Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.
Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area. To review clinical study reports of placebo-controlled randomised trials, regulatory comments and reviews ('regulatory information') of the effects of the NIs oseltamivir and zanamivir for influenza in all age groups and appraise trial programmes, rather than single studies.Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methods analysis plans, trial results and organisational documents (such as contracts). A series of clinical studies designed and conducted by one sponsor represents a trial programme of a drug indication (for example treatment of influenza). We searched trial registries, cross-referencing published and unpublished sources and corresponded with manufacturers and regulators. We searched the archives of the US Food and Drug Administration (FDA) and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to 12 April 2011. We included regulatory information based on assessments of randomised controlled trials (RCTs) conducted in people of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or place of residence. We included information which had been made available by our deadline. We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement-based templates. To progress to Stage 2 (full analysis) we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline (GSK) offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical study reports. In Stage 2 we intended to analyse trials with validated data (i.e. assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalisations using the intention-to-treat (ITT) population and tested five hypotheses generated post-protocol publication. We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data. The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. The studies had adequate randomisation and blinding procedures, but imbalances in the analysis populations available (ITT influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of NIs. Time to first alleviation of symptoms in people with influenza-like illness symptoms (i.e. ITT population) was a median of 160 hours (range 125 to 192 hours) in the placebo groups and oseltamivir shortened this by around 21 hours (95% confidence interval (CI) -29.5 to -12.9 hours, P < 0.001; five studies) but there was no evidence of effect on hospitalisations based on seven studies with a median placebo group event rate of 0.84% (range 0% to 11%): odds ratio (OR) 0.95; 95% CI 0.57 to 1.61, P = 0.86). These results are based on the comprehensive ITT population data and are unlikely to be biased. A post-protocol analysis showed that participants randomised to oseltamivir in treatment trials had a reduced odds being diagnosed with influenza (OR 0.83; 95% CI 0.73 to 0.94, P = 0.003; eight studies), probably due to an altered antibody response. Zanamivir trials showed no evidence of this. Due to limitations in the design, conduct and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission. We postponed analysis of zanamivir evidence because of the offer of individual patient data (IPD) from its manufacturer. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.


Myoepithelioma of Soft Tissues: A Single Institution Retrospective Case Series.
Myoepithelioma of the soft tissues is a rare entity and little is known about how best to manage locally recurrent and high-grade disease. Here, we retrospectively examined outcomes of surgery, chemotherapy, and radiation therapy (RT) for treatment of low-grade and high-grade myoepithelioma of soft tissues. We reviewed 20 cases of myoepithelioma of soft tissues seen at Mayo Clinic between 1994 and 2014. The effect of histologic grade and therapies received on relapse and survival were assessed. We identified 13 patients with low-grade disease and 7 patients with high-grade disease. We found that low-grade disease was frequently effectively managed with surgical resection alone, whereas high-grade disease frequently metastasized and was often fatal. The 5-year event-free survival was 88% (confidence interval, 46%-98%) for low-grade disease versus 36% (confidence interval, 7%-75%; P=0.04) for high-grade disease. The relapse rate in low-grade disease was 29% at 5 years versus 64% (P=0.04) in high-grade disease. No significant responses to chemotherapy were noted, however, excellent responses to perioperative RT were seen. Surgery continues as the primary modality of treatment for myoepithelioma of soft tissues. Our study did not show a clear benefit of chemotherapy in the metastatic disease setting, but supports the use of perioperative RT in the management of high-grade disease; further investigation is warranted.


Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney.
Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein-coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.


The Fisher grading correlated to outcome in patients with subarachnoid haemorrhage.
Cerebral vasospasm is the major cause of delayed ischemia in patients with subarachnoid haemorrhage (SAH). The Fisher grading scale has been used to predict patients in risk of developing vasospasm. Improved radiological techniques and treatment may have changed the relevance of the Fisher scale. We have now evaluated the Fisher scale, Hunt and Hess and age in relation to outcome in patients with SAH. Eighty- three patients were admitted with SAH during two years, and 84 aneurysms were treated in 78 patients. The Glasgow outcome score (GOS) within 3 months were as follows; GOS 1 (19%), GOS 2 (2%), GOS 3 (11%), GOS 4 (9%), GOS 5 (59%). There was a significant correlation between both the Fisher grading scale, Hunt and Hess scale and outcome. Age was not correlated to the Fisher grading scale or the Hunt and Hess scale. Age was also not correlated to outcome in our patients. Despite the correlation to outcome both Hunt and Hess and the Fisher grading scale had a limited predictive value of outcome due to a low specificity and/or sensitivity.


The role of formalin-induced pain in morphine tolerance, withdrawal, and reward.
The effect of a commonly used experimental pain-induction procedure (formalin injection into a hindpaw site) on morphine tolerance, withdrawal, and reward was examined in rats. Results suggest that the effects of morphine are different in the organism that is experiencing pain at the time it receives the drug than in the organism that is pain free. The presence of pain at the time of each morphine administration decreased analgesic tolerance, decreased naloxone-precipitated withdrawal, and enhanced the rewarding effect of the opiate. These findings, together with those of previous studies, suggest that theories of opiate tolerance, withdrawal, and reward should incorporate the effects of pain.


RNA-Seq of human whole blood: Evaluation of globin RNA depletion on Ribo-Zero library method.
Peripheral blood is a highly accessible biofluid providing a rich source of information about human physiology and health status. However, for studies of the blood transcriptome with RNA sequencing (RNA-Seq) techniques, high levels of hemoglobin mRNAs (hgbRNA) present in blood can occupy valuable sequencing space, impacting detection and quantification of non-hgbRNAs. In this study, we evaluated two methods for preparing ribosomal RNA (rRNA)-depleted sequencing libraries for RNA-Seq of whole blood, one of which is also designed to deplete hgbRNAs. Two experiments were performed: one evaluating library performance across 6 human blood samples and the other examining library reproducibility and performance in a two-subject subset. We find that addition of hgbRNA depletion to the rRNA-depletion protocol for library preparation from blood RNA effectively reduces highly abundant hgbRNA reads; however, it does not result in a statistically significant increase in differentially expressed genes in our patient-control study. Bioinformatic removal of globin gene counts in non-hgbRNA depleted libraries provides improvement in overall performance of these libraries. We conclude that use of a standard ribosomal RNA depletion method for library preparation coupled with bioinformatic removal of globin gene counts is sufficient for reproducible and sensitive measurement of both coding and noncoding RNAs in the blood transcriptome.


Boron and nitrogen impurities in SiC nanoribbons: an ab initio investigation.
Using ab initio calculations based on density-functional theory we have performed a theoretical investigation of substitutional boron and nitrogen impurities in silicon carbide (SiC) nanoribbons. We have considered hydrogen terminated SiC ribbons with zigzag and armchair edges. In both systems we verify that the boron and nitrogen atoms energetically prefer to be localized at the edges of the nanoribbons. However, while boron preferentially substitutes a silicon atom, nitrogen prefers to occupy a carbon site. In addition, our electronic-structure calculations indicate that (i) substitutional boron and nitrogen impurities do not affect the semiconducting character of the armchair SiC nanoribbons, and (ii) the half-metallic behavior of the zigzag nanoribbons is maintained in the presence of substitutional boron impurities. In contrast, nitrogen atoms occupying edge carbon sites transform half-metallic zigzag nanoribbons into metallic systems.


The effect of definitions of activities of daily living on estimates of changing ability among older people.
Physical functioning status is often assessed using scales of activities of daily living and instrumental activities of daily living. Different ways of defining change in adequacy of performance of both activities of daily living and instrumental activities of daily living tasks may be used, including increasing difficulty in performance, the need for assistance and inability to do tasks. In this prospective study, we investigated the effect of different definitions of decline on estimates of physical function, and explored the relationships between decline in each activity of daily living individually and potential predictors. The study was based on a sample of 999 individuals aged 65 years or more who participated in a national survey of quality of life, of whom 531 (68% of those eligible for follow up) responded 12-18 months later. Different definitions of decline were used and the prevalence of decline was, depending on the individual activities of daily living item, used as an outcome in logistic regression models. The results showed that the strength of association with chronic diseases, demographic, psychological and environmental factors varied by altering the activities of daily living item used. Decline in ability to walk 400 yards was strongly associated with respiratory problems (odds ratio 3.5 [95% confidence interval 1.3-9.0]) while decline in ability to get on a bus was associated with musculoskeletal problems (odds ratio 2.8 [95% confidence interval 1.4-5.6]). In conclusion, the prevalence of decline varies by definition, and summary measures which are customarily used to describe disability, may be inadequate for the assessment and identification of predictors of decline in functional ability.


Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism.
We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by (1)H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.


