomic mRNA depends on the minus strand. Do these activities occur independently on different templates, or can replication and transcription take place simultaneously on the same template? We describe the appearance of a SIN-specific, plus-sense RNA that is intermediate in size between the genomic and subgenomic RNA species. This RNA, designated RNA II, is observed in a number of different cell lines, both early and late in infection. The number of RNA II species, their sizes, and their abundances are influenced by the subgenomic promoter. We have mapped the 3' end of RNA II to a site within the subgenomic promoter, four nucleotides before the initiation site of the subgenomic mRNA. Our results indicate that the appearance of RNA II is correlated with subgenomic mRNA transcription, such that strong or active promoters tend to increase the abundance of RNA II, relative to weak or less active promoters. RNA II is most abundantly detected with the full promoter and is at much lower abundance with the minimal promoter. The possible origins of RNA II are discussed.


Comparison of bronchoalveolar lavage and mini-bronchoalveolar lavage in the diagnosis of pneumonia in immunocompromised patients.
Pneumonia is a major cause of morbidity and mortality in immunocompromised patients. Bronchoalveolar lavage (BAL) is commonly used to help diagnose and characterize pneumonia in these patients. Mini-BAL is a less-invasive, less-costly and less-cumbersome diagnostic tool than BAL. In this study, we compared the diagnostic value of BAL and mini-BAL in the evaluation of pneumonia in immunocompromised patients with respiratory failure. Sixty-four respiratory samples were collected from 32 immunocompromised patients admitted to our respiratory intensive care unit with a clinical diagnosis of pneumonia and respiratory failure requiring invasive mechanical ventilation. A single BAL sample and a single mini-BAL sample were collected from each patient. Samples were examined for bacteriologic, mycologic, mycobacteriologic, and viral organisms. The mean age of the patients was 56.0 ± 14.4 years. Of the 32 BAL samples, bacterial isolates were detected in 11 patients (34.4%) and on the other hand bacterial isolates were detected in 10 patients (31.3%) of the mini-BAL samples. Fungal isolates were detected in 11 patients (34.4%) from BAL samples and 13 patients (40.6%) from mini-BAL samples. Our analysis demonstrated a strong positive correlation between the results of BAL and mini-BAL testing (r = 0.850 and r = 0.821, respectively). In this study, we demonstrated a strong correlation between the isolation rates of bacteria and fungi in BAL and mini-BAL samples obtained from immunocompromised patients with pneumonia and respiratory failure. The data strongly support the use of mini-BAL sampling in such patients as a less-invasive, less-costly and simpler alternative to traditional BAL.


Medicaid 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder.
This research aims to describe the characteristics of 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder across states and over time. While increasingly popular, little is known about these Medicaid waivers. Understanding the characteristics of these programs is important to clinicians and policymakers in designing programs to meet the needs of this vulnerable population and to set the stage for evaluating changes that occur with the implementation of health-care reform. Home- and Community-Based Services waiver applications that included children with autism spectrum disorder as a target population were collected from the Centers for Medicare and Medicaid Services website, state websites, and state administrators. A data extraction tool was used to document waiver inclusions and restrictions, estimated service provision and institutional costs, and the inclusion of four core autism spectrum disorder services: respite, caregiver support and training, personal care, and evidence-based treatments. Investigators identified 50 current or former waivers across 29 states that explicitly included children with autism spectrum disorder in their target populations. Waivers differed substantially across states in the type and breadth of autism spectrum disorder coverage provided. Specifically, waivers varied in the populations they targeted, estimated cost of services, cost control methods employed, and services offered to children with autism spectrum disorder. Home- and Community-Based Services waivers for children with autism spectrum disorder are very complex and are not consistent across states or over time. Further efforts are needed to examine the characteristics of programs that are associated with improved access to care and clinical outcomes to maximize the benefits to individuals with autism spectrum disorder and their families.


Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release.
Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [35S]-GTPgammaS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long (hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (pK(b) = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [35S]-GTPgammaS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 microM apomorphine (Emax = 100%). pEC50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only affected prolactin at the highest dose tested (41 ng/ml at 40 mg/kg). Prolactin levels of the corresponding vehicle-treated animals were <4.3 ng/ml. These data show that (1) SSR181507, aripiprazole and bifeprunox, but not SLV313, are partial agonists at dopamine hD2 L receptors in vitro; (2) SSR181507, bifeprunox and aripiprazole exhibit reduced prolactin release in vivo compared with drugs that are neutral antagonists at dopamine D2 receptors.


Multipotent stromal cells stimulate liver regeneration by influencing the macrophage polarization in rat.
To investigate the influence of the umbilical cord-derived multipotent stromal cells (MSCs) on recovery of the liver after the subtotal resection, that is, removal of 80% of the organ mass, a renowned model of the small-for-size liver remnant syndrome. The MSCs were obtained from the intervascular tissue of umbilical cords, dissected from rat fetuses, by the explant culture technique. The vital labeling of MSCs with РКН26 was carried out on the 3rd passage. The subtotal resection was performed on male Sprague-Dawley rats. The experimental group animals received a transplant 106 MSCs infused into the spleen. Hepatocyte proliferation was assessed by counting of either mitotic figures or Ki67-positive cells in microscopic images. MSC differentiation was assessed with antibodies to hepatocyte-specific marker cytokeratin 18 (CK18), cholangiocyte-specific protein CK19, smooth muscle cell-specific protein α-SMA, the endothelial cell marker CD31, or the active fibroblast marker FAPα. Total macrophages of the liver were selectively stained in cryosections incubated with anti-CD68 antibodies (1:100, Abcam), while the M2a and M2c macrophage populations were selectively stained with anti-CD206 antibodies. Expression of interleukin and growth factor genes was evaluated with PCR-RT. Intrasplenic allogeneic transplantation of the umbilical cord-derived multipotent stromal cells stimulates reparative processes within the residual liver tissue after subtotal resection (removal of 80% of the organ mass), as indicated by increased rates of hepatocyte proliferation and accelerated organ mass recovery. These effects may result from paracrine influence of the transplanted cells on the resident macrophage population of the liver. The transplantation favors polarization of macrophages to M2 phenotype (the M2-polarized macrophages specifically express CD206; they are known to suppress inflammation and support tissue repair). No differentiation of the transplanted cells into any of the liver cell types have been observed in the study. We found no direct evidence for the paracrine effect of MSCs on liver regeneration after the subtotal liver resection in rats. However, the paracrine mechanism of the therapeutic activity of transplanted MSC is indirectly indicated by a decrease in the total number of CD68 + macrophages and an increase in the proportion of M2 pro-repair macrophages in the regenerating liver as compared to animals in which the transplantation was only mimicked.


