HIV exposure does not worsen outcome in stage III necrotizing enterocolitis with current treatment protocols.
The heavy burden of maternal HIV infection in developing countries such as South Africa has resulted in a high prevalence of premature birth and necrotizing enterocolitis (NEC). Uninfected infants born to HIV-infected mothers also demonstrate immune deficiencies. It is, therefore, essential to have a better understanding of how to mitigate HIV as an independent risk factor for surgically treated NEC and to evaluate the relevant contributing factors in the presence of an aggressive strategy of pasteurized breast milk feeding and antiretroviral prophylaxis. Infants with stage IIIb NEC presenting over a 4-year period were retrospectively reviewed. HIV-exposed infants were compared with non-HIV-exposed infants. Contributing factors were evaluated and studied by systematic statistical methods to evaluate risk. Twenty percent (17/87) infants were HIV-exposed, and 80% (70/87), unexposed, whereas a further 10 (total, n = 97) had unknown HIV exposure status. Demographics and other perinatal risk factors between the 2 groups were not significantly different other than that HIV-exposed infants received pasteurized breast milk and nonexposed infants received unpasteurized breast milk. There were no statistically significant differences between the groups with respect to disease presentation or severity, surgical findings or type of surgery, postoperative complications, survival, or timing of death. Trends toward higher antenatal steroid exposure and increased postoperative sepsis in the HIV-exposed group (P = .03) were noted but were not related. All HIV-exposed infants received antiretrovirals; there were no significant differences on subanalysis between different antiretroviral regimens. HIV-exposed infants do not have a more severe disease course nor more adverse outcomes in stage IIIb NEC than unexposed infants. Significant factors were antenatal steroids and post-NEC infective episodes.


Sludge accumulation in shallow maturation ponds treating UASB reactor effluent: results after 11 years of operation.
Polishing ponds are natural systems used for the post-treatment of upflow anaerobic sludge blanket (UASB) effluents. They are designed as maturation ponds and their main goal is the removal of pathogens and nitrogen and an additional removal of residual organic matter from the UASB reactor. This study aimed to evaluate organic matter and suspended solids removal as well as sludge accumulation in two shallow polishing ponds in series treating sanitary effluent from a UASB reactor with a population equivalent of 200 inhabitants in Brazil, operating since 2002. For this evaluation, long-term monitoring of biochemical oxygen demand and total suspended solids and bathymetric surveys have been undertaken. The ponds showed an irregular distribution of total solids mass in the sludge layer of the two ponds, with mean accumulation values of 0.020 m(3) person(-1) year(-1) and 0.004 m(3) person(-1) year(-1) in Ponds 1 and 2, leading to around 40% and 8% of the liquid volume occupied by the sediments after 11 years of operation. The first pond showed better efficiency in relation to organic matter removal, although its contribution was limited, due to algal growth. No simple input-output mass balance of solids can be applied to the ponds due to algal growth in the liquid phase and sludge digestion in the sludge.


Treatment of hepatitis C in renal transplantation candidates: a single-center experience.
There is no consensus on hepatitis C virus (HCV) treatment in patients with renal failure. Toxicity of pegylated interferon (PEG-IFN) and ribavirin limit options; hence the ideal approach for therapy in these patients deserves attention. We report the results of kidney transplantation (KTx) candidates infected with HCV treated with PEG-IFN monotherapy. KTx candidates with HCV infection treated with PEG-IFN monotherapy between January 2001 and February 2009 were included. Liver biopsies were performed before therapy. Response was assessed using accepted virological time points. From 2636 patients listed for KTx, 60 patients were tested positive for anti-HCV. Twenty-two patients were eligible for treatment. All patients were HCV treatment naïve. One patient had biopsy-confirmed cirrhosis. Mean Ishak-Knodell fibrosis stage was 1.3. Ten patients (45%) achieved sustained viral response. In genotype 1 patients, there were no relapsers among early responders, despite the limited regimen. Nine patients (40%) in the cohort have had KTx. Of these, there were four responders and five nonresponders. None of the responders have had recurrence of their HCV after their KTx. End-stage renal disease patients with HCV can be treated successfully with PEG-IFN monotherapy. Our sustained viral response rate was 45% (10/22) in patients treated before KTx.


Predicting the Cost of Health Care Services: A Comparison of Case-mix Systems and Comorbidity Indices That Use Administrative Data.
Case-mix systems and comorbidity indices aggregate clinical information about patients over time and are used to characterize need for health care services. These tools were validated for their original purpose, but those purposes are varied, and they have not been compared directly in the context of predicting costs of health care services. To compare predictions of next-year health care service costs across 4 tools, including: the Johns Hopkins Adjusted Clinical Groups (ACG), the Elixhauser Comorbidity Index, Charlson-Deyo Comorbidity Index, and the Canadian Institute for Health Information (CIHI) population grouper. British Columbia administrative data from fiscal years 2012-2013 were used to generate case-mix variables and the comorbidity indices. Outcome variables include next-year (2013-2014) total, physician, acute care, and pharmaceutical costs, Outcomes were modeled using 2-part models. Performance was compared using adjusted R, root mean squared error, and mean absolute error using the predicted and the actual next-year cost. Models including the CIHI grouper (239 conditions) and ACG system had similar performance in most cost categories and slightly better fit than Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI). Adding a dummy variable for nonusers in the models for CCI and ECI increased R values slightly. All these systems have empirical support for use in predicting health care costs, despite in some cases being developed for other purposes. No system is particularly effective at predicting next-year acute care cost, likely because acute events are often by definition unexpected. The freely available ECI and CCI comorbidity indices implemented using the highest-performing methods developed here may be a good choice in many circumstances.


Liquid Native MALDI Mass Spectrometry for the Detection of Protein-Protein Complexes.
Native mass spectrometry (MS) encompasses methods to keep noncovalent interactions of biomolecular complexes intact in the gas phase throughout the instrument and to measure the mass-to-charge ratios of supramolecular complexes directly in the mass spectrometer. Electrospray ionization (ESI) in nondenaturing conditions is now an established method to characterize noncovalent systems. Matrix-assisted laser desorption/ionization (MALDI), on the other hand, consumes low quantities of samples and largely tolerates contaminants, making it a priori attractive for native MS. However, so-called native MALDI approaches have so far been based on solid deposits, where the rapid transition of the sample through a solid state can engender the loss of native conformations. Here we present a new method for native MS based on liquid deposits and MALDI ionization, unambiguously detecting intact noncovalent protein complexes by direct desorption from a liquid spot for the first time. To control for aggregation, we worked with HUαβ, a heterodimer that does not spontaneously rearrange into homodimers in solution. Screening through numerous matrix solutions to observe first the monomeric protein, then the dimer complex, we settled on a nondenaturing binary matrix solution composed of acidic and basic organic matrices in glycerol, which is stable in vacuo. The role of temporal and spatial laser irradiation patterns was found to be critical. Both a protein-protein and a protein-ligand complex could be observed free of aggregation. To minimize gas-phase dissociation, source parameters were optimized to achieve a conservation of complexes above 50% for both systems. Graphical Abstract .


Dual-Positive (CD4+/CD8+) Acute Adult T-Cell Leukemia/Lymphoma Associated with Complex Karyotype and Refractory Hypercalcemia: Case Report and Literature Review.
We describe a rare case of adult T-cell leukemia characterized by an expansion of CD4+ CD8+ double-positive lymphocytes associated with human T-lymphotropic virus type 1 (HTLV-1) and a complex karyotype in a 43-year-old Caribbean male who was initially admitted to our hospital with significant lethargy, visual disturbances, dysphagia, right facial palsy and numbness in both feet for 3 days. He was found to have severe hypercalcemia (15.6 mg/dl). Peripheral blood smear showed multilobulated clover-shaped nuclei. Bone marrow and CSF flow cytometries revealed abnormal monoclonal expansion of T cells positive for CD4, CD5, CD8 and CD25 but negative for CD7, CD20, CD56, CD68 and terminal deoxynucleotidyl transferase. The polymerase chain reaction analysis showed a distinct band of the T-cell receptor γ gene, revealing T-cell clonal integration of the proviral DNA of HTLV-1, thus confirming the diagnosis of acute adult T-cell leukemia/lymphoma. Cytogenetic study revealed a male karyotype with monosomy 12, unbalanced translocation 5q and 13q and additional material on 5q, 7q, 14q and 17q. The patient underwent prednisone (EPOCH) chemotherapy followed by autologous transplantation with BEAM regimen. Although patients with a rare mixed CD4+ CD8+ immunophenotype usually present with an aggressive clinical course and have a poor prognosis, our patient was able to survive for 2.5 years.


