Pasireotide for postoperative pancreatic fistula.
Postoperative pancreatic fistula is a major contributor to complications and death associated with pancreatic resection. Pasireotide, a somatostatin analogue that has a longer half-life than octreotide and a broader binding profile, decreases pancreatic exocrine secretions and may prevent postoperative pancreatic fistula. We conducted a single-center, randomized, double-blind trial of perioperative subcutaneous pasireotide in patients undergoing either pancreaticoduodenectomy or distal pancreatectomy. We randomly assigned 300 patients to receive 900 μg of subcutaneous pasireotide (152 patients) or placebo (148 patients) twice daily beginning preoperatively on the morning of the operation and continuing for 7 days (14 doses). Randomization was stratified according to the type of resection and whether the pancreatic duct was dilated at the site of transection. The primary end point was the development of pancreatic fistula, leak, or abscess of grade 3 or higher (i.e., requiring drainage). The primary end point occurred in 45 of the 300 patients (15%). The rate of grade 3 or higher postoperative pancreatic fistula, leak, or abscess was significantly lower among patients who received pasireotide than among patients who received placebo (9% vs. 21%; relative risk, 0.44; 95% confidence interval [CI], 0.24 to 0.78; P=0.006). This finding was consistent among 220 patients who underwent pancreaticoduodenectomy (10% vs. 21%; relative risk, 0.49; 95% CI, 0.25 to 0.95) and 80 patients who underwent distal pancreatectomy (7% vs. 23%; relative risk, 0.32; 95% CI, 0.10 to 0.99), as well as among 136 patients with a dilated pancreatic duct (2% vs. 15%; relative risk, 0.11; 95% CI, 0.02 to 0.60) and 164 patients with a nondilated pancreatic duct (15% vs. 27%; relative risk, 0.55; 95% CI, 0.29 to 1.01). Perioperative treatment with pasireotide decreased the rate of clinically significant postoperative pancreatic fistula, leak, or abscess. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00994110.).


Inhibition of MHC class II-restricted T cell response by Lyt-2 alloantigen.
T cell hybridomas were established by fusing a CD8+ V beta 8.1+ CTL clone and a CD4+ V beta 8.1+ helper T lymphocyte (HTL) clone to the thymoma cell line BW5147. In contrast to the HTL x BW hybridomas, which retain the same antigen specificity as the original T cell clone, the CTL x BW hybridomas lost the class I MHC-restricted antigen response but acquired a new specificity to Mlsa antigen. Mlsa reactivity of CTL x BW hybridomas was shown to be mediated by the CTL TCR as assayed by inhibition using an anticlonotypic antibody to the CTL clone. Since hybridomas established with BW5147 lose CD8 expression, we have introduced the CD8 molecule into CTL x BW5147 hybridomas by gene transfection. The CD8+ V beta 8.1+ hybridoma was no longer capable of reacting to Mlsa antigen but exhibited the same antigen specificity as the parental CTL clone. Furthermore, the presence of the transfected CD8 molecule in the HTL x BW hybridomas was found to be inhibitory to class II MHC-restricted antigen reactivity. These results demonstrate that, besides its role in increasing the overall avidity of T cell-class I MHC/antigen interaction, the CD8 molecule inhibits T cell-class II MHC gene product/antigen interaction. This negative effect of the CD8 molecule on a class II MHC-restricted response may account for the failure of CD8+ T cells using either V beta 8.1 or V beta 6, which impart reactivity to the Mlsa antigen on CD4+ T cells, to respond to the Mlsa antigen.


Locus of control, self-control, and health outcomes.
We provide the first empirical evidence on the direct link between locus of control and self-control, and how they interact in explaining a range of health outcomes. Using rich Australian survey data, we find that, while the two traits are distinct constructs, a greater internal locus of control is associated with higher self-control. The association between locus of control and health is reduced once we control for self-control, suggesting that self-control mediates at least part of this relationship. Finally, an internal locus of control amplifies the beneficial effects of self-control particularly for physical health.


Forgery detection and value identification of Euro banknotes.
This paper describes both hardware and software components to detect counterfeits of Euro banknotes. The proposed system is also able to recognize the banknote values. Differently than other state-of-the-art methods, the proposed approach makes use of banknote images acquired with a near infrared camera to perform recognition and authentication. This allows one to build a system that can effectively deal with real forgeries, which are usually not detectable with visible light. The hardware does not use any mechanical parts, so the overall system is low-cost. The proposed solution is reliable for ambient light and banknote positioning. Users should simply lean the banknote to be analyzed on a flat glass, and the system detects forgery, as well as recognizes the banknote value. The effectiveness of the proposed solution has been properly tested on a dataset composed by genuine and fake Euro banknotes provided by Italy's central bank.


The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease.
We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.


Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells.
Interferon regulatory factor 3 (IRF3) plays a crucial role in mediating cellular responses to virus intrusion. The protein kinase TBK1 is a key regulator inducing phosphorylation of IRF3. The regulatory mechanisms during IRF3 activation remain poorly characterized. In the present study, we have identified by yeast two-hybrid approach a specific interaction between IRF3 and chaperone heat-shock protein of 90 kDa (Hsp90). The C-terminal truncation mutant of Hsp90 is a strong dominant-negative inhibitor of IRF3 activation. Knockdown of endogenous Hsp90 by RNA interference attenuates IRF3 activation and its target gene expressions. Alternatively, Hsp90-specific inhibitor geldanamycin (GA) dramatically reduces expression of IRF3-regulated interferon-stimulated genes and abolishes the cytoplasm-to-nucleus translocation and DNA binding activity of IRF3 in Sendai virus-infected cells. Significantly, virus-induced IRF3 phosphorylation is blocked by GA, whereas GA does not affect the protein level of IRF3. In addition, TBK1 is found to be a client protein of Hsp90 in vivo. Treatment of 293 cells with GA interferes with the interaction of TBK1 and Hsp90, resulting in TBK1 destabilization and its subsequent proteasome-mediated degradation. Besides maintaining stability of TBK1, Hsp90 also forms a novel complex with TBK1 and IRF3, which brings TBK1 and IRF3 dynamically into proximity and facilitates signal transduction from TBK1 to IRF3. Our study uncovers an essential role of Hsp90 in the virus-induced activation of IRF3.


2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis.
In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.


Using Cochrane reviews for oral diseases.
To provide readers with information about the Cochrane Oral Health Group and how the reviews on oral diseases have contributed to guideline developments and the commissioning of trials. Examples have been selected from the reviews published on The Cochrane Library. Descriptions are given of how these reviews have been used in guideline development and commissioning of trials. Readers are updated on reviews focused on the management of oral cancer and the new venture of diagnostic test reviews. Reviews on the management of oral diseases due to cancer treatments have been included in guidelines and changed practice in the UK. Cochrane reviews on Bell's Palsy have led to a randomised controlled trial which has changed the evidence base. The Cochrane review on recall intervals between routine appointments has input into the NICE guideline and resulted in a randomised controlled trial to look at different intervals including a risk-based interval. We hope this article will give readers information on the work of the Cochrane Oral Health Group and insight into the diversity of reviews in oral diseases. The reviews are successfully being used to change practice and as background for the funding of large-scale clinical trials.


Crystal structure of ErmE - 23S rRNA methyltransferase in macrolide resistance.
Pathogens often receive antibiotic resistance genes through horizontal gene transfer from bacteria that produce natural antibiotics. ErmE is a methyltransferase (MTase) from Saccharopolyspora erythraea that dimethylates A2058 in 23S rRNA using S-adenosyl methionine (SAM) as methyl donor, protecting the ribosomes from macrolide binding. To gain insights into the mechanism of macrolide resistance, the crystal structure of ErmE was determined to 1.75 Å resolution. ErmE consists of an N-terminal Rossmann-like α/ß catalytic domain and a C-terminal helical domain. Comparison with ErmC' that despite only 24% sequence identity has the same function, reveals highly similar catalytic domains. Accordingly, superposition with the catalytic domain of ErmC' in complex with SAM suggests that the cofactor binding site is conserved. The two structures mainly differ in the C-terminal domain, which in ErmE contains a longer loop harboring an additional 310 helix that interacts with the catalytic domain to stabilize the tertiary structure. Notably, ErmE also differs from ErmC' by having long disordered extensions at its N- and C-termini. A C-terminal disordered region rich in arginine and glycine is also a present in two other MTases, PikR1 and PikR2, which share about 30% sequence identity with ErmE and methylate the same nucleotide in 23S rRNA.


A post-market, prospective, multi-center, single-arm clinical investigation of Phasix™ mesh for VHWG grade 3 midline incisional hernia repair: a research protocol.
Incisional heia is a frequent complication of midline laparotomy. The use of mesh in hernia repair has been reported to lead to fewer recurrences compared to primary repair. However, in Ventral Hernia Working Group (VHWG) Grade 3 hernia patients, whose hernia is potentially contaminated, synthetic mesh is prone to infection. There is a strong preference for resorbable biological mesh in contaminated fields, since it is more able to resist infection, and because it is fully resorbed, the chance of a foreign body reaction is reduced. However, when not crosslinked, biological resorbable mesh products tend to degrade too quickly to facilitate native cellular ingrowth. Phasix™ Mesh is a biosynthetic mesh with both the biocompatibility and resorbability of a biological mesh and the mechanical strength of a synthetic mesh. This multi-center single-arm study aims to collect data on safety and performance of Phasix™ Mesh in Grade 3 hernia patients. A total of 85 VHWG Grade 3 hernia patients will be treated with Phasix™ Mesh in 15 sites across Europe. The primary outcome is Surgical Site Occurrence (SSO) including hematoma, seroma, infection, dehiscence and fistula formation (requiring intervention) through 3 months. Secondary outcomes include recurrence, infection and quality of life related outcomes after 24 months. Follow-up visits will be at drain removal (if drains were not placed, then on discharge or staple removal instead) and in the 1st, 3rd, 6th, 12th, 18th and 24th month after surgery. Based on evidence from this clinical study Depending on the results this clinical study will yield, Phasix™ Mesh may become a preferred treatment option in VHWG Grade 3 patients. The trial was registered on March 25, 2016 on clinicaltrials.gov: NCT02720042 .