Angiographic embolization of arterial hemorrhage following endoscopic US-guided cystogastrostomy for pancreatic pseudocyst drainage.
Pseudocyst development is a common complication of chronic pancreatitis. Endoscopic cystogastrostomy is an alternative to percutaneous drainage of pancreatic pseudocysts. Endoscopic ultrasound (EUS) guidance is thought to decrease the procedural risk by identifying and avoiding intervening vasculature. With EUS guidance, extreme care should be exercised to identify large gastric vessels in the path of the puncture. Preoperative imaging should be closely scrutinized for the presence of these vessels. In cases of hemorrhage, balloon tamponading is a rapid way to provide temporary control, allowing transfer of the patient for angiographic embolization. We present a case of arterial hemorrhage due to inadvertent puncture of a hypertrophied right gastric artery following EUS-guided cystogastrostomy, which was successfully treated with temporary balloon occlusion and coil embolization.


[Lymphoma of the marginal zone of the spleen. A case study].
Lymphomas of the marginal spleen zone are an entity recently considered as separate by the International Lymphoma Study Group. There are B-cell non Hodgkin's lymphomas (NHL) of low grade malignancy with a characteristic phenotype that allows to differentiate from mantle lymphomas and other B-cell lymphoproliferative syndromes. The case of a 69-year-old female patient admitted for abdominal pain due to large splenomegaly is reported. Pancytopenia and the presence of atypical large-sized lymphocytes with extensive cytoplasm and a rounded nucleus with indentations, reticulated appearing chromatin and one or several nucleoli were of note in the hemogram. Microscopic examination of the bone marrow demonstrated moderate-degree lymphocytary infiltration with grade I reticulin fibrosis. Laparotomy with splenectomy was performed. White pulp invasion with multifocal infiltration of the red pulp by lymphocytes of the same characteristics as those observed in the peripheral blood and bone marrow were observed on microscopic bone marrow examination. Immunophenotypic study of these lymphocytes was positive for CD19, CD20 and CD22 while being negative for CD5, CD10, CD23, CD25, CD11c and FMC7, the phenotype belonging to the lymphocytes of marginal spleen zone. Following splenectomy the patient recovered hemoperipheral counts and did not undergo additional treatment. The patient died due to septic shock of respiratory origin 4 months later. The clinical, morphologic and immunophenotypic features of marginal spleen zone lymphomas are reported with emphasis on the differences with other B-cell non Hodgkin's lymphomas of low malignancy.


Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells.
Despite notable advances in utilising PARP inhibitor monotherapy, many cancers are not PARP inhibitor-sensitive or develop treatment resistance. In this work, we show that the two structurally-related sesquiterpene lactones, a 2-bromobenzyloxy derivative of dehydrosantonin (BdS) and alantolactone (ATL) sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose treatment with the PARP inhibitor, olaparib. Exposure to combination treatments of olaparib with BdS or ATL induces cell-cycle changes, chromosomal instability, as well as considerable increases in nuclear area. Mechanistically, we uncover that mitotic errors likely depend on oxidative stress elicited by the electrophilic lactone warheads and olaparib-mediated PARP-trapping, culminating in replication stress. Combination treatments exhibit moderately synergistic effects on cell survival, probably attenuated by a p53-mediated, protective cell-cycle arrest in the G2 cell-cycle phase. Indeed, using a WEE1 inhibitor, AZD1775, to inhibit the G2/M cell-cycle checkpoint further decreased cell survival. Around half of all cancers diagnosed retain p53 functionality, and this proportion could be expected to increase with improved diagnostic approaches in the clinic. Utilising sublethal oxidative stress to sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose PARP-trapping could therefore serve as the basis for future research into the treatment of cancers currently refractory to PARP inhibition.


Tumor suppression by resistant maltodextrin, Fibersol-2.
Resistant maltodextrin Fibersol-2 is a soluble and fermentable dietary fiber that is Generally Recognized As Safe (GRAS) in the United States. We tested whether Fibersol-2 contains anti-tumor activity. Human colorectal cancer cell line, HCT116, and its isogenic cells were treated with FIbersol-2. Tumor growth and tumorigenesis were studied in vitro and in vivo. Apoptotic pathway and generation of reactive oxygen species (ROS) were investigated. We discovered that Fibersol-2 significantly inhibits tumor growth of HCT116 cells by inducing apoptosis. Fibersol-2 strongly induces mitochondrial ROS and Bax-dependent cleavage of caspase 3 and 9, which is shown by isogenic HCT116 variants. Fibersol-2 induces phosphorylation of Akt, mTOR in parental HCT116 cells, but not in HCT116 deficient for Bax or p53. It prevents growth of tumor xenograft without any apparent signs of toxicity in vivo. These results identify Fibersol-2 as a mechanism-based dietary supplement agent that could prevent colorectal cancer development.


What is the institutional financial impact of an MD-PhD program without extramural funding?
Training in the form of MD-PhD programs is an important part of the academic mission of medical schools, yet the costs incurred in providing these programs may be considerable. This research explores the financial impacts on a university of supporting an MD-PhD program. We estimate the net financial impact of an MD-PhD program under a variety of assumptions about the financial gain that the school obtains through MD-PhD students' contributions to externally funded research. Under certain assumptions, the net financial impact of the MD-PhD program is positive, and under the most unfavorable assumptions the cost per student year is less than $30, 000. The apparent costs of an MD-PhD program are ameliorated or even turned into gains when one considers the resources generated by MD-PhD students. Thus, such programs can serve as a means of increasing external awards and improving the overall quality in graduate schools.


Sucrose and dental caries: a review of the evidence.
The aim of this study was to conduct a review of the literature to assess the relationship between quantity and pattern of sucrose use and dental caries. Using hand and electronic methods (MEDLINE, EMBASE) the literature was searched for epidemiological papers concerning any relationship of sugars and dental caries published since 1856. Superficial hand searching was carried out between 1856 and 1940, detailed hand searching 1940-1966 and electronic 1966-2007. Selection criteria were set based on, but not confined to, Cochran style standards. Investigations were categorized as A, fulfilling all criteria; B1, relevant fulfilling 19 of 23 criteria; B2, relevant but fulfilling only between 12 and 18 of the selection criteria; and C, all other papers. There were 95 papers meeting most (more than 12) or all of the selected criteria. Only 1 paper was graded A; 31 as B1. There were in addition some 65 as B2 and all the rest as C, which were discarded. There were a wide variety of study designs and those graded A or B1 comprised 23 ecological cross-sectional, 7 cohort and 2 case control studies. Summary results showed that 6 papers found a positive, significant relationship of sugar quantity to dental caries, 19 of 31 studies reported a significant relationship of sugar frequency of use to dental caries. The balance of studies does not demonstrate a relationship between sugar quantity, but a moderately significant relationship of sugar frequency to dental caries.


Emotional intelligence: new ability or eclectic traits?
Some individuals have a greater capacity than others to carry out sophisticated information processing about emotions and emotion-relevant stimuli and to use this information as a guide to thinking and behavior. The authors have termed this set of abilities emotional intelligence (EI). Since the introduction of the concept, however, a schism has developed in which some researchers focus on EI as a distinct group of mental abilities, and other researchers instead study an eclectic mix of positive traits such as happiness, self-esteem, and optimism. Clarifying what EI is and is not can help the field by better distinguishing research that is truly pertinent to EI from research that is not. EI--conceptualized as an ability--is an important variable both conceptually and empirically, and it shows incremental validity for predicting socially relevant outcomes.


