Luminal-applied flagellin is internalized by polarized intestinal epithelial cells and elicits immune responses via the TLR5 dependent mechanism.
Bacteria release flagellin that elicits innate responses via Toll-like receptor 5 (TLR5). Here, we investigated the fate of apically administrated full length flagellin from virulent and avirulent bacteria, along with truncated recombinant flagellin proteins in intestinal epithelial cells and cellular responses. Flagellin was internalized by intestinal epithelial cell (IEC) monolayers of IEC-18. Additionally, apically applied flagellin was internalized by polarized human Caco-2BBe and T-84 cells in a TLR5 dependent mechanism. More, flagellin exposure did not affect the integrity of intestinal monolayers. With immunofluorescent staining, internalized flagellin was detected in both early endosomes as well as lysosomes. We found that apical exposure of polarized Caco-2BBe and T-84 to flagellin from purified Salmonella, Escherichia coli O83:H1 (isolate from Crohn's lesion) or avirulent E. coli K12 induced comparable levels of basolateral IL-8 secretion. A recombinant protein representing the conserved amino (N) and carboxyl (C) domains (D) of the flagellin protein (ND1/2ECHCD2/1) induced IL-8 secretion from IEC similar to levels elicited by full-length flagellins. However, a recombinant flagellin protein containing only the D3 hypervariable region elicited no IL-8 secretion in both cell lines compared to un-stimulated controls. Silencing or blocking TLR5 in Caco-2BBe cells resulted in a lack of flagellin internalization and decreased IL-8 secretion. Furthermore, apical exposure to flagellin stimulated transepithelial migration of neutrophils and dendritic cells. The novel findings in this study show that luminal-applied flagellin is internalized by normal IEC via TLR5 and co-localizes to endosomal and lysosomal compartments where it is likely degraded as flagellin was not detected on the basolateral side of IEC cultures.


Diagnostic utility of computer tomographic enterography for patients presenting with unexplained gastrointestinal symptoms.
Computer tomographic enterography (CTE) is gaining approval for evaluation of small bowel diseases. However, the diagnostic yields of CTE for diseases other than Crohn's disease have not yet been well elucidated. The aim of the present study was to determine the diagnostic utility of CTE and to ascertain the clinical factors predictive of the positive diagnostic rate in patients with unexplained gastrointestinal symptoms or signs. The clinical and radiological data of 193 patients with unexplained gastrointestinal symptoms that had a CTE examination at Severance Hospital between May 2007 and April 2010 were retrospectively analyzed. CTE revealed positive findings that explained the symptoms in 51 of the 193 patients (diagnostic yield 26.4%). Positive findings of diagnosis included cancer (12 patients), Crohn's disease (10), intestinal stricture/obstruction (9), small bowel bleeding (7), colitis (6), intestinal Behcet's disease (4), intestinal tuberculosis (2) and intestinal fistula (1). According to univariate analysis, the positive findings of CTE were significantly associated with higher segmentated neutrophil count (p<0.001), higher erythrocyte sedimentation rate (ESR) (p=0.003), higher C-reactive protein (CRP) level (p=0.008) and lower serum albumin level (p=0.037). Multivariate analysis indicated that elevated CRP level was a significant risk factor for the positive findings of CTE (odds ratio 1.950; 95% CI (1.165-3.265), p=0.011). The results of this study suggest that CTE could be helpful in patients suffering from unexplained gastrointestinal symptoms that cannot be explained by established examinations, especially those with elevated C-reactive protein levels.


Warming and CO2 effects under oligotrophication on temperate phytoplankton communities.
Eutrophication, global warming, and rising carbon dioxide (CO2) levels are the three most prevalent pressures impacting the biosphere. Despite their individual effects are well-known, it remains untested how oligotrophication (i.e. nutrients reduction) can alter the planktonic community responses to warming and elevated CO2 levels. Here, we performed an indoor mesocosm experiment to investigate the warming × CO2 interaction under a nutrient reduction scenario (40%) mediated by an in-lake management strategy (i.e. addition of a commercial solid-phase phosphorus sorbent -Phoslock®) on a natural freshwater plankton community. Biomass production increased under warming × CO2 relative to present-day conditions; however, a Phoslock®-mediated oligotrophication reduced such values by 30-70%. Conversely, the warming × CO2 × oligotrophication interaction stimulated the photosynthesis by 20% compared to ambient nutrient conditions, and matched with higher resource use efficiency (RUE) and nutrient demand. Surprisingly, at a group level, we found that the multi-stressors scenario increased the photosynthesis in eukaryotes by 25%, but greatly impaired in cyanobacteria (ca. -25%). This higher cyanobacterial sensitivity was coupled with a reduced light harvesting efficiency and compensation point. Since Phoslock®-induced oligotrophication unmasked a strong negative warming × CO2 effect on cyanobacteria, it becomes crucial to understand how the interplay between climate change and nutrient abatement actions may alter the, ecosystems functioning. With an integrative understanding of these processes, policy makers will design more appropriate management strategies to improve the ecological status of aquatic ecosystems without compromising their ecological attributes and functioning.


Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study.
A possible synergic role of serum uric acid (SUA) with thrombolytic therapies is controversial and needs further investigations. We therefore evaluated association of admission SUA with clinical improvement and clinical outcome in patients receiving rt-PA, early admitted patients not receiving rt-PA, and patients admitted after time window for rt-PA. SUA levels were obtained at admission and categorized as low, middle and high, based on 33° and 66° percentile values. Patients were categorized as patients admitted within 3 hours of symptom onset receiving rt-PA (rt-PA group), patients admitted within 3 hours of symptom onset not receiving rt-PA (non-rt-PA group), and patients admitted after time window for rt-PA (late group). Short-term clinical improvement was defined as the difference between NIHSS on admission minus NIHSS day 7. Favorable outcome was defined as mRS 0 - 3 and unfavorable outcome as mRS 4 - 6. SUA measurements were available in 1136 patients. Clinical improvement was significantly higher in patients with high SUA levels at admission. After adjustment for possible confounders, SUA level showed a positive correlation with clinical improvement (r = 0.012, 95% CI 0.002-0.022, p = 0.02) and was an independent predictor for favorable stroke outcome (OR 1.004; 95% CI 1.0002-1.009; p = 0.04) only in the rt-PA group. SUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.


Otostegia persica (Lamiaceae): A review on its ethnopharmacology, phytochemistry, and pharmacology.
The current study summarizes the updated information concerning the ethnopharmacology, Phytochemistry, and pharmacology of Otostegia persica Boiss. (Lamiaceae), an endemic medicinal plant in south and southeast of Iran. Information was collected through bibliographic investigation from scientific journals, books, theses, reports, and electronic search (databases SCOPUS, Google Scholar, Web of Science, and Science Direct). Moreover, documentation from unpublished resources and ethnobotanical surveys has been used. The present review covers the literature available from 2003 to 2013. In traditional systems of medicine, this plant is reputed for treating diabetes, arthritis, gastric discomfort, headache, rheumatism, sedative activities, regulating blood pressure, and hyperlipidemia. Phytochemical screening of active components and mineral element evaluation of this species have been reported. Several types of diterpenoids and flavonols including morin, kaempferol, and quercetin are identified from the plant. Most of the pharmacological activity of this plant resides in its flavonoid fraction which causes antimicrobial and antioxidant activities. Various pharmacological studies on O. persica show antimicrobial, antioxidant, anti-inflammatory, anti-diabetic, anti-aphid, and hepatoprotective activities. Being an endemic plant of Iran, this species is an important medicinal herb which can be used for various purposes. This review might be helpful for scientists and researchers to find new chemical entities responsible for its claimed traditional uses and discover new lead compounds for diseases mentioned.


Multiple sclerosis--Part 2. Treatment strategies.
Because it is a chronic, relapsing or progressive disease, multiple sclerosis has an unpredictable clinical course generally spanning 10 to 20 years. During that time, neurologic disability is cumulative. Therefore, it is difficult to evaluate the efficacy of a given mode of treatment in an individual patient. This second part of a two-part series reviews current and emerging modes of therapy for multiple sclerosis. Future treatment directions in multiple sclerosis will require a better understanding of the pathophysiology of the disease. Future therapeutic modalities will also rely on more accurate clinical markers, such as improved magnetic resonance imaging techniques or specific immune markers to follow the disease progression. Part 1 of this series appearing in the November 1999 issue of JAOA included several sections on multiple sclerosis, including an overview, pathophysiology, diagnostic evaluation, and clinical parameters.


Characterization of three novel delta chain hemoglobin variants and two delta-thalassemia alleles.
We report the characterization of five novel delta-globin gene mutations detected during routine screening for thalassemia. Three missense mutations were identified, resulting in the following delta chain hemoglobin (Hb) variants: Hb A(2)-Acacias [delta4 (ACT>AGT), Thr-->Ser, HBD c.14C>G], Hb A(2)-Toronto [delta74 (GGC>GAC), Gly-->Asp, HBD c.224G>A], and Hb A(2)-Calgary [delta99 (GAT>GGT), Asp-->Gly, HBD c.299A>G]. Two other mutations most likely result in delta(0)-thalassemia (delta(0)-thal). One mutation altered the translation initiation codon from ATG to ATA (HBD c.3G>A), and another changed the canonical splice donor sequence of IVS-II from GT to AT (HBD C.315+1G>A).


