Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This...Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.展开更多
BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfu...BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfunction,increasing CMV risk.Rarely,CMV infections present with critical illness such as septic shock.CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration.She did not have nausea,vomiting or,abdominal pain.She had been on monthly RTX infusions for neuromyelitis optica.She was admitted for septic shock due to pancolitis.Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA.Valganciclovir treatment led to disease resolution.CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock.High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.展开更多
Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side e...Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting,sustained drug release,and decreased adverse effects. Here,we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition,the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.展开更多
Microstructure and fracture behavior of ASTM 572 Grade 65 steels used for wind tower applications have been studied. Steels of two carbon level chemistries designed for this grade were used in the study. Fracture toug...Microstructure and fracture behavior of ASTM 572 Grade 65 steels used for wind tower applications have been studied. Steels of two carbon level chemistries designed for this grade were used in the study. Fracture toughness of the steels was studied using 3-point bend test on samples coated with zinc and not coated with zinc. Lower carbon steel showed higher resistance to fracture than medium carbon steel after zinc galvanization. SEM study suggests that zinc and zinc bath additives that migrated to crack tips are responsible for the loss in ductility. The phenomenon of Liquid Metal Embrittlement (LME) is suggested to have taken place. Zinc bath additives traced at crack zones are suggested to have migrated at the zinc galvanizing temperatures.展开更多
Microorganisms including bacteria,viruses,protozoa,and fungi living in the gastrointestinal tract are collectively known as the gut microbiota.Dysbiosis is the imbalance in microbial composition on or inside the body ...Microorganisms including bacteria,viruses,protozoa,and fungi living in the gastrointestinal tract are collectively known as the gut microbiota.Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state.Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus(T2DM)and metabolic syndrome.Pathophysiological mechanisms linking gut dysbiosis,and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids,interaction with gut hormones,increased gut microbial metabolite trimethylamine-N-oxide,bacterial translocation/Leaky gut syndrome,and endotoxin production such as lipopolysaccharides.The association between the gut microbiota and glycemic agents,however,is much less understood and is the growing focus of research and conversation.Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other,meaning that while anti-diabetic medications alter the gut microbiota,the gut microbiota also alters the efficacy of anti-diabetic medications.With increasing evidence regarding the significance of gut microbiota,it is imperative to review the role of gut microbiota in the pathogenesis of T2DM.This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.展开更多
Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute t...Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally;fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression was assessed. Bone marrowderived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(?) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(?) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(?) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast transdifferentiation that renders the “aging lung” susceptible to fibrosis.展开更多
BACKGROUND Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases.However,large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome(A...BACKGROUND Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases.However,large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome(ACS)-related hospitalizations and post-revascularization is inadequate.AIM To evaluate the impact of gout on in-hospital outcomes of ACS hospitalizations,subsequent healthcare burden and predictors of post-revascularization inpatient mortality.METHODS We used the national inpatient sample(2010-2014)to identify the ACS and goutrelated hospitalizations,relevant comorbidities,revascularization and postrevascularization outcomes using the ICD-9 CM codes.A multivariable analysis was performed to evaluate the predictors of post-revascularization in-hospital mortality.RESULTS We identified 3144744 ACS-related hospitalizations,of which 105198(3.35%)also had gout.The ACS-gout cohort were more often older white males with a higher prevalence of comorbidities.Coronary artery bypass grafting was required more often in the ACS-gout cohort.Post-revascularization complications including cardiac(3.2%vs 2.9%),respiratory(3.5%vs 2.9%),and hemorrhage(3.1%vs 2.7%)were higher whereas all-cause mortality was lower(2.2%vs 3.0%)in the ACSgout cohort(P<0.001).An older age(OR 15.63,CI:5.51-44.39),non-elective admissions(OR 2.00,CI:1.44-2.79),lower household income(OR 1.44,CI:1.17-1.78),and comorbid conditions predicted higher mortality in ACS-gout cohort undergoing revascularization(P<0.001).Odds of post-revascularization inhospital mortality were lower in Hispanics(OR 0.45,CI:0.31-0.67)and Asians(OR 0.65,CI:0.45-0.94)as compared to white(P<0.001).However,postoperative complications significantly raised mortality odds.Mean length of stay,transfer to other facilities,and hospital charges were higher in the ACS-gout cohort.CONCLUSION Although gout was not independently associated with an increased risk of postrevascularization in-hospital mortality in ACS,it did increase postrevascularization complications.展开更多
