Introduction: Maternal mortality rates have more than doubled in the U.S over the last two decades, making it one of the few places in the world where maternal mortality is increasing. Differences in maternal mortalit...Introduction: Maternal mortality rates have more than doubled in the U.S over the last two decades, making it one of the few places in the world where maternal mortality is increasing. Differences in maternal mortality among certain races and ethnicities are known but few studies examine maternal mortality among immigrants. Since immigrants represent 13.7% of the U.S. population, it is essential to examine immigrant subsets to understand maternal mortality among this vulnerable population. Methods: A literature search identified 318 articles on maternal mortality and immigrants, with 12 articles from the U.S. The keywords included maternal mortality, United States, migrants, asylum seekers, immigrants, and disparities. Maternal mortality statistics were obtained from the World Health Organization and Center for Disease Control. Results: Studies analyzed in this review found an overall lower maternal mortality rate among immigrant women compared to U.S.-born women, except for Hispanic immigrant women. Black women had the highest maternal mortality rate, regardless of immigration status. Conclusion: Although the literature points to lower maternal mortality among immigrants, the data is still somewhat mixed, making it challenging to draw comprehensive conclusions. Additional research examining maternal mortality among Im/migrants in the U.S. is needed to guide future training among healthcare professionals and policymakers.展开更多
AIM: To identify definitions of cytomegalovirus(CMV) infection and intestinal disease, in inflammatory bowel disease(IBD), to determine the prevalence associated with these definitions.METHODS: We conducted a systemat...AIM: To identify definitions of cytomegalovirus(CMV) infection and intestinal disease, in inflammatory bowel disease(IBD), to determine the prevalence associated with these definitions.METHODS: We conducted a systematic review and interrogated Pub Med, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both Me SH-terms and free searches were performed. We included all types of English-language(clinical) trials concerning diagnostics and prevalence of CMV in IBD.RESULTS: The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR > 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia.CONCLUSION: We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.展开更多
Background:2015 was the target year for malaria goals set by the World Health Assembly and other international institutions to reduce malaria incidence and mortality.A review of progress indicates that malaria program...Background:2015 was the target year for malaria goals set by the World Health Assembly and other international institutions to reduce malaria incidence and mortality.A review of progress indicates that malaria programme financing and coverage have been transformed since the beginning of the millennium,and have contributed to substantial reductions in the burden of disease.Findings:Investments in malaria programmes increased by more than 2.5 times between 2005 and 2014 from US$960 million to US$2.5 billion,allowing an expansion in malaria prevention,diagnostic testing and treatment programmes.In 2015 more than half of the population of sub-Saharan Africa slept under insecticide-treated mosquito nets,compared to just 2%in 2000.Increased availability of rapid diagnostic tests and antimalarial medicines has allowed many more people to access timely and appropriate treatment.Malaria incidence rates have decreased by 37%globally and mortality rates by 60%since 2000.It is estimated that 70%of the reductions in numbers of cases in sub-Saharan Africa can be attributed to malaria interventions.Conclusions:Reductions in malaria incidence and mortality rates have been made in every WHO region and almost every country.However,decreases in malaria case incidence and mortality rates were slowest in countries that had the largest numbers of malaria cases and deaths in 2000;reductions in incidence need to be greatly accelerated in these countries to achieve future malaria targets.Progress is made challenging because malaria is concentrated in countries and areas with the least resourced health systems and the least ability to pay for system improvements.Malaria interventions are nevertheless highly cost-effective and have not only led to significant reductions in the incidence of the disease but are estimated to have saved about US$900 million in malaria case management costs to public providers in sub-Saharan Africa between 2000 and 2014.Investments in malaria programmes can not only reduce malaria morbidity and mortality,thereb展开更多
This review outlines the current knowledge on the use of enrofloxacin in veterinary medicine from biochemical mechanisms to the use in the field conditions and even resistance and ecotoxicity. The basics of biochemist...This review outlines the current knowledge on the use of enrofloxacin in veterinary medicine from biochemical mechanisms to the use in the field conditions and even resistance and ecotoxicity. The basics of biochemistry, the mechanisms of action and resistance and pharmacokinetics are presented. Then an overview of available veterinary products, their efficacy and their toxicity against target species, human and environment is provided.展开更多
Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies a...Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.展开更多
Tyrosine kinase inhibitors(TKIs)targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials,suggesting the need for combination with other drugs.We investigated the combinat...Tyrosine kinase inhibitors(TKIs)targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials,suggesting the need for combination with other drugs.We investigated the combination of FLT3 TKIs(Gilteritinib or Sorafenib),with Venetodax,a BCL-2 selective inhibitor(BCL-2i),on FLT3/ITD leukemia cells.The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples.Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment,mediated through MAPK pathway inhibition.Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2.Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2.Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1,with an increased binding of BIM to the cell death mediator BAX,leading to increased apoptosis.These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression.This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.展开更多
To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel r...To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.展开更多
Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-l...Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers.展开更多
Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections.Novel optical tissue clearing techniques enabling three-dimensional imaging of entire o...Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections.Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain.To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats.The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence.The optical clearing was compatible with conventional laboratory techniques,including retrograde labeling studies,and computational image segmentation,providing fast and precise cell quantitation.Further,optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies,tracing of intramuscular nerve branches or mapping of neurovascular networks.Given their wide-ranging applicability,rapid processing times,and low costs,tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies.All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee(49871/9)on November 9,2019.展开更多
We use submultiplicative companion matrix norms to provide new bounds for roots for a given polynomial <i>P</i>(<i>X</i>) over the field C[<i>X</i>]. From a <i>n</i>...We use submultiplicative companion matrix norms to provide new bounds for roots for a given polynomial <i>P</i>(<i>X</i>) over the field C[<i>X</i>]. From a <i>n</i>×<i>n</i> Fiedler companion matrix <i>C</i>, sparse companion matrices and triangular Hessenberg matrices are introduced. Then, we identify a special triangular Hessenberg matrix <i>L<sub>r</sub></i>, supposed to provide a good estimation of the roots. By application of Gershgorin’s theorems to this special matrix in case of submultiplicative matrix norms, some estimations of bounds for roots are made. The obtained bounds have been compared to known ones from the literature precisely Cauchy’s bounds, Montel’s bounds and Carmichel-Mason’s bounds. According to the starting formel of <i>L<sub>r</sub></i>, we see that the more we have coefficients closed to zero with a norm less than 1, the more the Sparse method is useful.展开更多
In this article, we consider the construction of a SVIR (Susceptible, Vaccinated, Infected, Recovered) stochastic compartmental model of measles. We prove that the deterministic solution is asymptotically the average ...In this article, we consider the construction of a SVIR (Susceptible, Vaccinated, Infected, Recovered) stochastic compartmental model of measles. We prove that the deterministic solution is asymptotically the average of the stochastic solution in the case of small population size. The choice of this model takes into account the random fluctuations inherent to the epidemiological characteristics of rural populations of Niger, notably a high prevalence of measles in children under 5, coupled with a very low immunization coverage.展开更多
In this paper, we analyze the quasi-stationary distribution of the stochastic <em>SVIR</em> (Susceptible, Vaccinated, Infected, Recovered) model for the measles. The quasi-stationary distributions, as disc...In this paper, we analyze the quasi-stationary distribution of the stochastic <em>SVIR</em> (Susceptible, Vaccinated, Infected, Recovered) model for the measles. The quasi-stationary distributions, as discussed by Danoch and Seneta, have been used in biology to describe the steady state behaviour of population models which exhibit discernible stationarity before to become extinct. The stochastic <em>SVIR</em> model is a stochastic <em>SIR</em> (Susceptible, Infected, Recovered) model with vaccination and recruitment where the disease-free equilibrium is reached, regardless of the magnitude of the basic reproduction number. But the mean time until the absorption (the disease-free) can be very long. If we assume the effective reproduction number <em>R</em><em><sub>p</sub></em> < 1 or <img src="Edit_67da0b97-83f9-42ef-8a00-a13da2d59963.bmp" alt="" />, the quasi-stationary distribution can be closely approximated by geometric distribution. <em>β</em> and <em>δ</em> stands respectively, for the disease transmission coefficient and the natural rate.展开更多