Modelling future trajectories of obesity and body mass index in England.
Obesity is a leading risk for poor health outcomes in England. We examined best- and worst-case scenarios for the future trajectory of the obesity epidemic. Taking the last 27 years of Health Survey for England data, we determined both position and shape of the adult body mass index (BMI) distribution and projected these parameters 20 years forward in time. For the best-case scenario, we fitted linear models, allowing for a quadratic relationship between the outcome variable and time, to reflect a potential reversal in upwards trends. For the worst-case scenario, we fitted non-linear models that applied an exponential function to reflect a potential flattening of trends over time. Best-fitting models were identified using Monte Carlo cross-validation on 1991-2014 data, and predictions of population prevalence across five BMI categories were then validated using 2015-17 data. Both linear and non-linear models showed a close fit to observed data (mean absolute error <2%). In the best-case scenario, the proportion of the population at increased risk (BMI≥25kg/m2) is predicted to fall from 66% in 2017 to 53% (95% confidence interval: 41% to 64%) in 2035. In the worst-case scenario, this proportion is likely to remain relatively stable overall- 64% (37% to 90%) in 2035 -but with an increasing proportion of the population at highest risk (BMI≥35kg/m2). While obesity prediction depends on chosen modelling methods, even under optimistic assumptions it is likely that the majority of the English population will still be at increased risk of disease due to their weight until at least 2035, without greater allocation of resources to effective interventions.


Occlusal Stress Distribution on the Mandibular First Premolar - FEM Analysis.
The aim of this paper was to analyze the distribution of stress and deformation on the mandibular first premolar under two types of loading (axial and para-axial load of 200 N) using the FEM computer method. For this research a µCT scan of the first mandibular premolar was used, and the method used in this research was FEM analysis under two types of loading. The values of the von Mises stress measured in the cervical part of an intact tooth under axial load were up to 12 MPa, and under paraaxial load over 50 MPa. The values of the stress measured on the bottom of the noncarious lesion are very high ≈ 240 Mpa. Stress values in the cervical part of the intact tooth are higher in the zone of the sub-surface enamel. The deformation values of the tooth under para-axial loading were ≈ 10 times higher than the value of the deformation under axial load. The greatest deformations were seen in the area of the tooth crown. Occlusal loading leads to significant stress in the cervical part of teeth. The values of the measured stress are greater under the action of paraxial load. The values of stress in abfraction lesions measured under a paraxial load are extremely high. Exposing the lesion to further stress will lead to its deepening. The total deformation of the entire tooth under paraxial load was ≈ 10 times higher compared to the deformation value of the tooth under axial load.


Are child pedestrians at increased risk of injury on one-way compared to two-way streets?
To compare child pedestrian injury rates on one-way versus two-way streets in Hamilton, and examine whether the characteristics of child pedestrian injuries differ across street types. The rates of injury per child population, per kilometre, per year were calculated by age, sex and socio-economic status (SES). Child, environment and driver characteristics were investigated by street type. The injury rate was 2.5 times higher on one-way streets than on two-way streets and 3 times higher for children from the poorest neighbourhoods than for those from wealthier neighbourhoods. SES, injury severity, number of lanes, collision location and type of traffic control were also found to be significantly different across street types. One-way streets have higher rates of child pedestrian injuries than two-way streets in this community. Future risk factor and intervention studies should include the directionality of streets to further investigate its contribution to child pedestrian injuries.


Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339.
Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.


Genome Sequencing and Comparative Transcriptomics Provide a Holistic View of 4-Nitrophenol Degradation and Concurrent Fatty Acid Catabolism by Rhodococcus sp. Strain BUPNP1.
Rhodococcus sp.strain BUPNP1 can utilize the priority environmental pollutant 4-nitrophenol (4-NP) as its sole source of carbon and energy. In this study, genome and transcriptome sequencing were used to gain mechanistic insights into 4-NP degradation. The draft BUPNP1 genome is 5.56 Mbp and encodes 4,963 proteins, which are significantly enriched in hypothetical proteins compared to other Rhodococcus sp. A novel 4-NP catabolic 43 gene cluster "nph" was identified that encodes all the genes required for the conversion of 4-NP into acetyl-CoA and succinate, via 4-nitrocatechol. The cluster also encodes pathways for the catabolism of other diverse aromatic compounds. Comparisons between BUPN1 growing on either 4-NP or glucose resulted in significant changes in the expression of many nph cluster genes, and, during 4-NP growth, a loss of lipid inclusions. Moreover, fatty acid degradation/synthesis genes were found within the nph cluster, suggesting fatty acids may be concurrently catabolised with 4-NP. A holistic model for the action of the nph gene cluster is proposed which incorporates genetic architecture, uptake and metabolism of aromatic compounds, enzymatic activities and transcriptional regulation. The model provides testable hypotheses for further biochemical investigations into the genes of the nph cluster, for potential exploitation in bioremediation.


A review of Rett syndrome (RTT) with induced pluripotent stem cells.
Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs. For these reasons, hiPSCs have huge potential in translational medicine such as disease modeling, drug screening, and cellular therapy. Indeed, patient-specific hiPSCs have been generated for a multitude of diseases, including many with a neurological basis, in which disease phenotypes have been recapitulated in vitro and proof-of-principle drug screening has been performed. As the techniques for generating hiPSCs are refined and these cells become a more widely used tool for understanding brain development, the insights they produce must be understood in the context of the greater complexity of the human genome and the human brain. Disease models using iPS from Rett syndrome (RTT) patient's fibroblasts have opened up a new avenue of drug discovery for therapeutic treatment of RTT. The analysis of X chromosome inactivation (XCI) upon differentiation of RTT-hiPSCs into neurons will be critical to conclusively demonstrate the isolation of pre-XCI RTT-hiPSCs in comparison to post-XCI RTT-hiPSCs. The current review projects on iPSC studies in RTT as well as XCI in hiPSC were it suggests for screening new potential therapeutic targets for RTT in future for the benefit of RTT patients. In conclusion, patient-specific drug screening might be feasible and would be particularly helpful in disorders where patients frequently have to try multiple drugs before finding a regimen that works.


Association between Disability and Unmet Food Needs in the Venezuelan Migrant and Refugee Population: Analysis of a Population-Based Survey, 2022.
In Peru, Venezuelan migrants and refugees have been exposed to food shortages before their emigration. This problem could have worse outcomes in vulnerable populations (such as people with disabilities); however, the literature on the basic needs of this population is still scarce. The objective was to determine the association between the presence of disability and the unmet need for access to food in the household of the Venezuelan migrant and refugee population residing in Peru. A cross-sectional study was conducted using data from the Second Survey of the Venezuelan Population Residing in Peru (ENPOVE 2022). The outcome variable was unmet need for food, while the independent variable was the presence of disability. Poisson log generalized linear regression models (crude and adjusted for potential confounding variables) were fitted to evaluate the association between the variables of interest, reporting prevalence ratios (PR) and 95% confidence intervals (CIs). A total of 7739 migrants and refugees from Venezuela were included. The proportion of unmet need for access to food in the household was 45.2%, while the proportion of disability was 2.1%. People with disabilities were found to be more likely to have an unmet need for access to food at home (adjusted PR [aPR]: 1.25; 95% CI: 1.08-1.46; p = 0.003). According to our findings, almost half of Venezuelan households were found to have an unmet need for access to food. In addition, Venezuelan migrants and refugees with disabilities were more likely to have an unmet need for this basic need.


Quantitative automated assessment of myocardial perfusion at cardiac catheterization.
Perfusion assessed in the cardiac catheterization laboratory predicts outcomes after myocardial infarction. The aim of this study was to investigate a novel method of assessing perfusion using digital subtraction angiography to generate a time-density curve (TDC) of myocardial blush, incorporating epicardial and myocardial perfusion. Seven pigs underwent temporary occlusion of the left anterior descending coronary artery for 60 minutes. Angiography was performed in the same projections before, during, and after occlusion. Perfusion parameters were obtained from the TDC and compared with Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade. In addition, safety and feasibility were tested in 8 patients after primary percutaneous coronary intervention. The contrast density differential between the proximal artery and the myocardium derived from the TDC correlated well with TIMI myocardial perfusion grade (R = 0.54, p <0.001). The arterial transit time derived from the TDC correlated with TIMI frame count (R = 0.435, p = 0.011). Using a cutoff of 2.4, the density/time ratio, a ratio of density differential to transit time, had sensitivity and specificity of 100% for coronary arterial occlusion. The positive and negative predictive values were 100%. The generation of a TDC was safe and feasible in 7 patients after acute myocardial infarctions, but the correlation between TDC-derived parameters and TIMI parameters did not reach statistical significance. In conclusion, this novel method of digital subtraction angiography with rapid, automated, quantitative assessment of myocardial perfusion in the cardiac catheterization laboratory correlates well with established angiographic measures of perfusion. Further studies to assess the prognostic value of this technique are warranted.


