A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis.
Response to treatment with organic pentavalent antimonials, the standard first-line treatment for visceral leishmaniasis (VL), has been decreasing since their introduction into India. Combining sodium stibogluconate (SB) with paromomycin (PM) may be an efficient alternative to single-agent therapy. This trial was designed to assess the safety and efficacy of PM 12 or 18 mg/kg daily plus SB 20 mg/kg daily for 21 days compared to SB alone for 30 days. One hundred and fifty patients were randomly assigned in 1996 to 1 of the 3 treatments and followed-up for 180 days. At the end of treatment, 49 of 52 patients receiving PM12 + SB, 46 of 48 receiving PM18 + SB, and 27 of 49 patients receiving SB alone, were cured. During follow-up there was 1 relapse in each of the treatment groups, giving final cure rates of 48 of 52 (92.3%) for PM12 + SB, 45 of 48 (93.8%) for PM18 + SB, and 26 of 49 (53.1%) for SB. PM plus SB for 21 days at either 12 or 18 mg/kg daily was significantly more effective than SB alone for 30 days (chi 2 P < 0.001). One patient (SB alone) had experienced a serious adverse event: cardiotoxicity at day 8 (myocarditis and ECG changes) which caused withdrawal from the study. Only 19 of 100 patients enrolled in the PM treatment arms had a complete audiogram series conducted thus making it difficult to assess oto-toxicity. PM 12 or 18 mg/kg daily plus a standard dose of SB for 21 days was statistically more effective than SB in producing a final cure for patients with VL in Bihar, India.


Patterns of urinary catheter consults in a tertiary care hospital.
We reviewed the consultation patterns for difficult urethral catheter placement in tertiary care hospitals and developed a treatment algorithm for this common request. We identified all urethral catheter consults obtained by urology residents at three tertiary care hospitals from October 2009 through October 2010. Only consults for inability to place urethral catheter by the referring team were included; hematuria or clot retention were excluded. Patient age, date of consultation, consulting service, prior urologic history, initial number of attempts, and final outcome were recorded. Eighty-one consults were recorded. Seventy-seven (96%) were male; the median age was 65 years. The most common consulting services were internal medicine (35%), intraoperative consults (17%), and the intensive care unit (17%). In 90% of cases, an initial attempt at catheter placement was attempted; 62% of these were made by nurses. Over half of patients had known urologic pathology. In 70% of cases, successful placement without other adjuncts was achieved by the urology resident. Twenty percent of patients required cystoscopic manipulation; nine percent required suprapubic tube placement. Catheterization was achieved without adjunct procedures in the majority of consults. These results support an algorithm in which all patients without a prior history of lower urinary tract pathology should undergo an initial placement attempt by the primary service physician. They also underscore the need for educational efforts to improve non-urologists' comfort level with placement of a standard Foley or Coudé catheter.


Two combined residency programs in internal medicine and pediatrics.
Combined residency training in internal medicine and pediatrics is becoming a popular postgraduate program among graduating medical students. The number of such programs has increased rapidly but with little interchange of ideas and without the benefit of a national data base. In this paper, the authors review the experience of two combined programs. Initially established because of the desire to provide broad-based training in primary care, the programs now offer a curriculum that prepares residents for primary care or education in the subspecialties. The difficulty for residents of achieving competence in two disciplines is compounded by a lack of faculty role models. The two programs offer special advantages to the residents and the departments involved. The career outcomes of program graduates have varied from primary care or subspecialty practice in one or both disciplines to faculty positions in teaching institutions. Whether the program remains successful will depend on the ability of its graduates to offer special talents to academic and clinical practice settings and on the availability of funding.


Integrated optomechanical microelements.
We integrate the optical elements required to generate optical orbital angular momentum into a microdevice. This allows the rotation of either naturally occuring microparticles or specially fabricated optical rotors. We use a two photon photopolymerization process to create microscopic diffractive optical elements, customized to a wavelength of choice, which are integrated with micromachines in microfluidic devices. This enables the application of high optical torques with off-the-shelf optical tweezers systems.


AtATM is essential for meiosis and the somatic response to DNA damage in plants.
In contrast to yeast or mammalian cells, little is known about the signaling responses to DNA damage in plants. We previously characterized AtATM, an Arabidopsis homolog of the human ATM gene, which is mutated in ataxia telangiectasia, a chromosome instability disorder. The Atm protein is a protein kinase whose activity is induced by DNA damage, particularly DNA double-strand breaks. The phosphorylation targets of Atm include proteins involved in DNA repair, cell cycle control, and apoptosis. Here, we describe the isolation and functional characterization of two Arabidopsis mutants carrying a T-DNA insertion in AtATM. Arabidopsis atm mutants are hypersensitive to gamma-radiation and methylmethane sulfonate but not to UV-B light. In correlation with the radiation sensitivity, atm mutants failed to induce the transcription of genes involved in the repair and/or detection of DNA breaks upon irradiation. In addition, atm mutants are partially sterile, and we show that this effect is attributable to abundant chromosomal fragmentation during meiosis. Interestingly, the transcription of DNA recombination genes during meiosis was not dependent on AtATM, and meiotic recombination occurred at the same rate as in wild-type plants, raising questions about the function of AtAtm during meiosis in plants. Our results demonstrate that AtATM plays a central role in the response to both stress-induced and developmentally programmed DNA damage.


Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension.
The granulomatous reaction is the hallmark of the host response to infection with Mycobacterium tuberculosis. Despite its apparent importance to host defence against the tubercle bacillus, the granulomatous response remains to be completely defined. The present study used histological, immunohistochemical and flow-cytometric analyses to characterize pulmonic granulomatous tissues of tuberculous mice and humans. The kinetics of recruitment of neutrophils, macrophages, dendritic cells, and T and B lymphocytes into the lungs of mice infected aerogenically with the virulent Erdman strain of M. tuberculosis was evaluated in detail in both the acute and persistent phase of infection. A hypoxia-sensing compound based on the 2-nitroimidazole structure (EF5), together with immunohistochemical studies targeting endothelial cells were used to examine the relative oxygen tension in tuberculous granulomatous tissues in mice. The results have provided evidence that: (i) the granulomatous tissues are a highly organized structure whose formation is regulated by orderly recruitment of specific immune cells exhibiting distinct spatial relationship with one another; (ii) the granulomatous reaction, at least in the mouse, may represent an exaggerated response to the tubercle bacillus that can play a role in the development of immunopathology; (iii) B lymphoid aggregates are a prominent feature in both murine and human granulomatous tissues, although the immune cells that are most prominently associated with these clusters vary among the two species; (iv) murine tuberculous granulomatous tissues are relatively aerobic, suggesting that mouse models of persistent tuberculosis may not be suitable for the study of any hypoxic response of M. tuberculosis.


Cytosine derivatized bis(2,2'-bithienyl)methane molecularly imprinted polymer for selective recognition of 6-thioguanine, an antitumor drug.
A molecularly imprinted polymer (MIP) was designed and synthesized to serve as a functional material for selective recognition of 6-thioguanine (6TG), an antitumor drug. For that, the newly synthesized functional monomer, cytosine-bis(2,2'-bithienyl)-(4-carboxyphenyl)methane ester (Cyt-S4), revealed Watson-Crick type nucleobase pairing of 6TG. Formation of the Cyt-S4 and 6TG complex of the 2:1 stoichiometry was postulated based on the DFT calculations at the B3LYP/3-21G((⁎)) level and experimentally confirmed by fluorescence titration. The molecularly imprinted polymer (MIP) film was deposited by potentiodynamic electropolymerization on a Pt disk electrode as well as on an Au-coated glass slide and on an Au-quartz crystal resonator. The statistical model of formation of this film was successfully simulated by molecular dynamics. Completeness of the subsequent 6TG template extraction from MIP was confirmed by the UV-visible spectroscopy. An imprinting factor of 2.9 for the MIP film was determined by piezoelectric microgravimetry using ECQM. The double-layer capacity and alternating current measurements under flow-injection analysis (FIA) conditions were selected to transduce the 6TG recognition signal into the change of the double-layer capacity dependence on the 6TG concentration in solution for different supporting electrolyte concentrations. Detectability of the resulting chemosensor was 10 µM 6TG for the 0.5 M KF carrier solution in FIA. Selectivity of the chemosensor with respect to common interferences was high, e.g., it exceeded 130 to 2-amino-6-methylmercaptopurine, a 6TG metabolite.


