The implications of blood pressure targets from the 2018 European Society of Cardiology hypertension guidelines in Asian patients: a systematic review and meta-analysis.
The evidence for optimal blood pressure (BP) targets in Asian patients with hypertension is insufficient and controversial. Western guidelines should be used with caution in clinical practice until there is supporting evidence. Systematically synthesize the evidence on the efficacy of achieving the strict 2018 European Society of Cardiology (ESC) guideline BP targets versus standard BP targets in Asian patients. We searched PubMed, Web of Science, Scopus, the Cochrane Central Register of controlled trials, and additional databases to retrieve relevant Asian studies. Randomized controlled trials (RCTs) and observational studies that reported clinical endpoints, had a minimal follow-up period of one year and included Asian patients older than 18 years with essential hypertension. Two investigators independently conducted the study selection with any discrepancies resolved between team members. We selected 15 studies for analysis (4 RCTs, 7 observational studies, and 4 post-hoc analyses). The evidence for the strict BP targets in elderly patients was insufficient. In middle-aged patients, the meta-analysis of observational studies revealed a significant reduction in major adverse cardiac events (MACCE) (hazard ratio (HR)=0.78; 95% confidence interval (CI: 0.74-0.81). For studies that reported results for patients of any age, the tight systolic BP-lowering therapy was associated with a decrease in MACCE (HR=0.80; 95% CI: 0.69-0.92), stroke (HR=0.82; 95% CI: 0.71-0.94), but not in cardiac events (HR=0.91; 95% CI: 0.72-1.14, P=.41), all-cause (HR=0.80; 95% CI: 0.57-1.13) and cardiovascular mortality (HR=0.73; 95% CI: 0.40-1.33, P=.30). Similar findings were obtained for the strict diastolic BP targets. Our findings provide evidence for Asian patients that support the efficacy of the strict antihypertensive treatment with BP targets proposed by the 2018 ESC hypertension guidelines for the prevention of cardiovascular events. However, these data were obtained from only observational studies and the results were not confirmed by RCTs, probably due to insufficient power. Therefore, further high-quality RCTs are crucial. Use of aggregated data, the subgroup and meta-regression analyses are inconclusive, limited to English language, unable to estimate summary measures for some outcomes, publication bias difficult to assess, and unclear that results could be extrapolated. The protocol registered in PROSPERO (CRD42018115570). None.


Positive effects of oral β-glucan on mucositis and leukopenia in colorectal cancer patients receiving adjuvant FOLFOX-4 combination chemotherapy.
The present study aimed to determine the effect of oral β-glucan on mucositis and leukopenia in 62 consecutive patients with colorectal cancer treated with an adjuvant FOLFOX-4 regimen. The patients were retrospectively evaluated in 2 groups: one group received β-glucan and the other did not (control group). Leucocytes, neutrophils, and platelets were evaluated before and 1 week after chemotherapy and oral mucositis and diarrhea were noted. Leucocyte and neutrophil counts after chemotherapy in the β-glucan group were 7,300/mm3 and 3,800/mm3, respectively, and the reductions, as compared to baseline, were not significant (p=0.673 and 0.784). The median platelet count was 264,000/mm3 after chemotherapy in the β-glucan group and the reduction, as compared to baseline, was borderline significant (p=0.048). In the control group, reduction in leucocyte, neutrophil, and platelet counts was statistically significant. Oral mucositis and diarrhea were less common in the β-glucan group. We conclude that β-glucan can be used to reduce the adverse effects of chemotherapy.


Identifying priorities for the collection and use of data related to community first response and out-of-hospital cardiac arrest: protocol for a nominal group technique study.
Introduction: Out-of-hospital cardiac arrest (OHCA) is a devastating health event that affects over 2000 people each year in Ireland. Survival rate is low, but immediate intervention and initiation of cardiopulmonary resuscitation (CPR) and administration of an automated external defibrillator (AED) can increase chances of survival. It is not always possible for the emergency medical services (EMS) to reach OHCA cases quickly. As such, volunteers, including lay and professional responders (e.g. off-duty paramedics and fire-fighters), trained in CPR and AED use, are mobilised by the EMS to respond locally to prehospital medical emergencies (e.g. OHCA and stroke). This is known as community first response (CFR). Data on the impact of CFR interventions are limited. This research aims to identify the most important CFR data to collect and analyse, the most important uses of CFR data, as well as barriers and facilitators to data collection and use. This can inform policies to optimise the practice of CFR in Ireland. Methods: The nominal group technique (NGT) is a structured consensus process where key stakeholders (e.g. CFR volunteers, clinicians, EMS personnel, and patients/relatives) develop a set of prioritised recommendations. This study will employ the NGT, incorporating an online survey and online consensus meeting, to develop a priority list for the collection and use of CFR data in Ireland. Stakeholder responses will also identify barriers and facilitators to data collection and use, as well as indicators that improvements to these processes have been achieved. The maximum sample size for the NGT will be 20 participants to ensure sufficient representation from stakeholder groups. Discussion: This study, employing the NGT, will consult key stakeholders to establish CFR data collection, analysis, and use priorities. Results from this study will inform CFR research, practice, and policy, to improve the national CFR service model and inform international response programs.


Water extract of earthworms mitigates mouse liver fibrosis by potentiating hepatic LKB1/Nrf2 axis to inhibit HSC activation and hepatocyte death.
When left untreated, liver fibrosis (LF) causes various chronic liver diseases. Earthworms (Pheretima aspergillum) are widely used in traditional medicine because of their capacity to relieve hepatic diseases. This study aimed to explore the anti-LF effects of water extract of earthworms (WEE) and the underlying molecular mechanisms. A CCl4-induced mouse model of LF was used to study the impact of WEE on LF in vivo. The anti-LF activity of WEE in mice was compared with that of silybin, which can be clinically applied in LF intervention and was used as a positive control. Activation of LX-2 hepatic stellate cells (HSCs) and apoptosis and ferroptosis of AML-12 hepatocytes induced by TGFβ1 were used as in vitro models. WEE drastically improved LF in mice. WEE reduced markers of activated HSCs in mice and inhibited TGFβ1-induced activation of LX-2 HSCs in vitro. Additionally, WEE suppressed CCl4-induced apoptosis and ferroptosis in mouse hepatocytes. Mechanistically, WEE induced Nrf2 to enter the nuclei of the mouse liver cells, and the hepatic levels of Nrf2-downstream antioxidative factors increased. LKB1/AMPK/GSK3β is an upstream regulatory cascade of Nrf2. In the LF mouse model, WEE increased hepatic phosphorylated LKB1, AMPK, and GSK3β levels. Similar results were obtained for the LX-2 cells. In AML-12 hepatocytes and LX-2 HSCs, WEE elevated intracellular Nrf2 levels, promoted its nuclear translocation, and inhibited TGFβ1-induced ROS accumulation. Knocking down LKB1 abolished the impact of WEE on the AMPK/GSK3β/Nrf2 cascade and eliminated its protective effects against TGFβ1. Our findings reveal that WEE improves mouse LF triggered by CCl4 and supports its application as a promising hepatoprotective agent against LF. The potentiation of the hepatic antioxidative AMPK/GSK3β/Nrf2 cascade by activating LKB1 and the subsequent suppression of HSC activation and hepatocyte apoptosis and ferroptosis are implicated in WEE-mediated alleviation of LF.


Optical micromanipulation using supercontinuum Laguerre-Gaussian and Gaussian beams.
We characterize a single beam supercontinuum "white light" trap and determine the trap stiffness in the transverse trapping plane. We realize a holographic white light trapping system using a spatial light modulator, and explore the generation of a dual beam trap and characterize its performance. We also demonstrate optical trapping and rotation of particles using a supercontinuum vortex beam. It is shown that orbital angular momentum can be transferred to spheres trapped in a supercontinuum vortex. Quantified rotation rates are demonstrated.


An exploratory study of end-of-life prognostic communication needs as reported by widowed fathers due to cancer.
Effective physician communication about prognosis is a critical aspect of quality care for families affected by terminal illness. This is particularly important for spousal caregivers of terminally ill parents of dependent children, who may have unique needs for communication about anticipated death. The objective of this study was to explore end-of-life prognostic communication experiences reported by bereaved fathers whose wives died from cancer. From October 2012 to November 2013 we surveyed widowed fathers whose wives died from cancer through an open-access educational website. The survey included the following open-ended questions regarding prognostic communication: 'What is the most important thing you would like us to know about whether/how your wife's doctors communicated with you about her anticipated death? What do you wish had been different, if anything?' We performed traditional content analysis of responses. Two researchers coded and categorized the data. Two hundred forty-four men responded to the survey questions on prognostic communication. Major themes addressed by respondents were the importance of clear and honest communication and physician bedside manner. They also identified unmet information needs, including wanting to know prognosis sooner. Relevant sub-themes included death coming as a surprise, avoidance, and caregiver regret. Surviving spouses due to cancer can provide important insights for health care providers about optimum prognostic communication at the end of life. Increased physician attention to the communication preferences of both patients and their partners may improve bereavement outcomes for family members.


[Selected research problems of anthrax vaccine development].
The threat of bioterrorism with B. anthracis against civilian population is one of major concern. After successful bioterroristic attack in 2001 in US renewed research interest has prompted in the development of new and more effective vaccine against anthrax. There are two licensed vaccines against anthrax--AVA-Bio-Thrax US and UK--sterile culture filtrate prepared by alum precipitation. Both vaccines are based on PA antigen. There are several concerns regarding PA based vaccines. They require six sc injections and yearly booster, high rates of local reaction after vaccination is observed, the immunity is not long lasting, vaccination do not protect animals against different strains of B. anthracis. New strategies in the development of anthrax vaccines have been presented (recombinant PA, subunits vaccine, mutants, conjugated). Using proteomic approaches new antigens have been also identified as candidates for future vaccines. More effective and easy to perform methods of vaccination have been reviewed.


IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.


Midaortic syndrome in neurofibromatosis type 1 resulting in bilateral renal artery stenosis.
We describe the case of a 23-year-old white woman with a long history of hypertension. She was referred to us 7 years after her initial diagnosis of hypertension when her blood pressure control worsened during pregnancy. Clinical examination showed an abdominal bruit and weak femoral pulses. Imaging showed midaortic syndrome with bilateral renal artery stenosis as the cause of her hypertension, and further investigations showed neurofibromatosis type 1 as the underlying disorder. Midaortic syndrome, a rare disorder of the abdominal aorta that is different from classic coarctation, typically is associated with neurofibromatosis. Renal artery stenosis is common, as are weak femoral pulses and impaired development of the lower limbs. Because of the rarity of this syndrome, only anectodal evidence exists with regard to treatment. Surgery and interventional treatment with stent placement in the abdominal aorta have been reported, as well as good outcomes with long-term medical management. Our patient continues to be healthy without intervention, with reasonable blood pressure control and normal kidney function on a 4-drug antihypertensive regimen. We discuss midaortic syndrome with a focus on diagnosis, differential diagnosis, associated conditions, and management. Nephrologists, radiologists, and ultrasonographers should be aware of this rare cause of renovascular hypertension.


The efficacy of oral and subcutaneous antigen-specific immunotherapy in murine cow's milk- and peanut allergy models.
Antigen-specific immunotherapy (AIT) is a promising therapeutic approach for both cow's milk allergy (CMA) and peanut allergy (PNA), but needs optimization in terms of efficacy and safety. Compare oral immunotherapy (OIT) and subcutaneous immunotherapy (SCIT) in murine models for CMA and PNA and determine the dose of allergen needed to effectively modify parameters of allergy. Female C3H/HeOuJ mice were sensitized intragastrically (i.g.) to whey or peanut extract with cholera toxin. Mice were treated orally (5 times/week) or subcutaneously (3 times/week) for three consecutive weeks. Hereafter, the acute allergic skin response, anaphylactic shock symptoms and body temperature were measured upon intradermal (i.d.) and intraperitoneal (i.p.) challenge, and mast cell degranulation was measured upon i.g. challenge. Allergen-specific IgE, IgG1 and IgG2a were measured in serum at different time points. Single cell suspensions derived from lymph organs were stimulated with allergen to induce cytokine production and T cell phenotypes were assessed using flow cytometry. Both OIT and SCIT decreased clinically related signs upon challenge in the CMA and PNA model. Interestingly, a rise in allergen-specific IgE was observed during immunotherapy, hereafter, treated mice were protected against the increase in IgE caused by allergen challenge. Allergen-specific IgG1 and IgG2a increased due to both types of AIT. In the CMA model, SCIT and OIT reduced the percentage of activated Th2 cells and increased the percentage of activated Th1 cells in the spleen. OIT increased the percentage of regulatory T cells (Tregs) and activated Th2 cells in the MLN. Th2 cytokines IL-5, IL-13 and IL-10 were reduced after OIT, but not after SCIT. In the PNA model, no differences were observed in percentages of T cell subsets. SCIT induced Th2 cytokines IL-5 and IL-10, whereas OIT had no effect. We have shown clinical protection against allergic manifestations after OIT and SCIT in a CMA and PNA model. Although similar allergen-specific antibody patterns were observed, differences in T cell and cytokine responses were shown. Whether these findings are related to a different mechanism of AIT in CMA and PNA needs to be elucidated.


Gambling involvement and drug use among adolescents.
The literature on youth gambling often notes the relationship of gambling involvement to drug use. The extent of this association and its importance toward advancing knowledge about the origins and course of adolescent gambling are discussed. The authors contend that (a) adolescent gambling, like drug use, may be a normal part of adolescence from a statistical perspective, (b) claims that the prevalence rate of problem/pathological gambling is comparable or higher than the rate of substance use disorders are not supportable at this time given the weaker methodological studies in the gambling area, (c) while research suggests that similar risk factors may be important determinants for both behavior domains, prospective studies of adolescent development are needed to further clarify which factors are unique and common to adolescent gambling, and (d) greater documentation of the harm associated with adolescent gambling is a major barrier to garnering more prevention and treatment resources for this issue.


[Risk stratification in selective surgery of abdominal aortic aneurysm].
A retrospective analysis of data of 188 patients, who underwent a selective surgery for abdominal aortic aneurism showed, that all the patients had a cardiac pathology. Ischemic heart disease and arterial hypertension had 175 (93.0%) and 177 (94.1%) of patients, respectively. Chronic nonspecific lung disease was noted in 65.4% patients and kidney disease--in 48.9%. Different complications developed in early postoperative period in 47 (25%) patients, that resulted in fatal outcome in 20(10,6%). The most frequent complication was an acute renal insufficiency, which led to fatal outcome in 40% patients. Myocardial infarction and pneumonia took the second place in the structure of postoperative complications, one half of the fatal cases was due to these. Retrospective risk stratification assessment of the development of early postoperative complications and lethality was made by Glasgow Aneurysm Score (GAS) and angiosurgical model scale V-POSSUM. It was stated, that score was up to 84 according to GAS scale and up to 28 (V-POSSUM). That fact is the evidence of high risk of the operation. On the basis of ROC curves building, the conclusion was made about greater predictive ability of V-POSSUM scoring system.


Abnormalities of the complement system in Reye syndrome.
Sixteen patients with Reye syndrome had diminished concentration of serum complement proteins and/or hemolytic activity in the earliest blood sample. All 12 studied with hemolytic methods had significantly reduced C1 activity; total hemolytic complement activity was reduced in only three. Low Cl activity was accompanied by equivalent reduction of Cls in 11 of 12 patients; Clq was less than normal in only two of 12. Decreased levels of at least one other classical pathway complement hemolytic activity or protein concentration were found in 13 patients, whereas factor B or the alternate complement pathway was normal or elevated in the ten patients studied. The consistent reduction of Cls protein concentration in Reye syndrome suggests that early metabolic abnormalities regularly affect the production or catabolism of this protein. Although normal serum Clq concentration in the majority of these patients does not support an immune pathogenesis, decreased Clq, C4, and C2 in three patients does suggest that immune mechanisms may be responsible for the serum complement abnormalities in this latter group of patients.


The kinetics of clearance of human antibody/dsDNA immune complexes from rabbit circulation. Effects of dsDNA size, rheumatoid factor, and reduction and alkylation of the antibodies.
We have conducted in vivo investigations of the rate of clearance of prepared antibody/dsDNA immune complexes from the circulation of rabbits and have correlated the results with some in vitro immunologic properties of the complexes. Those complexes that fix complement most efficiently in vitro (as manifested by their complement-mediated binding to human red blood cells or rabbit platelets) are cleared most rapidly. Factors that decrease this binding such as reduction and alkylation of the antibodies or the use of dsDNA of a lower m.w. also tend to prolong the circulation times for the complexes. This study provides additional evidence in support of a complement-mediated platelet immune complex clearance mechanism in non-primates that parallels the erythrocyte immune complex clearance mechanism in primates first described by He bert. Finally, the implications of our findings with respect to the importance of dsDNA size in the pathogenesis of systemic lupus erythematosus are discussed.


Paired gill slits in a fossil with a calcite skeleton.
The chordates, hemichordates (such as acorn worms) and echinoderms (such as starfish) comprise the group Deuterostomia, well established as monophyletic. Among extant deuterostomes, a skeleton in which each plate has the crystallographic structure of a single crystal of calcite is characteristic of echinoderms and is always associated with radial symmetry and never with gill slits. Among fossils, however, such a skeleton sometimes occurs without radial symmetry. This is true of Jaekelocarpus oklahomensis, from the Upper Carboniferous of Oklahoma, USA, which, being externally almost bilaterally symmetrical, is traditionally placed in the group Mitrata (Ordovician to Carboniferous periods, 530-280 million years ago), by contrast with the bizarrely asymmetrical Cornuta (Cambrian to Ordovician periods, 540 to 440 million years ago). Using computer X-ray microtomography, we describe the anatomy of Jaekelocarpus in greater detail than formerly possible, reveal evidence of paired gill slits internally and interpret its functional anatomy. On this basis we suggest its phylogenetic position within the deuterostomes.


Evaluation of the applicability of the SWAT model in an arid piedmont plain oasis.
Hetao Oasis is located in a typical piedmont alluvial plain bounded by the Langshan Mountain Range in the north, desert in the west, and the Yellow River in the south. Agricultural activities within the oasis significantly impact the hydrological cycle and water quality in downstream locations. The research uses the Soil and Water Assessment Tool (SWAT) for a piedmont plain by defining the watershed boundary as coinciding with the natural mountain ridge, the border between the oasis and the desert, and the Yellow River. The model simulates water discharge with coefficient of determination and a Nash-Sutcliffe model efficiency of 0.78 and 0.62 during model calibration, and 0.75 and 0.69 during model validation, suggesting that delineation of the watershed as carried out in this research is suitable for piedmont plain topography. From the results, the mountains contribute 28.4% to the water discharge at the outlet of the watershed, and water-use efficiency of irrigated water is about 40%, which is consistent with field-based measurements. Methodologies used in delineating watershed boundaries and parameterizing SWAT provide a solid foundation for water balance studies in other regions of the world with similar topography.