Percutaneous glycerol rhizotomy for trigeminal neuralgia in patients with multiple sclerosis: a long-term retrospective cohort study.
The prevalence of trigeminal neuralgia (TN) in patients with multiple sclerosis (MS-TN) is higher than in the general population (idiopathic TN [ITN]). Glycerol rhizotomy (GR) is a percutaneous lesioning surgery commonly performed for the treatment of medically refractory TN. While treatment for acute pain relief is excellent, long-term pain relief is poorer. The object of this study was to assess the efficacy of percutaneous retrogasserian GR for the treatment of MS-TN versus ITN. A retrospective chart review was performed, identifying 219 patients who had undergone 401 GR procedures from 1983 to 2018 at a single academic institution. All patients were diagnosed with medically refractory MS-TN (182 procedures) or ITN (219 procedures). The primary outcome measures of interest were immediate pain relief and time to pain recurrence following initial and repeat GR procedures. Secondary outcomes included medication usage and presence of periprocedural hypesthesia. The initial pain-free response rate was similar between groups (p = 0.726): MS-TN initial GR 89.6%; MS-TN repeat GR 91.9%; ITN initial GR 89.6%; ITN repeat GR 87.0%. The median time to recurrence after initial GR was similar between MS-TN (2.7 ± 1.3 years) and ITN (2.1 ± 0.6 years) patients (p = 0.87). However, there was a statistically significant difference in the time to recurrence after repeat GR between MS-TN (2.3 ± 0.5 years) and ITN patients (1.2 ± 0.2 years; p < 0.05). The presence of periprocedural hypesthesia was highly predictive of pain-free survival (p < 0.01). Patients with MS-TN achieve meaningful pain relief following GR, with an efficacy comparable to that following GR in patients with ITN. Initial and subsequent GR procedures are equally efficacious.


CT angiography with spiral CT and maximum intensity projection.
The authors describe a technique for obtaining angiographic images by means of spiral computed tomography (CT), preprocessing of reconstructed three-dimensional sections to suppress bone, and maximum intensity projection. The technique has some limitations, but preliminary results in 48 patients have shown excellent anatomic correlation with conventional angiography in studies of the abdomen, the circle of Willis in the brain, and the extracranial carotid arteries. With continued development and evaluation, CT angiography may prove useful as a screening tool or replacement for conventional angiography in some patients.


Quantification of serum ovalbumin-specific immunoglobulin E titrevia in vivo passive cutaneous anaphylaxis assay.
Murine models of allergic airway disease are frequently used as a tool to elucidate the cellular and molecular mechanisms of tissue-specific asthmatic disease pathogenesis. Paramount to the success of these models is the induction of experimental antigen sensitization, as indicated by the presence of antigen-specific serum immunoglobulin E. The quantification of antigen-specific serum IgE is routinely performed via enzyme-linked immunosorbent assay. However, the reproducibility of these in vitro assays can vary dramatically in our experience. Furthermore, quantifying IgE via in vitro methodologies does not enable the functional relevance of circulating IgE levels to be considered. As a biologically appropriate alternative method, we describe herein a highly reproducible in vivo passive cutaneous anaphylaxis assay using Sprague Dawley rats for the quantification of ovalbumin-specific IgE in serum samples from ovalbumin-sensitized murine models. Briefly, this in vivo assay involves subcutaneous injections of serum samples on the back of a Sprague Dawley rat, followed 24 h later by intravenous injection of ovalbumin and a blue detection dye. The subsequent result of antigen-IgE mediated inflammation and leakage of blue dye into the initial injection site indicates the presence of ovalbumin-specific IgE within the corresponding serum sample.


Physical Activity-Related Drivers of Perceived Health Status in Adults With Congenital Heart Disease.
Data on the differential impact of physical activity on perceived health status (PHS) in a large adult congenital heart disease (ACHD) patient population are lacking. We conducted a cross-sectional assessment of 4,028 ACHD patients recruited from 24 ACHD-specialized centers in 15 countries across 5 continents to examine the association between physical activity and PHS in a large international cohort of ACHD patients. A linear analog scale of the EuroQol-5D 3 level version and the 12-item Short Form Health Survey-version 2 were used to assess self-reported health status and the Health-Behavior Scale-Congenital Heart Disease was used as a subjective measurement of physical activity type, participation, and level. Correlation analyses and Wilcoxon Rank Sum tests examined bivariate relations between sample characteristics and PHS scores. Then, multivariable models were constructed to understand the impact of physical activity on PHS. Only 30% of our sample achieved recommended physical activity levels. Physically active patients reported better PHS than sedentary patients; however, the amount of physical activity was not associated with PHS. Further statistical analyses demonstrated that specifically sport participation regardless of physical activity level was a predictor of PHS. In conclusion, the majority of ACHD patients across the world are physically inactive. Sport participation appears to be the primary physical activity-related driver of PHS. By promoting sport-related exercise ACHD specialists thus may improve PHS in ACHD patients.


Linking DNA replication checkpoint to MBF cell-cycle transcription reveals a distinct class of G1/S genes.
Reprogramming gene expression is crucial for DNA replication stress response. We used quantitative proteomics to establish how the transcriptional response results in changes in protein levels. We found that expression of G1/S cell-cycle targets are strongly up-regulated upon replication stress, and show that MBF, but not SBF genes, are up-regulated via Rad53-dependent inactivation of the MBF co-repressor Nrm1. A subset of G1/S genes was found to undergo an SBF-to-MBF switch at the G1/S transition, enabling replication stress-induced transcription of genes targeted by SBF during G1. This subset of G1/S genes is characterized by an overlapping Swi4/Mbp1-binding site and is enriched for genes that cause a cell cycle and/or growth defect when overexpressed. Analysis of the prototypical switch gene TOS4 (Target Of SBF 4) reveals its role as a checkpoint effector supporting the importance of this distinct class of G1/S genes for the DNA replication checkpoint response. Our results reveal that replication stress induces expression of G1/S genes via the Rad53-MBF pathway and that an SBF-to-MBF switch characterizes a new class of genes that can be induced by replication stress.


High Residual Tumor Rate for Early Breast Cancer Patients Receiving Vacuum-assisted Breast Biopsy.
Purpose: The objective of study is aiming to investigate the residual tumor rate after Vacuum-assisted Breast Biopsy (VABB) for early breast cancer excision and the efficacy of mammogram and ultrasound in detecting residual tumor. Methods: Patients who underwent VABB and were confirmed with breast cancer in Sun Yat-sen University Cancer Center from 2010 to 2015 were reviewed retrospectively. The residual tumor rate determined by histological examination was calculated, and then was compared with the results estimated by mammogram and ultrasound which were performed post VABB but before subsequent surgery. Univariate and multivariate analysis (logistic regression) were carried out to identify the independent risk factors associated with residual tumor. Results: In total, 126 eligible patients with early breast cancer were recruited for this study, of whom 79 (62.7%) had residual tumor and 47 (37.3 %) underwent complete excision. The residual tumor rates for lesions < 10mm, lesions 10 to 20 mm and lesions >20mm in size were 55.0%, 68.9% and 53.1%, respectively. The complete excision rates estimated by mammogram and ultrasound were 76.5% and 73.9%, with a negative predictive value of only 46.2% and 50.6%, respectively. In the multivariate logistic regression analysis, no specific factors were found associated with risk of residual tumor (all P > 0.05). Conclusions: There was a high residual tumor rate after VABB in early breast cancer. Both mammogram and ultrasound could not effectively detect the residual tumor after VABB.


Genotype and diet affect resistance, survival, and fecundity but not fecundity tolerance.
Insects are exposed to a variety of potential pathogens in their environment, many of which can severely impact fitness and health. Consequently, hosts have evolved resistance and tolerance strategies to suppress or cope with infections. Hosts utilizing resistance improve fitness by clearing or reducing pathogen loads, and hosts utilizing tolerance reduce harmful fitness effects per pathogen load. To understand variation in, and selective pressures on, resistance and tolerance, we asked to what degree they are shaped by host genetic background, whether plasticity in these responses depends upon dietary environment, and whether there are interactions between these two factors. Females from ten wild-type Drosophila melanogaster genotypes were kept on high- or low-protein (yeast) diets and infected with one of two opportunistic bacterial pathogens, Lactococcus lactis or Pseudomonas entomophila. We measured host resistance as the inverse of bacterial load in the early infection phase. The relationship (slope) between fly fecundity and individual-level bacteria load provided our fecundity tolerance measure. Genotype and dietary yeast determined host fecundity and strongly affected survival after infection with pathogenic P. entomophila. There was considerable genetic variation in host resistance, a commonly found phenomenon resulting from for example varying resistance costs or frequency-dependent selection. Despite this variation and the reproductive cost of higher P. entomophila loads, fecundity tolerance did not vary across genotypes. The absence of genetic variation in tolerance may suggest that at this early infection stage, fecundity tolerance is fixed or that any evolved tolerance mechanisms are not expressed under these infection conditions.


