Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase.
Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.


Population-based age adjustment tables for use in occupational hearing conservation programs.
Objective: In occupational hearing conservation programmes, age adjustments may be used to subtract expected age effects. Adjustments used in the U.S. came from a small dataset and overlooked important demographic factors, ages, and stimulus frequencies. The present study derived a set of population-based age adjustment tables and validated them using a database of exposed workers.Design: Cross-sectional population-based study and retrospective longitudinal cohort study for validation.Study sample: Data from the U.S. National Health and Nutrition Examination Survey (unweighted n = 9937) were used to produce these tables. Male firefighters and emergency medical service workers (76,195 audiograms) were used for validation.Results: Cross-sectional trends implied less change with age than assumed in current U.S. regulations. Different trends were observed among people identifying with non-Hispanic Black race/ethnicity. Four age adjustment tables (age range: 18-85) were developed (women or men; non-Hispanic Black or other race/ethnicity). Validation outcomes showed that the population-based tables matched median longitudinal changes in hearing sensitivity well.Conclusions: These population-based tables provide a suitable replacement for those implemented in current U.S. regulations. These tables address a broader range of worker ages, account for differences in hearing sensitivity across race/ethnicity categories, and have been validated for men using longitudinal data.


Does telaprevir possess a direct antidiabetic effect?
Hepatitis C virus (HCV) induces insulin resistance, which improves upon viral clearance. Telaprevir is a protease inhibitor effective against HCV genotype 1. We reported a case, whose history suggests that telaprevir may induce some antidiabetic effect independently of its suppression of HCV. A 56-year-old woman with obesity, type 2 diabetes treated with sitagliptin and metformin, and HCV-related cirrhosis was given triple therapy with pegylated interferon-alpha, ribavirin and telaprevir. After 2 weeks of treatment, HCV RNA was no longer detectable but the patient described a pronounced drop in the capillary glucose levels and episodes of hypoglycaemia that compelled her to stop all antidiabetic treatment. One month after stopping telaprevir, she had to resume her antidiabetic treatment, despite a persisting virological response. Despite reaching a sustained virological response, her diabetes progressed. Although the suppression of HCV replication may have played a role in reducing glucose intolerance, the fact that this patient resumed her prior antidiabetic treatment upon completing the telaprevir treatment, while still aviremic, suggests that telaprevir may have an additional antidiabetic effect. Further evidence about the possible role and mechanisms of telaprevir as antidiabetic agent is warranted.


Abnormal mandibular growth and the condylar cartilage.
Deviations in the growth of the mandibular condyle can affect both the functional occlusion and the aesthetic appearance of the face. The reasons for these growth deviations are numerous and often entail complex sequences of malfunction at the cellular level. The aim of this review is to summarize recent progress in the understanding of pathological alterations occurring during childhood and adolescence that affect the temporomandibular joint (TMJ) and, hence, result in disorders of mandibular growth. Pathological conditions taken into account are subdivided into (1) congenital malformations with associated growth disorders, (2) primary growth disorders, and (3) acquired diseases or trauma with associated growth disorders. Among the congenital malformations, hemifacial microsomia (HFM) appears to be the principal syndrome entailing severe growth disturbances, whereas growth abnormalities occurring in conjunction with other craniofacial dysplasias seem far less prominent than could be anticipated based on their often disfiguring nature. Hemimandibular hyperplasia and elongation undoubtedly constitute the most obscure conditions that are associated with prominent, often unilateral, abnormalities of condylar, and mandibular growth. Finally, disturbances of mandibular growth as a result of juvenile idiopathic arthritis (JIA) and condylar fractures seem to be direct consequences of inflammatory and/or mechanical damage to the condylar cartilage.


Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis.
The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16 years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9 mg/kg once daily) for 14 days or intravenous ceftriaxone (50 mg/kg once daily) for 3 days followed by oral ceftibuten for 11 days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6 years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14 days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6 months to 16 years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these children.


Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome.
Osmotic demyelination syndrome (ODS) is a serious demyelinating disease in the central nervous system usually caused by rapid correction of hyponatremia. In an animal model of ODS, we previously reported microglial accumulation expressing proinflammatory cytokines. Microglia and astrocytes secreting proinflammatory cytokines and neurotrophic factors are reported to be involved in the pathogenesis of demyelinative diseases. Therefore, to clarify the role of microglial and astrocytic function in ODS, we examined the time-dependent changes in distribution, morphology, proliferation, and mRNA/protein expression of proinflammatory cytokines, neurotrophic factors, and matrix metalloproteinase (MMP) in microglia and astrocytes 2 days (early phase) and 5 days (late phase) after the rapid correction of hyponatremia in ODS rats. The number of microglia time dependently increased at demyelinative lesion sites, proliferated, and expressed tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and MMP2, 9, and 12 at the early phase. Microglia also expressed leukemia inhibitory factor (a neurotrophic factor) and phagocytosed myelin debris at the late phase. The number of astrocytes time dependently increased around demyelinative lesions, extended processes to lesions, proliferated, and expressed nerve growth factor and glial cell line-derived neurotrophic factor at the late phase. Moreover, treatment with infliximab, a monoclonal antibody against TNF-α, significantly attenuated neurological impairments. Our results suggest that the role of microglia in ODS is time dependently shifted from detrimental to protective and that astrocytes play a protective role at the late phase. Modulation of excessive proinflammatory responses in microglia during the early phase after rapid correction may represent a therapeutic target for ODS.


Epidemiology, public health, and the rhetoric of false positives.
As an observational science, epidemiology is regarded by some researchers as inherently flawed and open to false results. In a recent paper, Boffetta et al. [Boffetta P, McLaughlin JK, LaVecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epistemological modesty. J Natl Cancer Inst 100:988-995 (2008)] argued that "epidemiology is particularly prone to the generation of false-positive results." They also said "the tendency to emphasize and over-interpret what appear to be new findings is commonplace, perhaps in part because of a belief that the findings provide information that may ultimately improve public health" and that "this tendency to hype new findings increases the likelihood of downplaying inconsistencies within the data or any lack of concordance with other sources of evidence." The authors supported these serious charges against epidemiology and epidemiologists with few examples. Although we acknowledge that false positives do occur, we view the position of Boffetta and colleagues on false positives as unbalanced and potentially harmful to public health. We aim to provide a more balanced evaluation of epidemiology and its contribution to public health discourse. Boffetta and colleagues ignore the fact that false negatives may arise from the very processes that they tout as generating false-positive results. We further disagree with their proposition that false-positive results from a single study will lead to faulty decision making in matters of public health importance. In practice, such public health evaluations are based on all the data available from all relevant disciplines and never to our knowledge on a single study. The lack of balance by Boffetta and colleagues in their evaluation of the impact of false-positive findings on epidemiology, the charge that "methodological vigilance is often absent" in epidemiologists' interpretation of their own results, and the false characterization of how epidemiologic findings are used in societal decision making all undermine a major source of information regarding disease risks. We reaffirm the importance of epidemiologic evidence as a critical component of the foundation of public health protection.


Why Oregon patients request assisted death: family members' views.
Physician assisted death (PAD) was legalized through Oregon's Death with Dignity Act in 1994 and enacted in 1997. The objective of this paper was to learn from family members why their loved ones requested PAD. This study used the cross-sectional survey. Participants of this study included family members of 83 Oregon decedents who made explicit requests for legalized PAD before their deaths, including 52 decedents who received prescriptions for a lethal medication and 32 who died of PAD. Family members rated the importance of 28 possible reasons their loved ones requested PAD on a 1-5 Likert scale, with higher scores representing greater importance. According to family members, the most important reasons that their loved ones requested PAD, all with a median score of 4.5 or greater, were wanting to control the circumstances of death and die at home, and worries about loss of dignity and future losses of independence, quality of life, and self-care ability. No physical symptoms at the time of the request were rated higher than a median of 2 in importance. Worries about symptoms and experiences in the future were, in general, more important reasons than symptoms or experiences at the time of the request. According to family members, the least important reasons their loved ones requested PAD included depression, financial concerns, and poor social support. Interventions that help patients maintain control, independence, and self-care in a home environment may be effective means of addressing serious requests for PAD.


Concentrations of organochlorine pesticides and polychlorinated biphenyls in human serum and adipose tissue from Bolivia.
Organochlorine pesticides and polychlorinated biphenyls (PCBs) are synthetic chemicals that are highly resistant to biodegradation and have proven adverse health effects. The objectives of this study were to determine concentrations of three selected organochlorine pesticides (p,p'-DDT, p,p'-DDE, HCB) and three specific PCB congeners (PCB 138, 153, 180) in adipose tissue and serum samples from an urban adult population (n=112) in the city of Santa Cruz de la Sierra, Bolivia, and to investigate their relationships within and between the two matrices and with selected socio-demographic characteristics. The percentages of samples positive for these compounds ranged from 40% for PCB 180 to 100% for p,p'-DDE in adipose tissue, and from 21% for HCB to 93% for p,p'-DDE in serum. Median number of residues per sample was five for adipose tissue and three for serum. Geometric mean concentrations indicate a considerable historical and recent exposure to organochlorine pesticides and PCBs in this population. Adipose tissue:serum ratios ranged from 149.3 to 590.3 (wet basis) and from 0.9 to 3.5 (lipid basis). We found positive and statistically significant correlations between adipose tissue and serum concentrations only in p,p'-DDE and HCB. This novel study in Bolivia underlines the need for human biomonitoring to assess exposure to environmental pollutants in South America.


Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours.
There are high expectations regarding the potential for the communication of DNA-based disease risk estimates to motivate behaviour change. To assess the effects of communicating DNA-based disease risk estimates on risk-reducing behaviours and motivation to undertake such behaviours. We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 2010), MEDLINE (1950 to April 2010), EMBASE (1980 to April 2010), PsycINFO (1985 to April 2010) using OVID SP, and CINAHL (EBSCO) (1982 to April 2010). We also searched reference lists, conducted forward citation searches of potentially eligible articles and contacted authors of relevant studies for suggestions. There were no language restrictions. Unpublished or in press articles were eligible for inclusion. Randomised or quasi-randomised controlled trials involving adults (aged 18 years and over) in which one group received actual (clinical studies) or imagined (analogue studies) personalised DNA-based disease risk estimates for diseases for which the risk could plausibly be reduced by behavioural change. Eligible studies had to include a primary outcome measure of risk-reducing behaviour or motivation (e.g. intention) to alter such behaviour. Two review authors searched for studies and independently extracted data. We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. For continuous outcome measures, we report effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we report effect sizes as odds ratios (ORs). We obtained pooled effect sizes with 95% confidence intervals (CIs) using the random effects model applied on the scale of standardised differences and log odds ratios. We examined 5384 abstracts and identified 21 studies as potentially eligible. Following a full text analysis, we included 14 papers reporting results of 7 clinical studies (2 papers report on the same trial) and 6 analogue studies.Of the seven clinical studies, five assessed smoking cessation. Meta-analyses revealed no statistically significant effects on either short-term (less than 6 months) smoking cessation (OR 1.35, 95% CI 0.76 to 2.39, P = 0.31, n = 3 studies) or cessation after six months (OR 1.07, 95% CI 0.64 to 1.78, P = 0.80, n = 4 studies). Two clinical studies assessed diet and found effects that significantly favoured DNA-based risk estimates (OR 2.24, 95% CI 1.17 to 4.27, P = 0.01). No statistically significant effects were found in the two studies assessing physical activity (OR 1.03, 95% CI 0.59 to 1.80, P = 0.92) or the one study assessing medication or vitamin use aimed at reducing disease risks (OR 1.26, 95% CI 0.58 to 2.72, P = 0.56). For the six non-clinical analogue studies, meta-analysis revealed a statistically significant effect of DNA-based risk on intention to change behaviour (SMD 0.16, 95% CI 0.04 to 0.29, P = 0.01).There was no evidence that communicating DNA-based disease risk estimates had any unintended adverse effects. Two studies that assessed fear arousal immediately after the presentation of risk information did, however, report greater fear arousal in the DNA-based disease risk estimate groups compared to comparison groups.The quality of included studies was generally poor. None of the clinical or analogue studies were considered to have a low risk of bias, due to either a lack of clarity in reporting, or where details were reported, evidence of a failure to sufficiently safeguard against the risk of bias. Mindful of the weak evidence based on a small number of studies of limited quality, the results of this review suggest that communicating DNA-based disease risk estimates has little or no effect on smoking and physical activity. It may have a small effect on self-reported diet and on intentions to change behaviour. Claims that receiving DNA-based test results motivates people to change their behaviour are not supported by evidence. Larger and better-quality RCTs are needed.


Prospects for developing new antibacterials targeting bacterial type IIA topoisomerases.
The modulation of DNA topology by DNA gyrase and topoisomerase IV, both of which are type IIA topoisomerases and found in most bacteria, is a function vital to DNA replication, repair and decatenation. Despite the potential for resistance development, DNA gyrase and/or topoisomerase IV have been proven to be and remain highly attractive targets in antibacterial drug discovery due to their potential for dual targeting. The search for new GyrA and/or ParC inhibitors that can overcome the increasing spread of multidrug-resistant bacteria has been successfully focused in the last decades on the modification of the known fluoroquinolone scaffold as primarily guided by ligand-based design via classical structure-activity relationship studies and the optimisation of physicochemical properties. This focus has resulted in several novel fluoroquinolones that have been introduced into clinical practice since 2000, and several of these new compounds are currently in different phases of clinical trials. Due to increasing resistance to fluoroquinolones, a significant part of DNA gyrase research has shifted to the discovery of new GyrB and/or ParE inhibitors, which are commonly identified through fragment-based design as well as virtual screening techniques and structure-based hit optimisation programs. This research often results in lead compounds with potent inhibitory activity and promising antibacterial activity profiles. Nevertheless, it is important to understand how different physicochemical properties (e.g., logD and total polar surface area) and different structural motifs influence the compounds' permeability to ensure the efficient discovery of potent, small-molecule antibacterials particularly against Gram-negative strains.


Electronic cigarettes: a survey of users.
Little is known about users of electronic cigarettes, or their opinions, satisfaction or how and why they use such products. An internet survey of 81 ever-users of ecigarettes in 2009. Participants answered open-ended questions on use of, and opinions about, ecigarettes. Respondents (73 current and 8 former users) lived in France, Canada, Belgium or Switzerland. Most respondents (77%) were men; 63% were former smokers and 37% were current smokers. They had used e-cigarettes for 100 days (median) and drew 175 puffs per day (median). Participants used the ecigarette either to quit smoking (53 comments), to reduce their cigarette consumption (14 comments), in order not to disturb other people with smoke (20 comments), or in smoke-free places (21 comments). Positive effects reported with ecigarettes included their usefulness to quit smoking, and the benefits of abstinence from smoking (less coughing, improved breathing, better physical fitness). Respondents also enjoyed the flavour of ecigarettes and the sensation of inhalation. Side effects included dryness of the mouth and throat. Respondents complained about the frequent technical failures of ecigarettes and had some concerns about the possible toxicity of the devices and about their future legal status. Ecigarettes were used mainly to quit smoking, and may be helpful for this purpose, but several respondents were concerned about potential toxicity. There are very few published studies on ecigarettes and research is urgently required, particularly on the efficacy and toxicity of these devices.


Developing core competencies for monitoring and evaluation tracks in South Asian MPH programs.
Monitoring and evaluation (M&E) provides vital information for decision-making and its structures, systems and processes are expected to be integrated throughout the life-cycle of public health programs. The acquisition of these skills should be developed in a structured manner and needs educational systems to identify core competencies in M&E teaching. This article presents our work on harmonizing M&E competencies for Masters level programs in the South Asian context and undertaking the global review of M&E track/ concentration offered in various Masters of Public Health (MPH) programs. Through an online search and snow-balling, we mapped institutions offering M&E tracks/ concentrations in Masters of Public Health (MPH) programs globally. We obtained detailed information about their M&E curriculum from university websites and brochures. The data on curricular contents was extracted and compiled. We analyzed the curricular contents using the framework for core competencies developed by the Association of Schools of Public Health (ASPH); and the Miller's triangle. This data was then used to inform a consultative exercise aimed at identifying core competencies for an M&E track/ concentration in MPH programs in the South Asian context. Our curricular review of M&E content within MPH programs globally showed that different domains or broad topic areas relating to M&E are covered differently across the programs. The quantitative sciences (Biostatistics and Epidemiology) and Health Policy and Management are covered in much greater depth than the other two domains (Social & Behavioral Sciences and Environmental Health Sciences). The identification of core competencies for an M&E track/ concentration in the South Asian context was undertaken through a consultative group exercise involving representation from 11 institutions across Bangladesh, India, Nepal and Sri Lanka. During the consultation, the group engaged in a focused discussion to reach consensus on a set of 15 core competencies for an M&E track in South Asian MPH programs. This work presents an opportunity for institutions to identify and re-examine their M&E competencies as a part of their specialized tracks within MPH programs. Our curricular analysis approach has the potential for adaptation and further use in curriculum analysis across different academic specialties.


Characteristics associated with inappropriate hospital use in elderly patients admitted to a general internal medicine service.
Our objective was to identify patient characteristics associated with inappropriate hospital days in a cohort of elderly medical inpatients. This prospective cohort study included a total of 196 patients aged 75 years and older, who were consecutively admitted over eight months to the internal medicine service of a regional, non-academic public hospital located in a rural area of Western Switzerland. Patients with severe cognitive impairment, terminal disease, or previously living in a nursing home were excluded. Data on demographics, medical, physical, social and mental status were collected at admission. A blinded hospitalization review was performed concurrently using a modified version of the Appropriateness Evaluation Protocol (AEP). Subjects' mean age was 82.4 years; 63.3% were women. Median length of stay was 8 days. Overall, 68 patients (34.7%) had at least one inappropriate day during their stay, including 18 patients (9.2%) whose hospital admission and entire stay were considered inappropriate. Most inappropriate days were due to discharge delays (87.10%), primarily to nursing homes (59.30%). Univariate analysis showed that subjects with inappropriate days were more likely to be living alone (69.1 vs 48.4%, p=0.006), and receiving formal in-home help (48.5 vs 32.8%, p=0.031). In addition, they were more impaired in basic and instrumental activities of daily living (BADLs, and IADLs, p<0.001 and p=0.015, respectively), and more frequently had a depressed mood [29.4 vs 10.9%, p=0.001 with a score > 6 at the Geriatric Depression Scale (GDS), short form]. Using multivariate analysis, independent associations remained for patients living alone (OR 2.6, 95%CI 1.2-5.8, p=0.016), those with a depressed mood (OR 2.8, 95%CI 1.1-7.3, p=0.032), with BADL dependencies (OR 1.5, 95%CI 1.2-1.8, p=0.001), and IADL dependencies (OR 1.3, 95%CI 1.0-1.6, p=0.032). Cardiovascular (OR 0.2, 95%CI 0.1-0.7, p=0.008) and pulmonary admission diagnoses (OR 0.1, 95%CI 0.0-0.7, p=0.022) were inversely associated with inappropriate hospital days. In conclusion, patients living alone, functionally impaired and showing depressive symptoms were at increased risk for inappropriate hospital days. These characteristics might permit better targeting for early discharge planning in these at-risk subjects, and contribute to avoiding premature discharge of other vulnerable elderly patients. Whether these interventions for at-risk patients will also result in prevention of hospitalization hazards, such as deconditioning and related functional decline, will require further study.


