Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial.
Improved influenza vaccines are needed to reduce influenza-associated complications in older adults. The aim of this study was to identify the optimal formulation of adjuvanted seasonal influenza vaccine for use in elderly people. This observer-blind, randomized study assessed the optimal formulation of adjuvanted seasonal influenza vaccine based on immunogenicity and safety in participants aged ≥65 years. Participants were randomized (~200 per group) to receive one dose of non-adjuvanted vaccine or one of eight formulations of vaccine formulated with a squalene and tocopherol oil-in-water emulsion-based Adjuvant System (AS03(C), AS03(B) or AS03(A), with 2.97, 5.93 and 11.86 mg tocopherol, respectively) together with the immunostimulant monophosphoryl lipid A (MPL, doses of 0, 25 or 50 mg). Hemagglutination-inhibition (HI) antibody responses and T-cell responses were assessed on Day 0 and 21 days post-vaccination. The ratio of HI-based geometric mean titers in adjuvanted versus non-adjuvanted vaccine groups were calculated and the lower limit of the 90% confidence interval was transformed into a desirability index (a value between 0 and 1) in an experimental domain for each vaccine strain, and plotted in relation to the AS03 and MPL dose combination in the formulation. This model was used to assess the optimal formulation based on HI antibody titers. Reactogenicity and safety were also assessed. The immunogenicity and safety analyses were used to evaluate the optimal formulation of adjuvanted vaccine. In the HI antibody-based model, an AS03 dose-response was evident; responses against the A/H1N1 and A/H3N2 strains were higher for all adjuvanted formulations versus non-adjuvanted vaccine, and for the AS03(A)-MPL25, AS03(B)-MPL25 and AS03(B)-MPL50 formulations against the B strain. Modelling using more stringent criteria (post hoc) showed a clear dose-range effect for the AS03 component against all strains, whereas MPL showed a limited effect. Higher T-cell responses for adjuvanted versus non-adjuvanted vaccine were observed for all except two formulations (AS03(C) and AS03(B)-MPL25). Reactogenicity increased with increasing AS03 dosage, and with MPL. No safety concerns were raised. Five formulations containing AS03(A) or AS03(B) were identified as potential candidates to improve immune responses to influenza vaccination; AS03(B) without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity. This trial is registered at ClinicalTrials.gov, NCT00540592.


The Relationship between PID-5 Personality Traits and Mental States. A Study on a Group of Young Adults at Risk of Psychotic Onset.
The diagnosis of psychosis is a challenge for the scientific community, both in terms of its definition and treatment. Some recent studies have investigated the relationship between personality and psychosis onset to prevent or intervene early. Sixty young adults were recruited during their first access in 2019 near the Community Mental Health Service of Niguarda Hospital, Milan, Italy. The assessment included the Social and Occupational Functioning Assessment Scale (SOFAS), the Global Assessment of Functioning (GAF) (clinician scales), the 16-item Version of the Prodromal Questionnaire (PQ-16), the Personality Inventory for DSM-5 (PID-5) (self-report), and a clinical session. Statistical analysis was performed by SPSS. The results show a negative correlation between the Detachment domain and the GAF scores. Correlational analysis also highlights that all PID-5 domains, except for Antagonism, have positive correlations with high scores in the PQ-16. The multivariate analysis of variance showed that patients diagnosed with versus without a psychotic disorder significantly differed on Detachment, Antagonism and Psychoticism PID-5 domains. The involvement of the personality construct in psychopathological development is displayed. In particular, higher levels of Detachment and Psychoticism can distinguish people who are more vulnerable to psychosis or who already have overt psychosis from those who do not have a psychotic predisposition. The study highlights the fundamental role of personality traits, emerging from PID-5, to distinguish young adults at risk of onset.


Occurrence and predictors of the fatigue in high-grade glioma patients.
A better knowledge of the fatigue could be of the greatest importance for the high-grade glioma (HGG) patients, who are a unique and vulnerable population. The aim of this study was to evaluate the occurrence and the predictors of the fatigue in HGG patients, using a specific fatigue scale. The study was designed as a cross-sectional study. The study population included sixty-seven consecutive outpatients with HGG. We used these measures: Brief Fatigue Inventory, Karnofsky Performance Scale, Functional Independence Measure, Brief Psychiatric Rating Scale and Psychological Distress Inventory and SF-36, EORTC QLQ-30 and EORTC QLQ-BN20 for quality of life (QoL). Sixteen out of sixty-seven (23.9 %) patients were affected by Anaplastic Astrocytoma and 51/67 (76.1 %) by Glioblastoma Multiforme. About one-third (36.2 %) of patients had a clinically relevant fatigue (Brief Fatigue Inventory ≥3). In regression analysis, physical and mental aspects of QoL were statistically significant related with fatigue (p < 0.01 and p < 0.02, respectively). Our data underlined the relevant occurrence of fatigue in HGG patients and support the development of further studies exploring a tailored rehabilitation program.


Caprine arthritis-encephalitis in the Basque country, Spain.
A goat herd severely affected by arthritis was studied. The most representative clinical signs consisted of articular swelling, mainly of the carpal joints, and the subsequent locomotor disorders. Some goats also showed signs of central nervous system involvement. Examinations of joint fluid revealed an increased number of mononuclear blood cells, mostly lymphocytes. Gross and microscopic articular lesions were of inflammatory and degenerative types. Periarticular connective tissue, synovial bursae, tendons and tendon sheaths were predominantly affected. Inflammatory lesions were those of a chronic hyperplastic tenosynovitis with fibrosis of the connective tissue components. Degenerative changes consisted mainly of necrosis and mineralisation of articular-related structures. Histological lesions in the central nervous system were those of a nonpurulent encephalitis initially located in periventricular areas, but in one case extensive encephalomalacia was also seen. Of the 80 animals sampled 82.5 per cent showed seropositive reactions against an ovine progressive pneumonia virus antigen. None was seropositive to brucella and titres to chlamydia were low. Attempts to isolate chlamydia and mycoplasma from affected joints and several organs failed. Different bacteria were recovered from a few samples but did not seem significant. Syncytium-forming viral particles were isolated from several organs, mainly the lungs, synovial membranes and lymphoid tissue of almost all the slaughtered animals. These particles were identified as lentiviruses by electron microscopy. The clinical signs, lesions serological results and microbiological findings, led to a diagnosis of caprine arthritis-encephalitis. This syndrome has not been recognised in Spain previously.


Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys.
Fibrosis is considered as a central factor in the loss of renal function in chronic kidney diseases. The origin of fibroblasts and myofibroblasts that accumulate in the interstitium of the diseased kidney is still a matter of debate. It has been shown that accumulation of myofibroblasts in inflamed and fibrotic kidneys is associated with upregulation of fibroblast-specific protein 1 (FSP1, S100A4), not only in the renal interstitium but also in the injured renal epithelia. The tubular expression of FSP1 has been taken as evidence of myofibroblast formation by epithelial-mesenchymal transition (EMT). The identity of FSP1/S100A4 cells has not been defined in detail. We originally intended to use FSP1/S100A4 as a marker of putative EMT in a model of distal tubular injury. However, since the immunoreactivity of FSP1 did not seem to fit with the distribution and shape of fibroblasts or myofibroblasts, we undertook the characterization of FSP1/S100A4-expressing cells in the interstitium of rodent kidneys. We performed immunolabeling for FSP1/S100A4 on thin cryostat sections of perfusion-fixed rat and mouse kidneys with peritubular inflammation, induced by thiazides and glomerulonephritis, respectively, in combination with ecto-5'-nucleotidase (5'NT), recognizing local cortical peritubular fibroblasts, with CD45, MHC class II, CD3, CD4 and Thy 1, recognizing mononuclear cells, with alpha smooth muscle actin (alphaSMA), as marker for myofibroblasts, and vimentin for intracellular intermediate filaments in cells of mesenchymal origin. In the healthy interstitium of rodents the rare FSP1/S100A4+ cells consistently co-expressed CD45 or lymphocyte surface molecules. Around the injured distal tubules of rats treated for 3-4 days with thiazides, FSP1+/S100A4+, 5'NT+, alphaSMA+, CD45+ and MHC class II+ cells accumulated. FSP1+/S100A4+ cells consistently co-expressed CD45. In the inflamed regions, alphaSMA was co-expressed by 5'NT+ cells. In glomerulonephritic mice, FSP1+/S100A4+ cells co-expressed Thy 1, CD4 or CD3. Thus, in the inflamed interstitium around distal tubules of rats and of glomerulonephritic mice, the majority of FSP1+ cells express markers of mononuclear cells. Consequently, the usefulness of FSP1/S100A4 as a tool for detection of (myo)fibroblasts in inflamed kidneys and of EMT in vivo is put into question. In the given rat model the consistent co-expression of alphaSMA and 5'NT suggests that myofibroblasts originate from resident peritubular fibroblasts.