Moxalactam for treatment of pelvic infections after cesarean delivery.
Moxalactam was given to 136 women for treatment of uterine infections after cesarean delivery. After an intravenous loading dose of 2 g, 36 women received 3 g daily and 100 were given 6 g daily. The clinical success rates of these two regimens were 86% and 89%, respectively; however, in four of five women for whom treatment with the 3-g daily dose failed, extensive surgery was necessary for cure. A total of 395 pathogens was isolated from these women with polymicrobial infections, and almost 90% were susceptible to moxalactam at less than or equal to 32 micrograms/ml. Adverse effects of therapy were minimal. Thus, moxalactam given initially as a dosage of 6 g daily is effective for treatment of women with pelvic infections after cesarean delivery.


Nonoperative treatment of muscle injuries - recommendations from the GOTS expert meeting.
Muscle injuries are some of the most common injuries in sports; they have a high recurrence rate and can result in the loss of ability to participate in training or competition. In clinical practice, a wide variety of treatment strategies are commonly applied. However, a limited amount of evidence-based data exists, and most therapeutic approaches are solely based on "best practice". Thus, there is a need for consensus to provide strategies and recommendations for the treatment of muscle injuries. The 2016 GOTS Expert Meeting, initiated by the German-Austrian-Swiss Society for Orthopaedic Traumatologic Sports Medicine (GOTS), focused on the topic of muscle and tendon injuries and was held in Spreewald/Berlin, Germany. The committee was composed of twenty-two medical specialists. Nine of them were delegated to a subcommittee focusing on the nonoperative treatment of muscle injuries. The recommendations and statements that were developed were reviewed by the entire consensus committee and voted on by the members. The committee reached a consensus on the utility and effectiveness of the management of muscle injuries. the "PRICE" principle to target the first inflammatory response is one of the most relevant steps in the treatment of muscle injuries. Haematoma aspiration may be considered in the early stages after injury. There is presently no clear evidence that intramuscular injections are of use in the treatment of muscle injuries. The ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) should be regarded critically because there is currently no hard evidence to support their use, although they are appropriate in exceptional cases. The present work provides a structured overview of the various nonoperative treatment strategies of muscle injuries and evaluates their effectiveness with respect to the existing scientific evidence and clinical expertise in the context of basic science on the healing process of muscle injuries. The committee agreed that there is a compelling need for further studies, including high-quality randomized investigations to completely evaluate the effectiveness of the existing therapeutic approaches. The given recommendations may be updated and adjusted as further evidence will be generated.


Psoriasis treatment: bathing in a thermal lagoon combined with UVB, versus UVB treatment only.
We have compared bathing in a thermal lagoon in Iceland, combined with UVB treatment, to UVB treatment only in an open comparative study. Twenty-three psoriasis patients bathed 3 times daily and were treated with UVB 5 times a week for 4 weeks. The control group was only treated with UVB 5 times a week for 4 weeks. Psoriasis Area and Severity Index (PSAI) was used to estimate the severity of the disease. The mean PASI score in the bathing group decreased from 20.8 to 2.8 (p < 0.01). In the control UVB group, the PASI score decreased from 16. 7 to 6.9. The percentage difference between the groups was significant after 1, 2, 2 and 4 weeks. Bathing in the lagoon combined with UVB was found to be a very effective treatment and better than UVB treatment in our control group.


Targeting Abnormal Nrf2/HO-1 Signaling in Amyotrophic Lateral Sclerosis: Current Insights on Drug Targets and Influences on Neurological Disorders.
The nuclear erythroid 2-related-factor (Nrf2) transcription factor/hemoxygenase 1 (HO-1) is a key regulator of an important neuroprotection response by driving the interpretation of various cytoprotective gene to encode for anti-inflammatory, antioxidant, and detoxifying proteins. Various studies investigated that the upregulation of Nrf2/HO-1 has become the potential therapeutic approach in amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis is a motor neuron disease in which there is a progressive loss of upper motor neuron and lower motor neurons of the motor cortex, brain stem, and corticospinal tract. A result of this upregulation of Nrf2/HO-1 indicates that in the brain, anti-oxidant capacity is reinforced. Further, this shows a cytoprotective effect against oxidative stress in amyotrophic lateral sclerosis. A study reported functions associated with the Nrf2/HO-1 in the neuronal cell, oligodendrocytes, microglia, and astrocytes. Although ALS's pathogenesis is not yet clear, but it is compelling. The evidence shows any dysfunction in the brain such as mitochondrial dysfunction, protein aggregation, glial cell activation, excitotoxicity, and apoptosis which gives ALS-like symptoms. In this review, we have mainly focused on detailing the downregulation of Nrf2/HO-1, which may be the prime reason and may further serve as a pathological hallmark for ALS development. As surveyed, there are limited targetbased interventions that only provide symptomatic relief but do not cure the disease completely. Dysregulation of the Nrf2/HO-1 signaling pathway leads to many physiological changes contributing to neurological conditions, including ALS. Based on the above view, we summarized the combined role of Nrf2/HO-1 signaling in ALS and explored potential therapeutic strategies for disease improvement through pathway modulators.


Effects of Honokiol on CYP450 Activity and Transporter mRNA Expression in Type 2 Diabetic Rats.
This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups (n = 6). The activities of hepatic CYP1A2, CYP2E1, CYP2C, CYP2B, CYP3A and CYP4A, and the mRNA expression levels of hepatic and renal transporters, were determined. Compared to the NC group, the activities of CYP1A2, CYP2E1, CYP4A and CYP2C in DC group were increased by 2.36-, 2.10-, 2.55- and 1.86-fold, respectively. The mRNA expression levels of hepatic Oat2, Oatp2b1 and Oatp1a5, and renal Oct1, Octn2, Oatp2b1 and Oatp1a5, were significantly down-regulated, while the mRNA expression levels of hepatic Octn2, Oatp3a1, Oatp1a1 and Mdr2, and renal Oat2, Mrp4 and Bcrp, were significantly upregulated. Compared to the DC group, Hon treatment significantly inhibited the activity of hepatic CYP2E1, CYP4A, 3A and CYP1A2 by 45.6%, 29.2%, 22.7% and 20.7% in Hon high dose group, respectively. Moreover, Hon treatment significantly inhibited the mRNA expression levels of renal Bcrp and Mrp4 by 2.63-fold and 1.54-fold, while significantly upregulated the mRNA expression levels of hepatic Oat2 and Oatp2b1 by 1.52-fold and 1.54-fold in Hon high dose group, respectively. The results suggested that under the diabetes condition, the changes of CYP450 activity and transporter expression inevitably interfere the normal transport, metabolism and efficacy of drugs. The present work firstly reported that Hon treatment ameliorated the abnormal change of hepatic CYP activity (including CYP2E1, CYP4A and CYP1A2) and the transporter mRNA expression (including hepatic Oat2 and Oatp2b1, renal Bcrp and Mrp4) in type 2 diabetic rats induced by high-fat diet and strepotozotocin, which are associated with the occurrence and development of diabetes.


SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19.
Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021. We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs. Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE. We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision). Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16). Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs. Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included. Bamlanivimab compared to placebo We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported. AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.


Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.
Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10-8) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.


Rutin protects the neural damage induced by transient focal ischemia in rats.
Free radical induced neural damage is implicated in cerebral ischemia-reperfusion (IR) injury and antioxidants are reported to have neuroprotective activity. The present study was designed to assess the neuroprotective role of rutin (Vitamin P), and mechanism of action. The middle cerebral artery (MCA) of an adult male Wistar rat was occluded for 2 h and reperfused for 22 h. The administration of rutin (25 mg/kg bwt., orally) once daily for 21 days before middle cerebral artery occlusion (MCAO) showed marked reduction in infarct size, reduced the neurological deficits in terms of behaviors, suppressed neuronal loss and diminished the p53 expression in MCAO rats. A significantly depleted activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) and content of glutathione (GSH) in MCAO group were protected significantly in MCAO group pretreated with rutin. Conversely, the elevated level of thiobarbituric acid reactive species (TBARS), H(2)O(2) and protein carbonyl (PC) in MCAO group was attenuated significantly in rutin-pretreated group when compared with MCAO group. These results indicate that rutin attenuates ischemic neural apoptosis by reducing the expression of p53, preventing morphological changes and increasing endogenous antioxidant enzymatic activities. Thus, rutin treatment may represent a novel approach in lowering the risk or improving the function of ischemia-reperfusion brain injury-related disorders.