Bond-coating in plasma-sprayed calcium-phosphate coatings.
The influence of bond-coating on the mechanical properties of plasma-spray coatings of hydroxyatite on Ti was investigated. Plasma-spray powder was produced from human teeth enamel and dentine. Before processing the main apatite coating, a very thin layer of Al2O3/TiO2 was applied on super clean and roughened, by Al2O3 blasting, Ti surface as bond-coating. The experimental results showed that bond-coating caused significant increase of the mechanical properties of the coating layer: In the case of the enamel powder from 6.66 MPa of the simple coating to 9.71 MPa for the bond-coating and in the case of the dentine powder from 6.27 MPa to 7.84 MPa, respectively. Both tooth derived powders feature high thermal stability likely due to their relatively high content of fluorine. Therefore, F-rich apatites, such those investigated in this study, emerge themselves as superior candidate materials for calcium phosphate coatings of producing medical devices. The methods of apatite powder production and shaping optimization of powder particles are both key factors of a successful coating. The methods used in this study can be adopted as handy, inexpensive and reliable ways to produce high quality of powders for plasma spray purposes.


Abnormal Amyloid Load in Mild Cognitive Impairment: The Effect of Reducing the PiB-PET Threshold.
In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.


MicroRNA expression profiles classify human cancers.
Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.


Critical windows of exposure to household pesticides and risk of childhood leukemia.
The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study. A total of 162 patients (0-14 years old) with newly diagnosed leukemia were rapidly ascertained during 1995-1999, and 162 matched control subjects were randomly selected from the birth registry. The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.4-5.7], and the exposure during year 2 was associated with the highest risk (OR = 3.6; 95% CI, 1.6-8.3). The ORs for exposure to insecticides during the 3 months before pregnancy, pregnancy, and years 1, 2, and 3 were 1.8 (95% CI, 1.1-3.1), 2.1 (95% CI, 1.3-3.5), 1.7 (95% CI, 1.0-2.9), 1.6 (95% CI, 1.0-2.7), and 1.2 (95% CI, 0.7-2.1), respectively. Insecticide exposures early in life appear to be more significant than later exposures, and the highest risk was observed for exposure during pregnancy. Additionally, more frequent exposure to insecticides was associated with a higher risk. In contrast to insecticides, the association between herbicides and leukemia was weak and nonsignificant. Pesticides were also grouped based on where they were applied. Exposure to indoor pesticides was associated with an increased risk, whereas no significant association was observed for exposure to outdoor pesticides. The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure.


Visible light amination/Smiles cascade: access to phthalazine derivatives.
We report the synthesis of various phthalazines via a new cascade reaction, initiated by visible light photocatalysis, involving a radical hydroamination reaction followed by a radical Smiles rearrangement. Phthalazine derivatives are obtained in high yields and from a broad scope readily accessible ortho-alkynylsulfonohydrazone precursors. The mild photoredox conditions ensure an excellent functional group tolerance. Application of this strategy to a one-pot protocol starting from the corresponding carbonyl compounds, and subsequent functionalization allow the rapid synthesis of structurally diverse structures.


The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites' boundaries.
Plasmodium falciparum and Toxoplasma gondii are obligate intracellular apicomplexan parasites that rapidly invade and extensively modify host cells. Protein phosphorylation is one mechanism by which these parasites can control such processes. Here we present a phosphoproteome analysis of peptides enriched from schizont stage P. falciparum and T. gondii tachyzoites that are either "intracellular" or purified away from host material. Using liquid chromatography-tandem mass spectrometry, we identified over 5,000 and 10,000 previously unknown phosphorylation sites in P. falciparum and T. gondii, respectively, revealing that protein phosphorylation is an extensively used regulation mechanism both within and beyond parasite boundaries. Unexpectedly, both parasites have phosphorylated tyrosines, and P. falciparum has unusual phosphorylation motifs that are apparently shaped by its A:T-rich genome. This data set provides important information on the role of phosphorylation in the host-pathogen interaction and clues to the evolutionary forces operating on protein phosphorylation motifs in both parasites.


Uniform Lipschitz Functions on the Triangular Lattice Have Logarithmic Variations.
Uniform integer-valued Lipschitz functions on a domain of size N of the triangular lattice are shown to have variations of order log N . The level lines of such functions form a loop O(2) model on the edges of the hexagonal lattice with edge-weight one. An infinite-volume Gibbs measure for the loop O(2) model is constructed as a thermodynamic limit and is shown to be unique. It contains only finite loops and has properties indicative of scale-invariance: macroscopic loops appearing at every scale. The existence of the infinite-volume measure carries over to height functions pinned at the origin; the uniqueness of the Gibbs measure does not. The proof is based on a representation of the loop O(2) model via a pair of spin configurations that are shown to satisfy the FKG inequality. We prove RSW-type estimates for a certain connectivity notion in the aforementioned spin model.


Properties and physiological function of Ca2+-dependent K+ currents in uniglomerular olfactory projection neurons.
Ca(2+)-activated potassium currents [IK(Ca)] are an important link between the intracellular signaling system and the membrane potential, which shapes intrinsic electrophysiological properties. To better understand the ionic mechanisms that mediate intrinsic firing properties of olfactory uniglomerular projection neurons (uPNs), we used whole cell patch-clamp recordings in an intact adult brain preparation of the male cockroach Periplaneta americana to analyze IK(Ca) In the insect brain, uPNs form the principal pathway from the antennal lobe to the protocerebrum, where centers for multimodal sensory processing and learning are located. In uPNs the activation of IK(Ca) was clearly voltage and Ca(2+) dependent. Thus under physiological conditions IK(Ca) is strongly dependent on Ca(2+) influx kinetics and on the membrane potential. The biophysical characterization suggests that IK(Ca) is generated by big-conductance (BK) channels. A small-conductance (SK) channel-generated current could not be detected. IK(Ca) was sensitive to charybdotoxin (CTX) and iberiotoxin (IbTX) but not to apamin. The functional role of IK(Ca) was analyzed in occlusion experiments under current clamp, in which portions of IK(Ca) were blocked by CTX or IbTX. Blockade of IK(Ca) showed that IK(Ca) contributes significantly to intrinsic electrophysiological properties such as the action potential waveform and membrane excitability.


Comparison of ultrasound and CT in the evaluation of pneumonia complicated by parapneumonic effusion in children.
The purpose of our study was to compare chest ultrasound and chest CT in children with complicated pneumonia and parapneumonic effusion. We retrospectively compared chest ultrasound and chest CT in 19 children (nine girls and 10 boys; age range, 8 months-17 years) admitted with complicated pneumonia and parapneumonic effusion between December 2006 and January 2009. Images were evaluated for effusion, loculation, fibrin strands, parenchymal consolidation, necrosis, and abscess. In the subset of patients who underwent surgical management, imaging findings were correlated with operative findings. Eighteen of 19 patients had an effusion on both chest ultrasound and chest CT. The findings of effusion loculation as well as parenchymal consolidation and necrosis or abscess were similar between the two techniques. Chest ultrasound was better able to visualize fibrin strands within the effusions. Of the 14 patients who underwent video-assisted thoracoscopy, five had surgically proven parenchymal abscess or necrosis. Preoperatively, chest ultrasound was able to show parenchymal abscess or necrosis in four patients, whereas chest CT was able to show parenchymal abscess or necrosis in three. In our series, chest ultrasound and chest CT were similar in their ability to detect loculated effusion and lung necrosis or abscess resulting from complicated pneumonia. Chest CT did not provide any additional clinically useful information that was not also seen on chest ultrasound. We suggest that the imaging workup of complicated pediatric pneumonia include chest radiography and chest ultrasound, reserving chest CT for cases in which the chest ultrasound is technically limited or discrepant with the clinical findings.


Pathologic Findings on Hip Arthroscopy in High-Level Athletes Competing in Flexibility Sports.
Athletes who compete in flexibility sports (FS) place unique demands on their hip joints because of the supraphysiologic range of motion required. To compare the pathologic features, outcomes, and return-to-sports (RTS) rates of high-level athletes participating in FS who underwent hip arthroscopy for femoroacetabular impingement syndrome (FAIS) and labral tear against a propensity score-matched cohort of high-level athletes participating in non-flexibility sports (NFS). Cohort study; Level of evidence, 3. Data were prospectively collected and retrospectively reviewed for high-level athletes who underwent primary hip arthroscopy for FAIS from April 2008 to December 2018. Patients who participated in FS such as dancing, gymnastics, martial arts, figure skating, and cheerleading were propensity score matched by body mass index, age at time of surgery, sex, sports competition level, and labral treatment to a cohort of high-level athletes participating in all other sports, such as distance running, soccer, volleyball, and softball. Baseline patient characteristics, intraoperative findings, and surgical procedures were compared. Minimum 2-year patient-reported outcome measures were compared for the modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score-Sport Specific Subscale, and visual analog scale for pain and satisfaction. Rates of secondary surgery and RTS were compared. A total of 47 patients (50 hips) who participated in FS were included and propensity score matched to 130 patients (150 hips) who participated in NFS. Follow-up time was 37.5 ± 10.4 months (mean ± SD). Most patients (96.0%) were female with a mean age of 19.5 ± 7.3 years. FS athletes had significantly higher rates of femoral head cartilage lesions (Outerbridge ≥2; 12.0% vs 2.0%; P = .008) and ligamentum teres tears (48% vs 26%; P = .003). FS and NFS athletes demonstrated significant clinical improvements after surgery for all patient-reported outcome measures. Of the patients who attempted, 34 (75.6%) participating in FS were able to RTS while 11 (24.4%) were not because of ongoing hip issues. This was not significantly different than the NFS group (P = .073). High-level athletes who participated in FS and were treated for FAIS with hip arthroscopy exhibited higher rates of femoral head cartilage lesions and ligamentum teres tears requiring debridement when compared with a benchmark group of athletes who participated in other sports. Despite this, both groups demonstrated similar improvements in outcome scores and comparable rates of RTS at minimum 2-year follow-up.


