Telemedicine Use Among Caregivers of Cancer Patients: Systematic Review.
The number of published studies and systematic reviews examining different telehealth interventions targeting patients and their effects on patients' well-being and quality of life have grown in recent decades. However, the use of telemedicine tools aimed at the family members and caregivers of adult cancer patients is less defined. We aimed to conduct a systematic review to provide a more complete picture regarding telemedicine tools for informal caregivers (usually family members or close friends) implemented in all phases of cancer care. More specifically, the review aimed to better describe the study samples' characteristics, to analyze measured outcomes and the specific questionnaires used to assess them, and to describe in depth the implemented interventions and their formats. Finally, we examined the role of telehealth, and usability and feasibility trends in supporting patients' caregivers. We systematically searched the literature in the following databases: Web of Science, Cochrane Library, PubMed, Scopus, CINAHL, MEDLINE, EMBASE, Google Scholar, and PsycINFO. Inclusion criteria were being written in English, published in peer-reviewed journals, describing a telehealth-implemented intervention, and focusing on caregivers of adult cancer patients at any stage of the disease. We selected studies published up to November 2017. We critically appraised included articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and graded the quality of evidence by outcome using the Centre for Evidence-Based Medicine framework. We included 24 studies in the final selection. In 21 of the 24 studies, the patient-caregiver dyad was analyzed, and the study population dealt with different types of cancer at different stages. Included studies considered the caregiver's condition from both an individual and a relational point of view. Along with psychosocial variables, some studies monitored engagement and user satisfaction regarding Web-based platforms or telehealth interventions. All studies reported significant improvements in some of the investigated areas, but they often showed small effect sizes. Two types of telehealth intervention formats were used: Web-based platforms and telephone calls. Some of the included studies referred to the same project, but on study samples with different cancer diagnoses or with new versions of previously developed interventions. Reported outcomes seem to suggest that we are in an exploratory phase. More detailed and targeted research hypotheses are still needed. Clarifying caregivers' needs related to telehealth tools and better defining outcome measures may yield more significant results.


Genetic and environmental determinants of osteoporosis.
Osteoporosis is a common, complex disease that is influenced by genetic and environmental factors. Although molecular genetic studies have identified several potential regions of linkage, underlying susceptibility gene(s) are largely unknown. Genetic susceptibility to osteoporosis may be both context dependent and developmentally regulated, and epigenetic mechanisms are the likely link between gene and environment. In this paper we will review the status of genetic research into osteoporosis, and present the evidence for gene-environment interaction in its pathogenesis. Finally, the current challenges and future directions of research will be briefly discussed.


Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer's Disease Patients.
Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer's disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD.


Juvenile hormone and insulin regulate trehalose homeostasis in the red flour beetle, Tribolium castaneum.
Insulin/IGF-1 signaling (IIS) has been well studied for its role in the control of life span extension and resistance to a variety of stresses. The Drosophila melanogaster insulin-like receptor (InR) mutant showed extended life span due to reduced juvenile hormone (JH) levels. However, little is known about the mechanism of cross talk between IIS and JH in regulation of life span extension and resistance to starvation. In the current study, we investigated the role of IIS and JH signaling in regulation of resistance to starvation. Reduction in JH biosynthesis, JH action, or insulin-like peptide 2 (ILP2) syntheses by RNA interference (RNAi)-aided knockdown in the expression of genes coding for juvenile hormone acid methyltransferase (JHAMT), methoprene-tolerant (Met), or ILP2 respectively decreased lipid and carbohydrate metabolism and extended the survival of starved beetles. Interestingly, the extension of life span could be restored by injection of bovine insulin into JHAMT RNAi beetles but not by application of JH III to ILP2 RNAi beetles. These data suggest that JH controls starvation resistance by regulating synthesis of ILP2. More importantly, JH regulates trehalose homeostasis, including trehalose transport and metabolism, and controls utilization of stored nutrients in starved adults.


Human IL-1 beta processing and secretion in recombinant baculovirus-infected Sf9 cells is blocked by the cowpox virus serpin crmA.
Biologically active, mature IL-1 beta (mIL-1 beta) is released from activated monocytes after proteolytic processing from an inactive precursor (pIL-1 beta). IL-1 beta converting enzyme (ICE), the first member of a newly discovered family of cysteine proteinases, is required for this processing event. The cleaved cytokine is released from monocytes by an unknown mechanism which does not employ a standard hydrophobic signal sequence. As in mammalian fibroblasts, insect Sf9 cells do not normally process or secrete human IL-1 beta. The expression of active ICE enables Sf9 cells to process 31-kDa pIL-1 beta correctly at Asp27 and Asp116, and to export 17.5-kDa mIL-1 beta. The recombinant heterodimeric human enzyme purified from Sf9 cells possesses a sp. act. of 2.9 +/- 0.5 x 10(6) U/mg and is indistinguishable from native ICE with regard to its subunit composition and catalytic properties. In this system, co-expression of the cowpox virus crmA gene, an extremely potent serpin inhibitor of ICE (Ki < 7 pM), inhibits ICE activation completely and blocks pIL-1 beta processing and mIL-1 beta secretion by approximately 95%. The results indicate that ICE, in addition to its processing function, facilitates the transport of IL-1 beta across the plasma membrane.


The promise and the potential consequences of the global transport of mycorrhizal fungal inoculum.
Advances in ecology during the past decade have led to a much more detailed understanding of the potential negative consequences of species' introductions. Moreover, recent studies of mycorrhizal symbionts have led to an increased knowledge of the potential utility of fungal inoculations in agricultural, horticultural and ecological management. The intentional movement of mycorrhizal fungal species is growing, but the concomitant potential for negative ecological consequences of invasions by mycorrhizal fungi is poorly understood. We assess the degree to which introductions of mycorrhizal fungi may lead to unintended negative, and potentially costly, consequences. Our purpose is to make recommendations regarding appropriate management guidelines and highlight top priority research needs. Given the difficulty in discerning invasive species problems associated with mycorrhizal inoculations, we recommend the following. First, careful assessment documenting the need for inoculation, and the likelihood of success, should be conducted prior to inoculation because inoculations are not universally beneficial. Second, invasive species problems are costly and often impossible to control by the time they are recognized. We recommend using local inoculum sources whenever possible. Third, non-sterile cultures of inoculum can result in the movement of saprobes and pathogens as well as mutualists. We recommend using material that has been produced through sterile culture when local inoculum is not available. Finally, life-history characteristics of inoculated fungi may provide general guidelines relative to the likelihood of establishment and spread. We recommend that, when using non-local fungi, managers choose fungal taxa that carry life-history traits that may minimize the likelihood of deleterious invasive species problems. Additional research is needed on the potential of mycorrhizal fungi to spread to non-target areas and cause ecological damage.


Neuromodulation of cerebral blood flow by spinal cord electrical stimulation: the role of the Italian school and state of art.
Hosobuchi first studied the effect of spinal cord stimulation (SCS) on cerebral blood flow (CBF) in human beings along with the demonstration that SCS can improve peripheral blood flow. Following these clinical and experimental observations Hosobuchi first used cervical SCS for the treatment of cerebral ischemia in man. Further experimental reports suggested so far that SCS 1) drastically prevents cerebral infarction progression along with a reduction in infarct volume in cats; 2) improves clinical symptoms of patients in persistent vegetative states; 3) suppress headache attacks in migraneous patients; 4) significantly reduces ischemic brain oedema in rats; 5) increase locoregional blood flow in high grade brain tumors. The authors found that SCS can produce either an increase of CBF or a reduction or no effect. In patients studied with both SPECT technique and transcranial Doppler (TCD) the sign of the induced variations, when present in both, as the same. Cervical stimulation produces more frequently an increase in CBF (61% of cervical stimulations). The authors' experimental studies confirm that SCS 1) interacts with CO2 with the mechanism of regulation of CBF in a competitive way and produce a reversible functional sympathectomy; 2) produces similar flowmetric changes in the brain as well as in the eyes; 3) can improve both clinical and haemodynamic ischemic stroke in humans; 4) prevents hemodynamic deterioration in the experimental combined ischemic and traumatic brain injury; 5) prevents experimental early vasospasm.


Role of Changing Procedural Characteristics Versus Changing Risk Profile in Age-Based Trends of Outcomes in Patients With Transfemoral Transcatheter Aortic Valve Replacement From 2012 to 2018: A Nationwide Analysis.
Background The trends in outcomes in patients who undergo transcatheter aortic valve replacement are well described in the literature. Some of these trends are driven by the decreasing risk profile of patients because of changing indications for transcatheter aortic valve replacement. We aimed to evaluate these trends in different age groups and quantify how much of these trends are driven by changes in procedural characteristics. Methods and Results Using the National Inpatient Sample from 2012 to 2018, we identified 204 230 adult patients who underwent transfemoral aortic valve replacement. The study's primary objective was to evaluate the changes in age-based trends in in-hospital mortality driven by changes in procedural characteristics over time. The secondary objectives were to evaluate similar trends in cardiac and noncardiac complications and resource use. Univariate and multivariate linear and logistic regression were used to obtain effect sizes. From 2012 to 2018, in-hospital mortality decreased from 1.8% to 0.79% in the age group 18 to 64 years, from 3.8% to 1.6% in the age group 65 to 80 years, and from 5.3% to 1.5% in the age group >80 years (P trend<0.01 for all age groups); these trends remained statistically significant on adjusted analysis except in patients aged 18 to 64 years. The other outcomes also showed variable trends over time. Length of stay, cost, and early discharge rates improved even after adjusting for comorbidities, which is likely attributable to improvement in procedural characteristics. Conclusions The changes in outcomes related to transcatheter aortic valve replacement are partly driven by changing patient risk profiles over time, but procedural characteristics have likely contributed to these trends in all age groups.