A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease.
Extracellular vesicles including exosomes are released by a variety of cell types including neurons and exhibit molecular profiles that reflect normal and disease states. As their content represents a snapshot of the intracellular milieu, they could be exploited as biomarkers of the otherwise inaccessible brain microenvironment. In addition they may contribute to the progression of neurodegenerative disorders by facilitating the spread of misfolded proteins at distant sites or activating immune cells. This review summarizes recent advances in the study of exosomes in Parkinson's disease pathophysiology and their potential as disease biomarkers.


Identification of the Minimal Replicon of Lactococcus lactis subsp. lactis UC317 Plasmid pCI305.
Replication functions of the stable, cryptic 8.7-kilobase (kb) plasmid pCI305 from multi-plasmid-containing Lactococcus lactis subsp. lactis UC317 were studied. Analysis of this replicon was facilitated by the construction of replication probe vectors that consisted of the pBR322 replication region, a pUC18-derived multiple cloning site, and either the cat gene of pC194 (pCI341; 3.1 kb) or the erm gene of pAMbeta1 (pCI3330; 4.0 kb). Plasmid pCI305 was introduced into plasmid-free L. lactis subsp. lactis MG1363Sm, a streptomycin-resistant derivative of MG1363, by a transformation procedure with the 75-kb lactose-proteinase plasmid pCI301 of UC317 as a marker plasmid. A combination of transposon Tn5 mutagenesis and subcloning in pCI341 and pCI3330 with individual Tn5 insertions around the replication region facilitated the identification of a 1.6-kb minimal replicon on pCI305. This region was separable into two domains: (i) a 1.3-kb region (repB) encoding a trans-acting function (in vitro transcription-translation studies suggested the involvement of a 48-kilodalton protein); and (ii) a 0.3-kb region (repA) sufficient to direct replication when provided with repB in trans and thus probably containing the origin of replication. Lactococcus-Escherichia coli shuttle vectors based on the pCI305 replication region were constructed.


Tracking dynamics of plant biomass composting by changes in substrate structure, microbial community, and enzyme activity.
Understanding the dynamics of the microbial communities that, along with their secreted enzymes, are involved in the natural process of biomass composting may hold the key to breaking the major bottleneck in biomass-to-biofuels conversion technology, which is the still-costly deconstruction of polymeric biomass carbohydrates to fermentable sugars.However, the complexity of both the structure of plant biomass and its counterpart microbial degradation communities makes it difficult to investigate the composting process. In this study, a composter was set up with a mix of yellow poplar (Liriodendron tulipifera) wood-chips and mown lawn grass clippings (85:15 in dry-weight) and used as a model system. The microbial rDNA abundance data obtained from analyzing weekly-withdrawn composted samples suggested population-shifts from bacteria-dominated to fungus-dominated communities. Further analyses by an array of optical microscopic, transcriptional and enzyme-activity techniques yielded correlated results, suggesting that such population shifts occurred along with early removal of hemicellulose followed by attack on the consequently uncovered cellulose as the composting progressed. The observed shifts in dominance by representative microbial groups, along with the observed different patterns in the gene expression and enzymatic activities between cellulases, hemicellulases, and ligninases during the composting process, provide new perspectives for biomass-derived biotechnology such as consolidated bioprocessing (CBP) and solid-state fermentation for the production of cellulolytic enzymes and biofuels.


Control of renin secretion in vivo and in vitro in rats: arguments in favour of a precursor form of renin and of a role of a microtubular system.
1. The morphology of the juxtaglomerular apparatus, plasma renin activity, plasma renin substrate and renal renin have been studied in rats after maximal stimulation by bilateral adrenalectomy and salt depletion, and also after blocking this stimulation by deoxycorticosterone and salt load. 2. After stimulation the juxtaglomerular apparatus showed a well-developed granular endoplasmic reticulum and a low secretory granule content. Plasma renin activity was markedly elevated and plasma renin substrate was low. After blockade numerous specific granules with crystalline structures were seen and the granular endoplasmic reticulum was less developed. Plasma renin activity was now low and plasma renin substrate elevated. 3. After prior acidification of the kidney extract a significant increase of renal renin was observed in both conditions but was greater in the second group at the time when large numbers of young granules containing crystalline material were seen. 4. Kidney slices from the adrenalectomized salt-depleted rats released more renin than control slices. Vincristine did not affect this release, but inhibited release from slices stimulated by isoprenaline.


Acute mastoiditis in Southern Israel: a twelve year retrospective study (1990 through 2001).
Acute mastoiditis is a serious complication of acute otitis media (AOM) and has been increasingly reported in the last decade. To report the experience accumulated with acute mastoiditis at the Soroka University Medical Center, Beer-Sheva, Israel, in a period of increasing antimicrobial resistance with Streptococcus pneumoniae. We reviewed the records of all children with acute mastoiditis hospitalized from 1990 through 2001. Acute mastoiditis was diagnosed when one or more of the physical signs of mastoiditis (swelling, erythema, tenderness of the retroauricular area and anteroinferior displacement of the auricle) were diagnosed in the presence of concomitant or recent (< or =4 weeks) AOM. One hundred sixteen episodes of acute mastoiditis occurred in 101 children age 2 months to 14 years (median, 25 months; 19% <1 year old). The average yearly incidence was 6.1 cases per 100 000 population <14 years old, with a significant increase in the number of cases during the study period. Acute mastoiditis was the first evidence of AOM in 10 (10%) patients. Fever >38 degrees C and >15,000 WBC/mm3 were present in 67 and 43% of cases, respectively. Irritability, retroauricular swelling, redness and protrusion of the auricle occurred more commonly in patients <3 years old (79, 90, 84 and 76% vs. 28, 42, 45 and 30%, respectively, in patients > or =3 years old; P < 0.002). Computed tomography scans were performed in 54 of 116 (47%) cases and revealed bone destruction in 38 (70%). Periosteal abscess and lateral sinus vein thrombosis were diagnosed in 8 and 2 patients, respectively. Simple mastoidectomy was done in 32 of 116 (28%) cases, after no response to intravenous antibiotics was observed; ventilation tubes were inserted in 12 patients. Cultures were obtained at admission in 83 (72%) episodes (71 by tympanocentesis and 12 from ear discharges). Overall 43 pathogens were isolated: 34 at admission; 14 at surgery; and 5 at both occasions. The most commonly isolated organisms were S. pneumoniae (14 of 43, 33%; 4 penicillin-nonsusceptible), Streptococcus pyogenes (11 of 43, 26%), nontypable Haemophilus influenzae (6 of 43, 14%), Pseudomonas aeruginosa (5 of 43, 12%) and Escherichia coli (4 of 43, 9%). All S. pneumoniae organisms were isolated between 1996 and 2001. (1) The incidence of acute mastoiditis in children in Southern Israel is greater than that reported in the literature; (2) a significant increase in the number of cases was recorded during the study period; (3) the clinical picture of acute mastoiditis was more severe in infants and young children; (4) the pathogen distribution in acute mastoiditis differs from that of AOM with significantly higher rates of S. pyogenes and lower rates of nontypable H. influenzae recovery; (5) penicillin-nonsusceptible S. pneumoniae played only a minor role in the etiology of acute mastoiditis in Southern Israel.


The origins and genetic structure of three co-resident Chinese Muslim populations: the Salar, Bo'an and Dongxiang.
A genome-based investigation of three Muslim populations, the Salar, Bo'an, and Dongxiang, was conducted on 212 individuals (148 males, 64 females) co-resident in Jishisan County, a minority autonomous region located in the province of Gansu, PR China. The Salar are believed to be of Turkic origin, whereas the Bo'an and Dongxiang both speak Mongolian. Biparental dinucleotide markers on chromosomes 13 and 15 indicated elevated mean homozygosity in the Salar (0.32), Bo'an (0.32), and Dongxiang (0.27), equivalent to inbreeding coefficients ( F(is) ) of 0.16; 0.12; 0.01, confirming varying levels of endogamous and consanguineous marriage in all three communities. Y-chromosome unique event polymorphisms (UEPs) showed that males in the three communities shared common ancient origins, with 80-90% of haplotypes in common. However, the high levels of community-specific Y-chromosome STR haplotypes strongly suggested the action(s) of founder effect, genetic drift and preferential consanguinity during more recent historical time. By comparison with the marked inter-community differentiation revealed by the Y-chromosome STRs (29.4%), the mtDNA data indicated similarity between the female lineages of each community with just 1.2% inter-community variation. The combined use of these different marker systems gives an in-depth historical perspective, and provides evidence of past inter-marriage between genetically diverse male founders of each community and Han Chinese females with subsequent community endogamy.