Clinical application of the two-layer (University of Wisconsin solution/perfluorochemical plus O2) method of pancreas preservation before transplantation.
The two-layer method [University of Wisconson solution (UW)/perfluorochemical plus O2] for pancreas preservation has been demonstrated to be superior to simple UW storage alone in the canine model. For the first time, we applied the two-layer method to clinical whole-pancreas transplantation. Pancreases were placed in the two-layer method in 10 cases and UW alone in 44 cases before transplant. The mean cold ischemic time was 16.5 hr in the two-layer group versus 18.1 hr in the UW group (P=NS). We compared the condition of graft at the time of reperfusion, and then 3 months posttransplant graft function and complications. At the time of reperfusion, no grafts in the two-layer group were edematous, compared with 10(23.3%) of 43 in the UW group (P=0.18). Seven (70%) of 10 grafts in the two-layer group obtained the best overall quality score, compared with 24(57.1%) of 42 in the UW group (P=0.72). Nine (90%) of 10 recipients in the two-layer group became insulin-independent during hospitalization, compared with 31(70.5%) of 44 in the UW group (P=0.26). Time to insulin independence was no different between the two groups. No pancreas grafts preserved by the two-layer method suffered acute rejection. Conclusions. The two-layer preservation method is feasible in human clinical transplantation. It was at least equivalent and may be superior to UW alone in both morphologic and functional assessment of the transplanted pancreas.


Effect of prior immobilization on muscular glucose clearance in resting and running rats.
In vitro studies have shown that prior disuse impairs the glucose clearance of red skeletal muscle because of a developed insensitivity to insulin. We studied whether an impaired glucose clearance is present in vivo in 42-h immobilized muscles of resting rats and, furthermore, whether the exercise-induced increase in glucose clearance of red muscles is affected by prior immobilization. The 2-[3H]deoxy-D-glucose (2DG) bolus injection method was used to determine glucose clearance of individual muscles. At rest, glucose clearance was markedly impaired in rats with previously immobilized red muscles compared with nonimmobilized control rats (red gastrocnemius 0.46 +/- 0.02 vs. 0.99 +/- 0.08 and soleus 1.10 +/- 0.30 vs. 3.97 +/- 0.54 ml.min-1.100 g-1, P less than 0.005). During running (18 m/min), glucose clearance did not differ between muscles in previously immobilized and control rats. Insulin levels were always similar in the two groups and decreased during exercise. Intracellular nonphosphorylated 2DG was present in tissues with high glucose clearances. In conclusions, 42 h of immobilization markedly impairs glucose clearance of resting red muscle fibers in vivo. Apparently, physical inactivity in particular affects steps involved in insulin-mediated action that are not part of contraction-induced glucose uptake and metabolism. Presence of intracellular 2DG shows that separate determination of phosphorylated 2DG is necessary for accurate estimates of glucose metabolism and that accumulation of phosphorylated 2DG does not accurately reflect glucose transport.


Predictors of long-lasting insecticide-treated bed net ownership and utilization: evidence from community-based cross-sectional comparative study, Southwest Ethiopia.
Malaria is the notorious impediment of public health and economic development. Long-lasting insecticide-treated bed nets/insecticide-treated bed nets (LLINs/ITNs) are among major intervention strategies to avert the impact the disease. However, effectiveness of LLINs/ITNs depends on, inter alia, possessing sufficient number, proper utilization and timely replacement of nets. Thus, the World Health Organization (WHO) recommends surveys to evaluate possession and proper use of LLINs/ITNs by households. A cross-sectional comparative household survey was conducted during peak malaria transmission season using interviewer-introduced questionnaires in southwest Ethiopia. A study site was selected from villages around a man-made lake, Gilgel-Gibe (GG) and a control site, with similar geographic and socio-economic features but far away from the lake, was identified. A total of 2,373 households from randomly selected cluster of households were included into the study and heads/spouses of the households responded to interviews. Binary and multinomial logistic regressions were used to identify predictors of LLIN ownership and utilization. LLIN/ITN ownership among the study populations was 56.6%, while 43.4% of households did not own a net. A higher proportion of households in GG reported owning at least one LLITN/ITN compared to control village (OR =2. 2, P <0.001) and more households in GG reported having only one LLITN/ITN in contrast to households in the control village (OR = 2.1, P <0.001). The mean number of LLINs/ITNs owned was 1.6 for GG residents and 1.8 for control village with a mean difference of -0.26 (95% CI = - 0.34, -0.19). The age of household heads, household relative wealth index (RWI), distance to nearest health service and accessibility to transportation showed a significant association with ownership of LLINs/ITNs. The probability of owning two or more LLINs/ITNs was positively associated with age of household head. Marital status of household heads, RWI, distance to nearest health service, accessibility to transport, residence and household size showed a significant association with utilization of LLINs/ITNs. Attention needs to be given to the poor, distant and inaccessible households in the efforts of malaria intervention programmes, such as free distribution of LLINs/ITNs. Well-tailored information, education and communication is needed to address the problem of non-users.


Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathy.
A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich's ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.


Physiology of the orexinergic/hypocretinergic system: a revisit in 2012.
The neuropeptides orexins and their G protein-coupled receptors, OX(1) and OX(2), were discovered in 1998, and since then, their role has been investigated in many functions mediated by the central nervous system, including sleep and wakefulness, appetite/metabolism, stress response, reward/addiction, and analgesia. Orexins also have peripheral actions of less clear physiological significance still. Cellular responses to the orexin receptor activity are highly diverse. The receptors couple to at least three families of heterotrimeric G proteins and other proteins that ultimately regulate entities such as phospholipases and kinases, which impact on neuronal excitation, synaptic plasticity, and cell death. This article is a 10-year update of my previous review on the physiology of the orexinergic/hypocretinergic system. I seek to provide a comprehensive update of orexin physiology that spans from the molecular players in orexin receptor signaling to the systemic responses yet emphasizing the cellular physiological aspects of this system.


Assessing the content validity of the Manchester-Oxford Foot Questionnaire in surgically treated ankle fracture patients: a qualitative study.
Roughly 10% of fractures in adults are ankle fractures. These injuries are found in both sexes and present with different fracture characteristics. The treatment varies with the patients' biology and fracture type, and the goals are to restore stability, prevent pain and maintain ankle function. Clinicians generally use outcomes like assessment of radiography, pain level, or function. The use of patient-reported outcome measures is increasing, and the Manchester-Oxford Foot Questionnaire (MOXFQ) has been shown to have good measurement properties when validated in patients with foot and ankle disorders. However, the instrument has not been validated for ankle fracture patients. This study aims to assess the content validity of the items in MOXFQ in surgically treated ankle fracture patients. A qualitative deductive design was used to investigate patients' response process of the MOXFQ. Individual interviews were conducted using cognitive interviewing based on the theoretical framework of the 4-step model by Tourangeau. Adult patients that were surgically treated for an ankle fracture between four weeks and 18 months were purposively sampled, and interviews followed a semi-structured interview guide. The predetermined categories were comprehension, retrieval, judgement, and response. Seventeen respondents (65% females) were interviewed. Respondents' age ranged from 27 to 76 years. Some of the respondents in the early recovery phase were limited by post-operative restrictions and did not find the items in the walking/standing domain relevant. Respondents that were allowed weight-bearing as tolerated (WBAT) were able to recall relevant information for most items. Respondents with time since surgery more than 12 months had less pain and remembered fewer relevant episodes in the recall period. Items in the social interaction domain contained ambiguous questions and were generally considered less important by respondents. The summary index score lacked important concepts in measuring overall quality of life. Pain was a central concept in the post-operative recovery of ankle fracture patients. The MOXFQ-subscales for pain and walking/standing had acceptable content validity in patients that were allowed WBAT. The social interaction-subscale and the summary index score had insufficient content validity for this patient population.


CO₂ and inorganic nutrient enrichment affect the performance of a calcifying green alga and its noncalcifying epiphyte.
Ocean acidification studies in the past decade have greatly improved our knowledge of how calcifying organisms respond to increased surface ocean CO2 levels. It has become evident that, for many organisms, nutrient availability is an important factor that influences their physiological responses and competitive interactions with other species. Therefore, we tested how simulated ocean acidification and eutrophication (nitrate and phosphate enrichment) interact to affect the physiology and ecology of a calcifying chlorophyte macroalga (Halimeda opuntia (L.) J.V. Lamouroux) and its common noncalcifying epiphyte (Dictyota sp.) in a 4-week fully crossed multifactorial experiment. Inorganic nutrient enrichment (+NP) had a strong influence on all responses measured with the exception of net calcification. Elevated CO2 alone significantly decreased electron transport rates of the photosynthetic apparatus and resulted in phosphorus limitation in both species, but had no effect on oxygen production or respiration. The combination of CO2 and +NP significantly increased electron transport rates in both species. While +NP alone stimulated H. opuntia growth rates, Dictyota growth was significantly stimulated by nutrient enrichment only at elevated CO2, which led to the highest biomass ratios of Dictyota to Halimeda. Our results suggest that inorganic nutrient enrichment alone stimulates several aspects of H. opuntia physiology, but nutrient enrichment at a CO2 concentration predicted for the end of the century benefits Dictyota sp. and hinders its calcifying basibiont H. opuntia.