Objective:We used population-based data to examine the possible benefit of extended lymphadenectomy for patients with renal malignancy in the setting of more advanced disease.Methods:The Surveillance,Epidemiology,and ...Objective:We used population-based data to examine the possible benefit of extended lymphadenectomy for patients with renal malignancy in the setting of more advanced disease.Methods:The Surveillance,Epidemiology,and End Results(SEER)database was utilized to identify non-metastatic,T3-T4 renal cancer patients from 2004-2015 treated with removal of≥1 lymph node at the time of nephrectomy.Non-parametric bivariate statistics were used to assess associations between covariates of interest and extended lymphadenectomy(≥10 lymph nodes removed).Cancer-specific survival(CSS)and overall survival(OS)benefit was evaluated using Kaplane-Meier analysis.Results:Of the 4397 patients identified,816(18.6%)underwent extended lymphadenectomy.For patients with T3a disease,5-year CSS and OS benefit with extended lymphadenectomy did not reach statistical significance(CSS:hazard ratio[HR]0.98,95%confidence interval[CI]0.77-1.24;OS:HR 0.96,95%CI 0.77-1.20).Conversely,for those with T3b-T3c disease,extended lymphadenectomy led to statistically significant improvements in both 5-year CSS and OS compared to non-extended lymphadenectomy(CSS:HR 0.78,95%CI 0.61-0.99;OS:HR 0.72,95%CI 0.58-0.90).Finally,for those with T4 disease,use of extended lymphadenectomy had OS benefit after 5 years(OS:HR 0.51,HR 0.29-0.90,p = 0.02).Conclusion:Based on population-level data,extended lymphadenectomy was associated with improved survival in select patients with advanced renal malignancy treated with surgical nephrectomy.Understanding the basis of these real-world findings in the face of conflicting randomized trial results will be key,moving forward.展开更多
Dideoxy-2'-fluoro-3'-hydroxymethylarabinofuranosylthymine 10 and cytosine 12 were synthesized from L-xylose and were found to be inactive against HIV-1 in acutely infected lymphocytes.
Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited dis...Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.展开更多
Plant based proteins and fibers are attractive ingredients for weight management-dietary preventive strategies due to their positive satiety enhancement effects. The objective of this study was to evaluate the effect ...Plant based proteins and fibers are attractive ingredients for weight management-dietary preventive strategies due to their positive satiety enhancement effects. The objective of this study was to evaluate the effect of beverages high in plant-protein and soluble fiber on satiety, appetite, hunger and subsequent food intake in healthy young men. This was a randomized crossover study with 30 normal weight male participants, BMI 23.6 ± 1.6 and age 22 ± 1.4. Volunteers consumed one high carbohydrates control (B) and 3 treatments on different days with 3-day washout period. Beverages had similar viscosity and energy content (238 ± 3.8 Kcal). The blank contained (B)-0 g protein/2g fiber), High protein (HP)-30 g protein/2g fiber, High Fiber (HF)-0 g protein/11g fiber and High protein high fiber beverage (HPHF)-30g protein/11g fiber. Visual Analogue Scales VAS were used for subjective satiety, hunger and appetite. Subsequent energy and macronutrient intake was measured by difference after consuming lunch ad libitum. Beverages HP, HF and HPHF showed higher satiety effect than B after 2 and 3 hours post consumption (P = 0.02). HP showed the most prolonged effect on satiety (4 h) compared to the control (P = 0.02). Appetite control was not different between treatments but significant differences were observed against the control after 2 h of consumption (P = 0.01). No differences on hunger perception, subsequent energy or macronutrient intake were observed among all beverages (P > 0.05). The current study demonstrates that HPHF, HP and HF beverages led to improved satiety over high carbohydrate beverages. In conclusion, beverages formulated with plant-based proteins, soluble corn fiber or both may be an effective strategy to promote satiety as part of an overall weight management plan.展开更多
Objective:To examine the prognostic value of tumor major histocompatibility complex I(MHCI)expression on survival and recurrence in patients with clear cell renal cell carcinoma(RCC).Methods:Fifty-three patients that ...Objective:To examine the prognostic value of tumor major histocompatibility complex I(MHCI)expression on survival and recurrence in patients with clear cell renal cell carcinoma(RCC).Methods:Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC(T1eT3)with4 years of follow-up were queried from our nephrectomy database.Immunohistochemical staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis technique.Patients were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the KaplaneMeier method and log-rank test.Results:Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group(log-rank,p=0.036 and p=0.028,respectively).Patients alive at the end of the study had higher MHCI expression(mean positivity score 0.82)than those that died of disease(mean positivity score 0.76,t test,p=0.030).Patients that did not develop recurrence during the study period had higher MHCI expression(mean positivity score 0.83)than those that did develop recurrence(mean positivity score 0.78),but this difference was not significant(t test,p =0.079).展开更多