Primary stenting for acute ischemic stroke using the Enterprise vascular reconstruction device: early results.
Primary stenting for acute ischemic stroke (AIS) using the Wingspan stent delivery system has been reported. Major technical limitations in that study were difficulties in delivering the device and a few cases in which the Enterprise vascular reconstruction device (stent) was used as a bailout procedure. The Enterprise, which has relatively less radial force and more flexibility than other intracranial stents, is an ideal device for revascularization as it is easily delivered through tortuous intracranial vessels. We tested the safety and effectiveness of this stent as the primary revascularization device for AIS in an FDA-approved investigational device exemption prospective cohort study. Twenty patients presenting with AIS due to confirmed intracranial large vessel occlusion within 8 h of onset of stroke symptoms were treated with the Enterprise as the primary revascularization device. The primary outcome was recanalization to Thrombolysis In Myocardial Infarction (TIMI) flow of ≥2. Perioperative safety was measured by major complication incidence within 30 days of stent revascularization. A secondary measure of outcome was 30-day modified Rankin Scale (mRS) score. Recanalization to TIMI 2 (n=6) or 3 (n=12) flow was achieved in 18 patients (90% revascularization rate). Three major complications were noted (15%) including one myocardial infarction, one symptomatic intracranial hemorrhage and one ischemic stroke in a distribution other than the qualifying vessel. Good outcome (mRS ≤2) was obtained in 10 patients (50%). In this prospective study the Enterprise stent was found to be a safe and effective revascularization tool in the setting of AIS.


Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa.
We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRalpha promoter developed chronic colitis in concert with the expression of SRalpha/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4-12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell-depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor gamma/delta T cells and CD8alpha/alpha cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell-derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.


Impact of Rapid Molecular Diagnostic Testing of Respiratory Viruses on Outcomes of Adults Hospitalized with Respiratory Illness: a Multicenter Quasi-experimental Study.
A standard multiplex PCR offers comprehensive testing for respiratory viruses. However, it has traditionally been performed in a referral laboratory with a lengthy turnaround time, which can reduce patient flow through the hospital. We aimed to determine whether the introduction of a rapid PCR, but with limited targets (Cepheid Xpert Flu/RSV XC), was associated with improved outcomes for adults hospitalized with respiratory illness. A controlled quasi-experimental study was conducted across three hospitals in New South Wales, Australia. Intervention groups received standard multiplex PCR during the preimplementation, July to December 2016 (n = 953), and rapid PCR during the postimplementation, July to December 2017 (n = 1,209). Control groups (preimplementation, n = 937, and postimplementation, n = 1,102) were randomly selected from adults hospitalized with respiratory illness during the same periods. The outcomes were hospital length of stay (LOS) and microbiology test utilization (blood culture, urine culture, sputum culture, and respiratory bacterial and virus serologies). The introduction of rapid PCR was associated with a nonsignificant 8.9-h reduction in median LOS (95% confidence interval [CI], -21.5 h to 3.7 h; P = 0.17) for all patients and a significant 21.5-h reduction in median LOS (95% CI, -36.8 h to -6.2 h; P < 0.01) among patients with positive test results in an adjusted difference-in-differences analysis. For patients receiving test results before disposition, rapid PCR use was associated with a significant reduction in LOS, irrespective of test results. Compared with standard PCR testing, rapid PCR use was significantly associated with fewer blood culture (adjusted odds ratio [aOR], 0.67; 95% CI, 0.5 to 0.82; P < 0.001), sputum culture (aOR, 0.56; 95% CI, 0.47 to 0.68, P < 0.001), bacterial serology (aOR, 0.44; 95% CI, 0.35 to 0.55, P < 0.001) and viral serology (aOR, 0.42; 95% CI, 0.33 to 0.53, P < 0.001) tests, but not with fewer urine culture tests (aOR, 0.94; 95% CI, 0.78 to 1.12, P = 0.48). Rapid PCR testing of adults hospitalized with respiratory illnesses can deliver benefits to patients and reduce resource utilization. Future research should consider a formal economic analysis and assess its potential impacts on clinical decision making.


Prognostic factors associated with early gout flare recurrence in patients initiating urate-lowering therapy during an acute gout flare.
Lowering serum urate levels below the threshold for crystal formation with urate-lowering therapy (ULT) has been associated with a lower risk for gout flare reoccurrences. However, gout patients on ULT still commonly suffer from recurring gout flares. The purpose of this study was to explore prognostic factors associated with gout flare recurrence within the first 3 months, in gout patients starting ULT during an acute gout flare. Post-hoc analysis of trial data on acute gout patients randomized to either gout flare standard of care or anakinra treatment were used, including baseline demographic, laboratory, clinical, and patient-reported variables, as well as 3-month follow-up data on gout flare recurrences. Only patients starting ULT at baseline were included. Using variable selection based on clinical relevance, univariate, and multivariate binary logistic regression analyses were done to examine predictors of gout flare reoccurrence. A total of 75 patients were included in this study, of which 36 (48%) experienced a gout flare ≤ 3 months post baseline. The multivariate regression analysis revealed that CRP levels > 30 mg/L (OR 9.47) and lack of prophylaxis when starting ULT (OR 11.56) were independently associated with gout flare recurrence. Similar results were found for the univariate regression analyses. Our results show that CRP levels > 30 mg/L and lack of prophylaxis when starting ULT were prognostic factors for early gout flare reoccurrence in patients starting ULT during an acute gout flare. KEY POINTS: • Gout flare recurrences were common within the first 3 months after starting urate-lowering therapy in gout patients. • Intake of prophylaxis when starting ULT had a strong protective effect on gout flare recurrences. • C-reactive protein level > 30 mg/L was an additional prognostic factor for early (≤ 3 months) gout flare reoccurrence in patients starting ULT during an acute gout flare.


8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure.
8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transversion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sunlight. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.


Hybrid imaging using quantitative H215O PET and CT-based coronary angiography for the detection of coronary artery disease.
Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H(2)(15)O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H(2)(15)O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H(2)(15)O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H(2)(15)O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H(2)(15)O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H(2)(15)O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). The diagnostic accuracy of quantitative H(2)(15)O PET/CTCA is superior to either H(2)(15)O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.


Decision-Making, Cognitive Distortions and Alcohol Use in Adolescent Problem and Non-problem Gamblers: An Experimental Study.
In the psychological literature, many studies have investigated the neuropsychological and behavioral changes that occur developmentally during adolescence. These studies have consistently observed a deficit in the decision-making ability of children and adolescents. This deficit has been ascribed to incomplete brain development. The same deficit has also been observed in adult problem and pathological gamblers. However, to date, no study has examined decision-making in adolescents with and without gambling problems. Furthermore, no study has ever examined associations between problem gambling, decision-making, cognitive distortions and alcohol use in youth. To address these issues, 104 male adolescents participated in this study. They were equally divided in two groups, problem gamblers and non-problem gamblers, based on South Oaks Gambling Screen Revised for Adolescents scores. All participants performed the Iowa gambling task and completed the Gambling Related Cognitions Scale and the alcohol use disorders identification test. Adolescent problem gamblers displayed impaired decision-making, reported high cognitive distortions, and had more problematic alcohol use compared to non-problem gamblers. Strong correlations between problem gambling, alcohol use, and cognitive distortions were observed. Decision-making correlated with interpretative bias. This study demonstrated that adolescent problem gamblers appear to have the same psychological profile as adult problem gamblers and that gambling involvement can negatively impact on decision-making ability that, in adolescence, is still developing. The correlations between interpretative bias and decision-making suggested that the beliefs in the ability to influence gambling outcomes may facilitate decision-making impairment.