Does aspirin acetylate multiple cellular proteins? (Review).
Aspirin is a salicylate drug that is extensively used for its anti-inflammatory, antipyretic, analgesic and anti-thrombotic effects. More recently, it has been shown to decrease the incidence of cancers of epithelial origin. In most cases, aspirin is relatively safe. However, it does cause a host of adverse effects and toxicities, including gastrointestinal bleeding, ulcerations, nephrotoxicity and hypersensitivity reactions. Although the inhibition of cyclooxygenases by aspirin, which leads to its anti-inflammatory/analgesic properties, has been well studied, the mechanisms involved in its chemopreventive effects as well as some of its adverse effects are as yet ill-defined. Studies over the past decades suggest that, besides cyclooxygenases, aspirin acetylates other cellular proteins. These studies used radiolabeled 3H or 14C aspirin, the only approach used to date for the detection of proteins acetylated by aspirin. In a recent study using protein-specific anti-acetyl lysine antibodies and immunological methods, we demonstrated the ability of aspirin to acetylate the tumor suppressor protein p53. In this review, we present current research from the literature on the aspirin-induced acetylation of proteins. We also describe an immunological approach to detecting acetylated proteins in aspirin-treated cells, and demonstrate that multiple proteins are acetylated. Since post-translational modification of proteins, such as acetylation, may lead to the alteration of their function, it is possible that some of the hitherto unexplained beneficial or adverse effects of aspirin could occur as a result of these modifications. The identification of these novel acetylation targets of aspirin represents a new area for investigation.


Targeting autoimmune diabetes with gene therapy.
The autoimmune nature of insulin-dependent, or type 1, diabetes targets the beta-cells of the pancreas for destruction and results in a lifelong commitment to insulin replacement therapy. Although the number of formulations and dosing of insulin have become more sophisticated and more efficient in recent years, insulin therapy alone is unable to prevent nephropathy, retinopathy, or vascular and heart disease, which still occur in a large number of patients. Different approaches have been attempted to eliminate the requirement of exogenous insulin administration. Historically, these have included pancreatic and islet transplants, which were later combined with treatments intended to halt the destructive process directed against the islets. Despite significant advances made in all of these areas, each approach faces a hostile immunological response that frequently ends with the loss of the islets. Gene therapy-based approaches add a new dimension to the efforts aimed at specifically blocking the immunological attack against the islets in genetically at-risk individuals (autoimmunity) or the immunological response against transplanted allogeneic islets (rejection). This new technology may have an important role in the therapy and cure of type 1 diabetes.


Improvement of human myocardial mitochondria after dobutamine: a quantitative ultrastructural study.
Dobutamine is a new inotropic agent that may induce prolonged clinical improvement in patients with congestive cardiomyopathy. Sixteen patients with severe heart failure but without obstructive coronary disease were studied by serial functional class determinations and by noninvasive measurements of left ventricular function before and after bedrest control period and then after a 3-day infusion of dobutamine. An endomyocardial biopsy procedure was performed on 11 patients before and after the bedrest and on all 16 patients before and after dobutamine. Quantitative ultrastructural analysis of the biopsies was performed on electron micrographs (31,200 X) by a grid technique. The number of electron dense particles per 100 mitochondria did not change after bedrest but there was a significant decrease from 84 +/- 14 to 65 +/- 12 (P < .005) in the pre- to postdobutamine biopsies. The cristae to matrix ratio of the mitochondria did not change with bedrest but improved from 0.37 +/- 0.04 to 0.47 +/- 0.05 (P < .02) after dobutamine. The average mitochondrial size did not change significantly in the bedrest control nor in the dobutamine biopsy samples. However, when the 16 patients were divided into those who had a good clinical response (by functional class and noninvasive measurements of left ventricular function) and those who had no or little response, the 10 responders did decrease their average mitochondria size from 0.26 +/- 0.03 mu 2 to 0.23 +/- 0.02 mu 2 (P < .02). The mechanism by which a 3-day infusion of dobutamine induces a prolonged clinical improvement is not well understood. The use of quantitative ultrastructural technique in this study has demonstrated that there is a morphologic basis to the improvement.


Comparison of temperate and tropical freshwater species' acute sensitivities to chemicals: An update.
Toxicity data for tropical species are often lacking for deriving water quality guidelines (WQGs) and for conducting ecological risk assessment (ERA). To protect and safeguard valuable natural resources and important biodiversity in tropical freshwater ecosystems, a sound framework should be established to assess and manage the ecological risk of an ever-increasing number of chemicals that occur in the tropics. The present study aims to provide a more up-to-date comparison of the species sensitivity distributions (SSDs) between temperate and tropical freshwater species, by incorporating more acute toxicity data that have been documented. Results showed that temperate freshwater species are generally more sensitive to As, Cr, Pb, Hg, carbaryl, chlorpyrifos, DDT, lindane, and malathion than are their tropical counterparts, whereas tropical species tend to be more sensitive to un-ionized ammonia, Mn, chlordane, and phenol. No sensitivity differences were found between temperate and tropical freshwater species to Cu and pentachlorophenol. A general decline in sensitivity trend to chemicals was revealed by comparing taxon-specific SSDs, from crustaceans to mollusks, worms, fishes, and insects. On the basis of calculated 10% hazardous concentration (HC10) ratios from pairwise temperate and tropical SSDs, the temperate-to-tropic safe extrapolation factor was verified and refined as 5 for information. Integr Environ Assess Manag 2019;00:000-000. © 2019 SETAC.


Biomedical risk assessment as an aid for smoking cessation.
A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. For the most recent update, we searched the Cochrane Collaboration Tobacco Addiction Group Specialized Register in July 2012 for studies added since the last update in 2009. Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. Results were expressed as a relative risk (RR) for smoking cessation with 95% confidence intervals (CI). Where appropriate, a pooled effect was estimated using a Mantel-Haenszel fixed-effect method. We included 15 trials using a variety of biomedical tests. Two pairs of trials had sufficiently similar recruitment, setting and interventions to calculate a pooled effect; there was no evidence that carbon monoxide (CO) measurement in primary care (RR 1.06, 95% CI 0.85 to 1.32) or spirometry in primary care (RR 1.18, 95% CI 0.77 to 1.81) increased cessation rates. We did not pool the other 11 trials due to the presence of substantial clinical heterogeneity. Of the remaining 11 trials, two trials detected statistically significant benefits: one trial in primary care detected a significant benefit of lung age feedback after spirometry (RR 2.12, 95% CI 1.24 to 3.62) and one trial that used ultrasonography of carotid and femoral arteries and photographs of plaques detected a benefit (RR 2.77, 95% CI 1.04 to 7.41) but enrolled a population of light smokers and was judged to be at unclear risk of bias in two domains. Nine further trials did not detect significant effects. One of these tested CO feedback alone and CO combined with genetic susceptibility as two different interventions; none of the three possible comparisons detected significant effects. One trial used CO measurement, one used ultrasonography of carotid arteries and two tested for genetic markers. The four remaining trials used a combination of CO and spirometry feedback in different settings. There is little evidence about the effects of most types of biomedical tests for risk assessment on smoking cessation. Of the fifteen included studies, only two detected a significant effect of the intervention. Spirometry combined with an interpretation of the results in terms of 'lung age' had a significant effect in a single good quality trial but the evidence is not optimal. A trial of carotid plaque screening using ultrasound also detected a significant effect, but a second larger study of a similar feedback mechanism did not detect evidence of an effect. Only two pairs of studies were similar enough in terms of recruitment, setting, and intervention to allow meta-analyses; neither of these found evidence of an effect. Mixed quality evidence does not support the hypothesis that other types of biomedical risk assessment increase smoking cessation in comparison to standard treatment. There is insufficient evidence with which to evaluate the hypothesis that multiple types of assessment are more effective than single forms of assessment.


Implant dentistry at the focus of liability lawsuits.
In recent years, the growing readiness on the part of dental patients to take legal action has resulted in an increasing number of medical liability lawsuits. The aim of this retrospective analysis was to highlight aspects of these lawsuits of special significance, to subject them to both qualitative and quantitative analysis, and to show how conflicts can be avoided. Forty relevant court decisions from the year 1984 onwards were found in online databases and through direct inquiries at the courts. These were supplemented by 21 reports prepared by experts at the University of Muenster, Department of Dental Medicine, commissioned by courts in connection with ongoing lawsuits. Analysis was initially based on formal aspects of the cases and reports. It was later supplemented by differentiated assignment of the questions addressed by the courts to the expert consultants. The principles underlying the judgments as to the liability arising from the terms of the contract were also assigned to the expert consultants in a differentiated manner. The results revealed marked differences in the frequency of liability-prone aspects of treatment. While the majority of judgments referred to the obligation to take due care during the preparatory and treatment phases, infringement of the obligations to provide information and to keep records played more than a minor role. Moreover, 90% of all cases represented combined charges covering various aspects, including those related to consequential failings. The detailed qualitative analysis of the grounds quoted and of the lines of reasoning can therefore be summed up in clearly defined recommendations aimed at helping the clinician avoid conflicts by observing the judicial requirements.


Large coupling-strength expansion of the Møller-Plesset adiabatic connection: From paradigmatic cases to variational expressions for the leading terms.
We study in detail the first three leading terms of the large coupling-strength limit of the adiabatic connection that has as weak-interaction expansion the Møller-Plesset perturbation theory. We first focus on the H atom, both in the spin-polarized and the spin-unpolarized cases, reporting numerical and analytical results. In particular, we derive an asymptotic equation that turns out to have simple analytical solutions for certain channels. The asymptotic H atom solution for the spin-unpolarized case is then shown to be variationally optimal for the many-electron spin-restricted closed-shell case, providing expressions for the large coupling-strength density functionals up to the third leading order. We also analyze the H2 molecule and the uniform electron gas.


Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions.
Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments implicated in protein trafficking in Plasmodium-infected erythrocytes, the contribution of lipid-mediated sorting to this cellular process has been poorly investigated. In this study, we examined the proteome of cholesterol-rich membrane microdomains or lipid rafts, purified from erythrocytes infected by the rodent parasite Plasmodium berghei. Besides structural proteins associated with invasive forms, we detected chaperones, proteins implicated in vesicular trafficking, membrane fusion events and signalling. Interestingly, the raft proteome of mixed P. berghei blood stages included proteins encoded by members of a large family (bir) of putative variant antigens potentially implicated in host immune system interactions and targeted to the surface of the host erythrocytes. The generation of transgenic parasites expressing BIR/GFP fusions confirmed the dynamic association of members of this protein family with membrane microdomains. Our results indicated that lipid rafts in Plasmodium-infected erythrocytes might constitute a route to sort and fold parasite proteins directed to various host cell compartments including the cell surface.


Thyroid cancer: possible role of telemedicine.
Telemedicine is extremely useful when distance could hinder diagnostic procedures, disease management, or when severe side-effects may occur in patients not within easy reach of medical care and requiring prompt action and specific therapies. Telemedicine has been successfully adopted in the management of chronic patients, particularly in those with cardiologic or oncologic diseases. In the treatment of differentiated thyroid cancer, requiring long-term check-ups and visits as well as administration of high doses of levothyroxine (TSH - thyroid-stimulating hormone - suppression), also in elderly patients, telemedicine seems particularly indicated. Moreover, these distant monitoring techniques could not only reduce long-term management costs but also considerably decrease cardiovascular risks associated with these patients. The present review aims to provide some general information on telemedicine and its possible fields of action with regard to distant monitoring of patients with differentiated thyroid carcinoma.


Bursting as a source of non-linear determinism in the firing patterns of nigral dopamine neurons.
Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single-spikes and phasic bursts that encode information for certain types of reward-related learning and behavior. Non-linear dynamical analysis has previously demonstrated the presence of a non-linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non-linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non-linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter-spike interval data recorded in vivo from bursting and non-bursting DA neurons in the chloral hydrate-anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non-linear determinism in their firing patterns, whereas non-bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter-burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane-anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate-anesthetized rats. These results strongly indicate that bursting activity is the main source of low-dimensional, non-linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons.


Newer aspects of glutamine/glutamate metabolism: the role of acute pH changes.
This review focuses on the role of acute pH changes in the regulation of Gln/Glu metabolism in the kidney, liver, and brain. Alterations of proton concentration ([H(+)]) profoundly affect flux through phosphate-dependent glutaminase (PDG) or glutamate dehydrogenase (GDH), the primary enzymes responsible for mitochondrial metabolism of glutamine and glutamate, respectively. In the kidney, acute acidosis stimulates Gln uptake and its metabolism via the PDG pathway. The Glu formed from Gln can be removed via 1) oxidative deamination through the GDH reaction, 2) transamination reactions, and 3) transport of Glu from intracellular to extracellular compartment, thereby diminishing the intramitochondrial pool of glutamate sufficiently to stimulate flux through the PDG pathway. Converse changes may occur with increased pH. In the liver, acidosis diminishes the rate of Gln and Glu metabolism via the PDG and GDH pathways, but stimulates glutamine synthesis (i.e., glutamine recycling). Alkalosis has little effect. Hepatic Gln metabolism via the PDG pathway has a central role in ureagenesis via 1) supplementation of nitrogen for the synthesis of carbamyl phosphate, and 2) providing glutamate for N-acetylglutamate synthesis. In the brain, Gln/Glu metabolism links ammonia detoxification and energy metabolism via 1) detoxification of ammonia and excess glutamate by glutamine synthesis in astrocytes, 2) formation and export of glutamine to neurons where it is metabolized to glutamate and GABA, and 3) production of alpha-ketoglutarate and lactate from Glu and their transport to neurons. Changes in intracellular pH associated with changes in cellular [K(+)] may have a key role in the regulation of these processes of glial-neuronal metabolism of Gln/Glu metabolism.


Probable variant Creutzfeldt–Jakob disease in Asia: a case report from Taiwan and review of two prior cases.
New variant Creutzfeldt–Jakob disease (vCJD) was first identified in the UK in 1996, and was causally linked to bovine spongiform encephalopathy. Herein we report the first case of vCJD in Taiwan: a 34-year-old man who had lived in the UK between 1989 and 1997. The patient presented with depression, irritability, personality change, painful feet and allodynia, followed by gait ataxia and cognitive impairment. Electroencephalograms did not show the typical appearance of sporadic CJD. The cerebrospinal fluid 14-3-3 protein immunoassay was negative. Brain magnetic resonance imaging revealed high signal lesions involving bilateral caudate nuclei, left lentiform nucleus, bilateral dorsomedial thalami and pulvinar on fluid-attenuation inversion recovery, T2- and diffusion-weighted imaging. Prion protein gene analysis showed homozygous for methionine at codon 129. The patient developed akinetic mutism at 16 months and died at 28 months after onset. The clinical presentation and neuroimaging findings were compatible with the vCJD cases reported since 1996, and met the World Health Organization Case Definition for probable vCJD. In this communication, we also review two other cases of vCJD in Asia. All three cases were assumed as imported cases from the UK because of the residential or travel history of the patients.


Chains of cubic colloids at fluid-fluid interfaces.
Inspired by recent experimental observations of spontaneous chain formation of cubic particles adsorbed at a fluid-fluid interface, we theoretically investigate whether capillary interactions can be responsible for this self-assembly process. We calculate adsorption energies, equilibrium particle orientations, and interfacial deformations, not only for a variety of contact angles but also for single cubes as well as an infinite 2D lattice of cubes at the interface. This allows us to construct a ground-state phase diagram as a function of areal density for several contact angles, and upon combining the capillary energy of a 2D lattice with a simple expression for the entropy of a 2D fluid we also construct temperature-density or size-density phase diagrams that exhibit large two-phase regions and triple points. We identify several regimes with stable chainlike structures, in line with the experimental observations.


Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma.
Fenretinide is an effective inducer of apoptosis in many malignancies but its precise mechanism(s) of action in the induction of apoptosis in neuroblastoma is unclear. To characterize fenretinide-induced apoptosis, neuroblastoma cell lines were treated with fenretinide and flow cytometry was used to measure apoptosis, free radical generation, and mitochondrial permeability changes. Fenretinide induced high levels of caspase-dependent apoptosis accompanied by an increase in free radicals and the release of cytochrome c in the absence of mitochondrial permeability transition. Apoptosis was blocked by two retinoic acid receptor (RAR)-beta/gamma-specific antagonists, but not by an RARalpha-specific antagonist. Free radical induction in response to fenretinide was not blocked by the caspase inhibitor ZVAD or by RAR antagonists and was only marginally reduced in cells selected for resistance to fenretinide. Therefore, free radical generation may be only one of a number of intracellular mechanisms of apoptotic signaling in response to fenretinide. These results suggest that the effector pathway of fenretinide-induced apoptosis of neuroblastoma is caspase dependent, involving mitochondrial release of cytochrome c independently of permeability changes, and mediated by specific RARs. As the mechanism of action of fenretinide may be different from other retinoids, this compound may be a valuable adjunct to neuroblastoma therapy with retinoic acid and conventional chemotherapeutic drugs.


The impact of COVID-19 pandemic on pulmonary hypertension: What have we learned?
The coronavirus 2019 disease (COVID-19) pandemic threatened the Spanish health-care system. Patients with demanding conditions such as precapillary pulmonary hypertension (PH) faced a potentially severe infection, while their usual access to medical care was restricted. This prospective, unicentric study assessed the impact of COVID-19 on PH patients' outcomes and the operational changes in the PH network. Sixty-three PH patients (41 pulmonary arterial hypertension [PAH]; 22 chronic thromboembolic pulmonary hypertension [CTEPH]) experienced COVID-19. Overall mortality was 9.5% without differences when stratifying by hemodynamics or PAH-risk score. Patients who died were older (73.6 ± 5 vs. 52.2 ± 15.4; p = 0.001), with more comorbidities (higher Charlson index: 4.17 ± 2.48 vs. 1.14 ± 1.67; p = 0.0002). Referrals to the PH expert center decreased compared to the previous 3 years (123 vs. 160; p = 0.002). The outpatient activity shifted toward greater use of telemedicine. Balloon pulmonary angioplasty activity could be maintained after the first pandemic wave and lockdown while pulmonary thromboendarterectomy procedures decreased (19 vs. 36; p = 0.017). Pulmonary transplantation activity remained similar. The COVID-19 mortality in PAH/CTEPH patients was not related to hemodynamic severity or risk stratification, but to comorbidities. The pandemic imposed structural changes but a planned organization and resource reallocation made it possible to maintain PH patients' care.


Chromium speciation in environmental samples by solid- phase extraction using lewatit ionac SR-7 resin and flame atomic absorption spectrometry.
A new method for the speciation, preconcentration, and separation of Cr(lll) and Cr(VI) species in different matrixes was developed using SPE combined with flame atomic absorption spectrometry. Theprocedure is based on the exchange of Cr(VI) ions as CrO(4)(2-) with CI- ions on Lewatit lonac SR-7 ion-exchange resin. After the oxidation of Cr(lll) to CrO(4)(2-) ions by concentrated H202 in basic medium, the procedure was applied to the determination of total Cr. Cr(lll) was calculated as the difference between the total Cr and Cr(VI) contents. The influence of the analytical parameters including the pH of the solution, amount of resin, eluent type, sample volume, and flow rates of the sample and eluent solutions were investigated. No considerable interferences were observed from: other anions and cations investigated in the Cr speciation. The preconcentration factor was found to be 500. The LOD for Cr(VI), corresponding to three times the SD of the blank, was 0.003 μg/L. The sorption capacity and binding equilibrium constant were calculated as 17.2 mg/g and 2.54 L/mg, respectively. The accuracy of the method was verified by analyzing certified reference materials. The proposed method was applied to the speciation of Cr species in real samples with satisfactory results.