In this paper we introduce methods for approximating local standard time in the Northern Hemisphere using Polaris and the Big Dipper as well as alternative reference stars, and describe in detail how to construct a de...In this paper we introduce methods for approximating local standard time in the Northern Hemisphere using Polaris and the Big Dipper as well as alternative reference stars, and describe in detail how to construct a device we call a dipperclock to facilitate this process. An alternative method which does not require a dipperclock is also discussed. Ways of constructing dipperclocks which glow in the dark are presented. The accuracy of dipperclocks is examined, both theoretically and through field testing. A java program is provided for creating dipperclocks customized to a particular year-long time period and place to get improved accuracy. Basic astronomical definitions and justifications of the results are provided. We also discuss the use of dipperclocks to find longitude and latitude.展开更多
The presidential research program Brain Research through Advancing Innovative Neurotechnologies(BRAIN)Initiative was established5years ago in the United States;it has been a driving force of the United States governme...The presidential research program Brain Research through Advancing Innovative Neurotechnologies(BRAIN)Initiative was established5years ago in the United States;it has been a driving force of the United States government and private factors to promote technology development in basic and translational neuroscience research.We here summarize the research plan and recent progress in cellular neuroscience,electrical and optical engineering,chemical and systems neurobiology,and brain mapping technologies.The research plan recognizes the importance of identifying different cell populations and unknown cell types in the human brain and diseased models.Technological advances in multielectrode arrays and chemical flow measurement probes not only demonstrate the capacity of detecting neural activities in large areas,but also enable a new era of studying the neural coding information.Large-scale coordination of neuronal activity and brain mapping information will allow for the identification of therapeutic targets in neurological disorders,which is benefited by big data acquisition and analysis.Specifically,increased brain databases will expedite the dissection of thoughts,emotions,cognition,and will thereby help the development of better understanding and treatments of brain disorders.Since cell therapy demonstrates potential for regenerative medicine,the utilization of the newly advanced technologies may further improve the translational potentials and precision controls of transplanted grafts.The development of new diagnostic and therapeutic tools also requires international collaborations on science,technology,advocating,healthcare and medical ethics to advance the innovation and clinical practices.展开更多
Cutleaf teasel (Dipsacus laciniatus L.) is an invasive plant that is spreading through natural and disturbed areas. Teasel grows for two or more years as a rosette which stays green late in the growing season and begi...Cutleaf teasel (Dipsacus laciniatus L.) is an invasive plant that is spreading through natural and disturbed areas. Teasel grows for two or more years as a rosette which stays green late in the growing season and begins growth earlier in spring than its native competitors. The purpose of this study was to find a time both seasonally and in cutleaf teasel’s life history when herbicides could be applied to decrease teasel with the least impact on the surrounding vegetation. We tested the effects of three different herbicides (glyphosate (Round-UpTM), triclopyr amine (GarlonTM), and clopyralid (LontrelTM)) on cut and uncut teasel at three different times of the year (July and October 2005, and April 2006) near Clinton Lake in Dewitt Co. Illinois. Photosynthetic measurements were taken before application to determine teasel’s susceptibility to the herbicides, and we harvested seed heads and rosettes in late October 2006. Results indicated teasel was photosynthetically active at all three application times. Cutting before herbicide application had no significant effect on the number of seeds produced or the dry weight of the rosettes. Herbicide treatment in April significantly reduced the amount of seeds produced, but there were no significant differences among the three herbicides. Clopyralid application in April significantly reduced rosette biomass, but none of the herbicides significantly affected rosette biomass at the other two times. Our studies suggest herbicide application early in the growing season may be beneficial in controlling the spread of teasel, and that mowing at the time of spraying will not increase effectiveness of the herbicide.展开更多
Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD),including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their reg...Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD),including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiatedinto osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lackingthese loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containingthese loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes andAlizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMDassociatedloci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple genepromoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence.Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on theshorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removalremoved a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model inmice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMDassociatedvariants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuableinsights into genetic regulation of bone density and potential therapeutic targets.展开更多