Regulation of voltage dependence of the KAT1 channel by intracellular factors.
The KAT1 channel is a hyperpolarization-activated K+ channel cloned from the higher plant Arabidopsis. The deduced amino acid sequence suggests that its structural organization is similar to that of the Shaker-like K+ channel activated by depolarization. Electrophysiological properties of the KAT1 channel expressed in Xenopus oocytes indicate that voltage-dependent activation of the KAT1 channel is not caused by the divalent ion block and that it is intrinsic to the channel. Activity of the KAT1 channel progressively decreases upon patch excision. This rundown of the channel is accompanied by a large shift in the voltage dependence of the channel to a more negative direction. The voltage dependence is also regulated by pH, ATP, and cGMP.


Characterization of dendritic cell (DC)-10 in recurrent miscarriage and recurrent implantation failure.
During pregnancy, the maternal immune system must tolerate the persistence of semi-allogeneic fetus in the maternal tissue. Inadequate recognition of fetal antigens may lead to pregnancy complications, such as recurrent miscarriage (RM) and recurrent implantation failure (RIF). Dendritic cells (DCs) are key regulators of protective immune responses and the development and maintenance of tolerance. Regarding that DCs are important in the establishment of immune tolerance in human pregnancy, it would be important to study the microenvironment in which DCs reside or are activated may affect their functions toward tolerance rather than active immune response. IL-10 plays a critical role in the maintenance of normal pregnancy, and the increased production of IL-10 is associated with successful pregnancy. In this study, we provide an in-depth comparison of the phenotype and cytokine production by DC-10 and other DC subsets, such as iDC and mDC. CD14+ monocyte-derived DCs were differentiated in the presence of IL-10 (DC-10) in vitro from ten normal fertile controls, six RM women and seven RIF women, and characterized for relevant markers. DC-10 was characterized by relatively low expression of costimulatory molecule CD86, as well as MHC class II molecule HLA-DR, high expression of tolerance molecules HLA-G, ILT2, ILT4 and immunosuppressive cytokine IL-10, but produced little or no proinflammatory cytokines, such as TNF-α, IL-6 and IL-12p70. Our study provides a better understanding of the phenotypical properties of DC-10, which may participate in the complex orchestration that leads to maternal immune tolerance and homeostatic environment in human pregnancy.


Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.
Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.


Autologous large multivalent immunogen vaccine in patients with metastatic melanoma and renal cell carcinoma.
To evaluate the safety and activity of large multivalent immunogen (LMI), prepared by immobilizing autologous tumor cell plasma membrane on 5-microm diameter silica beads, in patients with melanoma and renal cell carcinoma (RCC). Thirty patients with stage IV metastatic melanoma and 31 patients with stage IV RCC were randomly assigned to 1 of 3 trial arms and received monthly treatment with (1) LMI alone, (2) cyclophosphamide followed 8 days later with LMI, or (3) the same treatment as in arm 2 with IL-2 given for 5 days beginning 1 week after LMI administration. No grade 4 toxicities were observed. For patients with melanoma, median overall survival time for all 30 patients was 20.4 months [95% confidence interval (CI): 8.0-not assessable], and median progression-free survival was 2.8 months (95% CI: 1.9-6.3). For patients with RCC, median overall survival exceeded 46.2 months (95% CI: 30.3-not assessable), and median progression-free survival was 12.2 months (95% CI: 4.6-not assessable). Two patients had a partial response to LMI treatment. Based on our results that demonstrate the safety and tolerability of LMI vaccine, further development of this therapy is warranted to evaluate its clinical efficacy.


Aldehyde dehydrogenase is a positional marker in the retina.
An asymmetrically distributed protein in the embryonic mouse retina was identified as an aldehyde dehydrogenase through protein microsequencing. It was characterized as a cytosolic isoform with basic isoelectric point and preference for aliphatic substrates, features that resemble those of the isoform AHD-2 which is known to oxidize retinaldehyde to retinoic acid. Immunohistochemistry with aldehyde dehydrogenase antisera showed strong labeling of the dorsal retina from the early eye vesicle stage into adulthood. In addition, optic axons originating from the dorsal retina were transiently labeled during their outgrowth phase. Whereas in the embryo the enzyme was expressed in undifferentiated cells and in neurons, in the retina of the adult mouse the asymmetrically distributed isoform was mainly expressed in Müller glia, with the number of labeled glial cells varying with retinal position.


Impact of acupuncture treatment on the lumbar surgery rate for low back pain in Korea: A nationwide matched retrospective cohort study.
Low back pain (LBP) is a globally prevalent disorder with high social significance. Invasive surgical procedures are increasingly being used to treat LBP despite a lack of solid evidence supporting their long-term benefits. This nationwide retrospective cohort study investigated the association between acupuncture treatment and lumbar surgery rate in patients with LBP. Using the National Health Insurance Service Sample Cohort Database for 2002-2013, we identified newly diagnosed LBP patients in Korea between 2004 and 2010 and divided them into an acupuncture group and control group according to whether or not they received acupuncture. Propensity scores based on age, sex, income, and Charlson Comorbidity Index were matched between the two study groups. The lumbar surgery rate in the two years following the first visit (control group) or the first acupuncture session (acupuncture group) was calculated. In addition to the overall analysis, stratified analyses were also conducted in different age, sex, and income strata. Sensitivity analyses were further performed using varying definitions of acupuncture treatment. After matching, 130,089 subjects were included in each study group. The lumbar surgery rate was significantly lower in the acupuncture group than in the control group (hazard ratio [HR] 0.633, 95% confidence interval [CI] 0.576-0.696). Decrease in HR was consistently observed in the acupuncture group for all age strata, except for patients in their 20s (HR 1.031, 95% CI 0.804-1.323). HR for lumbar surgery tended to be further reduced in the older age groups upon acupuncture treatment, with no apparent sex-related differences. Lowered HR in the acupuncture group was continuously observed across all income groups; the higher income group showed a tendency of greater decrease. Sensitivity analyses showed that the number of acupuncture sessions had no major impact on the likelihood of lumbar surgery, but also that more intensive acupuncture treatment was associated with further reduction in lumbar surgery rates. The present results found that administration of acupuncture treatment is associated with lower lumbar surgery rates for LBP patients in Korea. Prospective studies are warranted in the future to further investigate the effect of acupuncture treatment on lumbar surgery incidence.


Effectiveness of topical budesonide in preventing esophageal strictures after endoscopic resection of esophageal cancer.
Background and study aims A disadvantage of endoscopic resection (ER) of early esophageal cancer (EC) is the high stricture rate after resection. A risk factor for stricture development is a mucosal defect after ER of ≥ 75 % of the esophageal circumference. Stricture rates up to 94 % have been reported in these patients. The aim of this study was to investigate the effectiveness of oral treatment with topical budesonide for stricture prevention after ER of early EC. Patients and methods We performed a retrospective analysis of a prospective cohort study of patients who received topical budesonide after ER of EC between March 2015 and April 2020. The primary endpoint was the esophageal stricture rate after ER. Stricture rates of our cohort were compared with stricture rates of control groups in the literature. Results In total, 42 patients were treated with ER and topical budesonide. A total of 18 of 42 patients (44.9 %) developed a stricture. The pooled stricture rate of control groups in the literature was 75.3 % (95 % CI 68.8 %-81.9 %). Control groups consisted of patients with esophageal squamous cell carcinoma with a mucosal defect after ER of ≥ 75 % of the esophageal circumference. Comparable patients of our cohort had a lower stricture rate (47.8 % vs. 75.3 %, P = 0.007). Conclusions Topical budesonide therapy after ER for EC seems to be a safe and effective method in preventing strictures. The stricture rate after budesonide treatment is lower compared to the stricture rate of patients who did not receive a preventive treatment after ER reported in the literature.


Cardiac adrenergic nerve function and microvascular dysfunction in patients with cardiac syndrome X.
To assess whether abnormalities in cardiac uptake of (123)I-metaiodobenzylguanidine (MIBG) correlate with coronary microvascular dysfunction in patients with cardiac syndrome X (CSX). University hospital. 29 patients (aged 59 (SD 7) years, 11 men) with typical CSX and a matched group of 20 healthy subjects (aged 56 (7) years, 8 men) were studied. Planar and single photon emission computed tomography (SPECT) MIBG myocardial scintigraphy was performed in all subjects. Coronary flow response (CFR) to adenosine and to cold pressor test (CPT) in the left anterior descending (LAD) coronary artery was assessed in all CSX patients and in 12 controls by transthoracic Doppler echocardiography. Abnormalities in cardiac MIBG scintigraphy were observed in 25 CSX patients (86.2%), but in no healthy control (p<0.001). Compared to controls, CSX patients showed a lower heart/mediastinum (H/M) ratio of MIBG uptake (1.69 (0.24) vs 2.2 (0.3), p<0.001) and a higher cardiac MIBG defect score (25 (22) vs 4 (2), p = 0.002). Both CFR to adenosine (3.31 (1.1) vs 1.94 (0.6), p<0.001) and CFR to CPT (2.35 (0.5) vs 1.63 (0.4), p<0.001) were lower in CSX patients than in controls. In CSX patients, however, no correlation was found between MIBG H/M ratio and CFR to adenosine (r = 0.17; p = 0.38) and to CPT (r = -0.28; p = 0.13), as well as between MIBG uptake score in the LAD territory and CFR to adenosine (r = 0.14; p = 0.47) and to CPT (r = 0.06; p = 0.73). Our data show striking abnormalities in cardiac adrenergic nerve function and in coronary microvascular function in CSX patients. However, no significant relation between the two abnormalities was found. Further studies are needed to clarify the mechanisms and the role of MIBG defects in CSX patients.


POEMS syndrome: update on diagnosis, risk-stratification, and management.
POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with 3 of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.