Metabolic diversity in sweet potato (Ipomoea batatas, Lam.) leaves and storage roots.
Sweet potato (Ipomoea batatas, Lam.) is an important root vegetable in developing countries. After its domestication in Neotropical America, human migration led to the distribution of the sweet potato plant throughout the world. Both leaf and storage root are high in compounds of nutritional value. Yet, the storage roots are of particular value due to their significant content of provitamin A (β-carotene). The breeding effort for elite sweet potato lines led to the reduction of genetic diversity and the potential to improve other traits. The focus of the present study was to assess the metabolic diversity of 27 sweet potato cultivars including landraces and improved varieties. A metabolite profiling approach was optimised for sweet potato leaf and storage root tissue and 130 metabolites identified with three different analysis platforms. The data highlighted a lack of correlation between storage root phenotype and leaf metabolism. Furthermore, the metabolic diversity of storage roots was based on the secondary metabolism, including phenylpropanoids and carotenoids. Three cultivars of three different flesh colouration (yellow, orange and purple) showed a significant difference of the primary metabolism. This data demonstrates the value of metabolite profiling to breeding programs as a means of identifying differences in phenotypes/chemotypes and characterising parental material for future pre-breeding resources.


Monitoring RNA unwinding by the transcription termination factor Rho from Mycobacterium tuberculosis.
Transcription termination factor Rho is a ring-shaped, homo-hexamieric RNA translocase that dissociates transcription elongation complexes and transcriptional RNA-DNA duplexes (R-loops) in bacteria. The molecular mechanisms underlying these biological functions have been essentially studied with Rho enzymes from Escherichia coli or close Gram-negative relatives. However, phylo-divergent Rho factors may have distinct properties. Here, we describe methods for the preparation and in vitro characterization (ATPase and helicase activities) of the Rho factor from Mycobacterium tuberculosis, a specimen with uncharacteristic molecular and enzymatic features. These methods set the stage for future studies aimed at better defining the diversity of enzymatic properties of Rho across the bacterial kingdom.


Rat dorsal paired island skin flaps: a precise model for flap survival evaluation.
Rectangular flaps on the rat or mouse dorsum are frequently used for flap survival elongation research. However, since rectangular flaps are purely random, the survival rate varies among individuals. A reliable animal flap model with low individual variation is desirable for flap survival research, especially in the angiogenic field. We investigated the survival rate of paired flaps in the rat dorsum containing 3 vascular territories in each flap, and determined their usefulness for flap elongation research. Two symmetrical adjoining rectangular flaps (11 x 3 cm each) were drawn on the rat dorsum. Two days after material injection, flaps were elevated with only the deep circumflex iliac vessels as the vascular pedicle. Flaps were immediately sutured back and the flap survival area was measured 7 days after the operation. The control group (n = 9) had saline solution injected in both flaps. The bone marrow group (n = 8) had bone marrow injected in the right flap, and saline solution injected in the left flap. In the control group, the survival rate of the paired flaps was not statistically different (right flap, 89.0+/-5.6%; left flap, 89.3+/-4.5%). In the bone marrow group, the survival rate between the bone marrow injected flap (89.9+/-3.7%), and the saline flap (84.8+/-4.3%) was statistically different. The rat dorsal paired island skin flap model shows low difference in flap survival rate and uses an internal control. This is a suitable model for flap survival elongation research.


Simultaneous analysis of ochratoxin A and its major metabolite ochratoxin alpha in plasma and urine for an advanced biomonitoring of the mycotoxin.
Ochratoxin A (OTA) is a frequent mycotoxin contaminant found worldwide in foods and feedstuffs. Biomonitoring has been used to assess internal OTA exposure resulting from dietary intake and from other sources. Mycotoxin levels in blood and/or urine provide good estimates of past and recent exposure since OTA binds to serum proteins and is also partly excreted via the kidney. But, measuring OTA alone does not reflect its biotransformation. In light of scarce data on its metabolites in humans, it was the aim of this study to develop a method that allows analysis of OTA and its detoxication product ochratoxin alpha (OTα) in urine and in blood plasma. The method involves enzymatic hydrolysis of conjugates, liquid-liquid extraction, and analysis of sample extracts by liquid chromatography with fluorescence detection. Application of the validated method in a pilot study with 13 volunteers revealed the presence of OTA and OTα in all samples (limit of quantification: 0.05 ng/mL in urine, and 0.1 ng/mL in plasma). In line with negative findings of others, an OTA glucuronide was not detected, neither in urine nor in plasma. By contrast, conjugates of OTα (glucuronide and/or sulfate) are major products in these samples. This was confirmed by mass spectrometry detection. As OTα represents a large fraction of ingested mycotoxin, we propose to include analyses of this metabolite in future biomonitoring studies, also in light of the observed variations for urine OTα-levels that suggest different interindividual abilities for OTA-detoxification in humans.


Slow updating of the achromatic point after a change in illumination.
For a color constant observer, the color appearance of a surface is independent of the spectral composition of the light illuminating it. We ask how rapidly color appearance judgments are updated following a change in illumination. We obtained repeated binary color classifications for a set of stimuli defined by their reflectance functions and rendered under either sunlight or skylight. We used these classifications to derive boundaries in color space that identify the observer's achromatic point. In steady-state conditions of illumination, the achromatic point lay close to the illuminant chromaticity. In our experiment, the illuminant changed abruptly every 21 s (at the onset of every 10th trial), allowing us to track changes in the achromatic point that were caused by the cycle of illuminant changes. In one condition, the test reflectance was embedded in a spatial pattern of reflectance samples under consistent illumination. The achromatic point migrated across color space between the chromaticities of the steady-state achromatic points. This update took several trials rather than being immediate. To identify the factors that governed perceptual updating of appearance judgments, we used two further conditions, one in which the test reflectance was presented in isolation and one in which the surrounding reflectances were rendered under an inconsistent and unchanging illumination. Achromatic settings were not well predicted by the information available from scenes at a single time point. Instead, the achromatic points showed a strong dependence on the history of chromatic samples. The strength of this dependence differed between observers and was modulated by the spatial context.


Main Considerations of Cardiogenic Shock and Its Predictors: Systematic Review.
The mortality rate of post-infarction cardiogenic shock (CS) was 80.0-90.0%. Recent studies show a significant reduction of hospital mortality to approximately 50.0%. CS is defined as systemic tissue hypoperfusion resulting from systolic and/or diastolic heart dysfunction, the main cause of which is acute myocardial infarction (AMI). The main predictors are biological markers such as troponin, CKMB and lactate. A systematic literature review and meta-analysis is performed in order to present and correlate the main literary findings on CS and its evolution with possible changes in biomarkers such as troponin, lactate and CKMB. After criteria of literary search with the use of the mesh terms: cardiogenic shock; acute myocardial infarction; biomarkers; troponin; CKMB; lactate; clinical trials and use of the bouleanos "and" between the mesh terms and "or" among the historical findings. In the main databases such as Pubmed, Medline, Bireme, EBSCO, Scielo, etc., a total of 96 papers that were submitted to the eligibility analysis were collated and, after that, 41 studies were selected, following the rules of systematic review - PRISMA (Transparent reporting of systematic reviews and meta-analyzes-http://www.prisma-statement.org/). Some risk factors for its development in AMI are advanced age, female gender, anterior wall infarction, diabetes mellitus, systemic arterial hypertension, previous history of infarction and angina. The CS associated with AMI depends on its extent and its complications, being the main ones: mitral regurgitation, rupture of the interventricular septum and rupture of the free wall of the left ventricule. The diagnosis is based on the clinical manifestations, such as mental confusion, oliguria, hypotension, tachycardia, fine pulse, sweating, and cold extremities; in hemodynamic aspects: systolic blood pressure was < 90.0 mm Hg or 30 mm Hg below baseline, pulmonary capillary pressure was > 18.0 mm Hg and cardiac index was < 2.2 L/min/m2. Laboratory and imaging exams should be requested to evaluate the possible etiology of CS, its systemic repercussions and comorbidities. The treatment aims at the rapid reestablishment of the blood flow in the affected artery, to improve the patient's prognosis. The biomarkers dosage in the daily clinical practice of the different cardiological centers can facilitate the diagnosis and the conduction of the dubious cases and the best evaluation of the degree of myocardial suffering after CS.