Seduced by the dark side: integrating molecular and ecological perspectives on the influence of light on plant defence against pests and pathogens.
Plants frequently suffer attack from herbivores and microbial pathogens, and have evolved a complex array of defence mechanisms to resist defoliation and disease. These include both preformed defences, ranging from structural features to stores of toxic secondary metabolites, and inducible defences, which are activated only after an attack is detected. It is well known that plant defences against pests and pathogens are commonly affected by environmental conditions, but the mechanisms by which responses to the biotic and abiotic environments interact are only poorly understood. In this review, we consider the impact of light on plant defence, in terms of both plant life histories and rapid scale molecular responses to biotic attack. We bring together evidence that illustrates that light not only modulates defence responses via its influence on biochemistry and plant development but, in some cases, is essential for the development of resistance. We suggest that the interaction between the light environment and plant defence is multifaceted, and extends across different temporal and biological scales.


Chitosan for the treatment of inflammation of the oral mucosa: A systematic review.
Chitosan is a cheap, accessible, nontoxic, biocompatible, and biodegradable compound. Also, this polysaccharide possesses antibacterial and anti-inflammatory properties. Consequently, a wide range of chitosan applications in the dentistry field has been explored. This work aimed to conduct a systematic review to address the clinical efficacy of chitosan for the treatment of oral mucositis. The design of the included studies were observational studies, randomized clinical trials (RCT), and non-randomized clinical trials (non-RCT), whereas, a series of cases, in vivo, and in vitro studies were excluded. The search was performed in PubMed, Web of Science, Scopus, Dentistry and Oral Sciences Source, and ClinicalTrials. Gray literature was searched at Google Scholar. Relevant data from all included studies were recorded. The risk of bias (using RoB 2) and the quality (using Grading of Recommendations Assessment, Development, and Evaluation, GRADE) assessments were carried out. From the 8413 records screened, 5 clinical trials fully met the eligibility criteria, which comprised a total of 192 participants suffering oral lesions and pain related to oral mucositis. 100% of the included studies exhibited a high risk of bias. The quality of the studies was between low and very low. The results of the included studies suggest that chitosan can diminish pain and improve the healing of ulcers in oral mucositis. However, there is no conclusive evidence of chitosan as a superior treatment for oral mucositis compared with other current therapies.


Bladder Reconstruction Rates Differ among Centers Participating in National Spina Bifida Patient Registry.
We performed an exploratory analysis of data from the NSBPR (National Spina Bifida Patient Registry) to assess variation in the frequency of bladder reconstruction surgeries among NSBPR centers. We queried the 2009-2014 NSBPR to identify patients who had ever undergone bladder reconstruction surgeries. We evaluated demographic characteristics, spina bifida type, functional level, mobility and NSBPR center to determine whether any of these factors were associated with reconstructive surgery rates. Multivariable logistic regression was used to simultaneously adjust for the impact of these factors. We identified 5,528 patients with spina bifida enrolled in the NSBPR. Of these patients 1,129 (20.4%) underwent bladder reconstruction (703 augmentation, 382 continent catheterizable channel, 189 bladder outlet procedure). Surgical patients were more likely older, female, nonHispanic white, with a higher lesion level, myelomeningocele diagnosis, nonambulators (all p <0.001) and nonprivately insured (p=0.018). Bladder reconstruction surgery rates varied among NSBPR centers (range 12.1% to 37.9%, p <0.001). After correcting for known confounders NSBPR center, spina bifida type, mobility, gender and age (all p <0.001) were significant predictors of surgical intervention. Race (p=0.19) and insurance status (p=0.11) were not associated with surgical intervention. There is significant variation in rates of bladder reconstruction surgery among NSBPR centers. In addition to clinical factors such as mobility status, lesion type and lesion level, nonclinical factors such as patient age, gender and treating center are also associated with the likelihood of an individual undergoing bladder reconstruction.


Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways.
Hantaviruses infect humans via inhalation of virus-contaminated rodent excreta. Infection can cause severe disease with up to 40% mortality depending on the viral strain. The virus primarily targets the vascular endothelium without direct cytopathic effects. Instead, exaggerated immune responses may inadvertently contribute to disease development. Mononuclear phagocytes (MNPs), including monocytes and dendritic cells (DCs), orchestrate the adaptive immune responses. Since hantaviruses are transmitted via inhalation, studying immunological events in the airways is of importance to understand the processes leading to immunopathogenesis. Here, we studied 17 patients infected with Puumala virus that causes a mild form of hemorrhagic fever with renal syndrome (HFRS). Bronchial biopsies as well as longitudinal blood draws were obtained from the patients. During the acute stage of disease, a significant influx of MNPs expressing HLA-DR, CD11c or CD123 was detected in the patients' bronchial tissue. In parallel, absolute numbers of MNPs were dramatically reduced in peripheral blood, coinciding with viremia. Expression of CCR7 on the remaining MNPs in blood suggested migration to peripheral and/or lymphoid tissues. Numbers of MNPs in blood subsequently normalized during the convalescent phase of the disease when viral RNA was no longer detectable in plasma. Finally, we exposed blood MNPs in vitro to Puumala virus, and demonstrated an induction of CCR7 expression on MNPs. In conclusion, the present study shows a marked redistribution of blood MNPs to the airways during acute hantavirus disease, a process that may underlie the local immune activation and contribute to immunopathogenesis in hantavirus-infected patients.


Effective use of radiation shields to minimize operator dose during invasive cardiology procedures.
This study sought to measure the protection from scatter radiation offered to the primary physician by a variety of available shields and to provide best practice guidelines for shield use during invasive cardiology procedures. It is accepted that exposure to radiation includes a predicted increase in cancer risk. In the cardiac interventional laboratories, radiation shields are widely available; however, proper use of the shields to optimize protection during cardiac interventional procedures is not well understood. The protection from scatter radiation offered by a variety of shields used alone and in combination was measured. Protection was assessed from air-kerma measurements of scatter radiation from a phantom performed without and with the shields. Protection was assessed for 3 patient- access locations (right jugular vein, right femoral artery, and left anterior chest) and for elevations ranging from 25 to 175 cm from the floor. The influence of precise placement of the ceiling-mounted upper body shield was specifically assessed. The utility and protection of shielding varied for the 3 access points and with elevation. For femoral artery access locations, the shields can provide at least 80% protection from scatter at all elevations; however, protection depends substantially on upper body shield position. A disposable radiation-absorbing pad can provide 35% to 70% upper body protection for procedures during which the upper body shield cannot be used effectively. Radiation shields can provide substantial protection from radiation during cardiac interventional procedures. Shields must be thoughtfully and actively managed to provide optimum protection. Best practice guidelines for shield use are provided.


Robust RNAi-based resistance to mixed infection of three viruses in soybean plants expressing separate short hairpins from a single transgene.
Transgenic plants expressing double-stranded RNA (dsRNA) of virus origin have been previously shown to confer resistance to virus infections through the highly conserved RNA-targeting process termed RNA silencing or RNA interference (RNAi). In this study we applied this strategy to soybean plants and achieved robust resistance to multiple viruses with a single dsRNA-expressing transgene. Unlike previous reports that relied on the expression of one long inverted repeat (IR) combining sequences of several viruses, our improved strategy utilized a transgene designed to express several shorter IRs. Each of these short IRs contains highly conserved sequences of one virus, forming dsRNA of less than 150 bp. These short dsRNA stems were interspersed with single-stranded sequences to prevent homologous recombination during the transgene assembly process. Three such short IRs with sequences of unrelated soybean-infecting viruses (Alfalfa mosaic virus, Bean pod mottle virus, and Soybean mosaic virus) were assembled into a single transgene under control of the 35S promoter and terminator of Cauliflower mosaic virus. Three independent transgenic lines were obtained and all of them exhibited strong systemic resistance to the simultaneous infection of the three viruses. These results demonstrate the effectiveness of this very straight forward strategy for engineering RNAi-based virus resistance in a major crop plant. More importantly, our strategy of construct assembly makes it easy to incorporate additional short IRs in the transgene, thus expanding the spectrum of virus resistance. Finally, this strategy could be easily adapted to control virus problems of other crop plants.