Lymphovascular space invasion and the treatment of stage I endometrioid endometrial cancer.
Treatment of clinical early-stage endometrioid endometrial cancer (EEC) in The Netherlands consists of primary hysterectomy and bilateral salpingo-oophorectomy. Adjuvant radiotherapy is given when 2 or more the following risk factors are present: 60 years or older, grade 3 histology, and 50% or more myometrial invasion. Lymphovascular space invasion (LVSI) is a predictor of poor prognosis and early distant spread. It is unclear whether adjuvant radiotherapy is sufficient in patients with LVSI-positive EEC. Eighty-one patients treated from 1999 until 2011 for stage I LVSI-positive EEC in 11 Dutch hospitals were included. The outcomes of patients with 0 to 1 risk factors were compared with those with 2 to 3 risk factors, and both were compared with the known literature. Eighteen patients presented with recurrent disease, and 12 of those recurrences had a distant component. Overall and distant recurrence rates were 19.2% and 11.5% in patients with 0 to 1 risk factors followed by observation and 25.5% and 17% in patients with 2 to 3 risk factors who received adjuvant radiotherapy. Only 1 patient with grade 1 disease had a recurrence. In stage I LVSI-positive EEC with 0 to 1 risk factors, observation might not be adequate. Moreover, despite adjuvant radiotherapy, a high overall and distant recurrence rate was observed in patients with 2 to 3 risk factors. The use of systemic treatment in these patients, with the exception of patients with grade 1 disease, should be investigated.


Transduction of CpG DNA-stimulated primary human B cells with bicistronic lentivectors.
Recently, using HIV-1-derived lentivectors, we obtained efficient transduction of primary human B lymphocytes cocultured with murine EL-4 B5 thymoma cells, but not of isolated B cells activated by CD40 ligation. Coculture with a cell line is problematic for gene therapy applications or study of gene functions. We have now found that transduction of B cells in a system using CpG DNA was comparable to that in the EL-4 B5 system. A monocistronic vector with a CMV promoter gave 32 +/- 4.7% green fluorescent protein (GFP)+ cells. A bicistronic vector, encoding IL-4 and GFP in the first and second cistrons, respectively, gave 14.2 +/- 2.1% GFP+ cells and IL-4 secretion of 1.3 +/- 0.2 ng/10(5) B cells/24 h. This was similar to results obtained in CD34+ cells using the elongation factor-1alpha promoter. Activated memory and naive B cells were transducible. After transduction with a bicistronic vector encoding a viral FLIP molecule, vFLIP was detectable by FACS or Western blot in GFP+, but not in GFP-, B cells, and 57% of sorted GFP+ B cells were protected against Fas ligand-induced cell death. This system should be useful for gene function research in primary B cells and development of gene therapies.


Hepatocyte dedifferentiation and extinction is accompanied by a block in the synthesis of mRNA coding for the transcription factor HNF1/LFB1.
The promoter proximal sequences of a group of liver-specific genes including that of albumin interact with the same hepato-specific factor named HNF1, LFB1, APF or HP1, a distant member of the homeoprotein family. A distinct protein, termed variant HNF1 (vHNF1), of lower mol. wt but displaying identical sequence specificity is found both in dedifferentiated variants and in an extinguished somatic hybrid that fail to express most or all of the tissue-specific traits, including albumin. We show here that HNF1 transcripts are present only in differentiated hepatoma cells. No transcripts are detected in dedifferentiated variants or in the extinguished cell hybrid, strongly suggesting that the vHNF1 protein is encoded by a distinct gene. Finally, HNF1 transcripts reappear in revertants to the hepatic phenotype. Run-on transcription analysis in isolated nuclei demonstrates that the expression of HNF1 in these cell lines is regulated primarily at the transcriptional level. Contrary to HNF1, the mRNAs coding for two other nuclear factors involved in albumin transcription, C/EBP and NF1, do not follow the distribution of albumin transcripts in these cell lines. These results indicate that extinction in somatic hybrids or loss of expression upon dedifferentiation of liver-specific genes possessing an HNF1 recognition site is caused, at least in part, by a block in HNF1 gene expression.


Malpractice claims data as a quality improvement tool. I. Epidemiology of error in four specialties.
--To identify potentially preventable sources of medical injury in obstetrics and gynecology, general surgery, anesthesiology, and radiology. --Retrospective review of physician malpractice claim records. --Large New Jersey physician malpractice insurer. --Physicians practicing obstetrics and gynecology, general surgery, anesthesiology, and radiology and covered by the insurance carrier during any portion of 1977 through 1989. --Proportion of claims due to negligence associated with errors in (1) patient management, (2) technical performance, and (3) medical and nursing staff coordination and the clinical and financial consequences of such errors. --Among 1371 claims ascribed to negligence, patient management errors were cited most frequently in all four specialties (48% to 75%) and, compared with performance and coordination problems, were generally associated with a higher frequency of serious injury and higher median payments. Coordination problems accounted for about 9% of claims. In obstetrics and gynecology, newborn delivery claims usually arose from management errors (57% to 68%), whereas gynecologic procedure claims were most often associated with performance errors (55% to 73%). Underperformance of cesarean section was cited more frequently than overperformance (31% vs 3%). General surgery claims were about equally divided between management and performance types regardless of procedure. Failure to perform appropriate diagnostic testing or monitoring was the main problem in 3% to 8% of claims. --Malpractice data can be used to identify problem-prone clinical processes and suggest interventions that may reduce negligence.


Radiance and polarization of light reflected from optically thick clouds.
The reflected radiance and polarization are calculated for clouds with optical thicknesses from 10 to 100. The results are presented for both the haze C and nimbostratus model. The peak in the single scattered polarization at 140 degrees for the nimbostratus model persists even with all the multiple scattering events that occur for the largest optical thicknesses considered here. The calculations are made by a Monte Carlo technique, which includes the effect of multiple scattering through all orders and a realistic anisotropic phase function for single scattering appropriate for the distribution of particle sizes in the cloud. The effect of the surface albedo is included in the calculations for the optical thickness of 10. The variation of the radiance and polarization with both the nadir and azimuthal angle is given for several solar zenith angles.


The alliance of mesenchymal stem cells, bone, and diabetes.
Bone fragility has emerged as a new complication of diabetes. Several mechanisms in diabetes may influence bone homeostasis by impairing the action between osteoblasts, osteoclasts, and osteocytes and/or changing the structural properties of the bone tissue. Some of these mechanisms can potentially alter the fate of mesenchymal stem cells, the initial precursor of the osteoblast. In this review, we describe the main factors that impair bone health in diabetic patients and their clinical impact.


Longitudinal associations between motor competence and different physical activity intensities: LabMed physical activity study.
An appropriated level of motor competence is essential for children´s healthy growth and development and a key factor in the promotion of lifelong active lifestyles and health. The purpose of this study was to examine associations between motor competence and different physical activity intensities (light, moderate, moderate-to-vigorous and vigorous physical activity), as well as total physical activity, over a two-year period, in adolescents. The sample comprised of 103 adolescents (13.49 ± 0.87 years, 53 girls), from the north of Portugal. Motor competence was evaluated with the body coordination test, Körperkoordination-Test-für-Kinder. Physical activity was objectively assessed with GT1M accelerometers (ActiGraph, Pensacola, FL, USA). Physical activity variables were expressed as proportions of accelerometer wear time. Regression analyses showed positive longitudinal associations between motor competence at baseline and moderate physical activity (B = 0.0033, p = 0.018), moderate-to-vigorous physical activity (B = 0.0052, p = 0.024) and total physical activity (B = 0.067, p = 0.040) at follow up, after adjustments for age, sex, the corresponding physical activity intensity at baseline, body mass index, pubertal stage and socioeconomic status. Our findings highlight the importance of motor competence development to promote moderate-to-vigorous physical activity during adolescence.


Testing the validity and reliability of the shame questionnaire among sexually abused girls in Zambia.
The aim of the current study is to test the validity and reliability of the Shame Questionnaire among traumatized girls in Lusaka, Zambia. The Shame Questionnaire was validated through both classical test and item response theory methods. Internal reliability, criterion validity and construct validity were examined among a sample of 325 female children living in Zambia. Sub-analyses were conducted to examine differences in construct validity among girls who reported sexual abuse and girls who did not. All girls in the sample were sexually abused, but only 61.5% endorsed or reported that sexual abuse had occurred. Internal consistency was very good among the sample with alpha = .87. Criterion validity was demonstrated through a significant difference of mean Shame Questionnaire scores between girls who experienced 0-1 trauma events and more than one traumatic event, with higher mean Shame Questionnaire scores among girls who had more than one traumatic event (p = .004 for 0-1 compared to 2 and 3 events and p = .016 for 0-1 compared to 4+ events). Girls who reported a history of witnessing or experiencing physical abuse had a significantly higher mean Shame Questionnaire score than girls who did not report a history of witnessing or experiencing physical abuse (p<.0001). There was no significant difference in mean Shame Questionnaire score between girls who reported a sexual abuse history and girls who did not. Exploratory factor analysis indicated a two-factor model of the Shame Questionnaire, with an experience of shame dimension and an active outcomes of shame dimension. Item response theory analysis indicated adequate overall item fit. Results also indicate potential differences in construct validity between girls who did and did not endorse sexual abuse. This study suggests the general utility of the Shame Questionnaire among Zambian girls and demonstrates the need for more psychometric studies in low and middle income countries.