Bacteriocins, spite and virulence.
There has been much interest in using social evolution theory to predict the damage to a host from parasite infection, termed parasite virulence. Most of this work has focused on how high kinship between the parasites infecting a host can select for more prudent exploitation of the host, leading to a negative relationship between virulence and parasite kinship. However, it has also been shown that if parasites can cooperate to overcome the host, then high parasite kinship within hosts can select for greater cooperation and higher growth rates, hence leading to a positive relationship between virulence and parasite kinship. We examine the impact of a spiteful behaviour, chemical (bacteriocin) warfare between microbes, on the evolution of virulence, and find a new relationship: virulence is maximized when the frequency of kin among parasites' social partners is low or high, and is minimized at intermediate values. This emphasizes how biological details can fundamentally alter the qualitative nature of theoretical predictions made by models of parasite virulence.


The Pearling Transition Provides Evidence of Force-Driven Endosomal Tubulation during Salmonella Infection.
Bacterial pathogens exploit eukaryotic pathways for their own end. Upon ingestion, Salmonella enterica serovar Typhimurium passes through the stomach and then catalyzes its uptake across the intestinal epithelium. It survives and replicates in an acidic vacuole through the action of virulence factors secreted by a type three secretion system located on Salmonella pathogenicity island 2 (SPI-2). Two secreted effectors, SifA and SseJ, are sufficient for endosomal tubule formation, which modifies the vacuole and enables Salmonella to replicate within it. Two-color, superresolution imaging of the secreted virulence factor SseJ and tubulin revealed that SseJ formed clusters of conserved size at regular, periodic intervals in the host cytoplasm. Analysis of SseJ clustering indicated the presence of a pearling effect, which is a force-driven, osmotically sensitive process. The pearling transition is an instability driven by membranes under tension; it is induced by hypotonic or hypertonic buffer exchange and leads to the formation of beadlike structures of similar size and regular spacing. Reducing the osmolality of the fixation conditions using glutaraldehyde enabled visualization of continuous and intact tubules. Correlation analysis revealed that SseJ was colocalized with the motor protein kinesin. Tubulation of the endoplasmic reticulum is driven by microtubule motors, and in the present work, we describe how Salmonella has coopted the microtubule motor kinesin to drive the force-dependent process of endosomal tubulation. Thus, endosomal tubule formation is a force-driven process catalyzed by Salmonella virulence factors secreted into the host cytoplasm during infection.IMPORTANCE This study represents the first example of using two-color, superresolution imaging to analyze the secretion of Salmonella virulence factors as they are secreted from the SPI-2 type three secretion system. Previous studies imaged effectors that were overexpressed in the host cytoplasm. The present work reveals an unusual force-driven process, the pearling transition, which indicates that Salmonella-induced filaments are under force through the interactions of effector molecules with the motor protein kinesin. This work provides a caution by highlighting how fixation conditions can influence the images observed.


The Willow Hill Community Health Assessment: Assessing the Needs of Children in a Former Slave Community.
The overall purpose of this community needs assessment was to explore the perceptions of health and educational needs among youth residing in a rural Georgia community, document existing assets that could be utilized to meet those needs, and to identify socioeconomic barriers and facilitators in health education. A sequential mixed method design was used. Intercept surveys were conducted followed by individual, key informant interviews and a focus group. Survey data was entered into an Excel spreadsheet and SPSS for analysis and descriptive statistics including means and frequencies were calculated. For qualitative interviews, full transcripts were created from audio-recordings and uploaded into NVivo for content analysis. Several health issues were highlighted by the Willow Hill/Portal Georgia community members, including teachers, parents, youth and Willow Hill Heritage and Renaissance Center board members. Some of the health issues identified by youth in the community were low levels of physical activity, obesity, diabetes, lack of healthy food choices, and access to health care services. Including the issues identified by youth, the parents, teachers and board members identified additional health issues in the community such as asthma, hygiene and lack of dental and eye care facilities. Overall, there is a need for better infrastructure and awareness among community members. Utilizing identified assets, including active community leaders, involved faith-based organizations, commitment of community members, presence of land resources, and commitment to physical activity and sports, could modify the current community landscape.


Predicting human preferences using the block structure of complex social networks.
With ever-increasing available data, predicting individuals' preferences and helping them locate the most relevant information has become a pressing need. Understanding and predicting preferences is also important from a fundamental point of view, as part of what has been called a "new" computational social science. Here, we propose a novel approach based on stochastic block models, which have been developed by sociologists as plausible models of complex networks of social interactions. Our model is in the spirit of predicting individuals' preferences based on the preferences of others but, rather than fitting a particular model, we rely on a Bayesian approach that samples over the ensemble of all possible models. We show that our approach is considerably more accurate than leading recommender algorithms, with major relative improvements between 38% and 99% over industry-level algorithms. Besides, our approach sheds light on decision-making processes by identifying groups of individuals that have consistently similar preferences, and enabling the analysis of the characteristics of those groups.


Rate law analysis of water oxidation on a hematite surface.
Water oxidation is a key chemical reaction, central to both biological photosynthesis and artificial solar fuel synthesis strategies. Despite recent progress on the structure of the natural catalytic site, and on inorganic catalyst function, determining the mechanistic details of this multiredox reaction remains a significant challenge. We report herein a rate law analysis of the order of water oxidation as a function of surface hole density on a hematite photoanode employing photoinduced absorption spectroscopy. Our study reveals a transition from a slow, first order reaction at low accumulated hole density to a faster, third order mechanism once the surface hole density is sufficient to enable the oxidation of nearest neighbor metal atoms. This study thus provides direct evidence for the multihole catalysis of water oxidation by hematite, and demonstrates the hole accumulation level required to achieve this, leading to key insights both for reaction mechanism and strategies to enhance function.


Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling.
Children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging when they reach the fifth and sixth decades of life. One mechanistic hypothesis for this phenomenon suggests that social adversity in early life programs biological systems in a manner that persists across decades and thereby accentuates vulnerability to disease. Here we examine the basic tenets of this hypothesis by performing genome-wide transcriptional profiling in healthy adults who were either low or high in socioeconomic status (SES) in early life. Among subjects with low early-life SES, there was significant up-regulation of genes bearing response elements for the CREB/ATF family of transcription factors that conveys adrenergic signals to leukocytes, and significant down-regulation of genes with response elements for the glucocorticoid receptor, which regulates the secretion of cortisol and transduces its antiinflammatory actions in the immune system. Subjects from low-SES backgrounds also showed increased output of cortisol in daily life, heightened expression of transcripts bearing response elements for NF-kappaB, and greater stimulated production of the proinflammatory cytokine interleukin 6. These disparities were independent of subjects' current SES, lifestyle practices, and perceived stress. Collectively, these data suggest that low early-life SES programs a defensive phenotype characterized by resistance to glucocorticoid signaling, which in turn facilitates exaggerated adrenocortical and inflammatory responses. Although these response patterns could serve adaptive functions during acute threats to well-being, over the long term they might exact an allostatic toll on the body that ultimately contributes to the chronic diseases of aging.