Impact of adding therapeutic recommendations to risk assessments from a prediction model for postoperative nausea and vomiting.
In a large cluster-randomized trial on the impact of a prediction model, presenting the calculated risk of postoperative nausea and vomiting (PONV) on-screen (assistive approach) increased the administration of risk-dependent PONV prophylaxis by anaesthetists. This change in therapeutic decision-making did not improve the patient outcome; that is, the incidence of PONV. The present study aimed to quantify the effects of adding a specific therapeutic recommendation to the predicted risk (directive approach) on PONV prophylaxis decision-making and the incidence of PONV. A prospective before-after study was conducted in 1483 elective surgical inpatients. The before-period included care-as-usual and the after-period included the directive risk-based (intervention) strategy. Risk-dependent effects on the administered number of prophylactic antiemetics and incidence of PONV were analysed by mixed-effects regression analysis. During the intervention period anaesthetists administered 0.5 [95% confidence intervals (CIs): 0.4-0.6] more antiemetics for patients identified as being at greater risk of PONV. This directive approach led to a reduction in PONV [odds ratio (OR): 0.60, 95% CI: 0.43-0.83], with an even greater reduction in PONV in high-risk patients (OR: 0.45, 95% CI: 0.28-0.72). Anaesthetists administered more prophylactic antiemetics when a directive approach was used for risk-tailored intervention compared with care-as-usual. In contrast to the previously studied assistive approach, the increase in PONV prophylaxis now resulted in a lower PONV incidence, particularly in high-risk patients. When one aims for a truly 'PONV-free hospital', a more liberal use of prophylactic antiemetics must be accepted and lower-risk thresholds should be set for the actionable recommendations.


Lipid transfer proteins: classification, nomenclature, structure, and function.
The non-specific lipid transfer proteins (LTPs) constitute a large protein family found in all land plants. They are small proteins characterized by a tunnel-like hydrophobic cavity, which makes them suitable for binding and transporting various lipids. The LTPs are abundantly expressed in most tissues. In general, they are synthesized with an N-terminal signal peptide that localizes the protein to spaces exterior to the plasma membrane. The in vivo functions of LTPs are still disputed, although evidence has accumulated for a role in the synthesis of lipid barrier polymers, such as cuticular waxes, suberin, and sporopollenin. There are also reports suggesting that LTPs are involved in signaling during pathogen attacks. LTPs are considered as key proteins for the plant's survival and colonization of land. In this review, we aim to present an overview of the current status of LTP research and also to discuss potential future applications of these proteins. We update the knowledge on 3D structures and lipid binding and review the most recent data from functional investigations, such as from knockout or overexpressing experiments. We also propose and argument for a novel system for the classification and naming of the LTPs.


Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl)acetylerythromycin A derivatives.
A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.


Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts.
Isolation of cases and contact tracing is used to control outbreaks of infectious diseases, and has been used for coronavirus disease 2019 (COVID-19). Whether this strategy will achieve control depends on characteristics of both the pathogen and the response. Here we use a mathematical model to assess if isolation and contact tracing are able to control onwards transmission from imported cases of COVID-19. We developed a stochastic transmission model, parameterised to the COVID-19 outbreak. We used the model to quantify the potential effectiveness of contact tracing and isolation of cases at controlling a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-like pathogen. We considered scenarios that varied in the number of initial cases, the basic reproduction number (R0), the delay from symptom onset to isolation, the probability that contacts were traced, the proportion of transmission that occurred before symptom onset, and the proportion of subclinical infections. We assumed isolation prevented all further transmission in the model. Outbreaks were deemed controlled if transmission ended within 12 weeks or before 5000 cases in total. We measured the success of controlling outbreaks using isolation and contact tracing, and quantified the weekly maximum number of cases traced to measure feasibility of public health effort. Simulated outbreaks starting with five initial cases, an R0 of 1·5, and 0% transmission before symptom onset could be controlled even with low contact tracing probability; however, the probability of controlling an outbreak decreased with the number of initial cases, when R0 was 2·5 or 3·5 and with more transmission before symptom onset. Across different initial numbers of cases, the majority of scenarios with an R0 of 1·5 were controllable with less than 50% of contacts successfully traced. To control the majority of outbreaks, for R0 of 2·5 more than 70% of contacts had to be traced, and for an R0 of 3·5 more than 90% of contacts had to be traced. The delay between symptom onset and isolation had the largest role in determining whether an outbreak was controllable when R0 was 1·5. For R0 values of 2·5 or 3·5, if there were 40 initial cases, contact tracing and isolation were only potentially feasible when less than 1% of transmission occurred before symptom onset. In most scenarios, highly effective contact tracing and case isolation is enough to control a new outbreak of COVID-19 within 3 months. The probability of control decreases with long delays from symptom onset to isolation, fewer cases ascertained by contact tracing, and increasing transmission before symptoms. This model can be modified to reflect updated transmission characteristics and more specific definitions of outbreak control to assess the potential success of local response efforts. Wellcome Trust, Global Challenges Research Fund, and Health Data Research UK.


Oxi-Redox Selective Breast Cancer Treatment: An In Vitro Study of Theranostic In-Based Oxide Nanoparticles for Controlled Generation or Prevention of Oxidative Stress.
In this article, we demonstrate that specifically engineered oxide nanoparticles (NPs) have the potential to act as theranostic materials that are able to generate or prevent oxidative stress through their oxi-redox activity in various types of malignant and nonmalignant cells. The oxi-redox activity is related to the type and presence of surface defects, which is modified with appropriate synthesis conditions. In the present work, we used MDA-MB-231 and MCF-7 human breast cancer cells and nonmalignant MCF-10A human breast cells to demonstrate how controlled oxidative stress mediated by specifically nanoengineered indium tin oxide (ITO) NPs can selectively induce cell death in the cancer cells while reducing the oxidative stress in the normal cells and supporting their proliferation. The ITO NPs are also promising nanotheranostic materials for cancer therapy and contrast agents because of their multimodal imaging capabilities. We demonstrate that the synthesized ITO NPs can selectively increase the generation of reactive oxygen species (ROS) in both breast tumor cell lines, resulting in activation of apoptosis, and can also greatly suppress the cellular proliferation in both types of tumor cells. In contrast, the ITO NPs exhibit ROS scavenging-like behavior, significantly decreasing the ROS levels in MCF-10A cells exposed to the additional ROS, hydrogen peroxide (H2O2), so that they protect the proliferation of nonmalignant MCF-10A cells from ROS damage. In addition, fluorescent microscopy images revealed that the ITO NPs emit strong fluorescence that could be used to reveal their location. Moreover, computed tomography imaging demonstrated that the ITO NPs exhibited a comparable capability toward anatomical contrast enhancement. These results suggest that the synthesized ITO NPs have the potential to be a novel selective therapeutic agent with a multimodal imaging property for anticancer treatment.


Cross-sectional study to evaluate Trichomonas vaginalis positivity in women tested for Neisseria gonorrhoeae and Chlamydia trachomatis, attending genitourinary medicine and primary care clinics in Bristol, South West England.
Highly sensitive, commercial nucleic acid amplification tests (NAAT) for Trichomonas vaginalis have only recently been recommended for use in the UK. While testing for T. vaginalis is routine in symptomatic women attending genitourinary medicine (GUM) clinics, it is rare in asymptomatic women or those attending primary care. The aim of this study was to evaluate the positivity of T. vaginalis using a commercial NAAT, in symptomatic and asymptomatic women undergoing testing for chlamydia and gonorrhoea in GUM and primary care settings. Samples from 9186 women undergoing chlamydia and gonorrhoea testing in South West England between May 2013 and Jan 2015 were also tested for T. vaginalis by NAAT alongside existing tests. T. vaginalis positivity using NAAT was as follows: in GUM 4.5% (24/530, symptomatic) and 1.7% (27/1584, asymptomatic); in primary care 2.7% (94/3499, symptomatic) and 1.2% (41/3573, asymptomatic). Multivariable regression found that in GUM older age, black ethnicity and deprivation were independent risk factors for T. vaginalis infection. Older age and deprivation were also risk factors in primary care. Testing women presenting with symptoms in GUM and primary care using TV NAATs is estimated to cost £260 per positive case diagnosed compared with £716 using current microbiological tests. Aptima TV outperforms existing testing methods used to identify T. vaginalis infection in this population. An NAAT should be used when testing for T. vaginalis in women who present for testing with symptoms in primary care and GUM, based on test performance and cost.


Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase.
Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1''-2') ribose-ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.