Impact of exercise on lower activity levels in children with acute lymphoblastic leukemia: a randomized controlled trial from Turkey.
This randomized, controlled experimental study was carried out to determine the effects of an exercise program on both physical parameters and the quality of life of children with acute lymphoblastic leukemia (ALL). A total of 41 children with ALL (20 trial and 21 control cases) at two university hospitals were accepted into the study. Due to the demise of one of the children in the trial group, the study was completed with 19 trial and 21 control patients, a total of 40 children and their parents. Regular and systematic exercise regimens implemented by children with ALL have resulted in improved testing results, enhanced physical performance, and better laboratory results compared with a control group and to children's scores before the initiation of such a program.


WHO's supported interventions on salt intake reduction in the sub-Saharan Africa region.
Reduction of salt intake is an important and cost-effective way for reducing hypertension and the risk of cardiovascular diseases (CVDs). Current global salt intakes are estimated at around 10 g/day, well above the World Health Organization (WHO) recommended level of <5 g/day. The sub-Saharan Africa (SSA) region has a prevalence of hypertension of 46% among adults aged 25 and over and therefore strategies to reduce salt intake are necessary. This requires an understanding of salt intake behaviors in the population along with government commitment to increase awareness and take actions that would create an enabling environment. It is also important to have the food industry and other key stakeholders on board. A review of the developed WHO's norms and guidelines, technical support provided to countries by WHO as well as country initiatives shows that countries in the African region are at different stages in the implementation of salt reduction interventions. For example, South Africa has enacted legislation to make the food industry reduce the salt content of a number of its products while Mauritius is requesting bakery owners to reduce salt in bread. A number of countries are currently undertaking studies to measure salt intake in the populations. Overall progress is slow as the region experiences a double burden of communicable and noncommunicable diseases, competing health priorities and limited resources for health.


Surgical Resection for Crohn's and Cancer: A Comparison of Disease-Specific Risk Factors and Outcomes.
The goal of this study was to compare disease-specific risk factors and 30-day outcomes between patients with Crohn's disease (CD) and colon cancer (CC) undergoing right-sided surgical resection. The American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP®) was interrogated to extract all patients ≥18 years undergoing elective right-sided resection for CD versus CC. Independent risk factors for surgical complications were identified through multivariable logistic regression for both groups. In a second step, surgical and medical 30-day morbidity was compared after risk adjustment. The cohort consisted of 17,516 patients, of which 2,899 (16.6%) underwent surgery for CD versus 14,617 (83.4%) for CC. Independent risk factors for surgical complications in patients with CD were male gender, African American race, ASA score (III or IV), active smoking, prolonged surgery, and preoperative anemia. Independent risk factors for surgical complications in the cancer group were age ≥70 years, male gender, ASA score (III or IV), respiratory and cardiovascular comorbidities, and preoperative hypoalbuminemia (<3.5 g/dL). After risk adjustment, surgical complications (OR 1.25, p = 0.002), sepsis (OR 1.64, p = 0.012), and unplanned readmissions (OR 1.39, p = 0.004) were more common in patients with CD. Thirty-day mortality was higher in cancer patients (1.1 vs. 0.1%, p < 0.0001). Patients with Crohn's disease were more prone to surgical complications and postoperative sepsis compared to the cancer group undergoing the same procedure. Careful evaluation and correction of disease-specific modifiable risk factors of patients with CD and CC, respectively, are important.


Fire severity effects on soil carbon and nutrients and microbial processes in a Siberian larch forest.
Fire frequency and severity are increasing in tundra and boreal regions as climate warms, which can directly affect climate feedbacks by increasing carbon (C) emissions from combustion of the large soil C pool and indirectly via changes in vegetation, permafrost thaw, hydrology, and nutrient availability. To better understand the direct and indirect effects of changing fire regimes in northern ecosystems, we examined how differences in soil burn severity (i.e., extent of soil organic matter combustion) affect soil C, nitrogen (N), and phosphorus (P) availability and microbial processes over time. We created experimental burns of three fire severities (low, moderate, and high) in a larch forest in the northeastern Siberian Arctic and analyzed soils at 1, 8 days, and 1 year postfire. Labile dissolved C and N increased with increasing soil burn severity immediately (1 day) postfire by up to an order of magnitude, but declined significantly 1 week later; both variables were comparable or lower than unburned soils by 1 year postfire. Soil burn severity had no effect on P in the organic layer, but P increased with increasing severity in mineral soil horizons. Most extracellular enzyme activities decreased by up to 70% with increasing soil burn severity. Increasing soil burn severity reduced soil respiration 1 year postfire by 50%. However, increasing soil burn severity increased net N mineralization rates 1 year postfire, which were 10-fold higher in the highest burn severity. While fires of high severity consumed approximately five times more soil C than those of low severity, soil C pools will also be driven by indirect effects of fire on soil processes. Our data suggest that despite an initial increase in labile C and nutrients with soil burn severity, soil respiration and extracellular activities related to the turnover of organic matter were greatly reduced, which may mitigate future C losses following fire.


Age-associated changes in microglia activation and Sirtuin-1- chromatin binding patterns.
The aging process is associated with changes in mechanisms maintaining physiology, influenced by genetics and lifestyle, and impacting late life quality and longevity. Brain health is critical in healthy aging. Sirtuin 1 (Sirt1), a histone deacetylase with silencing properties, is one of the molecular determinants experimentally linked to health and longevity. We compared brain pathogenesis and Sirt1-chromatin binding dynamics in brain pre-frontal cortex from 2 groups of elder rhesus macaques, divided by age of necropsy: shorter-lived animals (18-20 years old (yo)), equivalent to 60-70 human yo; and longer-lived animals (23-29 yo), corresponding to 80-100 human yo and modeling successful aging. These were compared with young adult brains (4-7 yo). Our findings indicated drastic differences in the microglia marker Iba1, along with factors influencing Sirt1 levels and activity, such as CD38 (an enzyme limiting NAD that controls Sirt1 activity) and mir142 (a microRNA targeting Sirt1 transcription) between the elder groups. Iba1 was lower in shorter-lived animals than in the other groups, while CD38 was higher in both aging groups compared to young. mir142 and Sirt1 levels were inversely correlated in longer-lived brains (>23yo), but not in shorter-lived brains (18-20 yo). We also found that Sirt1 binding showed signs of better efficiency in longer-lived animals compared to shorter-lived ones, in genes associated with nuclear activity and senescence. Overall, differences in neuroinflammation and Sirt1 interactions with chromatin distinguished shorter- and longer-lived animals, suggesting the importance of preserving microglia and Sirt1 functional efficiency for longevity.