'There's just no flexibility': How space and time impact mental health consumer research.
Non-consumer researchers collaborating with consumer researchers can benefit from greater relevance of research and improved congruence between research processes and health policy. As with all research collaborations, such partnerships are both constrained and facilitated by research ecosystems. However, it seems that collaborations with consumer researchers are impacted in particular ways by the research ecosystem. Drawing on ecological systems theory, this study aims to improve understandings of how ecological structures impact collaborations between non-consumer and consumer researchers. Interviews were conducted with 11 non-consumer researchers from a range of mental health disciplines about their experiences collaborating with consumer researchers. One theme developed through analysis of the data set related to the research ecosystem. Data from this theme were extracted and discursively analysed using the principles of discursive psychology. Findings emphasize distinct factors that influence collaborations at each level of the ecosystem, encompassing both local research culture and broader research systems. Findings suggest that external pressures (such as deadlines for funding applications, or bureaucratic processes) from the broader ecosystemic levels need to be challenged at the local collaboration level. Non-consumer researchers might support collaborations through, for instance, working to create enhanced flexibility in research timelines, or making time for relationship building, thus fostering more meaningful collaborations.


Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study.
Differences in the interindividual response to dietary intervention could be modified by genetic variation in nutrient-sensitive genes. This study examined single nucleotide polymorphisms (SNPs) in presumed nutrient-sensitive candidate genes for obesity and obesity-related diseases for main and dietary interaction effects on weight, waist circumference, and fat mass regain over 6 mo. In total, 742 participants who had lost ≥ 8% of their initial body weight were randomly assigned to follow 1 of 5 different ad libitum diets with different glycemic indexes and contents of dietary protein. The SNP main and SNP-diet interaction effects were analyzed by using linear regression models, corrected for multiple testing by using Bonferroni correction and evaluated by using quantile-quantile (Q-Q) plots. After correction for multiple testing, none of the SNPs were significantly associated with weight, waist circumference, or fat mass regain. Q-Q plots showed that ALOX5AP rs4769873 showed a higher observed than predicted P value for the association with less waist circumference regain over 6 mo (-3.1 cm/allele; 95% CI: -4.6, -1.6; P/Bonferroni-corrected P = 0.000039/0.076), independently of diet. Additional associations were identified by using Q-Q plots for SNPs in ALOX5AP, TNF, and KCNJ11 for main effects; in LPL and TUB for glycemic index interaction effects on waist circumference regain; in GHRL, CCK, MLXIPL, and LEPR on weight; in PPARC1A, PCK2, ALOX5AP, PYY, and ADRB3 on waist circumference; and in PPARD, FABP1, PLAUR, and LPIN1 on fat mass regain for dietary protein interaction. The observed effects of SNP-diet interactions on weight, waist, and fat mass regain suggest that genetic variation in nutrient-sensitive genes can modify the response to diet. This trial was registered at clinicaltrials.gov as NCT00390637.


Assessing suppliers considering social sustainability innovation factors during COVID-19 disaster.
Innovation can be considered one of the fundamental elements for ensuring sustainability. Companies have started to enhance their sustainability level through the application of innovative practices. The importance of employing innovative social sustainability practices within the supply chain seems to have escalated with the advent of COVID-19. However, studies focusing on the social aspect of sustainability innovation when selecting suppliers during the COVID-19 disaster are non-existent. Selecting these types of suppliers can significantly help companies to be more socially innovative and obtain sustainable development targets. This work introduces a social sustainability innovation framework for assessing suppliers during the COVID-19 pandemic. A group grey-best worst method (Group GBWM) is utilized to identify the criteria weights and improved grey relational analysis (IGRA) is utilized for ranking the suppliers. Findings show that "safety and health practices", "remote working conditions", and "localization" are the most important social sustainability innovation criteria, respectively, in choosing suppliers during COVID-19. A manufacturing firm is utilized as an example for verifying the efficiency of the proposed model and framework. This work helps industrial experts and researchers to better understand and focus on the social aspect of sustainable innovation, particularly when selecting suppliers during the critical COVID-19 pandemic situation.


Metagenomic insights to understand transient influence of Yamuna River on taxonomic and functional aspects of bacterial and archaeal communities of River Ganges.
River confluences are interesting ecosystems to investigate for their microbial community structure and functional potentials. River Ganges is one of the most important and holy river of India with great mythological history and religious significance. The Yamuna River meets Ganges at the Prayagraj (formerly known as Allahabad), India to form a unique confluence. The influence of Yamuna River on taxonomic and functional aspects of microbiome at this confluence and its downstream, remains unexplored. To unveil this dearth, whole metagenome sequencing of the microbial (bacterial and archaeal) community from the sediment samples of December 2017 sampling expedition was executed using high throughput MinION technology. Results revealed differences in the relative abundance of bacterial and archaeal communities across the confluence. Grouped by the confluence, a higher abundance of Proteobacteria and lower abundance of Bacteroidetes and Firmicutes was observed for Yamuna River (G15Y) and at immediate downstream of confluence of Ganges (G15DS), as compared to the upstream, confluence, and farther downstream of confluence. A similar trend was observed for archaeal communities with a higher abundance of Euryarchaeota in G15Y and G15DS, indicating Yamuna River's influence. Functional gene(s) analysis revealed the influence of Yamuna River on xenobiotic degradation, resistance to toxic compounds, and antibiotic resistance interceded by the autochthonous microbes at the confluence and succeeding downstream locations. Overall, similar taxonomic and functional profiles of microbial communities before confluence (upstream of Ganges) and farther downstream of confluence, suggested a transient influence of Yamuna River. Our study is significant since it may be foundational basis to understand impact of Yamuna River and also rare event of mass bathing on the microbiome of River Ganges. Further investigation would be required to understand, the underlying cause behind the restoration of microbial profiles post-confluence farther zone, to unravel the rejuvenation aspects of this unique ecosystem.


A Boosting Algorithm for Estimating Generalized Propensity Scores with Continuous Treatments.
In this article, we study the causal inference problem with a continuous treatment variable using propensity score-based methods. For a continuous treatment, the generalized propensity score is defined as the conditional density of the treatment-level given covariates (confounders). The dose-response function is then estimated by inverse probability weighting, where the weights are calculated from the estimated propensity scores. When the dimension of the covariates is large, the traditional nonparametric density estimation suffers from the curse of dimensionality. Some researchers have suggested a two-step estimation procedure by first modeling the mean function. In this study, we suggest a boosting algorithm to estimate the mean function of the treatment given covariates. In boosting, an important tuning parameter is the number of trees to be generated, which essentially determines the trade-off between bias and variance of the causal estimator. We propose a criterion called average absolute correlation coefficient (AACC) to determine the optimal number of trees. Simulation results show that the proposed approach performs better than a simple linear approximation or L2 boosting. The proposed methodology is also illustrated through the Early Dieting in Girls study, which examines the influence of mothers' overall weight concern on daughters' dieting behavior.


A Rapid, Simple, Inexpensive, and Mobile Colorimetric Assay COVID-19-LAMP for Mass On-Site Screening of COVID-19.
To control the COVID-19 pandemic and prevent its resurgence in areas preparing for a return of economic activities, a method for a rapid, simple, and inexpensive point-of-care diagnosis and mass screening is urgently needed. We developed and evaluated a one-step colorimetric reverse-transcriptional loop-mediated isothermal amplification assay (COVID-19-LAMP) for detection of SARS-CoV-2, using SARS-CoV-2 isolate and respiratory samples from patients with COVID-19 (n = 223) and other respiratory virus infections (n = 143). The assay involves simple equipment and techniques and low cost, without the need for expensive qPCR machines, and the result, indicated by color change, is easily interpreted by naked eyes. COVID-19-LAMP can detect SARS-CoV-2 RNA with detection limit of 42 copies/reaction. Of 223 respiratory samples positive for SARS-CoV-2 by qRT-PCR, 212 and 219 were positive by COVID-19-LAMP at 60 and 90 min (sensitivities of 95.07% and 98.21%) respectively, with the highest sensitivities among nasopharyngeal swabs (96.88% and 98.96%), compared to sputum/deep throat saliva samples (94.03% and 97.02%), and throat swab samples (93.33% and 98.33%). None of the 143 samples with other respiratory viruses were positive by COVID-19-LAMP, showing 100% specificity. Samples with higher viral load showed shorter detection time, some as early as 30 min. This inexpensive, highly sensitive and specific COVID-19-LAMP assay can be useful for rapid deployment as mobile diagnostic units to resource-limiting areas for point-of-care diagnosis, and for unlimited high-throughput mass screening at borders to reduce cross-regional transmission.