Neisseria meningitidis tonB, exbB, and exbD genes: Ton-dependent utilization of protein-bound iron in Neisseriae.
We have recently cloned and characterized the hemoglobin (Hb) receptor gene, hmbR, from Neisseria meningitidis. To identify additional proteins that are involved in Hb utilization, the N. meningitidis Hb utilization system was reconstituted in Escherichia coli. Five cosmids from N. meningitidis DNA library enabled a heme-requiring (hemA), HmbR-expressing mutant of E. coli to use Hb as both porphyrin and iron source. Nucleotide sequence analysis of DNA fragments subcloned from the Hb-complementing cosmids identified four open reading frames, three of them homologous to Pseudomonas putida, E. coli, and Haemophilus influenzae exbB, exbD, and tonB genes. The N. meningitidis TonB protein is 28.8 to 33.6% identical to other gram-negative TonB proteins, while the N. meningitidis ExbD protein shares between 23.3 and 34.3% identical amino acids with other ExbD and TolR proteins. The N. meningitidis ExbB protein was 24.7 to 36.1% homologous with other gram-negative ExbB and TolQ proteins. Complementation studies indicated that the neisserial Ton system cannot interact with the E. coli FhuA TonB-dependent outer membrane receptor. The N. meningitidis tonB mutant was unable to use Hb, Hb-haptoglobin complexes, transferrin, and lactoferrin as iron sources. Insertion of an antibiotic cassette in the 3' end of the exbD gene produced a leaky phenotype. Efficient usage of heme by N. meningitidis tonB and exbD mutants suggests the existence of a Ton-independent heme utilization mechanism. E. coli complementation studies and the analysis of N. meningitidis hmbR and hpu mutants suggested the existence of another Hb utilization mechanism in this organism.


Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition.
Clinical and laboratory studies have suggested involvement of interferon-gamma (IFN-gamma) in the pathophysiology of aplastic anemia. T cells from aplastic anemia (AA) patients secrete IFN-gamma in vitro, activated cytotoxic lymphocytes infiltrate aplastic bone marrow (BM), and IFN-gamma mRNA, not detected in normal BM, is present in BM from most AA patients. Many patients respond to immunosuppressive therapy with antithymocyte globulin and cyclosporine. Using long-term BM cultures (LTBMC) as a tissue culture model of hematopoiesis, we show that IFN-gamma is a potent inhibitor in the long-term culture-initiating cell (LTC-IC) assay, the best in vitro surrogate test for human hematopoietic stem cells, as well as of the output of committed progenitor cells (colony-forming unit-granulocyte-macrophage [CFU-GM] and burst-forming unit-erythroid [BFU-E]). In LTBMC, continuous addition of relatively high IFN-gamma concentrations (1,000 U/mL weekly or 200 U/mL every 2 days) was required for inhibition of secondary colony formation, a measure of LTC-IC number and clonogenicity. To mimick local production of IFN-gamma, human stromal cells were engineered by retroviral-mediated gene transfer to express a transduced IFN-gamma gene. IFN-gamma secreted by stromal cells was far more potent than exogenous IFN-gamma in its effects in the LTC-IC assay. For purified CD34+ cells culture in the presence of IFN-gamma stroma dramatically reduced secondary colony numbers as well as production of CFU-GM and BFU-E. Supernatants from these cultures contained only about 20 U/mL of IFN-gamma; this quantity of cytokine, when added to LTBMC, had little effect on hematopoiesis. The mechanism of hematopoietic suppression was related to the inhibition of cell cycle progression and induction of apoptosis of CD34+ cells. There was no apparent effect of local low-level IFN-gamma production on stromal cell function, as reflected in cell morphology, cell surface phenotype, or expression of hematopoietic growth factor genes. LTBMC with genetically altered stromal cells offers an in vitro model of immune suppression of hematopoiesis in AA and may be helpful in testing certain therapeutic modalities. We infer from our data that local production of low levels of inhibitory cytokine is sufficient to markedly inhibit hematopoiesis and to destroy stem cells and more mature progenitor cells.


The burden of pediatric diarrhea: a cross-sectional study of incurred costs and perceptions of cost among Bolivian families.
Worldwide, acute gastroenteritis represents an enormous public health threat to children under five years of age, causing one billion episodes and 1.9 to 3.2 million deaths per year. In Bolivia, which has one of the lower GDPs in South America, an estimated 15% of under-five deaths are caused by diarrhea. Bolivian caregiver expenses related to diarrhea are believed to be minimal, as citizens benefit from universal health insurance for children under five. The goals of this report were to describe total incurred costs and cost burden associated with caregivers seeking treatment for pediatric gastroenteritis, and to quantify relationships among costs, cost burden, treatment setting, and perceptions of costs. From 2007 to 2009, researchers interviewed caregivers (n=1,107) of pediatric patients (<5 years of age) seeking treatment for diarrhea in sentinel hospitals participating in Bolivia's diarrheal surveillance program across three main geographic regions. Data collected included demographics, clinical symptoms, direct costs (e.g. medication, consult fees) and indirect costs (e.g. lost wages). Patient populations were similar across cities in terms of gender, duration of illness, and age, but familial income varied significantly (p<0.05) when stratified on appointment type. Direct, indirect, and total costs to families were significantly higher for inpatients as compared to outpatients of urban (p<0.001) and rural (p<0.05) residence. Consult fees and indirect costs made up a large proportion of total costs. Forty-five percent of patients' families paid ≥1% of their annual household income for this single diarrheal episode. The perception that cost was affecting family finances was more frequent among those with higher actual cost burden. This study demonstrated that indirect costs due to acute pediatric diarrhea were a large component of total incurred familial costs. Additionally, familial costs associated with a single diarrheal episode affected the actual and perceived financial situation of a large number of caregivers. These data serve as a baseline for societal diarrheal costs before and immediately following the implementation of the rotavirus vaccine and highlight the serious economic importance of a diarrheal episode to Bolivian caregivers.


Donation after cardio-circulatory death liver transplantation.
The renewed interest in donation after cardio-circulatory death (DCD) started in the 1990s following the limited success of the transplant community to expand the donation after brain-death (DBD) organ supply and following the request of potential DCD families. Since then, DCD organ procurement and transplantation activities have rapidly expanded, particularly for non-vital organs, like kidneys. In liver transplantation (LT), DCD donors are a valuable organ source that helps to decrease the mortality rate on the waiting lists and to increase the availability of organs for transplantation despite a higher risk of early graft dysfunction, more frequent vascular and ischemia-type biliary lesions, higher rates of re-listing and re-transplantation and lower graft survival, which are obviously due to the inevitable warm ischemia occurring during the declaration of death and organ retrieval process. Experimental strategies intervening in both donors and recipients at different phases of the transplantation process have focused on the attenuation of ischemia-reperfusion injury and already gained encouraging results, and some of them have found their way from pre-clinical success into clinical reality. The future of DCD-LT is promising. Concerted efforts should concentrate on the identification of suitable donors (probably Maastricht category III DCD donors), better donor and recipient matching (high risk donors to low risk recipients), use of advanced organ preservation techniques (oxygenated hypothermic machine perfusion, normothermic machine perfusion, venous systemic oxygen persufflation), and pharmacological modulation (probably a multi-factorial biologic modulation strategy) so that DCD liver allografts could be safely utilized and attain equivalent results as DBD-LT.


Influence of brain-derived neurotrophic factor (BDNF) on serotonin neurotransmission in the hippocampus of adult rodents.
Whereas SSRIs produce rapid blockade of the serotonin transporter (SERT) in vitro and in vivo, the onset of an observable clinical effect takes longer to occur and a variety of pharmacological effects caused by antidepressants have been speculated to be involved either in initiating antidepressant effects and/or enhancing their effects on serotonergic transmission so as to cause clinical improvement. Among such secondary factors is increased activity of brain-derived neurotrophic factor (BDNF), which requires the Tropomyosine-related kinase B receptor (TrkB) for its effects. To begin an analysis of the influence of BDNF on serotonergic activity, we studied the acute effects of BDNF on SERT activity. A single BDNF injection (either intracerebroventricularly or directly into the CA3 region of hippocampus) decreased the signal amplitude and clearance rate produced by exogenously applied 5-HT compared to what was measured in control rats, shown using in vivo chronoamperometry. It also reduced the ability of a locally applied SSRI to block the clearance of 5-HT. In awake freely moving mice, acute intrahippocampal injection of BDNF decreased extracellular levels of 5-HT in the hippocampus, as measured using microdialysis. In addition, perfusion with BDNF decreased KCl-evoked elevations of 5-HT. These effects of BDNF were blocked by the non-selective antagonist of TrkB receptors, K252a. Overall, it may be inferred that in the hippocampus, through TrkB activation, a single injection of BDNF enhances SERT function. Such acute effects of BDNF would be expected to counter early effects of SSRIs, which might, in part, account for some delay in therapeutic effect.