Spatiotemporal immune zonation of the human kidney.
Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.


Nicotinic receptor subtypes in the developing chick brain: appearance of a species containing the alpha4, beta2, and alpha5 gene products.
Increasing evidence suggests nicotinic receptors regulate developmental events in the nervous system. We used [3H]epibatidine and 125I-alpha-bungarotoxin, together with subunit-specific monoclonal antibodies, to distinguish and quantify nicotinic receptor subtypes in developing chick brain. The results show that more than three fourths of the epibatidine-binding receptors at both early and late embryonic stages contain alpha4 and beta2 subunits, representing receptors previously distinguished by high affinity nicotine binding. A fraction of these also contain the alpha5 gene product, which is consistent with studies on transfected cells showing that the alpha4, beta2, and alpha5 gene products coassemble to produce epibatidine-binding receptors. A small portion of the receptors contain alpha3 and beta4 subunits, assembled in part with either alpha4 or beta2 subunits. The most abundant nicotinic receptors, however, at both early and late embryonic stages are those having high affinity for alpha-bungarotoxin rather than epibatidine. Most contain alpha7 subunits, whereas about half contain alpha8 subunits as well. The sharpest developmental increase between embryonic days 8 and 17/18 occurs with receptors containing alpha5 subunits, whereas receptors containing alpha3 or beta4 subunits undergo no specific increase. The three major receptor species (containing alpha4 and beta2 but not alpha5 subunits; alpha7 subunits; or alpha7 and alpha8 subunits) each increase approximately 3-fold during the same period. The results indicate greater receptor complexity than appreciated previously; they provide information about the rules governing subunit assembly in neuronal nicotinic receptors and draw attention to the role of alpha5 subunits in late development.


Endoscopic management of pancreatic fistula after distal pancreatectomy and enucleation.
Preoperative endoscopic pancreatic sphincterotomy (EPS) has been proposed to prevent postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) or enucleation (EN). The use of EPS as a curative treatment for POPF has been scarcely reported. We reported 10 consecutive patients who were successfully treated by EPS for a prolonged POPF. Ten patients underwent EPS for prolonged POPF (median duration = 40 days, range 20-114; median daily output = 80 mL, range 50-250) after 6 DPs, 2 ENs, and 2 medial pancreatectomies. EPS was performed in all patients, with stent insertion in 4. No patient developed a specific complication because of EPS. POPF healed within a median delay of 4 days (range 1-12). One patient underwent a repeated endoscopy to treat stent malposition. The median delay of discharge after EPS was 13 days (range 8-15). With a 20-month median follow up, 1 patient developed early transient POPF recurrence because of spontaneous stent migration. EPS is indicated for prolonged POPF after DP or EN because it is highly feasible, shortens healing, and is well tolerated.


Safety considerations in learning new procedures: a survey of surgeons.
There exists a tension between surgical innovation and safety. The learning curve associated with the introduction of new procedures/technologies has been associated with preventable patient harm. Surgeon's perceptions regarding the safety of methods for learning new procedures/technologies are largely uncharacterized. A survey was designed to evaluate surgeons' perceptions related to learning new procedures/technologies. This included clinical vignettes across two domains: (1) experience with an operation (e.g., colectomy) and (2) experience with a technology (e.g., laparoscopy). This study also focuses on a surgeon's perceptions of existing credentialing/privileging requirements. Participants were faculty surgeons (n = 150) at two large Midwestern academic health centers. Survey response rate was 77% (116/150). 69% of respondents believed the processes of credentialing/privileging is "far too relaxed" or "too relaxed" for ensuring patient safety. Surgeons most commonly indicated a mini-fellowship is required to learn a new laparoscopic procedure. However, that requirement differed based on a surgeon's prior experience with laparoscopy. For example, to learn laparoscopic colectomy, 35% of respondents felt a surgeon with limited laparoscopic experience should complete a mini-fellowship, whereas 3% felt this was necessary if the surgeon had extensive laparoscopic experience. In the latter scenario, most respondents felt a surgeon should scrub in cases performed by an expert (38%) or perform cases under a proctor's supervision (33%) when learning laparoscopic colectomy. Many surgeons believe existing hospital credentialing/privileging practices may be too relaxed. Moreover, surgeons believe the "one-size-fits-all" approach for training practicing surgeons may not protect patients from unsafe introduction of new procedures/technologies.


Duration of anesthesia affects intraocular pressure, but not outflow facility in mice.
The study of aqueous humor dynamics (AHD) in mice is becoming more prevalent as more strains with elevated intraocular pressure (IOP) are developed. High IOP is usually associated with reduced outflow facility making this one of the more important AHD parameters to evaluate. Ocular measurements in mice require anesthesia that has profound effects on IOP but unknown effects on outflow facility. This study evaluates the effects of anesthesia duration and latanoprost treatment on outflow facility and IOP in BALB/c mice. IOPs were measured in conscious and anesthetized mice by tonometry. Outflow facility was evaluated in 15-min intervals at three pressure levels over two 45-min periods. Comparisons were made between latanoprost-treated eyes and untreated contralateral eyes. To determine the effect of anesthesia duration on IOP, a microneedle method was used to follow IOP for 120 min in separate mice. IOP was 9.7 +/- 0.3 mmHg (mean +/- SEM) in conscious mice and 7.1 +/- 0.02 within 10 min of anesthesia initiation (p < 0.01). IOP changed significantly between but not within assessment periods. IOP at 75 min was significantly (p = 0.004) reduced compared to IOP at 15 min after initial anesthesia. In control eyes, outflow facility did not change between the two 45-min assessment periods during the 120 min test (p = 0.80). In latanoprost-treated eyes, outflow facility increased compared with control eyes during both assessment periods (p = 0.03). A test of filters in series with known resistance found that the method was sensitive enough to detect a change in outflow facility of 0.001 microl/min/mmHg. Administration of ketamine/xylazine anesthesia for 120 min did not alter outflow facility or lessen the effect of latanoprost on outflow facility in mice as determined by a new analysis system. Accurate IOP measurements must be made within minutes of anesthesia administration but outflow facility measurements can be made with less haste.


Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study.
Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes. In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion. 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment. In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity. South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership.


Clinical Outcomes of Deferred Lesions by IVUS Versus FFR-Guided Treatment Decision.
There are limited data regarding the safety of deferral of percutaneous coronary intervention based on intravascular ultrasound (IVUS) findings. The current study sought to compare the prognosis between deferred lesions based on IVUS and fractional flow reserve (FFR)-guided treatment decision. This study is a post hoc analysis of the FLAVOUR randomized trial (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients With Intermediate Stenosis) that compared 2-year clinical outcomes between IVUS- and FFR-guided treatment decision on intermediate coronary artery lesions using predefined criteria. In both IVUS and FFR groups, vessels were classified into deferred or revascularized vessels, and patients were classified as those with or without deferred lesions. Vessel-oriented composite outcomes (cardiac death, target vessel myocardial infarction, or target vessel revascularization) in deferred vessels and patient-oriented composite outcomes (death, myocardial infarction, or any revascularization) in patients with deferred lesions were compared between the IVUS and FFR groups. A total of 1682 patients and 1820 vessels were analyzed, of which 922 patients and 989 vessels were deferred. At 2 years, there was no difference in the cumulative incidence of vessel-oriented composite outcomes in deferred vessels between IVUS (n=375) and FFR (n=614) groups (3.8% versus 4.1%; hazard ratio, 0.91 [95% CI, 0.47-1.75]; P=0.77). The risk of vessel-oriented composite outcomes was comparable between deferred and revascularized vessels following treatment decision by IVUS (3.8% versus 3.5%; hazard ratio, 1.09 [95% CI, 0.54-2.19]; P=0.81) and FFR (4.1% versus 3.6%; hazard ratio, 1.14 [95% CI, 0.56-2.32]; P=0.72). In comparison of patient-oriented composite outcomes in patients with deferred lesions, there was no significant difference between the IVUS (n=357) and FFR (n=565) groups (6.2% versus 5.9%; hazard ratio, 1.05 [95% CI, 0.61-1.80]; P=0.86). In patients with intermediate coronary artery stenosis, deferral of percutaneous coronary intervention based on IVUS-guided treatment decision showed comparable risk of clinical events with FFR-guided treatment decision. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02673424.


The Sum of Us: What Racism Costs Everyone and How We Can Prosper Together, by Heather McGhee.
In her book, The Sum of Us: What Racism Costs Everyone and How We Can Prosper Together, historian Heather McGhee tallies the cost of racism and identifies a zero-sum thinking for everyone who engages in the us-versus-them ideology. Chronicling racial hierarchy dating back to colonial America, McGhee uncovers the impact of racism in almost every societal sector including politics, the economy, education, housing, criminal justice, and climate change. McGhee challenges the fallacy that racial equity is only for people of color, demonstrating that political, socioeconomic, and financial equity for Black and Brown people is equity for all people.