Cannabis Use and Risk of Psychiatric Disorders: Prospective Evidence From a US National Longitudinal Study.
With rising rates of marijuana use in the general population and an increasing number of states legalizing recreational marijuana use and authorizing medical marijuana programs, there are renewed clinical and policy concerns regarding the mental health effects of cannabis use. To examine prospective associations between cannabis use and risk of mental health and substance use disorders in the general adult population. A nationally representative sample of US adults aged 18 years or older was interviewed 3 years apart in the National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-2002; wave 2, 2004-2005). The primary analyses were limited to 34 653 respondents who were interviewed in both waves. Data analysis was conducted from March 15 to November 30, 2015. We used multiple regression and propensity score matching to estimate the strength of independent associations between cannabis use at wave 1 and incident and prevalent psychiatric disorders at wave 2. Psychiatric disorders were measured with a structured interview (Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV). In both analyses, the same set of wave 1 confounders was used, including sociodemographic characteristics, family history of substance use disorder, disturbed family environment, childhood parental loss, low self-esteem, social deviance, education, recent trauma, past and present psychiatric disorders, and respondent's history of divorce. In the multiple regression analysis of 34 653 respondents (14 564 male [47.9% weighted]; mean [SD] age, 45.1 [17.3] years), cannabis use in wave 1 (2001-2002), which was reported by 1279 respondents, was significantly associated with substance use disorders in wave 2 (2004-2005) (any substance use disorder: odds ratio [OR], 6.2; 95% CI, 4.1-9.4; any alcohol use disorder: OR, 2.7; 95% CI, 1.9-3.8; any cannabis use disorder: OR, 9.5; 95% CI, 6.4-14.1; any other drug use disorder: OR, 2.6; 95% CI, 1.6-4.4; and nicotine dependence: OR, 1.7; 95% CI, 1.2-2.4), but not any mood disorder (OR, 1.1; 95% CI, 0.8-1.4) or anxiety disorder (OR, 0.9; 95% CI, 0.7-1.1). The same general pattern of results was observed in the multiple regression analyses of wave 2 prevalent psychiatric disorders and in the propensity score-matched analysis of incident and prevalent psychiatric disorders. Within the general population, cannabis use is associated with an increased risk for several substance use disorders. Physicians and policy makers should take these associations of cannabis use under careful consideration.


Abnormal Uterine Bleeding.
Abnormal uterine bleeding is a frequent condition in Gynecology. It may impact physical, emotional sexual and professional aspects of the lives of women, impairing their quality of life. In cases of acute and severe bleeding, women may need urgent treatment with volumetric replacement and prescription of hemostatic substances. In some specific cases with more intense and prolonged bleeding, surgical treatment may be necessary. The objective of this chapter is to describe the main evidence on the treatment of women with abnormal uterine bleeding, both acute and chronic. Didactically, the treatment options were based on the current International Federation of Gynecology and Obstetrics (FIGO) classification system (PALM-COEIN). The etiologies of PALM-COEIN are: uterine Polyp (P), Adenomyosis (A), Leiomyoma (L), precursor and Malignant lesions of the uterine body (M), Coagulopathies (C), Ovulatory dysfunction (O), Endometrial dysfunction (E), Iatrogenic (I), and Not yet classified (N). The articles were selected according to the recommendation grades of the PubMed, Cochrane and Embase databases, and those in which the main objective was the reduction of uterine menstrual bleeding were included. Only studies written in English were included. All editorial or complete papers that were not consistent with abnormal uterine bleeding, or studies in animal models, were excluded. The main objective of the treatment is the reduction of menstrual flow and morbidity and the improvement of quality of life. It is important to emphasize that the treatment in the acute phase aims to hemodynamically stabilize the patient and stop excessive bleeding, while the treatment in the chronic phase is based on correcting menstrual dysfunction according to its etiology and clinical manifestations. The treatment may be surgical or pharmacological, and the latter is based mainly on hormonal therapy, anti-inflammatory drugs and antifibrinolytics.


Willingness to use pre-exposure prophylaxis for HIV prevention among men who have sex with men in Malaysia: Findings from an online survey.
We examined willingness to use pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men (MSM) in Malaysia. An online survey of 990 MSM was conducted between March and April 2016. Eligibility criteria included being biological male, Malaysian citizen, 18 years of age or above, identifying as MSM, and being HIV negative or unknown status. Participants' demographics, sexual and drug use behaviors, attitudes towards PrEP, and preferences regarding future access to PrEP were collected. Bivariate analysis and logistic regression were performed to determine factors associated with willingness to use PrEP. Fewer than half of participants (44%) knew about PrEP before completing the survey. Overall, 39% of the sample were willing to take PrEP. Multivariate logistic regression indicated that Malay men (AOR: 1.73, 95% CI:1.12, 2.70), having 2 or more male anal sex partners in the past 6 months (AOR: 1.98, 95% CI: 1.29, 3.05), previous knowledge of PrEP (AOR: 1.40, 95%CI: 1.06, 1.86), lack of confidence in practising safer sex (AOR: 1.36, 95% CI: 1.02, 1.81), and having ever paid for sex with a male partner (AOR: 1.39, 95% CI: 1.01, 1.91) were independently associated with greater willingness to use PrEP, while men who identified as heterosexual were less willing to use PrEP (AOR, 0.36, 95% CI: 0.13, 0.97). Majority of participants preferred to access PrEP at affordable cost below 100 Malaysian Ringgit (USD25) per month from community based organisations followed by private or government hospitals. Overall, MSM in Malaysia reported a relatively low level of willingness to use PrEP, although willingness was higher among those previously aware of PrEP. There is a need to provide PrEP at affordable cost, increase demand and awareness of PrEP, and to provide access to this preventative medication via diverse, integrated and tailored sexual health services.


The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.
KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR.


Visual pigments in a palaeognath bird, the emu Dromaius novaehollandiae: implications for spectral sensitivity and the origin of ultraviolet vision.
A comprehensive description of the spectral characteristics of retinal photoreceptors in palaeognaths is lacking. Moreover, controversy exists with respect to the spectral sensitivity of the short-wavelength-sensitive-1 (SWS1) opsin-based visual pigment expressed in one type of single cone: previous microspectrophotometric (MSP) measurements in the ostrich (Struthio camelus) suggested a violet-sensitive (VS) SWS1 pigment, but all palaeognath SWS1 opsin sequences obtained to date (including the ostrich) imply that the visual pigment is ultraviolet-sensitive (UVS). In this study, MSP was used to measure the spectral properties of visual pigments and oil droplets in the retinal photoreceptors of the emu (Dromaius novaehollandiae). Results show that the emu resembles most other bird species in possessing four spectrally distinct single cones, as well as double cones and rods. Four cone and a single rod opsin are expressed, each an orthologue of a previously identified pigment. The SWS1 pigment is clearly UVS (wavelength of maximum absorbance [λmax] = 376 nm), with key tuning sites (Phe86 and Cys90) consistent with other vertebrate UVS SWS1 pigments. Palaeognaths would appear, therefore, to have UVS SWS1 pigments. As they are considered to be basal in avian evolution, this suggests that UVS is the most likely ancestral state for birds. The functional significance of a dedicated UVS cone type in the emu is discussed.


Screening for Moral Injury: The Moral Injury Symptom Scale - Military Version Short Form.
To develop a short form (SF) of the 45-item multidimensional Moral Injury Symptom Scale - Military Version (MISS-M) to use when screening for moral injury and monitoring treatment response in veterans and active duty military with PTSD. A total of 427 veterans and active duty military with PTSD symptoms were recruited from VA Medical Centers in Augusta, GA; Los Angeles, CA; Durham, NC; Houston, TX; and San Antonio, TX; and from Liberty University, Lynchburg, Virginia. The sample was randomly split in two. In the first half (n = 214), exploratory factor analysis identified the highest loading item on each of the 10 MISS scales (guilt, shame, moral concerns, loss of meaning, difficulty forgiving, loss of trust, self-condemnation, religious struggle, and loss of religious faith) to form the 10-item MISS-M-SF; confirmatory factor analysis was then performed to replicate results in the second half of the sample (n = 213). Internal reliability, test-retest reliability, and convergent, discriminant, and concurrent validity were examined in the overall sample. The study was approved by the institutional review boards and the Research & Development (R&D) Committees at Veterans Administration medical centers in Durham, Los Angeles, Augusta, Houston, and San Antonio, and the Liberty University and Duke University Medical Center institutional review boards. The 10-item MISS-M-SF had a median of 50 and a range of 12-91 (possible range 10-100). Over 70% scored a 9 or 10 (highest possible) on at least one item. Cronbach's alpha was 0.73 (95% CI 0.69-0.76), and test-retest reliability was 0.87 (95% CI 0.79-0.92). Convergent validity with the 45-item MISS-M was r = 0.92. Discriminant validity was demonstrated by relatively weak correlations with social, religious, and physical health constructs (r = 0.21-0.35), and concurrent validity was indicated by strong correlations with PTSD, depression, and anxiety symptoms (r = 0.54-0.58). The MISS-M-SF is a reliable and valid measure of MI symptoms that can be used to screen for MI and monitor response to treatment in veterans and active duty military with PTSD.