The study employed the triangulation approach to investigate the impact of climate variability on selected socioeconomic indicators, particularly food production, health and education, and how much climate variability...The study employed the triangulation approach to investigate the impact of climate variability on selected socioeconomic indicators, particularly food production, health and education, and how much climate variability and its impact on those indicators was realized and understood among the women living in Jambiani community in Zanzibar. The study used the explanatory, sequential mixed method to collect, datasets related to Jambiani communities (i.e. from the women in Kibigija village), other climate data acquired from Tanzania Meteorological Authority (TMA), Ministries of Agriculture and Health and Southern District in Zanzibar. The results obtained from the analysis of both anecdotal (interview, questionnaire among others) data shows that climate variability was imminent in Jambiani communities between 2010 and 2015 and had a negative impact on food production, health and education. Further results revealed that women working in informal sectors are more vulnerable to climate impacts than women working in formal sectors due to less knowledge and techniques to mitigate/cope with climate variability impacts. Conclusively the study has shown that climate variability affects more women with less awareness of what is happening and how to cope with it, thus the study calls for new research work and increasing the awareness on the impacts of climate on human basic needs.展开更多
Percutaneous coronary intervention(PCI) remains a major therapeutic option for the treatment of chronic coronary artery disease. In the COURAGE trial, 2287 patients with chronic coronary disease were randomized betwee...Percutaneous coronary intervention(PCI) remains a major therapeutic option for the treatment of chronic coronary artery disease. In the COURAGE trial, 2287 patients with chronic coronary disease were randomized between PCI with medical management and medical management alone. Embedded within the COURAGE trial is a detailed economic analysis being conducted in three health care systems: the US Veterans Administration(VA), Canada, and the US non-VA. Resource use and costs are being collected for each system and overall. Survival is assessed internally in the trial with mean follow-up of 4.5 years. Long-term mean survival will be estimated by projecting survival beyond the trial period by extrapolating the in-trial hazard rates. Utility is being assessed at baseline and at 1, 3, and 6 months and annually thereafter, using a computer-administered standard gamble. Quality-adjusted life years are calculated by multiplying survival by utility. The incremental cost-effectiveness ratio of PCI will be defined as the additional cost of PCI divided by the gain in life years and quality-adjusted life years. The 95%confidence regions of efficacy and costs will be determined by bootstrap over a range of acceptability thresholds, which will then be displayed in the cost-effectiveness plane and as a cost-effectiveness acceptability curve. A multilevel regression model will assess cost-effectiveness from a net benefit perspective. These approaches should provide the most detailed assessment available of the cost-effectiveness of PCI for coronary artery disease.展开更多
基金supported by National Health Institute(NIH)grant NS099596(to LW and SPY),NS114221(to LW and SPY)Veterans Affair(VA)SPiRE grant RX003865(to SPY)+1 种基金supported by the O.Wayne Rollins Endowment Fund(to SPY)John E.Steinhaus Endowment Fund(to LW)。
文摘Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.
文摘BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfunction,increasing CMV risk.Rarely,CMV infections present with critical illness such as septic shock.CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration.She did not have nausea,vomiting or,abdominal pain.She had been on monthly RTX infusions for neuromyelitis optica.She was admitted for septic shock due to pancolitis.Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA.Valganciclovir treatment led to disease resolution.CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock.High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.
基金Supported by the National Natural Science Foundation of China,No.51503172 and No.81571807the Fundamental Research Funds for the Central Universities,No.SWU114086 and No.XDJK2015C067+3 种基金the Scientific Research Foundation for the Returned Overseas Chinese Scholars(State Education Ministry)the Department of Veterans Affairs(Merit Award to Merlin D)the National Institutes of Health of Diabetes and Digestive and Kidney,No.RO1-DK-071594Career Scientist Award from the Department of Veterans Affairs(to Merlin D)
文摘Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting,sustained drug release,and decreased adverse effects. Here,we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition,the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.
文摘Microstructure and fracture behavior of ASTM 572 Grade 65 steels used for wind tower applications have been studied. Steels of two carbon level chemistries designed for this grade were used in the study. Fracture toughness of the steels was studied using 3-point bend test on samples coated with zinc and not coated with zinc. Lower carbon steel showed higher resistance to fracture than medium carbon steel after zinc galvanization. SEM study suggests that zinc and zinc bath additives that migrated to crack tips are responsible for the loss in ductility. The phenomenon of Liquid Metal Embrittlement (LME) is suggested to have taken place. Zinc bath additives traced at crack zones are suggested to have migrated at the zinc galvanizing temperatures.