[Knowledge production on family health care].
In this article we present an overview of the publication about the health care in the family context. We developed a bibliographical research taking as source the following databases: SciELO, MEDLINE and Lilacs using the keywords: health care and family caregivers considering the period from 1995 through 2007. We realized that there are few studies on the subject and some of them are quite superficial in their approach. Our focus was directed to the understanding of: types of methodologies applied; theoretical approach; "care" concepts; analysis of culture and social class; references to networking; gender considerations and finally consensus and gaps in the studies. The results show that most of the studies assume a qualitative methodology compatible with the high complexity level of the studied subject and theoretical approaches of comprehensive character exploring meanings and conceptions. The discussion of the role of culture, social class distinctions and gender relations in the production and sourcing of health care arise once in a while but without the proper depth. The importance of the role of woman-mother in producing and providing health care is generally disregarded of criticism. We noticed a trend to use broader health care concepts that synthesize material, affective and social aspects, although without a discussion in a concrete way.


High probability opening of NMDA receptor channels by L-glutamate.
Synaptic plasticity can be triggered by calcium flux into neurons through synaptically activated N-methyl-D-aspartate (NMDA) receptor channels. The amplitude and time course of the resulting intracellular calcium transient depend on the number of open NMDA receptor channels and the kinetics of their activation. Short applications of L-glutamate to outside-out patches from hippocampal neurons in the presence and absence of MK-801 revealed that about 30 percent of L-glutamate-bound channels are open at the peak of the current. This high probability of opening suggests that very few channels are required to guarantee a large, localized postsynaptic calcium transient.


Inhibition of the mammalian target of rapamycin promotes cyclic AMP-induced differentiation of NG108-15 cells.
To clarify the involvement of autophagy in neuronal differentiation, the effect of rapamycin, an mTOR complex inhibitor, on the dibutyryl cAMP (dbcAMP)-induced differentiation of NG108-15 cells was examined. Treatment of NG108-15 cells with 1 mM dbcAMP resulted in induction of differentiation, including neurite outgrowth and varicosity formation, enhanced voltage-sensitive Ca2+ channel activity and expression of microtubule-associated protein 2, and these effects involved phosphorylation of cAMP-response element binding protein (CREB) and extracellular signal regulated kinase (ERK). Simultaneous application of dbcAMP and rapamycin synergistically increased and accelerated differentiation. mTOR or raptor silencing with siRNA had a similar effect to rapamycin. Rapamycin and silencing of mTOR or raptor evoked autophagy, while blockade of autophagy by addition of 3-methyladenine or beclin 1 or Atg5 silencing prevented the potentiation of differentiation. Silencing of rictor also evokes autophagy, at a level 55% of that induced by raptor silencing and enhancement of differentiation is proportional. Rapamycin also caused increased ATP generation and cell cycle arrest in G0/G1 phase, but had no effect on CREB and ERK phosphorylation. dbcAMP also induced ATP generation, but not autophagy or cell cycle arrest. These results suggest that the increased autophagy, ATP generation and cell cycle arrest caused by mTOR inhibition promotes the dbcAMP-induced differentiation of NG108-15 cells.


Epileptiform electroencephalographic abnormalities in liver transplant recipients.
We retrospectively studied patients who had undergone orthotopic liver transplantation and who also had electroencephalography to determine whether epileptiform changes were associated with a poor neurological outcome. Study groups were 36 patients who died after transplantation (141 electroencephalograms) and underwent neuropathological examination, 11 who died (18 electroencephalograms) but did not have autopsy, and a third group of 34 (62 electroencephalograms) who remained alive. Epileptiform activity was seen in electroencephalograms of 14 of the patients who died (11 from the autopsy group) and in 2 of those who remained alive. All had multiple epileptiform abnormalities and clinical or subclinical seizures. The incidence of epileptiform activity after orthotopic liver transplantation was fivefold higher in the nonsurvivors. Serious cerebral structural changes were found in 10 of the 11 patients who underwent autopsy. Epileptiform activity in the electroencephalograms of patients who had undergone orthotopic liver transplantation indicates a poor prognosis. It should alert the clinician to investigate further for potentially treatable causes.


New insights into seaweed polyphenols on glucose homeostasis.
Polyphenol-rich marine macroalgae are gaining dietary importance due to their influence over diabetes mellitus and the role as a vital source of high-value nutraceuticals. Their assorted beneficial effects on human health include competitive inhibition of digestive enzymes, varying the activity of hepatic glucose-metabolizing enzymes, lowering the plasma glucose levels, and lipid peroxidation, delaying the aging process. In this paper, we review the health beneficial effects of polyphenols and phlorotannins from brown seaweeds with special emphasis on their inhibitory effects on carbohydrate-metabolizing enzymes. A survey of literature from databases such as Sciencedirect, Scopus, Pubmed, Springerlink, and Google Scholar from the year 1973 to 2013 was done to bring together the information relating to drug discovery from brown seaweeds as a source for diabetes treatment. Over the past two decades, 20 different bioactive polyphenols/phlorotannins have been isolated and studied from 10 different brown algae. Discussion of the positive effect on the inhibition of enzymes metabolizing carbohydrates in both in vitro and in vivo experiments are included. Despite the recent advancements in isolating bioactive compounds from seaweeds with potential health benefit or pharmaceutical behavior, studies on the polyphenol effectiveness on glucose homeostasis in human beings are very few in response to their functional characterization. Added research in this area is required to confirm the close connection of polyphenol rich seaweed-based diet consumption with glucose homeostasis and the exciting possibility of prescribing polyphenols to treat the diabetes pandemic.


Beneficial effects of vitamin E isomer supplementation on static and dynamic bone histomorphometry parameters in normal male rats.
Bone is a specialized connective tissue that functions as the load-bearing structure of the body. Free radicals may affect bone remodeling by regulating osteoclast activity in either the physiological or pathological condition. Vitamin E, a lipid-soluble antioxidant, has been demonstrated to offer protection against osteoporosis and to improve the bone material and structure of animal models. The aim of this study was to observe and compare the effects of alpha-tocopherol (alpha-tocopherol), delta-tocotrienol (delta-tocotrienol), and gamma-tocotrienol (gamma-tocotrienol) on the static and dynamic bone histomorphometric parameters in normal male rats. Thirty-two normal Sprague-Dawley male rats aged 3 months and weighing 200-250 g were randomly divided into four groups. The control group was supplemented with oral gavages of olive oil (vehicle), whereas the alpha-tocopherol, delta-tocotrienol, and gamma-tocotrienol groups were given oral gavages of 60 mg/kg alpha-tocopherol, delta-tocotrienol, and gamma-tocotrienol, respectively. The rats were injected twice with calcein to fluorochrome-label the bones. After 4 months of treatment, the rats were killed, and the left femurs were dissected out and prepared for bone histomorphometry. Both the static and dynamic parameters of the vitamin E-treated groups were better than those of the normal control group. Among the vitamin E-treated groups, the tocotrienol groups showed better histomorphometry results compared to the α-tocopherol group, with the γ-tocotrienol group demonstrating the best effects on both sets of parameters. We concluded that vitamin E can promote bone formation in normal rats, with gamma-tocotrienol being the most potent form of vitamin E.


GmCOI1, a soybean F-box protein gene, shows ability to mediate jasmonate-regulated plant defense and fertility in Arabidopsis.
The F-box protein gene COI1 from Arabidopsis plays a fundamental role in response to jasmonates, which regulate plant root growth, pollen fertility, wounding and healing, and defense against pathogens and insects. Null mutations in COI1 were previously found to abolish all the jasmonate responses, and the Arabidopsis coil-1 mutant is male sterile and susceptible to pathogen infection. In this study, we isolated an F-box protein gene from soybean, which shares significant homology with the Arabidopsis COI1 and similarly contains an F-box motif and leucine rich repeats (LRR), here designated GmCOI1 (Glycine max L. (Merr.) COI1). To test whether the sequence homology and structural similarity are indicative of functional conservation, we expressed GmCOI1 in the Arabidopsis coil-1 mutant. The transgenic coil-1 plants with expression of the GmCOI1 gene were found to exhibit normal jasmonate responses, including jasmonate-regulated plant defense and fertility. In addition, the chimerical proteins with swapped domain of the F-box motif or LRR between GmCOI1 and COI1 were shown to functionally complement the coil-1 mutation. Furthermore, GmCOI1 was found to assemble into the Skpl-Cullin-F-box (SCF) complexes, similar to the formation of the Arabidopsis SCF(COO1). These data demonstrate the soybean F-box protein gene GmCOI1 is able to mediate jasmonate-regulated plant defense and fertility in Arabidopsis, which implies a generic jasmonate pathway with conserved signal components in different plant species.


Activity of δ-aminolevulinic acid dehydratase at Ramonda nathaliae and Ramonda serbica plants during dehydration and rehydration.
Ramonda nathaliae and Ramonda serbica are resurrection plants belonging to homoiochlorophyllous desiccation-tolerant angiosperms. Chlorophyll biosynthesis is one of the most important metabolic pathways to tolerate desiccation in these plant species. To better understand the early pathway steps of chlorophyll biosynthesis, we have analyzed the enzyme δ-aminolevulinic acid dehydratase (ALA-D) and contents of δ-aminolevulinic acid (ALA) and total chlorophyll as a final product during dehydration and rehydration stages for these plant species. Our results showed that the activity of ALA-D in R. nathaliae and R. serbica plants rapidly decreased during dehydration and in the final stage of desiccation the activity of this enzyme was decreased by 79% and 86%, respectively. After rehydration of plants, the ALA-D activity was fully restored. In contrast, the ALA content of both plant species significantly increased during desiccation and decreased after 48 hr of rewatering. In each stage of dehydration or rehydration, a significant negative correlation was established between ALA-D activity and ALA content in both plant species. Total chlorophyll content was preserved more in R. nathaliae than in R. serbica during desiccation. Moreover, ALA-D activity was decreased to a minimal level but preserved its function during desiccation, and this suggests one possible mechanism of desiccation tolerance to retain the chlorophyll of these plant species.