Occupational and leisure-time physical activity and workload among construction workers - a randomized control study.
There is a lack of quantification of occupational physical activity (OPA) and leisure time physical activity (LTPA) among construction workers. To describe physical activity energy expenditure (PAEE), physical workload, and the effect of a PA-intervention among construction workers. Sixty-seven Construction workers self-reported their physical activity (PA), had PA assessed directly (PAEE), and observed OPA using the tool "Posture, Activity, Tools and Handling." The PA-intervention (Intervention; n = 29, Controls; n = 24) included 3x20-min training/week for 12 weeks. Baseline median OPA was 5036 MET-min/week and LTPA 2842 MET-min/week, p < 0.01. OPA directly recorded was (mean ± SE): 56.6 ± 3.2 J/kg/min and LTPA was: 35.7 ± 2.2 J/kg/min (p < 0.001). Manual material handling was performed for ≥ 25% of working time by more than 50% of the participants. Post-intervention, the training group reduced overall PAEE compared to the control group but not specifically during work. OPA was within the maximum recommended level of 1/3 proposed in consensus guidelines but did not decrease with PA-intervention.


Evaluation of the GADD45α-GFP GreenScreen HC assay for rapid and reliable in vitro early genotoxicity screening.
Twenty-two of Galderma's proprietary compounds were tested in the GADD45α-GFP 'GreenScreen HC' assay (GS), the SOS-ChromoTest and the Mini-Ames to evaluate GSs performance for early genotoxicity screening purposes. Forty more characterized compounds were also tested, including antibiotics: metronidazole, clindamycin, tetracycline, lymecycline and neomycin; and catecholamines: resorcinol mequinol, hydroquinone, one aneugen carbendazim, one corticoid dexamethasone, one peroxisome proliferator-activated receptor rosiglitazone, one pesticide carbaryl and two further proprietary molecules with in vitro genotoxicity data. With proprietary molecules, this study concluded that the GS renders the SOS-ChromoTest obsolete for in vitro screening. The GS confirmed all results of the Mini-Ames test (100% concordance). Compared with the micronucleus test, the GS showed a concordance of 82%. With known compounds, the GS ranked the potency of positive results for catecholamines in accordance with other genotoxicity tests and showed very reproducible results. It confirmed positive results for carbendazim, for tetracycline antibiotics and for carbaryl. The GS produced negative results for metronidazole, a nitroreduction-specific bacterial mutagen, for dexamethasone (a non-genotoxic apoptosis inducer), for rosiglitazone (a GADD45γ promoter inducer) and for clindamycin and neomycin (inhibitors of macromolecular synthesis in bacteria). As such, the GS appears to be a reproducible, robust, specific and sensitive test for genotoxicity screening.


Interactive semiautomatic contour delineation using statistical conditional random fields framework.
Contouring a normal anatomical structure during radiation treatment planning requires significant time and effort. The authors present a fast and accurate semiautomatic contour delineation method to reduce the time and effort required of expert users. Following an initial segmentation on one CT slice, the user marks the target organ and nontarget pixels with a few simple brush strokes. The algorithm calculates statistics from this information that, in turn, determines the parameters of an energy function containing both boundary and regional components. The method uses a conditional random field graphical model to define the energy function to be minimized for obtaining an estimated optimal segmentation, and a graph partition algorithm to efficiently solve the energy function minimization. Organ boundary statistics are estimated from the segmentation and propagated to subsequent images; regional statistics are estimated from the simple brush strokes that are either propagated or redrawn as needed on subsequent images. This greatly reduces the user input needed and speeds up segmentations. The proposed method can be further accelerated with graph-based interpolation of alternating slices in place of user-guided segmentation. CT images from phantom and patients were used to evaluate this method. The authors determined the sensitivity and specificity of organ segmentations using physician-drawn contours as ground truth, as well as the predicted-to-ground truth surface distances. Finally, three physicians evaluated the contours for subjective acceptability. Interobserver and intraobserver analysis was also performed and Bland-Altman plots were used to evaluate agreement. Liver and kidney segmentations in patient volumetric CT images show that boundary samples provided on a single CT slice can be reused through the entire 3D stack of images to obtain accurate segmentation. In liver, our method has better sensitivity and specificity (0.925 and 0.995) than region growing (0.897 and 0.995) and level set methods (0.912 and 0.985) as well as shorter mean predicted-to-ground truth distance (2.13 mm) compared to regional growing (4.58 mm) and level set methods (8.55 mm and 4.74 mm). Similar results are observed in kidney segmentation. Physician evaluation of ten liver cases showed that 83% of contours did not need any modification, while 6% of contours needed modifications as assessed by two or more evaluators. In interobserver and intraobserver analysis, Bland-Altman plots showed our method to have better repeatability than the manual method while the delineation time was 15% faster on average. Our method achieves high accuracy in liver and kidney segmentation and considerably reduces the time and labor required for contour delineation. Since it extracts purely statistical information from the samples interactively specified by expert users, the method avoids heuristic assumptions commonly used by other methods. In addition, the method can be expanded to 3D directly without modification because the underlying graphical framework and graph partition optimization method fit naturally with the image grid structure.


Diel periodicity in the production of green leaf volatiles by wild and cultivated host plants of stemborer moths, Chilo partellus and Busseola fusca.
The volatile chemicals produced by four poaceous plant species, blue thatching grass, Hyparrhenia tamba, Napier grass, Pennisetum purpureum, sorghum, Sorghum bicolor, and maize, Zea mays, which are host plants for the lepidopterous stemborers, Chilo partellus and Busseola fusca, were collected by air entrainment and analyzed by gas chromatography. The total quantities of volatiles collected hourly, over a 9-hr period, from P. purpureum and H. tamba showed an approximately hundredfold increase in the first hour of the scotophase. Thereafter, the amount decreased rapidly to levels present during photophase. Although onset of scotophase also triggered an increase in quantities of volatiles collected from two cultivars of S. bicolor and two out of three cultivars of Z. mays, these increases were less dramatic than in the two wild grasses, being only up to 10 times as much as in the last hour of photophase. Analysis showed that up to 95% of the increase in volatiles at the onset of the scotophase was due to just four compounds, the green leaf volatiles hexanal, (E)-2-hexenal, (Z)-3-hexen-1-ol, and (Z)-3-hexen-1-yl acetate, with the latter dominating the volatile profile. Volatiles from P. purpureum were also collected at 10-min intervals for 70 min spanning the transition from light to dark. The vast increase in production of the green leaf volatiles in this species occurs in the first 10 min of the scotophase followed by a rapid decline within the next 20 min. The relevance of these results to the control of stemborers in a "push-pull" strategy is discussed.


Metabolomics insights into pathophysiological mechanisms of interstitial cystitis.
Interstitial cystitis (IC), also known as painful bladder syndrome or bladder pain syndrome, is a chronic lower urinary tract syndrome characterized by pelvic pain, urinary urgency, and increased urinary frequency in the absence of bacterial infection or identifiable clinicopathology. IC can lead to long-term adverse effects on the patient's quality of life. Therefore, early diagnosis and better understanding of the mechanisms underlying IC are needed. Metabolomic studies of biofluids have become a powerful method for assessing disease mechanisms and biomarker discovery, which potentially address these important clinical needs. However, limited intensive metabolic profiles have been elucidated in IC. The article is a short review on metabolomic analyses that provide a unique fingerprint of IC with a focus on its use in determining a potential diagnostic biomarker associated with symptoms, a response predictor of therapy, and a prognostic marker.


Increased protein oxidation and decreased creatine kinase BB expression and activity after spinal cord contusion injury.
Traumatic injury to the spinal cord triggers several secondary effects, including oxidative stress and compromised energy metabolism, which play a major role in biochemical and pathological changes in spinal cord tissue. Free radical generation and lipid peroxidation have been shown to be early events subsequent to spinal cord injury. In the present study, we demonstrated that protein oxidation increases in rat spinal cord tissue after experimental injury. As early as h after injury, the level of protein carbonyls at the injury epicenter was significantly higher than in control (169%, p < 0.05) and increased gradually over the next 4 weeks to 1260% of control level. Both caudal and rostral parts of the injured spinal cord demonstrated a mild increase of protein carbonyls by 4 weeks postinjury (135-138%, p < 0.05). Immunocytochemical analysis of protein carbonyls in the spinal cord cross-sections showed increased protein carbonyl immunoreactivity in the epicenter section compared to rostral and caudal sections of the same animal or control laminectomy animals. Increased protein carbonyl formation in damaged spinal cord tissue was associated with changes in activity and expression of an oxidative sensitive enzyme, creatine kinase BB, which plays an important role in the maintenance of ATP level in the CNS tissue. Damage to CK function in the CNS may severely aggravate the impairment of energy metabolism. The results of our study indicate that events associated with oxidative damage are triggered immediately after spinal cord trauma but continue to occur over the subsequent 4 weeks. These results suggest that antioxidant therapeutic strategies may be beneficial to lessen the consequences of the injury and potentially improve the restoration of neurological function.


Psychiatric reform in Italy--how does it work in Piedmont?
Psychiatric reform in Piedmont following new mental health legislation in Italy (1978) is described. The process of reform is characterised by a drastic reduction in psychiatric hospital populations and the setting-up of a new system of community-based services. The number of hospital admissions remains stable, but the character of inpatient care has changed. The reform involves problems of care for chronic patients.