Participation in and a critical review of educational audit.
In this reflection I discuss my first engagement with the educational audit process. Audit of the environment is a crucial element in the education of student midwives; educational audit is complex as placement areas are dynamic, fast-changing environments. It is important for all involved parties to recognise that the quality of the learning experience is far more reliant on the 'virtual environment' provided by quality mentors rather than on the more concrete practice setting.


Evidence for an intrinsic toxicity of phosphatidylcholine to Sec14p-dependent protein transport from the yeast Golgi complex.
Yeast phosphatidylinositol-transfer protein (Sec14p) is essential for Golgi secretory function and cell viability. This requirement of Sec14p is relieved by genetic inactivation of the cytidine diphosphate-choline pathway for phosphatidycholine (PtdCho) biosynthesis. Standard phenotypic analyses indicate that inactivation of the phosphatidylethanolamine (PtdEtn) pathway for PtdCho biosynthesis, however, does not rescue the growth and secretory defects associated with Sec14p deficiency. We now report inhibition of choline uptake from the media reveals an efficient "bypass Sec14p" phenotype associated with PtdEtn-methylation pathway defects. We further show that the bypass Sec14p phenotype associated with PtdEtn-methylation pathway defects resembles other bypass Sec14p mutations in its dependence on phospholipase D activity. Finally, we find that increased dosage of enzymes that catalyze phospholipase D-independent turnover of PtdCho, via mechanisms that do not result in a direct production of phosphatidic acid or diacylglycerol, effect a partial rescue of sec14-1(ts)-associated growth defects. Taken together, these data support the idea that PtdCho is intrinsically toxic to yeast Golgi secretory function.


Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy that most often presents at an advanced, incurable stage. After the failure of standard first-line cisplatin/antifolate chemotherapy, there is no accepted treatment. The vascular endothelial growth factor pathway may be a relevant therapeutic target in MPM. This open-labeled phase II trial evaluated single-agent sunitinib, an inhibitor of multiple receptor tyrosine kinases including the vascular endothelial growth factor receptors, given at 50 mg daily orally for 4 weeks followed by a 2-week rest, in patients with advanced MPM. Two cohorts were studied: cohort 1, in which patients had previously received cisplatin-based chemotherapy, and cohort 2, consisting of previously untreated patients. A two-stage design was used for both cohorts; the primary outcome was objective response rate as determined by the RECIST criteria modified for MPM. Secondary outcomes included rates and duration of disease control, progression-free survival and overall survival, and safety and tolerability. A total of 35 eligible patients were enrolled (17 to cohort 1 and 18 to cohort 2). Neither cohort met the criteria for continuing to the second stage of accrual; only one objective response, confirmed by independent review, was observed in a previously untreated patient. Median progression-free and overall survivals were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2, respectively. Observed toxicity was within that expected for sunitinib. Sunitinib, similar to other angiogenesis inhibitors, has limited activity in MPM. Future trials of angiogenesis inhibitors given as single agents in unselected patients with MPM are not warranted.


ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation.
Phosphorylation of the p53 tumor suppressor protein is likely to play an important role in regulating its activity. Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner. Recently, p53 was reported to be activated and phosphorylated at serine 15 following UV radiation. However, the signaling pathway that mediates UV-induced phosphorylation is less well characterized. Here, we provide evidence that UVB-induced phosphorylation of p53 at serine 15 is mediated directly by ERKs and p38 kinase. We find that in a mouse JB6 epidermal cell line, ERKs and p38 kinase form a complex with p53 following UVB radiation. Inhibition of ERKs or p38 kinase activity by the use of a dominant negative mutant of ERK2 or p38 kinase or their respective specific inhibitor, PD98059 or SB202190, results in abrogation of UVB-induced phosphorylation of p53 at serine 15. Strikingly, incubation of UVB-activated ERKs or p38 kinase immunoprecipitated complex with exogenous p53 shows serine 15 phosphorylation of both exogenous and co-precipitated endogenous p53 protein. Additionally, active recombinant ERK1/2 and p38 kinase but not JNKs are also able to phosphorylate p53 at serine 15 in vitro. Furthermore, pretreatment of cells with PD98059 or SB202190 blocks p53-dependent transcription activity but increases the level of p53 co-precipitated murine double minute. These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo.


Draft genome of the sea cucumber Apostichopus japonicus and genetic polymorphism among color variants.
The Japanese sea cucumber (Apostichopus japonicus Selenka 1867) is an economically important species as a source of seafood and ingredient in traditional medicine. It is mainly found off the coasts of northeast Asia. Recently, substantial exploitation and widespread biotic diseases in A. japonicus have generated increasing conservation concern. However, the genomic knowledge base and resources available for researchers to use in managing this natural resource and to establish genetically based breeding systems for sea cucumber aquaculture are still in a nascent stage. A total of 312 Gb of raw sequences were generated using the Illumina HiSeq 2000 platform and assembled to a final size of 0.66 Gb, which is about 80.5% of the estimated genome size (0.82 Gb). We observed nucleotide-level heterozygosity within the assembled genome to be 0.986%. The resulting draft genome assembly comprising 132 607 scaffolds with an N50 value of 10.5 kb contains a total of 21 771 predicted protein-coding genes. We identified 6.6-14.5 million heterozygous single nucleotide polymorphisms in the assembled genome of the three natural color variants (green, red, and black), resulting in an estimated nucleotide diversity of 0.00146. We report the first draft genome of A. japonicus and provide a general overview of the genetic variation in the three major color variants of A. japonicus. These data will help provide a comprehensive view of the genetic, physiological, and evolutionary relationships among color variants in A. japonicus, and will be invaluable resources for sea cucumber genomic research.


Methodological and statistical problems in uvulopalatopharyngoplasty research: a follow-up study.
To review the published literature on uvulopalatopharyngoplasty (UPPP) and assess the methodological quality of the research and compare it with a similar article published in 1995; and to determine what, if any, improvement in the methodological quality of the research resulted during the ensuing 10 years. Methodological and statistical evaluation of the published literature on UPPP. Thirty articles representing the clinical studies on UPPP and related procedures written from January 1996 to August 2005 were reviewed. Only articles reporting polysomnography data were included. Overall, the articles demonstrated fair methodological and statistical quality. Compared with the previous review by Schechtman et al, there was a slight increase in the number of articles that discussed statistical power and reported confidence intervals. There were increases in the mean sample size, the percentage of randomized controlled studies, the number of end points, and the use of validated subjective outcome measures; longer mean follow-up time; and more complete reporting of age and sex information. There was no increase in the percentage of published studies that used a prospective study design. None of the studies that required minimum acceptable baseline values of objective sleep parameter measures for enrollment indicated the use of separate screening and baseline assessments. There were 7 different definitions of sleep apnea and 17 different definitions of success in treatment. There has been an overall improvement in the quality of the articles published on UPPP since 1995. Several areas still need improvement: use of more prospective studies, decrease in number of end points, use of separate screening and baseline assessments, and consensus in the definitions of sleep apnea and success.