Alemtuzumab for the treatment of multiple sclerosis.
Alemtuzumab is a monoclonal antibody that targets for the destruction CD52+ cells, particularly B and T cells. Alemtuzumab is approved in more than 50 countries around the world for the treatment of adult patients with relapsing remitting multiple sclerosis (MS). Areas covered: In this review, the authors summarize biological, clinical and safety data related to the use of alemtuzumab in patients with MS. The authors then provide their expert opinion on alemtuzumab and the field as of whole before providing their perspectives for the future. Expert opinion: Alemtuzumab is highly efficacious; more so than first line treatments but comparable to natalizumab. Treatment schedule makes alemtuzumab administration easy and attractive to patients. However, its safety profile makes it a choice for a very limited number of patients, in a specific disease window. As of now, a cure for MS remains elusive and there is an unmet need for a safe and highly potent agent at the level of and beyond the blood brain barrier.


Gender differences in the effect of age on electrical field stimulation (EFS)-induced adrenergic vasoconstriction in rat mesenteric resistance arteries.
The objective of this study was to examine the effects of gender and age on electrical field stimulation (EFS)-induced vasoconstriction. Fisher 344 rats were studied: young females (YF, n = 38), young males (YM, n = 29), old females (OF, n = 33), and old males (OM, n = 30). Isolated mesenteric resistance arteries (endothelium-intact or denuded) were pressurized, and outer diameter was monitored. Dose-response curves were performed to KCl and phenylephrine (PE). EFS (0.1-16 Hz) responses were expressed as percentage of constriction from baseline. Area under the curve (AUC) was calculated and comparisons were made using analysis of variance and t tests. Females became less responsive to EFS-induced constriction with age, whereas constrictor responses among males were unaffected (AUC: YF = 454 +/- 15, OF = 284 +/- 22, p < 0.001; YM = 391 +/- 35, OM = 357 +/- 31, p = 0.22). Endothelial denudation produced a significant increase in EFS-induced constriction in OF and OM. Endothelium removal in OF increased the EFS constrictor response to the level seen in arteries from YF. BQ 123 (ET(A) receptor antagonist) significantly decreased EFS-induced constriction in YM and OM. In YM, SQ 29,548 [thromboxane A(2) (TXA(2))/PGH(2) receptor antagonist] and indomethacin depressed constrictor responses. There were no differences among groups in the sensitivity to KCl, but YF were the most sensitive to PE. In conclusion, EFS-induced vasoconstriction declined with age among females but not males. The decrease in EFS constrictor responses in OF may be due to a selective decrease in vascular smooth muscle sensitivity to adrenergic agonists and an increase in the production of an endothelium-derived vasodilator. Among males there is also an endothelin-1 and TXA(2)/PGH(2) component to EFS-induced constriction that is absent among females.


[The clinico-radiographic picture of pulmonary-pleural complications in sepsis].
Proceeding from the investigation and therapy of 106 patients with pleuropulmonary complications of sepsis the authors described clinical and x-ray features of different types of their course, complications and outcomes. In 58% of cases pulmonary lesions were detected at the stage of pyodestruction and pleural empyema; interstitial-focal and infiltrative pneumonias of considerable spreading with the development of a respiratory type of septic shock were observed less frequently. Pulmonary lesions in 24% were the only sign of septicopyemia, in 58% they prevailed in the clinical picture of polyorganic lesions; pleural complications developed in 32% of the patients. Convalescence was observed in 88 (83%) patients; they had residual bullous-sclerotic pulmonary changes. The lethality rate was 17%.


Experimental evidence for a new transmission route in a parasitic mite and its mucus-dependent orientation towards the host snail.
The route of transmission and host finding behaviour are fundamental components of a parasite's fitness. Riccardoella limacum, a haematophagous mite, lives in the mantle cavity of helicid land snails. To date it has been assumed that this parasitic mite is transmitted during courtship and mating of the host. Here we present experimental evidence for a new transmission route in the host snail Arianta arbustorum. Parasite-free snails were kept on soil on which previously infected host snails had been maintained for 6 weeks. R. limacum was successfully transmitted via soil without physical contact among hosts in 10 out of 22 (45.5%) cases. In a series of experiments we also examined the off-host locomotion of R. limacum on snail mucus and control substrates using an automated camera system. Parasitic mites showed a preference to move on fresh mucus. Our results support the hypothesis that R. limacum uses mucus trails to locate new hosts. These findings should be considered in commercial snail farming and when examining the epidemiology of wild populations.


Spiritual expression and immune status in women with metastatic breast cancer: an exploratory study.
This exploratory study examined relationships between spirituality and immune function in 112 women with metastatic breast cancer. Spirituality was assessed by patient reports of frequency of attendance at religious services and importance of religious or spiritual expression. White blood cell counts, absolute numbers of lymphocytes, T-lymphocyte subsets, and natural killer cells were assessed by flow cytometry. Assessments of natural killer cell activity and delayed-type hypersensitivity responses to skin test antigens provided two measures of functional immunity. In analyses controlling for demographic, disease status, and treatment variables, women who rated spiritual expression as more important had greater numbers of circulating white blood cells and total lymphocyte counts. Upon examination of relationships with lymphocyte subsets, both helper and cytotoxic T-cell counts were greater among women reporting greater spirituality.


Effects of Habitat Partitioning on the Distribution of Bacterioplankton in Deep Lakes.
In deep lakes, many investigations highlighted the existence of exclusive groups of bacteria adapted to deep oxygenated and hypoxic and anoxic hypolimnia. Nevertheless, the extent of bacterial strain diversity has been much less scrutinized. This aspect is essential for an unbiased estimation of genetic variation, biodiversity, and population structure, which are essential for studying important research questions such as biogeographical patterns, temporal and spatial variability and the environmental factors affecting this variability. This study investigated the bacterioplankton community in the epilimnetic layers and in the oxygenated and hypoxic/anoxic hypolimnia of five large and deep lakes located at the southern border of the Alps using high throughput sequencing (HTS) analyses (16S rDNA) and identification of amplicon sequence variants (ASVs) resolving reads differing by as little as one nucleotide. The study sites, which included two oligomictic (Garda and Como) and three meromictic lakes (Iseo, Lugano, and Idro) with maximum depths spanning from 124 to 410 m, were chosen among large lakes to represent an oxic-hypoxic gradient. The analyses showed the existence of several unique ASVs in the three layers of the five lakes. In the case of cyanobacteria, this confirmed previous analyses made at the level of strains or based on oligotyping methods. As expected, the communities in the hypoxic/anoxic monimolimnia showed a strong differentiation from the oxygenated layer, with the exclusive presence in single lakes of several unique ASVs. In the meromictic lakes, results supported the hypothesis that the formation of isolated monimolimnia sustained the development of highly diversified bacterial communities through ecological selection, leading to the establishment of distinctive biodiversity zones. The genera identified in these layers are well-known to activate a wide range of redox reactions at low O2 conditions. As inferred from 16S rDNA data, the highly diversified and coupled processes sustained by the monimolimnetic microbiota are essential ecosystem services that enhance mineralization of organic matter and formation of reduced compounds, and also abatement of undesirable greenhouse gasses.


Role of catecholaminergic and cyclic AMP systems in psychological dependence on phencyclidine: a study in mutant mice.
Catecholaminergic and/or cyclic AMP (cAMP) systems have been demonstrated to be involved in the development of drug dependence. We investigated the involvement of both systems in psychological dependence on phencyclidine (PCP) by using tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg once a day for 28 days). In these mice, the level of cAMP in the striatum, but not in the thalamus, was increased one day after the last injection of PCP (10 mg/kg). In TH+/- and CBP+/- mice pretreated with PCP (10 mg/kg per day for 28 days), however, no PCP (8 mg/kg)-induced place preference was observed. The level of cAMP in the striatum was increased in CBP+/- mice, but not TH+/- mice. Furthermore, we have demonstrated that the place preference induced by PCP is attenuated by 6-hydroxydopamine, a dopaminergic neurotoxin, and (+) SCH-23390, a dopamine-D1 receptor antagonist, but not by DSP-4, a noradrenergic neurotoxin, and (-) sulpiride, a dopamine-D2 receptor antagonist. These findings suggest that catecholamines and CBP are involved in the development of psychological dependence on PCP and that changes in dopaminergic and/or cAMP systems induced by repeated PCP treatment play an important role in the addiction to PCP.


Suicides in Beijing, China, 1992-1993.
Analyzing the raw data of suicides reported to the Beijing Public Security Bureau in 1992 and 1993, this study reveals for the first time to the academic public in the West the rate, gender difference, the timing, causes, and means of Chinese suicides. In comparison with suicide patterns in Western societies, mainly reported by Durkheim (1897/1951), Diekstra (1990) and the National Center for Health Statistics (1991), the findings of this study suggest more differences than similarities. The comparatively low suicide rate (4.8 per 100,000 population), the reversed gender effect (55.4% of suicides are female and 44.6% male), alleged causes, and reported means of suicides in China are explained in terms of history, culture, and social forces. However, the direct relationship of warm seasons to Chinese suicide rates is consistent with what is known about Western societies.