Highly variable spread rates in replicated biological invasions: fundamental limits to predictability.
Although mean rates of spread for invasive species have been intensively studied, variance in spread rates has been neglected. Variance in spread rates can be driven exogenously by environmental variability or endogenously by demographic or genetic stochasticity in reproduction, survival, and dispersal. Endogenous variability is likely to be important in spread but has not been studied empirically. We show that endogenously generated variance in spread rates is remarkably high between replicated invasions of the flour beetle Tribolium castaneum in laboratory microcosms. The observed variation between replicate invasions cannot be explained by demographic stochasticity alone, which indicates inherent limitations to predictability in even the simplest ecological settings.


The Drosophila eyes absent gene directs ectopic eye formation in a pathway conserved between flies and vertebrates.
The fly eyes absent (eya) gene which is essential for compound eye development in Drosophila, was shown to be functionally replaceable in eye development by a vertebrate Eya homolog. The relationship between eya and that of the eyeless gene, a Pax-6 homolog, critical for eye formation in both flies and man, was defined: eya was found to be essential for eye formation by eyeless. Moreover, eya could itself direct ectopic eye formation, indicating that eya has the capacity to function as a master control gene for eye formation. Finally, we show that eya and eyeless together were more effective in eye formation than either gene alone. These data indicate conservation of the pathway of eya function between flies and vertebrates; they suggest a model whereby eya/Eya gene function is essential for eye formation by eyeless/Pax-6, and that eya/Eya can in turn mediate, via a regulatory loop, the activity of eyeless/Pax-6 in eye formation.


Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial.
Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.


Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance.
Despite advances in biology and therapeutic modalities, existence of highly tumorigenic glioma stem-like cells (GSCs) makes glioblastomas (GBMs) invincible. N6-methyl adenosine (m6A), one of the abundant mRNA modifications catalyzed by methyltransferase-like 3 and 14 (METTL3/14), influences various events in RNA metabolism. Here, we report the crucial role of METTL3-mediated m6A modification in GSC (neurosphere) maintenance and dedifferentiation of glioma cells. METTL3 expression is elevated in GSC and attenuated during differentiation. RNA immunoprecipitation studies identified SOX2 as a bonafide m6A target of METTL3 and the m6A modification of SOX2 mRNA by METTL3 enhanced its stability. The exogenous overexpression of 3'UTR-less SOX2 significantly alleviated the inhibition of neurosphere formation observed in METTL3 silenced GSCs. METTL3 binding and m6A modification in vivo required intact three METTL3/m6A sites present in the SOX2-3'UTR. Further, we found that the recruitment of Human antigen R (HuR) to m6A-modified RNA is essential for SOX2 mRNA stabilization by METTL3. In addition, we found a preferential binding by HuR to the m6A-modified transcripts globally. METTL3 silenced GSCs showed enhanced sensitivity to γ-irradiation and reduced DNA repair as evidenced from the accumulation of γ-H2AX. Exogenous overexpression of 3'UTR-less SOX2 in METTL3 silenced GSCs showed efficient DNA repair and also resulted in the significant rescue of neurosphere formation from METTL3 silencing induced radiosensitivity. Silencing METTL3 inhibited RasV12 mediated transformation of mouse immortalized astrocytes. GBM tumors have elevated levels of METTL3 transcripts and silencing METTL3 in U87/TIC inhibited tumor growth in an intracranial orthotopic mouse model with prolonged mice survival. METTL3 transcript levels predicted poor survival in GBMs which are enriched for GSC-specific signature. Thus our study reports the importance of m6A modification in GSCs and uncovers METTL3 as a potential molecular target in GBM therapy.


Visual stimulation affects the perception of voluntary leg movements during walking.
When a limb is used for locomotion, patterns of afferent and efferent activity related to its own motion are present as well as visual, vestibular, and other proprioceptive information about motion of the whole body. A study is reported in which it was asked whether visual stimulation present during whole-body motion can influence the perception of the leg movements propelling the body. Subjects were tested in conditions in which the stepping movements they made were identical but the amount of body displacement relative to inertial space and to the visual surround varied. These test conditions were created by getting the subjects to walk on a rotatable platform centered inside a large, independently rotatable, optokinetic drum. In each test condition, subjects, without looking at their legs, compared, against a standard condition in which the floor and drum were both stationary, their speed of body motion, their stride length and stepping rate, the direction of their steps, and the perceived force they exerted during stepping. When visual surround motion was incompatible with the motion normally associated with the stepping movements being made, changes in apparent body motion and in the awareness of the frequency, extent, and direction of the voluntary stepping movements resulted.


Exchange coupling mediated through-bonds and through-space in conformationally constrained polyradical scaffolds: calix[4]arene nitroxide tetraradicals and diradical.
Calix[4]arenes constrained to the 1,3-alternate conformation and functionalized at the upper rim with four and two tert-butylnitroxides have been synthesized and characterized by X-ray crystallography, magnetic resonance (EPR and (1)H NMR) spectroscopy, and magnetic studies. The 1,3-alternate nitroxide tetraradical and diradical provide unique polyradical scaffolds for dissection of the through-bond and through-space intramolecular exchange couplings. In addition, detailed magnetic studies of the previously reported calix[4]arene nitroxide tetraradical, which possesses cone conformation in solution, reveal conformational dependence of exchange coupling. Through-bond coupling between the adjacent nitroxide radicals is mediated by the nitroxide-m-phenylene-CH(2)-m-phenylene-nitroxide coupling pathway, and through-space coupling is found between the diagonal nitroxide radicals at the conformationally constrained N...N distance of 5-6 A. Magnetic studies of the calix[4]arene polyradical scaffolds in frozen solutions show that the through-bond exchange coupling in the 1,3-alternate calix[4]arene tetraradical is antiferromagnetic, while that in cone calix[4]arene tetraradical is ferromagnetic. The through-space exchange couplings are antiferromagnetic in both cone and 1,3-alternate calix[4]arene tetraradical, as well as in the 1,3-alternate calix[4]arene diradical. The exchange coupling constants (|J/k|) are of the order of 1 K.


Trigeminal neuralgia: New classification and diagnostic grading for practice and research.
Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic. Diagnostic certainty is graded possible when pain paroxysms occur in the distribution of the trigeminal nerve branches. Triggered paroxysms permit the designation of clinically established TN and probable neuropathic pain. Imaging and neurophysiologic tests that establish the etiology of classical or secondary TN determine definite neuropathic pain.


Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping.
Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension. To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone γ-H2A.X (γ-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P = 0.29). Arterial telomere uncapping and P53/P21-induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P = 0.04 and P = 0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r = -0.02, P = 0.44 and r = 0.01, P = 0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r = 0.62, P < 0.001, η(p)(2) = 0.35). Finally, telomere uncapping was a significant predictor of hypertension status (P = 0.03), whereas mean telomere length was not (P = 0.68). Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.


A spatial model of Wild Poliovirus Type 1 in Kano State, Nigeria: calibration and assessment of elimination probability.
Since the launch of the Global Polio Eradication Initiative, all but three countries (Nigeria, Pakistan, and Afghanistan) have apparently interrupted all wild poliovirus (WPV) transmission, and only one of three wild serotypes has been reported globally since 2012. Countrywide supplemental immunization campaigns in Nigeria produced dramatic reduction in WPV Type 1 paralysis cases since 2010 compared to the 2000's, and WPV1 has not been observed in Nigeria since July 24, 2014. This article presents the development and calibration of a spatial metapopulation model of wild poliovirus Type 1 transmission in Kano State, Nigeria, which was the location of the most recent WPV1 case and 5 out of 6 of the reported WPV1 paralytic cases in Nigeria in 2014. The model is calibrated to data on the case counts and age at onset of paralysis from 2003-2009. The features of the data drive model development from a simple susceptible-exposed-infective-recovered (SEIR) model to a spatial metapopulation model featuring seasonal forcing and age-dependent transmission. The calibrated parameter space is then resampled, projected forward, and compared to more recent case counts to estimate the probability that Type 1 poliovirus has been eliminated in Kano state. The model indicates a 91 % probability that Type 1 poliovirus has been eliminated from Kano state as of October 2015. This probability rises to >99 % if no WPV1 paralysis cases are detected for another year. The other states in Nigeria have experienced even longer case-free periods (the only other state with a WPV1 case was Yobe, on April 19, 2014), and Nigeria is the last remaining country in Africa to experience endemic WPV1 transmission, so these results can be interpreted as an upper bound on the probability that WPV1 transmission is currently interrupted continent-wide. While the results indicate optimism that WPV1 transmission has been interrupted in Kano state, the model also assumes that frequent SIAs with high coverage continue to take place in Kano state through the end of the certification period. We conclude that though WPV1 appears to be on the brink of continent-wide elimination (WHO officially removed Nigeria from the list of polio-endemic countries on September 25, 2015), it is important for the polio program to maintain vigilance in surveillance and vaccination activities to prevent WPV1 resurgence through the WHO's 3-year eradication certification period.