The up-to-date pathophysiology of Kawasaki disease.
Kawasaki disease (KD) is an acute systemic vasculitis of an unknown aetiology. A small proportion of children exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or infected by Yersinia reproducibly develop principal symptoms of KD in various ethnic areas, but not in all studies. These microbes provoke a rapid cell-damaging process, called 'pyroptosis', which is characterised by a subsequent release of proinflammatory cellular components from damaged endothelial and innate immune cells. In agreement with these molecular events, patients with KD show elevated levels of damage-associated molecular patterns derived from cell death. In addition, an overwhelming amount of oxidative stress-associated molecules, including oxidised phospholipids or low-density lipoproteins, are generated as by-products of inflammation during the acute phase of the disease. These molecules induce abnormalities in the acquired immune system and activate innate immune and vascular cells to produce a range of proinflammatory molecules such as cytokines, chemokines, proteases and reactive oxygen species. These responses further recruit immune cells to the arterial wall, wherein inflammation and oxidative stress closely interact and mutually amplify each other. The inflammasome, a key component of the innate immune system, plays an essential role in the development of vasculitis in KD. Thus, innate immune memory, or 'trained immunity', may promote vasculitis in KD. Hence, this review will be helpful in understanding the pathophysiologic pathways leading to the development of principal KD symptoms and coronary artery lesions in patients with KD, as well as in subsets of patients with SARS-CoV-2 and Yersinia infections.


Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study.
To identify if gestational diabetes mellitus (GDM) is a clinically useful marker of future cardiovascular disease (CVD) risk and if GDM combined with other risks (smoking, hypertension or body mass) identifies high-risk groups. Population-based matched case-control study. National Swedish register data from 1991 to 2008. A total of 2639 women with a cardiovascular event and matched controls. Conditional logistic regression examined associations with CVD before and after adjustment for conventional risk factors and confounders. Effect modification for the association of GDM with CVD by body mass index (BMI), smoking and chronic hypertension was assessed by stratification and interaction testing. Adjustment for diabetes post-pregnancy evaluated its mediating role. Inpatient diagnoses or causes of death identifying ischemic heart disease, ischemic stroke, atherosclerosis or peripheral vascular disease. The adjusted odds ratios (and 95% confidence intervals) for the association of CVD with GDM are 1.51 (1.07-2.14), 2.23 (2.01-2.48) for smoking, 1.98 (1.71-2.29) for obesity and 5.10 (3.18-8.18) for chronic hypertension. In stratified analysis the association of CVD with GDM was only seen among women with BMI ≥25, with an odds ratio of 2.39 (1.39-4.10), but only women with a BMI <30 accounted for this increased risk. Adjustment for post-pregnancy diabetes attenuated it somewhat to 1.99 (1.13-3.52). In the absence of other recognised cardiovascular risk factors, such as smoking, obesity or chronic hypertension, GDM is a useful marker of raised CVD risk among women with BMI between 25 and 29.


Impaired cellular responses to cytosolic DNA or infection with Listeria monocytogenes and vaccinia virus in the absence of the murine LGP2 protein.
Innate immune signaling is crucial for detection of and the initial response to microbial pathogens. Evidence is provided indicating that LGP2, a DEXH box domain protein related to the RNA recognition receptors RIG-I and MDA5, participates in the cellular response to cytosolic double-stranded DNA (dsDNA). Analysis of embryonic fibroblasts and macrophages from mice harboring targeted disruption in the LGP2 gene reveals that LGP2 can act as a positive regulator of type I IFN and anti-microbial gene expression in response to transfected dsDNA. Results indicate that infection of LGP2-deficient mice with an intracellular bacterial pathogen, Listeria monocytogenes, leads to reduced levels of type I IFN and IL12, and allows increased bacterial growth in infected animals, resulting in greater colonization of both spleen and liver. Responses to infection with vaccinia virus, a dsDNA virus, are also suppressed in cells lacking LGP2, reinforcing the ability of LGP2 to act as a positive regulator of antiviral signaling. In vitro mechanistic studies indicate that purified LGP2 protein does not bind DNA but instead mediates these responses indirectly. Data suggest that LGP2 may be acting downstream of the intracellular RNA polymerase III pathway to activate anti-microbial signaling. Together, these findings demonstrate a regulatory role for LGP2 in the response to cytosolic DNA, an intracellular bacterial pathogen, and a DNA virus, and provide a plausible mechanistic hypothesis as the basis for this activity.


Nonrigid image registration in shared-memory multiprocessor environments with application to brains, breasts, and bees.
One major problem with nonrigid image registration techniques is their high computational cost. Because of this, these methods have found limited application to clinical situations where fast execution is required, e.g., intraoperative imaging. This paper presents a parallel implementation of a nonrigid image registration algorithm. It takes advantage of shared-memory multiprocessor computer architectures using multithreaded programming by partitioning of data and partitioning of tasks, depending on the computational subproblem. For three different biomedical applications (intraoperative brain deformation, contrast-enhanced MR mammography, intersubject brain registration), the scaling behavior of the algorithm is quantitatively analyzed. The method is demonstrated to perform the computation of intra-operative brain deformation in less than a minute using 64 CPUs on a 128-CPU shared-memory supercomputer (SGI Origin 3800). It is shown that its serial component is no more than 2% of the total computation time, allowing a speedup of at least a factor of 50. In most cases, the theoretical limit of the speedup is substantially higher (up to 132-fold in the application examples presented in this paper). The parallel implementation of our algorithm is, therefore, capable of solving nonrigid registration problems with short execution time requirements and may be considered an important step in the application of such techniques to clinically important problems such as the computation of brain deformation during cranial image-guided surgery.


Optimizing the analysis of human intestinal microbiota with phylogenetic microarray.
Phylogenetic microarrays present an attractive strategy to high-throughput interrogation of complex microbial communities. In this work, we present several approaches to optimize the analysis of intestinal microbiota with the recently developed Microbiota Array. First, we determined how 16S rDNA-specific PCR amplification influenced bacterial detection and the consistency of measured abundance values. Bacterial detection improved with an increase in the number of PCR amplification cycles, but 25 cycles were sufficient to achieve the maximum possible detection. A PCR-caused deviation in the measured abundance values was also observed. We also developed two mathematical algorithms that aimed to account for a predicted cross-hybridization of 16S rDNA fragments among different species, and to adjust the measured hybridization signal based on the number of 16S rRNA gene copies per species genome. The 16S rRNA gene copy adjustment indicated that the presence of members of the class Clostridia might be overestimated in some 16S rDNA-based studies. Finally, we show that the examination of total community RNA with phylogenetic microarray can provide estimates of the relative metabolic activity of individual community members. Complementary profiling of genomic DNA and total RNA isolated from the same sample presents an opportunity to assess population structure and activity in the same microbial community.


Nephroprotective effects of Datura metel extract in gentamicin induced mice model: biochemical and histological evidences.
Datura metel is traditionally used as a remedy for renal toxicity. However, the nephroprotection has not been scientifically validated yet. To evaluate the nephroprotective like effect of methanolic extract of D. metel in gentamicin induced mice model, mice of either sex were divided into groups. One group received normal saline as negative control. The 2nd group received gentamicin 100mg/kg for 8 days as positive control, 3rd group received 50mg/kg silymarin as standard, while the reaming groups received 100, 200 and 300 mg/kg of MEDM and gentamicin 100mg/kg, for 8 days. The blood and urine samples were collected on 9th day, animals were then dissected and whole kidneys were removed and preserved in formalin for later histological examinations. The level of serum creatinine, blood urea nitrogen, urine creatinine and urine urea were significantly (P<0.05) elevated and the renal MDA level was also elevated significantly (P<0.05) by gentamicin in mice. After the treatment of test animals with MEDM, the elevated level of serum and urine biomarkers by gentamicin were reversed by MEDM. The nephroprotective effect was found in dose dependent manner. As the MEDM significantly protected the nephrotoxicity via its antioxidant effect. The findings of our study thus proved the scientific background for the nephroprotective effect of MEDM.


Dose painting in radiotherapy for head and neck squamous cell carcinoma: value of repeated functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI.
The purpose of this work was to evaluate the potential of functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI to provide an appropriate and reliable biologic target for dose painting in radiotherapy for head and neck squamous cell carcinoma (HNSCC). Fifteen patients with locally advanced HNSCC, treated with concomitant chemoradiotherapy, were prospectively enrolled in a bioimaging protocol. Sequential PET ((18)F-FDG and (18)F-fluoromisonidazole) and MRI (T1, T2, dynamic enhanced, and diffusion-weighted sequences) were performed before, during, and after radiotherapy. Median follow-up was 30.7 mo (range, 6.3-56.3 mo); in 7 patients, disease recurred. Disease-free survival correlated negatively with the maximum tissue-to-blood (18)F-fluoromisonidazole ratio (T/B(max)) on the baseline (18)F-fluoromisonidazole scan (P = 0.04), with the size of the initial hypoxic volume (P = 0.04), and with T/B(max) on the (18)F-fluoromisonidazole scan during treatment (P = 0.02). All locoregional recurrences were within the (18)F-FDG-avid regions on baseline (18)F-FDG PET; 3 recurrences mapped outside the hypoxic volume on baseline (18)F-fluoromisonidazole PET. Lesions (primary tumor and lymph nodes) where a locoregional recurrence developed during follow-up had significantly lower apparent diffusion coefficients on diffusion-weighted MRI during week 4 of radiotherapy (0.0013 vs. 0.0018 mm(2)/s, P = 0.01) and at 3 wk after treatment (0.0014 vs. 0.0018 mm(2)/s, P = 0.01) and a significantly higher initial slope on baseline dynamic enhanced MRI (26.2 vs. 17.5/s, P = 0.03) than did lesions that remained controlled. These results confirm the added value of (18)F-FDG PET and (18)F-fluoromisonidazole PET for radiotherapy planning of HNSCC and suggest the potential of diffusion-weighted and dynamic enhanced MRI for dose painting and early response assessment.