Modeling site-specific amino-acid preferences deepens phylogenetic estimates of viral sequence divergence.
Molecular phylogenetics is often used to estimate the time since the divergence of modern gene sequences. For highly diverged sequences, such phylogenetic techniques sometimes estimate surprisingly recent divergence times. In the case of viruses, independent evidence indicates that the estimates of deep divergence times from molecular phylogenetics are sometimes too recent. This discrepancy is caused in part by inadequate models of purifying selection leading to branch-length underestimation. Here we examine the effect on branch-length estimation of using models that incorporate experimental measurements of purifying selection. We find that models informed by experimentally measured site-specific amino-acid preferences estimate longer deep branches on phylogenies of influenza virus hemagglutinin. This lengthening of branches is due to more realistic stationary states of the models, and is mostly independent of the branch-length extension from modeling site-to-site variation in amino-acid substitution rate. The branch-length extension from experimentally informed site-specific models is similar to that achieved by other approaches that allow the stationary state to vary across sites. However, the improvements from all of these site-specific but time homogeneous and site independent models are limited by the fact that a protein's amino-acid preferences gradually shift as it evolves. Overall, our work underscores the importance of modeling site-specific amino-acid preferences when estimating deep divergence times-but also shows the inherent limitations of approaches that fail to account for how these preferences shift over time.


Terms and nomenclature used for plant-derived components in nutrition and related research: efforts toward harmonization.
Many terms for plant-derived food components are commonly used in the literature, but there is a notable lack of standardization and definition of nomenclature. The use of terms is often field-specific, leading to misunderstanding and problems with literature searches and systematic reviews, and results in isolated and divided research; this impacts not only publication quality but also innovation, regulatory compliance, and enforcement. To begin to address this issue, this narrative review describes the current use and definition of terms. The terms are either chemical and/or origin-based, such as phytochemical (chemicals from plants), or function-based, such as phytonutrient, bioactive, or nutraceutical. The ultimate goal is to establish a common harmonized, evidence-based understanding for when to use each term, thereby providing clarity and a specific scientific basis for such nomenclature. Neither the quality nor the quantity of evidence needed to allow the use of functional terms such as phytonutrient or nutraceutical is specifically discussed here; rather, it is simply noted that evidence is needed to apply these terms. The next step would be to define the evidence necessary for a compound to have a functional descriptor. The aim in this article is to establish scientific criteria for definitions that could be applied to clearly define and differentiate commonly used terms and thus ensure their consistent application in the scientific literature.


Apoptotic photoreceptor cell death after traumatic retinal detachment in humans.
To determine the mechanism of photoreceptor cell death after traumatic retinal detachment in humans. Clinical records from 1975 to 1993 of 75 patients, whose eyes were enucleated after traumatic retinal detachment, were reviewed for age, sex, previous ocular or systemic medical history, interval from initial trauma to enucleation, visual acuity, and types of trauma. The patients were divided into five groups of 15 cases each, based on the interval from initial trauma to enucleation. The retinal tissue was examined for two markers of apoptosis: (1) nicked nuclear DNA in situ by the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) technique and (2) apoptotic bodies by light and electron microscopy. Of the 75 cases of ruptured globe and traumatic retinal detachment that were evaluated, 19 eyes (25.3%) showed TUNEL-positive labeling of photoreceptor cells. Nicked nuclear DNA was detected in photoreceptor cells of detached retinas as early as 8 hours after trauma. The detached retinas in seven of 15 eyes enucleated within 2 days after ocular trauma showed TUNEL-positive photoreceptor nuclei. The number of cases showing TUNEL-positive photoreceptor nuclei decreased as the interval between initial trauma and enucleation increased. The TUNEL-positive photoreceptor cells could still be seen in the detached retinas of two eyes enucleated 22 days after trauma. Light microscopy disclosed condensation and fragmentation of photoreceptor nuclei in the detached retinas. Electron microscopy showed structures resembling apoptotic bodies phagocytosed by neighboring cells in the TUNEL-positive retinas. Apoptosis is an important mechanism of photoreceptor cell degeneration in the early stage after traumatic retinal detachment in humans.


Peripheral sympathectomy as a novel treatment option for distal digital necrosis following parenteral administration of promethazine.
Promethazine is a commonly used medication to treat nausea and motion sickness. Case reports have recently surfaced on the dangers of parenteral administration of promethazine. We present a case report of a presumed intravenous injection of promethazine into an antecubital intravenous line resulting in necrosis of the ring finger distal to the DIP joint and hypoperfusion of the digits. Peripheral sympathectomy was performed to improve nutritional flow and improve ischemic pain. However, although this novel treatment option was successful, ultimately the patient had an amputation of her ring finger at the level of her middle phalanx. Although no proven successful treatment exists, the updated treatment options following inadvertent intra-arterial or perivascular administration are presented. Given the limited success of current treatment options for intra-arterial or perivascular extravasation, the staggering medical malpractice awards in such cases, and the numerous therapeutic alternatives to promethazine, the medical community should question the safety and continued administration of promethazine by an intravenous route.


Solid Ehrlich tumor growth treatment by magnetic waves.
In this work the retardation of Ehrlich tumor growth implanted in mice was studied by employing 4.5 Hz magnetic field. Eighty female Balb/c mice were used, twenty as normal group; the other sixty mice were inoculated with Ehrlich tumor, then they were divided equally into three groups namely A, B and C. Group A (control group) animals were not exposed to the magnetic field. The tumors in the thigh of the animals of group B were exposed to 4.5 Hz, 2 Gauss square wave magnetic field by using a small solenoid connected to a power square wave generator. Group C animals were whole body exposed inside a large solenoid to 4.5 Hz, 2 Gauss square wave magnetic field. Both groups B and C were exposed for a period of 2 weeks at a rate 2 hours per day. Tumor volume, survival period, histological examination and dielectric relaxation of the tumor were measured to investigate the activity of the tumor of the exposed and the unexposed animals. The results indicated that exposing the tumor tissue to 4.5 Hz square wave magnetic field for 2 weeks at a rate 2 hours/day inhibited tumor growth and increased the survival period of the animals. However, group B showed more improvements than did group C. This was attributed to some distortions in the square waveform in the large solenoid (group C). By comparing data from current and previous work, it was concluded that the use of magnetic waves showed better results over previously published work using amplitude modulated electromagnetic waves with the same frequency.


Selection criteria for the analysis of data-driven clusters in cerebral FMRI.
Functional MRI (fMRI) may be possible without a priori models of the cerebral hemodynamic response. First, such data-driven fMRI requires that all cerebral territories with distinct patterns be identified. Second, a systematic selection method is necessary to prevent the subjective interpretation of the identified territories. This paper addresses the second point by proposing a novel method for the automated interpretation of identified territories in data-driven fMRI. Selection criteria are formulated using: 1) the temporal cross-correlation between each identified territory and the paradigm and 2) the spatial contiguity of the corresponding voxel map. Ten event-design fMRI data sets are analyzed with one prominent algorithm, fuzzy c-means clustering, before applying the selection criteria. For comparison, these data are also analyzed with an established, model-based method: statistical parametric mapping. Both methods produced similar results and identified potential activation in the expected territory of the sensorimotor cortex in all ten data sets. Moreover, the proposed method classified distinct territories in separate clusters. Selected clusters have a mean temporal correlation coefficient of 0.39+/-0.07 (n=19) with a mean 2.7+/-1.4 second response delay. At most, four separate contiguous territories were observed in 87% of these clusters. These results suggest that the proposed method may be effective for exploratory fMRI studies where the hemodynamic response is perturbed during cerebrovascular disease.


Physical activity promotion in the primary care setting in pre- and type 2 diabetes - the Sophia step study, an RCT.
Physical activity prevents or delays progression of impaired glucose tolerance in high-risk individuals. Physical activity promotion should serve as a basis in diabetes care. It is necessary to develop and evaluate health-promoting methods that are feasible as well as cost-effective within diabetes care. The aim of Sophia Step Study is to evaluate the impact of a multi-component and a single component physical activity intervention aiming at improving HbA1c (primary outcome) and other metabolic and cardiovascular risk factors, physical activity levels and overall health in patients with pre- and type 2 diabetes. Sophia Step Study is a randomized controlled trial and participants are randomly assigned to either a multi-component intervention group (A), a pedometer group (B) or a control group (C). In total, 310 patients will be included and followed for 24 months. Group A participants are offered pedometers and a website to register steps, physical activity on prescription with yearly follow-ups, motivational interviewing (10 occasions) and group consultations (including walks, 12 occasions). Group B participants are offered pedometers and a website to register steps. Group C are offered usual care. The theoretical framework underpinning the interventions is the Health Belief Model, the Stages of Change Model, and the Social Cognitive Theory. Both the multi-component intervention (group A) and the pedometer intervention (group B) are using several techniques for behavior change such as self-monitoring, goal setting, feedback and relapse prevention. Measurements are made at week 0, 8, 12, 16, month 6, 9, 12, 18 and 24, including metabolic and cardiovascular biomarkers (HbA1c as primary health outcome), accelerometry and daily steps. Furthermore, questionnaires were used to evaluate dietary intake, physical activity, perceived ability to perform physical activity, perceived support for being active, quality of life, anxiety, depression, well-being, perceived treatment, perceived stress and diabetes self- efficacy. This study will show if a multi-component intervention using pedometers with group- and individual consultations is more effective than a single- component intervention using pedometers alone, in increasing physical activity and improving HbA1c, other metabolic and cardiovascular risk factors, physical activity levels and overall health in patients with pre- and type 2 diabetes. ClinicalTrials.gov Identifier: NCT02374788 . Registered 28 January 2015.