Fluorescence imaging of changes in intracellular chloride in living brain slices.
In brain slice preparations, chloride movements across the cell membrane of living cells are measured traditionally with 36Cl- tracer methods, Cl--selective microelectrodes, or whole-cell recording using patch clamp analysis. We have developed an alternative, noninvasive technique that uses the fluorescent Cl- ion indicator, 6-methoxy-N-ethylquinolinium iodide (MEQ), to study changes in intracellular Cl- by epifluorescence or UV laser scanning confocal microscopy. In brain slices taken from rodents younger than 22 days of age, excellent cellular loading is achieved with the membrane-permeable form of the dye, dihydro-MEQ. Subsequent intracellular oxidation of dihydro-MEQ to the Cl--sensitive MEQ traps the polar form of the dye inside the neurons. Because MEQ is a single-excitation and single-emission dye, changes in intracellular Cl- concentrations can be calibrated from the Stern-Volmer relationship, determined in separate experiments. Using MEQ as the fluorescent indicator for Cl-, Cl- flux through the gamma-aminobutyric acid (GABA)-gated Cl- channel (GABAA receptor) can be studied by dynamic video imaging and either nonconfocal (epifluorescence) or confocal microscopy in the acute brain slice preparation. Increases in intracellular Cl- quench MEQ fluorescence, thereby reflecting GABAA receptor activation. GABAA receptor functional activity can be measured in discrete cells located in neuroanatomically defined populations within areas such as the neocortex and hippocampus. Changes in intracellular Cl- can also be studied under various conditions such as oxygen/glucose deprivation ("in vitro ischemia") and excitotoxicity. In such cases, changes in cell volume may also occur due to the dependence of cell volume regulation on Na+, K+, and Cl- flux. Because changes in cell volume can affect optical fluorescence measurements, we assess cell volume changes in the brain slice using the fluorescent indicator calcein-AM. Determination of changes in MEQ fluorescence versus calcein fluorescence allows one to distinguish between an increase in intracellular Cl- and an increase in cell volume.


Interaction of silver nanoparticles with serum proteins affects their antimicrobial activity in vivo.
The emergence of multidrug-resistant bacteria is a global threat for human society. There exist recorded data that silver was used as an antimicrobial agent by the ancient Greeks and Romans during the 8th century. Silver nanoparticles (AgNPs) are of potential interest because of their effective antibacterial and antiviral activities, with minimal cytotoxic effects on the cells. However, very few reports have shown the usage of AgNPs for antibacterial therapy in vivo. In this study, we deciphered the importance of the chosen methods for synthesis and capping of AgNPs for their improved activity in vivo. The interaction of AgNPs with serum albumin has a significant effect on their antibacterial activity. It was observed that uncapped AgNPs exhibited no antibacterial activity in the presence of serum proteins, due to the interaction with bovine serum albumin (BSA), which was confirmed by UV-Vis spectroscopy. However, capped AgNPs [with citrate or poly(vinylpyrrolidone)] exhibited antibacterial properties due to minimized interactions with serum proteins. The damage in the bacterial membrane was assessed by flow cytometry, which also showed that only capped AgNPs exhibited antibacterial properties, even in the presence of BSA. In order to understand the in vivo relevance of the antibacterial activities of different AgNPs, a murine salmonellosis model was used. It was conclusively proved that AgNPs capped with citrate or PVP exhibited significant antibacterial activities in vivo against Salmonella infection compared to uncapped AgNPs. These results clearly demonstrate the importance of capping agents and the synthesis method for AgNPs in their use as antimicrobial agents for therapeutic purposes.


It is not all bad for the grey city - A crossover study on physiological and psychological restoration in a forest and an urban environment.
Today, urbanization presents a challenge to urban planning with regard to creating healthy living environments. The aim of this research is to gain further knowledge of the restorativeness of a best case urban and natural environment: that is a historic down town urban environment and forest environment located in an arboretum. The study has a cross-over design where 51 (N) female university students are exposed to the two environments through both seated viewing and walking. A mixed method approach is used with both physiological measurements of blood pressure (BP) and heart rate variability (HRV) and psychological measurements of mood change and perceived restorativeness. The HRV results show no significant differences between the two environments, and both environments are found to be more physiologically restorative than being at the office or on the minibus. The results of the psychological measures indicate that the forest walk has a positive effect on mood, while the walk in the urban environment has no effect. The forest environment is also rated more highly with regard to perceived restorativeness than the urban environment. The results support the current research that shows natural environments as more restorative than urban environments. The study also adds to the ongoing debate on healthy urban planning by indicating that architectural and historical qualities may be associated with the physiological well-being of citizens.


[Clinical application of modified upper gluteal rhomboid fasciocutaneous flap in repairing sacrococcygeal pressure sores].
To investigate the method and effectiveness of repairing sacrococcygeal pressure sores with modified upper gluteal rhomboid fasciocutaneous flap. Between January 2004 and March 2011, 43 patients with sacrococcygeal pressure sores were treated. There were 25 males and 18 females with an average age of 63 years (range, 38-95 years). The disease duration was 3 months to 2 years and 6 months (mean, 8.5 months). The size of pressure sores ranged from 6 cm x 5 cm to 18 cm x 13 cm. According to the extent and lesion degree of pressure scores, 23 pressure sores were rated as degree III and 20 pressure sores as degree IV. The modified upper gluteal rhomboid flap was designed, one-side upper gluteal fasciocutaneous flaps were transplanted to repair sacrococcygeal pressure sores in 19 cases and two-side flaps in 24 cases. The size of one side flap ranged from 6.5 cm x 4.5 cm to 18.0 cm x 11.5 cm. Fluid under flap occurred in 1 case and edge necrosis of the flaps in 3 cases at 7 days after operation, which were cured after drainage and dressing change; the other flaps survived, and incisions healed by first intention. All patients were followed up 6 months to 3 years with an average of 11 months. Two patients relapsed at 5 months and 8 months, respectively; the other patients had no recurrence. The color of the flaps was normal, and the appearance and elasticity of the flaps were good. The modified upper gluteal rhomboid fasciocutaneous flap has the advantages of simple design and operation, less injury, and reliable effect in repairing sacrococcygeal pressure sores.


Identification of key genes related to high-risk gastrointestinal stromal tumors using bioinformatics analysis.
The purpose of this study was to identify predictive biomarkers used for clinical therapy and prognostic evaluation of high-risk gastrointestinal stromal tumors (GISTs). In this study, microarray data GSE31802 were used to identify differentially expressed genes (DEGs) between high-risk GISTs and low-risk GISTs. Then, enrichment analysis of DEGs was conducted based on the gene ontology and kyoto encyclopedia of genes and genomes pathway database. In addition, the transcription factors and cancer-related genes in DEGs were screened according to the TRANSFAC, TSGene, and TAG database. Finally, protein-protein interaction (PPI) network was constructed and analyzed to look for critical genes involved in high-risk GISTs. A total of forty DEGs were obtained and these genes were mainly involved in four pathways, including melanogenesis, neuroactive ligand-receptor interaction, malaria, and hematopoietic cell lineage. The enriched biological processes were related to the regulation of insulin secretion, integrin activation, and neuropeptide signaling pathway. Transcription factor analysis of DEGs indicated that POU domain, class 2, associating factor 1 (POU2AF1) was significantly downregulated in high-risk GISTs. By constructing the PPI network of DEGs, ten genes with high degrees formed local networks, such as PNOC, P2RY14, and SELP. Four genes as POU2AF1, PNOC, P2RY14, and SELP might be used as biomarkers for prognosis of high-risk GISTs.


Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain.
Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood, but brain dopamine systems have been implicated. Here, we test whether one night of sleep deprivation changes dopamine brain activity. We studied 15 healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/D3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects were tested twice: after one night of rested sleep and after one night of sleep deprivation. The specific binding of [11C]raclopride in the striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast, sleep deprivation did not affect the specific binding of [11C]cocaine in the striatum. Because [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, we interpret the decreases in binding to reflect dopamine increases with sleep deprivation. However, we cannot rule out the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, we postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment.