文摘Microorganisms including bacteria,viruses,protozoa,and fungi living in the gastrointestinal tract are collectively known as the gut microbiota.Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state.Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus(T2DM)and metabolic syndrome.Pathophysiological mechanisms linking gut dysbiosis,and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids,interaction with gut hormones,increased gut microbial metabolite trimethylamine-N-oxide,bacterial translocation/Leaky gut syndrome,and endotoxin production such as lipopolysaccharides.The association between the gut microbiota and glycemic agents,however,is much less understood and is the growing focus of research and conversation.Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other,meaning that while anti-diabetic medications alter the gut microbiota,the gut microbiota also alters the efficacy of anti-diabetic medications.With increasing evidence regarding the significance of gut microbiota,it is imperative to review the role of gut microbiota in the pathogenesis of T2DM.This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.
文摘Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally;fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression was assessed. Bone marrowderived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(?) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(?) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(?) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast transdifferentiation that renders the “aging lung” susceptible to fibrosis.
文摘BACKGROUND Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases.However,large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome(ACS)-related hospitalizations and post-revascularization is inadequate.AIM To evaluate the impact of gout on in-hospital outcomes of ACS hospitalizations,subsequent healthcare burden and predictors of post-revascularization inpatient mortality.METHODS We used the national inpatient sample(2010-2014)to identify the ACS and goutrelated hospitalizations,relevant comorbidities,revascularization and postrevascularization outcomes using the ICD-9 CM codes.A multivariable analysis was performed to evaluate the predictors of post-revascularization in-hospital mortality.RESULTS We identified 3144744 ACS-related hospitalizations,of which 105198(3.35%)also had gout.The ACS-gout cohort were more often older white males with a higher prevalence of comorbidities.Coronary artery bypass grafting was required more often in the ACS-gout cohort.Post-revascularization complications including cardiac(3.2%vs 2.9%),respiratory(3.5%vs 2.9%),and hemorrhage(3.1%vs 2.7%)were higher whereas all-cause mortality was lower(2.2%vs 3.0%)in the ACSgout cohort(P<0.001).An older age(OR 15.63,CI:5.51-44.39),non-elective admissions(OR 2.00,CI:1.44-2.79),lower household income(OR 1.44,CI:1.17-1.78),and comorbid conditions predicted higher mortality in ACS-gout cohort undergoing revascularization(P<0.001).Odds of post-revascularization inhospital mortality were lower in Hispanics(OR 0.45,CI:0.31-0.67)and Asians(OR 0.65,CI:0.45-0.94)as compared to white(P<0.001).However,postoperative complications significantly raised mortality odds.Mean length of stay,transfer to other facilities,and hospital charges were higher in the ACS-gout cohort.CONCLUSION Although gout was not independently associated with an increased risk of postrevascularization in-hospital mortality in ACS,it did increase postrevascularization complications.
基金the American Cancer Society during completion of this project(MSRG-18-1-CPHPS).
文摘Objective:We used population-based data to examine the possible benefit of extended lymphadenectomy for patients with renal malignancy in the setting of more advanced disease.Methods:The Surveillance,Epidemiology,and End Results(SEER)database was utilized to identify non-metastatic,T3-T4 renal cancer patients from 2004-2015 treated with removal of≥1 lymph node at the time of nephrectomy.Non-parametric bivariate statistics were used to assess associations between covariates of interest and extended lymphadenectomy(≥10 lymph nodes removed).Cancer-specific survival(CSS)and overall survival(OS)benefit was evaluated using Kaplane-Meier analysis.Results:Of the 4397 patients identified,816(18.6%)underwent extended lymphadenectomy.For patients with T3a disease,5-year CSS and OS benefit with extended lymphadenectomy did not reach statistical significance(CSS:hazard ratio[HR]0.98,95%confidence interval[CI]0.77-1.24;OS:HR 0.96,95%CI 0.77-1.20).Conversely,for those with T3b-T3c disease,extended lymphadenectomy led to statistically significant improvements in both 5-year CSS and OS compared to non-extended lymphadenectomy(CSS:HR 0.78,95%CI 0.61-0.99;OS:HR 0.72,95%CI 0.58-0.90).Finally,for those with T4 disease,use of extended lymphadenectomy had OS benefit after 5 years(OS:HR 0.51,HR 0.29-0.90,p = 0.02).Conclusion:Based on population-level data,extended lymphadenectomy was associated with improved survival in select patients with advanced renal malignancy treated with surgical nephrectomy.Understanding the basis of these real-world findings in the face of conflicting randomized trial results will be key,moving forward.