Dynamics of a short cavity swept source OCT laser.
We investigate the behaviour of a short cavity swept source laser with an intra cavity swept filter both experimentally and theoretically. We characterise the behaviour of the device with real-time intensity measurements using a fast digital oscilloscope, showing several distinct regimes, most notably regions of mode-hopping, frequency sliding mode-locking and chaos. A delay differential equation model is proposed that shows close agreement with the experimental results. The model is also used to determine important quantities such as the minimum and maximum sweep speeds for the mode-locking regime. It is also shown that by varying the filter width the maximum sweep speed can be increased but at a cost of increasing the instantaneous linewidth. The consequent impacts on optical coherence tomography applications are analysed.


Substance Use among Spanish Adolescents: The Information Paradox.
This aim of this paper is to determine the relationship between the consumption of tobacco, cannabis, and alcohol (including drunkenness and binge drinking consumption patterns) in the previous 30 days by Spanish adolescents and the information that is available to adolescents on drug consumption. This cross-sectional study employed data from the Survey on Drug Use in Secondary Education in Spain (ESTUDES 2016), which was conducted on students aged 14 to 18 (n = 35,369). Contingency tables, mean comparison tests, and logistic regression analyses were conducted and prevalence ratios (PR) were obtained. The results show that the probability that an adolescent will smoke tobacco is associated with whether their mother and/or father smoke (PR: 1.30), whether some of their friends smoke (PR: 14.23), whether the majority of their friends smoke (PR: 94.05) and how well informed they perceive themselves to be (PR: 1.30). Cannabis use is mainly associated with whether most of their friends also use cannabis (PR: 93.05) and whether they are sufficiently informed regarding this consumption (PR: 1.59). Alcohol consumption is associated with whether their mothers drink regularly (PR: 1.21), whether most of their friends drink (PR: 37.29), and whether they are well informed (PR: 1.28). Getting drunk and binge drinking are associated with whether their friends have these behaviors (PR: 44.81 and 7.36, respectively) and whether they are sufficiently informed (PR: 1.23 for both behaviors). In conclusion, the consumption of these substances is more frequent among Spanish adolescents who believe that they are better informed and whose friends have similar patterns of consumption.


Exercise builds brain health: key roles of growth factor cascades and inflammation.
Human and other animal studies demonstrate that exercise targets many aspects of brain function and has broad effects on overall brain health. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in elderly populations. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. Such exercise-induced structural and functional change has been documented in various brain regions but has been best-studied in the hippocampus - the focus of this review. A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration. A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function.


Reward modulates the effect of visual cortical microstimulation on perceptual decisions.
Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.


Advanced microscopy analysis of the micro-nanoscale architecture of human menisci.
The complex inhomogeneous architecture of the human meniscal tissue at the micro and nano scale in the absence of artefacts introduced by sample treatments has not yet been fully revealed. The knowledge of the internal structure organization is essential to understand the mechanical functionality of the meniscus and its relationship with the tissue's complex structure. In this work, we investigated human meniscal tissue structure using up-to-date non-invasive imaging techniques, based on multiphoton fluorescence and quantitative second harmonic generation microscopy complemented with Environmental Scanning Electron Microscopy measurements. Observations on 50 meniscal samples extracted from 6 human menisci (3 lateral and 3 medial) revealed fundamental features of structural morphology and allowed us to quantitatively describe the 3D organisation of elastin and collagen fibres bundles. 3D regular waves of collagen bundles are arranged in "honeycomb-like" cells that are comprised of pores surrounded by the collagen and elastin network at the micro-scale. This type of arrangement propagates from macro to the nanoscale.


Effects of dextran 70 on hemodynamics and lung liquid and protein exchange in awake sheep.
We studied the effect of intravenous dextran 70 infusion on lung liquid and protein exchange to determine whether its effects were due to altered hemodynamics or to altered microvascular permeability. In each of six instrumented awake sheep with chronic lung lymph fistulas, we performed three experiments: 1) control, 2) a 30-minute infusion of 1 l of 6% dextran 70, and 3) an infusion of 1 l of 0.9% NaCl. In addition to pulmonary hemodynamics and lymph dynamics, we measured the plasma-to-lung lymph equilibration rate of [125I] albumin. We followed all the sheep for 10 hours, including a 2-hour baseline period. Dextran was more effective in expanding plasma volume (63 +/- 15% [mean +/- SD]) than saline (11 +/- 6%) at the end of the 30-minute infusion. Pulmonary vascular pressures increased after dextran and remained elevated for 8 hours, whereas after saline the pressures returned to baseline within 1 hour. After dextran, lung lymph flow increased and remained elevated. It was only transiently increased after saline. We confirmed that dextran equilibrated rapidly with lung lymph (half-time, less than 0.6 hour), even though it maintained plasma volume expansion for the whole body (half-time, 11.1 +/- 2.7 hours). The dextran increased both plasma and lymph total macromolecular osmotic pressure but did not increase the plasma-interstitial (lymph) osmotic pressure difference in the lung, except transiently during the infusion. The lymph/plasma protein concentration ratio increased after dextran due mainly to plasma protein dilution. There were no differences in the half-time of tracer albumin equilibration between plasma and lung lymph (control, 2.2 +/- 0.6 hours; saline, 2.0 +/- 0.6 hours; dextran, 2.3 +/- 0.6 hours). Dextran 70 increased liquid filtration mainly by increasing microvascular pressure and possibly filtration surface area. There was no evidence for a change in the leakiness of the lung microvascular barrier to albumin.


A giant retention cyst of the pancreas (cystic dilatation of dorsal pancreatic duct) associated with pancreas divisum.
We describe a rare case of pancreas divisum associated with a giant retention cyst (cystic dilatation of the dorsal pancreatic duct), presumably formed following obstruction of the minor papilla. The patient was treated by pancreatico(cysto)jejunostomy. A 50-year-old man was admitted with complaints of increasing upper abdominal distension and body weight loss. There was no previous history of pancreatitis, gallstones, drinking, or abdominal injury. An elastic-hard tumor-like resistance was palpable in the upper abdomen. Computed tomography and ultrasound (US) examinations revealed a giant cystic lesion expanding from the pancreas head to the tail. Endoscopic retrograde cholangiopancreatography findings showed a looping pancreatic duct which drained only the head and uncinate process of the pancreas to the main papilla. A US-guided puncture to the cystic lesion revealed that the lesion continued to the main pancreatic duct in the tail of pancreas. The lesion was connected to a small cystic lesion, which was located inside the minor papilla, and ended there. The amylase level in liquid aspirated from the cyst was 37 869 IU/l, and the result of cytological examination of the liquid showed class II. A pancreatico(cysto)jejunostomy was performed, with the diagnosis being pancreas divisum associated with a retention cyst following obstruction of the minor papilla. The histological findings of a specimen from the cyst wall revealed that the wall was a pancreatic duct covered with mildly inflammatory duct epithelium; there was no evidence of neoplasm. The patient is currently well, and a CT examination 2 years after the operation showed disappearance of the cyst and normal appearance of the whole pancreas.


Automatic parameter optimization of the local model fitting method for single-shot surface profiling.
The local model fitting (LMF) method is a single-shot surface profiling algorithm. Its measurement principle is based on the assumption that the target surface to be profiled is locally flat, which enables us to utilize the information brought by nearby pixels in the single interference image for robust LMF. Given that the shape and size of the local area is appropriately determined, the LMF method was demonstrated to provide very accurate measurement results. However, the appropriate choice of the local area often requires prior knowledge on the target surface profile or manual parameter tuning. To cope with this problem, we propose a method for automatically determining the shape and size of local regions only from the single interference image. The effectiveness of the proposed method is demonstrated through experiments.