Association of Involutional Lower Eyelid Entropion with Reduced Upper Eyelid Position Relative to the Corneal Light Reflex: Quantification of Facial Asymmetry.
To investigate the association between upper eyelid position relative to the corneal light reflex (MRD1) and to delineate an association between eyelid height and involutional lower eyelid entropion. Retrospective study of patients presenting for entropion repair to an academic ophthalmic plastic surgery service. A total of 111 patients were included in the study; 95 had unilateral involutional lower eyelid entropion, and 16 had bilateral lower eyelid entropion. Patients with a history of previous eyelid surgery, trauma, upper eyelid entropion, or cicatricial changes were excluded from the study. Of the 95 patients with unilateral involutional lower eyelid entropion, 45 (47.4%) had a lesser MRD1 on the side ipsilateral to the involutional lower eyelid entropion. In this unilateral group, the mean MRD1 (± standard deviation) on the ipsilateral to the involutional lower eyelid entropion was 2.9 (±1.2) mm, while the mean MRD1 on the contralateral side was 3.3 (±1.0) mm. This difference was 0.4 mm and was statistically significant (p < 0.0001). Most patients with unilateral involutional entropion demonstrated a right-sided involutional lower eyelid entropion (56 of 95; 58.9%), although this finding was not statistically significant (p = 0.083). The frequency of true blepharoptosis (MRD1 ≤ 2.0 mm) was 24 of 95 (25.3%) in the unilateral involutional entropion group and was even higher in the bilateral involutional lower eyelid entropion group, with 7 of 16 (43.8%) patients exhibiting bilateral blepharoptosis. Patients presenting with involutional lower eyelid entropion tend to have a relatively reduced MRD1 on the ipsilateral (affected) side. When both lower eyelids are affected by involutional entropion, the reduced MRD1 tends to be more pronounced.


Accuracy of 68Ga-PSMA-11 PET/CT and multiparametric MRI for the detection of local tumor and lymph node metastases in early biochemical recurrence of prostate cancer.
Anatomical and functional imaging plays a decisive role for detection and staging, of prostate cancer both primarily and post-treatment. While multiparametric MRI offers anatomic imaging with excellent soft tissue contrast, hybrid imaging based on positron emission tomography in combination with computed tomography (PET/CT) contributes functional imaging capacities. Since 68Ga-PSMA-11 was expected to be more efficient than the prior Choline-based PET radiotracers, it was the aim of the study to evaluate the diagnostic performance of the 68Ga-PSMA-11 PET/CT and multiparametric MRI in patients with recurrent prostate cancer and low PSA levels. 32 out of a cohort of 128 prostate cancer patients with biochemical relapse were referred for 68Ga-PSMA-11 PET/CT, MRI and bone scintigraphy. According to the histopathologically or clinically defined reference standard all results were classified as true positive, false positive, true negative or false negative. Local recurrence was present in 11/32 patients, lymph node metastases - in 13/32 patients and, bone metastases - in 6/32 patients. Against the standard of reference, sensitivity, specificity and accuracy for local recurrence of PET/CT were 63.6 %; 73.7%; 77.8%, respectively. MRI reached 90.9%; 94.7%; 92.3%, respectively. For local lymph node metastases PET/CT - 83.3%; 80.0% and 90.6%, respectively. MRI - 41.7%; 94.4%; 72.0%, respectively. For evaluation of bone metastases in PET/CT - 83.3%; 92.0%; 71.0%, respectively. Bone scintigraphy - 50.0%; 84.0%; 77.4%, respectively. In conclusion, mpMRI offered the better diagnostic accuracy in the detection of local recurrence and while PSMA PET/CT was superior in the detection of distant and lymph node metastases.


Effects of disuse on growing and adult chick skeletal muscle.
The effects of long-term muscle inactivity, throughout post-hatching development, have been examined. Continuous immobilization of the chicken posterior latissimus dorsi (PLD) muscle from the first hour after hatching for varying periods up to 330 days, resulted in a significantly greater decrease in myofibre size (40-64% less than control) than occurred when adult muscles were immobilized for similar periods (20-40% less than control). The myofibre atrophy resulting from long-term immobilization of adult muscle is reversible, after removal of the plaster cast. In contrast, the myofibres immobilized immediately after hatching, for similar periods of time, were unable to recover one the casts were removed. On the basis of myofibre cross-sectional area, 2 populations of cells were seen in muscles immobilized during postnatal development: small myofibres of 0.5-200 micron 2 and larger myofibres of 500-800 micron 2. The distribution of fibre cross-sectional area within immobilized adult muscles was similar to controls, suggesting a uniform response (i.e. atrophy) by all of the myofibres within the muscle. Immobilization in both newly hatched and adult PLD muscles did not appear to alter the pattern of motor endplate distribution within the muscle. Small, multiple motor endplates were observed associated with immobilized and control myofibres near their terminal ends. This finding suggests that the embryonic pattern of myofibre innervation is not entirely lost from all the fibres during postnatal development.


Mesenteric amyloid deposition as the initial presentation of multiple myeloma.
Despite many recent progresses in diagnostic modalities, occasionally the initial manifestation of the diseases may be misleading. Therefore, to consider the uncommon presentations of prevalent diseases may be of help. Plasma-cell dyscrasia is one of the most well-known haematological malignancies. Clonal expansion of plasma cells results in diverse clinical findings, such as renal failure, lytic bone lesion, anaemia, hyperviscosity syndrome and so forth. However, this disease entity rarely presents with abdominal mass due to mesenteric amyloid deposition. Here we report a case of a 53-year-old Iranian woman who presented with a 4-month history of abdominal pain and fullness; she was finally found to suffer from small bowel mesenteric amyloidosis in the context of multiple myeloma.


Cross-family small GTPase ubiquitination by the intracellular pathogen Legionella pneumophila.
The intracellular bacterial pathogen Legionella pneumophila (L.p.) manipulates eukaryotic host ubiquitination machinery to form its replicative vacuole. While nearly 10% of L.p.'s arsenal of ~330 secreted effector proteins have been biochemically characterized as ubiquitin ligases or deubiquitinases, a comprehensive measure of temporally resolved changes in the endogenous host ubiquitinome during infection has not been undertaken. To elucidate how L.p hijacks ubiquitin signaling within the host cell, we undertook a proteome-wide analysis of changes in protein ubiquitination during infection. We discover that L.p. infection results in increased ubiquitination of host proteins regulating subcellular trafficking and membrane dynamics, most notably 63 of ~160 mammalian Ras superfamily small GTPases. We determine that these small GTPases predominantly undergo non-degradative monoubiquitination, and link ubiquitination to recruitment to the Legionella-containing vacuole membrane. Finally, we find that the bacterial effectors SidC/SdcA play a central, but likely indirect, role in cross-family small GTPase ubiquitination. This work highlights the extensive reconfiguration of host ubiquitin signaling by bacterial effectors during infection and establishes simultaneous ubiquitination of small GTPases across the Ras superfamily as a novel consequence of L.p. infection. This work positions L.p. as a tool to better understand how small GTPases can be regulated by ubiquitination in uninfected contexts.


Peptidylarginine deiminase type 4 and methyl-CpG binding domain 4 polymorphisms in Chinese patients with rheumatoid arthritis.
Peptidylarginine deiminase type 4 (PADI4) and methyl-CpG binding domain 4 (MBD4) are closely related with rheumatoid arthritis (RA). We hypothesized that PADI4 and MBD4 polymorphisms may contribute to RA susceptibility. We studied PADI4 rs2240340 G/A, PADI4 rs874881 C/G, MBD4 rs140693 G/A, and MBD4 rs2005618 T/C gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). When the PADI4 rs2240340 GG homozygote genotype was used as the reference group, the AA genotype was associated with a significantly increased risk of RA. In the recessive model, when PADI4 rs2240340 GG/GA genotypes were used as the reference group, the AA homozygote genotype was associated with a significant increased susceptibility to RA. PADI4 rs874881 C/G was in complete linkage disequilibrium with PADI4 rs2240340 G/A. MBD4 rs140693 G/A and MBD4 rs2005618 T/C polymorphisms were not associated with the risk of RA. In stratification analyses, a significantly increased risk for RA associated with the PADI4 rs2240340 AA genotype was evident among older patients and patients who were anticitrullinated protein antibody (ACPA)-positive compared with the PADI4 rs2240340 GG/GA genotype. These findings suggest that the functional single-nucleotide polymorphism PADI4 rs2240340 G/A variant allele is associated with RA development, especially among older patients and ACPA-positive patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. Validation by a larger study from a more diverse ethnic population is needed to confirm these findings.


CD14+CD16- monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK.
Monocytes as precursors of osteoclasts in rheumatoid arthritis (RA) are well demonstrated, while monocyte subsets in osteoclast formation are still controversial. Tyro3 tyrosine kinase (Tyro3TK) is a member of the receptor tyrosine kinase family involved in immune homeostasis, the role of which in osteoclast differentiation was reported recently. This study aimed to compare the osteoclastic capacity of CD14+CD16+ and CD14+CD16- monocytes in RA and determine the potential involvement of Tyro3TK in their osteoclastogenesis. Osteoclasts were induced from CD14+CD16+ and CD14+CD16- monocyte subsets isolated from healthy control (HC) and RA patients in vitro and evaluated by tartrate-resistant acid phosphatase (TRAP) staining. Then, the expression of Tyro3TK on CD14+CD16+ and CD14+CD16- monocyte subsets in the peripheral blood of RA, osteoarthritis (OA) patients, and HC were evaluated by flow cytometry and qPCR, and their correlation with RA patient clinical and immunological features was analyzed. The role of Tyro3TK in CD14+CD16- monocyte-mediated osteoclastogenesis was further investigated by osteoclast differentiation assay with Tyro3TK blockade. The results revealed that CD14+CD16- monocytes were the primary source of osteoclasts. Compared with HC and OA patients, the expression of Tyro3TK on CD14+CD16- monocytes in RA patients was significantly upregulated and positively correlated with the disease manifestations, such as IgM level, tender joint count, and the disease activity score. Moreover, anti-Tyro3TK antibody could inhibit Gas6-mediated osteoclast differentiation from CD14+CD16- monocytes in a dose-dependent manner. These findings indicate that elevated Tyro3TK on CD14+CD16- monocytes serves as a critical signal for osteoclast differentiation in RA.