Glittre-ADL test without backpack: A qualitative study of perceptions of people with chronic obstructive pulmonary disease.
The Glittre Activities of Daily Living (Glittre-ADL) test without backpack was recently validated to assess the functional capacity of people with chronic obstructive pulmonary disease (COPD) OBJECTIVE: To understand the perceptions of people with COPD about the Glittre-ADL test with and without backpack and the possible similarities with their activities of daily living (ADLs). Participants performed 2 Glittre-ADL tests with a backpack (visit 1). On visit 2, participants randomly performed the Glittre-ADL test with and without backpack and completed a semi-structured interview with questions about the tests. Interviews were analyzed according to thematic analysis. Twelve participants aged between 57 and 76 years with mild to severe COPD were included. Interviews were grouped into four thematic categories: (1) Glittre-ADL test with a backpack: does the backpack make the test worse, or does it not matter?; (2) test tasks and ADL: what is in common between them?; (3) "I enjoyed taking the test": the possibility of learning and new expectations; and (4) symptoms during the Glittre-ADL tests. The following perceptions while performing the Glittre-ADL test with and without the backpack were observed: dyspnea and fatigue sensation, difficulty using the backpack while performing tasks such as squatting, and similarities to ADLs tasks despite different perspectives regarding the degree of ease and expectations on how to perform test tasks at home.


Neofunctionalization in vertebrates: the example of retinoic acid receptors.
Understanding the role of gene duplications in establishing vertebrate innovations is one of the main challenges of Evo-Devo (evolution of development) studies. Data on evolutionary changes in gene expression (i.e., evolution of transcription factor-cis-regulatory elements relationships) tell only part of the story; protein function, best studied by biochemical and functional assays, can also change. In this study, we have investigated how gene duplication has affected both the expression and the ligand-binding specificity of retinoic acid receptors (RARs), which play a major role in chordate embryonic development. Mammals have three paralogous RAR genes--RAR alpha, beta, and gamma--which resulted from genome duplications at the origin of vertebrates. By using pharmacological ligands selective for specific paralogues, we have studied the ligand-binding capacities of RARs from diverse chordates species. We have found that RAR beta-like binding selectivity is a synapomorphy of all chordate RARs, including a reconstructed synthetic RAR representing the receptor present in the ancestor of chordates. Moreover, comparison of expression patterns of the cephalochordate amphioxus and the vertebrates suggests that, of all the RARs, RAR beta expression has remained most similar to that of the ancestral RAR. On the basis of these results together, we suggest that while RAR beta kept the ancestral RAR role, RAR alpha and RAR gamma diverged both in ligand-binding capacity and in expression patterns. We thus suggest that neofunctionalization occurred at both the expression and the functional levels to shape RAR roles during development in vertebrates.


[Improvements of standards in clinical diagnosis of stroke are needed].
A detailed history, neurological examination, and assessment of function are essential procedures in all patients with stroke. Findings need to be adequately documented in the medical records. In a recent study, the documentation of 106 core items in stroke management, as specified in the Swedish National Guidelines for Stroke Management, was evaluated in the records of 70 randomly selected stroke patients treated at 17 hospitals in two county councils between March and May of 2001. The initial screening process and neurological examination were adequately documented in fewer than 50% of the patients. Clinical workup of stroke in routine practice needs to be improved. It is proposed that the documentation of core items be standardized, and that a well validated stroke scale (NIH Stroke Scale), at present mainly used in conjunction with acute thrombolytic therapy, be generally applied to all patients with stroke.


Tuning electronic structure of hedgehog-like nickel cobaltite via molybdenum-doping for enhanced electrocatalytic oxygen evolution catalysis.
As a typical spinel oxide, nickel cobaltite (NiCo2O4) is considered to be a promising and reliable oxygen evolution reaction (OER) catalyst due to its abundant oxidation states and the synergistic effect of multiple metal species. However, the electrocatalytic OER performance of NiCo2O4 has always been limited by the low specific surface area and poor intrinsic conductivity of spinels. Herein, the hedgehog-like molybdenum-doped NiCo2O4 (Mo-NiCo2O4) catalyst was prepared as an efficient OER electrocatalyst via a facile hydrothermal method followed with high-temperature annealing. The Mo-NiCo2O4-0.075 with Mo doping concentration of ∼ 1.95 wt% exhibits excellent OER performance with a low overpotential of 265 mV at a current density of 10 mA·cm-2and a Tafel slope of 126.63 mV·dec-1, as well as excellent cyclingstability.The results demonstrated that the hedgehog-like structure provides Mo-NiCo2O4 with the high surface area and mesopores that enhance electrolyte diffusion and optimal active site exposure. The in-situ Raman spectra and density functional theory calculations show that the Mo cations doping improve the intrinsic conductivity of the NiCo2O4 while modulating the chemisorption of intermediates. Meanwhile, the energy barriers of *OH and O* formation decrease significantly after Mo doping, effectively facilitating water dissociation and optimizing the reaction kinetics.


Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth.
Maternal separation and poor maternal care in animals have been shown to have important effects on the developing hippocampus and amygdala. In humans, children exposed to abuse/maltreatment or orphanage rearing do not present changes in hippocampal volumes. However, children reared in orphanages present enlarged amygdala volumes, suggesting that the amygdala may be particularly sensitive to severely disturbed (i.e., discontinous, neglectful) care in infancy. Maternal depressive symptomatology has been associated with reductions in overall sensitivity to the infant, and with an increased rate of withdrawn, disengaged behaviors. To determine if poor maternal care associated with maternal depressive symptomatology has a similar pattern of association to the volumes of the hippocampus and amygdala in children, as is the case for severely disturbed infant care (orphanage rearing), we measured hippocampal and amygdala volumes as well as stress hormone (glucocorticoid) levels in children exposed (n = 17) or not (n = 21) to maternal depressive symptomatology since birth. Results revealed no group difference in hippocampal volumes, but larger left and right amygdala volumes and increased levels of glucocorticoids in the children of mothers presenting depressive symptomatology since birth. Moreover, a significant positive correlation was observed between mothers' mean depressive scores and amygdala volumes in their children. The results of this study suggest that amygdala volume in human children may represent an early marker of biological sensitivity to quality of maternal care.


Sacropelvic resection and intraoperative electron irradiation in the management of recurrent anorectal cancer.
To provide local control and palliation of pain, a multimodal ity approach, including external beam radiation therapy, surgical resection, and intraoperative electron irradiation (IOERT), has been used for patients with locally advanced anal or recurrent rectal cancers involving the sacrum. Sixteen consecutive patients (11 males; 5 females; ages, 44-76) underwent surgical exploration, sacrectomy, and IOERT, between 1990 and 1994. Proximal extent of resection was S2-3 in four patients, S3-4 in five, and S4-5 in five. Two patients had resection of the anterior table of the sacrum. Margins were clear in 11, close in 3, and microscopically involved in 2 patients. Operative times ranged from 6 to 17 (median, 12.5) hours, and blood loss ranged from 300 to 12,600 (median, 3,350) ml. No operative deaths resulted. Major postoperative complications occurred in eight patients (50 percent): posterior wound infections and dehiscence, urinary leak, and ileal fistula. Five (31 percent) and 3 (19 percent) patients developed no or minor complications, respectively. Intensive Care Unit stay was one night for all patients, and overall hospital stay ranged from 11 to 30 (median, 16.5) days. Follow-up was available on all 16 patients. Kaplan-Meier survival was 68 percent at one year and 48 percent at two years. At the time of analysis, 9 of 16 patients were alive. Of the nine alive patients who responded to a questionnaire, eight reported a reduction in pain and improved quality of life postoperatively. Sacropelvic resection, in conjunction with IOERT, provides palliation and offers potential for cure in patients with locally advanced or recurrent anorectal cancer.


Peritoneal dialysis in hypernatraemic, ketoacidotic diabetic coma.
Hypertonic dehydration in a 13-year-old boy with ketoacidotic diabetic coma has been treated successfully with peritoneal dialysis and isotonic fluids. Modes of treatment with either hypotonic or isotonic fluids are discussed, as is the feasibility of peritoneal dialysis. We recommend isotonic solutions composed of equal parts of 5.5% glucose and 0.9% sodium chloride combined with peritoneal dialysis in order to secure a relatively slow correction of the hypertonic state.


Vascular wall dysfunction in JCR:LA-cp rats: effects of age and insulin resistance.
We tested the hypothesis that aging and insulin resistance interact to increase vascular dysfunction by comparing the function of isolated mesenteric resistance arteries in obese, insulin-resistant JCR:LA-cp rats and lean, insulin-sensitive rats of the same strain at 3, 6, 9, and 12 mo of age. The peak constrictor responses to norepinephrine, phenylephrine, and high potassium were elevated in arteries from obese rats. Responses to these agents increased with age in both obese and lean rats. An eicosanoid constrictor contributed substantially to vasoconstriction in the arteries from both lean and obese animals. Inhibition of nitric oxide synthase increased the vasoconstrictor response to norepinephrine in both obese and lean rats. This effect increased with age in lean rats only. Vascular relaxation in response to acetylcholine and sodium nitroprusside was impaired in the obese rats and did not alter with age. The results suggest that obese JCR:LA-cp rats have enhanced maximal constriction, which originates in the arterial smooth muscle and increases with age. There is evidence that the ability of the arteries to compensate for the enhanced contractility is impaired in obese rats, particularly with advanced age.