Subtyping of gliomas of various WHO grades by the application of immunohistochemistry.
In 2010, four subtypes (classical, proneural, mesenchymal, and neural) of glioblastoma multiforme (GBM) were defined by molecular genetic analyses. The objective of this study was to assess whether gliomas, independently of the type and grade, could be subdivided into protein-based subtypes. A tissue microarray (TMA) approach was applied to incorporate tissue samples of low-grade and high-grade gliomas into five TMAs. High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor α, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC). Glioma could be subdivided into four subtypes by IHC. The majority of the low-grade gliomas were of the proneural subtype, i.e. high p53 expression (63% of grade II). The classical subtype, with high EGFR and low p53 expression, was most common in GBMs (39%), followed by the proneural (29%) and mesenchymal (with high CD44 and MERTK expression) (29%) subtypes, a frequency that is in line with previously published data based on molecular genetics. Assessment of the expression of the five proteins EGFR, CD44, MERTK, p53 and OLIG2 is sufficient for subtyping gliomas, and can be recommended for implementation in clinical practice for both low-grade and high-grade gliomas.


[Glass ionomer cement used as a retrograde filling material after apicoectomy: a review].
When an apicoectomy is performed, using retrograde sealing with amalgam, the healing of the periapical area is not always perfect. In a number of cases the cause of this imperfect healing may be due to the improper sealing ability and the moderate tissue compatibility of amalgam. A literature study has been carried out, based on the assumption that glass ionomer cement will provide a better sealing and will cause less tissue reaction. It appeared that, at least in theory, glass ionomer cement is to be preferred to amalgam when it comes to apical sealing properties and tissue reaction. In terms of usability, resorption, hardness and costs no significant differences were found. The conclusion is drawn that glass ionomer cement is an equal or perhaps even better alternative for retrograde amalgam.


Quality of life among HIV-tuberculosis co-infected patients.
India is the world's third leading country in terms of people living with human deficiency virus (HIV) (2.1 million) with 0.4 million deaths due to HIV-associated tuberculosis (TB). Physical and mental stress degrades the quality of life (QOL) in these patients. Studies have been done in HIV patients but very few on HIV-TB co-infected patients. Our study aims at assessing and comparing the QOL in HIV patients with and without TB. It was a cross-sectional study done at Antiretroviral Treatment Center of KMC, Mangalore and District Wenlock Hospital, Mangalore, over 6 months. A sample size was 104. Semi-structured questionnaire to collect clinico-demographic data, World Health Organization QOL (WHOQOL)-HIV BREF to assess the QoL, and Beck's Depression Inventory Scale (Physical health, psychological well-being, social relationship, environmental health, level of independence, and spiritual health) to identify depression were used. The Cronbach's alpha was used to measure the internal consistency for each domain of the WHOQOL-HIV instrument. HIV-TB co-infected patients had a lower mean score in all domains as compare to only HIV patients, suggesting that HIV-TB co-infected patients had a poor QOL (P < 0.05). Internal consistency of each domain was good (α >0.7). To improve the QOL in HIV patients, it is important to identify the determinants of QOL and work toward its improvement.


Determination of threshold exposure and intensity for recording holograms in thick green-sensitive acrylamide-based photopolymer.
For optical data storage applications, it is essential to determine the lowest intensity (also known as threshold intensity) below or at which no data page or grating can be recorded in the photosensitive material, as this in turn determines the data capacity of the material. Here, experiments were carried out to determine the threshold intensity below which the formation of a simple hologram--a holographic diffraction grating in a green-sensitized acrylamide-based photopolymer--is not possible. Two main parameters of the recording layers--dye concentration and thickness--were varied to study the influence of the density of the generated free radicals on the holographic properties of these layers. It was observed that a minimum concentration per unit volume of free radicals is required for efficient cross-linking of the created polymer chains and for recording a hologram. The threshold intensity below which no hologram can be recorded in the Erythrosin B sensitized layers with absorbance less than 0.16 was 50 μW/cm(2). The real-time diffraction efficiency was analyzed in the early stage of recording. It was determined that the minimum intensity required to obtain diffraction efficiency of 1% was 90 μW/cm(2), and the minimum required exposure was 8 mJ/cm(2). It was also determined that there is an optimum dye concentration of 1.5 × 10(-7) mol/L for effective recording above which no increase in the sensitivity of the layers is observed.


Munchausen syndrome by proxy: a case report.
Munchausen syndrome by proxy is difficult to diagnose unless healthcare providers are astute to its clinical features and management. A case is presented to educate nurses and advanced practice nurses, of the nursing, medical, legal, and social complexities associated with Munchausen syndrome by proxy. This article also provides a brief review of the definition of Munchausen syndrome by proxy, its epidemiology, common features of the perpetrator, implications for healthcare personnel, and the legal and international ramifications of Munchausen syndrome by proxy.


The Clinical Efficacy of Prostate Cancer Screening in Worldwide and Iran: Narrative Review.
Prostate cancer (CaP) imposes a great health burden on men, while its incidence has significantly increased in recent years. The screening program for CaP is still controversial and recent large trials have failed to present a significant reduction in prostate-specific mortality and all-cause mortality. An entire body of data obtained from worldwide studies conducted on CaP screening is required to better evaluate health policy decisions and patient decision-making. In current review, the clinical efficacy of screening programs on CaP was discussed in numerous parts of the world, such as in the US, Europe, and Asia, to provide an updated screening recommendation. Finally, we discuss about CaP screening status in Iran and update the screening recommendation in Iran.


Environmental justice implications of arsenic contamination in California's San Joaquin Valley: a cross-sectional, cluster-design examining exposure and compliance in community drinking water systems.
Few studies of environmental justice examine inequities in drinking water contamination. Those studies that have done so usually analyze either disparities in exposure/harm or inequitable implementation of environmental policies. The US EPA's 2001 Revised Arsenic Rule, which tightened the drinking water standard for arsenic from 50 μg/L to 10 μg/L, offers an opportunity to analyze both aspects of environmental justice. We hypothesized that Community Water Systems (CWSs) serving a higher proportion of minority residents or residents of lower socioeconomic status (SES) have higher drinking water arsenic levels and higher odds of non-compliance with the revised standard. Using water quality sampling data for arsenic and maximum contaminant level (MCL) violation data for 464 CWSs actively operating from 2005-2007 in California's San Joaquin Valley we ran bivariate tests and linear regression models. Higher home ownership rate was associated with lower arsenic levels (ß-coefficient= -0.27 μg As/L, 95% (CI), -0.5, -0.05). This relationship was stronger in smaller systems (ß-coefficient = -0.43, CI, -0.84, -0.03). CWSs with higher rates of homeownership had lower odds of receiving an MCL violation (OR, 0.33; 95% CI, 0.16, 0.67); those serving higher percentages of minorities had higher odds (OR, 2.6; 95% CI, 1.2, 5.4) of an MCL violation. We found that higher arsenic levels and higher odds of receiving an MCL violation were most common in CWSs serving predominantly socio-economically disadvantaged communities. Our findings suggest that communities with greater proportions of low SES residents not only face disproportionate arsenic exposures, but unequal MCL compliance challenges.


CIP2A Promotes Proliferation, Invasion and Chemoresistance to Cisplatin in Renal Cell Carcinoma.
CIP2A is a well-known oncoprotein whose expression is elevated in multiple human solid tumor types. However, its role in renal cell carcinoma (RCC) development is poorly understood. Thus, in our present study, we used the renal cancer cell lines 786-O, A498 and CAKI-1 and the renal epithelial cell line HK-2 to clarify the function of CIP2A in RCC. We found that CIP2A expression is much higher in the RCC cells than in the normal renal epithelial cell. Lentivirus covered coding region CIP2A cDNA sequence and CIP2A siRNA were used to up and down regulate CIP2A expression in vitro. We found that overexpression of CIP2A promoted G1/S transition and cell proliferation. In addition, up-regulation of CIP2A significantly enhanced the invasion and migration capabilities of the cells. Furthermore, CIP2A promoted epithelial-mesenchymal transformation (EMT) and chemoresistance to cisplatin in RCC cells. Taken together, our findings demonstrate that CIP2A plays an important role in proliferation, invasion and chemoresistance to cisplatin in RCC cells. CIP2A may serve as an ideal molecular target for RCC therapeutics.


Binary mixture effects by PBDE congeners (47, 153, 183, or 209) and PCB congeners (126 or 153) in MCF-7 cells: biochemical alterations assessed by IR spectroscopy and multivariate analysis.
Target organisms are continuously and variously exposed to contaminant mixtures in the environment. We noted that treatment with brominated diphenyl ether (BDE)47 or polychlorinated biphenyl (PCB)126 (toxic equivalency factor [TEF] = 0.1) induces similar alterations in MCF-7 cells when these were determined using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy with multivariate analysis. Because this method appears sensitive enough to signature low-dose effects, we examined how various test agents interact in binary mixtures to induce cell alterations. MCF-7 cells were exposed for 24 h to low concentrations (10(-12) M) of polybrominated diphenyl ether (PBDE) congeners (47, 153, 183, or 209) with or without the coplanar PCB126 or nonplanar PCB153. Following treatment, ethanol-fixed cellular material was interrogated using ATR-FTIR spectroscopy; derived IR spectra in the biochemical-cell fingerprint region (1800 cm(-1)-900 cm(-1)) were then subjected to principal component analysis-linear discriminant analysis. Assuming that if two test agents independently induce the same cell alteration that in combination they'll give rise to an additive effect, we examined predicted versus observed differences in induced alterations by binary mixtures. Compared to corresponding control clusters, treatment with PBDE congener plus PCB126 appeared to cancel out their respective induced alterations. However, treatment with binary mixtures including PCB153 gave rise to an enhanced segregation. Our findings suggest that test agents which mediate their cellular effects via similar mechanisms might result in inhibition within a binary mixture whereas independently acting agents could exacerbate induced alterations in overall cell status.