High potassium seawater inhibits ascidian sperm chemotaxis, but does not affect the male gamete chemotaxis of a brown alga.
Male gamete chemotaxis towards the female gamete is a general strategy to facilitate the sexual reproduction in many marine eukaryotes. Biochemical studies of chemoattractants for male gametes of brown algae have advanced in the 1970s and 1980s, but the molecular mechanism of male gamete responses to the attractants remains elusive. In sea urchin, a K+ channel called the tetraKCNG channel plays a fundamental role in sperm chemotaxis and inhibition of K+ efflux through this channel by high K+ seawater blocks almost all cell responses to the chemoattractant. This signalling mechanism could be conserved in marine invertebrates as tetraKCNG channels are conserved in the marine invertebrates that exhibit sperm chemotaxis. We confirmed that high K+ seawater also inhibited sperm chemotaxis in ascidian, Ciona intestinalis (robusta), in this study. Conversely, the male gamete chemotaxis towards the female gamete of a brown alga, Mutimo cylindricus, was preserved even in high K+ seawater. This result indicates that none of the K+ channels is essential for male gamete chemotaxis in the brown alga, suggesting that the signalling mechanism for chemotaxis in this brown alga is quite different from that of marine invertebrates. Correlated to this result, we revealed that the channels previously proposed as homologues of tetraKCNG in brown algae have a distinct domain composition from that of the tetraKCNG. Namely, one of them possesses two repeats of the six transmembrane segments (diKCNG) instead of four. The structural analysis suggests that diKCNG is a cyclic nucleotide-modulated and/or voltage-gated K+ channel.


Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function.
Electroacupuncture is well known for its advantageous neuroanalgesic and therapeutic effects on myocardial ischemia-reperfusion injury. The purpose of the present research was to verify whether electroacupuncture can alleviate bupivacaine-induced myocardial injury. Specific pathogen-free Wistar rats were used to establish the bupivacaine-induced myocardial injury model. Western blot, PCR, transmission electron microscope and enzyme-linked immunosorbent (ELISA) methods were used to evaluate bupivacaine-induced structure injury and dysfunction of the mitochondria as well as the alleviating effects of lipid emulsion, acupoint injection, and electroacupuncture pre-treatment of the oxidase stress response. Bupivacaine caused structural damage, degradation, and swelling of mitochondria. Furthermore, it reduced adenosine triphosphate (ATP) synthesis and impaired energy metabolism in the mitochondria. Structural and functional impairment of the mitochondria was alleviated via lipid emulsion injection, acupoint injection, and electroacupuncture pre-treatment. Electroacupuncture pre-treatment of PC6 yielded a greater alleviating effect than others approaches. Following electroacupuncture pre-treatment of PC6 point, the number of mitochondria increased; apoptosis was reduced, enzymatic activity of cytochrome C oxidase (COX) and superoxide dismutase and expression of uncoupling protein 2, voltage-dependent anion channel 1, and Bcl 2 were upregulated and SLC25A6, MDA levels were downregulated. Additionally, our findings indicated that electroacupuncture pre-treatment of PC6 point exerted an effect on the mitochondria via the mitochondrial-transcription-factor-A/nuclear-respiratory-factor-1/proliferator-activated-receptor-gamma-coactivator-1 pathway. The present study revealed that electroacupuncture pre-treatment of PC6 could effectively alleviate bupivacaine-induced myocardial mitochondrial damage, thereby providing a theoretical basis for clinical studies and applications of this treatment method.


Genetic Variation of MT-ND Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation.
Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Over the last few decades, a growing number of evidence suggests mitochondrial involvement in neurodegeneration, namely modifications of mitochondrial DNA (mtDNA) contributing to energy impairment. To sequence the 7 mitochondrially encoded complex I (MT-ND) genes in 70 FTLD patients and investigate mitochondrial respiratory chain (MRC) complex I activity. A sample of 70 patients was studied (39 females and 31 males; age range: 38-82 years, mean ± SD: 63 ± 11 years) with a probable diagnosis of FTLD. Total DNA was extracted from peripheral blood, and sequencing analysis of 7 MT-NDn (1, 2, 3, 4L, 4, 5, 6) genes was performed. Variants identified were submitted to in silico study. Spectrophotometric evaluation of MRC activity in lymphocytes was performed, and results were compared with age-matched controls. A total of 358 (161 different) alterations were found in 92.9% of patients. According to in silico analysis of nonsynonymous variants, only 5 variations are possibly or probably damaging. Complex I activity is significantly decreased in patients. To our knowledge, this is the first report of the complete sequence of the MT-ND genes in FTLD patients and correlation with MRC activity. The high number of mtDNA variations identified and a significant decrease in complex I activity suggest a possible involvement of mtDNA alterations in FTLD. Although the majority of these alterations are not primarily pathogenic, an interaction with other mutations may occur, leading to the disease, worsening its expression or influencing age of onset.


Pathway of C6-NBD-Ceramide on the host cell infected with Toxoplasma gondii.
Fluorescence microscopy, with dyes analog of ceramide, and transmission electron microscopy, were used to analyze lipid traffic during interaction of Toxoplasma gondii with host cells. It is C6-NBD-Ceramide (C6-NBD-Cer), a fluorescent analog of ceramide, stained the Golgi complex where was metabolized into fluorescent sphingolipid and glucosylceramide, and translocated via the Golgi complex to the plasma membrane of living cells. In uninfected cells, C6-NBD-Cer initially concentrated at the perinuclear region, and after its fluorescent products were present in the cytoplasm and the plasma membrane. In infected cells, the probe initially is stained the Golgi complex. After 4 hours incubation with C6-NBD-Cer, the parasites within the parasitophorous vacuole began to be stained, and at 5 hours incubation, the parasites are completely fluorescent. The Golgi complex, as revealed by fluorescent probe and electron microscopy, maintained its perinuclear position throughout the evolution of intracellular parasitism. These results suggested that the intracellular parasite used the lipid pathway of the host cell.


Decision-Making about Healthcare Related Tests and Diagnostic Strategies: User Testing of GRADE Evidence Tables.
To develop guidance on what information to include and how to present it in tables summarizing the evidence from systematic reviews of test accuracy following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To design and refine the evidence tables, we used an iterative process based on the analysis of data from four rounds of discussions, feedback and user testing. During the final round, we conducted one-on-one user testing with target end users. We presented a number of alternative formats of evidence tables to participants and obtained information about users' understanding and preferences. More than 150 users participated in initial discussions and provided their formal and informal feedback. 20 users completed one-on-one user testing interviews. Almost all participants preferred summarizing the results of systematic reviews of test accuracy in tabular format rather than plain text. Users generally preferred less complex tables but found presenting sensitivity and specificity estimates only as too simplistic. Users found the presentation of test accuracy for several values of prevalence initially confusing but modifying table layout and adding sample clinical scenarios for each prevalence reduced this confusion. Providing information about clinical consequences of testing result was viewed as not feasible for authors of systematic reviews. We present the current formats for tables presenting test accuracy following the GRADE approach. These tables can be developed using GRADEpro guidelines development tool (www.guidelinedevelopment.org or www.gradepro.org) and are being further developed into electronic interactive tables that will suit the needs of different end users. The formatting of these tables, and how they influence result interpretation and decision-making will be further evaluated in a randomized trial.


Differences between migrasome, a 'new organelle', and exosome.
The migrasome is a new organelle discovered by Professor Yu Li in 2015. When cells migrate, the membranous organelles that appear at the end of the retraction fibres are migrasomes. With the migration of cells, the retraction fibres which connect migrasomes and cells finally break. The migrasomes detach from the cell and are released into the extracellular space or directly absorbed by the recipient cell. The cytoplasmic contents are first transported to the migrasome and then released from the cell through the migrasome. This release mechanism, which depends on cell migration, is named 'migracytosis'. The main components of the migrasome are extracellular vesicles after they leave the cell, which are easy to remind people of the current hot topic of exosomes. Exosomes are extracellular vesicles wrapped by the lipid bimolecular layer. With extensive research, exosomes have solved many disease problems. This review summarizes the differences between migrasomes and exosomes in size, composition, property and function, extraction method and regulation mechanism for generation and release. At the same time, it also prospects for the current hotspot of migrasomes, hoping to provide literature support for further research on the generation and release mechanism of migrasomes and their clinical application in the future.


Effect of acute alterations in small bowel transit time upon the biliary excretion rate of bile acids.
The rate of biliary bile acid excretion is a product of bile acid pool size and enterohepatic cycling frequency. Cycling frequency, in turn, is determined by the time necessary for bile acid to travel from the ampulla of Vater to its small bowel absorptive site, from its absorptive site to the liver, and from the liver to the duodenum. In 10 subjects receiving constant intraduodenal infusion of an isocaloric formula containing the nonabsorbable markers polyethylene glycol and beta-sitosterol, the authors altered small intestinal transit time and measured the effect upon biliary bile acid excretion rate. Sorbitol (15% formula) shortened transit time by 38% and increased hourly bile acid excretion rate by 31%. Atropine (0.04 mg i.m. q 2 hr) increased transit time by 38% and decreased hourly bile acid excretion rate by 38%. Biliary excretion rates of cholesterol and of bilirubin, substances excreted in bile but not subject to enterohepatic circulation, did not change with changes in transit time. This suggests that sorbitol and atropine were not acting upon the biliary limb of the enterohepatic circulation but rather on the intestinal limb. The authors conclude that small bowel transit time is a major determinant of enterohepatic cycling frequency.