Upregulated expression of voltage-gated sodium channel Nav1.3 in cortical lesions of patients with focal cortical dysplasia type IIb.
Focal cortical dysplasia (FCD) is one of the causes of intractable epilepsy in humans. Cytomegalic neurons, not balloon cells, are considered to be the putative generators of epileptic activity in FCD type IIb (FCDIIb). Voltage-gated sodium channel III α-isoforms (Nav1.3) play crucial roles in the initiation and propagation of action potentials and are important regulators of neuronal excitability. Here, we examined 12 FCDIIb surgical specimens from patients undergoing surgery for epilepsy and used age-matched normal control cortical tissue (CTX) from 10 autopsy samples as controls. Using reverse transcription-PCR and western blot techniques, we found that the mRNA and protein levels of Nav1.3 were clearly upregulated in FCDIIb surgical specimens compared with the controls (CTX). Results of immunohistochemistry analyses demonstrated that Nav1.3 immunoreactivity was widely present in FCDIIb lesion tissue; specifically, high levels of Nav1.3 immunoreactive proteins were located mainly in cytomegalic neurons of different sizes and shapes, not in balloon cells. Double-labeling studies showed most cytomegalic neurons expressing Nav1.3 colabeled with neuronal markers and glutamate receptors-1. Taken together, our results show an upregulation of Nav1.3 protein and a specific cellular distribution of Nav1.3 proteins in FCDIIb lesion tissue samples, suggesting that Nav1.3 may be involved in the generation of epileptic activity in FCDIIb.


Thin-section CT in patients with cystic fibrosis: correlation with peak exercise capacity and body mass index.
To evaluate whether thin-section chest computed tomographic (CT) findings correlate with exercise capacity, body mass index (BMI), dyspnea, and leg discomfort in patients with cystic fibrosis (CF). Institutional ethics committee approval was obtained, and patients provided written informed consent. Twenty-two patients (13 male and nine female patients; mean age, 22 years +/- 5.9; age range, 17-41 years) with stable CF underwent thin-section CT and exercise testing on a cycle ergometer. Three radiologists blinded to the clinical severity of disease and the spirometric findings of all patients independently and randomly scored all scans with a modified Bhalla scoring system. The primary measurement of the outcome of exercise testing was percentage of predicted peak O2 uptake. Univariate (Spearman rank correlation) and multivariate analyses were used to compare thin-section CT, clinical (age, sex, spirometric data, and BMI), and exercise measurements. The correlation between total thin-section CT score and percentage of predicted peak O2 uptake was stronger than the correlation between the percentage of predicted peak O2 uptake and any clinical measurement (R = -0.60, P < .01). The thin-section CT structural abnormalities that had the strongest correlation with percentage of predicted peak O2 uptake were severity of bronchiectasis and presence of sacculations or abscesses (R = -0.70 and -0.71, respectively; P < .01). Multivariate analysis showed total thin-section CT score to be the only significant predictor of exercise capacity, accounting for 42% of the variance in percentage of predicted peak O2 uptake. In patients with CF, the correlation between thin-section CT score and exercise limitation is stronger than that between spirometry results or BMI and exercise limitation.


Identification of Arabidopsis mutants exhibiting an altered hypersensitive response in gene-for-gene disease resistance.
A mutational study was carried out to isolate Arabidopsis thaliana plants that exhibit full or partial disruption of the RPS2-mediated hypersensitive response (HR) to Pseudomonas syringae that express avrRpt2. Five classes of mutants were identified including mutations at RPS2, dnd mutations causing a "defense, no death" loss-of-HR phenotype, a lesion-mimic mutant that also exhibited an HR- phenotype, and a number of intermediate or partial-loss-of-HR mutants. Surprisingly, many of these mutants displayed elevated resistance to virulent P. syringae and, in some cases, to Peronospora parasitica. Constitutively elevated levels of pathogenesis-related (PR) gene expression and salicylic acid were also observed. In the lesion-mimic mutant, appearance of elevated resistance was temporally correlated with appearance of lesions. For one of the intermediate lines, resistance was shown to be dependent on elevated levels of salicylic acid. A new locus was identified and named IHR1, after the mutant phenotype of "intermediate HR." Genetic analysis of the intermediate-HR plant lines was difficult due to uncertainties in distinguishing the partial/intermediate mutant phenotypes from wild type. Despite this difficulty, the intermediate-HR mutants remain of interest because they reveal potential new defense-related loci and because many of these lines exhibit partially elevated disease resistance without dwarfing or other apparent growth defects.


Influence of trans fatty acids on health.
The contribution of dietary trans fatty acids (TFAs) on the risk of ischemic heart disease (IHD) has recently gained further support due to the results from large, prospective, population-based studies. Compared to saturated fat, TFAs are, gram to gram, associated with a considerably (2.5- to >10-fold) higher risk increment for IHD. A negative effect on the human fetus and on newborns and an increase in colon cancer risk in adults are possible but, however, still equivocal. Recent findings justify further studies concerning the effect of TFAs on allergic diseases in children and on the risk of type-2 diabetes in adults. The intake of industrially produced TFAs in European countries is decreasing. However, determination of the TFA content in various popular food items collected in Danish shops showed that it is likely that persons with a frequent intake of, e.g., French fries, microwave oven popcorn, chocolate bars, fast food, etc., consume industrially produced TFAs in amounts far exceeding the average intake, and are thereby exposed to an unnecessary health risk. The Danish government has decided that oils and fats containing more than 2% industrially produced TFAs will not be sold in Denmark after the January 1, 2004.


Cutaneous siderosis after intramuscular iron injections: a case report.
Skin reactions against injected or implanted foreign materials are not rare. Siderosis is a disease characterized by the accumulation of iron in various tissues. Brownish-gray discoloration of the skin can be seen as a side-effect on the injection area after the parenteral iron treatment. Here, we present cutaneous siderosis case developed after multiple intramuscular iron injection on the gluteal region for iron-deficiency anemia. Development of cutaneous siderosis after intramuscular iron injection rarely has been reported in the literature before.


Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.
Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks' postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks' postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation > or =90%). Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.


Genetic diversity and gene flow decline with elevation in montane mayflies.
Montane environments around the globe are biodiversity 'hotspots' and important reservoirs of genetic diversity. Montane species are also typically more vulnerable to environmental change than their low-elevation counterparts due to restricted ranges and dispersal limitations. Here we focus on two abundant congeneric mayflies (Baetis bicaudatus and B. tricaudatus) from montane streams over an elevation gradient spanning 1400 m. Using single-nucleotide polymorphism genotypes, we measured population diversity and vulnerability in these two species by: (i) describing genetic diversity and population structure across elevation gradients to identify mechanisms underlying diversification; (ii) performing spatially explicit landscape analyses to identify environmental drivers of differentiation; and (iii) identifying outlier loci hypothesized to underlie adaptive divergence. Differences in the extent of population structure in these species were evident depending upon their position along the elevation gradient. Heterozygosity, effective population sizes and gene flow all declined with increasing elevation, resulting in substantial population structure in the higher elevation species (B. bicaudatus). At lower elevations, populations of both species are more genetically similar, indicating ongoing gene flow. Isolation by distance was detected at lower elevations only, whereas landscape barriers better predicted genetic distance at higher elevations. At higher elevations, dispersal was restricted due to landscape effects, resulting in greater population isolation. Our results demonstrate differentiation over small spatial scales along an elevation gradient, and highlight the importance of preserving genetic diversity in more isolated high-elevation populations.


Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review.
Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions.


Utilization of somatic specialist services among psychiatric immigrant patients: the Norwegian patient registry study.
Amongst psychiatric patients, the leading causes of reduced quality of life and premature death are chronic viral infections and cardiovascular diseases. In spite of this, there are extremely high levels of disparity in somatic healthcare amongst such populations. Little research has explored patterns of healthcare utilisation and, therefore, this study aims to examine the use of somatic specialist healthcare for infectious diseases and diseases of circulatory system among psychiatric patients from different immigrant groups and ethnic Norwegians. Register data from the Norwegian Patient Registry and Statistics Norway were used. The sample (ages 0-90+) consisted of 276,890 native-born Norwegians and 52,473 immigrants from five world regions - Western countries, East Europe, Africa, Asia, and Latin America, all of whom had contacts with specialist mental healthcare during the period 2008-2011. Statistical analyses were applied using logistic regression models. Rates of outpatient consultation for circulatory system diseases were significantly lower amongst patients from Africa, Asia and Latin America compared with ethnic Norwegian psychiatric patients. Only patients from Eastern Europeans had a higher rate. With regard to hospital admission, all psychiatric patients had a lower rate than ethnic Norwegians with the exception of those from Africa where the finding was non-significant. In terms of infectious diseases, patients from African countries had significantly higher outpatient and admission rates than ethnic Norwegians. Outpatient consultation rates were lower amongst those from Western and Latin America and hospital admission rates were lower amongst those from Eastern Europe and Asia. The findings suggest that the majority of immigrant psychiatric patients have lower hospitalization rates for circulatory system diseases than Norwegian psychiatric patients. This may suggest that poor access for immigrants is a contributing factor, though the findings were less pronounced for infectious diseases.