文摘Dideoxy-2'-fluoro-3'-hydroxymethylarabinofuranosylthymine 10 and cytosine 12 were synthesized from L-xylose and were found to be inactive against HIV-1 in acutely infected lymphocytes.
文摘Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.
文摘Plant based proteins and fibers are attractive ingredients for weight management-dietary preventive strategies due to their positive satiety enhancement effects. The objective of this study was to evaluate the effect of beverages high in plant-protein and soluble fiber on satiety, appetite, hunger and subsequent food intake in healthy young men. This was a randomized crossover study with 30 normal weight male participants, BMI 23.6 ± 1.6 and age 22 ± 1.4. Volunteers consumed one high carbohydrates control (B) and 3 treatments on different days with 3-day washout period. Beverages had similar viscosity and energy content (238 ± 3.8 Kcal). The blank contained (B)-0 g protein/2g fiber), High protein (HP)-30 g protein/2g fiber, High Fiber (HF)-0 g protein/11g fiber and High protein high fiber beverage (HPHF)-30g protein/11g fiber. Visual Analogue Scales VAS were used for subjective satiety, hunger and appetite. Subsequent energy and macronutrient intake was measured by difference after consuming lunch ad libitum. Beverages HP, HF and HPHF showed higher satiety effect than B after 2 and 3 hours post consumption (P = 0.02). HP showed the most prolonged effect on satiety (4 h) compared to the control (P = 0.02). Appetite control was not different between treatments but significant differences were observed against the control after 2 h of consumption (P = 0.01). No differences on hunger perception, subsequent energy or macronutrient intake were observed among all beverages (P > 0.05). The current study demonstrates that HPHF, HP and HF beverages led to improved satiety over high carbohydrate beverages. In conclusion, beverages formulated with plant-based proteins, soluble corn fiber or both may be an effective strategy to promote satiety as part of an overall weight management plan.
文摘Objective:To examine the prognostic value of tumor major histocompatibility complex I(MHCI)expression on survival and recurrence in patients with clear cell renal cell carcinoma(RCC).Methods:Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC(T1eT3)with4 years of follow-up were queried from our nephrectomy database.Immunohistochemical staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis technique.Patients were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the KaplaneMeier method and log-rank test.Results:Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group(log-rank,p=0.036 and p=0.028,respectively).Patients alive at the end of the study had higher MHCI expression(mean positivity score 0.82)than those that died of disease(mean positivity score 0.76,t test,p=0.030).Patients that did not develop recurrence during the study period had higher MHCI expression(mean positivity score 0.83)than those that did develop recurrence(mean positivity score 0.78),but this difference was not significant(t test,p =0.079).
文摘In this paper we introduce methods for approximating local standard time in the Northern Hemisphere using Polaris and the Big Dipper as well as alternative reference stars, and describe in detail how to construct a device we call a dipperclock to facilitate this process. An alternative method which does not require a dipperclock is also discussed. Ways of constructing dipperclocks which glow in the dark are presented. The accuracy of dipperclocks is examined, both theoretically and through field testing. A java program is provided for creating dipperclocks customized to a particular year-long time period and place to get improved accuracy. Basic astronomical definitions and justifications of the results are provided. We also discuss the use of dipperclocks to find longitude and latitude.
文摘The presidential research program Brain Research through Advancing Innovative Neurotechnologies(BRAIN)Initiative was established5years ago in the United States;it has been a driving force of the United States government and private factors to promote technology development in basic and translational neuroscience research.We here summarize the research plan and recent progress in cellular neuroscience,electrical and optical engineering,chemical and systems neurobiology,and brain mapping technologies.The research plan recognizes the importance of identifying different cell populations and unknown cell types in the human brain and diseased models.Technological advances in multielectrode arrays and chemical flow measurement probes not only demonstrate the capacity of detecting neural activities in large areas,but also enable a new era of studying the neural coding information.Large-scale coordination of neuronal activity and brain mapping information will allow for the identification of therapeutic targets in neurological disorders,which is benefited by big data acquisition and analysis.Specifically,increased brain databases will expedite the dissection of thoughts,emotions,cognition,and will thereby help the development of better understanding and treatments of brain disorders.Since cell therapy demonstrates potential for regenerative medicine,the utilization of the newly advanced technologies may further improve the translational potentials and precision controls of transplanted grafts.The development of new diagnostic and therapeutic tools also requires international collaborations on science,technology,advocating,healthcare and medical ethics to advance the innovation and clinical practices.