Involvement of relatives in chronic non-malignant pain rehabilitation at multidisciplinary pain centres: part one - the patient perspective.
Chronic non-malignant pain (CNP) is a significant healthcare problem with considerable consequences for patients, relatives and society. CNP is a lifelong condition that calls for acceptance and self-management. Existing research indicates that the involvement of relatives improves patients' and relatives' management of CNP, but the area is, at present, scarcely described. Research is required to obtain knowledge about the patients' experiences, needs and preferences concerning the involvement of their relatives within the frame of CNP rehabilitation, which is the aim of this study. The study applied a qualitative phenomenological-hermeneutic design conducting individual interviews with 10 patients with CNP from three selected Multidisciplinary Pain Centres (MPC). The analysis was guided by Paul Ricoeur's philosophy of interpretation of the text. The findings illuminated the patients' perspectives on the involvement of relatives within three key themes, each having two or three sub-themes. The analysis revealed that patients in CNP rehabilitation had various interpretations of the substance of involving relatives, reflecting their sparse experiences. It seemed arbitrary, who during the rehabilitation actually experienced the involvement of their relatives, leaving the impression of an area short of structure. This shortage was troublesome, due to a heartrending impact of CNP. Patients' reduced functional level, combined with their surroundings difficulties in grasping the magnitude of CNP led to a loss of relationships and a risk of social isolation. Patients' close relationships became essential but were under pressure as well. Patients living with a spouse/cohabitant experienced that the relationship was affected by a disrupted balance and pain-related emotional outbursts. The patients experienced a profound need for being understood, but the text also revealed a need for mutual understanding to acknowledge the relatives' strain as well. Particular patients with children living at home experienced to be under great strain, complicated by a deep concern for long-term consequences for their children growing up influenced by parental CNP. Experienced involvement of relatives, even to a minor extend was perceived as beneficial for the patients, who experienced increased understanding and support from the relatives. However, due to the lack of a structured service, the patients' access to the involvement of relatives became dependent on their ability to define their need and pick it out. Thus the patients also expressed a general preference for mandatory and structured involvement, yet tailored to the specific patient. The study showed an overwhelming need for the involvement of relatives among patients with CNP, indicating that increased attention and investigation of relevant interventions are required. Despite differences between the MPC, our primary impression was that the involvement of relatives reached a minimal level of what was expected, which might entail desertion of patients scarce of resources. Individualised adjusted involvement of relatives is assumed to improve patient's management of CNP in everyday life. A family systems nursing (FSN) approach is a relevant proposal for intervention, useful in other illness areas. Still, research needs to shed light on the appropriateness of FSN when involving relatives in the rehabilitation of CNP.


Tricarboxylic acid cycle enzymes and morphogenesis in Blastocladiella emersonii.
During exponential growth, ordinary colorless (OC) plants of Blastocladiella emersonii consumed little glucose and produced no lactic acid. Similarly, resistant sporangial (RS) plants did not utilize glucose or produce lactic acid during the first 24 hr of exponential growth. During the next 24 hr of RS development, glucose was consumed with the concomitant production of lactic acid which was then reutilized. Lactic acid gradually accumulated again at maturity. Enzyme studies on cell-free extracts indicated the presence of all tricarboxylic cycle enzymes except alpha-ketoglutarate dehydrogenase at all stages of development of both RS and OC plants. Included among the enzymes detected were an adenosine monophosphate-stimulated, nicotinamide adenine dinucleotide-isocitric dehydrogenase, and citrate-condensing enzyme. When measured on a per plant basis, tricarboxylic cycle enzyme levels increased during the exponential growth of both kinds of plants. Only after the bicarbonate ceased to have effect on RS plant morphogenesis was there a decrease in the levels of the tricarboxylic cycle enzymes when measured on a per plant basis. Specific activity measurements indicated some differences in the differential rates of synthesis among the enzymes studied previous to 36 hr. Preliminary studies utilizing short periods of (14)C-bicarbonate fixation in young RS plants indicated that during the first 4 min most of the label was located in aspartic acid. These results are discussed in terms of previous results and particularly Cantino's hypothesis concerning the relationship between bicarbonate induction and tricarboxylic-cycle enzymes in the morphogenesis of B. emersonii.


A systematic review and meta-analysis of clinical trials investigating the effects of flaxseed supplementation on plasma C-reactive protein concentrations.
Many experimental and clinical trials have suggested that flaxseed might be a potent antihypertensive, but the evidence concerning the effects of flaxseed supplements on plasma C-reactive protein (CRP) concentrations has not been fully conclusive. We assessed the impact of the effects of flaxseed supplementation on plasma CRP concentrations through a systematic review of literature and meta-analysis of available randomised controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL, and PUBMED databases up to 1st February 2016 to identify RCTs investigating the effect of flaxseed supplements on plasma CRP concentrations. Meta-analysis was performed using a random-effects model, and effect size was expressed as weighed mean difference (WMD) and 95% confidence interval (CI). Meta-analysis of 17 selected RCTs with 1256 individuals did not suggest a significant change in plasma CRP concentrations following supplementation with flaxseed-containing products (WMD: -0.25 mg/l, 95% CI: -0.53, 0.02, p = 0.074). The effect size was robust in the leave-one-out sensitivity analysis. Subgroup analysis did not suggest any significant difference in terms of changing plasma CRP concentrations among different types of flaxseed supplements used in the included studies, i.e. flaxseed oil (WMD: -0.67 mg/l, 95% CI: -2.00, 0.65, p = 0.320), lignan extract (WMD: -0.32 mg/l, 95% CI: -0.71, 0.06, p = 0.103) and ground powder (WMD: -0.18 mg/l, 95% CI: -0.42, 0.06, p = 0.142). The meta-analysis of RCTs did not show a significant change in plasma CRP concentrations following supplementation with various flaxseed products. Large, well-designed studies should be still performed to validate the current results.


The Von Restorff effect in the Brazilian version of the Rey Auditory Verbal Learning Test in an elderly population.
The Von Restorff (isolation) effect refers to a stimulus that is more likely to be remembered amongst other stimuli in memory tasks. It has been demonstrated with different age ranges and methodologies. To investigate: a) the presence of the isolation effect in elders tested with the new Brazilian Portuguese version of the Rey Auditory Verbal Learning Task (RAVLT) in which a word with potential emotional weight (mother) was introduced; b) whether isolation effects persist in memory disorders of different degrees of severity (Mild Cognitive Impairment [MCI]; Alzheimer's Dementia [AD]). The RAVLT was administered to 287 consecutive volunteers. Individuals underwent medical and neuropsychological evaluation and were further sub-grouped into normal controls (n=114), MCI (n=87) and AD (n=86) patients. One-way analysis of variance (ANOVA) and Chi-squared tests were performed. Post-hoc Tukey analysis was conducted to assess significance of group differences. There were significant group effects on the learning curve. A W-shape - instead of the classical U-shape - was found for the serial position curve in all groups. The new Brazilian version of the RAVLT exhibited the Von Restorff effect, where this phenomenon was evident not only in older adults but also patients with MCI and AD, providing further psychometric measures for inter-group analyses.


[The hygiene hypothesis: a fruitful concept in immunological research].
There is no longer any discussion about the first part of the hygiene hypothesis: insufficient stimulation of the developing immune system in young children leads to a disordered immune system that does not know when to react and when not to react to external or internal stimuli. The second part of the hypothesis states that this disordered immune response is responsible for the worldwide increase in allergies during the past 30 years. Randomised studies on this subject are impossible. It is clear, however, that micro-organisms can contribute to the development of a vigorous immune system and thus decrease the risk of allergy. The hygiene hypothesis is very much alive in immunological research.


The effect of STM parameters on tip-enhanced Raman spectra.
In this work, we evaluate the dependence of tip-enhanced Raman (TER) spectra of a monolayer of thiophenol at a Au(111) electrode on the scanning tunneling microscope's tunneling current set-point and bias voltage parameters. We find an increase of the TER intensity upon set-point increase or bias decrease as expected from a gap-distance reduction. The relations obtained follow a theoretical model considering a simple gap-distance change when tuning the mentioned parameters. We find that the value of the bias voltage affects the TER intensity to a larger extent than the current set-point. Therefore it is advisable to work in a low-bias regime when aiming for ultrasensitive TER measurements.


The wave form of luminescence emitted by noctiluca.
The wave shape, intensity, and time course of the flash were examined with the aid of electronic operations in order to characterize the luminescence response and examine the in vivo dynamics of the light reaction. The most prominent single component of the flash shape is its exponential decay, beginning several milliseconds after the intensity maximum, with a mean rate constant at 23 degrees C of -0.088 msec(-1). Earlier components of the flash curve are more complex, exhibiting no pure exponentials with time. As predicted from previous observations, the time course of the flash triggered by a propagated action potential, and therefore influenced by the conduction time of the triggering potential, is measurably slower than that of the synchronously triggered flash. The time course of emission from individual specimens is otherwise quite stable, undergoing only limited slowing with short-interval fatigue or specimen deterioration in spite of marked changes in the amplitude of the wave form. Relative stability of amplitude is obtained when flashes are elicited at regular intervals greater than 10 sec. On the basis of an analogue computer simulation (Appendix) the dynamics of the luminescence wave shape were found to be compatible with a short sequence of first order processes acting on an initial brief transient.


Second messengers involved in the control of renin secretion in cultured human nephroblastoma cells.
We aimed to study the intracellular signaling mechanisms involved in the stimulation and suppression of renin secretion from human nephroblastoma cells. Isoproterenol and forskolin increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) concentration and stimulated renin secretion as did the addition of dibutyryl-cAMP. Atrial natriuretic peptide (ANP) suppressed basal renin secretion and increased the concentration of extracellular guanosine 3',5'-cyclic monophosphate (cGMP). When ANP was added in the presence of isoproterenol or forskolin, the increase in cGMP was reduced. ANP attenuated the cAMP response to isoproterenol but not forskolin. Nephroblastoma cell membranes contained the guanosine-binding proteins Gs and Gi2, and the isoforms were similar to those in vascular smooth muscle. A functional role for Gi was indicated because the ANP-induced suppression of basal renin secretion was blocked by pertussis toxin. We conclude that cAMP stimulates and cGMP suppresses basal renin secretion, but neither fully accounts for the suppression of stimulated renin secretion by ANP.