Cerenkov luminescence imaging of interscapular brown adipose tissue using a TSPO-targeting PET probe in the UCP1 ThermoMouse.
Rationale: [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) has been widely used as an imaging technique to measure interscapular brown adipose tissue (iBAT) activity. However, it is challenging to obtain iBAT-specific images using [18F]FDG-PET because increased uptake of [18F]FDG is observed in tumors, muscle, and inflamed tissues. Uncoupling protein 1 (UCP1) in the mitochondrial membrane, a well-known molecular marker of BAT, has been proposed as a useful BAT imaging marker. Recently, the UCP1 ThermoMouse was developed as a reporter mouse for monitoring UCP1 expression and investigating BAT activation. In addition, Translocator protein-18 kDa (TSPO) located in the outer mitochondrial membrane is also overexpressed in BAT, suggesting that TSPO-targeting PET has potential for iBAT imaging. However, there are no studies monitoring BAT using TSPO-targeting PET probes in the UCP1 ThermoMouse. Moreover, the non-invasive Cerenkov luminescence imaging (CLI) using Cerenkov radiation from the PET probe has been proposed as an alternative option for PET as it is less expensive and user-friendly. Therefore, we selected [18F]fm-PBR28-d 2 as a TSPO-targeting PET probe for iBAT imaging to evaluate the usefulness of CLI in the UCP1 ThermoMouse. Methods: UCP1 ThermoMouse was used to monitor UCP1 expression. Western blotting and immunohistochemistry were performed to measure the level of protein expression. [18F]fm-PBR28-d 2 and [18F]FDG were used as radioactive probes for iBAT imaging. PET images were acquired with SimPET, and optical images were acquired with IVIS 100. Results: UCP1 ThermoMouse showed that UCP1 and TSPO expressions were correlated in iBAT. In both PET and CLI, the TSPO-targeting probe [18F]fm-PBR28-d 2 was superior to [18F]FDG for acquiring iBAT images. The high molar activity of the probe was essential for CLI and PET imaging. We tested the feasibility of TSPO-targeting probe under cold exposure by imaging with TSPO-PET/CLI. Both signals of iBAT were clearly increased after cold stimulation. Under prolonged isoflurane anesthesia, TSPO-targeting images showed higher signals from iBAT in the short-term than in long-term groups. Conclusion: We demonstrated that TSPO-PET/CLI reflected UCP1 expression in iBAT imaging better than [18F]FDG-PET/CLI under the various conditions. Considering convenience and cost, TSPO-CLI could be used as an alternative TSPO-PET technique for iBAT imaging.


Road traffic noise, noise sensitivity and psychological disorder.
The relationship between traffic noise exposure and psychological morbidity was assessed using the population-based Caerphilly Collaborative Survey of 2398 men from Caerphilly, South Wales. The findings showed that traffic noise exposure levels were strongly associated with annoyance to noise. Noise-sensitive men were more likely to be highly annoyed by noise exposure than less noise-sensitive men. There was no direct association between noise exposure level and psychological morbidity but there were provocative interactions with noise sensitivity. The role of noise sensitivity is discussed as an indicator of vulnerability to environmental stressors and a measure of negative affectivity and over-reporting.


Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial.
It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018. Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported. A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD. ClinicalTrials.gov Identifier: NCT01471522.


External validation of the preoperative Karakiewicz nomogram in a large multicentre series of patients with renal cell carcinoma.
To perform a formal external validation of the preoperative Karakiewicz nomogram (KN) for the prediction of cancer-specific survival (CSS) using a large series of surgically treated patients diagnosed with organ-confined or metastatic renal cell carcinoma (RCC). Patient population originated from a series of retrospectively gathered cases that underwent radical or partial nephrectomy between years 1995 and 2007 for suspicion of kidney cancer. The original Cox coefficients were used to generate the predicted risk of CSS at 1, 2, 5, and 10 years following surgery and compared to the observed risk of CSS in the current population. External validation was quantified using measures of predictive accuracy, defined as model discrimination and calibration. A total of 3,374 patients were identified. Relative to the original development cohort, the current sample population had a larger proportion of patients with localized (40.0 vs. 26.3 %, P < 0.001) and non-metastatic (92.2 vs. 88.1 %, P = 0.03) disease at presentation. Model discrimination for the prediction of CSS was 87.8 % (95 % CI, 84.4-91.4) at 1 year, 87.0 % (95 % CI, 84.4-89.5) at 2 years, 84.7 % (95 % CI, 82.3-87.1) at 5 years, and 85.9 % (95 % CI, 83.2-88.6) at 10 years. The relationship between predicted and observed CSS risk was adequate in the calibration plot. The use of the KN for the prediction of CSS in patients diagnosed with renal cell carcinoma was validated in the current study. In consequence, this tool may be recommended for routine clinical counseling in patients with various stages of RCC in the preoperative setting.


Pharmacokinetics of golimumab in moderate to severe ulcerative colitis: the GO-KINETIC study.
Background: Golimumab (GLM) is approved for the treatment of moderate to severe ulcerative colitis (UC). Higher serum concentrations of anti-tumor necrosis factor (TNF) agents are associated with improved clinical and endoscopic outcomes. Correlations between GLM serum concentrations and clinical and endoscopic outcomes were investigated during induction and maintenance treatment. In addition, a population pharmacokinetic model was developed to identify factors associated with the pharmacokinetics of GLM in UC. Methods: A prospective observational trial (GO-KINETIC) was conducted in patients with moderate to severe UC receiving induction and maintenance treatment with GLM. Clinical and endoscopic outcomes were evaluated, fecal GLM concentrations were measured and pharmacokinetic data were analyzed. Results: A total of 20 patients were enrolled. At week 8 (after induction treatment), 12 out of 20 patients (60%) showed an endoscopic response (≥1 point reduction in endoscopic Mayo score). Patients with endoscopic response at week 8 had numerically higher median GLM serum concentrations at week 2 compared to endoscopic non-responders: 9.1 µg/ml [5.9-12.3] vs. 7.1 µg/mL [5.2-9.0]; p = .384, respectively. At week 52, 3/20 patients (15%) achieved endoscopic remission (endoscopic Mayo score ≤1) and continued GLM treatment. Population pharmacokinetic analysis showed an inverse association between albumin concentrations and GLM clearance. GLM concentrations were undetectable in fecal samples. Conclusions: After induction therapy, 60% of the patients showed endoscopic response. During maintenance therapy, about one third of patients discontinued GLM treatment because of loss of response. These patients might benefit from dose optimization.


Discussing childhood overweight and obesity with parents: a health communication dilemma.
Childhood obesity has reached alarming levels and the problem has assumed great significance for health care staff who work with overweight children and their families. Anecdotal accounts of the difficulties that may emerge when health care providers communicate that a child's weight is outside of the normal range, were a key stimulus for this review. A local government health department commissioned a review of literature on communicating with parents about childhood overweight and obesity. Literature concerned with communicating a child's overweight to parents was limited and, as a result, this review draws upon a disparate body of literature to examine what is known and what might be helpful for health care providers when discussing a child's weight with the child and parents. This paper identifies a range of factors influencing communication between health care workers and parents and offers a number of practical approaches and strategies for facilitating successful communication between health practitioners and the parents of children.


Canadian Health Personnel Attitudes Toward Refugee Claimants' Entitlement to Health Care.
Health care personnel attitudes toward refugee claimant entitlement to health care are influenced by multilevel factors including institutional and societal culture. Although individual attitudes may be modified through training, macro- and meso-issues require system-level interventions. This paper analyzes the role of individual-, institutional-, and city-level factors in shaping attitudes toward refugee claimants' access to health care among Canadian health care personnel. A total of 4207 health care personnel in 16 institutions located in Montreal and Toronto completed an online survey on attitudes regarding health care access for refugee claimants. We used multilevel logistic regression analysis to identify individual-, institutional-, and city-level predictors of endorsing access to care. Participants who had prior contact with refugee claimants had greater odds of endorsing access to care than those who did not (OR 1.13; 95% CI 1.05, 1.21). Attitudes varied with occupation: social workers had the highest probability of endorsing equal access to health care (.83; 95% CI .77, .89) followed by physicians (.77; 95% CI .71, .82). An estimated 7.97% of the individual variation in endorsement of equal access to health care was attributable to differences between institutions, but this association was no longer statistically significant after adjusting for city residence. Results indicate that the contexts in which health care professionals live and work are important when understanding opinions on access to health care for vulnerable populations. They suggest that institutional interventions promoting a collective mission to care for vulnerable populations may improve access to health care for precarious status migrants.


Rapid identification and 3D reconstruction of complex cardiac malformations in transgenic mouse embryos using fast gradient echo sequence magnetic resonance imaging.
Developmental malformations of the heart in mouse embryos are commonly studied by histological sectioning. This is slow, labour intensive, and results in the loss of three-dimensional (3D) information. Magnetic resonance studies of embryos typically use spin-echo sequences, using prolonged acquisition times (>36 h) or perfusion with contrast agents to enhance resolution and contrast. This is technically difficult, and requires significant amounts of operator time. We imaged paraformaldehyde fixed embryos using a fast spoiled 3D gradient echo sequence with T(1)-weighting, in unattended overnight runs of less than 9 h. In wild-type embryos, we visualised normal cardiac structures, including cardiac chambers, the ventricular septum, primary and secondary atrial septa, valves, superior and inferior vena cava, aorta, pulmonary artery, and ductus arteriosus. In embryos lacking Cited2 (a transcriptional co-activator required for normal heart development), we identified cardiac malformations including atrial and ventricular septal defects, cono-truncal defects, and aortic arch malformations. We generated 3D reconstructions of normal and mutant hearts using contour identification and surface rendering computer software. The malformations were confirmed by histological sectioning. Our data indicate that fast gradient echo sequence magnetic resonance imaging can be used to rapidly and accurately identify complex cardiovascular malformations in transgenic and mutant mouse embryos.