Overexpression of Transient Receptor Protein Cation Channel Subfamily A Member 1, Confers an Independent Prognostic Indicator in Nasopharyngeal Carcinoma.
Detection of oncogenes provides chances to understand tumor development and progression. Transient receptor protein cation channel subfamily A, member 1 (TRPA1) transcript was significantly upregulated in nasopharyngeal carcinoma (NPC) with a stepwise upregulation from low- to high-stage NPCs from a preliminary data analysis in the Gene Expression Omnibus database. The TRPA1 gene is a member of the TRP channel family, encoding integral membrane proteins that functions as cation channels. Loss of calcium homeostasis takes place in cancer cells. Immunostaining of TRPA1 was analyzed on 124 biopsies from NPC patients retrospectively. The H-score method was used to evaluate the immunoexpression of TRPA1. The correlations between H-score of TRPA1 protein level and clinicopathological factors, as well as the significances of TRPA1 protein level for disease-specific, distal-metastasis-free and local recurrence-free survivals were assessed. These patients were characterized to be no initial metastasis and medicated with the traditional procedure. The TRPA1 score was found to be associated with clinicopathological parameters and patient survivals. Along with the guideline of 7(th) edition of the American Joint Committee on Cancer, we found that TRPA1 upregulation (50%) was associated with advanced primary tumor (P = 0.009) and overall clinical stage (P = 0.019). In univariate log-rank testing, primary tumor, nodal status, stage and TRPA1 protein level significantly contributed to worse disease-specific survival, distal metastasis-free survival and local recurrence-free survival. In multivariate analysis, high TRPA1 protein level and tumor stage emerged as independent prognostic indicators for inferior disease-specific survival (P = 0.014; P = 0.003), distal metastasis-free survival (P = 0.004; P = 0.034) and recurrence-free survival (P = 0.017; P = 0.015). The upregulation of TRPA1 protein level is frequently correlated to unfavorable prognosticators and gives rise to cancer progression in NPC patients.


Implications for viral uncoating from the structure of bovine enterovirus.
We have determined the crystal structure of a bovine enterovirus, revealing that the topologies of the major capsid proteins and the overall architecture of the virion are similar to those of related picornaviruses. The external loops joining beta-strands are truncated and the canyon region is partially filled by an extension of the VP3 G-H loop giving the viral capsid a relatively smooth appearance. These changes may have implications for cell attachment. In spite of these differences the virus maintains a hydrophobic pocket within VP1, occupied by a specific 'pocket factor' which appears to be myristic acid. These observations support the proposal that a kinetic equilibrium exists between occupied and unoccupied pocket states, with occupation inhibiting uncoating.


Genome-wide variation in DNA methylation is associated with stress resilience and plumage brightness in a wild bird.
Individuals often differ in their ability to cope with challenging environmental and social conditions. Evidence from model systems suggests that patterns of DNA methylation are associated with variation in coping ability. These associations could arise directly if methylation plays a role in controlling the physiological response to stressors by, among other things, regulating the release of glucocorticoids in response to challenges. Alternatively, the association could arise indirectly if methylation and resilience have a common cause, such as early-life conditions. In either case, methylation might act as a biomarker for coping ability. At present, however, relatively little is known about whether variation in methylation is associated with organismal performance and resilience under natural conditions. We studied genome-wide patterns of DNA methylation in free-living female tree swallows (Tachycineta bicolor) using methylated DNA immunoprecipitation (MeDIP) and a tree swallow genome that was assembled for this study. We identified areas of the genome that were differentially methylated with respect to social signal expression (breast brightness) and physiological traits (ability to terminate the glucocorticoid stress response through negative feedback). We also asked whether methylation predicted resilience to a subsequent experimentally imposed challenge. Individuals with brighter breast plumage and higher stress resilience had lower methylation at differentially methylated regions across the genome. Thus, widespread differences in methylation predicted both social signal expression and the response to future challenges under natural conditions. These results have implications for predicting individual differences in resilience, and for understanding the mechanistic basis of resilience and its environmental and social mediators.


Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.


alpha-Crystallin localizes to the leading edges of migrating lens epithelial cells.
alpha-crystallin (alphaA and alphaB) is a major lens protein, which belongs to the small heat-shock family of proteins and binds to various cytoskeletal proteins including actin, vimentin and desmin. In this study, we investigated the cellular localization of alphaA and alphaB-crystallins in migrating epithelial cells isolated from porcine lens. Immunofluorescence localization and confocal imaging of alphaB-crystallin in confluent and in migrating subconfluent cell cultures revealed a distinct pattern of subcellular distribution. While alphaB-crystallin localization was predominantly cytoplasmic in confluent cultures, it was strongly localized to the leading edges of cell membrane or the lamellipodia in migrating cells. In accordance with this pattern, we found abundant levels of alphaB-crystallin in membrane fractions compared to cytosolic and nuclear fractions in migrating lens epithelial cells. alphaA-crystallin, which has 60% sequence identity to alphaB-crystallin, also exhibited a distribution profile localizing to the leading edge of the cell membrane in migrating lens epithelial cells. Localization of alphaB-crystallin to the lamellipodia appears to be dependent on phosphorylation of residue serine-59. An inhibitor of p38 MAP kinase (SB202190), but not the ERK kinase inhibitor PD98059, was found to diminish localization of alphaB-crystallin to the lamellipodia, and this effect was found to be associated with reduced levels of Serine-59 phosphorylated alphaB-crystallin in SB202190-treated migrating lens epithelial cells. alphaB-crystallin localization to the lamellipodia was also altered by the treatment with RGD (Arg-Ala-Asp) peptide, dominant negative N17 Rac1 GTPase, cytochalasin D and Src kinase inhibitor (PP2), but not by the Rho kinase inhibitor Y-27632 or the myosin II inhibitor, blebbistatin. Additionally, in migrating lens epithelial cells, alphaB-crystallin exhibited a clear co-localization with the actin meshwork, beta-catenin, WAVE-1, a promoter of actin nucleation, Abi-2, a component of WAVE-1 protein complex and Arp3, a protein of the actin nucleation complex, suggesting potential interactions between alphaB-crystallin and regulatory proteins involved in actin dynamics and cell adhesion. This is the first report demonstrating specific localization of alphaA and alphaB-crystallins to the lamellipodia in migrating lens epithelial cells and our findings indicate a potential role for alpha-crystallin in actin dynamics during cell migration.


Attempted suicide among immigrants in European countries: an international perspective.
This study compares the frequencies of attempted suicide among immigrants and their hosts, between different immigrant groups, and between immigrants and their countries of origin. The material, 27,048 persons, including 4,160 immigrants, was obtained from the WHO/EURO Multicentre Study on Suicidal Behaviour, the largest available European database, and was collected in a standardised manner from 11 European centres in 1989-2003. Person-based suicide-attempt rates (SARs) were calculated for each group. The larger immigrant groups were studied at each centre and compared across centres. Completed-suicide rates of their countries of origin were compared to the SARs of the immigrant groups using rank correlations. 27 of 56 immigrant groups studied showed significantly higher, and only four groups significantly lower SARs than their hosts. Immigrant groups tended to have similar rates across different centres. Moreover, positive correlation between the immigrant SAR and the country-of-origin suicide rate was found. However, Chileans, Iranians, Moroccans, and Turks displayed high SARs as immigrants despite low suicide rates in the home countries. The similarity of most immigrant groups' SARs across centres, and the correlation with suicidality in the countries of origin suggest a strong continuity that can be interpreted in either cultural or genetic terms. However, the generally higher rates among immigrants compared to host populations and the similarity of the rates of foreign-born and those immigrants who retained the citizenship of their country of origin point to difficulties in the acculturation and integration process. The positive correlation found between attempted and completed suicide rates suggests that the two are related, a fact with strong implications for suicide prevention.