Reference-wave solutions for the high-frequency fields in inhomogeneous-background random media.
Ray theory plays an important role in determining the propagation properties of high-frequency fields and their statistical measures in complicated random environments. For computations of the statistical measures it is therefore desirable to have a solution for the high-frequency field propagating along an isolated ray trajectory. A new reference wave is applied to obtain an analytic solution of the parabolic wave equation that describes propagation along the ray trajectory of the deterministic-background medium. The methodology is based on defining a paired-field measure as a product of an unknown field propagating in a disturbed medium and the complex-conjugate component propagating in a medium without random fluctuations. When a solution of the equation for the paired-field measure is obtained, the solution of the deterministic component can be extracted from the paired solution to determine the solution of the unknown field in an explicit form.


A single exposure to the American flag shifts support toward Republicanism up to 8 months later.
There is scant evidence that incidental cues in the environment significantly alter people's political judgments and behavior in a durable way. We report that a brief exposure to the American flag led to a shift toward Republican beliefs, attitudes, and voting behavior among both Republican and Democratic participants, despite their overwhelming belief that exposure to the flag would not influence their behavior. In Experiment 1, which was conducted online during the 2008 U.S. presidential election, a single exposure to an American flag resulted in a significant increase in participants' Republican voting intentions, voting behavior, political beliefs, and implicit and explicit attitudes, with some effects lasting 8 months after the exposure to the prime. In Experiment 2, we replicated the findings more than a year into the current Democratic presidential term. These results constitute the first evidence that nonconscious priming effects from exposure to a national flag can bias the citizenry toward one political party and can have considerable durability.


Aerobic swimming performance of juvenile largemouth bronze gudgeon (Coreius guichenoti) in the Yangtze River.
Largemouth bronze gudgeon (Coreius guichenoti), a fish species once abundant in the Yangtze River, has been rapidly declining in recent years. One important factor, among many, is the interruption of the free-flowing rivers by dams. To obtain data that can be applied to the design of an effective fishway for C. guichenoti and other species in the fish community, a laboratory study of juvenile C. guichenoti's swimming ability and energetics was conducted in a flume-type respirometer equipped with a high-speed video camera system to record swimming behavior. The critical swimming speed (Ucrit ), standard metabolic rate (SMR), and maximum metabolic rate (MO2,max ) were determined during steady swimming at four water temperatures (10, 15, 20, and 25°C). A power function accurately describes the relationship between oxygen consumption rate (MO2 ) and swimming speed (U) at the four temperatures. The Ucrit , SMR, MO2,max , and metabolic scope increased with increasing temperature. The relationship between cost of transport (COT) and U was characteristically inverse bell-shaped, with minimum COT at Uopt = 4.5-5.0 body lengths per second (bl sec(-1)). This investigation provides data on the swimming ability of C. guichenoti that will add to the basic science required for fishway design.


Influence of illumination-collection geometry on fluorescence spectroscopy in multilayer tissue.
Device-tissue interface geometry influences both the intensity of detected fluorescence and the extent of tissue sampled. Previous modelling studies have often investigated fluorescent light propagation using generalised tissue and illumination-collection geometries. However, the implementation of approaches that incorporate a greater degree of realism may provide more accurate estimates of light propagation. In this study, Monte Carlo modelling was performed to predict how illumination-collection parameters affect signal detection in multilayer tissue. Using the geometry and optical properties of normal and atherosclerotic aortas, results for realistic probe designs and a semi-infinite source-detection scheme were generated and compared. As illumination-collection parameters, including single-fibre probe diameter and fibre separation distance in multifibre probes, were varied, the signal origin deviated significantly from that predicted using the semi-infinite geometry, The semi-infinite case under-predicted the fraction of fluorescence originating from the superficial layer by up to 23% for a 0.2mm diameter single-fibre probe and over-predicted by 10% for a multifibre probe. These results demonstrate the importance of specifying realistic illumination-collection parameters in theoretical studies and indicate that targeting of specific tissue regions may be achievable through customisation of the illumination-collection interface. The device- and tissue-specific approach presented has the potential to facilitate the optimisation of minimally invasive optical systems for a wide variety of applications.


NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis.
Interferons (IFNs) are cytokines with well-described immunomodulatory and antiviral properties, but less is known about the mechanisms by which they promote cell survival or cell death. Here, we show that IFN-γ induces RIP1 kinase-dependent necroptosis in mammalian cells deficient in NF-κB signaling. Induction of necroptosis by IFN-γ was found to depend on Jak1 and partially on STAT1. We also demonstrate that IFN-γ activates IκB kinase β (IKKβ)-dependent NF-κB to regulate a transcriptional program that protects cells from necroptosis. IFN-γ induced progressive accumulation of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential in cells lacking the NF-κB subunit RelA. Whole-genome microarray analyses identified sod2, encoding the antioxidant enzyme manganese superoxide dismutase (MnSOD), as a RelA target and potential antinecroptotic gene. Overexpression of MnSOD inhibited IFN-γ-mediated ROS accumulation and partially rescued RelA-deficient cells from necroptosis, while RNA interference (RNAi)-mediated silencing of sod2 expression increased susceptibility to IFN-γ-induced cell death. Together, these studies demonstrate that NF-κB protects cells from IFN-γ-mediated necroptosis by transcriptionally activating a survival response that quenches ROS to preserve mitochondrial integrity.


Lateral Thoracolumbar Listhesis as an Independent Predictor of Disability in Adult Scoliosis Patients: Multivariable Assessment Before and After Surgical Realignment.
Lateral (ie, coronal) vertebral listhesis may contribute to disability in adult scoliosis patients. To assess for a correlation between lateral listhesis and disability among patients with adult scoliosis. This was a retrospective multi-center analysis of prospectively collected data. Patients eligible for a minimum of 2-yr follow-up and with coronal plane deformity (defined as maximum Cobb angle ≥20º) were included (n = 724). Outcome measures were Oswestry Disability Index (ODI) and leg pain numeric scale rating. Lateral thoracolumbar listhesis was measured as the maximum vertebral listhesis as a percent of the superior endplate across T1-L5 levels. Linear and logistic regression was utilized, as appropriate. Multivariable analyses adjusted for demographics, comorbidities, surgical invasiveness, maximum Cobb angle, and T1-PA. Minimally clinically important difference (MCID) in ODI was defined as 12.8. In total, 724 adult patients were assessed. The mean baseline maximum lateral thoracolumbar listhesis was 18.3% (standard deviation 9.7%). The optimal statistical grouping for lateral listhesis was empirically determined to be none/mild (<6.7%), moderate (6.7-15.4%), and severe (≥15.4%). In multivariable analysis, listhesis of moderate and severe vs none/mild was associated with worse baseline ODI (none/mild = 33.7; moderate = 41.6; severe = 43.9; P < .001 for both comparisons) and leg pain NSR (none/mild = 2.9, moderate = 4.0, severe = 5.1, P < .05). Resolution of severe lateral listhesis to none/mild was independently associated with increased likelihood of reaching MCID in ODI at 2 yr postoperatively (odds ratio 2.1 95% confidence interval 1.2-3.7, P = .0097). Lateral thoracolumbar listhesis is associated with worse baseline disability among adult scoliosis patients. Resolution of severe lateral listhesis following deformity correction was independently associated with increased likelihood of reaching MCID in ODI at 2-yr follow-up.


Health information technology in ambulatory care in a developing country.
Physicians need to apply new technologies in ambulatory care. At present, with regard to the extended use of information technology in other departments in Iran it has yet to be considerably developed by physicians and clinical technicians in the health department. To determine the rate of use of health information technology in the clinics of specialist- and subspecialist physicians in Semnan city, Iran. This was a 2016 cross-sectional study conducted in physicians' offices of Semnan city in Iran. All physicians' offices in Semnan (130) were studied in this research. A researcher made and Likert-type questionnaire was designed, and consisted of two sections: the first section included demographic items and the second section consisted of four subscales (telemedicine, patient's safety, electronic patient record, and electronic communications). In order to determine the validity, the primary questionnaire was reviewed by one medical informatics- and two health information management experts from Semnan University of Medical Sciences. Utilizing the experts' suggestions, the questionnaire was rewritten and became more focused. Then the questionnaire was piloted on forty participants, randomly selected from different physicians' offices. Participants in the pilot study were excluded from the study. Cronbach's alpha was used to calculate the reliability of the instruments. Finally, SPSS version 16 was used to conduct descriptive and inferential statistics. The minimum mean related to the physicians' use of E-mail services for the purpose of communicating with the patients, the physicians' use of computer-aided diagnostics to diagnose the patients' illnesses, and the level of the physicians' access to the electronic medical record of patients in the other treatment centers were 2.01, 3.58, and 1.43 respectively. The maximum mean score was related to the physicians' use of social networks to communicate with other physicians (3.64). The study showed that the physicians used less computerized systems in their clinic for the purpose of managing their patients' safety and there was a significant difference between the mean of the scores (p<0.001). The results showed that the physicians used some aspects of health information technology for the reduction of medical risks and increase of the patient's safety, by collecting the medical data of patients and the rapid and apropos recovering of them for adaptation of clinical decisions.


Behavioral cardiology --has its time finally arrived?
Traditional cardiology has taken a mechanistic approach to heart disease. But the new discipline of behavioral cardiology takes a broader view, concluding that heart disease is not inevitable, but develops largely from unhealthy lifestyles, such as smoking, overeating and physical inactivity, and from psychosocial stress. Physical inactivity and excessive caloric intake are also responsible for the epidemic of obesity, which is associated with a dramatic increase in the prevalence of diabetes. This increase in the incidence of diabetes may, in turn, reverse the recent decline of cardiovascular deaths in the US. A variety of psychosocial stressors have been implicated in the development of cardiovascular disease. These include occupational stress, anxiety, social isolation, hostility, anger, and type A behavior. There is clearly some overlap between these stressors, all of which may affect the heart adversely. Both the lifestyle and psychosocial factors can be altered by behavioral treatment, in which the patient and the practitioner work together. Unfortunately, various barriers can impair the successful implementation of behavioral treatment. These barriers include poor compliance by the patient, lack of skill in providing effective interventions by the health care provider, and lack of incentives within the health care system, particularly reimbursement.