HTLV infection in Brazil's second-largest indigenous reserve.
Human T-lymphotropic viruses 1 and 2 (HTLV-1/2) have a worldwide distribution. HTLV-1 has been associated with several diseases, including an aggressive malignant disease known as adult T-cell leukemia/lymphoma and a chronic inflammatory neurological disease called HTLV-1-associated myelopathy, while HTLV-2 has not been definitively associated with diseases. HTLV-2 is most prevalent in specific groups such as injecting drug users and the indigenous population. In Brazil, most studies about HTLV in indigenous are carried out in indigenous communities from the north of the country. Mato Grosso do Sul (MS), Central Brazil, has the second-largest indigenous population in Brazil. However, there is no available data about HTLV infection in this group. We conducted the first investigation of HTLV-1/2 infection prevalence in the indigenous population from Jaguapiru and Bororó villages in Dourados City, MS, to provide the prevalence and molecular characterization of HTLV. For that, a total of 1875 indigenous participated in the study. All the serum samples were screened by an enzyme-linked immunosorbent assay commercial kit for the presence of anti-HTLV-1/2 antibodies. Positive samples were confirmed by HTLV-1/2 Western Blot assay. The HTLV-1 5'LTR region was detected by nested PCR amplification and sequenced by Sanger. Most of the study population declared belonging to Guarani-Kaiowá ethnicity (69.18%), 872 (46.51%), and 1003 (53.49%) were from Jaguapiru and Bororó villages, respectively. The median age of participants was 31 years, and 74.24% were females. Two individuals were detected with HTLV-1 (0.1%; CI 95% 0.1-0.2). The phylogenetic analysis revealed that isolates belong to the Cosmopolitan subtype and the Transcontinental subgroup (HTLV-1aA). The low HTLV-1 prevalence found in this study is similar to that observed among blood donors, and pregnant populations from Mato Grosso do Sul. The absence of HTLV-2 infection among these Brazilian indigenous communities would suggest a distinct behavior pattern from other indigenous populations in Brazil.


Membrane Dynamics Induced by a Phosphatidylinositol 3,4,5-Trisphosphate Optogenetic Tool.
Membrane dynamic structures such as filopodia, lamellipodia, and ruffles have important cellular functions in phagocytosis and cell motility, and in pathological states, such as cancer metastasis. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) is a crucial lipid that regulates PIP3 dynamics. Investigations of how PIP3 is involved in these functions have mainly relied on pharmacological interventions, and therefore have not generated detailed spatiotemporal information concerning membrane dynamics upon PIP3 production. In the present study, we applied an optogenetic approach using the CRY2-CIBN system. Using this system, we revealed that local PIP3 generation induced directional cell motility and membrane ruffles in COS7 cells. Furthermore, combined with structured illumination microscopy (SIM), membrane dynamics were investigated with high spatial resolution. We observed PIP3-induced apical ruffles and unique actin fiber behavior in that a single actin fiber protruded from the plasma membrane was taken up into the plasma membrane without depolymerization. This system has the potential to investigate other high-level cell motility and dynamic behaviors, such as cancer cell invasion and wound healing with high spatiotemporal resolution, and could provide new insights of biological sciences for membrane dynamics.


Estimating exposure in studies of residential magnetic fields and cancer: importance of short-term variability, time interval between diagnosis and measurement, and distance to power line.
Validity of exposure assessment methods has been a major concern in epidemiologic studies of magnetic field exposure and cancer. We conducted a study to evaluate the relative importance of distance to power lines and calculated historical magnetic fields when estimating past magnetic field exposure. Another goal was to compare results based on various estimates of magnetic field exposure, to assess the importance of short-term variability in magnetic fields, time between diagnosis and measurement, and sources of magnetic field exposure. We used data from a Swedish case-control study of residential exposure to magnetic fields and cancer. Childhood leukemia risk was associated with calculated historical annual average magnetic fields regardless of distance, and the association with distance disappeared when both variables were entered into the same logistic regression model. Relative risks for measurements at the time of the study (contemporary annual average fields, spot calculations, and spot measurements) were all close to or below unity. The results support the hypothesis that the difference between results using historical calculations and spot measurements is explained by the time interval between diagnosis and contemporary magnetic field estimates.


Improved response by peers after witnessed heroin overdose in Melbourne.
In response to concerns about the prevalence of heroin-related morbidity and mortality, overdose response training programs have been implemented in Victoria, with the aim of improving outcomes after heroin overdose. The aim of this study was to examine reported overdose response by current injecting drug users (IDU) during overdose events, in comparison with previous studies. A total of 99 IDU (median age 35 years, 72% male) were administered a questionnaire that collected information on knowledge and experience regarding recognition of heroin overdose and response. The primary outcome measure was the rate of ambulance notification and expired air resuscitation during witnessed heroin overdose. Data were analysed using descriptive statistics and univariate analysis. Sixty participants had overdosed at least once, and 84% had witnessed an overdose. 78% recognised altered consciousness as a sign of heroin overdose, but less were aware of depressed breathing (42%) or cyanosis (61%). Reported overdose interventions included correct positioning (39%), expired air resuscitation (32%), ambulance notification (76%) and staying with the victim (87%). Our study has found improved responses to heroin overdose during witnessed heroin overdose among current IDU, compared with earlier work. However, a lack of knowledge regarding appropriate first-aid response persists, which might improve with the development and implementation of training initiatives in this area, ranging from identification of overdose to the administration of life-saving measures.


Ursolic acid: Pharmacokinetics process in vitro and in vivo, a mini review.
Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. UA has a widespread pharmacologic effect, including antitumor, anti-inflammatory, anti-oxidant, anti-apoptotic, anti-allergy, and anti-carcinogenic effects. UA can be used as an alternative medicine for the treatment and prevention of many diseases. However, the bioavailability of UA by oral administration is low since it is absorbed by the intestine through passive diffusion. Therefore, some novel technologies are used to produce UA preparations that can change the pharmacokinetics process and increase its solubility and bioavailability. At present, pharmacokinetic studies on UA are few. In this paper, we will review the pharmacokinetics features of free UA and some novel UA preparations in vitro and in vivo, in order to provide a reference for rational utilization and drug design of UA.


Unexpected decline in tuberculosis cases coincident with economic recession - United States, 2009.
Since 1953, through the cooperation of state and local health departments, the U.S. Centers for Disease Control and Prevention (CDC) has collected information on incident cases of tuberculosis (TB) disease in the United States. In 2009, TB case rates declined -11.4%, compared to an average annual -3.8% decline since 2000. The unexpectedly large decline raised concerns that TB cases may have gone unreported. To address the unexpected decline, we examined trends from multiple sources on TB treatment initiation, medication sales, and laboratory and genotyping data on culture-positive TB. We analyzed 142,174 incident TB cases reported to the U. S. National Tuberculosis Surveillance System (NTSS) during January 1, 2000-December 31, 2009; TB control program data from 59 public health reporting areas; self-reported data from 50 CDC-funded public health laboratories; monthly electronic prescription claims for new TB therapy prescriptions; and complete genotyping results available for NTSS cases. Accounting for prior trends using regression and time-series analyses, we calculated the deviation between observed and expected TB cases in 2009 according to patient and clinical characteristics, and assessed at what point in time the deviation occurred. The overall deviation in TB cases in 2009 was -7.9%, with -994 fewer cases reported than expected (P < .001). We ruled out evidence of surveillance underreporting since declines were seen in states that used new software for case reporting in 2009 as well as states that did not, and we found no cases unreported to CDC in our examination of over 5400 individual line-listed reports in 11 areas. TB cases decreased substantially among both foreign-born and U.S.-born persons. The unexpected decline began in late 2008 or early 2009, and may have begun to reverse in late 2009. The decline was greater in terms of case counts among foreign-born than U.S.-born persons; among the foreign-born, the declines were greatest in terms of percentage deviation from expected among persons who had been in the United States less than 2 years. Among U.S.-born persons, the declines in percentage deviation from expected were greatest among homeless persons and substance users. Independent information systems (NTSS, TB prescription claims, and public health laboratories) reported similar patterns of declines. Genotyping data did not suggest sudden decreases in recent transmission. Our assessments show that the decline in reported TB was not an artifact of changes in surveillance methods; rather, similar declines were found through multiple data sources. While the steady decline of TB cases before 2009 suggests ongoing improvement in TB control, we were not able to identify any substantial change in TB control activities or TB transmission that would account for the abrupt decline in 2009. It is possible that other multiple causes coincident with economic recession in the United States, including decreased immigration and delayed access to medical care, could be related to TB declines. Our findings underscore important needs in addressing health disparities as we move towards TB elimination in the United States.


Monomer adsorption on equilateral triangular lattices with attractive first-neighbor interactions.
We have recently studied a model of monomer adsorption on infinitely long equilateral triangular lattices with terraces of finite width M and nonperiodic boundaries. This study was restricted to the case of repulsive adsorbate-adsorbate first-neighbor interactions but included attractive, repulsive, and negligible second-neighbor interactions. The present work extends this study to the case of attractive first-neighbors, and the phases are determined, as before, with a confidence exceeding 10 significant figures. Phase diagrams are included for terrace widths M < or =11. Most of the occupational characteristics of the phases fit exact analytic expressions in M. The infinite-M limit of these expressions, combined with other analyses, provide the complete phase diagram for the infinite two-dimensional lattice. In addition to the empty and full coverage phases, there are three phases exhibiting stripe and cluster features that were not observed in the case of repulsive first-neighbors.