Design and synthesis of a mimetic from an antibody complementarity-determining region.
A technique for producing non-peptide compounds (mimetics) of designed specificities was developed that permitted the synthesis of a conformationally restricted molecule that mimicked the binding and functional properties of monoclonal antibody (MAb) 87.92.6, which recognizes the reovirus type 3 cellular receptor. Binding of either MAb 87.92.6, peptide analogs, or 87.1-mimetic to the cellular receptor inhibited cellular proliferation. The mimetic was a synthetic beta-loop structure that mimics the second complementarity-determining region of the MAb. These studies may lead to strategies for the synthetic design of antibody complementarity regions, ligands, and other pharmacologically active agents that are water soluble, resistant to proteolysis, and nonimmunogenic.


Calcium Influx Caused by ER Stress Inducers Enhances Oncolytic Adenovirus Enadenotucirev Replication and Killing through PKCα Activation.
Oncolytic viruses represent an emerging approach to cancer therapy. However, better understanding of their interaction with the host cancer cell and approaches to enhance their efficacy are needed. Here, we investigate the effect of chemically induced endoplasmic reticulum (ER) stress on the activity of the chimeric group B adenovirus Enadenotucirev, its closely related parental virus Ad11p, and the archetypal group C oncolytic adenovirus Ad5. We show that treatment of colorectal and ovarian cancer cell lines with thapsigargin or ionomycin caused an influx of Ca2+, leading to an upregulation in E1A transcript and protein levels. Increased E1A protein levels, in turn, increased levels of expression of the E2B viral DNA polymerase, genome replication, late viral protein expression, infectious virus particle production, and cell killing during Enadenotucirev and Ad11p, but not Ad5, infection. This effect was not due to the induction of ER stress, but rather the influx of extracellular Ca2+ and consequent increase in protein kinase C activity. These results underscore the importance of Ca2+ homeostasis during adenoviral infection, indicate a signaling pathway between protein kinase C and E1A, and raise the possibility of using Ca2+ flux-modulating agents in the manufacture and potentiation of oncolytic virotherapies.


Public health and pork and pork products: regional perspectives of Denmark.
An ambitious programme to eliminate pork as an important source of human salmonellosis was initiated in Denmark in 1993 by the Ministry of Food, Agriculture and Fisheries. The programme comprises control of feedmills, breeding and multiplying herds, slaughter herds and slaughter plants, as well as the final product, fresh pork. As a consequence, the level of occurrence of Salmonella spp. in fresh pork produced in Denmark is approximately 1%. Yersinia enterocolitica 0:3 infections are common in slaughter pig herds in Denmark, and pork is considered to be the only source of human infection in the country. The incidence of pork-related occurrences of human salmonellosis and yersiniosis in 1996 was approximately nine cases per 100,000 inhabitants for both diseases. All swine in Denmark are screened for Trichinella spp. infection, although no positive results have been obtained since 1930. Swine are not considered to be a source for Campylobacter jejuni or enterohaemorrhagic Escherichia coli in Denmark. Listeria monocytogenes can be detected in relatively high rates in pork: however, the incidence of human listeriosis is only 0.5 cases per 100,000 inhabitants. Toxoplasma gondii antibodies have been demonstrated in 3% of slaughter pigs, though the importance of pork as a source of infection is probably very low. Denmark is officially free from Brucella abortus, B. melitensis and Mycobacterium bovis.


Photochemically induced increase in endothelial permeability regulated by RhoA activation.
Photochemical reactions used in photodynamic therapy are reported to damage normal cells and tissues in ways that increase endothelial permeability and thereby cause excessive neointimal formation and subsequent restenosis. To investigate the mechanisms of this permeability increase in vitro, human umbilical vein endothelial cells were incubated with the porphyrin precursor delta-aminolevulinic acid and then irradiated with a 646 nm light-emitting diode (LED). Results using Transwells supports showed that the photochemical reaction increased endothelial permeability by 200%, and fluorescence microscopy revealed that destruction of the capillary-like structures due to cell shrinkage was accompanied by VE-cadherin mislocalization and stress fiber formation. The generated gaps between cells were observed using dyed beta1-integrin and total internal reflection fluorescence microscopy. Western blotting indicated that the photochemical reaction phosphorylated GDP-RhoA to GTP-RhoA, a protein that promotes stress fiber formation and inhibits VE-cadherin production. When forskolin/rolipram or 8CPT-2'O-Me-cAMP, both of which inhibit further reaction of phosphorylated RhoA, were added, no formation of stress fibers or mislocalization of VE-cadherin was observed, thus preventing an increase in endothelial permeability. Taken together, photochemically induced RhoA activation appears to play a key role in increasing endothelial permeability during changes in morphology of endothelial cells.


Population-based incidence, seasonality and serotype distribution of invasive salmonellosis among children in Nanoro, rural Burkina Faso.
Bloodstream infections (BSI) caused by Salmonella Typhi and invasive non-Typhoidal Salmonella (iNTS) frequently affect children living in rural sub-Saharan Africa but data about incidence and serotype distribution are rare. The present study assessed the population-based incidence of Salmonella BSI and severe malaria in a Health and Demographic Surveillance System in a rural area with seasonal malaria transmission in Nanoro, Burkina Faso. Children between 2 months-15 years old with severe febrile illness were enrolled during a one-year surveillance period (May 2013-May 2014). Thick blood films and blood cultures were sampled and processed upon admission. Population-based incidences were corrected for non-referral, health seeking behavior, non-inclusion and blood culture sensitivity. Adjusted incidence rates were expressed per 100,000 person-years of observations (PYO). Among children < 5 years old, incidence rates for iNTS, Salmonella Typhi and severe malaria per 100,000 PYO were 4,138 (95% Confidence Interval (CI): 3,740-4,572), 224 (95% CI: 138-340) and 2,866 (95% CI: 2,538-3,233) respectively. Among those aged 5-15 years, corresponding incidence rates were 25 (95% CI: 8-60), 273 (95% CI: 203-355) and 135 (95% CI: 87-195) respectively. Most iNTS occurred during the peak of the rainy season and in parallel with the increase of Plasmodium falciparum malaria; for Salmonella Typhi no clear seasonal pattern was observed. Salmonella Typhi and iNTS accounted for 13.3% and 55.8% of all 118 BSI episodes; 71.6% of iNTS (48/67) isolates were Salmonella enterica serovar Typhimurium and 25.4% (17/67) Salmonella enterica serovar Enteritidis; there was no apparent geographical clustering. The present findings from rural West-Africa confirm high incidences of Salmonella Typhi and iNTS, the latter with a seasonal and Plasmodium falciparum-related pattern. It urges prioritization of the development and implementation of Salmonella Typhi as well as iNTS vaccines in this setting.


Adiposity and Blood Pressure in 110 000 Mexican Adults.
Previous studies have reached differing conclusions about the importance of general versus central markers of adiposity to blood pressure, leading to suggestions that population-specific adiposity thresholds may be needed. We examined the relevance of adiposity to blood pressure among 111 911 men and women who, when recruited into the Mexico City Prospective Study, were aged 35 to 89 years, had no chronic disease, and were not taking antihypertensives. Linear regression was used to estimate the effects on systolic and diastolic blood pressure of 2 markers of general adiposity (body mass index and height-adjusted weight) and 4 markers of central adiposity (waist circumference, hip circumference, waist:hip ratio, and waist:height ratio), adjusted for relevant confounders. Mean (SD) adiposity levels were: body mass index (28.7±4.5 kg/m2), height-adjusted weight (70.2±11.2 kg), waist circumference (93.3±10.6 cm), hip circumference (104.0±9.0 cm), waist:hip ratio (0.90±0.06), and waist:height ratio (0.60±0.07). Associations with blood pressure were linear with no threshold levels below which lower general or central adiposity was not associated with lower blood pressure. On average, each 1 SD higher measured adiposity marker was associated with a 3 mm Hg higher systolic blood pressure and 2 mm Hg higher diastolic blood pressure (SEs <0.1 mm Hg), but for the waist:hip ratio, associations were only approximately half as strong. General adiposity associations were independent of central adiposity, but central adiposity associations were substantially reduced by adjustment for general adiposity. Findings were similar for men and women. In Mexican adults, often overweight or obese, markers of general adiposity were stronger independent predictors of blood pressure than measured markers of central adiposity, with no threshold effects.


Evaluation of Relationship Between Childhood Maltreatment and Medication Overuse Headache.
We aimed to evaluate the prevalence and relationship between childhood maltreatment (CMT) among patients with medication overuse headache (MOH) and to investigate whether CMT is associated with medication overuse in patients having headaches or with headaches that become chronic. Epidemiological studies report a relationship between childhood abuse and headache. There is growing knowledge about the evidence that childhood maltreatment leads to neurobiological sequel. Medication overuse is the most important problem for migraine to become chronic. But in the literature, there was no information about the role of childhood abuse in MOH and for migraine to become chronic. A total of 116 patients with headache, aged from 15 to 65 years, were included in the study. Patients having chronic migraine (CM), MOH and episodic migraine (EM) were selected out of patients presented to the headache outpatient clinic. Types of headache were determined according to the revised International Headache Society (IHS) criteria published in 2004. The Childhood Trauma Questionnaire, Beck Depression Inventory and Beck Anxiety Inventory were performed. Presence of psychiatric co-morbidities was evaluated by a clinician using Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, the Fourth Edition. A total of 116 patients with headache were included in the study. Of patients, 64 had MOH, 25 had CM and 27 had EM. The prevalence of CMT, particularly emotional neglect (62%), physical neglect (44%) and emotional abuse (36.2%), was determined higher in all headache groups. There was no statistically significant difference in prevalence of childhood maltreatment between MOH, CM and EM groups. No statistically significant difference was detected between educational status, psychiatric co-morbidities and childhood trauma, except for physical neglect. Childhood maltreatment was observed in MOH as in other forms of migraine and headache. However, no significant difference was observed between the three groups of patients with headache.


Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members.
Wnt signaling pathways have fundamental roles in animal development and tumor progression. Here, employing Xenopus embryos and mammalian cell lines, we report that the degradation machinery of the canonical Wnt pathway modulates p120-catenin protein stability through mechanisms shared with those regulating β-catenin. For example, in common with β-catenin, exogenous expression of destruction complex components, such as GSK3β and axin, promotes degradation of p120-catenin. Again in parallel with β-catenin, reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. At the primary sequence level, we resolved conserved GSK3β phosphorylation sites in the amino-terminal region of p120-catenin present exclusively in isoform-1. Point-mutagenesis of these residues inhibited the association of destruction complex components, such as those involved in ubiquitylation, resulting in stabilization of p120-catenin. Functionally, in line with predictions, p120 stabilization increased its signaling activity in the context of the p120-Kaiso pathway. Importantly, we found that two additional p120-catenin family members, ARVCF-catenin and δ-catenin, associate with axin and are degraded in its presence. Thus, as supported using gain- and loss-of-function approaches in embryo and cell line systems, canonical Wnt signals appear poised to have an impact upon a breadth of catenin biology in vertebrate development and, possibly, human cancers.


Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury.
Hypoxia-ischemia (H-I) in the developing brain results in brain injury with prominent features of both apoptosis and necrosis. A peptide-based pan-caspase inhibitor is neuroprotective against neonatal H-I brain injury, suggesting a central role of caspases in brain injury. Because previously studied peptide-based caspase inhibitors are not potent and are only partially selective, the exact contribution of specific caspases and other proteases to injury after H-I is not clear. In this study, we explored the neuroprotective effects of a small, reversible caspase-3 inhibitor M826. M826 selectively and potently inhibited both caspase-3 enzymatic activity and apoptosis in cultured cells in vitro. In a rat model of neonatal H-I, M826 blocked caspase-3 activation and cleavage of its substrates, which begins 6 h and peaks 24 h after H-I. Although M826 significantly reduced DNA fragmentation and brain tissue loss, it did not prevent calpain activation in the cortex. This activation, which is associated with excitotoxic/necrotic cell injury, occurred within 30 min to 2 h after H-I even in the presence of M826. Similar to calpain activation, we found evidence of caspase-2 processing within 30 min to 2 h after H-I that was not affected by M826. Caspase-2 processing appeared to be secondary to calpain-mediated cleavage and was not associated with caspase-2 activation. These data suggest that caspase-3 specifically contributes to delayed cell death and brain injury after neonatal H-I and that calpain activation is associated with and likely a marker for the early component of excitotoxic/necrotic brain injury previously demonstrated in this model.


Increased tumorigenicity in the human pancreatic cell line MIA PaCa-2 is associated with an aberrant regulation of an IGF-1 autocrine loop and lack of expression of the TGF-beta type RII receptor.
The growth characteristics associated with tumorigenicity were determined in clones of MIA PaCa-2 and PANC-1 pancreatic carcinoma cells. MIA PaCa-2 cells differed from PANC-1 cells in that they rapidly formed tumors in nude mice, formed colonies more rapidly and formed larger colonies in soft agar, and were cloned more efficiently when seeded at low density. MIA PaCa-2 cells but not PANC-1 cells were stimulated to escape quiescence and undergo DNA synthesis with nutrient media lacking growth factors. Both cell lines were stimulated to proliferate with serum-free media containing EGF, transferrin, and insulin. Antibody neutralization assays indicated that an IGF-1 autocrine loop was required for the nutrient stimulation of growth in MIA PaCa-2 cells and for the growth-factor stimulation in both MIA PaCa-2 and PANC-1 cells. Both cell lines were stimulated to proliferate with exogenous IGF-1 in basal media; this stimulation was specifically blocked by antibodies to IGF-1 or its receptor. MIA PaCa-2 and PANC-1 cells expressed similar levels of IGF-1 receptor mRNA and showed similar binding kinetics in receptor binding assays. In contrast to PANC-1 cells, MIA PaCa-2 cells were insensitive to TGF-beta 1 and did not express TGF-beta receptor type II. The results suggest that the growth-factor independence is representative of a more tumorigenic phenotype. We hypothesize that growth-factor independence of MIA PaCa-2 cells is mediated by an aberrant regulation of an IGF-1 autocrine loop. A decreased regulation of this IGF-1 loop may be potentiated by loss of response to TGF-beta.


Ecological significance of dorsal polymorphism in a Batesian mimic snake.
Batesian mimicry is the process in which harmless species adopt the appearance of a dangerous, aposematic species. In some prey species, both Batesian mimetic and non-Batesian morphs coexist, presupposing that both morphs have to be evolutionarily advantageous. The viperine snake, Natrix maura, exhibits a zigzag dorsal pattern and antipredatory behavior that mimics European vipers. This snake also has a striped dorsal pattern that coexists with the zigzag pattern. We have examined whether individuals belonging to different geographically structured clades were more likely to exhibit a certain dorsal pattern, and whether the zigzag pattern has a protective function by exposing artificial snakes to predation in natural environments, in addition to comparing antipredatory behavior between zigzag and striped snakes also in natural environments. Our results indicate that the striped pattern was not geographically structured, but habitat-dependent. Aerial predators less frequently attacked zigzag plasticine models than striped or unpatterned models. We detected a shift in antipredator behavior between the 2 morphs, as Batesian mimicking N. maura responded to an approaching potential predator by remaining immobile or fleeing at shorter distances than did striped ones. We conclude that Batesian mimics maintain the cryptic and aposematic value by resembling vipers, whereas in open habitats the non-Batesian mimic has altered its antipredator behavior to maintain its fitness.


Comparing universal Lynch syndrome tumor-screening programs to evaluate associations between implementation strategies and patient follow-through.
Universal tumor screening (UTS) for all colorectal cancer patients can improve the identification of Lynch syndrome, the most common cause of hereditary colorectal cancer. This multiple-case study explored how variability in UTS procedures influenced patient follow-through (PF) with germ-line testing after a screen-positive result. Data were obtained through Web-based surveys and telephone interviews with institutional informants. Institutions were categorized as Low-PF (≤10% underwent germ-line testing), Medium-PF (11-40%), or High-PF (>40%). To identify implementation procedures (i.e., conditions) unique to High-PF institutions, qualitative comparative analysis was performed. Twenty-one informants from 15 institutions completed surveys and/or interviews. Conditions present among all five High-PF institutions included the following: (i) disclosure of screen-positive results to patients by genetic counselors; and (ii) genetic counselors either facilitate physician referrals to genetics professionals or eliminate the need for referrals. Although both of these High-PF conditions were present among two Medium-PF institutions, automatic reflex testing was lacking and difficulty contacting screen-positive patients was a barrier. The three remaining Medium-PF and five Low-PF institutions lacked the conditions found in High-PF institutions. METHODS for streamlining UTS procedures, incorporating a high level of involvement of genetic counselors in tracking and communication of results and in reducing barriers to patient contact, are reviewed within a broader discussion on maximizing the effectiveness and public health impact of UTS.


Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.
While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, "No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time". The panelists' assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.


Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins.
Synergistic activity between both azlocillin and mezlocillin and aminoglycosides or cefazolin could be demonstrated by checkerboard dilution, isobologram, and killing curve techniques. Azlocillin and mezlocillin combined with gentamicin, netilmicin, or amikacin were synergistic against Escherichia coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and indole-positive Proteus. Synergy was observed with isolates that were susceptible or resistant to azlocillin or mezlocillin. Synergy was seen most often when azlocillin or mezlocillin were combined with amikacin, gentamicin, or netilmicin against Pseudomonas aeruginosa. The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside. No antagonism was seen when aminoglycoside antibiotics were combined with azlocillin or mezlocillin. Cefazolin was synergistic against Pseudomonas, Providencia, P. mirabilis, indole-positive Proteus, Citrobacter, Klebsiella, and Escherichia coli, when combined with azlocillin or mezlocillin. However, the combination of either agent with cefazolin was antagonistic when tested against selected indole-positive Proteus and Enterobacter isolates.


Fast and accurate tumor segmentation of histology images using persistent homology and deep convolutional features.
Tumor segmentation in whole-slide images of histology slides is an important step towards computer-assisted diagnosis. In this work, we propose a tumor segmentation framework based on the novel concept of persistent homology profiles (PHPs). For a given image patch, the homology profiles are derived by efficient computation of persistent homology, which is an algebraic tool from homology theory. We propose an efficient way of computing topological persistence of an image, alternative to simplicial homology. The PHPs are devised to distinguish tumor regions from their normal counterparts by modeling the atypical characteristics of tumor nuclei. We propose two variants of our method for tumor segmentation: one that targets speed without compromising accuracy and the other that targets higher accuracy. The fast version is based on a selection of exemplar image patches from a convolution neural network (CNN) and patch classification by quantifying the divergence between the PHPs of exemplars and the input image patch. Detailed comparative evaluation shows that the proposed algorithm is significantly faster than competing algorithms while achieving comparable results. The accurate version combines the PHPs and high-level CNN features and employs a multi-stage ensemble strategy for image patch labeling. Experimental results demonstrate that the combination of PHPs and CNN features outperform competing algorithms. This study is performed on two independently collected colorectal datasets containing adenoma, adenocarcinoma, signet, and healthy cases. Collectively, the accurate tumor segmentation produces the highest average patch-level F1-score, as compared with competing algorithms, on malignant and healthy cases from both the datasets. Overall the proposed framework highlights the utility of persistent homology for histopathology image analysis.