Prevalence of antibodies anti-Bartonella henselae in western Sicily: children, blood donors, and cats.
To evaluate seroprevalence of B. henselae infection both in Sicilian children and healthy blood donors. Furthermore, circulation of Bartonella in the natural reservoir was also studied. Two hundred forty-three children, living in Sicily (Palermo), affected by various diseases, without clinical features suggesting B. henselae infection, together with 122 healthy blood donors were serologically investigated for IgG and IgM antibodies by indirect fluorescent antibody test (IFAT). One hundred twenty stray and 62 pet cats were also analyzed only for IgG. Among children 25.1% had IgG antibodies to B. henselae; 18.5% showed a titer 1:64, 2.4% 1:128, 2.4% 1:256, 0.8% 1:512, 0.4% 1:1024, and 0.4% 1:5120. Among healthy blood donors 11.4% had IgG class antibodies to B. henselae; 9.8% showed a titer 1:64 and 1.6% 1:128. All the human serum samples did not show positive results for B. henselae IgM class antibodies. Stray cats (68.3%) and pet cats (35.4%) also had IgG class antibodies to B. henselae. We demonstrated high frequency of serologic evidence of past B. henselae infection, in young Italian children, affected by various diseases, apparently free of any clinical features suggesting B. henselae infection. This observation is supported by high circulation of Bartonella in cats.


Assessment of van der Waals inclusive density functional theory methods for adsorption and selective dehydrogenation of formic acid on Pt(111) surface.
In this work, we studied the adsorption and catalytic dehydrogenation of formic acid (HCOOH) on Pt(111) surface using different van der Waals inclusive density functional theory (DFT) methods. Our results indicate that the PBE + dDsC method has the best overall performance on the description of adsorption and catalytic selectivity. We found the improved van der Waals (vdW) corrected methods (PBE + D3, PBE + TS, PBE + TS-SCS, PBE + TS/IH, PBE + MBD@rsSCS, and PBE + dDsC) and optimized vdW functionals (optPBE-vdW, optB88-vdW, and optB86b-vdW) perform well to estimate the adsorption energies of HCOOH and HCOO molecules on Pt(111) surface. The vdW-inclusive DFT approaches as well as the conventional PBE functional predict a higher activation barrier for C-H breaking by comparison of O-H breaking in the selective dehydrogenation of formic acid. However, the optimized vdW functionals evidently underestimate the rate constant of C-H breaking reaction, and then fail to describe the catalytic selectivity of the HCOOH's dehydrogenation. Both PBE + dDsC and PBE predict a similar temperature dependence of the ratio of reaction rate constants for O-H breaking versus C-H breaking, though PBE functional underestimate the adsorption energies.


Phylogenetic analysis of Ureaplasma urealyticum--support for the establishment of a new species, Ureaplasma parvum.
In this study, the phylogenetic relationships between the two biovars and 14 serovars of Ureaplasma urealyticum were studied using the sequences of four different genes or genetic regions, namely: 16S rRNA genes; 16S-23S rRNA gene spacer regions; urease gene subunits ureA, ureB, partial ureC and adjoining regions upstream of ureA, ureA-ureB spacer and ureB-ureC spacer; the 5'-ends of the multiple-banded antigen (MBA) genes. U. urealyticum genotypes, based on all four genomic sequences, could be clearly separated into two clusters corresponding with currently recognized biovars 1 and 2. Sequences were generally conserved within each biovar. However, there was heterogeneity within the 5'-end regions of the MBA genes of the four serovars of biovar 1; the sequence of serovar 3 was identical with the previously published sequence and differed by only three bases from that of serovar 14; but there were significant differences between the sequences of serovars 3 and 14 and those of serovars 1 and 6. Based on the phylogenetic analysis, support is given to previous recommendations that the two biovars of U. urealyticum be classified as distinct species, namely U. parvum and U. urealyticum for biovars 1 and 2, respectively. In the future, the relationship between the new species and clinical manifestations of ureaplasma infections should be studied.


Synostosis of the joint between the body and greater cornu of the human hyoid bone.
The structure of the joint between the body and the greater cornu in the human hyoid bone was examined histologically in 259 cadavers (16-98 years). Joints were classified into three grades based on histological observations. Grade I showed fibrocartilage without degenerative change in the marginal region of the joint. Grade II showed prominent calcification or ossification on the outer margin of the joint without fusion. Grade III showed bony fusion. Histological changes with age were revealed by a comparison of the prevalences of these three grades among individuals of three age groups: young adult (16-39 years), middle aged (40-69 years), and elderly (70+ years). The frequency of hyoid bones with diarthrodial structure of this joint was compared between the age groups. The mean age of subjects with each grade of histological changes was calculated. Results show that, with age, the proportion of Grade I decreased significantly (P < 0.05) and that of Grade III increased significantly. Joints with diarthrodial structure decreased significantly with age relative to all subjects (P < 0.05). Clefts with necrotic tissue were observed in cartilage along with progressive calcification. The mean age of subjects with the histological changes was significantly higher than that of individuals without such changes (P < 0.05). Calcification and ossification of joints were induced with age from fibrous tissue and cartilage on the outer margin of a joint. The authors suggest that the age changes in the joint between the body and greater cornu of the hyoid bone may affect the mobility of this joint and may be related to masticatory and swallowing functions.


Sandwich-type Na6B7- and Na8B7+ clusters: charge-transfer complexes, four-fold π/σ aromaticity, and dynamic fluxionality.
Boron-based clusters possess unusual structural and bonding properties owing to boron's electron-deficiency. We report on the theoretical prediction of two binary B-Na clusters, Na6B7- and Na8B7+, which assume unique sandwich geometries, featuring a perfectly planar B7 wheel and two triangular Na3 or quasi-tetrahedral Na4 ligands. Despite distinct electronegativities of B/Na, the B-Na clusters do not form typical salts. Both sandwich species are dynamically fluxional at 300 K and beyond. Two dynamic modes are observed: an in-plane rotation of the B7 wheel versus twisting of the two Na3/Na4 ligands. Their energy barriers are negligibly small. Natural bond orbital calculations show that the clusters are charge-transfer complexes [Na3]+[B7]3-[Na3]+ and [Na4]2+[B7]3-[Na4]2+, respectively. Chemical bonding analyses indicate that the B7 wheel in the clusters has 6π/6σ double aromaticity and the Na3/Na4 ligands are 2σ aromatic, collectively leading to four-fold π/σ aromaticity. The quasi-tetrahedral Na4 ligand is the simplest example of spherical aromaticity and can also be considered a superatom. Interlayer bonding in the sandwiches is greater than 20 eV, due to electrostatics, which should not be confused with weakly bound species. Four-fold π/σ aromaticity and robust interlayer ionic bonding offer uniform and dilute electron clouds over the sandwiches, facilitating their dual-mode dynamic fluxionality. The Na8B7+ cluster is also a superalkali cation.


Targeting connexin 43 prevents platelet-derived growth factor-BB-induced phenotypic change in porcine coronary artery smooth muscle cells.
We previously reported that reducing the expression of the gap junction protein connexin (Cx)43 in mice restricts intimal thickening formation after acute vascular injury by limiting the inflammatory response and the proliferation and migration of smooth muscle cells (SMCs) toward the damaged site. SMC populations isolated from porcine coronary artery exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). S-SMCs are predominant in the normal media, whereas R-SMCs are recovered in higher proportion from stent-induced intimal thickening, suggesting that they participate in the restenotic process. Here, we further investigate the relationship between connexin expression and SMC phenotypes using porcine coronary artery SMCs. Cx40 was highly expressed in normal media of porcine coronary artery in vivo, whereas Cx43 was barely detectable. In contrast, Cx40 was downregulated and Cx43 was markedly upregulated in stent-induced intimal thickening. In vitro, S-SMCs expressed Cx40 and Cx43. In R-SMCs, Cx43 expression was increased and Cx40 was absent. We confirmed that S-SMCs treated with platelet-derived growth factor-BB acquire an R phenotype. This was accompanied by an upregulation of Cx43 and a loss of Cx40. Importantly, platelet-derived growth factor-BB-induced S-to-R phenotypic change was prevented by a reduction of Cx43 expression with antisense, ie, S-SMCs retained their typical elongated appearance and the expression of alpha-smooth muscle actin, a well-known SMC differentiation marker, whereas the expression of S100A4, a typical marker of R-SMCs, was prevented. In conclusion, limiting Cx43 expression in S-SMCs prevents platelet-derived growth factor-BB-induced S-to-R modulation. This suggests that Cx43 may be an additional target for local delivery strategies aimed at reducing restenosis.


Improving outcomes in rehabilitation. A call to arms (and legs).
In rehabilitation, assessment of outcomes requires refinement of existing measurement and analysis tools. A suitable taxonomy of outcomes, risk factors, and treatment modalities must be developed to reflect the field's complexity and the multiplicity of care providers. The goal of outcomes studies is to distinguish the effects of treatment from improvement resulting from the natural course of illness. Outcomes researchers must adjust for casemix and be alert to possible selection effects. A common set of outcome measures is needed to measure disability. Those currently in use reflect both nursing home and rehabilitation care. They rely on provider information and measure patients' performance, but they do not record patients' perceptions of important components of outcomes. Current techniques for describing treatment are inadequate. Outcomes assessment must include adjustment for prognostic factors and must be measured against baseline information at the onset of treatment. Although patients' perception of care is recognized as important to outcomes assessment, patients should also play a central role in decision-making about care and in weighting the importance of the various outcomes. In an era of managed care, the major challenge for rehabilitation care is to demonstrate its cost-effectiveness. Clear and precise analysis of the salient issues and a dynamic model of outcomes measurement will facilitate this goal and will permit incorporation of new learning in this field.