The val66met polymorphism of the bdnf gene, which is associated with compromised brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and impaired learning, may increase one’s susceptibil...The val66met polymorphism of the bdnf gene, which is associated with compromised brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and impaired learning, may increase one’s susceptibility to stress- and anxiety-related disorders. Indeed, previous work has reported greater anxiety-related behaviors and impairments of fear conditioning and extinction in individuals who carry the met allele that results from this polymorphism. Nevertheless, findings in this area of research have been equivocal. Thus, we examined the influence of the val66met polymorphism on fear conditioning, extinction, and extinction memory testing. One hundred and twenty healthy participants completed differential fear conditioning in a fear-potentiated startle paradigm, followed by extinction and extinction memory testing 24 and 48 hr later, respectively. Participants were genotyped for the val66met polymorphism and divided into met allele carriers and non-carriers. Results revealed that, although both met-carriers and non-carriers developed conditioned fear, met-carriers exhibited significantly weaker fear acquisition than non-carriers. This difference persisted throughout extinction and extinction memory testing and, during these last two days of testing, was primarily evident in females. These results are consistent with previous work demonstrating that this polymorphism is associated with impaired amygdala-dependent fear learning and extend such findings by demonstrating that females may be more sensitive to such effects.展开更多
Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow ove...Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow over long distances to reinnervate distal targets. Nerve transfers, where small fascicles from an adjacent intact nerve are coapted to the nerve stump of a nearby denervated muscle, allow for functional return but at the expense of reduced numbers of innervating nerves. A 1-hour period of 20 Hz electrical nerve stimulation via electrodes proximal to an injury site accelerates axon outgrowth to hasten target reinnervation in rats and humans, even after delayed surgery. A novel strategy of enticing donor axons from an otherwise intact nerve to grow through small nerve grafts（cross-bridges） into a denervated nerve stump, promotes improved axon regeneration after delayed nerve repair. The efficacy of this technique has been demonstrated in a rat model and is now in clinical use in patients undergoing cross-face nerve grafting for facial paralysis. In conclusion, brief electrical stimulation, combined with the surgical technique of promoting the regeneration of some donor axons to ‘protect＇ chronically denervated Schwa nn cells, improves nerve regeneration and, in turn, functional outcomes in the management of peripheral nerve injuries.展开更多
Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship betw...Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear.Here,we show,both in vitro and in a Caenorhabditis elegans model of PD,thatα-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state,which converts into an amyloid-rich hydrogel with Lewy-body-like properties.This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.Taken together,these results suggest that the formation of Lewy bodies may be linked to the arrested maturation ofα-synuclein condensates in the presence of lipids and other cellular components.展开更多
The goal of this study is to propose a method of estimation of bounds for roots of polynomials with complex coefficients. A well-known and easy tool to obtain such information is to use the standard Gershgorin’s theo...The goal of this study is to propose a method of estimation of bounds for roots of polynomials with complex coefficients. A well-known and easy tool to obtain such information is to use the standard Gershgorin’s theorem, however, it doesn’t take into account the structure of the matrix. The modified disks of Gershgorin give the opportunity through some geometrical figures called Ovals of Cassini, to consider the form of the matrix in order to determine appropriated bounds for roots. Furthermore, we have seen that, the Hessenbeg matrices are indicated to estimate good bounds for roots of polynomials as far as we become improved bounds for high values of polynomial’s coefficients. But the bounds are better for small values. The aim of the work was to take advantages of this, after introducing the Dehmer’s bound, to find an appropriated property of the Hessenberg form. To illustrate our results, illustrative examples are given to compare the obtained bounds to those obtained through classical methods like Cauchy’s bounds, Montel’s bounds and Carmichel-Mason’s bounds.展开更多