Effective attenuation of glyphosate-induced oxidative stress and granulosa cell apoptosis by vitamins C and E in caprines.
Pesticides are known to cause a wide range of reproductive problems that possess degenerative effects on mammalian fertility. Glyphosate (GLP), a broad-spectrum organophosphate herbicide, is known to be a potent mammalian toxicant. The present study aims at assessing the GLP-induced (0.1, 2.0, and 4.0 mg/ml) granulosa cells toxicity and evaluating the mitigating effects of vitamins C and E (0.5 mM and 1.0 mM) in healthy caprine antral follicles, cultured in vitro in a dose- and time-dependent manner (24, 48, and 72 hr) and subjected to various cytotoxic and geno-toxic analysis, namely, classic histology, EB/AO differential staining, oxidative stress parameters, and antioxidant enzymatic activity. The histomorphological analysis and EB/AO staining elucidated increase in the incidence of apoptotic attributes within granulosa cells with increasing dose and duration of the GLP treatment. The highest apoptotic frequency was observed at 4.0 mg/ml GLP after 72-hr exposure duration in comparison with the control. GLP exposure also led to a significant decline in the antioxidant enzymes' activity, namely, SOD, catalase, and GST along with enhanced lipid peroxidation and reduced FRAP activity in a dose- and time-dependent manner. Vitamins C and E supplementation decreased oxidative stress-mediated granulosa cells apoptosis, suggesting its efficiency to diminish GLP-mediated GCs cytotoxicity and thereby, preventing associated fertility disorders.


The Promise of Prevention Science for Addressing Intergenerational Poverty.
This paper reviews research suggesting that the prevention of intergenerational poverty will be enhanced if we add evidence-based family and school prevention programs to existing efforts to reduce poverty in order to address the adverse social environments that often accompany poverty. Government policies such as the Earned Income Tax Credit can reduce family poverty, but simply improving the economic stability of the family will not necessarily prevent the development of child and adolescent problems such as academic failure, antisocial behavior, drug abuse, and depression, all of which can undermine future economic wellbeing. We briefly review the evidence linking family poverty to adverse social environments, which can have deleterious effects on children's psychological, behavioral, neurological, and physical development. We then document the value of evidence-based family- and school-based prevention programs in effectively addressing these behavioral, emotional, cognitive, and neurophysiological factors that can put children at risk for continued poverty in adulthood. We also describe three family-based prevention programs that have been found to have a direct effect on families' future economic wellbeing. The evidence indicates that widely disseminating effective and efficient family- and school-based prevention programs can help to address both poverty itself and the effects of adverse social environments, making future poverty less likely. We conclude with specific recommendations for federal and state policymakers, researchers, and practitioners.


[Cross-border cooperation in Europe: what are Euregios?].
In cross-border cooperation, much importance has been attributed to the so-called "Euregios", synonymously also called "Euroregions". These are cross-border structures in which, above all, local and regional authorities have joined together across one or several national borders. As early as 1958, the first Euregio was established along the German-Dutch border. Meanwhile many other Euregios have been set up. Euregios provide the testing ground for pilot projects to examine practical solutions of cooperation. Euregios are therefore also called "laboratories of Europe" or "testing laboratories of European integration". Also in the health sector, several cross-border projects are being and have already been carried out. According to what has been found out so far, above all Euregios with long years of experience in cross-border cooperation seem to commit themselves to the health issue. A huge number of the projects is co-financed by the European Union. Compared to other thematic areas, in some border regions the health issue has, on the whole been, underrepresented in cross-border cooperation. In this respect, there is potential for development. Information on existing projects as well as their experiences can facilitate the successful implementation of health-relevant cross-border projects also in those regions which have up to now not carried out any or only a few projects of this kind. The EU-funded Euregio project, carried out by lögd NRW, is the first project in which a systematic inventory analysis of cross-border health care projects will be drawn up.


Neighbor-dependent Ramachandran probability distributions of amino acids developed from a hierarchical Dirichlet process model.
Distributions of the backbone dihedral angles of proteins have been studied for over 40 years. While many statistical analyses have been presented, only a handful of probability densities are publicly available for use in structure validation and structure prediction methods. The available distributions differ in a number of important ways, which determine their usefulness for various purposes. These include: 1) input data size and criteria for structure inclusion (resolution, R-factor, etc.); 2) filtering of suspect conformations and outliers using B-factors or other features; 3) secondary structure of input data (e.g., whether helix and sheet are included; whether beta turns are included); 4) the method used for determining probability densities ranging from simple histograms to modern nonparametric density estimation; and 5) whether they include nearest neighbor effects on the distribution of conformations in different regions of the Ramachandran map. In this work, Ramachandran probability distributions are presented for residues in protein loops from a high-resolution data set with filtering based on calculated electron densities. Distributions for all 20 amino acids (with cis and trans proline treated separately) have been determined, as well as 420 left-neighbor and 420 right-neighbor dependent distributions. The neighbor-independent and neighbor-dependent probability densities have been accurately estimated using Bayesian nonparametric statistical analysis based on the Dirichlet process. In particular, we used hierarchical Dirichlet process priors, which allow sharing of information between densities for a particular residue type and different neighbor residue types. The resulting distributions are tested in a loop modeling benchmark with the program Rosetta, and are shown to improve protein loop conformation prediction significantly. The distributions are available at http://dunbrack.fccc.edu/hdp.


Effects of α-tocopherol supplementation on liver of rats chronically exposed to ethanol.
Chronic alcoholism is characterized by hepatotoxicity associated with antioxidant and redox status imbalance. Continuous ethanol intake induces free radical synthesis, resulting in the depletion of antioxidants, especially α-tocopherol, which has an important role in lipid peroxidation. This study aimed to evaluate if α-tocopherol supplementation can restore liver phenotype in rats chronically exposed to ethanol. α-Tocopherol levels were determined and histologic analysis of liver was performed. Hepatic gene expression was analyzed through oligonucleotide microarray and real-time PCR. Alcohol exposure for 6 weeks did not decrease hepatic α-tocopherol levels; however, both groups exposed to ethanol (supplemented or not with α-tocopherol) displayed fatty liver. The antioxidant supplementation prevented Mallory bodies and inflammatory infiltration, but not apoptosis, in liver of the rats exposed to ethanol. Gene expression analysis showed evidence of adaptive response to chronic alcohol consumption, where antioxidant components were not regulated. Nevertheless, differentially expressed genes reflected the change in cellular homeostasis. The hepatic α-tocopherol content was coherent with the antioxidant gene expression in this study. Cells are likely to have adapted and restored their antioxidant status after long-term ethanol exposure, which might be the reason for such conflicting reports concerning α-tocopherol status in chronic alcoholism.


The C-MAC® video laryngoscope is superior to the direct laryngoscope for the rescue of failed first-attempt intubations in the emergency department.
To compare the effectiveness of the C-MAC® video laryngoscope (CMAC) to the direct laryngoscope (DL) when used to rescue a failed first attempt intubation in the emergency department (ED). Data were prospectively collected on all patients intubated in an academic ED center over a five-year period from February 1, 2009 to January 31, 2014 when both the CMAC and the DL were available. Following each intubation the operator completed a continuous quality improvement (CQI) form documenting patient, operator and intubation characteristics. All orotracheal intubations attempted by emergency physicians (EPs) on adult patients with a failed first intubation attempt, and in which the CMAC or the DL was used for the second attempt, were included. The primary outcome was successful intubation on the second attempt using either the CMAC or the DL. A multivariate logistic regression analysis was performed to adjust for potential confounders. During the five-year study period, there were 460 adult orotracheal intubation attempts by EPs which were not successful on the first attempt. In 398 (86.5%) of these cases the same operator performed the second attempt. The CMAC was utilized for the second attempt in 141 cases and was successful in 116 (82.3%; 95% CI 75.0%-88.2%) and the DL was utilized in 94 cases and was successful in 58 (61.7%; 95% CI 51.1%-71.5%). In a multivariate logistic regression analysis the CMAC was associated with an increased odds (adjusted OR 3.5; 95% CI 1.9-6.7) of a second attempt success compared to the DL. After a failed first intubation attempt in the ED, regardless of the initial device used, the CMAC was more successful than the DL when used for the second attempt. This suggests that the CMAC is the preferred rescue device after an initial intubation attempt in the ED fails.


Development of agglomerated directly compressible diluent consisting of brittle and ductile materials.
The objective of this investigation was to develop a novel multifunctional coprocessed adjuvant consisting of three known diluents that show different consolidation mechanisms. The method of wet granulation was adopted for the preparation of coprocessed product. Microcrystalline cellulose (MCC) and colloidal silicon dioxide (X1), lactose monohydrate (X2), and dibasic calcium phosphate dihydrate (X3, DCP) were used as independent variables in a simplex lattice design. Croscarmellose sodium was used at 4% level intragranularly in all the batches. The granules (44/120 #) were characterized for angle of repose, bulk density, tapped density, and Carr's index. The tablets of coprocessed adjuvants were characterized for crushing strength, friability, and disintegration time. Multiple linear regression was adopted for evolving refined mathematical models. A checkpoint batch was prepared and evaluated for particle size distribution, moisture uptake, and dilution potential by using nimesulide as a model drug. Microcrystalline cellulose shows poor flowability due to irregular shape and interlocking. Moreover, it loses a part of its compactibility on wet granulation. To attend these problems, a physical blend of 97% microcrystalline cellulose and 3% colloidal silicon dioxide M5 was prepared and used. The blend of MCC and colloidal silicon dioxide showed better flow than that of the original MCC. Hence, it may be easier to mix with lactose and dibasic calcium phosphate. The loss in compactibility of microcrystalline cellulose on wet granulation was also reduced due to presence of colloidal silicon dioxide. As expected, all the batches exhibited acceptable angle of repose (<35 degrees) and quick disintegration (<1 min). Full and refined models for Carr's index and crushing strength were evaluated. Based on the results of grid analysis, a checkpoint (50% MCC, 40% lactose, and 10% DCP) that satisfies both the conditions of Carr's index and crushing strength was selected. The adjuvants absorb very little moisture in the moisture uptake study. The results of dilution potential study reveal that up to 30% nimesulide, a poorly compressible drug, can be incorporated in the coprocessed product. In vitro drug dissolution from capsules containing pure drug powder and compressed tablets was comparable (f2 = 79). The results reveal that the desired product characters can be obtained by varying the quantity of MCC (a ductile material that undergoes plastic deformation), lactose (brittle material with low-fragmentation propensity), and DCP (brittle material with high-fragmentation propensity).