A novel medium for the enhanced cell growth and production of prodigiosin from Serratia marcescens isolated from soil.
Prodigiosin produced by Serratia marcescens is a promising drug owing to its reported characteristics of having antifungal, immunosuppressive and antiproliferative activity. From an industrial point of view the necessity to obtain a suitable medium to simultaneously enhance the growth of Serratia marcescens and the pigment production was the aim of this work. The usage of individual fatty acid as substrate in industries would be cost-effective in the long run and this paved the way for us to try the effect of different fatty acid-containing seeds and oils of peanut, sesame and coconut as source of substrate. The addition of sugars only showed slight enhancement of prodigiosin production in nutrient broth but not in fatty acid containing seed medium. The powdered peanut broth had supported better growth of Serratia marcescens and higher yield of prodigiosin when compared with the existing nutrient broth and peptone glycerol broth. A block in prodigiosin production was seen above 30 degrees C in nutrient broth, but the fatty acid seed medium used by us supported prodigiosin production upto 42 degrees C though the yields were lower than what was obtained at 28 degrees C. From the results, the fatty acid form of carbon source has a role to play in enhanced cell growth and prodigiosin production. We conclude by reporting that the powdered and sieved peanut seed of different quality grades were consistent in yielding a fourty fold increase in prodigiosin production over the existing media. A literature survey on the composition of the different media components in nutrient broth, peptone glycerol broth and the fatty acid containing seeds and oils enabled us to propose that the saturated form of fatty acid has a role to play in enhanced cell growth and prodigiosin production. This work has also enabled us to report that the temperature related block of prodigiosin biosynthesis varies with different media and the powdered peanut broth supports prodigiosin production at higher temperatures. The medium suggested in this work is best suitable from an industrial point of view in being economically feasible, in terms of the higher prodigiosin yield and the extraction of prodigiosin described in this paper is simple with minimal wastage.


Tactile imaging of an imbedded palpable structure for breast cancer screening.
Apart from texture, the human finger can sense palpation. The detection of an imbedded structure is a fine balance between the relative stiffness of the matrix, the object, and the device. If the device is too soft, its high responsiveness will limit the depth to which the imbedded structure can be detected. The sensation of palpation is an effective procedure for a physician to examine irregularities. In a clinical breast examination (CBE), by pressing over 1 cm(2) area, at a contact pressure in the 70-90 kPa range, the physician feels cancerous lumps that are 8- to 18-fold stiffer than surrounding tissue. Early detection of a lump in the 5-10 mm range leads to an excellent prognosis. We describe a thin-film tactile device that emulates human touch to quantify CBE by imaging the size and shape of 5-10 mm objects at 20 mm depth in a breast model using ∼80 kPa pressure. The linear response of the device allows quantification where the greyscale corresponds to the relative local stiffness. The (background) signal from <2.5-fold stiffer objects at a size below 2 mm is minimal.


Carrier recovery time in semiconductor optical amplifiers that employ holding beams.
An analytical expression for the carrier recovery time in semiconductor optical amplifiers (SOAs) that employ holding beams is presented. The amplifier model from which the expression is derived assumes a uniform carrier density along the SOA's length and that the signal and the holding beams both receive amplification. Simulations and experiments show that the expression predicts the recovery time well over a wide range of amplifier gains, holding beam powers, and configurations.


Evaluation of two group therapies to reduce fear of progression in cancer patients.
This paper aims to evaluate the effects of two psychotherapeutic interventions on dysfunctional fear of progression (FoP) in cancer patients and to investigate illness-specific influences. One hundred seventy-four cancer patients were recruited from two rehabilitation clinics and randomly assigned to either a four-session cognitive-behavioral group therapy or a supportive-experiential group therapy. The main outcome criterion was FoP that was assessed with the Fear of Progression Questionnaire (FoP-Q) directly before (T1) and after (T2) the intervention, as well as 3 (T3) and 12 months (T4) after discharge. Secondary outcomes were anxiety, depression, and quality of life that were assessed with the following questionnaires: Questions on Life Satisfaction, Questionnaire for General Health Status, and the Hospital Anxiety and Depression Scale. Patients from the control group (n = 91) who received treatment as usual were recruited 1 year later with the same inclusion criteria and assessed with the FoP-Q at T1, T2, and T4. Analyses showed a significant main effect for time and a significant interaction for group x time for the main outcome variable. FoP decreased significantly over time in both intervention groups in contrast to the control group that showed only short-term improvements. The interventions were also effective in improving secondary outcomes except general life satisfaction. Analyses of cancer specific influences on FoP indicated a significant influence of disease status, i.e., patients with metastases and recurrence of cancer gained most from the interventions. Fear of progression, one of the main sources of distress for cancer patients, can be reduced with short psychotherapeutic interventions.


Salivary caffeine in Parkinson's disease.
We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson's disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.


Ion channels and insulin secretion.
We review the role of ion channels in regulating insulin secretion from pancreatic beta-cells. By controlling ion permeability, ion channels at the membrane play a major role in regulating both electrical activity and signal transduction in the beta-cell. A proximal step in the cascade of events required for stimulus-secretion coupling is the closure of ATP-sensitive K+ channels, resulting in cell depolarization. Of particular relevance is the finding that this channel is directly regulated by a metabolite of glucose, which is the primary insulin secretagogue. In addition, this channel, or a closely associated protein, contains the sulfonylurea-binding site. Another K+ channel, the Ca2(+)-activated K+ channel, may be involved in cell repolarization to create homeostasis. Voltage-dependent Ca2+ channels are activated by cell depolarization and regulate Ca2+ influx into the cell. By controlling cytosolic free-Ca2+ levels ([Ca2+]i), these channels play an important role in transducing the initial stimulus to the effector systems that modulate insulin secretion. The link between a rise in [Ca2+]i and the terminal event of exocytosis is the least-understood aspect of stimulus-secretion coupling. However, phosphorylation studies have identified substrate proteins that may correspond to those involved in smooth muscle contraction, suggesting an analogy in the processes of stimulus secretion and excitation contraction. The advent of new methodology, particularly the patch-clamp technique, has fostered a more detailed characterization of the beta-cell ion channels. Furthermore, biochemical and molecular approaches developed for the structural analysis of ion channels in other tissues can now be applied to the isolation and characterization of the beta-cell ion channels. This is of particular significance because there appear to be tissue-specific variations in the different types of ion channels. Given the importance of ion channels in cell physiology, a knowledge of the structure and properties of these channels in the beta-cell is required for understanding the abnormalities of insulin secretion that occur in non-insulin-dependent diabetes mellitus. Ultimately, these studies should also provide new therapeutic approaches to the treatment of this disease.


Oxygen saturation monitoring in experimental surgery: a comparison of pulse oximetry and arterial blood gas measurement.
Experimental surgery in animal models often requires prolonged periods of general anesthesia. Animals undergoing these procedures may have difficulty maintaining normal ventilation and oxygenation and therefore may require physiologic monitoring and endotracheal intubation to avoid hypoxia that could adversely affect the results of the investigation. Monitoring has traditionally included measurements of PaO2, PCO2, pH, and oxygen saturation calculated from arterial blood. Endotracheal intubation and placement of arterial catheters necessary for the intraoperative collection of specimens for blood gas analysis are labor-intensive and time-consuming. In this study, rats undergoing thoracic laminectomy as part of a study on spinal cord injury were monitored by noninvasive pulse oximetry, with a reflectance transducer placed on the skin/fur of the neck overlying the cervical carotid artery. Comparison of these data with intermittent arterial blood gas measurements in the same animals indicated > 90% concordance with the pulse oximetry values. We also determined the fraction of inspired oxygen (FiO2) that, delivered via facemask, can achieve at least the minimal normal oxygen saturation (SaO2) of 90%. These findings suggest that physiologic monitoring during experimental rodent surgery can be substantially simplified by pulse oximetry and by delivery of oxygen via facemask, eliminating the need for arterial blood gas determinations or endotracheal intubation.


Stored light in an optical fiber via stimulated Brillouin scattering.
We describe a method for storing sequences of optical data pulses by converting them into long-lived acoustic excitations in an optical fiber through the process of stimulated Brillouin scattering. These stored pulses can be retrieved later, after a time interval limited by the lifetime of the acoustic excitation. In the experiment reported here, smooth 2-nanosecond-long pulses are stored for up to 12 nanoseconds with good readout efficiency: 29% at 4-nanosecond storage time and 2% at 12 nanoseconds. This method thus can potentially store data packets that are many bits long. It can be implemented at any wavelength where the fiber is transparent and can be incorporated into existing telecommunication networks because it operates using only commercially available components at room temperature.