Paint removal is a common maintenance requirement for aircraft as well as naval and land vehicles, since external paint gets damaged and loses much of its corrosion protection effectiveness with time. Paint removal is...Paint removal is a common maintenance requirement for aircraft as well as naval and land vehicles, since external paint gets damaged and loses much of its corrosion protection effectiveness with time. Paint removal is also conducted when metallic aircraft structures are inspected periodically for fatigue cracks and corrosion. The conventional methods of removing paint employed throughout the Canadian Forces mainly include chemical stripping and abrasive media blasting. Chemical stripping involves the use of hazardous chemicals, which are high in Volatile Organic Compounds (VOC) and Hazardous Air Pollutants (HAP). Abrasive media blasting typically results in a substantial quantity of solid waste consisting of paint and blast residues. Such waste is subject to control under increasingly stringent environmental and safety regulations and its disposal is costly. The new Atmospheric Plasma (AP) paint removal process purports to be a high chemical energy, low thermal energy (cold plasma process), that should not damage temperature sensitive substructures, such as heat treated aerospace aluminium alloys. Fatigue strength is one of the key properties in aircraft structures. In order for AP paint stripping to be accepted as an aerospace industry standard paint removal process, it must be thoroughly tested to demonstrate that it does not adversely affect the fatigue properties of the substrate. This paper investigates effect of the paint removal process on fatigue crack growth of 7075-T6 and 2024-T3 aluminium panels.展开更多
Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnanc...Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnancy. We conducted studies to ask whether microchimerism that a woman acquired from her own mother is detectable before or during pregnancy in women with recurrent miscarriage. Fetal microchimerism was also assayed. Women with primary idiopathic recurrent miscarriage （n=23） and controls （n=31） were studied. Genotyping was conducted for probands, their mothers and the fetus, a non-shared polymorphism identified and quantitative polymerase chain reaction performed to measure microchimerismin peripheral blood mononuclear cells. Preconception comparisons were made between recurrent miscarriage subjects and controls, using logistic regression and Wilcoxon rank sum. Longitudinal microchimerism in subsequent pregnancies of recurrent miscarriage subjects was described. There was a trend toward lower preconception detection of microchimerism in recurrent miscarriage versus controls, 6% vs. 19% （1/16 vs. 6/31, P=0.2）. During pregnancy, 3111 （27%） of recurrent miscarriage subjects who went on to have a birth had detection of microchimerism from their own mother, whereas neither of two subjects who went on to miscarry had detection （0/2）. This initial data suggest that microchimerism from a woman＇s own mother, while detectable in women with recurrent miscarriage, may differ from controls and according to subsequent pregnancy outcome. Further studies are needed to determine the cell types,quantities and any potential functional role of microchimerism in recurrent miscarriage.展开更多
文摘Introduction: Maternal mortality rates have more than doubled in the U.S over the last two decades, making it one of the few places in the world where maternal mortality is increasing. Differences in maternal mortality among certain races and ethnicities are known but few studies examine maternal mortality among immigrants. Since immigrants represent 13.7% of the U.S. population, it is essential to examine immigrant subsets to understand maternal mortality among this vulnerable population. Methods: A literature search identified 318 articles on maternal mortality and immigrants, with 12 articles from the U.S. The keywords included maternal mortality, United States, migrants, asylum seekers, immigrants, and disparities. Maternal mortality statistics were obtained from the World Health Organization and Center for Disease Control. Results: Studies analyzed in this review found an overall lower maternal mortality rate among immigrant women compared to U.S.-born women, except for Hispanic immigrant women. Black women had the highest maternal mortality rate, regardless of immigration status. Conclusion: Although the literature points to lower maternal mortality among immigrants, the data is still somewhat mixed, making it challenging to draw comprehensive conclusions. Additional research examining maternal mortality among Im/migrants in the U.S. is needed to guide future training among healthcare professionals and policymakers.
文摘AIM: To identify definitions of cytomegalovirus(CMV) infection and intestinal disease, in inflammatory bowel disease(IBD), to determine the prevalence associated with these definitions.METHODS: We conducted a systematic review and interrogated Pub Med, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both Me SH-terms and free searches were performed. We included all types of English-language(clinical) trials concerning diagnostics and prevalence of CMV in IBD.RESULTS: The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR > 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia.CONCLUSION: We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.
基金Funding for the World malaria report 2015 was received from the United Kingdom Department for International Developmentthe United States Agency for International Development and the Swiss Agency for Development and Cooperation,through a grant to the Swiss Tropical and Public Health Institute.Collection of malaria programme data was also supported by the“Accelerated Malaria Control towards Pre-elimination in East and Southern Africa by 2015”sponsored by the Government of Monaco.