Seasonal changes in the cardiovascular, respiratory and metabolic responses to temperature and hypoxia in the bullfrog rana catesbeiana
We assessed seasonal variations in the effects of temperature on hypoxia-induced alterations in the bullfrog Rana catesbeiana by measuring the heart rate, arterial blood pressure, breathing frequency, metabolic rate, blood gas levels, acid-base status and plasma glucose concentration. Regardless of the season, decreased body temperature was accompanied by a reduction in heart and breathing frequencies. Lower temperatures caused a significant decrease in arterial blood pressure during all four seasons. Hypoxia-induced changes in breathing frequency were proportional to body temperature and were more pronounced during winter, less so during spring and autumn and even smaller during summer. Season had no effect on the relationship between hypoxia and heart rate. At any temperature tested, the rate of oxygen consumption had a tendency to be highest during summer and lowest during winter, but the difference was significant only at 35 degrees C. The PaO2 and pH values showed no significant change during the year, but PaCO2 was almost twice as high during winter than in summer and spring, indicating increased plasma bicarbonate levels. Lower temperatures were accompanied by decreased plasma glucose levels, and this effect was greater during summer and smaller during autumn. Hypoxia-induced hyperglycaemia was influenced by temperature and season. During autumn and winter, plasma glucose level remained elevated regardless of temperature, probably to avoid dehydration and/or freezing. In winter, the bullfrog may be exposed not only to low temperatures but also to hypoxia. These animals show temperature-dependent responses that may be beneficial since at low body temperatures the set-points of most physiological responses to hypoxia are reduced, regardless of the season. <P>


The AVR4 elicitor protein of Cladosporium fulvum binds to fungal components with high affinity.
The interaction between tomato and the fungal pathogen Cladosporium fulvum complies with the gene-for-gene system. Strains of C. fulvum that produce race-specific elicitor AVR4 induce a hypersensitive response, leading to resistance, in tomato plants that carry the Cf-4 resistance gene. The mechanism of AVR4 perception was examined by performing binding studies with 125I-AVR4 on microsomal membranes of tomato plants. We identified an AVR4 high-affinity binding site (KD = 0.05 nM) which exhibited all the characteristics expected for ligand-receptor interactions, such as saturability, reversibility, and specificity. Surprisingly, the AVR4 high-affinity binding site appeared to originate from fungi present on infected tomato plants rather than from the tomato plants themselves. Detailed analysis showed that this fungus-derived, AVR4-specific binding site is heat- and proteinase K-resistant. Affinity crosslinking demonstrated that AVR4 specifically binds to a component of approximately 75 kDa that is of fungal origin. Our data suggest that binding of AVR4 to a fungal component or components is related to the intrinsic virulence function of AVR4 for C. fulvum.


Alpha Oscillations in the Human Brain Implement Distractor Suppression Independent of Target Selection.
In principle, selective attention is the net result of target selection and distractor suppression. The way in which both mechanisms are implemented neurally has remained contested. Neural oscillatory power in the alpha frequency band (∼10 Hz) has been implicated in the selection of to-be-attended targets, but there is lack of empirical evidence for its involvement in the suppression of to-be-ignored distractors. Here, we use electroencephalography recordings of N = 33 human participants (males and females) to test the preregistered hypothesis that alpha power directly relates to distractor suppression and thus operates independently from target selection. In an auditory spatial pitch discrimination task, we modulated the location (left vs right) of either a target or a distractor tone sequence, while fixing the other in the front. When the distractor was fixed in the front, alpha power relatively decreased contralaterally to the target and increased ipsilaterally. Most importantly, when the target was fixed in the front, alpha lateralization reversed in direction for the suppression of distractors on the left versus right. These data show that target-selection-independent alpha power modulation is involved in distractor suppression. Although both lateralized alpha responses for selection and for suppression proved reliable, they were uncorrelated and distractor-related alpha power emerged from more anterior, frontal cortical regions. Lending functional significance to suppression-related alpha oscillations, alpha lateralization at the individual, single-trial level was predictive of behavioral accuracy. These results fuel a renewed look at neurobiological accounts of selection-independent suppressive filtering in attention.SIGNIFICANCE STATEMENT Although well established models of attention rest on the assumption that irrelevant sensory information is filtered out, the neural implementation of such a filter mechanism is unclear. Using an auditory attention task that decouples target selection from distractor suppression, we demonstrate that two sign-reversed lateralized alpha responses reflect target selection versus distractor suppression. Critically, these alpha responses are reliable, independent of each other, and generated in more anterior, frontal regions for suppression versus selection. Prediction of single-trial task performance from alpha modulation after stimulus onset agrees with the view that alpha modulation bears direct functional relevance as a neural implementation of attention. Results demonstrate that the neurobiological foundation of attention implies a selection-independent alpha oscillatory mechanism to suppress distraction.


[Testing a methodology to evaluate organization, access, and technical quality of care for childhood diarrhea].
In order to evaluate the issues of access and technical quality in actions to control diarrhea in a selected municipality in the State of Bahia, Brazil, a study of multiple cases was conducted with two levels of analysis: practices themselves and the coordination between them. Cases were defined as hospitalization (8) or death (3) due to diarrhea. All deaths were investigated, and hospitalizations were submitted to intentional selection. Aspects and approaches vis-a-vis technical quality evaluation and estimation of the degree of implementation in diarrhea control measures were derived from the theoretical model. Health care trajectories for diarrhea were reconstituted from interviews and patient chart data. The results identified: organizational barriers related to long waiting time at primary care units; geographic barriers, or the distance from users' place of residence to health services; and financial barriers due to shortage of financial resources for transportation. Quality of care was considered inadequate, and diarrhea control measures were classified as insufficient in practically all of the dimensions analyzed.


Anti-silencing: overcoming H-NS-mediated repression of transcription in Gram-negative enteric bacteria.
The H-NS nucleoid-associated DNA-binding protein is an important global repressor of transcription in Gram-negative bacteria. Recently, H-NS has been implicated in the process of xenogeneic silencing, where it represses the transcription of foreign genes acquired by horizontal transfer. This raises interesting questions about the integration of the horizontally acquired genes into the existing gene regulatory networks of the microbe. In particular, how do bacteria derepress silenced genes in order to benefit from their expression without compromising competitive fitness through doing so inappropriately? This article reviews current knowledge about the derepression of genes that are transcriptionally silenced by H-NS. It describes a variety of anti-silencing mechanisms involving (i) protein-independent processes that operate at the level of local DNA structure, (ii) DNA-binding proteins such as Ler, LeuO, RovA, SlyA, VirB, and proteins related to AraC, and (iii) modulatory mechanisms in which H-NS forms heteromeric protein-protein complexes with full-length or partial paralogues such as StpA, Sfh, Hha, YdgT, YmoA or H-NST. The picture that emerges is one of apparently ad hoc solutions to the problem of H-NS-mediated silencing, suggesting that microbes are capable of evolving anti-silencing methods based on the redeployment of existing regulatory proteins rather than employing dedicated, bespoke antagonists. There is also evidence that in a number of cases more sophisticated regulatory processes have been superimposed on these rather simple anti-silencing mechanisms, broadening the range of environmental signals to which H-NS-repressed genes respond.


Loneliness, social isolation, and healthcare utilization in the general population.
Due to increasing pressure on healthcare resources, knowledge of factors that affect healthcare utilization (HCU) is important. However, the evidence of a longitudinal association between loneliness and social isolation respectively, and HCU is limited. The present prospective cohort study investigated the association of loneliness and social isolation with HCU in the general population over time. Data from the 2013 Danish "How are you?" survey (n = 27.501) were combined with individual-level register data with almost complete follow-up over a 6-year follow-up period (2013-2018). Negative binomial regression analyses were performed while adjusting for baseline demographics and preexisting chronic disease. Loneliness measured was significantly associated with more general practice contacts (incident rate ratio [IRR] = 1.03, 95% confidence interval [CI] [1.02, 1.04]), more emergency treatments (IRR = 1.06, [1.03, 1.10]), more emergency admissions (IRR = 1.06, [1.03, 1.10]), and hospital admission days (IRR = 1.05, [1.00, 1.11]) across the 6-year follow-up period. No significant associations were found between social isolation and HCU with one minor exception, in which social isolation was associated with fewer planned outpatient treatments (IRR = 0.97, [0.94, 0.99]). Wald test demonstrated that the association of loneliness with emergency admissions and hospital admissions days was not significantly different from the effects of social isolation on those outcomes. Our findings suggest that loneliness slightly increased the number of general practice contacts and emergency room treatments. Overall, the effects of loneliness and social isolation on HCU were small. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Community Health Worker Support for Disadvantaged Patients With Multiple Chronic Diseases: A Randomized Clinical Trial.
To determine whether a community health worker (CHW) intervention improved outcomes in a low-income population with multiple chronic conditions. We conducted a single-blind, randomized clinical trial in Philadelphia, Pennsylvania (2013-2014). Participants (n = 302) were high-poverty neighborhood residents, uninsured or publicly insured, and diagnosed with 2 or more chronic diseases (diabetes, obesity, tobacco dependence, hypertension). All patients set a disease-management goal. Patients randomly assigned to CHWs also received 6 months of support tailored to their goals and preferences. Support from CHWs (vs goal-setting alone) led to improvements in several chronic diseases (changes in glycosylated hemoglobin: -0.4 vs 0.0; body mass index: -0.3 vs -0.1; cigarettes per day: -5.5 vs -1.3; systolic blood pressure: -1.8 vs -11.2; overall P = .08), self-rated mental health (12-item Short Form survey; 2.3 vs -0.2; P = .008), and quality of care (Consumer Assessment of Healthcare Providers and Systems; 62.9% vs 38%; P < .001), while reducing hospitalization at 1 year by 28% (P = .11). There were no differences in patient activation or self-rated physical health. A standardized CHW intervention improved chronic disease control, mental health, quality of care, and hospitalizations and could be a useful population health management tool for health care systems. clinicaltrials.gov identifier: NCT01900470.


Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy.
The combined effects of balanced transfusion ratios and use of procoagulant and antifibrinolytic therapies on trauma-induced exsanguination are not known. The aim of this study was to investigate the combined effect of transfusion ratios, tranexamic acid and products containing fibrinogen on the outcome of injured patients with bleeding. A prospective multicentre observational study was performed in six level 1 trauma centres. Injured patients who received at least 4 units of red blood cells (RBCs) were analysed and divided into groups receiving a low (less than 1 : 1) or high (1 or more : 1) ratio of plasma or platelets to RBCs, and in receipt or not of tranexamic acid or fibrinogen products (fibrinogen concentrates or cryoprecipitate). Logistic regression models were used to assess the effect of transfusion strategies on the outcomes 'alive and free from massive transfusion' (at least 10 units of RBCs in 24 h) and early 'normalization of coagulopathy' (defined as an international normalized ratio of 1·2 or less). A total of 385 injured patients with ongoing bleeding were included in the study. Strategies that were independently associated with an increased number of patients alive and without massive transfusion were a high platelet to RBC ratio (odds ratio (OR) 2·67, 95 per cent c.i. 1·24 to 5·77; P = 0·012), a high plasma to RBC ratio (OR 2·07, 1·03 to 4·13; P = 0·040) and treatment with tranexamic acid (OR 2·71, 1·29 to 5·71; P = 0·009). No strategies were associated with correction of coagulopathy. A high platelet or plasma to RBC ratio, and use of tranexamic acid were associated with a decreased need for massive transfusion and increased survival in injured patients with bleeding. Early normalization of coagulopathy was not seen for any transfusion ratio, or for use of tranexamic acid or fibrinogen products.


Association of Cumulative Childhood Adversity and Adolescent Violent Offending With Suicide in Early Adulthood.
Childhood adversity (CA) is associated with an increased risk of suicide in young adulthood that might be explained by maladaptive trajectories during adolescence. Although adolescent violent offending is linked with suicide, little is known about its role in the association between CA and suicide. To examine whether adolescent violent offending mediates the association between CA and suicide in early adulthood. This population-based, longitudinal cohort study with a follow-up time spanning 5 to 9 years included 476 103 individuals born in Sweden between 1984 and 1988. The study population was prospectively followed up from 20 years of age until December 31, 2013, with respect to suicide. Data analysis was performed from January 1, 1984, to December 31, 2013. Register-based CAs included parental death, parental substance abuse and psychiatric disorder, parental criminal offending, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Adolescent violent offending was defined as being convicted of a violent crime between the ages of 15 and 19 years. Estimates of risk of suicide after 20 years of age (from 2004 if born in 1984 and from 2008 if born in 1988) until the end of 2013 were calculated as incidence rate ratios (IRRs) with 95% CIs using Poisson regression analysis. Adjustments were made for demographics and psychiatric disorder. In addition, binary mediation analysis with logistic regression was used. A total of 476 103 individuals (231 699 [48.7%] female) were included in the study. Those with a conviction for violent offending had been exposed to all CAs to a greater extent than those with no violent offending. Cumulative CA was associated with risk of suicide in nonconvicted (adjusted IRR, 2.4; 95% CI, 1.5-3.9) and convicted youths, who had a higher risk of suicide (adjusted IRR, 8.5; 95% CI, 4.6-15.7). Adolescent violent offending partly mediated the association between CA and suicide. Individuals with a history of CA who also engage in violent offending in adolescence have a high risk of suicide. Interventions to prevent externalizing behavior during childhood and increased support to youths with delinquent behavior may have the potential to prevent suicide related to CA.


Folliculinid ciliates: a new threat to Caribbean corals?
This is the first report of a putative pathogenic ciliate protozoan that has been associated with Caribbean corals. Previously, only 2 species of the phylum Ciliophora had been linked to coral diseases, and they were exclusive to the Indo-Pacific region. In this study, a ciliate of the genus Halofolliculina was found on 10 hard coral species at the National Parks of Los Roques and Morrocoy, Venezuela. The general morphology of this ciliate is very similar to that of Halofolliculina corallasia from the Indo-Pacific, which is known to cause skeletal eroding band. None of the other 31 genera in the family Folliculinidae are known to cause diseases in corals or in any other animal species. The presence of this ciliate, which shows a prevalence comparable to that of other epizootics in the Caribbean, suggests it could be a new threat to the coral reefs of this region.


Neglecting uncertainties biases house-elevation decisions to manage riverine flood risks.
Homeowners around the world elevate houses to manage flood risks. Deciding how high to elevate a house poses a nontrivial decision problem. The U.S. Federal Emergency Management Agency (FEMA) recommends elevating existing houses to the Base Flood Elevation (the elevation of the 100-year flood) plus a freeboard. This recommendation neglects many uncertainties. Here we analyze a case-study of riverine flood risk management using a multi-objective robust decision-making framework in the face of deep uncertainties. While the quantitative results are location-specific, the approach and overall insights are generalizable. We find strong interactions between the economic, engineering, and Earth science uncertainties, illustrating the need for expanding on previous integrated analyses to further understand the nature and strength of these connections. Considering deep uncertainties surrounding flood hazards, the discount rate, the house lifetime, and the fragility can increase the economically optimal house elevation to values well above FEMA's recommendation.


Otto Aufranc Award: Dual-mobility Constructs in Revision THA Reduced Dislocation, Rerevision, and Reoperation Compared With Large Femoral Heads.
Dislocation is one of the most common complications after revision THA. Dual-mobility constructs and large femoral heads (ie, 40 mm) are two contemporary, nonconstrained bearing options used in revision THA to minimize the risk of dislocation; however, it is not currently established if there is a clear benefit to using dual-mobility constructs over large femoral heads in the revision setting. We sought to determine if dual-mobility constructs would provide a reduction in dislocation, rerevision for dislocation, and reoperation or other complications as compared with large femoral heads in revision THA. From 2011 to 2014, a series of 355 THAs underwent revision for any reason and received either a dual-mobility construct (146 THAs) or a 40-mm large femoral head (209 THAs). Indications for either construct were based on surgeon judgment; however, there is a preference to use dual-mobility constructs in patients believed to be at higher risk of dislocation. In the dual-mobility group, 20 of 146 (14%) were excluded because of loss of followup before 2 years or because they had a dual-mobility shell cemented into a preexisting acetabular component. In the large head group, 33 of 209 (16%) were lost to followup before 2 years. Followup in the dual-mobility group was 3.3 ± 0.8 years and followup in the large head group was 3.9 ± 0.9 years. Primary endpoints included dislocation, rerevisions for dislocation, and reoperations, which were determined through our institution's total joint registry and verified by individual patient chart review. Age and body mass index were not different with the numbers available between the groups, but there was a slight predominance of females in the dual-mobility group (52% [66 of 126] female) versus the 40-mm large head group (41% [72 of 176] female) (p = 0.05). Notably, 33% (41 of 126) of patients receiving the dual-mobility constructs had the index revision THA done for a diagnosis of recurrent dislocation versus 9% (17 of 176) in the 40-mm large head group. Mean effective head size in the dual-mobility group was 47 mm (range, 38-58 mm). The subsequent frequency of dislocation in the dual-mobility construct group was less (3% [four of 126] dual-mobility versus 10% [17 of 176] in the 40-mm large head group; hazard ratio, 3.2 [1.1-9.4]; p = 0.03). Rerevision for dislocation in the dual-mobility construct group was less frequent (1% [one of 126] dual-mobility versus 6% [10 of 176] in the 40-mm large head group; hazard ratio, 7.1 [0.9-55.6]; p = 0.03). Reoperation for any cause in the dual-mobility construct group was less frequent (6% [eight of 126] dual-mobility versus 15% [27 of 176] in the 40-mm large head group; hazard ratio, 2.5 [1.1-5.5]; p = 0.02); there were no differences between the groups in terms of the overall percentage of complications in each group. When compared with patients treated with a 40-mm large femoral head, patients undergoing revision THA who received a dual-mobility construct had a lower risk of subsequent dislocation, rerevision for dislocation, and reoperation for any reason in the first several years postoperatively. Those findings were present despite selection bias in this study to use the dual-mobility construct in patients at the highest risk for subsequent dislocation. Given the lower risk of subsequent dislocation, rerevision, and reoperation with the dual-mobility construct, some surgeons may wish to consider whether the role of dual-mobility should be judiciously expanded in contemporary revision THA. Level III, therapeutic study.


Triple-clad large-pitch fibers for compact high-power pulsed fiber laser systems.
We present a novel ytterbium (Yb)-doped large-pitch fiber design with significantly increased pump absorption and higher energy storage/gain per unit length, which enables high-peak-power fiber laser systems with smaller footprints. Up to now index matching between core and surrounding material in microstructured fibers was achieved by co-doping the active core region with fluorine. Here we carry out the index matching by passively doping the cladding with germanium, thus raising its index of refraction. Hence, the fluorine in the core can be omitted, which leads to an effective increase of the core doping concentration, while detrimental effects such as photo-darkening and lifetime quenching are avoided by maintaining the bulk Yb concentration. Experiments and simulations show that a gain higher than 50 dB/m and an output average power higher than 100 W with excellent beam quality are feasible even with a fiber length of only 40 cm.