Foot and mouth disease: the future of vaccine banks.
The authors briefly review the history of vaccine banks for foot and mouth disease, their current location and their constituent serotypes and strains, together with the occasions on which they have been activated. Experimental studies on emergency vaccines are summarised and areas identified for further investigation. The future of such banks is considered, including the principal strengths and weaknesses of existing banks, and suggestions are made for potential improvements. The fact that the banks have been activated on relatively few occasions over the 25 years of their existence testifies in part to the relatively rare calls which have been made upon them, but also reflects the difficulty in deciding when and how to utilise emergency vaccination. Nevertheless, in an era of increasing global risks of the spread of foot and mouth disease, banks will most certainly continue to have strategic and tactical importance in the control of this most readily communicable of animal diseases.


Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells.
We have probed for the presence of interleukin 6 (IL6) receptors in prostatic carcinoma cell lines (LNCaP, DU 145, and PC3) by examining their sensitivity to the cytotoxic effects of a chimeric toxin composed of IL6 and Pseudomonas exotoxin (PE). All three cell lines were killed by IL6-PE66(4)Glu, a version of IL6-PE in which the binding domain of native PE has been mutated to debilitate PE binding to its own receptor. This cytotoxic activity confirmed the presence of IL6 receptors on prostatic carcinoma cells. We have measured the number of IL6 receptors found on these cells and have further determined that they secrete IL6. These data provide evidence that IL6 and its receptor may play an important role in human prostate cancer.


The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination.
Human bone marrow-derived mesenchymal stromal cells (hMSCs) have the capacity to differentiate into several cell types including osteoblasts and are therefore an important cell source for bone tissue regeneration. A crucial issue is to identify mechanisms that trigger hMSC osteoblast differentiation to promote osteogenic potential. Casitas B lineage lymphoma (Cbl) is an E3 ubiquitin ligase that ubiquitinates and targets several molecules for degradation. We hypothesized that attenuation of Cbl-mediated degradation of receptor tyrosine kinases (RTKs) may promote osteogenic differentiation in hMSCs. We show here that specific inhibition of Cbl interaction with RTKs using a Cbl mutant (G306E) promotes expression of osteoblast markers (Runx2, alkaline phosphatase, type 1 collagen, osteocalcin) and increases osteogenic differentiation in clonal bone marrow-derived hMSCs and primary hMSCs. Analysis of molecular mechanisms revealed that the Cbl mutant increased PDGF receptor α and FGF receptor 2 but not EGF receptor expression in hMSCs, resulting in increased ERK1/2 and PI3K signaling. Pharmacological inhibition of FGFR or PDGFR abrogated in vitro osteogenesis induced by the Cbl mutant. The data reveal that specific inhibition of Cbl interaction with RTKs promotes the osteogenic differentiation program in hMSCs in part by decreased Cbl-mediated PDGFRα and FGFR2 ubiquitination, providing a novel mechanistic approach targeting Cbl to promote the osteogenic capacity of hMSCs.


Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas.
The ethnic and geographic distributions of several common chronic diseases show distinct patterns that are consistent with the distribution of genes and genetic admixture. For example, diabetes and gallbladder disease occur most frequently among Amerindians, while those genetically admixed with them (such as Mexican-Americans) have intermediate rates, and lowest rates are found among Whites and Blacks. Because there will be heterogeneity from individual to individual in ancestral affinity within an admixed population, a method is developed for estimating each person's admixture probability. Results confirm that there is substantial heterogeneity of individual admixture among Mexican-Americans in Starr County, Texas, with a mean value indicating that 65% of genes in this population are Caucasian derived and 35% Amerindian derived. The individual estimates are shown to be unrelated to the probability of being diabetic and only marginally related to gallbladder disease, with those having the most Amerindian affinity being at increased risk. These results are a consequence of the independent assortment of loci and indicate that unless the markers employed are related (including linkage) to the disease of interest, the method will have limited utility. Individual admixture estimates will be useful, however, for examining aspects of population structure and will find increased utility for predicting disease and examining disease associations as more and more of the genome is represented by markers, a very probable prospect with the abundance of DNA polymorphism being identified by restriction enzymes.


The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site.
NIH-12848 (NCGC00012848-02), a putative phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) inhibitor, was explored as a tool for investigating this enigmatic, low activity, lipid kinase. PI5P4K assays in vitro showed that NIH-12848 inhibited PI5P4Kγ with an IC50 of approximately 1 μM but did not inhibit the α and β PI5P4K isoforms at concentrations up to 100 μM. A lack of inhibition of PI5P4Kγ ATPase activity suggested that NIH-12848 does not interact with the enzyme's ATP-binding site and direct exploration of binding using hydrogen-deuterium exchange (HDX)-MS (HDX-MS) revealed the putative PI5P-binding site of PI5P4Kγ to be the likely region of interaction. This was confirmed by a series of mutation experiments which led to the identification of a single PI5P4Kγ amino acid residue that can be mutated to its PI5P4Ks α and β homologue to render PI5P4Kγ resistant NIH-12848 inhibition. NIH-12848 (10 μM) was applied to cultured mouse principal kidney cortical collecting duct (mpkCCD) cells which, we show, express PI5P4Kγ that increases when the cells grow to confluence and polarize. NIH-12848 inhibited the translocation of Na⁺/K⁺-ATPase to the plasma membrane that occurs when mpkCCD cells grow to confluence and also prevented reversibly their forming of 'domes' on the culture dish. Both these NIH-12848-induced effects were mimicked by specific RNAi knockdown of PI5P4Kγ, but not that of PI5P4Ks α or β. Overall, the data reveal a probable contribution of PI5P4Kγ to the development and maintenance of epithelial cell functional polarity and show that NIH-12848 is a potentially powerful tool for exploring the cell physiology of PI5P4Ks.


The relation between tooth loss and bone mass in postmenopausal osteoporotic women in Turkey: a multicenter study.
The purpose of this study was to investigate the associations of tooth loss with skeletal bone mass, years since menopause, educational level, current smoking status, dietary calcium intake, and number of pregnancies in postmenopausal osteoporotic women in Turkey. The study population consisted of 1171 postmenopausal women aged 40-86 years (mean age, 61.19 +/- 7.28 years). A detailed history was obtained from all women, including relevant lifestyle parameters, risk factors, and measurements of weight and height. Women were separated into three groups according to the number of teeth remaining as group 1 (edentulous, 457 women), group 2 (10 or fewer teeth, 232 women), and group 3 (more than 10 teeth remaining, 482 women). There was no significant difference among the three groups in mean age and menopausal age ( P < 0.05). Body mass index of group 1 was significantly higher than that of group 2 ( P< 0.01). Educational level was significantly different between three groups: groups 1 and 2 ( P< 0.001), groups 1 and 3 ( P< 0.0001), and groups 2 and 3 ( P< 0.001). Educational level was lowest in group 1 and highest in group 3. Despite a low ratio of cigarette smoking in general, a smoking habit was most prevalent in group 3 and least in group 2. The ratio of women receiving adequate calcium was significantly lower in group 1 than in other groups ( P< 0.001); mean calcium intake was similar in all groups. The number of pregnancies was significantly higher in group 1 than in other groups ( P< 0.001). Lumbar bone mineral density (BMD) of group 1 was significantly lower than that of groups 2 and 3 ( P< 0.001). Although no significant difference was found between groups 1 and 3, femoral neck BMD of group 2 was less than in others, and differences between groups 1 and 2 and between groups 2 and 3 ( P< 0.001) were significant. Lumbar bone mineral content (BMC) of group 1 was significantly lower than that of groups 2 and 3 ( P< 0.001), and lumbar BMC in group 2 was significantly higher than in group 3 ( P< 0.05). Femoral neck BMC in group 1 was significantly higher than in groups 2 and 3 ( P< 0.001). In conclusion, lumbar BMD and BMC in the edentulous group were significantly lower, whereas femoral neck BMD and BMC were significantly higher in edentulous group compared with the others. Our findings indicated that improvement in lifestyle factors and nutritional strategies for the treatment and prevention of osteoporosis may have additional benefit in reducing tooth loss.