文摘Background:2015 was the target year for malaria goals set by the World Health Assembly and other international institutions to reduce malaria incidence and mortality.A review of progress indicates that malaria programme financing and coverage have been transformed since the beginning of the millennium,and have contributed to substantial reductions in the burden of disease.Findings:Investments in malaria programmes increased by more than 2.5 times between 2005 and 2014 from US$960 million to US$2.5 billion,allowing an expansion in malaria prevention,diagnostic testing and treatment programmes.In 2015 more than half of the population of sub-Saharan Africa slept under insecticide-treated mosquito nets,compared to just 2%in 2000.Increased availability of rapid diagnostic tests and antimalarial medicines has allowed many more people to access timely and appropriate treatment.Malaria incidence rates have decreased by 37%globally and mortality rates by 60%since 2000.It is estimated that 70%of the reductions in numbers of cases in sub-Saharan Africa can be attributed to malaria interventions.Conclusions:Reductions in malaria incidence and mortality rates have been made in every WHO region and almost every country.However,decreases in malaria case incidence and mortality rates were slowest in countries that had the largest numbers of malaria cases and deaths in 2000;reductions in incidence need to be greatly accelerated in these countries to achieve future malaria targets.Progress is made challenging because malaria is concentrated in countries and areas with the least resourced health systems and the least ability to pay for system improvements.Malaria interventions are nevertheless highly cost-effective and have not only led to significant reductions in the incidence of the disease but are estimated to have saved about US$900 million in malaria case management costs to public providers in sub-Saharan Africa between 2000 and 2014.Investments in malaria programmes can not only reduce malaria morbidity and mortality,thereb
文摘This review outlines the current knowledge on the use of enrofloxacin in veterinary medicine from biochemical mechanisms to the use in the field conditions and even resistance and ecotoxicity. The basics of biochemistry, the mechanisms of action and resistance and pharmacokinetics are presented. Then an overview of available veterinary products, their efficacy and their toxicity against target species, human and environment is provided.
基金supported by the German Research Foundation(DA 2255/1-1to SCD)+4 种基金a SickKids Research Training Competition(RESTRACOMP)Graduate Scholarship(to KJWS)an Ontario Graduate Scholarship(to KJWS)a grant from Natural Sciences and Engineering Research Council of Canada(NSERC)(to KJWS)a Kickstarter grant from the Institute of Biomedical Engineering(BME)at the University of Toronto(to KJWS)the Abe Frank Fund from the Riley’s Children Foundation(GHB)。
文摘Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
基金supported by NIH grants(R01 CA090668 and P30 CA006973)the Giant Food Pediatric Cancer Fund.D.S.is also supported by the Kyle Haydock Professorship.R.Z.is supported by the China Scholarship Council(CSC)Joint Scholarship Program.
文摘Tyrosine kinase inhibitors(TKIs)targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials,suggesting the need for combination with other drugs.We investigated the combination of FLT3 TKIs(Gilteritinib or Sorafenib),with Venetodax,a BCL-2 selective inhibitor(BCL-2i),on FLT3/ITD leukemia cells.The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples.Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment,mediated through MAPK pathway inhibition.Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2.Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2.Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1,with an increased binding of BIM to the cell death mediator BAX,leading to increased apoptosis.These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression.This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.
基金supported by the National Natural Science Foundation of China(Grant No.81972492)National Science Fund for Young Scholars(Grant No.21904107)+7 种基金Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars(Grant No.LR19C050001)Hangzhou Agriculture and Society Advancement Program(Grant No.20190101A04)Westlake Startup Grantresearch funds from the National Cancer Centre Singapore and Singapore General Hospital,Singaporethe National Key R&D Program of China(Grant No.2016YFC0901704)Zhejiang Innovation Discipline Project of Laboratory Animal Genetic Engineering(Grant No.201510)the Netherlands Cancer Society(Grant No.NKI 2014-6651)The Netherlands Organization for Scientific Research(NWO)-Middelgroot(Grant No.91116017)
文摘To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.
基金Supported by AIRC/Start-Up(to Giovannetti E)Istituto Toscano Tumori ITT-2011(to Caparello C,Funel N,Vasile E and Giovannetti E)+2 种基金Regione Toscana“Fas Salute”(to Funel N and Giovannetti E)Bennink Foundation(to Meijer LL,Le Large TY,Giovannetti E and Kazemier G)CCA Foundation(to Giovannetti E)
文摘Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers.
基金the German Research Foundation(DA 2255/1-1,to SCD).
文摘Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections.Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain.To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats.The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence.The optical clearing was compatible with conventional laboratory techniques,including retrograde labeling studies,and computational image segmentation,providing fast and precise cell quantitation.Further,optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies,tracing of intramuscular nerve branches or mapping of neurovascular networks.Given their wide-ranging applicability,rapid processing times,and low costs,tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies.All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee(49871/9)on November 9,2019.