Potent bombesin antagonists with C-terminal Leu-psi(CH2-N)-Tac-NH2 or its derivatives.
Various pseudononapeptide bombesin (BN)-(6-14) antagonists with a reduced peptide bond (CH2-NH) between positions 13 and 14 can suppress the mitogenic activity of BN or gastrin-releasing peptide in 3T3 fibroblast cells and small cell lung carcinoma. In the search for more potent BN antagonists, 10 modified nonapeptide BN antagonists containing N-terminal D-Phe, D-Cpa, and D- or L-Tpi and C-terminal Leu-psi(CH2-N)-Tac-NH2, Leu-psi(CH2-N)-MeTac-NH2, or Leu-psi(CH2-N)-Me2Tac-NH2 have been synthesized by incubating [13 psi 14,CH2-NH,Cys14]BN-(6-14) or [13 psi 14-CH2-NH,Pen14]BN-(6-14) with formaldehyde or acetaldehyde (Cpa = 4-chlorophenylalanine, Tac = thiazolidine-4-carboxylic acid, Tpi = 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-3-carboxylic acid, and Pen = penicillamine). The biological activities of these compounds were then evaluated. [D-Phe6,13 psi 14,CH2-N,Tac14]BN-(6-14) (RC-3950-II) and [D-Phe6,13 psi 14,CH2-N,Me2Tac14]BN-(6-14) (RC-3985-II) exhibited greater potency in inhibition of 125I-labeled [Tyr4]BN binding to Swiss 3T3 cells than their parent compounds [D-Phe6,13 psi 14,CH2-NH,Cys14]BN-(6-14) (RC-3950-I) and [D-Phe6,13 psi 14,CH2-NH,Pen14]BN-(6-14) (RC-3985-I). The order of binding affinities of these compounds was as follows: [13 psi 14,CH2-N,Tac14]BN-(6-14) > [13 psi 14,CH2-N,Me2Tac14]BN-(6-14) > [13 psi 14,CH2-N,MeTac14]BN-(6-14). In most cases, the analogs with C-terminal Leu-psi(CH2-N)-Tac-NH2 were also more potent growth inhibitors of 3T3 cells than compounds containing C-terminal Leu-psi(CH2-N)-Me2Tac-NH2 or Leu-psi(CH2-N)-MeTac-NH2. The best BN antagonists of this series, RC-3950-II and [D-Cpa6,13 psi 14,CH2-N,Tac14]BN- (6-14) (RC-3925-II), inhibited gastrin-releasing peptide-stimulated growth of Swiss 3T3 cells with IC50 values of 1 nM and 6 nM, respectively. Since antagonists of this class inhibit growth of various tumors in animal cancer models, some of them may have clinical applications.


Purification and characterization of a thermostable xylanase from Bacillus stearothermophilus T-6.
Bacillus stearothermophilus T-6 produces an extracellular xylanase that was shown to optimally bleach pulp at pH 9 and 65 degrees C. The enzyme was purified and concentrated in a single adsorption step onto a cation exchanger and is made of a single polypeptide with an apparent M(r) of 43,000 (determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Xylanase T-6 is an endoxylanase that completely degrades xylan to xylose and xylobiose. The pIs of the purified protein were 9 and 7 under native and denaturing conditions, respectively. The optimum activity was at pH 6.5; however, 60% of the activity was still retained at pH 10. At 65 degrees C and pH 7, the enzyme was stable for more than 10 h; at 65 degrees C and pH 9, the half-life of the enzyme was approximately 6 h. Kinetic experiments at 55 degrees C gave Vmax and Km values of 288 U/mg and 1.63 mg/ml, respectively. The enzyme had no apparent requirement for cofactors, and its activity was strongly inhibited by Zn2+, Cd2+, and Hg2+. Xylan completely protected the protein from inactivation by N-bromosuccinimide. The N-terminal sequence of the first 45 amino acids of the enzyme showed high homology with the N-terminal region of xylanase A from the alkalophilic Bacillus sp. strain C-125.


Response Center Services: An Exploratory Study.
The population aging has facilitated a growing number of welfare technologies and smart home solutions. These technologies enable clinical staff and health care professionals to provide health services in an intelligent way with the trend of patient-centric digital health platforms. As one of the health services, response center service is facing new challenges when connected with welfare technologies, such as false alarms, security threats, privacy leakage, etc. This paper introduces the mechanism of the response center and the role it plays in healthcare. We conduct an exploratory study to find out the benefits and challenges of the response center service from the results of a structured interview. Based on the findings, we identify the required services to improve the intelligent response center mechanism.


Eurasian house mouse (Mus musculus L.) differentiation at microsatellite loci identifies the Iranian plateau as a phylogeographic hotspot.
The phylogeography of the house mouse (Mus musculus L.), an emblematic species for genetic and biomedical studies, is only partly understood, essentially because of a sampling bias towards its most peripheral populations in Europe, Asia and the Americas. Moreover, the present-day phylogeographic hypotheses stem mostly from the study of mitochondrial lineages. In this article, we complement the mtDNA studies with a comprehensive survey of nuclear markers (19 microsatellite loci) typed in 963 individuals from 47 population samples, with an emphasis on the putative Middle-Eastern centre of dispersal of the species. Based on correspondence analysis, distance and allele-sharing trees, we find a good coherence between geographical origin and genetic make-up of the populations. We thus confirm the clear distinction of the three best described peripheral subspecies, M. m. musculus, M. m. domesticus and M. m. castaneus. A large diversity was found in the Iranian populations, which have had an unclear taxonomic status to date. In addition to samples with clear affiliation to M. m. musculus and M. m. domesticus, we find two genetic groups in Central and South East Iran, which are as distinct from each other as they are from the south-east Asian M. m. castaneus. These groups were previously also found to harbor distinct mitochondrial haplotypes. We propose that the Iranian plateau is home to two more taxonomic units displaying complex primary and secondary relationships with their long recognized neighbours. This central region emerges as the area with the highest known diversity of mouse lineages within a restricted geographical area, designating it as the focal place to study the mechanisms of speciation and diversification of this species.


ASSESSING TIME-VARYING CAUSAL EFFECT MODERATION IN THE PRESENCE OF CLUSTER-LEVEL TREATMENT EFFECT HETEROGENEITY AND INTERFERENCE.
The micro-randomized trial (MRT) is a sequential randomized experimental design to empirically evaluate the effectiveness of mobile health (mHealth) intervention components that may be delivered at hundreds or thousands of decision points. MRTs have motivated a new class of causal estimands, termed "causal excursion effects", for which semiparametric inference can be conducted via a weighted, centered least squares criterion (Boruvka et al., 2018). Existing methods assume between-subject independence and non-interference. Deviations from these assumptions often occur. In this paper, causal excursion effects are revisited under potential cluster-level treatment effect heterogeneity and interference, where the treatment effect of interest may depend on cluster-level moderators. Utility of the proposed methods is shown by analyzing data from a multi-institution cohort of first year medical residents in the United States.


Induced autophagy reduces virus output in dengue infected monocytic cells.
While several studies have shown a role for autophagy in the replication of dengue virus (DENV), these studies have been performed in directly infected cells. However, in severe cases of DENV infection the critical cell in the disease is believed to be monocytes which are poorly infected directly, but are highly susceptible to antibody enhanced infection. This study sought to determine the involvement of autophagy in the DENV infection of monocytic cells, using U937 cells as a model system. While the induction of autophagy was seen in response to DENV-2 infection, biochemical induction of autophagy resulted in a significant decrease in virus output. Down regulation of autophagy resulted in only a very slight increase in intracellular virus levels. In monocytic cells autophagy is not a significant part of the DENV replication mechanism, and there are distinct cell type specific differences in the DENV-autophagy interaction.


An R124C mutation in TGFBI caused lattice corneal dystrophy type I with a variable phenotype in three Chinese families.
A genetic and clinical study of three unrelated Chinese pedigrees with a variable phenotype of lattice corneal dystrophy type I (LCD I). The eyes of the patients were examined by slit lamp microscopy, and other clinical records were also collected. Genomic DNA was extracted from peripheral leukocytes of the affected patients and their family members. Exons of the transforming growth factor beta induced TGFBI gene were amplified by polymerase chain reaction and directly sequenced to verify the mutation. Fifty healthy volunteers were analyzed as normal controls. Variable atypical clinical features of LCD I were found by slit lamp microscopy in these three Chinese pedigrees. A heterozygous single base-pair transition from C to T (C417T), leading to amino acid substitution (R124C) in the encoded TGFBI protein, was detected in all of the affected patients. No mutation was found in unaffected family members and 50 normal controls. Clinical features of Chinese patients with the same R124C mutation are quite variable even within the same family. Molecular genetic analysis of TGFBI can offer a rapid, accurate diagnosis of patients with atypical corneal dystrophies.