Contributions from the silent majority dominate dengue virus transmission.
Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmission. However, recent blood-feeding experiments with Aedes aegypti mosquitoes showed that people with asymptomatic and pre-symptomatic DENV infections are capable of infecting mosquitoes. To place those findings into context, we used models of within-host viral dynamics and human demographic projections to (1) quantify the net infectiousness of individuals across the spectrum of DENV infection severity and (2) estimate the fraction of transmission attributable to people with different severities of disease. Our results indicate that net infectiousness of people with asymptomatic infections is 80% (median) that of people with apparent or inapparent symptomatic infections (95% credible interval (CI): 0-146%). Due to their numerical prominence in the infectious reservoir, clinically inapparent infections in total could account for 84% (CI: 82-86%) of DENV transmission. Of infections that ultimately result in any level of symptoms, we estimate that 24% (95% CI: 0-79%) of onward transmission results from mosquitoes biting individuals during the pre-symptomatic phase of their infection. Only 1% (95% CI: 0.8-1.1%) of DENV transmission is attributable to people with clinically detected infections after they have developed symptoms. These findings emphasize the need to (1) reorient current practices for outbreak response to adoption of pre-emptive strategies that account for contributions of undetected infections and (2) apply methodologies that account for undetected infections in surveillance programs, when assessing intervention impact, and when modeling mosquito-borne virus transmission.


Development of the Diabetes Indicators and Data Sources Internet Tool (DIDIT).
Developing a Web-based tool that involves the input, buy-in, and collaboration of multiple stakeholders and contractors is a complex process. Several elements facilitated the development of the Web-based Diabetes Indicators and Data Sources Internet Tool (DIDIT). The DIDIT is designed to enhance the ability of staff within the state-based Diabetes Prevention and Control Programs (DPCPs) and the Centers for Disease Control and Prevention (CDC) to perform diabetes surveillance. It contains information on 38 diabetes indicators (measures of health or factors associated with health) and 12 national- and state-level data sources. Developing the DIDIT required one contractor to conduct research on content for diabetes indicators and data sources and another contractor to develop the Web-based application to house and manage the information. During 3 years, a work group composed of representatives from the DPCPs and the Division of Diabetes Translation (DDT) at the CDC guided the development process by 1) gathering information on and communicating the needs of users and their vision for the DIDIT, 2) reviewing and approving content, and 3) providing input into the design and system functions. Strong leadership and vision of the project lead, clear communication and collaboration among all team members, and a commitment from the management of the DDT were essential elements in developing and implementing the DIDIT. Expertise in diabetes surveillance and software development, enthusiasm, and dedication were also instrumental in developing the DIDIT.


Percutaneous endoscopic versus radiologic gastrostomy for enteral feeding: a retrospective analysis on outcomes and complications.
Background and study aims Percutaneous endoscopic gastrostomy (PEG) and percutaneous radiologic gastrostomy (PRG) are techniques used for long-term enteral feeding. Our primary aim was to analyze procedure-related and 30-day mortality and complications between PEG and PRG in relation to indications. Patients and methods A single-center retrospective analysis was performed thath included all adult patients receiving initial PEG (January 2008 until April 2016) and PRG (January 2010 until April 2016). Outcomes were mortality (procedure-related, 30-day), complications (early (≤ 30 days) and late) and success rates. Results A total of 760 procedures (469 PRG and 291 PEG) were analyzed. Most common indications were head and neck cancer (HNC), cerebrovascular accident (CVA) and amyotrophic lateral sclerosis (ALS). Success rates for placement were 91.2 % for PEG and 97.1 % for PRG ( P = 0.001). Procedure-related mortality was 1.7 % in PEG and 0.4 % in PRG ( P = 0.113). The 30-day mortality was 10.7 % in PEG and 5.1 % in PRG ( P = 0.481 after multivariate logistic regression) CVA was associated with higher 30-day mortality, whereas ALS, higher body weight, and prophylactic placements in HNC were associated with lower rates. Tube-related complications were less frequent in PEG, both early (2.7 % vs. 26.4 %, P ≤ 0.001) and late (8.6 % vs. 31.5 %, P ≤ 0.001). The percentage of major complications and infections did not differ. Conclusions With respect to procedure-related and 30-day mortality, PEG and PRG compare equally. PRG had a higher procedural success rate. Tube-related complications and pain are less frequent after PEG compared to PRG. The choice for either PEG or PRG therefore should primarily be based on local facilities and expertise.


Calcium transients and relaxation in single muscle fibers.
Muscle contraction is initiated by an elevation in intracellular calcium. The transient change in free calcium to a brief depolarization, the calcium transient, can be recorded using a calcium luminescent protein, aequorin. The calcium transient precedes force, peaking while force is rising and returning to the resting level as peak force is achieved. In single barnacle muscle fibers microinjected with aequorin, shortening the muscle during the declining phase of the calcium transient produces an addition light signal, indicating extra free calcium in the sarcoplasm. The amount of additional light is larger with larger length changes. It is also larger if the shortening occurs early in the calcium transient rather than later. The amount of this extra calcium correlates well with the instantaneous level of the calcium transient and not with the instantaneous force level. It is argued in a speculative manner that this extra calcium is coming from the myofilaments. This supports the hypothesis that calcium binding to the myofilaments is rapid and reversible, that reaccumulation of calcium into the sarcoplasmic reticulum (SR) could occur long before relaxation begins and that relaxation of tension could occur by some process other than the mere removal of calcium from the myofilaments.


Pension Wealth and the Gender Wealth Gap.
We examine the gender wealth gap with a focus on pension wealth and statutory pension rights. By taking into account employment characteristics of women and men, we are able to identify the extent to which the redistributive effect of pension rights reduces the gender wealth gap. The data for our analysis come from the German Socio-Economic Panel (SOEP), one of the few surveys that collects information on wealth and pension entitlements at the individual level. Pension wealth data are available in the SOEP for 2012 only. While the relative raw gender wealth gap is about 35% (or 31,000 euros) when analysing the standard measure of net worth, it shrinks to 28% when pension wealth is added. This reduction is due to redistributive elements such as caregiver credits provided through the statutory pension scheme. Results of a recentred influence functions (RIF) decomposition show that pension wealth reduces the gap substantially in the lower half of the distribution. At the 90th percentile, the gender wealth gap in net worth and in augmented wealth remains more stable at roughly 27-30%.


Detailed structure of the Drosophila melanogaster stellate genes and their transcripts.
The X-linked Stellate locus contains two major size classes of a tandemly repeated gene. An example of each class has been sequenced. The steady-state level of Stellate RNA is much higher in XO testis than in XY testis. Sequencing of six cDNA clones derived from XO testis RNA shows that there are two major introns in the Stellate genes. Primer extension and RNase protection analyses show that these introns are spliced much more efficiently in XO than in XY testis. These results also indicate the major transcriptional start site for Stellate RNA. P element transformation results with a marked Stellate gene demonstrate that at least one of the genes sequenced contains a functional promoter, which generates low levels of RNA in XY testis and high levels of RNA in XO testis. This promoter does not contain a TATA element in the -30 region relative to the transcriptional start. Previous results had implicated a specific region of the Y chromosome, designated here as the Su(Ste) locus, in the control of the Stellate genes on the X. Analysis using segmental Y deficiencies shows that the Su(Ste) region suppresses both the high levels and efficient splicing of Stellate RNA.


Multilineage differentiation of rhesus monkey embryonic stem cells in three-dimensional culture systems.
In the course of normal embryogenesis, embryonic stem (ES) cells differentiate along different lineages in the context of complex three-dimensional (3D) tissue structures. In order to study this phenomenon in vitro under controlled conditions, 3D culture systems are necessary. Here, we studied in vitro differentiation of rhesus monkey ES cells in 3D collagen matrixes (collagen gels and porous collagen sponges). Differentiation of ES cells in these 3D systems was different from that in monolayers. ES cells differentiated in collagen matrixes into neural, epithelial, and endothelial lineages. The abilities of ES cells to form various structures in two chemically similar but topologically different matrixes were different. In particular, in collagen gels ES cells formed gland-like circular structures, whereas in collagen sponges ES cells were scattered through the matrix or formed aggregates. Soluble factors produced by feeder cells or added to the culture medium facilitated ES cell differentiation into particular lineages. Coculture with fibroblasts in collagen gel facilitated ES cell differentiation into cells of a neural lineage expressing nestin, neural cell adhesion molecule, and class III beta-tubulin. In collagen sponges, keratinocytes facilitated ES cell differentiation into cells of an endothelial lineage expressing factor VIII. Exogenous granulocyte-macrophage colony-stimulating factor further enhanced endothelial differentiation. Thus, both soluble factors and the type of extracellular matrix seem to be critical in directing differentiation of ES cells and the formation of tissue-like structures. Three-dimensional culture systems are a valuable tool for studying the mechanisms of these phenomena.