Gold nanoparticle core-europium(iii) chelate fluorophore-doped silica shell hybrid nanocomposites for the lateral flow immunoassay of human thyroid stimulating hormone with a dual signal readout.
Hybrid nanocomposite particles composed of a gold core coated with a europium(iii)-chelate fluorophore-doped silica shell (AuNPs@SiO2-Eu3+) have been synthesized and applied as antibody labels in lateral flow immunoassay (LFIA) devices for the determination of human thyroid stimulating hormone (hTSH). Labeling of monoclonal anti-hTSH antibodies with AuNPs@SiO2-Eu3+ nanocomposites allows for both colorimetric and fluorometric observation of assay results on LFIA devices, relying on visible light absorption due to the localized surface plasmon resonance of the Au-core and the fluorescence emission of the Eu(iii)-chelate-modified shell under UV hand lamp irradiation (365 nm), respectively. The possibility for a dual signal readout provides an attractive alternative for LFIAs: instantaneous naked eye observation of the AuNP colorimetric signal as in conventional LFIAs for hypothyroidism detection, and more sensitive fluorescence detection to assess hyperthyroidism. The limits of detection (LOD) for naked eye observation of LFIA devices are 5 μIU mL-1 and 0.1 μIU mL-1 for the colorimetric and fluorimetric detection, respectively. Using the fluorescence detection scheme in combination with a smartphone and digital color analysis, a quantitative linear relationship between the red intensity and the logarithmic concentration of hTSH was observed (R2 = 0.988) with an LOD of 0.02 μIU mL-1. Finally, LFIA devices were effectively applied for detecting hTSH in spiked diluted human serum with recovery values between 100-116%.


Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.
Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. To determine whether depletion of haCBG is related to mortality in septic shock. A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.


Catalytic effects of mutations of distant protein residues in human DNA polymerase β: theory and experiment.
We carried out free-energy calculations and transient kinetic experiments for the insertion of the right (dC) and wrong (dA) nucleotides by wild-type (WT) and six mutant variants of human DNA polymerase β (Pol β). Since the mutated residues in the point mutants, I174S, I260Q, M282L, H285D, E288K, and K289M, were not located in the Pol β catalytic site, we assumed that the WT and its point mutants share the same dianionic phosphorane transition-state structure of the triphosphate moiety of deoxyribonucleotide 5'-triphosphate (dNTP) substrate. On the basis of this assumption, we have formulated a thermodynamic cycle for calculating relative dNTP insertion efficiencies, Ω = (k(pol)/K(D))(mut)/(k(pol)/K(D))(WT) using free-energy perturbation (FEP) and linear interaction energy (LIE) methods. Kinetic studies on five of the mutants have been published previously using different experimental conditions, e.g., primer-template sequences. We have performed a presteady kinetic analysis for the six mutants for comparison with wild-type Pol β using the same conditions, including the same primer/template DNA sequence proximal to the dNTP insertion site used for X-ray crystallographic studies. This consistent set of kinetic and structural data allowed us to eliminate the DNA sequence from the list of factors that can adversely affect calculated Ω values. The calculations using the FEP free energies scaled by 0.5 yielded 0.9 and 1.1 standard deviations from the experimental log Ω values for the insertion of the right and wrong dNTP, respectively. We examined a hybrid FEP/LIE method in which the FEP van der Waals term for the interaction of the mutated amino acid residue with its surrounding environment was replaced by the corresponding van der Waals term calculated using the LIE method, resulting in improved 0.4 and 1.0 standard deviations from the experimental log Ω values. These scaled FEP and FEP/LIE methods were also used to predict log Ω for R283A and R283L Pol β mutants.


Specific structural features of the N-acetylmuramoyl-L-alanine amidase AmiD from Escherichia coli and mechanistic implications for enzymes of this family.
AmiD is the fifth identified N-acetylmuramoyl-L-alanine zinc amidase of Escherichia coli. This periplasmic lipoprotein is anchored in the outer membrane and has a broad specificity. AmiD is capable of cleaving the intact peptidoglycan (PG) as well as soluble fragments containing N-acetylmuramic acid regardless of the presence of an anhydro form or not, unlike the four other amidases, AmiA, AmiB, AmiC, and AmpD, which have some specificity. AmiD function is, however, not clearly established but it could be part of the enzymatic machinery involved in the PG turnover in E. coli. We solved three structures of the E. coli zinc amidase AmiD devoid of its lipidic anchorage: the holoenzyme, the apoenzyme in complex with the substrate anhydro-N-acetylmuramic-acid-L-Ala-gamma-d-Glu-L-Lys, and the holoenzyme in complex with the L-Ala-gamma-D-Glu-L-Lys peptide, the product of the hydrolysis of this substrate by AmiD. The AmiD structure shows a relatively flexible N-terminal extension that allows an easy reach of the PG by the enzyme inserted into the outer membrane. The C-terminal domain provides a potential extended geometrical complementarity to the substrate. AmiD shares a common fold with AmpD, the bacteriophage T7 lysozyme, and the PG recognition proteins, which are receptor proteins involved in the innate immune responses of a wide range of organisms. Analysis of the different structures reveals the similarity between the catalytic mechanism of zinc amidases of the AmiD family and the thermolysin-related zinc peptidases.


The alkyne-tag Raman imaging of coronatine, a plant pathogen virulence factor, in Commelina communis and its possible mode of action.
We previously reported that coronatine, a virulence factor of plant bacteria, facilitates bacterial infection through an ER (endoplasmic reticulum)-mediated, non-canonical mechanism in the model dicot plant, Arabidopsis thaliana. Here, we report that this same ER-mechanism is ubiquitous among dicots and monocots, and works by affecting the ethylene signaling pathway widely found in plants. The subcellular localization of coronatine by the alkyne-tag Raman imaging (ATRI) approach provided a convincing clue.


Invasive, paediatric, vaccine strains of Streptococcus pneumoniae: are there differences in clinical characteristics?
Invasive pneumococcal infections in 777 adults caused by 'invasive' (1, 7; n=187), 'paediatric' (6, 9, 14, 19, 23; n=304) and other (n=286) serogroups were compared. Infections caused by 'invasive' strains caused pneumonia more often than other serogroups and were more often isolated from younger patients without concomitant conditions and had lower case-fatality rate than 'paediatric' and other strains. The 2 latter groups differed little from each other. Infections caused by strains in the 7-valent pneumococcal conjugate vaccine differed little from infections caused by non-vaccine types indicating that widespread use of this vaccine will not markedly change the clinical characteristics of invasive pneumococcal infections in adults.


Varicocele is associated with erectile dysfunction: a population-based case-control study.
While many studies have been conducted investigating the efficacy of varicocele treatment on fertility, the literature is comparatively sparse concerning the association between varicocele, varicocelectomy, and erectile dysfunction (ED). This study aimed to estimate the associations between varicocele, varicocelectomy, and ED using a population-based dataset. This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. A total of 32,856 cases and 98,568 randomly selected controls were included in this study. Conditional logistic regression analyses were used to examine associations between ED and having been previously diagnosed with varicocele or having underwent a varicocelectomy. The odds of prior varicocele or having underwent a varicocelectomy between cases and controls. Of the sampled patients, the prevalence of prior varicocele was 3.3% and 1.2% for cases and controls, respectively (P < 0.001). Conditional logistic regression analysis suggested that the odds ratio (OR) of being previously diagnosed with varicocele for cases was 3.09 (95% confidence interval [CI] = 2.67-3.49) when compared with controls after adjusting for monthly income, geographic location, hypertension, diabetes, coronary heart disease, hyperlipidemia, hypogonadism, obesity, and alcohol abuse/alcohol dependence syndrome. Furthermore, cases were 1.92 (95% CI = 1.52-2.43) times more likely to have undergone a varicocelectomy than controls. Furthermore, subjects aged between 18 and 29 had the highest ORs for prior varicocele among cases when compared with controls (OR = 5.20; 95% CI = 3.27-8.28). This investigation succeeded in identifying an association between both varicocele and ED. We also realized that varicocele patients who underwent a varicocelectomy had lower magnitudes of association with ED than those who did not.


DNA and RNA telomeric G-quadruplexes: what topology features can be inferred from ion mobility mass spectrometry?
Maintenance of the telomeres is key to chromosome integrity and cell proliferation. The G-quadruplex structures formed by telomeric DNA and RNA (TTAGGG and UUAGGG repeats, respectively) are key to this process. However, because these sequences are particularly polymorphic, solving high-resolution structures is not always possible, and there is a need for new methodologies to characterize the multiple structures coexisting in solution. In this context, we evaluated whether ion mobility spectrometry coupled to native mass spectrometry could help separate and assign the G-quadruplex topologies. We explored the circular dichroism spectra, multimer formation, cation binding, and ion mobility spectra of several 4-repeat and 8-repeat telomeric DNA and RNA sequences, both in NH4+ and in K+. In 1 mM K+ and 100 mM trimethylammonium acetate, all RNAs fold intramolecularly (no multimer). In 8-repeat sequences, the subunits are not independent: in DNA the first subunit disfavors the folding of the second one, whereas in RNA the two subunits fold cooperatively via cation-mediated stacking. Ion mobility spectrometry shows that gas-phase structures keep a memory of - but are not identical to - the solution ones. At the native charge states, the loops can rearrange in a variety of ways (unless they are constrained by pre-formed hydrogen bonds), thereby wrapping the core and masking the strand arrangements. Our study highlights that, to progress towards structural assignment from IM-MS experiments, deeper understanding of the solution-to-gas-phase rearrangement mechanisms is warranted.