Modulating the gut microbiota is involved in the effect of low-molecular-weight Glycyrrhiza polysaccharide on immune function.
Low molecular weight (6.5 kDa) Glycyrrhiza polysaccharide (GP) exhibits good immunomodulatory activity, however, the mechanism underlying GP-mediated regulation of immunity and gut microbiota remains unclear. In this study, we aimed to reveal the mechanisms underlying GP-mediated regulation of immunity and gut microbiota using cyclophosphamide (CTX)-induced immunosuppressed and intestinal mucosal injury models. GP reversed CTX-induced intestinal structural damage and increased the number of goblet cells, CD4+, CD8+ T lymphocytes, and mucin content, particularly by maintaining the balance of helper T lymphocyte 1/helper T lymphocyte 2 (Th1/Th2). Moreover, GP alleviated immunosuppression by down-regulating extracellular regulated protein kinases/p38/nuclear factor kappa-Bp50 pathways and increasing short-chain fatty acids level and secretion of cytokines, including interferon-γ, interleukin (IL)-4, IL-2, IL-10, IL-22, and transforming growth factor-β3 and immunoglobulin (Ig) M, IgG and secretory immunoglobulin A. GP treatment increased the total species and diversity of the gut microbiota. Microbiota analysis showed that GP promoted the proliferation of beneficial bacteria, including Muribaculaceae_unclassified, Alistipes, Lachnospiraceae_NK4A136_group, Ligilactobacillus, and Clostridia_vadinBB60_group, and reduced the abundance of Proteobacteria and CTX-derived bacteria (Clostridiales_unclassified, Candidatus_Arthromitus, Firmicutes_unclassified, and Clostridium). The studies of fecal microbiota transplantation and the pseudo-aseptic model conformed that the gut microbiota is crucial in GP-mediated immunity regulation. GP shows great potential as an immune enhancer and a natural medicine for treating intestinal inflammatory diseases.


Identification and characterization of cryptic polyadenylation sites in the 3' region of a pea ribulose-1,5-bisphosphate carboxylase small subunit gene.
The polyadenylation signal of a pea ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit (rbcS) gene has been studied using in vitro mutagenesis and Ti plasmid-mediated transformation of tobacco. Analysis of a mutant that is lacking sequences upstream from -6 (relative to the "normal" site of polyadenylation of RNAs from the rbcS-E9 gene) reveals a number of alternate polyadenylation sites located downstream from the normal poly(A) site. Transcripts carrying these sequences end at any one of at least seven sites between 20 and 300 bases downstream from the normal site. These sites are seen in populations of transgenic plant cells, and also in independent transgenic plants.


Rest Is the First Casualty of Constant Messaging.
This drawing considers how sources of patient demand are also sources of light pollution in a room in which a clinician tries, in vain, to rest.


Effect of different tumor types on resting energy expenditure.
The purpose of this study was to investigate whether the presence of a malignant tumor influences energy metabolism of the host. Resting energy expenditure (REE) was measured in 104 gastric and colorectal (GCR) cancer patients and in 47 non-small cell lung cancer patients and was compared with REE values in 40 healthy controls. REE expressed per kilogram of fat-free mass (FFM) in lung cancer patients was elevated, in comparison with healthy controls (33.6 +/- 4.6 and 29.6 +/- 2.9 kcal, respectively; P less than 0.001), in contrast to REE/FFM in GCR cancer patients, which showed no difference, compared with these controls (29.8 +/- 4.3 kcal). In 47 patients with GCR cancer and in 14 patients with lung cancer, REE was also determined after tumor resection. REE in GCR cancer patients measured 1.5 years after tumor resection showed a small but significant increase. No differences were observed between GCR cancer patients with or without signs of tumor recurrence. REE in lung cancer patients with no signs of tumor recurrence measured 1 year after tumor resection had a significant decrease in REE (REE/FFM, -6.8%; P less than 0.05), while patients who had evidence of tumor recurrence showed no change in REE or even an increase. After curative surgery REE returned to a normal level in the lung cancer patients. These results suggest that tumor type is a major determinant of an increased energy expenditure in cancer patients.


Culture, health, and healing.
Americans are increasingly interested in and willing to participate in alternative or adjunctive healthcare, which is sometimes called complementary healthcare. Some believe this is because of wide-spread cultural diversity or an increasing awareness of options in health practice, while others contend it is a reaction to dissatisfaction with Western health practices. Diversity among cultures and subcultures has posed challenges for clinicians. This article addresses the impact of culture on health and healing, examining alternative health practices and their impact on chronic care, specifically chronic wound care.


[Ureteral replacement with appendix].
The scant references in the literature on the use of the appendix in ureteral substitution prompted us to describe the present case in whom this technique was utilized. The surgical technique of appendiceal interposition to repair a defect approximately 10 cm long in the right ureter is described. Following excision of a mass arising from the adnexa that entrapped the ureter at the level of the pelvis, the defect was repaired with the appendix. At two years follow-up, the patient is well and right excretory system function is normal. Ureteral repair with the appendix is simple and easy to perform. However, the indications for appendiceal interposition are more limited than those of the classical surgical techniques.


Microenvironmental Snail1-induced immunosuppression promotes melanoma growth.
Melanoma is an aggressive form of skin cancer due to its high metastatic abilities and resistance to therapies. Melanoma cells reside in a heterogeneous tumour microenvironment that acts as a crucial regulator of its progression. Snail1 is an epithelial-to-mesenchymal transition transcription factor expressed during development and reactivated in pathological situations including fibrosis and cancer. In this work, we show that Snail1 is activated in the melanoma microenvironment, particularly in fibroblasts. Analysis of mouse models that allow stromal Snail1 depletion and therapeutic Snail1 blockade indicate that targeting Snail1 in the tumour microenvironment decreases melanoma growth and lung metastatic burden, extending mice survival. Transcriptomic analysis of melanoma-associated fibroblasts and analysis of the tumours indicate that stromal Snail1 induces melanoma growth by promoting an immunosuppressive microenvironment and a decrease in anti-tumour immunity. This study unveils a novel role of Snail1 in melanoma biology and supports its potential as a therapeutic target.


Light-induced synchronous conidiation in the fungus Botrytis cinerea.
Botrytis cinerea Pers. ex Fr. in stationary liquid cultures conidiated asynchronously in darkness after 4 days' growth. Synchronous conidiation was induced by irradiating dark-grown cultures with near-ultraviolet light for 12 h. The number of conidia increased very rapidly 10 h after the end of the photo-induction period, and conidiation was completed by the 14th hour. Filter paper cultures of the fungus also showed synchronous conidiation upon irradiation with near-ultraviolet light, but the rapid increase in the number of conidia took place 2 h earlier, conidiation being completed by the 12th hour. Cultures irradiated with blue light, however, produced sterile mycelia and showed complete suppression of conidiation.


The effects of esomeprazole combined with aspirin or rofecoxib on prostaglandin E2 production in patients with Barrett's oesophagus.
Reducing mucosal cyclo-oxygenase-2 and prostaglandin E(2) production and suppressing intraoesophageal acid may be effective chemopreventive strategies in patients with Barrett's oesophagus. To compare the effects of aspirin and rofecoxib when administered with esomeprazole on prostaglandin E(2) production, cyclo-oxygenase-2 expression and proliferating cell nuclear antigen expression in patients with Barrett's oesophagus. This exploratory, multicentre, randomized, open-label, four-way crossover study in 45 patients with Barrett's oesophagus evaluated prostaglandin E(2) content, proliferating cell nuclear antigen expression, and cyclo-oxygenase-2 expression after 10 days of sequential treatments with: esomeprazole 40 mg twice daily plus aspirin 325 mg once daily (E40 b.d. + A325); E40 b.d. plus rofecoxib 25 mg once daily (E40 b.d. + R25); E40 b.d.; and rofecoxib 25 mg once daily (R25). Prostaglandin E(2) content reduction in Barrett's oesophagus tissue was significantly greater with E40 b.d. + A325 compared with E40 b.d. + R25, E40 b.d. or R25 (P < 0.05). All treatments containing E40 b.d. significantly decreased proliferating cell nuclear antigen expression from baseline (P < 0.05). None of the treatments significantly reduced cyclo-oxygenase-2 expression. The combined treatment of esomeprazole 40 mg b.d. and aspirin 325 mg significantly decreased mucosal prostaglandin E(2) content and all treatments containing esomeprazole significantly reduced proliferating cell nuclear antigen expression in patients with Barrett's oesophagus.


Reduced blue cone electroretinogram in cocaine-withdrawn patients.
The main reinforcing effect of cocaine is alteration of dopaminergic neurotransmission in the brain reward systems. Since dopamine is found in high concentrations in the retina, we investigated whether cocaine dependence may be associated with abnormalities of the electroretinogram. We compared recently withdrawn cocaine-dependent patients (n = 20) with age-, sex-, and race-matched normal subjects (n = 20) for responses of cone photoreceptors to light flashes on full-field electroretinograms. Cocaine-dependent patients had significantly reduced blue cone electroretinogram responses compared with matched normal subjects. This result suggests that cocaine-withdrawn patients have a dysregulation of blue cone function. The electroretinogram may be useful in future studies of cocaine-dependent patients.


Zerumbone, Sesquiterpene Photochemical from Ginger, Inhibits Angiogenesis.
Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.


Number of kinesins engaged in axonal cargo transport: A novel biomarker for neurological disorders.
Kinesin motor proteins play crucial roles in anterograde transport of cargo vesicles in neurons, moving them along axons from the cell body towards the synaptic region. Not only the transport force and velocity of single motor protein, but also the number of kinesin molecules involved in transporting a specific cargo, is pivotal for synapse formation. This collective transport by multiple kinesins ensures stable and efficient cargo transport in neurons. Abnormal increases or decreases in the number of engaged kinesin molecules per cargo could potentially act as biomarkers for neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), spastic paraplegia, polydactyly syndrome, and virus transport disorders. We review here a model constructed using physical measurements to quantify the number of kinesin molecules associated with their cargo, which could shed light on the molecular mechanisms of neurodegenerative diseases related to axonal transport.