Elastographic characteristics of the metacarpal tendons in horses without clinical evidence of tendon injury.
Tendon and ligament injuries are common causes of impaired performance in equine athletes. Gray-scale ultrasonography is the current standard method for diagnosing and monitoring these injuries, however this modality only provides morphologic information. Elastography is an ultrasound technique that allows detection and measurement of tissue strain, and may provide valuable mechanical information about equine tendon and ligament injuries. The purpose of this study was to determine the feasibility, reproducibility, and repeatability of elastography; and to describe elastographic characteristics of metacarpal tendons in sound horses. Nineteen legs for 17 clinically sound horses without evidence of musculoskeletal pathology were included. Elastographic images of the superficial and deep digital flexor tendons and the branches of the suspensory ligament (tendon of the interosseous muscle) were described quantitatively and qualitatively. There was no statistically significant difference between operators (P = 0.86) nor within operators (P = 0.93). For qualitative assessments, reproducibility (0.46) was moderate and repeatability (0.78) was good. Similar to human Achilles tendons, equine tendons were classified as predominantly hard using elastography. There was no statistically significant difference in stiffness of the flexor tendons (P = 0.96). No significant difference in stiffness was found with altered leg position during standing (P = 0.84) and while nonweight bearing (P = 0.61). The flexor tendons were softer when imaged in longitudinal versus transverse planes (P < 0.01) however, the suspensory branches were not (P = 0.67). Findings supported future clinical application of elastography as a noninvasive "stall-side" imaging modality for evaluation of the tendons and ligaments of the distal forelimb in horses.


[Effect of a single dose of anaprilin and corinfar on the results of the bicycle ergometric test in patients with stenocardia].
Bicycle ergometry was conducted in conjunction with the consecutive administration of the placebo, 80 mg anaprylin, 30 mg corinfar, and 80 mg anaprylin + 30 mg corinfar in patients with 2nd--4th class angina of effort. Both anaprylin and corinfar significantly raised patients' physical stress tolerance, increased the total amount of work done, and reduced the magnitude of St depression during exercise. Combined use of anaprylin and corinfar produced the greatest rise in physical stress tolerance in more favorable hemodynamic conditions. Bicycle ergometry in conjunction with anaprylin and corinfar can supply additional functional information on angina pectoris and its pathogenetic mechanisms.


In-vitro characterization of the pharmacological effects induced by (-)-α-bisabolol in rat smooth muscle preparations.
The present study deals with the pharmacological effects of the sesquiterpene alcohol (-)-α-bisabolol on various smooth-muscle preparations from rats. Under resting tonus, (-)-α-bisabolol (30-300 µmol/L) relaxed duodenal strips, whereas it showed biphasic effects in other preparations, contracting endothelium-intact aortic rings and urinary bladder strips, and relaxing these tissues at higher concentrations (600-1000 µmol/L). In preparations precontracted either electromechanically (by 60 mmol/L K(+)) or pharmacomechanically (by phenylephrine or carbachol), (-)-α-bisabolol showed only relaxing properties. The pharmacological potency of (-)-α-bisabolol was variable, being higher in mesenteric vessels, whereas it exerted relaxing activity with a lesser potency on tracheal or colonic tissues. In tissues possessing spontaneous activity, (-)-α-bisabolol completely decreased spontaneous contractions in duodenum, whereas it increased their amplitude in urinary bladder tissue. Administered in vivo, (-)-α-bisabolol attenuated the increased responses of carbachol in tracheal rings of ovalbumin-sensitized rats challenged with ovalbumin, but was without effect in the decreased responsiveness of urinary bladder strips in mice treated with ifosfamide. In summary, (-)-α-bisabolol is biologically active in smooth muscle. In some tissues, (-)-α-bisabolol preferentially relaxed contractions induced electromechanically, especially in tracheal smooth muscle. The findings from tracheal rings reveal that (-)-α-bisabolol may be an inhibitor of voltage-dependent Ca(2+) channels.


Safflower polysaccharide inhibits the proliferation and metastasis of MCF-7 breast cancer cell.
Breast cancer accounts for 22.9% of all types of cancer in females worldwide. Safflower polysaccharide (SPS) is an active fraction purified from safflower petals (Carthamus tinctorius L). The present study investigated the effects of safflower polysaccharide on the proliferation and metastasis of breast cancer cells. Cell viability was analyzed using an MTT assay following treatment of the MCF‑7 cells with increasing concentrations of SPS. The results demonstrated that the SPS compound significantly inhibited the proliferation of the MCF‑7 human breast cancer cell line and these inhibitory effects increased in a dose‑ and time‑dependent manner. The half maximal inhibitory concentration (IC50) value of SPS on breast cancer cells, following treatment for 72 h, was detected using an MTT assay and was calculated as 0.12 mg/ml. The apoptotic rate was detected using flow cytometry in the MCF‑7 human breast cancer cell line and the results revealed that SPS induced cell apoptosis. The apoptotic rate of the MCF‑7 cells treated with SPS was significantly higher compared with that of the untreated cells and increased in a dose‑dependent manner. The expression of B‑cell lymphoma 2 (Bcl‑2) was downregulated and the expression of Bcl‑2‑associated X protein was upregulated in the MCF‑7 cells treated with SPS in a time‑dependent manner. Additionally, the expression of matrix metalloproteinase‑9 was significantly reduced and the expression of tissue inhibitor of metalloproteinase‑1 was increased in the MCF‑7 human breast cancer cell treated with SPS. These results demonstrated that SPS inhibited the metastasis of MCF‑7 breast cancer cells and understanding the underlying mechanisms may provide novel strategies in breast cancer therapy.


[Incidence of the pseudo-exfoliation syndrome in enucleated eyes].
A total of 455 enucleated globes were examined for a pseudoexfoliation syndrome. The typical alterations could be diagnosed most clearly from the ciliary processes. The diagnosis is frequently missed in first examinations of routine sections. Among 323 nonselected eyes with secondary glaucoma, which had to be enucleated following painful amaurosis, pseudoexfoliation syndrome was found in 3.4%. On the other hand, in 132 eyes with intraocular tumors it was found only once. Our examinations provide indications that pseudoexfoliation syndrome possibly causes an unusually high incidence of deleterious secondary changes which render enucleation necessary.


Precision-cut liver slices of Atlantic cod (Gadus morhua): an in vitro system for studying the effects of environmental contaminants.
The Atlantic cod (Gadus morhua) is an economically important species commonly consumed by humans. The widespread distribution of cod in the North Atlantic Ocean makes it vulnerable to effluents from human activities, such as coastal industries and offshore petroleum exploration. It has been demonstrated that many effluents have adverse effects on cod reproduction and health, e.g. by disrupting endocrine signaling pathways. The liver, expressing important components of the biotransformation and the endocrine system, is one of the main target organs. Thus, reliable and reproducible in vitro systems of the liver are important for studying effects of environmental contaminants. The aim of this study was to investigate precision-cut liver slices (PCLS) as an alternative in vitro system for toxicological studies of the Atlantic cod liver. Slices of 8 mm in diameter and 250 μm thickness were prepared and cultivated from immature cod. Several analyses to measure the liver slice viability were performed: enzyme assays, histology, and morphometric analysis, all confirming cell viability for up to 72 h in culture. The liver slices were also exposed to two well-known model environmental contaminants, β-naphthoflavone (BNF) and 17α-ethynylestradiol (EE2), representing established agonists for the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER), respectively. The results showed increased transcription of the target genes cytochrome P450 1A (CYP1A) and vitellogenin (VTG), both well-established biomarkers for exposure of fish to the selected compounds. In conclusion, PCLS is a promising in vitro system for toxicological studies of cod liver cells. The liver slices are viable in culture for several days and respond to environmental contaminants in a dose- and time-specific manner.


Oral immunization with an attenuated Salmonella Gallinarum encoding the H9N2 haemagglutinin and M2 ectodomain induces protective immune responses against H9N2 infection in chickens.
H9N2, a low pathogenic avian influenza virus, causes significant economic losses in the poultry industry worldwide. Herein, we describe the construction of an attenuated Salmonella Gallinarum (SG) strain for expression and delivery of H9N2 haemagglutinin (HA) 1 (SG-HA1), HA2 (SG-HA2) and/or the conserved matrix protein 2 ectodomain (SG-M2e). We demonstrated that recombinant SG strains expressing HA1, HA2 and M2e antigens were immunogenic and safe in a chicken model. Chickens (n = 8) were vaccinated once orally with SG alone, SG-HA1, SG-HA2, SG-M2e, or mixture of SG-HA1, SG-HA2 and SG-M2e, or vaccinated once intramuscularly with an oil-adjuvant inactivated H9N2 vaccine. Our results demonstrated that vaccination with SG mutants encoding influenza antigens, administered individually or as a mixture, elicited significantly (P < 0.05) greater antigen-specific humoral and cell-mediated immune responses in chickens compared with those vaccinated with SG alone. A conventional H9N2 vaccine induced significantly (P < 0.05) greater HA1 and HA2 antibody responses than SG-based H9N2 vaccine strains, but significantly (P < 0.05) less robust M2e-specific responses. Upon challenge with the virulent H9N2 virus on day 28 post-vaccination, chickens vaccinated with either the SG-based H9N2 or conventional H9N2 vaccines exhibited comparable lung inflammation and viral loads, although both were significantly lower (P < 0.05) than in the group vaccinated with SG alone. In conclusion, our results showed that SG-based vaccination stimulated efficient immune responses against virulent H9N2. Further studies are needed to fully develop this approach as a preventive strategy for low pathogenic avian influenza viruses affecting poultry. RESEARCH HIGHLIGHTS S. gallinarum expressing HA1, HA2 and M2e antigens are immunogenic and safe. Salmonella has dual function of acting as a delivery system and as a natural adjuvant. Vaccine constructs elicit specific humoral and cell-mediated immune responses.


Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum.
Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity toward the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.


Global Impact of Peripheral Obstructive Arterial Disease in Portugal: An Eight Year Study.
Peripheral arterial disease has an important impact on morbidity/mortality. The objective of this study was to quantify the impact of this disease in Portugal during the last eight years, expressed by the volume of admissions, treatment strategies and associated morbidity and mortality. We collected data from the Diagnosis Related Group national database on primary diagnosis, procedures codes, demographic variables, a number of risk factors, and mortality of all cases admitted from 2009 to 2016 with a primary diagnosis of peripheral arterial disease coded according to the 9th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-9). In this study, peripheral arterial disease led to 27 684 hospitalisations, which corresponded to 26.7% of all admissions for vascular disease in this period. Approximately 49.9% of patients were admitted to the emergency department. The volume of procedures in patients with claudication decreased over the eight years, unlike patients with critical ischaemia, in which the number of procedures increased. Age and the presence of cardiovascular risk factors have been associated with the severity of disease, as observed in our series. Overall hospital mortality varied, being significantly higher in patients with more advanced severity of the disease. Peripheral arterial disease represents an important burden in the overall volume of admissions in Portuguese public hospitals. A large number of patients was admitted in the context of emergency.


Age-related differences in the human vitreoretinal interface.
Age-related differences in vitreoretinal adhesion were investigated in 59 human eyes from donors aged from 33 weeks of gestation to 94 years with the use of dark-field and electron microscopy of whole vitreous. In all eyes from individuals aged 21 years or older, dissection of the retina off the vitreous resulted in cleavage between the vitreous cortex and the internal limiting lamina. However, in six (40%) of 15 eyes from individuals aged 20 years or younger, the internal limiting lamina remained adherent to the vitreous cortex in an area that encompassed the macula, temporal arcades, and peripapillary posterior pole. Ultrastructural studies revealed inner portions of Müller's cells that were attached to the posterior aspect of the internal limiting lamina. These results suggested that, in youth, there is adhesion between the vitreous cortex and internal limiting lamina that is stronger than Müller's cell itself and is topographically more extensive than previously thought.


Strengthening students' well-being and nutritional balance in Grand Est (France): "Lycéen Bouge" program intervention logic
As part of a national health policy to fight excess weight and obesity, the "Lycéen Bouge" program aims to fight against social inequalities in health among adolescents by improving their well-being and nutritional balance. The aim of this article is to present the intervention logic of this program and to identify the key functions that are essential for the project to function properly and to be transferable. Data was collected through interviews with project officers, observation sessions in several high schools. A documentary analysis was also carried out. The data was then analyzed thematically, in a collaborative process with the project leader, in order to develop the program logic model. The analysis and development of the logic model identified the program's objectives and components, as well as six key functions. The key functions identified concern the format and co-construction of activities, local partnerships, high-school volunteering, social skills training and project length. In some respects, the program differs from the literature and the evidence and could therefore draw on it for improvement. These include the involvement of beneficiaries and the implementation of a comprehensive approach and a gender-sensitive approach, which would make it possible to reach more students.


Self-reported quality of life of adolescents with cerebral palsy: a cross-sectional and longitudinal analysis.
Children with cerebral palsy who can self-report have similar quality of life (QoL) to their able-bodied peers. Is this similarity also found in adolescence? We examined how self-reported QoL of adolescents with cerebral palsy varies with impairment and compares with the general population, and how factors in childhood predict adolescent QoL. We report QoL outcomes in a longitudinal follow-up and cross-sectional analysis of individuals included in the SPARCLE1 (childhood) and SPARCLE2 (adolescent) studies. In 2004 (SPARCLE1), a cohort of 818 children aged 8-12 years were randomly selected from population-based cerebral palsy registers in nine European regions. We gathered data from 500 participants about QoL with KIDSCREEN (ten domains); frequency of pain; child psychological problems (Strengths and Difficulties Questionnaire); and parenting stress (Parenting Stress Index). At follow-up in 2009 (SPARCLE2), 355 (71%) adolescents aged 13-17 years remained in the study and self-reported QoL (longitudinal sample). 76 additional adolescents self-reported QoL in 2009, providing data for 431 adolescents in the cross-sectional sample. Researchers gathered data at home visits. We compared QoL against matched controls in the general population. We used multivariable regression to relate QoL of adolescents with cerebral palsy to impairments (cross-sectional analysis) and to childhood QoL, pain, psychological problems, and parenting stress (longitudinal analysis). Severity of impairment was significantly associated (p<0·01) with reduced adolescent QoL on only three domains (Moods and emotions, Autonomy, and Social support and peers); average differences in QoL between the least and most able groups were generally less than 0·5 SD. Adolescents with cerebral palsy had significantly lower QoL than did those in the general population in only one domain (Social support and peers; mean difference -2·7 [0·25 SD], 95% CI -4·3 to -1·4). Pain in childhood or adolescence was strongly associated with low adolescent QoL on eight domains. Childhood QoL was a consistent predictor of adolescent QoL. Child psychological problems and parenting stress in childhood or their worsening between childhood and adolescence predicted only small reductions in adolescent QoL. Individual and societal attitudes should be affected by the similarity of the QoL of adolescents with and without cerebral palsy. Adolescents with cerebral palsy need particular help to maintain and develop peer relationships. Interventions in childhood to alleviate psychological difficulties, parenting stress, and especially pain, are justified for their intrinsic value and for their longer term effect on adolescent QoL. SPARCLE1 was funded by the European Union Research Framework 5 Program (grant number QLG5-CT-2002-00636), the German Ministry of Health GRR-58640-2/14, and the German Foundation for the Disabled Child. SPARCLE2 was funded by: Wellcome Trust WT086315 A1A (UK and Ireland); Medical Faculty of the University of Lübeck E40-2009 and E26-2010 (Germany); CNSA, INSERM, MiRe-DREES, and IRESP (France); Ludvig and Sara Elsass Foundation, The Spastics Society and Vanforefonden (Denmark); Cooperativa Sociale "Gli Anni in Tasca" and Fondazione Carivit, Viterbo (Italy); Göteborg University-Riksforbundet for Rorelsehindrade Barn och Ungdomar and the Folke Bernadotte Foundation (Sweden).


Endoscopic and pharmacological treatment for prophylaxis against postendoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis and systematic review.
Postendoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) is the most common complication following ERCP. We carried out a systematic review and meta-analysis of the global literature on PEP prevention to provide clinical guidance and a framework for future research in this important field. PubMed, Embase, Science Citation Index, Ovid, and the Cochrane Controlled Trials Register were searched by two independent reviewers to identify full-length, prospective, randomized controlled trials (RCTs) published up until March 2016 investigating the use of pancreatic duct stents and pharmacological agents to prevent PEP. Twelve RCTs comparing the risk of PEP after pancreatic duct stent placement (1369 patients) and 30 RCTs comparing pharmacological agents over placebo (10251 patients) fulfilled the inclusion criteria and were selected for final review and analysis. Meta-analysis showed that prophylactic pancreatic stents significantly decreased the odds of post-ERCP pancreatitis [odds ratio (OR), 0.28; 95% confidence interval (CI), 0.18-0.42]. Significant OR reduction of PEP was also observed in relation to rectal administration of diclofenac (OR, 0.24; 95% CI, 0.12-0.48) and rectal administration of indometacin (OR, 0.59; 95% CI, 0.44-0.79) compared with placebo. Subgroup analysis showed a significant reduction with bolus-administered somatostatin (OR, 0.23; 95% CI, 0.11-0.49). Subgroup analysis showed a significant reduction with bolus-administered somatostatin (OR, 0.23; 95% CI, 0.11-0.49). Pancreatic stent placement, rectal diclofenac, and bolus administration of somatostatin appear to be most effective in preventing post-ERCP pancreatitis.


Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.
RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.


Investigation of the reciprocal relationship between the expression of two gap junction connexin proteins, connexin46 and connexin43.
Connexins are the transmembrane proteins that form gap junctions between adjacent cells. The function of the diverse connexin molecules is related to their tissue-specific expression and highly dynamic turnover. Although multiple connexins have been previously reported to compensate for each other's functions, little is known about how connexins influence their own expression or intracellular regulation. Of the three vertebrate lens connexins, two connexins, connexin43 (Cx43) and connexin46 (Cx46), show reciprocal expression and subsequent function in the lens and in lens cell culture. In this study, we investigate the reciprocal relationship between the expression of Cx43 and Cx46. Forced depletion of Cx43, by tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate, is associated with an up-regulation of Cx46 at both the protein and message level in human lens epithelial cells. An siRNA-mediated down-regulation of Cx43 results in an increase in the level of Cx46 protein, suggesting endogenous Cx43 is involved in the regulation of endogenous Cx46 turnover. Overexpression of Cx46, in turn, induces the depletion of Cx43 in rabbit lens epithelial cells. Cx46-induced Cx43 degradation is likely mediated by the ubiquitin-proteasome pathway, as (i) treatment with proteasome inhibitors restores the Cx43 protein level and (ii) there is an increase in Cx43 ubiquitin conjugation in Cx46-overexpressing cells. We also present data that shows that the C-terminal intracellular tail domain of Cx46 is essential to induce degradation of Cx43. Therefore, our study shows that Cx43 and Cx46 have novel functions in regulating each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells.