Dual role of PKA in phenotypic modulation of vascular smooth muscle cells by extracellular ATP.
Extracellular ATP is released from activated platelets and endothelial cells and stimulates proliferation of vascular smooth muscle cells (VSMC). We found that ATP stimulates a profound but transient activation of protein kinase A (PKA) via purinergic P2Y receptors. The specific inhibition of PKA by adenovirus-mediated transduction of the PKA inhibitor (PKI) attenuates VSMC proliferation in response to ATP, suggesting a positive role for transient PKA activation in VSMC proliferation. By contrast, isoproterenol and forskolin, which stimulate a more sustained PKA activation, inhibit VSMC growth as expected. On the other hand, the activity of serum response factor (SRF) and the SRF-dependent expression of smooth muscle (SM) genes, such as SM-alpha-actin and SM22, are extremely sensitive to regulation by PKA, and even transient PKA activation by ATP is sufficient for their downregulation. Analysis of the dose responses of PKA activation, VSMC proliferation, SRF activity, and SM gene expression to ATP, with or without PKI overexpression, suggests the following model for the phenotypic modulation of VSMC by ATP, in which the transient PKA activation plays a critical role. At low micromolar doses, ATP elicits a negligible effect on DNA synthesis but induces profound SRF activity and SM gene expression, thus promoting the contractile VSMC phenotype. At high micromolar doses, ATP inhibits SRF activity and SM gene expression and promotes VSMC growth in a manner dependent on transient PKA activation. Transformation of VSMC by high doses of ATP can be prevented and even reversed by inhibition of PKA activity.


Selenium and iodine intakes and status in New Zealand and Australia.
Most New Zealand soils contain relatively low concentrations of the anionic trace elements F, I and Se. Some areas of Australia also have a history of I deficiency. In view of current interest in establishing nutrient reference intakes for Se and I in New Zealand and Australia, it is timely to review current understanding of the intakes and status of these two elements. In spite of a recent increase in Se status, the status of New Zealanders remains low compared with populations of many other countries and may still be considered marginal, although the clinical consequences of the marginal Se status are unclear. There are no recent reports of blood Se levels in Australia, but earlier reports indicate that they were generally greater than those of New Zealanders. Similarly, the consequences of decreasing I status in Australia and New Zealand are unclear. Mild I deficiency in New Zealand has resulted in enlarged thyroid glands indicating an increased risk of goitre. Currently there is little evidence, however, of any associated clinical disease. Public health recommendations to reduce salt intake, together with the reduction in I content of dairy products, are likely to result in further decreases in the I status of New Zealand and Australian residents. Some action is needed to prevent this decline and it may be necessary to consider other means of fortification than iodized salt. The consequences of possible interactions between Se and I in human nutrition are also unclear and no practical recommendations can be made.


Quinoa Seed Quality Response to Sodium Chloride and Sodium Sulfate Salinity.
Quinoa (Chenopodium quinoa Willd.) is an Andean crop with an edible seed that both contains high protein content and provides high quality protein with a balanced amino acid profile in embryonic tissues. Quinoa is a halophyte adapted to harsh environments with highly saline soil. In this study, four quinoa varieties were grown under six salinity treatments and two levels of fertilization, and then evaluated for quinoa seed quality characteristics, including protein content, seed hardness, and seed density. Concentrations of 8, 16, and 32 dS m(-1) of NaCl and Na2SO4, were applied to the soil medium across low (1 g N, 0.29 g P, 0.29 g K per pot) and high (3 g N, 0.85 g P, 0.86 g K per pot) fertilizer treatments. Seed protein content differed across soil salinity treatments, varieties, and fertilization levels. Protein content of quinoa grown under salinized soil ranged from 13.0 to 16.7%, comparable to that from non-saline conditions. NaCl and Na2SO4 exhibited different impacts on protein content. Whereas the different concentrations of NaCl did not show differential effects on protein content, the seed from 32 dS m(-1) Na2SO4 contained the highest protein content. Seed hardness differed among varieties, and was moderately influenced by salinity level (P = 0.09). Seed density was affected significantly by variety and Na2SO4 concentration, but was unaffected by NaCl concentration. The samples from 8 dS m(-1) Na2SO4 soil had lower density (0.66 g/cm(3)) than those from 16 dS m(-1) and 32 dS m(-1) Na2SO4, 0.74 and 0.72g/cm(3), respectively. This paper identifies changes in critical seed quality traits of quinoa as influenced by soil salinity and fertility, and offers insights into variety response and choice across different abiotic stresses in the field environment.


Global patterns of adverse drug reactions over a decade: analyses of spontaneous reports to VigiBase™.
Although systems to collect information about suspected adverse drug reactions (ADRs) were established in many countries and by the WHO in the 1960s, few studies have examined reported ADRs related to national income. The aim of the study was to characterize ADRs reported to the WHO-ADR database, VigiBase™, and to relate data to national income. We analysed ADR reports submitted to VigiBase™ from 2000 to 2009 with respect to reporting rate, age and sex of patient, type, seriousness and medications. Reports were also analysed with respect to national income level, classified in accordance with the World Bank definition: low, lower-middle, upper-middle and high. We analysed 1,359,067 ADR reports including 3,013,074 ADRs. Overall, 16% of reports were serious and 60% were reported for females. High-income countries had the highest ADR reporting rates (range 3-613 reports/million inhabitants/year) and low-income countries the lowest (range 0-21). Distribution of ADRs across income groups with respect to age group, seriousness and sex was non-significant. Overall, the majority of ADRs were reported for nervous system medications, followed by cardiovascular medicines. Low-income countries reported relatively more ADRs for antiinfectives for systemic use than high-income countries, and high-income countries reported more ADRs for antineoplastic and immunomodulating agents than lower-income groups. This study showed that high-income countries had the highest ADR reporting rates and low-income countries the lowest, with large variations across countries in each group. Significant differences in ADR reporting rates were only found for ADRs of the type 'skin and subcutaneous tissue disorders' and for the therapeutic groups 'antiinfectives for systemic use' and 'antineoplastic and immunomodulation agents'. To strengthen ADR reporting rates, especially in low-income countries, more research is needed about the impact of organizational structures and economic resources of national pharmacovigilance centres and ADR reporting practices on the large variations in ADR reporting rates within income groups.


Early cost-utility analysis of tissue-engineered heart valves compared to bioprostheses in the aortic position in elderly patients.
Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions. Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact. Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (- 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2-€12.8 million (TAVI) for TEHV substitution rates of 25-100%. Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.


The structure and function of the T3-Ti molecular complex on human T lymphocytes.
Recent studies using cloned antigen-specific T lymphocytes and monoclonal antibodies directed at their various surface glycoprotein components have led to identification of the human T cell antigen receptor as a surface complex composed of a clonotypic 90-kDa Ti heterodimer and the invariant 20- and 25-kDa T3 molecules. Approximately 30,000-40,000 Ti and T3 molecules exist on the surface of human T lymphocytes. These glycoproteins are acquired and expressed during late thymic ontogeny, thus providing the structural basis for immunologic competence. The Ti alpha and Ti beta subunits bear no precursor-to-product relationship and are encoded by separate germ line V, D, J, and C segments, which rearrange during intrathymic differentiation to form an active gene set. Triggering of the T3-Ti receptor complex induces a rapid increase in free cytoplasmic Ca2+ and gives rise to specific antigen-induced proliferation through an autocrine pathway involving endogenous IL 2 production, release, and subsequent binding to IL 2 receptors.


Relationship Between Circulating Serpina3g, Matrix Metalloproteinase-9, and Tissue Inhibitor of Metalloproteinase-1 and -2 with Chronic Obstructive Pulmonary Disease Severity.
Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A protease-antiprotease imbalance has been suggested as a possible pathogenic mechanism for COPD. Here, we examined the relationship between circulating serpina3g, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and -2, respectively) and severity of COPD. We included 150 stable COPD patients and 35 control subjects in the study. The COPD patients were classified into four groups (I, II, III, and IV), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines based on the severity of symptoms and the exacerbation risk. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in the all patients than in control subjects. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in groups III and IV than in groups I and II. A negative correlation between serpina3g, MMP-9, and TIMP-1 and -2 levels and the forced expiratory volume in 1 s (FEV1) was observed. MMP-9 concentration and the MMP-9/TIMP-1 ratio were higher in patients with emphysema than in other phenotypes (both with p < 0.01). The findings of this study suggest that circulating serpina3g, MMP-9, and TIMP-1 and -2 levels may play an important role in airway remodeling in COPD pathogenesis. Disrupted protease-antiprotease imbalance in patients with COPD is related to the presence of airway injury. MMP-9 concentration and the MMP-9/TIMP-1 ratio are the best predictors of emphysema in COPD patients.