Hemorrhagic Fever with Renal Syndrome.
In Korea, hemorrhagic fever with renal syndrome (HFRS) was first reported in a United Nations (UN) soldier stationed in the central front, also known as the "Iron Triangle". In 1976, professor Ho Wang Lee discovered an antigen in the lung and kidney tissues of Apodemus agrarius. In 1980, this novel virus was named Hantaan virus after the Hantaan river. The Old World Hantaviruses, which are usually found in East Asia and Europe, are generally transmitted to humans via the respiratory pathway during dry seasons, usually in late spring and fall. Currently, 300 - 600 cases per year are reported in Korea with a mortality rate of 1 - 2%. The typical clinical course of HFRS is classified into five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. And treatment for HFRS is mostly conservative. A vaccine for the Hantaan virus was developed in 1988 and marketed in 1990. Because HFRS outbreaks mostly occur in regions near the truce line in Korea, vaccination is virtually the only protection against the virus among military personnel working in such regions and local residents. Therefore, proving the effectiveness of the HFRS vaccine and devising efficient vaccination plans have been considered a major task for Korea's health authorities.


Between empowerment and self-discipline: Governing patients' conduct through technological self-care.
Recent health policy renders patients increasingly responsible for managing their health via digital technology such as health apps and online patient platforms. This paper discusses underlying tensions between empowerment and self-discipline embodied in discourses of technological self-care. It presents findings from documentary analysis and interviews with key players in the English digital health context including policy makers, health designers and patient organisations. We show how discourses ascribe to patients an enterprising identity, which is inculcated with economic interests and engenders self-discipline. However, this reading does not capture all implications of technological self-care. A governmentality lens also shows that technological self-care opens up the potential for a de-centring of medical knowledge and its subsequent communalization. The paper contributes to Foucauldian healthcare scholarship by showing how technology could engender agential actions that operate at the margins of an enterprising discourse.


Use of the VS-sense swab in diagnosing vulvovaginitis.
Although pH assessment of vaginal secretions is beneficial for diagnosing vaginitis, it is not commonly done. The purpose of this study was to determine the performance characteristics of the VS-Sense (pH test) swab (Common Sense, Ltd., Caesarea, Israel) in augmenting the diagnosis of vaginitis. We prospectively studied 193 women with acute vulvovaginal symptoms and 74 asymptomatic controls at three medical centers. The VS-Sense swab was administered intravaginally, and results were interpreted by a nurse. These results were compared with final clinical and laboratory diagnoses. In women with an elevated pH caused by bacterial vaginosis (BV), trichomonas, and other types of vaginitis, the VS-Sense test sensitivity and specificity were 82.3% (102 of 124) (95% CI 74.4%-88.5%) and 94.2% (129 of 137) (95% CI 88.8%-97.4%), respectively. There was an 86.2% (95% CI 81.3%-90.1%) overall agreement between pH paper and VS-Sense swab results. The VS-Sense test offers an alternative approach to measuring vaginal pH with nitrazine paper. Use of this simple, more rapid test may facilitate the diagnosis of vulvovaginitis.


Acute heart failure after myocardial infarction.
We compared two groups of patients after acute myocardial infarction. First group was treated with fibrinolytics and they were hospitalized within six hours from the beginning of the first chest-symptoms, and second group that did not come within optimal time was treated with anticoagulants only. The patients were classified according to Killip-classification, shock-index and TIMI-risk-score after myocardial infarction. Results prove great benefit of fibrinolytic therapy in optimal time, concerning both keeping myocardial muscle mass and myocardial pump function.


A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria.
Although sepsis was described more than 2,000 years ago, and clinicians still struggle to define it, there is no "gold standard," and multiple competing approaches and terms exist. Challenges include the ever-changing knowledge base that informs our understanding of sepsis, competing views on which aspects of any potential definition are most important, and the tendency of most potential criteria to be distributed in at-risk populations in such a way as to hinder separation into discrete sets of patients. We propose that the development and evaluation of any definition or diagnostic criteria should follow four steps: 1) define the epistemologic underpinning, 2) agree on all relevant terms used to frame the exercise, 3) state the intended purpose for any proposed set of criteria, and 4) adopt a scientific approach to inform on their usefulness with regard to the intended purpose. Usefulness can be measured across six domains: 1) reliability (stability of criteria during retesting, between raters, over time, and across settings), 2) content validity (similar to face validity), 3) construct validity (whether criteria measure what they purport to measure), 4) criterion validity (how new criteria fare compared to standards), 5) measurement burden (cost, safety, and complexity), and 6) timeliness (whether criteria are available concurrent with care decisions). The relative importance of these domains of usefulness depends on the intended purpose, of which there are four broad categories: 1) clinical care, 2) research, 3) surveillance, and 4) quality improvement and audit. This proposed methodologic framework is intended to aid understanding of the strengths and weaknesses of different approaches, provide a mechanism for explaining differences in epidemiologic estimates generated by different approaches, and guide the development of future definitions and diagnostic criteria.


Mechanism of death in heart failure. The Vasodilator-Heart Failure Trials. The V-HeFT VA Cooperative Studies Group.
The Vasodilator-Heart Failure Trial (V-HeFT) data base provides information on the mechanism of death of male veterans entered into two trials that evaluated the effect of vasodilator therapy on survival in heart failure. Men aged 18-75 years with heart failure were recruited at 13 Department of Veterans Affairs Medical Centers. In V-HeFT I, 283 of 642 patients (44%) died during follow-up (average, 2.3 years), and in V-HeFT II, 285 of 804 randomized patients (35.5%) died during follow-up (average, 2.5 years). Mechanism of death was established centrally using a standardized classification. In V-HeFT I, 124 of the 283 deaths (43.8%) were sudden with no worsening of symptoms; in V-HeFT II, 104 of the 285 deaths (36.5%) were sudden. An average of 31.5% of the deaths (31.4% and 31.6%, respectively) in the two trials was due to pump failure. The proportion of sudden deaths that occurred without worsening of symptoms was similar in patients with and without ischemic heart failure. Sudden deaths tended to occur earlier and pump failure deaths later in both V-HeFT studies. There was a trend for a lower percentage of cardiac deaths from pump failure and a higher percentage from sudden death in subgroups with higher peak exercise oxygen consumption (VO2), higher ejection fraction, and lower plasma norepinephrine levels. The proportion of deaths that occurred suddenly was similar in placebo, prazosin, and hydralazine plus isosorbide dinitrate treatment groups but was significantly lower in the enalapril treatment group. In V-HeFT I, measures of cardiac function and VO2 predicted pump failure death and sudden death. In V-HeFT II, VO2 and cardiothoracic ratio were independent predictors of all-cause deaths and pump failure deaths; only ejection fraction was an independent predictor of both pump failure and sudden death. Although mechanistically distinct terminal events can be identified in patients with heart failure and physiological measurements can provide some insight into the risk of these disparate events, sudden death and pump failure death both appear largely to be linked to the severity of cardiac dysfunction and symptoms. Strategies to identify individuals for selective preventive therapy are not yet practical.


Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function.
L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Cavβ2 chaperone regulates channel density at the plasma membrane. On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Cavα1.2 and the Akt-dependent phosphorylation status of Cavβ2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Cavβ2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Cavα1.2 retrograde trafficking and protein degradation through the prevention of dynamin-mediated LTCC endocytosis; promotion of Cavα1.2 anterograde trafficking by blocking Kir/Gem-dependent sequestration of Cavβ2, thus facilitating the chaperoning of Cavα1.2; and promotion of Cavα1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Cavβ2 to the nucleus, where it limits the transcription of Cavα1.2 through recruitment of the heterochromatin protein 1γ epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Cavβ2, corrects LTCC life-cycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Cavβ2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function.


Association of Nausea and Vomiting During Pregnancy With Pregnancy Loss: A Secondary Analysis of a Randomized Clinical Trial.
Nausea and vomiting during pregnancy have been associated with a reduced risk for pregnancy loss. However, most prior studies enrolled women with clinically recognized pregnancies, thereby missing early losses. To examine the association of nausea and vomiting during pregnancy with pregnancy loss. A randomized clinical trial, Effects of Aspirin in Gestation and Reproduction, enrolled women with 1 or 2 prior pregnancy losses at 4 US clinical centers from June 15, 2007, to July 15, 2011. This secondary analysis was limited to women with a pregnancy confirmed by positive results of a human chorionic gonadotropin (hCG) test. Nausea symptoms were ascertained from daily preconception and pregnancy diaries for gestational weeks 2 to 8. From weeks 12 to 36, participants completed monthly questionnaires summarizing symptoms for the preceding 4 weeks. A week-level variable included nausea only, nausea with vomiting, or neither. Peri-implantation (hCG-detected pregnancy without ultrasonographic evidence) and clinically recognized pregnancy losses. A total of 797 women (mean [SD] age, 28.7 [4.6] years) had an hCG-confirmed pregnancy. Of these, 188 pregnancies (23.6%) ended in loss. At gestational week 2, 73 of 409 women (17.8%) reported nausea without vomiting and 11 of 409 women (2.7%), nausea with vomiting. By week 8, the proportions increased to 254 of 443 women (57.3%) and 118 of 443 women (26.6%), respectively. Hazard ratios (HRs) for nausea (0.50; 95% CI, 0.32-0.80) and nausea with vomiting (0.25; 95% CI, 0.12-0.51) were inversely associated with pregnancy loss. The associations of nausea (HR, 0.59; 95% CI, 0.29-1.20) and nausea with vomiting (HR, 0.51; 95% CI, 0.11-2.25) were similar for peri-implantation losses but were not statistically significant. Nausea (HR, 0.44; 95% CI, 0.26-0.74) and nausea with vomiting (HR, 0.20; 95% CI, 0.09-0.44) were associated with a reduced risk for clinical pregnancy loss. Among women with 1 or 2 prior pregnancy losses, nausea and vomiting were common very early in pregnancy and were associated with a reduced risk for pregnancy loss. These findings overcome prior analytic and design limitations and represent the most definitive data available to date indicating the protective association of nausea and vomiting in early pregnancy and the risk for pregnancy loss. clinicaltrials.gov Identifier: NCT00467363.