文摘Cutleaf teasel (Dipsacus laciniatus L.) is an invasive plant that is spreading through natural and disturbed areas. Teasel grows for two or more years as a rosette which stays green late in the growing season and begins growth earlier in spring than its native competitors. The purpose of this study was to find a time both seasonally and in cutleaf teasel’s life history when herbicides could be applied to decrease teasel with the least impact on the surrounding vegetation. We tested the effects of three different herbicides (glyphosate (Round-UpTM), triclopyr amine (GarlonTM), and clopyralid (LontrelTM)) on cut and uncut teasel at three different times of the year (July and October 2005, and April 2006) near Clinton Lake in Dewitt Co. Illinois. Photosynthetic measurements were taken before application to determine teasel’s susceptibility to the herbicides, and we harvested seed heads and rosettes in late October 2006. Results indicated teasel was photosynthetically active at all three application times. Cutting before herbicide application had no significant effect on the number of seeds produced or the dry weight of the rosettes. Herbicide treatment in April significantly reduced the amount of seeds produced, but there were no significant differences among the three herbicides. Clopyralid application in April significantly reduced rosette biomass, but none of the herbicides significantly affected rosette biomass at the other two times. Our studies suggest herbicide application early in the growing season may be beneficial in controlling the spread of teasel, and that mowing at the time of spraying will not increase effectiveness of the herbicide.
基金supported by NIH-R21 Award (R21AR071536) to HDfunds from Emory University。
文摘Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD),including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiatedinto osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lackingthese loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containingthese loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes andAlizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMDassociatedloci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple genepromoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence.Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on theshorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removalremoved a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model inmice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMDassociatedvariants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuableinsights into genetic regulation of bone density and potential therapeutic targets.
文摘The study employed the triangulation approach to investigate the impact of climate variability on selected socioeconomic indicators, particularly food production, health and education, and how much climate variability and its impact on those indicators was realized and understood among the women living in Jambiani community in Zanzibar. The study used the explanatory, sequential mixed method to collect, datasets related to Jambiani communities (i.e. from the women in Kibigija village), other climate data acquired from Tanzania Meteorological Authority (TMA), Ministries of Agriculture and Health and Southern District in Zanzibar. The results obtained from the analysis of both anecdotal (interview, questionnaire among others) data shows that climate variability was imminent in Jambiani communities between 2010 and 2015 and had a negative impact on food production, health and education. Further results revealed that women working in informal sectors are more vulnerable to climate impacts than women working in formal sectors due to less knowledge and techniques to mitigate/cope with climate variability impacts. Conclusively the study has shown that climate variability affects more women with less awareness of what is happening and how to cope with it, thus the study calls for new research work and increasing the awareness on the impacts of climate on human basic needs.
文摘Percutaneous coronary intervention(PCI) remains a major therapeutic option for the treatment of chronic coronary artery disease. In the COURAGE trial, 2287 patients with chronic coronary disease were randomized between PCI with medical management and medical management alone. Embedded within the COURAGE trial is a detailed economic analysis being conducted in three health care systems: the US Veterans Administration(VA), Canada, and the US non-VA. Resource use and costs are being collected for each system and overall. Survival is assessed internally in the trial with mean follow-up of 4.5 years. Long-term mean survival will be estimated by projecting survival beyond the trial period by extrapolating the in-trial hazard rates. Utility is being assessed at baseline and at 1, 3, and 6 months and annually thereafter, using a computer-administered standard gamble. Quality-adjusted life years are calculated by multiplying survival by utility. The incremental cost-effectiveness ratio of PCI will be defined as the additional cost of PCI divided by the gain in life years and quality-adjusted life years. The 95%confidence regions of efficacy and costs will be determined by bootstrap over a range of acceptability thresholds, which will then be displayed in the cost-effectiveness plane and as a cost-effectiveness acceptability curve. A multilevel regression model will assess cost-effectiveness from a net benefit perspective. These approaches should provide the most detailed assessment available of the cost-effectiveness of PCI for coronary artery disease.