Clinical evaluation of the Mycobacteria Growth Indicator Tube (MGIT) compared with radiometric (Bactec) and solid media for isolation of Mycobacterium species.
The aim of this study was to evaluate the clinical use of a new culture system for the isolation of mycobacteria. Routine clinical specimens were cultured in the Mycobacteria Growth Indicator Tube, the radiometric Bactec 460 TB system and on Lowenstein Jensen (LJ) medium to compare recovery rates and times for detection of mycobacteria and contamination rates. MGIT was tested for its ability to support the growth of a wide range of mycobacterial species. Acid-fast bacilli (AFB) were detected on direct smears of 76 of 603 clinical specimens and mycobacteria were isolated by at least one method from 109 specimens; 93% of these were detected in the MGIT, 95% in the Bactec 460 TB system and 87% on LJ medium. The MGIT, Bactec and LJ media detected 92%, 97% and 95%, respectively, of 61 M. tuberculosis isolates and 94%, 94% and 77% of the 48 isolates belonging to the M. avium complex (MAC). The mean detection times in MGIT, Bactec and LJ media for M. tuberculosis were 22, 14 and 27 days respectively, and for MAC were 14, 12, and 29 days, respectively. Growth of M. tuberculosis was detected in Bactec, within 4 weeks, in 93% of the 61 culture-positive specimens, compared with only 61% in MGIT and 66% on LJ. The number of MAC detected within 4 weeks was similar in Bactec and MGIT, but less in LJ medium. Differences in sensitivity and time to detection of growth between media were greater for specimens in which AFB were not detected on direct smear than those on which AFB were seen. Contamination rates were similar in the three systems (3-4%). MGIT supported the growth of all 28 Mycobacterium spp. inoculated. MGIT has significant safety advantages and is less labour intensive than other methods, but the time to detection of M. tuberculosis, especially in smear-negative specimens, was longer in MGIT than in Bactec.


Comparison between Online and Offline Price of Tobacco Products Using Novel Datasets.
Price of tobacco products has traditionally been relevant both for the industry, to respond to policy changes, and for governments, as an effective tobacco control measure. However, monitoring prices across a wide range of brands and brand variants requires access to expensive commercial sales databases. This study aims to investigate the comparability of average tobacco prices from two commercial sources and an in-house monitoring database which provides daily data in real time at minimal cost. We used descriptive and regression analysis to compare the monthly average numbers of brands, brand variants, products and prices of cigarettes and hand-rolling tobacco using commercial data from Nielsen Scantrack and Kantar Worldpanel, and an online price database (OPD) created in Nottingham, for the period from May 2013 to February 2017. There were marked differences in the number of products tracked in the three data sources. Nielsen was the most comprehensive and Kantar Worldpanel the least. Though average prices were very similar between the three datasets, Nottingham OPD prices were the highest and Kantar Worldpanel the lowest. However, regression analysis demonstrated that after adjustment for differences in product range, price differences between the datasets were very small. After allowing for differences in product range these data sources offer representative prices for application in price research. Online price tracking offers an inexpensive and near real-time alternative to the commercial datasets.


[Spatial structure of apamin in solution].
The calculation of the complete spatial structure of the bee venom peptide neurotoxin apamin has been carried out by means of a method elaborated earlier. It is based on the joint utilization of the molecular mechanics algorithms and NMR spectroscopy data. It was established that the molecule backbone conformation in solution may be represented as the combination of the beta-turn III (residues 2-5) and alpha-helical segment (9-18) both separated by the non-standard bend IV (5-8). The most probable system of the intramolecular hydrogen bonds in the apamin polypeptide backbone was proposed. Certain amino acid residues have been shown to be characterized by the lack of strict determination of the conformations of their side chains which may be realized in a few states providing approximately equal stabilization of the same form of the main chain. The conformational parameters of the proposed apamin structural model are appropriate to the NMR spectroscopy data derived from the literature and used in the calculations and are not contradictory to other experimental information.


Retrospective analysis of 18F-FDG PET/CT for staging asymptomatic breast cancer patients younger than 40 years.
National Comprehensive Cancer Network guidelines consider (18)F-FDG PET/CT for only clinical stage III breast cancer patients. However, there is debate whether TNM staging should be the only factor in considering if PET/CT is warranted. Patient age may be an additional consideration, because young breast cancer patients often have more aggressive tumors with potential for earlier metastases. This study assessed PET/CT for staging of asymptomatic breast cancer patients younger than 40 y. In this Institutional Review Board-approved retrospective study, our hospital information system was screened for breast cancer patients younger than 40 y who underwent staging PET/CT before any treatment. Patients with symptoms or conventional imaging findings suggestive of distant metastases or with prior malignancy were excluded. Initial stage was based on physical examination, mammography, ultrasound, and breast MR imaging. PET/CT was then evaluated to identify unsuspected extraaxillary regional nodal and distant metastases. One hundred thirty-four patients with initial breast cancer stage I to IIIC met inclusion criteria. PET/CT findings led to upstaging to stage III or IV in 28 patients (21%). Unsuspected extraaxillary regional nodes were found in 15 of 134 patients (11%) and distant metastases in 20 of 134 (15%), with 7 of 134 (5%) demonstrating both. PET/CT revealed stage IV disease in 1 of 20 (5%) patients with initial clinical stage I, 2 of 44 (5%) stage IIA, 8 of 47 (17%) stage IIB, 4 of 13 (31%) stage IIIA, 4 of 8 (50%) stage IIIB, and 1 of 2 (50%) stage IIIC. All 20 patients upstaged to stage IV were histologically confirmed. Four synchronous thyroid and 1 rectal malignancies were identified. PET/CT revealed distant metastases in 17% of asymptomatic stage IIB breast cancer patients younger than 40 y. Although guidelines of the National Comprehensive Cancer Network recommend against systemic staging in patients with stage II disease, our data suggest that PET/CT might be valuable in younger patients with stage IIB and III disease. Use of PET/CT in younger patients has the potential to reduce the morbidity and cost of unnecessary therapies in young breast cancer patients.


Mechanisms of cortical neural synchronization related to healthy and impaired consciousness: evidence by quantitative electroencephalographic studies.
In this paper, we review the contribution of our research group to the study of human consciousness by quantitative electroencephalographic (EEG) techniques. We posit that EEG techniques can be extremely useful for a direct measurement of brain electrophysiological activity related to human consciousness for their unsurpassable high temporal resolution (milliseconds). This activity can be expressed in terms of event-related potentials as well as changes of EEG rhythms of interest, for example the dominant alpha rhythms (about 8-12 Hz). The results of our studies, and those of several independent groups, lead support to the hypothesis that these techniques provide important insights about the neurophysiologic mechanisms underlying cortical neural synchronization/desynchronization and the regulation of neuromodulatory systems (e.g. dopaminergic, noradrenergic, cholinergic, etc.) at the basis of brain arousal and consciousness in healthy subjects and in patients with impairment of the consciousness. A possible interaction of these mechanisms and the drugs administered to patients with consciousness disorders is discussed.


NMR-derived solution conformations of a hybrid synthetic peptide containing multiple epitopes of envelope protein gp120 from the RF strain of human immunodeficiency virus.
Solution conformations of a 40-residue hybrid peptide containing T-helper epitopes and B-cell determinants from envelope glycoprotein gp120 of human immunodeficiency virus (HIV) have been investigated with NMR. Peptides of this general design are highly immunogenic and induce HIV-neutralizing antibodies and T-lymphocyte responses. The 16-residue N-terminal segment of the peptide contains a T-helper epitope, while the 24-residue C-terminal segment is derived from the V3 loop of HIV strain RF and contains epitopes that elicit neutralizing antibodies as well as T-cell responses. On the basis of 2D proton NMR spectra (COSY, TOCSY, and NOESY) of the peptide in aqueous solution, the resonances of nearly all hydrogens are assigned. The peptide is largely disordered, but specific medium-range NOEs demonstrate conformational preferences in certain regions. Part of the N-terminal segment exhibits nascent helical conformation, consistent with a finding that many T-cell antigens can be modeled as amphipathic helices. In the V3-derived segment of the peptide, one region shows evidence of a tight turn conformation, corresponding to a turn found previously in V3 peptides of HIV strains MN and IIIB. Other conformational features are also detected in the V3 region, such as a stretch of beta strand and a kink that may arise from side-chain interactions.


Simultaneous production of amylases and proteases by Bacillus subtilis in brewery wastes.
The simultaneous production of amylase (AA) and protease (PA) activity by Bacillus subtilis UO-01 in brewery wastes was studied by combining the response surface methodology with the kinetic study of the process. The optimum conditions (T=36.0°C and pH=6.8) for high biomass production (0.92g/L) were similar to the conditions (T=36.8°C and pH=6.6) for high AA synthesis (9.26EU/mL). However, the maximum PA level (9.77EU/mL) was obtained at pH 7.1 and 37.8°C. Under these conditions, a considerably high reduction (between 69.9 and 77.8%) of the initial chemical oxygen demand of the waste was achieved. In verification experiments under the optimized conditions for production of each enzyme, the AA and PA obtained after 15h of incubation were, respectively, 9.35 and 9.87EU/mL. By using the Luedeking and Piret model, both enzymes were classified as growth-associated metabolites. Protease production delay seemed to be related to the consumption of non-protein and protein nitrogen. These results indicate that the brewery waste could be successfully used for a high scale production of amylases and proteases at a low cost.


Functional reconstitution in Escherichia coli of the yeast mitochondrial matrix peptidase from its two inactive subunits.
The matrix processing peptidase from yeast (Saccharomyces cerevisiae) mitochondria was expressed in Escherichia coli via a plasmid-borne operon encoding the mature forms of the alpha and beta subunits of the enzyme. The subunits assembled into a fully active, soluble enzyme. The mature subunits were also expressed individually. The alpha subunit accumulated in large amounts and was obtained at a purity of 80% after a single chromatographic step. The beta-subunit-producing strain expressed an intact and a degraded form of the beta subunit, both of them soluble in the cytoplasm. Extract from either the alpha- or the beta-subunit-producing strain (S-alpha or S-beta extract, respectively), as well as the purified alpha subunit, was enzymatically inactive. However, precursor cleavage activity was restored by mixing either the S-alpha extract or the purified alpha subunit with the S-beta extract. The reconstituted processing activity was indistinguishable from the authentic holopeptidase.