Association between Measures of Women's Empowerment and Use of Modern Contraceptives: An Analysis of Nigeria's Demographic and Health Surveys.
Women's empowerment is hypothesized as a predictor of reproductive health outcomes. It is believed that empowered girls and women are more likely to delay marriage, plan their pregnancies, receive prenatal care, and have their childbirth attended by a skilled health provider. The objective of this study was to assess the association between women's empowerment and use of modern contraception among a representative sample of Nigerian women. This study used the 2003, 2008, and 2013 Nigeria Demographic and Health Survey data. The analytic sample was restricted to 35,633 women who expressed no desire to have children within 2 years following each survey, were undecided about timing for children, and who reported no desire for more children. Measures of women's empowerment included their ability to partake in decisions pertaining to their healthcare, large household purchases, and visit to their family or relatives. Multivariable regression models adjusting for respondent's age at first birth, religion, education, wealth status, number of children, and geopolitical region were used to measure the association between empowerment and use of modern contraceptives. The proportion of women who participated in decisions to visit their relatives increased from 42.5% in 2003 to 50.6% in 2013. The prevalence of women involved in decision-making related to large household purchases increased from 24.3% in 2003 to 41.1% in 2013, while the proportion of those who partook in decision related to their health care increased from 28.4% in 2003 to 41.9% in 2013. Use of modern contraception was positively associated with women's participation in decisions related to large household purchases [2008: adjusted OR (aOR) = 1.15; 95% CI = 1.01-1.31] and (2013; aOR = 1.60; 1.40-1.83), health care [2008: (aOR = 1.20; 1.04-1.39) and (2013; aOR = 1.39; 1.22-1.59)], and visiting family or relatives [2013; aOR = 1.58; 1.36-1.83]. The prevalence of modern contraceptive use among women with need for contraception increased marginally from 11.1% in 2003 to 12.8% in 2013. Although there were marked improvements in all measures of women's empowerment between 2003 and 2013 in Nigeria, the use of modern contraceptives increased only marginally during this period. Beyond women's participation in household decision-making, further research is needed to elucidate how measures of women's empowerment interact with cultural values and health system factors to influence women's uptake of contraceptives.


Loop-mediated isothermal amplification for Rickettsia typhi (the causal agent of murine typhus): problems with diagnosis at the limit of detection.
Murine typhus is a flea-borne disease of worldwide distribution caused by Rickettsia typhi. Although treatment with tetracycline antibiotics is effective, treatment is often misguided or delayed due to diagnostic difficulties. As the gold standard immunofluorescence assay is imperfect, we aimed to develop and evaluate a loop-mediated isothermal amplification (LAMP) assay. LAMP assays have the potential to fulfill the WHO ASSURED criteria (affordable, sensitive, specific, user friendly, robust and rapid, equipment free, deliverable to those who need them) for diagnostic methodologies, as they can detect pathogen-derived nucleic acid with low technical expenditure. The LAMP assay was developed using samples of bacterial isolates (n=41), buffy coat specimens from R. typhi PCR-positive Lao patients (n=42), and diverse negative controls (n=47). The method was then evaluated prospectively using consecutive patients with suspected scrub typhus or murine typhus (n=266). The limit of detection was ∼40 DNA copies/LAMP reaction, with an analytical sensitivity of <10 DNA copies/reaction based on isolate dilutions. Despite these low cutoffs, the clinical sensitivity was disappointing, with 48% (95% confidence interval [95% CI], 32.5 to 62.7%) (specificity, 100% [95% CI, 100 to 100%]) in the developmental phase and 33% (95% CI, 9.2 to 56.8%) (specificity, 98.5% [95% CI, 97.0% to 100%]) in the prospective study. This low diagnostic accuracy was attributed to low patient R. typhi bacterial loads (median, 210 DNA copies/ml blood; interquartile range, 130 to 500). PCR-positive but LAMP-negative samples demonstrated significantly lower bacterial loads than LAMP-positive samples. Our findings highlight the diagnostic challenges for diseases with low pathogen burdens and emphasize the need to integrate pathogen biology with improved template production for assay development strategies.


Recent infections are associated with decreased risk of rheumatoid arthritis: a population-based case-control study.
Do recent infections affect the risk of rheumatoid arthritis (RA)? We used the population-based case-control study EIRA (N=6401) on incident RA and healthy controls, matched for sex, age, calendar period and area of residence. Gastroenteritis, urinary tract infection, genital infection, prostatitis, sinusitis, tonsillitis and pneumonia during the 2 years before inclusion in the study were investigated. Conditional logistic regression was used to calculate OR, adjusting for smoking and socioeconomic status. Infections in the gastrointestinal and urogenital tract before clinical onset were associated with a lowered risk of RA: gastroenteritis (OR=0.71 (95% CI 0.63 to 0.80)), urinary tract infections (OR=0.78 (95% CI 0.68 to 0.90)) and genital infections (OR=0.80 (95% CI 0.64 to 1.00)), while a non-significant association of similar magnitude was observed for the less common prostatitis (OR=0.64 (95% CI 0.38 to 1.08)). In contrast, no associations were observed for sinusitis, tonsillitis or pneumonia. Gastrointestinal and urogenital infections, but not respiratory infections, are associated with a significantly lowered risk of RA. The results indicate that infections in general do not affect the risk for RA, but that certain infections, hypothetically associated with changes in the gut microbiome, could diminish the risk.


Protein kinase C theta regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL.
Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8(+)) and less (CD4(+)) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8(+) but not CD4(+) CTL to lyse target cells despite having no effect of the amount of released granules by both CD8(+) and CD4(+) CTL. Consistent with this, CD4(+) CTL break their synapses more often than do CD8(+) CTL, which leads to the escape of the cytolytic molecules from the interface. CD4(+) CTL treatment with a protein kinase Ctheta inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Ctheta, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.


In the Best Interest of the. . .Parents: Norwegian Health Personnel on the Proper Role of Parents in Neonatal Decision-making.
The role of parents in life-and-death decision-making for infants born at the border of viability is challenging. Some argue that parents should have the final say in decisions about life-sustaining treatment. Others disagree. In this article, we report views from health care personnel (HCP) on the appropriate parental role. Focus group interviews with 5 different groups of HCP (neonatal nurses, midwifes, obstetricians, mother-fetal specialists, and neonatologists) dealing with life-and-death decisions throughout pregnancy and birth were performed at the Norwegian University of Science and Technology and at St Olav's Hospital in Trondheim, Norway in 2014-2017. Interviews were taped and transcribed. Inductive analysis was performed for each group discussion for emergent ethical themes. A summary of the transcribed discussion was sent to the relevant focus group participants for comments. Our participants felt strongly that doctors, not parents, should have the final say. They did not think parents should have to live with the burden of the decision. The possible disagreement between parents, lack of necessary knowledge, experience, time, and emotional stability all point toward the neonatologist as the optimal decision-maker, within a model of "Patient Preference-Satisfaction Paternalism." The general attitude of our groups was that parents should have a say and be included in a thorough information and decision-making process. The doctor, or a team of HCP, however, should make the final decision, being in the best position both epistemologically and normatively to promote the best interest of both parents and the child.


Controversies in EUS-guided treatment of walled-off necrosis.
This review gives an overview of different techniques in the treatment of post-acute complications of acute pancreatitis. The endoscopic treatment of those complications is currently standard of care. EUS opened up the broad implementation of internal drainage methods to make them safe and effective. Due to different endoscopic approaches worldwide, controversies have arisen that are pointed out in this paper. The main focus was placed on weighing up evidence to find the optimal approach. However, if no evidence can be provided, the authors, experienced in the field, give their personal advice.


Cerebral cysticercosis and stroke.
In 1985 we initiated a protocol for examining the relationship between cerebral cysticercosis and stroke. In 420 stroke patients admitted to our department, our standard protocol of tests included blood tests, cardiac investigations, angiography, and immunologic cerebrospinal fluid measures. We assessed the following possible risk factors: arterial hypertension, diabetes, cardiopathy, high levels of cholesterol and triglycerides, smoking, alcohol abuse, and cerebral cysticercosis. Of the 420 patients with stroke, we found cerebral cysticercosis in 31, five of whom were greater than 65 years of age and 26 of whom were less than or equal to 65 years. We determined that cerebral cysticercosis was the only possible risk factor for stroke in one of the five older patients and 15 of the 26 younger and middle-aged patients. Cortical infarctions were found in five of the 31 patients, with cerebral cysticercosis and lacunar infarctions in nine of these patients. One patient had intracystic hemorrhage. In 16 cases, neurological deficit was related to single or multiple cysts, colloids, granulomas, diffuse lesions, or pericystic edema. All patients with cerebral cysticercosis quickly recovered from their neurological deficit, except one who had a hemorrhagic cyst and died and another who remained disabled. We established that, in patients with neurocysticercosis, occlusion of the small cortical or penetrating vessels at the base of the brain caused by arteriopathy was the most common mechanism of the stroke. Moreover, there is a probable association between cerebral cysticercosis and the susceptibility to stroke, particularly among young and middle-aged patients.


Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.
B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.