文摘We use submultiplicative companion matrix norms to provide new bounds for roots for a given polynomial <i>P</i>(<i>X</i>) over the field C[<i>X</i>]. From a <i>n</i>×<i>n</i> Fiedler companion matrix <i>C</i>, sparse companion matrices and triangular Hessenberg matrices are introduced. Then, we identify a special triangular Hessenberg matrix <i>L<sub>r</sub></i>, supposed to provide a good estimation of the roots. By application of Gershgorin’s theorems to this special matrix in case of submultiplicative matrix norms, some estimations of bounds for roots are made. The obtained bounds have been compared to known ones from the literature precisely Cauchy’s bounds, Montel’s bounds and Carmichel-Mason’s bounds. According to the starting formel of <i>L<sub>r</sub></i>, we see that the more we have coefficients closed to zero with a norm less than 1, the more the Sparse method is useful.
文摘In this article, we consider the construction of a SVIR (Susceptible, Vaccinated, Infected, Recovered) stochastic compartmental model of measles. We prove that the deterministic solution is asymptotically the average of the stochastic solution in the case of small population size. The choice of this model takes into account the random fluctuations inherent to the epidemiological characteristics of rural populations of Niger, notably a high prevalence of measles in children under 5, coupled with a very low immunization coverage.
文摘In this paper, we analyze the quasi-stationary distribution of the stochastic <em>SVIR</em> (Susceptible, Vaccinated, Infected, Recovered) model for the measles. The quasi-stationary distributions, as discussed by Danoch and Seneta, have been used in biology to describe the steady state behaviour of population models which exhibit discernible stationarity before to become extinct. The stochastic <em>SVIR</em> model is a stochastic <em>SIR</em> (Susceptible, Infected, Recovered) model with vaccination and recruitment where the disease-free equilibrium is reached, regardless of the magnitude of the basic reproduction number. But the mean time until the absorption (the disease-free) can be very long. If we assume the effective reproduction number <em>R</em><em><sub>p</sub></em> < 1 or <img src="Edit_67da0b97-83f9-42ef-8a00-a13da2d59963.bmp" alt="" />, the quasi-stationary distribution can be closely approximated by geometric distribution. <em>β</em> and <em>δ</em> stands respectively, for the disease transmission coefficient and the natural rate.
文摘The val66met polymorphism of the bdnf gene, which is associated with compromised brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and impaired learning, may increase one’s susceptibility to stress- and anxiety-related disorders. Indeed, previous work has reported greater anxiety-related behaviors and impairments of fear conditioning and extinction in individuals who carry the met allele that results from this polymorphism. Nevertheless, findings in this area of research have been equivocal. Thus, we examined the influence of the val66met polymorphism on fear conditioning, extinction, and extinction memory testing. One hundred and twenty healthy participants completed differential fear conditioning in a fear-potentiated startle paradigm, followed by extinction and extinction memory testing 24 and 48 hr later, respectively. Participants were genotyped for the val66met polymorphism and divided into met allele carriers and non-carriers. Results revealed that, although both met-carriers and non-carriers developed conditioned fear, met-carriers exhibited significantly weaker fear acquisition than non-carriers. This difference persisted throughout extinction and extinction memory testing and, during these last two days of testing, was primarily evident in females. These results are consistent with previous work demonstrating that this polymorphism is associated with impaired amygdala-dependent fear learning and extend such findings by demonstrating that females may be more sensitive to such effects.
文摘Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow over long distances to reinnervate distal targets. Nerve transfers, where small fascicles from an adjacent intact nerve are coapted to the nerve stump of a nearby denervated muscle, allow for functional return but at the expense of reduced numbers of innervating nerves. A 1-hour period of 20 Hz electrical nerve stimulation via electrodes proximal to an injury site accelerates axon outgrowth to hasten target reinnervation in rats and humans, even after delayed surgery. A novel strategy of enticing donor axons from an otherwise intact nerve to grow through small nerve grafts（cross-bridges） into a denervated nerve stump, promotes improved axon regeneration after delayed nerve repair. The efficacy of this technique has been demonstrated in a rat model and is now in clinical use in patients undergoing cross-face nerve grafting for facial paralysis. In conclusion, brief electrical stimulation, combined with the surgical technique of promoting the regeneration of some donor axons to ‘protect＇ chronically denervated Schwa nn cells, improves nerve regeneration and, in turn, functional outcomes in the management of peripheral nerve injuries.