Prospective of Ras signaling in stem cells.
The Ras signaling pathway plays a predominant role during development and controls diverse biological process in all eukaryotic cells. It is a member of the large family of GTPases proteins that binds and hydrolyzes GTP. Ras is a lipid-anchored protein on the intracellular membrane compartments, and cycles between inactive GDP-bound and the signaling competent GTP-bound conformation. Studies have demonstrated Ras to be a central regulator in signal transduction pathways responding to diverse extracellular and intracellular stimuli. Much progress has been made towards delineating specific genes involved in the process of pluripotency and differentiation of stem cells. Here, we discuss recent aspects of Ras signaling pathways in mediating stem cell properties.


Which tasks best discriminate between dyslexic university students and controls in a transparent language?
The need for a battery for testing adult dyslexia, and especially university students, is being increasingly recognized in view of the increased number of adult requests for a dyslexia examination in relation to both assistance and protection from discrimination. The present study examines the discriminative validity of a battery we have developed-the Battery for the Assessment of Reading and Writing in Adulthood-through comparison of the performance of 24 university students with a history of severe developmental dyslexia and 99 controls. All the reading, writing, lexical decision and spelling tasks of the battery, except omissions in a lexical decision task and reading comprehension, showed a good discriminatory power. In addition, use of just two of these tasks (fluency in reading a text and spelling under articulatory suppression) gave 87% sensitivity and 97% specificity. Our results confirm that in transparent languages, measures of phonological automaticity are the best indexes of reading decoding competence, particularly in adults.


Reducing sugar, fat, and salt for prevention and control of noncommunicable diseases (NCDs) as an adopted health policy in Iran.
Background: Tackling noncommunicable diseases (NCDs) and their multifaceted, complex risk factors requires identifying policy gaps and translation of successful experiences for each setting. As advocated by World Health Organization (WHO), reducing sugar, salt, and fat are among best buys for prevention and control of NCDs. This article reports the status of existing policies to reduce the consumption of sugar, salt, and fat in Iran. Methods: We created a comprehensive repository of available policy documents about sugar, salt, and fat policies in Iran and conducted content analysis and interviews with relevant stakeholders. Then, we compared policies and their content with the WHO's best buys' recommendations. Results: We categorized policies in 3 groups: red colour (no mention in the policy documents), amber (inspirational policy mention without action), and green (policy in operation). For example, regarding sugar, we found 8 policies in green, 1 in amber. Our matrix of policies on all 3 topics created a platform for further policy analysis and transferrable lessons to improve national actions towards 30% reduction of death due to NCDs in Iran. Conclusion: It has been globally recognized that beyond technical solutions to combat NCDs, feasible and meaningful policy solutions must be created that are aligned with the political economy of each context. This necessitates learning from national, regional, and global experiences to manage the political economy of NCDs' main determinants. To this end, our study provides a systematic and evidence-based framework, which may also be beneficial for other nations.


Augmentation of antitumor effect on syngeneic murine solid tumors by an interleukin 2 slow delivery system, the IL-2 mini-pellet.
We evaluated the antitumor effect of an interleukin 2 (IL-2) slow delivery system, the IL-2 mini-pellet, in two murine solid tumor models, and also investigated the enhancement of its therapeutic effect by serial administration. The IL-2 mini-pellet contains 1 x 10(6) units of IL-2 and releases it slowly in vivo. In our experiment, the IL-2 mini-pellet was administered subcutaneously near the tumor site in combination with the intravenous injection of lymphokine-activated killer (LAK) cells. When this regimen was given on days 8 and 11 after the subcutaneous inoculation of Meth A fibrosarcoma into BALB/c mice, tumor growth was significantly inhibited (p less than 0.05) compared to tumor growth in untreated controls. Moreover, the IL-2 mini-pellet alone was also effective in inhibiting tumor growth. In another experiment, MH134 hepatoma was inoculated into C3H/He mice. Both administration of the IL-2 mini-pellet alone and in combination with LAK cells resulted in complete tumor regression in four of five mice. In a third experiment, serial administration of the IL-2 mini-pellet at 3- or 5-day intervals prolonged the suppression of Meth A fibrosarcoma growth in BALB/c mice. These results suggested that the IL-2 mini-pellet could be applied to cancer immunotherapy and that its antitumor effect could be prolonged by serial administration.


NRAS mutation causes a human autoimmune lymphoproliferative syndrome.
The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4(-), CD8(-) alphabeta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders.


Efficacy of the Lunch is in the Bag intervention to increase parents' packing of healthy bag lunches for young children: a cluster-randomized trial in early care and education centers.
Lunches that parents pack for their young children to eat at school or the Early Care and Education (ECE) center fall short of recommended standards. Lunch is in the Bag is a multi-level behavioral nutrition intervention to increase parents' packing of fruit, vegetables, and whole grains in their children's lunches. Designed for implementation in ECE centers, the five-week long intervention is followed three months later with a one-week booster. Efficacy of Lunch is in the Bag was tested in cluster randomized trial. Participants were 633 families from 30 ECE centers (15 intervention, 15 control) across Austin, San Antonio, and Houston, Texas, USA. Primary outcomes were servings of fruit, vegetables, and whole grains observed in the children's parent-packed bag lunches. Servings of refined grains, meats/beans/eggs/nuts, dairy, chips, and sweets also were observed. Data were collected at baseline, post-intervention (6-week follow-up), pre-booster (22-weeks follow-up), and post-booster (28-week follow-up). Time-by-treatment interactions were analyzed separately for each of the food groups using multi-level models to compare changes from baseline. Analyses were adjusted for relevant demographic variables and clustering within centers and parents. The intervention effected increases from baseline to 6-week follow-up in vegetables (0.17 servings, SE = 0.04, P < 0.001) and whole grains (0.30 servings, SE = 0.13, P = 0.018). The increase in whole grains was maintained through the 28-week follow-up (0.34 servings, SE = 0.13, P = 0.009). Fruit averaged more than 1.40 servings with no differences between groups or across time. The intervention prevented increase in sweets (-0.43 servings, SE = 0.11, P < .001, at the 22-week follow-up). Parents persisted, however, in packing small amounts of vegetables (averages of 0.41 to 0.52 servings) and large amounts of sweets and chips (averages of 1.75 to 1.99 servings). The need for and positive effects of the Lunch is in the Bag intervention at ECE centers where parents send bag lunch for their preschool-aged children was confirmed. An important direction for future research is discovery of more options for leveraging the partnership of ECE centers and families to help young children learn to eat and enjoy vegetables and other healthy foods in preference to less healthy choices such as chips and sweets. The Clinical Trials Number is NCT01292434 .


The role of mental health in primary prevention of sexual and gender-based violence.
In this short communication, we assert that mental health has a crucial role in the primary prevention of sexual and gender-based violence (SGBV). However, we found that most research and practice to date has focused on the role of mental health post-violence, and SGBV primary prevention is relying on public health models that do not explicitly include mental health. Yet, key concepts, processes, and competencies in the mental health field appear essential to successful SGBV primary prevention. For example, empathy, self-esteem, compassion, emotional regulation and resilience, stress management, relationship building, and challenging problematic social norms are crucial. Furthermore, competencies such as rapport building, group processing, emotional nurturing, modelling, and the prevention of vicarious trauma among staff are important for the successful implementation of SGBV primary prevention programmes. SGBV primary prevention work would benefit from increased collaboration with mental health professionals and integration of key mental health concepts, processes, and skills in SGBV research.


The fate of sulfonamides in microenvironments of rape and hot pepper rhizosphere soil system.
Sulfonamides (SAs) in agricultural soils can be degraded in rhizosphere, but can also be taken up by vegetables, which thereby poses human health and ecological risks. A glasshouse experiment was conducted using multi-interlayer rhizoboxes to investigate the fate of three SAs in rape and hot pepper rhizosphere soil systems to examine the relationship between the accumulation and their physicochemical processes. SAs mainly entered pepper shoots in which the accumulation ranged from 0.40 to 30.64 mg kg-1, while SAs were found at high levels in rape roots ranged from 3.01 to 16.62 mg kg-1. The BCFpepper shoot exhibited a strong positive linear relationship with log Dow, while such relationship was not observed between other bioconcentration factors (BCFs) and log Dow. Other than lipophilicity, the dissociation of SAs may also influence the uptake and translocation process. Larger TF and positive correlation with log Dow indicate preferential translocation of pepper SAs. There was a significant (p < 0.05) dissipation gradient of SAs observed away from the vegetable roots. In addition, pepper could uptake more SAs under solo exposure, while rape accumulated more SAs under combined exposure. When SAs applied in mixture, competition between SAs might occur to influence the translocation and dissipation patterns of SAs.


Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis.
Until recently, NADPH oxidase (NOX) enzymes were thought to be a property of multicellularity, where the reactive oxygen species (ROS) produced by NOX acts in signaling processes or in attacking invading microbes through oxidative damage. We demonstrate here that the unicellular yeast and opportunistic fungal pathogen Candida albicans is capable of a ROS burst using a member of the NOX enzyme family, which we identify as Fre8. C. albicans can exist in either a unicellular yeast-like budding form or as filamentous multicellular hyphae or pseudohyphae, and the ROS burst of Fre8 begins as cells transition to the hyphal state. Fre8 is induced during hyphal morphogenesis and specifically produces ROS at the growing tip of the polarized cell. The superoxide dismutase Sod5 is co-induced with Fre8 and our findings are consistent with a model in which extracellular Sod5 acts as partner for Fre8, converting Fre8-derived superoxide to the diffusible H2O2 molecule. Mutants of fre8Δ/Δ exhibit a morphogenesis defect in vitro and are specifically impaired in development or maintenance of elongated hyphae, a defect that is rescued by exogenous sources of H2O2. A fre8Δ/Δ deficiency in hyphal development was similarly observed in vivo during C. albicans invasion of the kidney in a mouse model for disseminated candidiasis. Moreover C. albicans fre8Δ/Δ mutants showed defects in a rat catheter model for biofilms. Together these studies demonstrate that like multicellular organisms, C. albicans expresses NOX to produce ROS and this ROS helps drive fungal morphogenesis in the animal host.