Establishment and quantitative imaging of a 3D lung organotypic model of mammary tumor outgrowth.
The lung is the second most common site of metastatic spread in breast cancer and experimental evidence has been provided in many systems for the importance of an organ-specific microenvironment in the development of metastasis. To better understand the interaction between tumor and host cells in this important secondary site, we have developed a 3D in vitro organotypic model of breast tumor metastatic growth in the lung. In our model, cells isolated from mouse lungs are placed in a collagen sponge to serve as a scaffold and co-cultured with a green fluorescent protein-labeled polyoma virus middle T antigen (PyVT) mammary tumor cell line. Analysis of the co-culture system was performed using flow cytometry to determine the relative constitution of the co-cultures over time. This analysis determined that the cultures consisted of viable lung and breast cancer cells over a 5-day period. Confocal microscopy was then used to perform live cell imaging of the co-cultures over time. Our studies determined that host lung cells influence the ability of tumor cells to grow, as the presence of lung parenchyma positively affected the proliferation of the mammary tumor cells in culture. In summary, we have developed a novel in vitro model of breast tumor cells in a common metastatic site that can be used to study tumor/host interactions in an important microenvironment.


PRICKLE1 gene methylation and abnormal transcription in Chinese patients with ankylosing spondylitis.
Ankylosing spondylitis (AS) is a common inflammatory arthritis without a reliable biomarker. The role of methylation and mRNA expression of PRICKLE1 promoter in the pathogenesis of ankylosing spondylitis remains unclear. A two-stage case-control design was used to detect the characteristics of methyl group and transcriptome of PRICKLE1 gene in Ankylosing spondylitis. The methylation degree of PRICKLE1 gene promoter region was tested by phosphate-sequencing, and further analyzed whether there was significant difference in methylation level of PRICKLE1 gene. The expression levels of PRICKLE1 mRNA in 50 AS patients and 50 healthy controls were detected by real-time quantitative PCR (RT-qPCR). Compared with healthy control group, the intensity of methylation in 4 ponds of PRICKLE1 in patients with Ankylosing spondylitis was low, and the mRNA levels were overexpressed (P = 0.017). ROC results showed that the sensitivity of PRICKLE1 was 68.67% and specificity was 71.43%. There is a significant change in the concentration of serum PRICKLE1 mRNAin patients with Ankylosing spondylitis, and the degree of gene methylation is significantly reduced, suggesting that PRICKLE1 gene maybe involved in the pathogenesis of Ankylosing spondylitis, which may be useful for predicting the occurrence of AS and finding new early screening indicators.


Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections.
Pf bacteriophage are temperate phages that infect the bacterium Pseudomonas aeruginosa, a major cause of chronic lung infections in cystic fibrosis (CF) and other settings. Pf and other temperate phages have evolved complex, mutualistic relationships with their bacterial hosts that impact both bacterial phenotypes and chronic infection. We and others have reported that Pf phages are a virulence factor that promote the pathogenesis of P. aeruginosa infections in animal models and are associated with worse skin and lung infections in humans. Here we review the biology of Pf phage and what is known about its contributions to pathogenesis and clinical disease. First, we review the structure, genetics, and epidemiology of Pf phage. Next, we address the diverse and surprising ways that Pf phages contribute to P. aeruginosa phenotypes including effects on biofilm formation, antibiotic resistance, and motility. Then, we cover data indicating that Pf phages suppress mammalian immunity at sites of bacterial infection. Finally, we discuss recent literature implicating Pf in chronic P. aeruginosa infections in CF and other settings. Together, these reports suggest that Pf bacteriophage have direct effects on P. aeruginosa infections and that temperate phages are an exciting frontier in microbiology, immunology, and human health.


Screening intrinsic capacity and its epidemiological characterization: a secondary analysis of the Mexican Health and Aging Study.
To describe the levels of intrinsic capacity and those factors related to its decline in Mexican older adults, using the Mexican Health and Aging Study. This is a cross-sectional secondary analysis of the 2015 data of the Mexican Health and Aging Study, including adults aged 50 years and above. Selected questions were included to represent each domain of intrinsic capacity screening: cognition, depression, hearing, vision, anorexia, weight loss, and mobility. Sociodemographic characteristics, psychosocial factors, and health conditions were included to assess their association with intrinsic capacity. Further categories were established to assess not only individual characteristics but also different groupings. Along with descriptive statistics, multinomial regression models were performed. From a total of 12 459 adults aged 50 years and above, 54.7% were women and the average age was 71.2 years; 87.8% of the individuals had at least one intrinsic capacity domain affected, and mobility had the highest frequency (47.6%). All domains showed a trend of increasing with age and were higher among women. Self-rated health, chronic diseases, number of visits to a physician in the last year, and ≥2 affected activities of daily living were consistently associated with more intrinsic capacity domains affected. Decreased levels of intrinsic capacity in Mexican older people are associated with less schooling, self-rated health, chronic diseases, visits to a physician, and activities of daily living.


ESCRT-0 protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is targeted to endosomes independently of signal-transducing adaptor molecule (STAM) and the complex formation with STAM promotes its endosomal dissociation.
The ESCRT-0 complex, consisting of the hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and the signal-transducing adaptor molecule (STAM) proteins, recognizes ubiquitylated cargo during the initial step of endosomal sorting. The endosomal accumulation of overexpressed Hrs has been reported previously to be associated with endosome enlargement. In this study, we have found that co-expressing exogenous STAM1 in Hrs-overexpressing cells leads to a diffuse localization for a large part of the Hrs accumulated on endosomes and a recovery of the impaired cargo protein degradation process, thus suggesting that exogenous STAM abrogates the abnormalities of the Hrs-positive endosomes. A fluorescently labeled Hrs, introduced into the cells by membrane permeabilization, exhibited endosomal localization in the absence of STAM1 and gradually dissociated from the endosomes upon the sequential addition of recombinant STAM1. Furthermore, when microinjected into cells, the fluorescently labeled Hrs also showed endosomal accumulation; however, ESCRT-0 complexes formed prior to the microinjection did not. Analysis of the state of the complex in HeLa cells using blue-native PAGE revealed that the membrane-associated Hrs exists partly as a monomer and not only in the STAM1-bound form. Thus, our data suggest that the membrane binding and dissociation cycle of the ESCRT-0 proteins on the endosomal membrane is a critical step during the cargo sorting process.


Factor V Leiden and prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center.
This study was conducted to identify the prevalence of FV1691A and PT20210A mutations in neonates with symptomatic thromboembolism and in healthy neonates and adults. A review of 137 healthy neonates, 368 healthy adults, and 9 neonates with clinical thrombosis was done to investigate for hereditary prothrombotic mutations. For the neonates with thromboembolism, data were collected to reveal the underlying diagnosis, site of thrombosis, and associated risk factors. Investigations included screening for factor V 1691A and prothrombin 20210A. Seven of 9 neonates had one or more risk factors at the time of thromboembolism. Seventy percent (5/7) had underlying congenital thrombophilia (4/7 FV Leiden, 1/7 homozygote protein C deficiency). Among the healthy population, 11.9% of the neonates and 9% of the adults had FV1691A mutation, 4.8% of the neonates and 2.7% of the adults had PT 20210A mutation. Incidence of FV1691A mutation in the neonates with symptomatic thromboembolism was very high. The prevalence of both FV1691A and PT20210A mutations were remarkably higher than previously reported.


Healthcare epidemiology: quorum sensing: bacteria talk sense.
Cell communication in bacteria occurs through a vernacular of small diffusible chemical signals that impact gene regulation during times of high cell density. This form of intercellular signaling, known as quorum sensing, optimizes the metabolic and behavioral activities of a community of bacteria for life in close quarters. Quorum sensing is best characterized as a means of communication within a bacterial species, whereas competitive or cooperative signaling can occur between groups of bacteria or between bacteria and the host. These systems are often integrated into complex, multilayered signal transduction networks that control numerous multicellular behaviors, including biofilm formation and other virulence traits. In addition, quorum signals, sensors, and signaling pathways are increasingly recognized as having biological properties that extend beyond cell communication. The deeper understanding of microbial cell communication promises to shed light on the complexities of the host-microbe relationship and may lead to novel therapeutic applications.


Queering poppers literature: A critical interpretive synthesis of health sciences research on alkyl nitrite use and Canadian policy.
Poppers (alkyl nitrites) are vasodilators used by many gay, bisexual, and other men who have sex with men (GBMSM) to relieve pain, enhance pleasure, and facilitate penetration during sex. In 2013, the Canadian government cracked down on the sale of poppers products, however prevalence of poppers use among GBMSM in Canada remains high. Poppers have been studied by medical researchers since the 1980s, yet qualitative and community-based research to inform federal policy, remains somewhat less common. We conducted a critical interpretive synthesis (CIS) to better understand poppers health literature using the medical model of health as a point of reference. Analysis was performed using inductive and deductive methods including reflexive note-taking, mind-mapping, and close coding. 153 publications were identified to inform this review of which 5 were chosen for coding based on a purposive sampling framework. Our findings are unified within a theoretical construct we term responsibility. Responsibility is a construct we use to describe the bias we identified in health sciences literature regarding poppers use that tends to exaggerate the necessity for poppers cessation, and devalue both the benefits of poppers use and the perspectives and experiences of people who use poppers. The emphasis on individual behavior change within the literature appears to be motivated less by objective measures or assessments of health risks and outcomes, and more by harmful stereotypes that position gay men and people who use drugs as inherently irresponsible. We conclude by discussing how these findings have important implications for the review of current policy on poppers sales in Canada which remains influenced by a literature base prejudiced by factors such as homophobia, heteronormativity, and drug stigma, and recommend areas for future work.


Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis.
The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets. To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis. The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3-intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways. These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.