基金G.S.K.S.acknowledges funding from the Wellcome Trust(065807/Z/01/Z and 203249/Z/16/Z)the UK Medical Research Council(MRC,MR/K02292X/1)+2 种基金Alzheimer Research UK(ARUK,ARUK-PG013-14)Michael J Fox Foundation(16238)from Infinitus China Ltd.S.T.D.acknowledges funding from the Biotechnology and Biological Sciences Research Council(BBSRC,BB/M011194/1).
文摘Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear.Here,we show,both in vitro and in a Caenorhabditis elegans model of PD,thatα-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state,which converts into an amyloid-rich hydrogel with Lewy-body-like properties.This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.Taken together,these results suggest that the formation of Lewy bodies may be linked to the arrested maturation ofα-synuclein condensates in the presence of lipids and other cellular components.
文摘The goal of this study is to propose a method of estimation of bounds for roots of polynomials with complex coefficients. A well-known and easy tool to obtain such information is to use the standard Gershgorin’s theorem, however, it doesn’t take into account the structure of the matrix. The modified disks of Gershgorin give the opportunity through some geometrical figures called Ovals of Cassini, to consider the form of the matrix in order to determine appropriated bounds for roots. Furthermore, we have seen that, the Hessenbeg matrices are indicated to estimate good bounds for roots of polynomials as far as we become improved bounds for high values of polynomial’s coefficients. But the bounds are better for small values. The aim of the work was to take advantages of this, after introducing the Dehmer’s bound, to find an appropriated property of the Hessenberg form. To illustrate our results, illustrative examples are given to compare the obtained bounds to those obtained through classical methods like Cauchy’s bounds, Montel’s bounds and Carmichel-Mason’s bounds.
文摘Paint removal is a common maintenance requirement for aircraft as well as naval and land vehicles, since external paint gets damaged and loses much of its corrosion protection effectiveness with time. Paint removal is also conducted when metallic aircraft structures are inspected periodically for fatigue cracks and corrosion. The conventional methods of removing paint employed throughout the Canadian Forces mainly include chemical stripping and abrasive media blasting. Chemical stripping involves the use of hazardous chemicals, which are high in Volatile Organic Compounds (VOC) and Hazardous Air Pollutants (HAP). Abrasive media blasting typically results in a substantial quantity of solid waste consisting of paint and blast residues. Such waste is subject to control under increasingly stringent environmental and safety regulations and its disposal is costly. The new Atmospheric Plasma (AP) paint removal process purports to be a high chemical energy, low thermal energy (cold plasma process), that should not damage temperature sensitive substructures, such as heat treated aerospace aluminium alloys. Fatigue strength is one of the key properties in aircraft structures. In order for AP paint stripping to be accepted as an aerospace industry standard paint removal process, it must be thoroughly tested to demonstrate that it does not adversely affect the fatigue properties of the substrate. This paper investigates effect of the paint removal process on fatigue crack growth of 7075-T6 and 2024-T3 aluminium panels.
文摘Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnancy. We conducted studies to ask whether microchimerism that a woman acquired from her own mother is detectable before or during pregnancy in women with recurrent miscarriage. Fetal microchimerism was also assayed. Women with primary idiopathic recurrent miscarriage （n=23） and controls （n=31） were studied. Genotyping was conducted for probands, their mothers and the fetus, a non-shared polymorphism identified and quantitative polymerase chain reaction performed to measure microchimerismin peripheral blood mononuclear cells. Preconception comparisons were made between recurrent miscarriage subjects and controls, using logistic regression and Wilcoxon rank sum. Longitudinal microchimerism in subsequent pregnancies of recurrent miscarriage subjects was described. There was a trend toward lower preconception detection of microchimerism in recurrent miscarriage versus controls, 6% vs. 19% （1/16 vs. 6/31, P=0.2）. During pregnancy, 3111 （27%） of recurrent miscarriage subjects who went on to have a birth had detection of microchimerism from their own mother, whereas neither of two subjects who went on to miscarry had detection （0/2）. This initial data suggest that microchimerism from a woman＇s own mother, while detectable in women with recurrent miscarriage, may differ from controls and according to subsequent pregnancy outcome. Further studies are needed to determine the cell types,quantities and any potential functional role of microchimerism in recurrent miscarriage.