Stable tetrabenzo-Chichibabin's hydrocarbons: tunable ground state and unusual transition between their closed-shell and open-shell resonance forms.
Stable open-shell polycyclic aromatic hydrocarbons (PAHs) are of fundamental interest due to their unique electronic, optical, and magnetic properties and promising applications in materials sciences. Chichibabin's hydrocarbon as a classical open-shell PAH has been investigated for a long time. However, most of the studies are complicated by their inherent high reactivity. In this work, two new stable benzannulated Chichibabin's hydrocarbons 1-CS and 2-OS were prepared, and their electronic structure and geometry in the ground state were studied by various experiments (steady-state and transient absorption spectra, NMR, electron spin resonance (ESR), superconducting quantum interference device (SQUID), FT Raman, X-ray crystallographic etc.) and density function theory (DFT) calculations. 1-CS and 2-OS exhibited tunable ground states, with a closed-shell quinoidal structure for 1-CS and an open-shell biradical form for 2-OS. Their corresponding excited-state forms 1-OS and 2-CS were also chemically approached and showed different decay processes. The biradical 1-OS displayed an unusually slow decay to the ground state (1-CS) due to a large energy barrier (95 ± 2.5 kJ/mol) arising from severe steric hindrance during the transition from an orthogonal biradical form to a butterfly-like quinoidal form. The quick transition from the quinoidal 2-CS (excited state) to the orthogonal biradicaloid 2-OS (ground state) happened during the attempted synthesis of 2-CS. Compounds 1-CS and 2-OS can be oxidized into stable dications by FeCl(3) and/or concentrated H(2)SO(4). The open-shell 2-OS also exhibited a large two-photon absorption (TPA) cross section (760 GM at 1200 nm).


Minimized extracorporeal circulation in non-coronary surgery.
Minimally invasive extracorporeal circulation (MiECC) technology is characterized by improved biocompatibility due to closed-loop design, minimized priming, and markedly reduced artificial surface. Despite well-evidenced clinical advantages in coronary surgery, MiECC penetration in complex open-heart surgery is low. Concerns have been raised by surgeons and perfusionist regarding safety of perfusion in situations when the heart is opened and air is entering the closed system. Moreover, issues of blood and volume management are deemed impractical without having a reservoir. In the evolution of MiECC safety aspects as well as means of air and volume management have been addressed. The integration of active air removal devices, and the possibility of venting and volume buffering made MiECC suitable for valvular or even more complex surgery. However, typical clinical benefits found with MiECC in coronary artery bypass grafting (CABG) surgery, in particular blood sparing effects, were not reproducible. Air handling and blood management remain the main issues of MiECC in non-coronary surgery. With the introduction of modular (type IV) MiECC systems containing a second, accessory circuit for immediate conversion to open cardiopulmonary bypass (CPB), the last obstacles seem to be cleared away. The first reports using this latest development in MiECC technology sound promising. It is now up to the cardiac surgical community to adopt this technology and produce data helping to answer the question whether MiECC is the best perfusion strategy for all comer's cardiac surgery.


Controlling an actively-quenched single photon detector with bright light.
We control using bright light an actively-quenched avalanche single-photon detector. Actively-quenched detectors are commonly used for quantum key distribution (QKD) in the visible and near-infrared range. This study shows that these detectors are controllable by the same attack used to hack passively-quenched and gated detectors. This demonstrates the generality of our attack and its possible applicability to eavsdropping the full secret key of all QKD systems using avalanche photodiodes (APDs). Moreover, the commercial detector model we tested (PerkinElmer SPCM-AQR) exhibits two new blinding mechanisms in addition to the previously observed thermal blinding of the APD, namely: malfunctioning of the bias voltage control circuit, and overload of the DC/DC converter biasing the APD. These two new technical loopholes found just in one detector model suggest that this problem must be solved in general, by incorporating generally imperfect detectors into the security proof for QKD.


Shell-dependent blinking behavior and fluorescence dynamics of single ZnSe/CdS core/shell quantum dots.
An understanding of blinking behavior and photodynamics is crucial for improving the optical properties of quantum dots (QDs). Here we report the emission blinking behavior and dynamical mechanisms of single ZnSe/CdS core/shell QDs with the shell thickness varying from 1 to 6 monolayers. We find that the emission blinking behavior can be efficiently suppressed in the single-exciton regime and that the photoluminescence (PL) quantum yields (QY) and the corresponding fraction-bright of ZnSe/CdS QDs can be optimized by regulating the shell thickness. Specifically, the PL QY reaches a maximum of 93% when the shell thickness is 4 monolayers. The intensity-resolved and time-resolved fluorescence dynamics of single QDs indicate that three exciton decay pathways via trion emission, band-edge emission and shallow surface trap-state emission contribute to the blinking behavior of ZnSe/CdS QDs. The competitive contribution ratios of these three decay components are responsible for the significant difference in emission properties of ZnSe/CdS QDs with different shell thicknesses. Our findings in this work demonstrate that an effective way to improve the quantum yields and fraction-bright of core/shell QDs is to enhance the band-edge emission while suppressing the trion emission and surface trap-state emission.


Structure and magnetic properties of polydisperse ferrofluids: a molecular dynamics study.
We study by Langevin molecular dynamics simulations systematically the influence of polydispersity in the particle size, and subsequently in the dipole moment, on the physical properties of ferrofluids. The polydispersity is in a first approximation modeled by a bidisperse system that consists of small and large particles at different ratios of their volume fractions. In the first part of our investigations the total volume fraction of the system is fixed, and the volume fraction phiL of the large particles is varied. The initial susceptibility chi and magnetization curve of the systems show a strong dependence on the value of phiL. With the increase of phiL, the magnetization M of the system has a much faster increment at weak fields, and thus leads to a larger chi. We performed a cluster analysis that indicates that this is due to the aggregation of the large particles in the systems. The average size of these clusters increases with increasing phiL. In the second part of our investigations, we fixed the volume fraction of the large particles, and increased the volume fraction phiS of the small particles in order to study their influence on the chain formation of the large ones. We found that the average aggregate size formed by large particles decreases when phiS is increased, demonstrating a significant effect of the small particles on the structural properties of the system. A topological analysis of the structure reveals that the majority of the small particles remain nonaggregated. Only a small number of them are attracted to the ends of the chains formed by large particles.


Use of the Rey-Osterrieth Complex Figure Test for neurotoxicity evaluation of mixtures in children.
The aim of this study was to assess the value of the children's version of the Rey-Osterrieth Complex Figure Test as a screening test in a population exposed to different mixtures of neurotoxicants. Copy and Immediate Recall scores were evaluated through the test. Children were recruited from three sites; an area with natural contamination by fluoride and arsenic (F-As), a mining-metallurgical area with lead and arsenic contamination (Pb-As) and a malaria zone with the evidence of fish contaminated with dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs). Children aged 6-11 years old, living in one of the three polluted sites since birth were recruited (n=166). The exposure was evaluated as follows: fluoride and arsenic in urine, lead in blood and DDT, dichlorodiphenyldichloroethylene (DDE) and PCBs in serum. To evaluate the test performance, z-scores for Copy and Immediate Recall were calculated. The proportion of children by residence area with performance lower than expected by age (below -1 SD) for Copy and Immediate Recall was in the F-As area (88.7% and 59%) and in the DDT-PCBs area (73% and 43.8%), respectively. In the Pb-As area, the proportion was 62% for both tests. After adjustment, Copy correlated inversely with fluoride in urine (r=-0.29; p<0.001) and Immediate Recall correlated inversely with fluoride in urine (r=-0.27; p<0.05), lead in blood (r=-0.72; p<0.01), arsenic in urine (r=-0.63; p<0.05) and DDE (r=-0.25; p<0.05). This study provided evidence that children included in this research are living in high risk areas and were exposed to neurotoxicants. Poor performance in the test could be explained in some way by F, Pb, As or DDE exposure, however social factors or the low quality of school education prevalent in the areas could be playing an important role.


Comprehensive geriatric care for patients with hip fractures: a prospective, randomised, controlled trial.
Most patients with hip fractures are characterised by older age (>70 years), frailty, and functional deterioration, and their long-term outcomes are poor with increased costs. We compared the effectiveness and cost-effectiveness of giving these patients comprehensive geriatric care in a dedicated geriatric ward versus the usual orthopaedic care. We did a prospective, single-centre, randomised, parallel-group, controlled trial. Between April 18, 2008, and Dec 30, 2010, we randomly assigned home-dwelling patients with hip-fractures aged 70 years or older who were able to walk 10 m before their fracture, to either comprehensive geriatric care or orthopaedic care in the emergency department, to achieve the required sample of 400 patients. Randomisation was achieved via a web-based, computer-generated, block method with unknown block sizes. The primary outcome, analysed by intention to treat, was mobility measured with the Short Physical Performance Battery (SPPB) 4 months after surgery for the fracture. The type of treatment was not concealed from the patients or staff delivering the care, and assessors were only partly masked to the treatment during follow-up. This trial is registered with ClinicalTrials.gov, number NCT00667914. We assessed 1077 patients for eligibility, and excluded 680, mainly for not meeting the inclusion criteria such as living in a nursing home or being aged less than 70 years. Of the remaining patients, we randomly assigned 198 to comprehensive geriatric care and 199 to orthopaedic care. At 4 months, 174 patients remained in the comprehensive geriatric care group and 170 in the orthopaedic care group; the main reason for dropout was death. Mean SPPB scores at 4 months were 5·12 (SE 0·20) for comprehensive geriatric care and 4·38 (SE 0·20) for orthopaedic care (between-group difference 0·74, 95% CI 0·18-1·30, p=0·010). Immediate admission of patients aged 70 years or more with a hip fracture to comprehensive geriatric care in a dedicated ward improved mobility at 4 months, compared with the usual orthopaedic care. The results suggest that the treatment of older patients with hip fractures should be organised as orthogeriatric care. Norwegian Research Council, Central Norway Regional Health Authority, St Olav Hospital Trust and Fund for Research and Innovation, Liaison Committee between Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Department of Neuroscience at the Norwegian University of Science and Technology, Foundation for Scientific and Industrial Research at the Norwegian Institute of Technology (SINTEF), and the Municipality of Trondheim.