Distinguishing between emotional distress and psychiatric disorder in primary care attenders: A cross sectional study of the four-dimensional symptom questionnaire (4DSQ).
Detection of psychiatric disorder in primary care is a complex issue. Distinctions between 'normal' emotional distress and psychiatric disorder depend on how disorder is conceptualized. Our aim was to explore two different conceptualizations by examining patients' scores on one-dimensional depression measures and scores on the Four Dimensional Symptom Questionnaire (4DSQ), a measure that uniquely has separate dimensions for general distress and depressive disorder. This was a cross sectional study of 487 primary care patients attending general clinics in Hampshire, UK. Patients completed the 4DSQ, Patient Health Questionnaire-9 (PHQ-9), General Health Questionnaire-12 (GHQ-12) and the Hospital Anxiety and Depression Scale (HADS) whilst in the waiting room. The 4DSQ classified 26% (126/485) of patients as having heightened distress levels and 8% (38/468) as possible cases of depressive disorder. Casesness was consistently higher across the one-dimensional measures (PHQ-9: 16%, GHQ-12: 28%, HADS-D: 13%). Of those patients deemed possible cases by the PHQ-9 (≥ 10), the 4DSQ classified 91% (71/78) as having heightened distress and 44% (32/72) as possible cases of depressive disorder. The sample was predominately older and white, which may limit generalizability of the findings to more diverse patient groups. There are limits to self-report measures in the assessment of complex diagnostic issues. Inclusion of a distinct general distress dimension alongside a dimension focusing on specific depression symptomatology lowered the number of primary care patients classified as possible cases of disorder. This view of symptoms may have implications for the targeting of existing treatments, and may be useful in guiding the development of novel self-management interventions.


Tracheal tumors.
This article provides the most recent literature and experienced guidance about diagnosis and management of tracheal tumors, including future directions. Tracheal tumors are challenging to diagnose given their nonspecific and late-onset symptoms. Critical airway obstruction is the most feared complication. The cornerstone in management of them is surgical resection whenever is possible. Different diagnostic tests (i.e., imaging and bronchoscopy) help in the assessment of resectability. Alternative management including interventional bronchoscopic techniques can be offered to patients who are not suitable for surgical resection. Radiation and chemotherapy can also be used as adjuvant, neoadjuvant or sole treatment in malignant tumors. Recent advances in tracheal transplantation and bioengineering with tracheal reconstruction have shown a new direction in the management of these tumors. All these topics will be discussed in this article. Despite advances in diagnostic and therapeutic techniques, tracheal tumors are still a medical challenge. Although studies are still trying to find the best surgical techniques as well as the role for chemotherapy and radiation, most recent studies are addressing tracheal reconstruction and transplantation as the new horizon for management.


Changes in snoring characteristics after 30 days of nasal continuous positive airway pressure in patients with non-apnoeic snoring: a controlled trial.
A study was performed to evaluate the effect of discontinuation of nasal continuous positive airway pressure (NCPAP) treatment on snoring characteristics. Eighteen non-apnoeic snoring subjects were randomly allocated to either a no treatment control group or an NCPAP treatment group. The control group was studied twice (baseline and day 30 of follow up). In the NCPAP group the level of NCPAP that abolished snoring was determined and part abolished snoring was determined and patients were placed on NCPAP every night for one month. A sleep study was performed on the first night without NCPAP after completing 30 days of treatment (follow up 1). A fourth polysomnographic study was performed 8-10 days after NCPAP was stopped (follow up 2) in six subjects. In both groups total sleep time (TST) and sleep architecture remained unchanged at the different visits. Baseline snoring characteristics in the two groups were similar. In the control group the mean (SE) number of snoring episodes/hour of sleep (snoring index) and the percentage of TST > 60 decibels (dB) were 380 (36)/h and 11.1 (2.0)% TST respectively at baseline, and was unchanged at follow up. In the NCPAP group the snoring index decreased from 387 (50)/h to 320 (57)/h after NCPAP therapy, but the % TSTS > 60 dB decreased from 10.3 (1.8)% to 7.4 (1.5)%. The snoring index and intensity returned to baseline values at follow up 2 (374 (74)/h, 9.8 (2.1)% TST). Changes in snoring characteristics could not be explained by changes in body position between the different sleep studies. NCPAP improves snoring but this effect is lost soon after stopping treatment.


The pathology of dry eye: the interaction between the ocular surface and lacrimal glands.
Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female. Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye. Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic. Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.


Taking the EEG Back Into the Brain: The Power of Multiple Discrete Sources.
Background: In contrast to many neuroimaging modalities, clinical interpretation of EEG does not take advantage of post-processing and digital signal analysis. In most centers, EEG is still interpreted at sensor level, exactly as half a century ago. A major task in clinical EEG interpretation is the identification of interictal epileptiform discharges (IEDs). However, due to the overlap of background activity, IEDs can be hard to detect in the scalp EEG. Since traditional montages, like bipolar and average reference, are linear transformations of the recorded channels, the question is whether we can provide linear transformations of the digital EEG to take it back into the brain, at least on a macroscopic level. The goal is to improve visibility of epileptiform activities and to separate out most of the overlap. Methods: Multiple discrete sources provide a stable linear inverse to transform the EEG into source space with little cross-talk between source regions. The model can be based on a few dipoles or regional sources, adapted to the individual EEG and MRI data, or on selected standard sources evenly distributed throughout the brain, e.g. below the 25 EEG standard electrodes. Results: Auditory and somatosensory evoked potentials serve as teaching examples to show how various source spaces can reveal the underlying source components including their loss or alteration due to lesions. Source spaces were able to reveal the propagation of source activities in frontal IEDs and the sequential activation of the major nodes of the underlying epileptic network in myoclonic epilepsy. The power of multiple discrete sources in separating the activities of different brain regions was also evident in the ongoing EEG of cases with frontal cortical dysplasia and bitemporal lobe epilepsy. The new source space 25 made IEDs more clearly visible over the EEG background signals. The more focal nature of source vs. scalp space was quantitatively confirmed using a new measurement of focality. Conclusion: Multiple discrete sources have the power to transform the EEG back into the brain by defining new EEG traces in source space. Using standard source space 25, these can provide for improved clinical interpretation of EEG.


Ethnic/racial and socioeconomic differences in dieting behaviors and body image perceptions in adolescents.
This study examined differences in perceptions of body weight, dieting, unhealthy eating behaviors, and weight control methods among adolescent males and females of various racial/ethnic and socioeconomic (SES) subgroups. Data were derived from a comprehensive health survey administered to 36,320 students in grades 7 through 12 in Minnesota. Differences among ethnic/racial and SES groups were assessed using multivariate logistic regression controlling for grade and body mass index (BMI). Results showed that unhealthy weight control behaviors are not confined to upper SES white females. Compared to white females, Hispanic females reported greater use of diuretics; Asians reported more binge eating; and blacks reported higher rates of vomiting. Black and American Indian females were more likely to be satisfied with their body. Among males and females, higher SES was associated with greater weight satisfaction and lower rates of pathological weight control behaviors. Findings from this study suggest that future research should focus on the validity of self-reports of dieting and weight control behaviors in different ethnic subgroups.


How the primate fornix is affected by age.
The effects of age on nerve fibers and neuroglial cells in the fornix were examined in 25 rhesus monkeys between 4 and 33 years of age. There is no age-related change in the cross-sectional area of the fornix, but there is a significant loss of myelinated nerve fibers. The loss of myelinated nerve fibers is accompanied by a significant increase in the numbers of nerve fibers that show degeneration of their axons and alterations in myelin sheaths. Aging also brings about an increase in the frequency of profiles of paranodes, indicating that some of the nerve fibers are being remyelinated. Aging also affects neuroglial cells. Each type shows inclusions in their perikarya, and in the case of astrocytes and microglial cells some of these inclusions are phagocytosed myelin. Numbers of astrocytes and microglial cells do not appear to increase with age, but there is a 20% increase in oligodendrocytes. When correlations with cognitive impairments displayed by individual monkeys are examined, the decreased packing density of nerve fibers and the increasing frequency of nerve fibers with degenerating axons and of nerve fibers with altered myelin sheaths all correlate with increasing cognitive impairment. It is suggested that these correlations result from some disconnection of the hippocampus from the thalamus, septal nuclei, and medial frontal cortex and from reductions in the conduction velocity brought about by the shorter internodal lengths of remyelinated nerve fibers in the fornix.


R7BP: a surprising new link between G proteins, RGS proteins, and nuclear signaling in the brain.
The regulators of G protein signaling (RGS proteins) bind directly to G protein alpha (Galpha) subunits in brain and other tissues to determine the strength, duration, and fidelity of neurotransmitter receptor signaling. A recent study shows, quite unexpectedly, that one class of RGS proteins [the R7 subfamily bound to Gbeta(5) (R7-Gbeta(5))] shuttles between the plasma membrane and the nucleus with assistance from a novel shuttle protein, R7BP. R7BP binds directly to R7-Gbeta(5) and the protein complex is tethered to the plasma membrane by addition of a lipid, palmitate, on R7BP. Removal of palmitate results in the translocation of the R7BP-R7-Gbeta(5) complex to the nucleus, presumably for nontraditional signaling functions. These findings suggest an entirely novel mechanism for regulating neurotransmitter signaling. That is, R7BP transduces signals directly from receptors and G proteins at the plasma membrane to the nucleus, and this plasma membrane-nuclear shuttling is controlled by reversible palmitoylation of R7BP.


The nanostructure of a lithium glyme solvate ionic liquid at electrified interfaces.
Solvate ionic liquids are a subclass of ionic liquids that have the potential to be used in a range of electrochemical devices. We present molecular dynamics simulations of the interfacial structure of thin films of one such lithium based solvate ionic liquid, [Li(G4)][TFSI], an equimolar solution of tetraglyme and lithium bistriflimide. This solvate ionic liquid is shown to form a novel interfacial structure at a plane electrode, which differs in a number of ways from the nanostructure observed for a conventional ionic liquid at similar interfaces. This paper explores the structural composition of the interfacial layers of this solvate ionic liquid, including their variation with surface charge, and the relation between chemical structure and interfacial arrangement.