Association between Primary Perioperative CEA Ratio, Tumor Site, and Overall Survival in Patients with Colorectal Cancer.
There are differences in the incidence, clinical presentation, molecular pathogenesis, and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that the perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between CEA ratio, tumor location, and overall survival (OS) among patients with CRC. We analyzed 427 patients who underwent resection for CRC at the University of Kansas Medical Center. After excluding those without pre- or post-operative CEA data, 207 patients were classified as either high (≥0.5) or low (<0.5) ratio. Primary outcomes were as follows: (1) OS stratified by CEA ratio; (2) OS stratified by tumor location; (3) OS stratified by tumor location among those with CEA elevation > 5 ng/mL at the time of recurrence. The Kaplan-Meier method was used to estimate survival rates. The median age was 62 years (inter-quartile range 51-71), 55% were male, 41% were smokers, 71% had left-sided tumors, the median pre-operative CEA was 3.1 ng/mL (inter-quartile range (IQR) 1.5-9.7), and 57% had a CEA ratio ≥0.5. The OS rates were 65.1% and 86.3% in patients with high versus low CEA ratios, respectively (log-rank p-value = 0.045). The OS rates were 64.4% and 77.3% in patients with right-sided vs. left-sided tumors, respectively (log-rank p-value = 0.5). Among patients with CEA levels greater than 5 at the time of recurrence, the OS rates were 42.9% and 43.4% in patients with right-sided vs. left-sided tumors, respectively (log-rank p-value = 0.7). There was a significantly higher survival among patients with low CEA ratios than among those with high CEA ratios. There was no difference in OS between left- versus right-sided tumors. Among patients with CEA elevation > 5 ng/mL at the time of recurrence, there was no difference in OS between left versus right-sided tumors. These findings warrant validation in a larger cohort as our sample size was limited.


A Pedagogical approach of schistosomiasis -- an experience in health education in Minas Gerais, Brazil.
The experience described here is part of an extensive program that aims to stimulate schools to develop health integrated projects from theme generators, i.e., themes that have a meaning for the community. It was developed in Jaboticatubas, a town in the metropolitan region of Belo Horizonte, capital of the state of Minas Gerais, Brazil, and the focus was schistosomiasis. The selection was based on the expressive and historical prevalence of this disease in the county, which has been known as the "capital of schistosomiasis", in a national press release since the 1960's. Schistosomiasis is also a theme pointed out by teachers as requiring more information and methodologies to work with their students, most of them living in areas of high risk of transmission. In addition, during the last years, this disease has been transmitted silently through an increasing rural tourism in that region, requiring integrated and effective control actions. The developed strategy included four schools, whose teachers, students, and families took part in the process. It emphasizes in a critical pedagogy approach, which focuses on health issues as themes that may mobilize the school community and awake the population to a work which integrates environment, health, and citizenship. The results demonstrate that teachers and students not only acquired new knowledge and methodological skills, but also gained confidence in their ability to improve their health conditions. Thus, the project promotes a critical education that can result a more permanent effect on the control of schistosomiasis as well as other benefits for the schools and for the population.


Intracranial Haemorrhage in Haemophilia Patients Is Still an Open Issue: The Final Results of the Italian EMO.REC Registry.
Background: Intracranial hemorrhage (ICH) is a highly serious event in patients with haemophilia (PWH) which leads to disability and in some cases to death. ICH occurs among all ages but is particularly frequent in newborns. Aim: The primary aim was to assess the incidence and mortality due to ICH in an Italian population of PWH. Secondary aims were to evaluate the risk factors for ICH, the role of prophylaxis, and the clinical management of patients presenting ICH. Methods: A retrospective-prospective registry was established in the network of the Italian Association of Haemophilia Centers to collect all ICHs in PWH from 2009 to 2019 reporting clinical features, treatments, and outcomes. Results: Forty-six ICHs were collected from 13 Centers. The ICHs occurred in 15 children (10 < 2 years), and in 31 adults, 45.2% of them with mild hemophilia. Overall, 60.9% patients had severe haemophilia (15/15 children). Overall ICH incidence (×1000 person/year) was 0.360 (0.270−0.480 95% CI), higher in children <2 years, 1.995 (1.110−3.442 95% CI). Only 7/46 patients, all with severe haemophilia, had received a prophylactic regimen before the ICH, none with mild. Inhibitors were present in 10.9% of patients. In adult PWHs 17/31 suffered from hypertension; 85.7% of the mild subjects and 29.4% of the moderate/severe ones (p < 0.05). ICH was spontaneous in the 69.6% with lower rate in children (46.7%). Surgery was required in 21/46 patients for cerebral hematoma evacuation. Treatment with coagulation factor concentrates for at least three weeks was needed in 76.7% of cases. ICH was fatal in 30.4% of the cases. Of the survivors, 50.0% became permanently disabled. Only one-third of adult patients received long term prophylaxis after the acute treatment. Conclusion: The results from our Registry confirm the still high incidence of ICH in infants <2 years and in adults, particularly in mild PWHs presenting hypertension and its unfavorable outcomes. The majority of PWHs were treated on-demand before ICH occurred, suggesting the important role of prophylaxis in preventing such life-threatening bleeding.


Reversible transformation between ionic liquids and coordination polymers by application of light and heat.
Reversible transformation between an ionic liquid and a coordination polymer by application of light and heat has been achieved. Ultraviolet light irradiation transforms the transparent liquid to a yellow solid; a reverse reaction occurs due to the application of heat. The transformation accompanies drastic switching of intra- and intermolecular coordination bonds of a ruthenium complex. This is a novel material conversion methodology that connects the fields of ionic liquids and coordination polymers.


The challenges of community-based research: the beauty shop stroke education project.
Public knowledge of stroke warning signs and risk factors is poor, especially in higher risk groups such as blacks. We sought to design a creative new way to educate black women by working through local beauty salons and measuring the results of the intervention. Thirty black beauticians were educated about stroke warning signs and risk factors in 2 large urban areas in the US. The beauticians then educated their clientele during appointments. Stroke knowledge gained was measured via de-identified pre- and post-intervention (at 6 weeks and 5 months) surveys that included open-ended questions. Stroke warning signs were taught using the "FAST" (Face, Arm, Speech, Time) method. There were 383 completed baseline surveys, and 318 surveys were completed at 5 months. Of the 383 women, 78% were <60 years old, 69% had some college education, 41% had hypertension, and 12% had diabetes. The percentage of women who knew 3 warning signs significantly improved from the baseline survey (40.7%) to the final survey (50.6%), and similar improvements in knowledge were seen in both study regions. There was no improvement in knowledge of 3 risk factors (16.5% versus 18.2%). After our educational intervention, 94% knew to call 911 for stroke symptoms, an 8% improvement over baseline (P=0.002). Despite the challenges of community-based research encountered within our project, we found that stroke education in the beauty shop significantly improved knowledge regarding stroke warning signs and calling 911 among a group of black women. This improvement in knowledge was sustained for at least 5 months. Knowledge of stroke risk factors, however, did not improve. The use of the beauty shop as an educational site is a novel approach to stroke education for women that can be practically applied in the community. Education regarding stroke risk factors remains a challenge that warrants further study.


Gastrointestinal and hepatic manifestations of COVID-19: A comprehensive review.
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease-2019 (COVID-19) is a global pandemic, manifested by an infectious pneumonia. Although patients primarily present with fever, cough and dyspnea, some patients also develop gastrointestinal (GI) and hepatic manifestations. The most common GI symptoms reported are diarrhea, nausea, vomiting, and abdominal discomfort. Liver chemistry abnormalities are common and include elevation of aspartate transferase, alanine transferase, and total bilirubin. Studies have shown that SARS-CoV-2 infects the GI tract via its viral receptor angiotensin converting enzyme II, which is expressed on enterocytes of the ileum and colon. Viral RNA has also been isolated from stool specimens of COVID-19 patients, which raised the concern for fecal-oral transmission in addition to droplet transmission. Although indirect evidence has suggested possible fecal-oral transmission of SARS-CoV-2, more effort is needed to establish the role of the fecal-oral transmission route. Further research will help elucidate the association between patients with underlying GI diseases, such as chronic liver disease and inflammatory bowel disease, and severity of COVID-19. In this review, we summarize the data on GI involvement to date, as well as the impact of COVID-19 on underlying GI diseases.


The Analogy between Tinnitus and Chronic Pain: A Phenomenological Approach.
Tinnitus is an auditory sensation without external acoustic stimulation or significance, which may be lived as an unpleasant experience and impact the subject's quality of life. Tinnitus loudness, which is generally low, bears no relation to distress. Factors other than psychoacoustic (such as psychological factors) are therefore implicated in the way tinnitus is experienced. The aim of this article is to attempt to understand how tinnitus can, like chronic pain, generate a 'crisis' in the process of existence, which may go as far as the collapse of the subject. The main idea put forward in the present article is that tinnitus may be compared to the phenomenon of pain from the point of view of the way it is experienced. Although the analogy between tinnitus and pain has often been made in the literature, it has been limited to a parallel concerning putative physiopathological mechanisms and has never really been explored in depth from the phenomenological point of view. Tinnitus is comparable to pain inasmuch as it is felt, not perceived: it springs up (without intention or exploration), abolishes the distance between the subject and the sensation (there is only a subject and no object), and has nothing to say about the world. Like pain, tinnitus is formless and abnormal and can alter the normal order of the world with maximum intensity. Finally, tinnitus and pain enclose the subject within the limits of the body, which then becomes in excess. Tinnitus may be a source of suffering, which affects not only the body but a person's very existence and, in particular, its deployment in time. Plans are thus abolished, so time is no longer 'secreted', it is enclosed in an eternal present. If the crisis triggered by tinnitus is not resolved, the subject may buckle and collapse (depression) when their resources for resisting are depleted. The path may be long and winding from the moment when tinnitus emerges to when it assaults existence and its eventual integration into a new existential norm where tinnitus is no longer a source of disturbance.


Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes.
Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior.


Diabetes diminishes a typical metabolite of litchi pericarp oligomeric procyanidins (LPOPC) in urine mediated by imbalanced gut microbiota.
Animal studies and clinical trials have shown that dietary polyphenols and polyphenol-rich foods can reduce the risk of type 2 diabetes (T2D) and its complications, but how diabetes regulates the metabolism of polyphenol has not been fully elucidated. This study investigated the effects of diabetes on litchi pericarp oligomeric procyanidin (LPOPC) dynamic metabolism and its major static metabolites in urine. First, a high-fat and streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rat model was established. In the diabetic rat model, elevated fasting blood glucose, severely impaired glucose tolerance test, and increased reactive oxygen species (ROS) levels in serum and the liver were observed. Subsequently, 200 mg per kg body weight of LPOPC was administrated to control and diabetic SD rats, and the gastrointestinal tract was collected at 0.5 h, 1 h, 3 h, and 6 h. The results showed that the retention time of LPOPC was not changed in our diabetic rat model. However, the gut microbiota were significantly altered, with elevated Proteobacteria and Verrucomicrobia abundance in diabetic rats and decreased short chain fatty acid (SCFA)-producing bacteria. Interestingly, after one dose of 300 mg per kg body weight LPOPC, the total antioxidant capacity of urine in diabetic rats significantly decreased. We then tested the static metabolites of LPOPC, demonstrating that epicatechin had not changed in urine in diabetic rats, but that shikimic acid was significantly reduced in urine in diabetic rats. The changes in shikimic acid may be due to the alteration of gut microbiota and elevated ROS levels in serum.


Occupational lead neurotoxicity: improvement in behavioural effects after reduction of exposure.
To evaluate critical exposure levels and the reversibility of lead neurotoxicity a group of lead exposed foundry workers and an unexposed reference population were followed up for three years. During this period, tests designed to monitor neurobehavioural function and lead dose were administered. Evaluations of 160 workers during the first year showed dose dependent decrements in mood, visual/motor performance, memory, and verbal concept formation. Subsequently, an improvement in the hygienic conditions at the plant resulted in striking reductions in blood lead concentrations over the following two years. Attendant improvement in indices of tension (20% reduction), anger (18%), depression (26%), fatigue (27%), and confusion (13%) was observed. Performance on neurobehavioural testing generally correlated best with integrated dose estimates derived from blood lead concentrations measured periodically over the study period; zinc protoporphyrin levels were less well correlated with function. This investigation confirms the importance of compliance with workplace standards designed to lower exposures to ensure that individual blood lead concentrations remain below 50 micrograms/dl.


Human pharmacology of the opioid neuropeptide dynorphin A(1-13).
We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can modulate naloxone-precipitated withdrawal effects. Such information could help determine its receptor mechanism of action and whether dynorphin is useful for treating opioid dependence. Six opioid-experienced subjects participated in a within-subject, placebo-controlled design. There were two phases, each with four test sessions. In phase 1, volunteers who were not physically dependent were administered 0, 0.1, 0.32 and 1 mg/kg dynorphin (15-min i.v. infusion) in ascending order, and subjective, observer-rated and physiological effects were monitored. Dynorphin produced brief, dose-related increases in drug effect ratings with both good and bad drug effects reported by different subjects. There were no significant changes in pupil size, respiratory rate, skin temperature, heart rate or blood pressure, These data are consistent with preclinical findings that dynorphin has a short duration of action and does not primarily exert its direct effects through mu-opioid receptors. In four separate sessions of phase 2, acute morphine pretreatment (45 mg/70 kg i.m.) was followed 15 or 18 hr later by dynorphin (0 vs. 1 mg/kg, 15-min i.v.) and then naloxone (1 or 3 vs. 10 mg/70 kg, 5-min i.v.). Under these conditions, dynorphin weakly potentiated naloxone-precipitated withdrawal. These data contrast with those of previous preclinical studies showing dependence-attenuating effects of dynorphin and fail to support its use as an antiwithdrawal agent in humans.


Ontogeny of B cells in the chicken. I. Sequential development of clonal diversity in the bursa.
The initial development and distribution of lymphocytes expressing surface IgM (sIgM) and of specific antigen-binding cells (ABC) were studied in the chicken in an attempt to gain information on the process by which B-cell diversity is generated. The antigens used were sheep erythrocytes (SE), keyhole limpet hemocyanin (KLH), and poly-L(Tyr, Glu)poly-D,L-Ala-poly-L-Lys (TGAL). The results indicate that generation of the total sIgM-positive population begins in the bursa and that specific clones of ABC develop in a fixed sequential pattern which is not influenced by either deprivation of or deliberate exposure to exogenous antigens. Cells bearing sIgM by immunofluorescence (IgM-positive cells) were detected first in the bursa on the 12th day of incubation, KLH-ABC and TGAL-ABC by the 16th day, and SE-ABC on the 18th day. The doubling time of the sIgM-positive population of bursal cells was determined to be approximately 10 h before significant antigen-independent seeding to the spleen began a few days before hatching. Clonal expansion of SE-ABC in the bursa also appeared to be antigen independent as was the initial development of SE-ABC in the blood and spleen which ceased abruptly after bursectomy at hatching. Specific ABC were observed to develop in multiple bursal follicles as small foci of ABC among the much larger total population of sIgM-positive cells within an individual follicle. Intravenously infused SE-ABC homed to the embryonic spleen but not to the bursa. The results are interpreted as favoring a hypothetical model in which individual stem cells give rise to multiple clones of B cells by a predetermined pattern of sequential expression of variable region genes.


Understanding bacteriophage specificity in natural microbial communities.
Studying the coevolutionary dynamics between bacteria and the bacteriophage viruses that infect them is critical to understanding both microbial diversity and ecosystem functioning. Phages can play a key role in shaping bacterial population dynamics and can significantly alter both intra- and inter-specific competition among bacterial hosts. Predicting how phages might influence community stability and apparent competition, however, requires an understanding of how bacteria-phage interaction networks evolve as a function of host diversity and community dynamics. Here, we first review the progress that has been made in understanding phage specificity, including the use of experimental evolution, we then introduce a new dataset on natural bacteriophages collected from the phyllosphere of horse chestnut trees, and finally we highlight that bacterial sensitivity to phage is rarely a binary trait and that this variation should be taken into account and reported. We emphasize that there is currently insufficient evidence to make broad generalizations about phage host range in natural populations, the limits of phage adaptation to novel hosts, or the implications of phage specificity in shaping microbial communities. However, the combination of experimental and genomic approaches with the study of natural communities will allow new insight to the evolution and impact of phage specificity within complex bacterial communities.


Biomarkers and the design of clinical trials in cancer.
Scientific innovation has promoted the rapid discovery and development of cancer-related biomarkers. This has fostered improved mechanistic understandings of disease biology, facilitated the development of novel targeted therapies and offers the potential to better define the natural history of a disease and to predict response to specific treatment. Clinical trials are evolving, from the use of exploratory 'correlative studies' that assist in the understanding of disease mechanisms, to the use of validated biomarkers that are integral to the design of definitive prospective studies. A rigorous process for biomarker development and validation, followed by evaluation in well-designed, prospective clinical trials that demonstrate improved patient outcomes is required for new biomarkers to change clinical practice. To date, the number of biomarkers considered clinically useful is disappointingly small because of conflicting conclusions generated from trials with practical and methodological limitations. This review will highlight several important aspects related to the design and analysis of clinical trials that incorporate a biomarker as a central component. First, we review biomarker development, how biomarkers may be used as targets and how biomarkers can influence methodology to optimize efficiency of drug development through the use of surrogate outcomes. Second, we focus on issues related to trials evaluating potential prognostic biomarkers and how the predictive properties of biomarkers may be used to determine which patients might optimally benefit from a specific intervention.


Low prevalence of inhibitor antibodies in the Canadian haemophilia population.
Annual reporting of inhibitors to factors (FVIII) and IX (FIX) to the Canadian Haemophilia Registry has suggested a lower prevalence than that published in the literature. We performed a prospective study to determine the prevalence of patients with inhibitors directed against either FVIII or FIX. Patients with inhibitors were classified as: (i) inhibitor test positive; (ii) inhibitor test negative but on immune tolerance induction (ITI); (iii) inhibitor test negative but bypass treatment recommended; or (iv) inhibitor resolved. One year later, the cohort was re-classified. The prevalence of inhibitors on 1 May, 2007 was 3.3% for haemophilia A, 0.6% for haemophilia B and 8.9% and 2.1% for severe haemophilia A and B. One year later 17 individuals gained and 11 individuals lost inhibitor status (10 of these with ITI). This study suggests that the prevalence of inhibitors in our population is lower than that was previously published. We hypothesize that this is primarily due to the increased use of ITI, but other factors may be the unselected nature of the cohort and the restriction of the study to one date thereby conforming as close as practical to the definition of prevalence rather than incidence. The classification system used in this study was easy for clinics to apply and was important in defining the population with inhibitors.