Transcorporal Artificial Urinary Sphincter Technique Video.
The artificial urethral sphincter (AUS) is the gold standard treatment for male stress urinary incontinence which commonly results from prostatectomy or pelvic radiation for prostate cancer. Patients with prior pelvic radiation history experience increased risk of developing urethral erosion. Transcorporal AUS (TAUS) placement can be used as an alternative for compromised urethras to incorporate a small portion of the corporal bodies for additional support. The inclusion of an additional tissue barrier has been shown to improve outcomes. Patients who undergo this technique require device explanation and AUS revision less often than those with AUS devices placed in the standard fashion. Additionally, TAUS placement has been shown to improve functional urinary outcomes such as postoperative Internal prostate symptom score (IPSS), and postoperative IPSS Quality of Life (QoL) scores. A 67-year-old male with a past medical history of prostate cancer treated with surgery and radiation underwent a TAUS placement which was filmed to demonstrate placement technique and tips. Informed consent was obtained prior to filming this video. This technique can serve as a successful primary or salvage AUS placement technique as seen in this video. This video is used to demonstrate the technique of TAUS placement.


Phosphorylation of serine 106 in Asef2 regulates cell migration and adhesion turnover.
Asef2, a 652-amino acid protein, is a guanine nucleotide exchange factor (GEF) that regulates cell migration and other processes via activation of Rho family GTPases, including Rac. Binding of the tumor suppressor adenomatous polyposis coli (APC) to Asef2 is known to induce its GEF activity; however, little is currently known about other modes of Asef2 regulation. Here, we investigated the role of phosphorylation in regulating Asef2 activity and function. Using high-resolution mass spectrometry (MS) and tandem mass spectrometry (MS/MS), we obtained complete coverage of all phosphorylatable residues and identified six phosphorylation sites. One of these, serine 106 (S106), was particularly intriguing as a potential regulator of Asef2 activity because of its location within the APC-binding domain. Interestingly, mutation of this serine to alanine (S106A), a non-phosphorylatable analogue, greatly diminished the ability of Asef2 to activate Rac, while a phosphomimetic mutation (serine to aspartic acid, S106D) enhanced Rac activation. Furthermore, expression of these mutants in HT1080 cells demonstrated that phosphorylation of S106 is critical for Asef2-promoted migration and for cell-matrix adhesion assembly and disassembly (adhesion turnover), which is a process that facilitates efficient migration. Collectively, our results show that phosphorylation of S106 modulates Asef2 GEF activity and Asef2-mediated cell migration and adhesion turnover.


Glioma: application of whole-tumor texture analysis of diffusion-weighted imaging for the evaluation of tumor heterogeneity.
To apply a texture analysis of apparent diffusion coefficient (ADC) maps to evaluate glioma heterogeneity, which was correlated with tumor grade. Forty patients with glioma (WHO grade II (n = 8), grade III (n = 10) and grade IV (n = 22)) underwent diffusion-weighted imaging (DWI), and the corresponding ADC maps were obtained. Regions of interest containing the lesions were drawn on every section of the ADC map containing the tumor, and volume-based data of the entire tumor were constructed. Texture and first order features including entropy, skewness and kurtosis were derived from the ADC map using in-house software. A histogram analysis of the ADC map was also performed. The texture and histogram parameters were compared between low-grade and high-grade gliomas using an unpaired student's t-test. Additionally, a one-way analysis of variance analysis with a post-hoc test was performed to compare the parameters of each grade. Entropy was observed to be significantly higher in high-grade gliomas than low-grade tumors (6.861±0.539 vs. 6.261±0.412, P = 0.006). The fifth percentiles of the ADC cumulative histogram also showed a significant difference between high and low grade gliomas (836±235 vs. 1030±185, P = 0.037). Only entropy proved to be significantly different between grades III and IV (6.295±0.4963 vs. 7.119±0.3165, P<0.001). The diagnostic accuracy of ADC entropy was significantly higher than that of the fifth percentile of the ADC histogram (P = 0.0034) in distinguishing high- from low-grade glioma. A texture analysis of the ADC map based on the entire tumor volume can be useful for evaluating glioma grade, which provides tumor heterogeneity.


Cancer-associated epiphora: a retrospective analysis of referrals to a tertiary oculoplastic practice.
To report the underlying causes and treatment outcome of lacrimal drainage obstruction in patients with cancer-associated epiphora. A single-centre retrospective review was performed for consecutive referrals to an oculoplastic surgeon for cancer-associated epiphora between 2010 and 2016. Charts were reviewed for underlying neoplastic conditions, pharmacy records, radiotherapy records, levels of obstruction of the lacrimal drainage apparatus and treatment methods and outcome. Forty-three patients (70 eyes) were included in this study. The most common cause of epiphora was radiotherapy on the head and neck (35%), followed by oral S-1 (33%) and docetaxel (23%). The nasolacrimal duct was the most common obstruction site in patients who underwent radiotherapy (59%), whereas the punctum or canaliculus was mostly affected in patients treated with S-1 (94%) or docetaxel (100%). S-1-treated patients showed severe obstruction of the entire canaliculus (11/24 (46%)) with the lowest success rate at 58% (S-1 vs radiotherapy: p=0.012; S-1 vs docetaxel: p=0.002). Moreover, the patients treated within 1 year after the first symptom showed a significantly higher proportion of symptom improvement (85%) than did those treated after 1 year (27%) in the S-1 group (p=0.011). Cancer-associated epiphora can have various causes. The level of obstruction and treatment outcome vary according to underlying causes, and S-1-associated epiphora and delayed treatment are related to unsatisfactory results. Given the importance of early intervention, oncologists should be alert to tearing symptoms and cooperate with ophthalmologists in the early stages to improve patients' quality of life.


14-year hip survivorship after periacetabular osteotomy: a follow-up study on 1,385 hips.
Background and purpose - Few studies have evaluated the long- and mid-term outcomes after minimally invasive periacetabular osteotomy (PAO). We investigated: (1) the long-term hip survival rate after PAO; (2) the risk of complications and additional surgery after PAO; and (3) the hip function at different follow-up points.Patients and methods - We reviewed 1,385 hips (1,126 patients) who underwent PAO between January 2004 and December 2017. Through inquiry to the Danish National Patient Registry we identified conversions to total hip arthroplasty (THA) and complications after PAO. We evaluated the Hip disability and Osteoarthritis Outcome Score (HOOS) obtained preoperatively, and at 6 months, 2-, 5-, and 10-years' follow-up.Results - 73 of the 1,385 hips were converted to THA. The overall Kaplan-Meier hip survival rate was 80% (95% CI 68-88) at 14 years with a mean follow-up of 5 years (0.03-14). 1.1% of the hips had a complication requiring surgical intervention. The most common additional surgery was removal of screws (13%) and 11% received a hip arthroscopy. At the 2-year follow-up, HOOS pain improved by a mean of 26 points (CI 24-28) and a HOOS pain score > 50 was observed in 86%.Interpretation - PAO preserved 4 of 5 hips at 14 years, with higher age leading to lower survivorship. The PAO technique was shown to be safe; 1.1% of patients had a complication that demanded surgical intervention. The majority of the patients with preserved hips have no or low pain. The operation is effective with a good clinical outcome.