MiR-593 mediates curcumin-induced radiosensitization of nasopharyngeal carcinoma cells via MDR1.
Curcumin (Cur) exhibits radiosensitization effects to a variety of malignant tumors. The present study investigates the radiosensitizing effect of Cur on nasopharyngeal carcinoma (NPC) cells and whether its mechanism is associated with microRNA-593 (miR-593) and multidrug resistance gene 1 (MDR1). A clonogenic assay was performed to measure the radiosensitizing effect. The expression of miR-593 and MDR1 was analyzed by quantitative polymerase chain reaction (qPCR) or western blot assay. A transplanted tumor model was established to identify the radiosensitizing effect in vivo. A luciferase-based reporter was constructed to evaluate the effect of direct binding of miR-593 to the putative target site on the 3' UTR of MDR1. The clonogenic assay showed that Cur enhanced the radiosensitivity of cells. Cur (100 mg/kg) combined with 4 Gy irradiation inhibited the growth of a transplanted tumor model in vivo, resulting in the higher inhibition ratio compared with the radiotherapy-alone group. These results demonstrated that Cur had a radiosensitizing effect on NPC cells in vivo and in vitro; Cur-mediated upregulation of miR-593 resulted in reduced MDR1 expression, which may promote radiosensitivity of NPC cells.


Evaluating nanoparticle sensor design for intracellular pH measurements.
Particle-based nanosensors have over the past decade been designed for optical fluorescent-based ratiometric measurements of pH in living cells. However, quantitative and time-resolved intracellular measurements of pH in endosomes and lysosomes using particle nanosensors are challenging, and there is a need to improve measurement methodology. In the present paper, we have successfully carried out time-resolved pH measurements in endosomes and lyosomes in living cells using nanoparticle sensors and show the importance of sensor choice for successful quantification. We have studied two nanoparticle-based sensor systems that are internalized by endocytosis and elucidated important factors in nanosensor design that should be considered in future development of new sensors. From our experiments it is clear that it is highly important to use sensors that have a broad measurement range, as erroneous quantification of pH is an unfortunate result when measuring pH too close to the limit of the sensitive range of the sensors. Triple-labeled nanosensors with a pH measurement range of 3.2-7.0, which was synthesized by adding two pH-sensitive fluorophores with different pK(a) to each sensor, seem to be a solution to some of the earlier problems found when measuring pH in the endosome-lysosome pathway.


Neighborhood-resources for the development of a strong SOC and the importance of understanding why and how resources work: a grounded theory approach.
Providing individuals with psychosocial resources such as sense of coherence (SOC) seems a beneficial strategy for health promotion in the neighborhood. In order to become a supporting theory for health promotion, Salutogenesis should renew its focus on resources for health, and explore how the development of a strong SOC can be facilitated. Relevant issues were explored using a Grounded Theory- approach. Three focus-group-sessions and three in-depth interviews were conducted with strategically sampled participants. The transcripts of the focus groups were initially analyzed line-by-line to ensure that insights emerged from the data. We then applied focused and systemic analyses to achieve axial coding, and to include insights into how social interactions during focus groups may reveal social processes in real-life-neighborhoods. The data from the in-depth interviews were used to validate and fill emerging categories, as well as to ensure data-saturation. Findings indicate the importance of repeated experiences with resources and every-day-challenges to develop a strong SOC. Active engagement with resources is a favorable condition for significant experiences, which enhance the internalization of resources. Core experiences are characterized by a re-organization of resources. Participation in intellectual meaning-making through equal power dialogue seems to broaden perspectives and promote the strengthening of SOC. A strong SOC can also be described as a deeper understanding of how and why resources work, which allows for a more flexible use of resources, including replacing missing resources. A new understanding of SOC as an intuitive understanding of how, why and under which circumstances resources work, as well as a new focus on everyday life and repeated experiences might facilitate new approaches to a purposeful strengthening of SOC through the planning and implementation of public measures.


The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis.
In the recent years, we have provided evidence that Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) is a key stress protein with antioxidant-associated tumor suppressive function. The TP53INP1 gene, which is highly conserved in mammals, is over-expressed during stress responses including inflammation. This gene encodes two protein isoforms with nuclear or cytoplasmic subcellular localization depending on the context. TP53INP1 contributes to stress responses, thus preventing stress-induced dysfunctions leading to pathologies such as cancer. Two major mechanisms by which TP53INP1 functions have been unveiled. First, in the nucleus, TP53INP1 was shown to regulate the transcriptional activity of p53 and p73 by direct interaction, and to mediate the antioxidant activity of p53. Second, independently of p53, TP53INP1 contributes to autophagy and more particularly mitophagy through direct interaction with molecular actors of autophagy. TP53INP1 is thus required for the homeostasis of the mitochondrial compartment, and is therefore involved in the regulation of energetic metabolism. Finally, the antioxidant function of TP53INP1 stems from the control of mitochondrial reactive oxygen species production. In conclusion, TP53INP1 is a multifaceted protein endowed with multiple functions, including metabolic regulation, as is its main functional partner p53.


Particle size and surfactant effects on chemical mechanical polishing of glass using silica-based slurry.
This study explores the effect of particle size and surfactant on the chemical mechanical polishing (CMP) of glass using colloidal silica-based slurry. It was found that the material removal rate strongly depends on the particle size and the types of surfactants and that the rms roughness was independent of particle size and correlated to surfactants. On the basis of polishing results, it was concluded that the main polishing mechanism was changed from indentation mechanism to surface-area mechanism, with the variation of particle size. In addition, the molecular structure, charge type, and lubricating effect of the surfactants play an important role in the dispersion of abrasive particles and in the CMP performance.


Cardiac autonomic regulation differentiates reflux disease with and without erosive esophagitis.
Impaired autonomic function has been observed in patients with gastroesophageal reflex disease (GERD), but little is known about autonomic function in patients with non-erosive reflux disease (NERD). The objective of this study was to investigate potential differences in autonomic function by means of heart rate variability in GERD patients with and without erosive esophagitis. Thirty-five GERD patients and 20 healthy controls participated in the study. Seventeen subjects with NERD and 18 patients with erosive reflux disease (ERD) were identified based on typical reflux symptoms, endoscopic findings, and 24-h esophageal pH. Spectral analysis of heart rate variability was performed to calculate the low-frequency (LF) band, the high-frequency (HF) band, and the LF/HF ratio. No significant differences were found in age, gender, body mass index, or current tobacco use among the reflux patients and controls. The Helicobacter pylori status and severity of reflux symptoms were similar between the two groups. The HF band power was significantly lower in patients with ERD than in NERD patients (p < 0.01) and controls (p < 0.05). LF band power (%) and LF/HF ratio were significantly lower in the NERD patients compared with ERD patients (p < 0.05) and controls (p < 0.05). There was no statistically significant correlation between any heart rate variability parameter and symptom severity score in either the ERD or NERD group. Patients with ERD and NERD display a similar degree of symptom severity, but the pattern of autonomic function appears to differ between NERD and ERD.


From Sediment to Top Predators: Broad Exposure of Polyhalogenated Carbazoles in San Francisco Bay (U.S.A.).
The present study provides the first comprehensive investigation of polyhalogenated carbazoles (PHCZs) contamination in an aquatic ecosystem. PHCZs have been found in soil and aquatic sediment from several different regions, but knowledge of their bioaccumulation and trophodynamics is extremely scarce. This work investigated a suite of 11 PHCZ congeners in San Francisco Bay (United States) sediment and organisms, including bivalves (n = 6 composites), sport fish (n = 12 composites), harbor seal blubber (n = 18), and bird eggs (n = 8 composites). The most detectable congeners included 3,6-dichlorocarbazole (36-CCZ), 3,6-dibromocarbazole (36-BCZ), 1,3,6-tribromocarbazole (136-BCZ), 1,3,6,8-tetrabromocarbazole (1368-BCZ), and 1,8-dibromo-3,6-dichlorocarbazole (18-B-36-CCZ). The median concentrations of ΣPHCZs were 9.3 ng/g dry weight in sediment and ranged from 33.7 to 164 ng/g lipid weight in various species. Biomagnification was observed from fish to harbor seal and was mainly driven by chlorinated carbazoles, particularly 36-CCZ. Congener compositions of PHCZs differed among species, suggesting that individual congeners may be subject to different bioaccumulation or metabolism in species occupying various trophic levels in the studied aquatic system. Toxic equivalent (TEQ) values of PHCZs were determined on the basis of their relative effect potencies (REP) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The median TEQ was 1.2 pg TEQ/g dry weight in sediment and 4.8-19.5 pg TEQ/g lipid weight in biological tissues. Our study demonstrated the broad exposure of PHCZs in San Francisco Bay and their characteristics of bioaccumulation and biomagnification along with dioxin-like effects. These findings raise the need for additional research to better elucidate their sources, environmental behavior, and fate in global environments.