A 16-Channel Dipole Antenna Array for Human Head Magnetic Resonance Imaging at 10.5 Tesla.
For ultra-high field and frequency (UHF) magnetic resonance imaging (MRI), the associated short wavelengths in biological tissues leads to penetration and homogeneity issues at 10.5 tesla (T) and require antenna transmit arrays for efficiently generated 447 MHz B1+ fields (defined as the transmit radiofrequency (RF) magnetic field generated by RF coils). Previously, we evaluated a 16-channel combined loop + dipole antenna (LD) 10.5 T head array. While the LD array configuration did not achieve the desired B1+ efficiency, it showed an improvement of the specific absorption rate (SAR) efficiency compared to the separate 8-channel loop and separate 8-channel dipole antenna arrays at 10.5 T. Here we compare a 16-channel dipole antenna array with a 16-channel LD array of the same dimensions to evaluate B1+ efficiency, 10 g SAR, and SAR efficiency. The 16-channel dipole antenna array achieved a 24% increase in B1+ efficiency in the electromagnetic simulation and MR experiment compared to the LD array, as measured in the central region of a phantom. Based on the simulation results with a human model, we estimate that a 16-channel dipole antenna array for human brain imaging can increase B1+ efficiency by 15% with similar SAR efficiency compared to a 16-channel LD head array.


Prokineticin Ligands and Receptors Are Expressed in the Human Fetal Ovary and Regulate Germ Cell Expression of COX2.
Fetal ovarian development and primordial follicle formation underpin future female fertility. Prokineticin (PROK) ligands regulate cell survival, proliferation, and angiogenesis in adult reproductive tissues including the ovary. However, their expression and function during fetal ovarian development remains unclear. This study aimed to investigate expression and localization of the PROK ligands, receptors, and their downstream transcriptional targets in the human fetal ovary. This study was conducted at the University of Edinburgh. Ovaries were collected from 37 morphologically normal human fetuses. mRNA and protein expression of PROK ligands and receptors was determined in human fetal ovaries using qRT-PCR, immunoblotting, and immunohistochemistry. Functional studies were performed using a human germ cell tumor line (TCam-2) stably transfected with Prokineticin receptor 1 (PROKR1). Expression of PROK1 and PROKR1 was significantly higher in mid-gestation ovaries (17-20 wk) than at earlier gestations (8-11 and 14-16 wk). PROK2 significantly increased across the gestations examined. PROKR2 expression remained unchanged. PROK ligand and receptor proteins were predominantly localized to germ cells (including oocytes within primordial follicles) and endothelial cells, indicating these cell types to be the targets of PROK signaling in the human fetal ovary. PROK1 treatment of a germ cell line stably expressing PROKR1 resulted in ERK phosphorylation and elevated COX2 expression. Developmental changes in expression and regulation of COX2 and phosphorylated ERK (pERK) by PROK1 suggest that PROK ligands may be novel regulators of germ cell development in the human fetal ovary, interacting within a network of growth and survival factors prior to primordial follicle formation.


On the application of active learning and Gaussian processes in postcryopreservation cell membrane integrity experiments.
Biological cell cryopreservation permits storage of specimens for future use. Stem cell cryostorage in particular is fast becoming a broadly spread practice due to their potential for use in regenerative medicine. For the optimal cryopreservation process, ultralow temperatures are needed. However, elevated temperatures are often unavoidable in a typical sample handling cycle which in turn negatively affects the postcryopreservation integrity of cells. In this paper, we present an application of active learning using an underlying Gaussian Process (GP) model in an experimental study on postcryopreservation membrane integrity response to a range of elevated temperature conditions. We tailored this technique for the current investigation and developed an algorithm which enabled identification of the sampling locations for the experiments in order to obtain the highest information return about the process from a limited size sample set. We applied this algorithm in the experimental study investigating the effects of severe temperature elevation (ranging from -40 to 20 °C) over a short term event (48 hours) on the postcryopreservation membrane integrity of Mesenchymal Stem Cells (MSCs) derived from human bone marrow. The algorithm showed excellent performance by selecting the locations which maximized the reduction of variance of the process response estimate. An approximating GP model developed from this experimental data shows that the elevated temperatures during cryopreservation have an imminent detrimental effect on cell integrity.


Activation of AMP-activated protein kinase is essential for lysophosphatidic acid-induced cell migration in ovarian cancer cells.
Lysophosphatidic acid (LPA) is a bioactive phospholipid that affects various biological functions, such as cell proliferation, migration, and survival, through LPA receptors. Among them, the motility of cancer cells is an especially important activity for invasion and metastasis. Recently, AMP-activated protein kinase (AMPK), an energy-sensing kinase, was shown to regulate cell migration. However, the specific role of AMPK in cancer cell migration is unknown. The present study investigated whether LPA could induce AMPK activation and whether this process was associated with cell migration in ovarian cancer cells. We found that LPA led to a striking increase in AMPK phosphorylation in pathways involving the phospholipase C-β3 (PLC-β3) and calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) in SKOV3 ovarian cancer cells. siRNA-mediated knockdown of AMPKα1, PLC-β3, or (CaMKKβ) impaired the stimulatory effects of LPA on cell migration. Furthermore, we found that knockdown of AMPKα1 abrogated LPA-induced activation of the small GTPase RhoA and ezrin/radixin/moesin proteins regulating membrane dynamics as membrane-cytoskeleton linkers. In ovarian cancer xenograft models, knockdown of AMPK significantly decreased peritoneal dissemination and lung metastasis. Taken together, our results suggest that activation of AMPK by LPA induces cell migration through the signaling pathway to cytoskeletal dynamics and increases tumor metastasis in ovarian cancer.


Primary and secondary breast angiosarcoma: single center report and a meta-analysis.
Primary and secondary breast angiosarcoma is a rare and aggressive malignancy with limited published literature. Optimal management is mostly based on expert opinion. Our study aims to describe a single institution experience with breast angiosarcoma and evaluate other publications on this topic to further clarify prognostic outcomes and treatment modalities in this disease. Twenty two cases of breast angiosarcoma from Roswell Park Comprehensive Cancer Center were retrospectively analyzed. Additionally, a systemic review and meta-analysis was conducted to study the association between survival outcomes, overall survival (OS), and recurrence-free survival (RFS) in both primary (PAS) and secondary breast angiosarcoma (SAS). 9 PAS patients (41%) and 13 SAS patients (59%) were retrospectively analyzed. No significant differences were noted in tumor characteristics and survival outcomes between PAS and SAS. Treatment modality had no significant effects on survival outcomes although adjuvant chemotherapy demonstrated a trend towards improved RFS in high grade tumors. 380 PAS and 595 SAS patients were included in the outcome meta-analysis. Survival outcomes were significantly worse with high grade tumors and tumor size of > 5 cm. Adjuvant radiation therapy demonstrated significantly better RFS, while adjuvant chemotherapy had no effect on survival outcomes. Tumor size and grade seem to be reliable predictors of survival in both PAS and SAS. Mastectomy does not seem to be adding any additional benefit to BCS. Adjuvant radiation therapy showed statistically significant RFS benefit, while adjuvant chemotherapy can be beneficial in high grade tumors.


Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome.
Previous investigations have allowed for stratification of patients with postural tachycardia syndrome (POTS) on the basis of peripheral blood flow. One such subset, comprising "normal-flow POTS" patients, is characterized by normal peripheral resistance and blood volume in the supine position but thoracic hypovolemia and splanchnic blood pooling in the upright position. We studied 32 consecutive 14- to 22-yr-old POTS patients comprising 13 with low-flow POTS, 14 with normal-flow POTS, and 5 with high-flow POTS and 12 comparably aged healthy volunteers. We measured changes in impedance plethysmographic (IPG) indexes of blood volume and blood flow within thoracic, splanchnic, pelvic (upper leg), and lower leg regional circulations in the supine posture and during incremental tilt to 20 degrees, 35 degrees, and 70 degrees. We validated IPG measures of thoracic and splanchnic blood flow against indocyanine green dye-dilution measurements. We validated IPG leg blood flow against venous occlusion plethysmography. Control subjects developed progressive vasoconstriction with incremental tilt. Splanchnic blood flow was increased in the supine position in normal-flow POTS, despite marked peripheral vasoconstriction, and did not change during incremental tilt, producing progressive splanchnic hypervolemia. Absolute hypovolemia was present in low-flow POTS, all supine flows and volumes were reduced, there was no vasoconstriction with tilt in all segments, and segmental volumes tended to increase uniformly throughout tilt. Lower body (pelvic and leg) flows were increased in high-flow POTS at all angles, with consequent lower body hypervolemia during tilt. Our main finding is selective and maintained orthostatic splanchnic vasodilation in normal-flow POTS, despite marked peripheral vasoconstriction in these same patients. Local splanchnic vasoregulatory factors may counteract vasoconstriction and venoconstriction in these patients. Lower body vasoconstriction in high-flow POTS was abnormal, and vasoconstriction in low-flow POTS was sustained at initially elevated supine levels.


Determination of the nucleoside triphosphate contents of eggs and oocytes of Xenopus laevis.
The ribonucleotide and deoxyribonucleotide contents of eggs and oocytes of Xenopus laevis were measured. Eggs contained most deoxyribonucleotide in the form of triphosphates. dCTP, dTTP, dATP and dGTP were present in similar amounts. The egg contained sufficient deoxynucleotide triphosphate to make approximately 2500 nuclei. Oocytes contained less pyrimidine deoxyribonucleoside triphosphates than did eggs, and purine deoxyribonucleoside triphosphates were not detected. These differences may be correlated with the ability of eggs to induce nuclear DNA synthesis, a property not shown by oocytes. Both oocytes and eggs seem to contain non-phosphorylated, alpha-unsubstituted aldehydes, which may be deoxyribose derivatives. Eggs and oocytes contain similar amounts of ribonucleoside triphosphates. The low rate of RNA synthesis found in eggs, but not in oocytes, is therefore not caused by simple precursor control.


Mechanistic reconciliation of community and invasion ecology.
Community and invasion ecology have mostly grown independently. There is substantial overlap in the processes captured by different models in the two fields, and various frameworks have been developed to reduce this redundancy and synthesize information content. Despite broad recognition that community and invasion ecology are interconnected, a process-based framework synthesizing models across these two fields is lacking. Here we review 65 representative community and invasion models and propose a common framework articulated around six processes (dispersal, drift, abiotic interactions, within-guild interactions, cross-guild interactions, and genetic changes). The framework is designed to synthesize the content of the two fields, provide a general perspective on their development, and enable their comparison. The application of this framework and of a novel method based on network theory reveals some lack of coherence between the two fields, despite some historical similarities. Community ecology models are characterized by combinations of multiple processes, likely reflecting the search for an overarching theory to explain community assembly and structure, drawing predominantly on interaction processes, but also accounting largely for the other processes. In contrast, most models in invasion ecology invoke fewer processes and focus more on interactions between introduced species and their novel biotic and abiotic environment. The historical dominance of interaction processes and their independent developments in the two fields is also reflected in the lower level of coherence for models involving interactions, compared to models involving dispersal, drift, and genetic changes. It appears that community ecology, with a longer history than invasion ecology, has transitioned from the search for single explanations for patterns observed in nature to investigate how processes may interact mechanistically, thereby generating and testing hypotheses. Our framework paves the way for a similar transition in invasion ecology, to better capture the dynamics of multiple alien species introduced in complex communities. Reciprocally, applying insights from invasion to community ecology will help us understand and predict the future of ecological communities in the Anthropocene, in which human activities are weakening species' natural boundaries. Ultimately, the successful integration of the two fields could advance a predictive ecology that is urgently required in a rapidly changing world.


Islands of knowledge: science and agriculture in the history of Latin America and the Caribbean.
This essay explores the participation of Latin America and the Caribbean in the construction and circulation of tropical agricultural science during the nineteenth century and the first half of the twentieth century. It uses the term "islands of knowledge" to underscore the idea that each producing region across the global tropics, including Latin America and the Caribbean, was instrumental in the creation, adoption, and application of scientific procedures. At the same time, it emphasizes the value of interchange and interconnection between these regions, as well as the many and heterogeneous local areas, for analyzing what it calls "global archipelago agricultural scientific knowledge." This focus challenges the traditional center/periphery hierarchy and opens it to a wider vision of science and practice in agriculture. This essay shows how writing in related areas of research--specifically, commodity histories, biological exchange studies, and knowledge exchange studies--introduces approaches and case studies that are useful for the history of tropical agricultural science. In particular, this work provides analytical frameworks for developing studies of exchanges across the Global South.


[Chlamydia infections in South Trøndelag--treatment and follow-up].
According to Norwegian guidelines, infections caused by Chlamydia trachomatis should be treated rapidly with antibiotics and a control test should be offered after 5-6 weeks. The purpose of the present registry study was to investigate Chlamydia treatment and the use of control tests among men and women tested for Chlamydia in South Trøndelag county in the period 2004-2006. Data on all Chlamydia tests from men and women 15-59 years of age resident in South Trøndelag County were retrieved from the Department of Medical Microbiology at St. Olavs Hospital. Information about Norwegian pharmacies' handling of prescriptions for antibiotics were obtained from the Norwegian Prescription Database (NorPD). 8.5% (3,127/36 590) of those tested for Chlamydia in the study period were positive. Among those who were positive 87% (1,681/1 920) of women and 74% (909/1,207) of men bought antibiotics from a pharmacy within 4 weeks after the test was analyzed. The average time from available test result to treatment was 13.1 days (95% CI 12.7-13.5). Among those who received antibiotics, 41% (689/1,681) of women and 27% (247/909) of men were registered with a control test 4-16 weeks after the prescription was handled. Compliance to guidelines for treatment and follow-up of people with a positive Chlamydia test is poor, especially among men.