AIM: To investigate the vasoactive intestinal peptides(VIP) expression in irritable bowel syndrome(IBS) and trinitrobenzene sulfonic acid(TNBS) induced colitis.METHODS: The VIP gene expression and protein plasma level...AIM: To investigate the vasoactive intestinal peptides(VIP) expression in irritable bowel syndrome(IBS) and trinitrobenzene sulfonic acid(TNBS) induced colitis.METHODS: The VIP gene expression and protein plasma levels were measured in adult participants(45.8% male) who met Rome Ⅲ criteria for IBS for longer than 6 mo and in a rat model of colitis as induced by TNBS.Plasma and colons were collected from naive and inflamed rats.Markers assessing inflammation(i.e.,weight changes and myeloperoxidase levels) were assessed on days 2,7,14 and 28 and compared to controls.Visceral hypersensitivity of the rats was assessed with colo-rectal distension and mechanical threshold testing on hind paws.IBS patients(n = 12) were age,gender,race,and BMI-matched with healthy controls(n = 12).Peripheral whole blood and plasma from fasting participants was collected and VIP plasma levels were assayed using a VIP peptide-enzyme immunoassay.Human gene expression of VIP was analyzed using a custom PCR array.RESULTS: TNBS induced colitis in the rats was confirmed with weight loss(13.7 ± 3.2 g) and increased myeloperoxidase activity.Visceral hypersensitivity tocolo-rectal distension was increased in TNBS treated rats up to 21 d and resolved by day 28.Somatic hypersensitivity was also increased up to 14 d post TNBS induction of colitis.The expression of an inflammatory marker myeloperoxidase was significantly elevated in the intracellular granules of neutrophils in rat models following TNBS treatment compared to naive rats.This confirmed the induction of inflammation in rats following TNBS treatment.VIP plasma concentration was significantly increased in rats following TNBS treatment as compared to naive animals(P < 0.05).Likewise,the VIP gene expression from peripheral whole blood was significantly upregulated by 2.91-fold in IBS patients when compared to controls(P < 0.00001; 95%CI).VIP plasma protein was not significantly different when compared with controls(P = 0.193).CONCLUSION: Alterations in VIP expression may play a role in IBS.Therefore,a better understanding of the physiology of VIP could lead to new therapeutics.展开更多
AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus...AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus and Embase in February 2015.Date filters were applied from the year2009 and onward,and studies were limited to those written in the English language and those performed upon human subjects.The initial search yielded 797articles,out of which 38 were pulled for full text review and 27 were included for study analysis.Investigations were reviewed to determine study design,methodology and results,and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.RESULTS:Analysis of study data resulted in the abstraction of four key themes:Neurohormonal differences,anatomic measurements of brain structure and connectivity,differences in functional responsiveness of the brain during rectal distention,and confounding/correlating patient factors.Studies in this review noted alterations of glutamate in the left hippocampus(HIPP),commonalities across IBS subjects in terms of brain oscillation patterns,cortical thickness/gray matter volume differences,and neuroanatomical regions withincreased activation in patients with IBS:Anterio cingulate cortex,mid cingulate cortex,amygdala anterior insula,posterior insula and prefrontal cortex.A striking finding among interventions was the substantia influence that patient variables(e.g.,sex,psychologica and disease related factors)had upon the identification of neuroanatomical differences in structure and con nectivity.CONCLUSION:The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.展开更多
Neurodegenerative diseases are an ever-increasing burden in an aging society.Currently no cure is available for any of these diseases and treatment is based on managing symptoms.Despite many candidate therapeutics dem...Neurodegenerative diseases are an ever-increasing burden in an aging society.Currently no cure is available for any of these diseases and treatment is based on managing symptoms.Despite many candidate therapeutics demonstrating promise in animal models,none has yet shown efficacy in human trials.It is self-evident that humans are different from the animals used to model our diseases,especially models that have been highly manipulated to generate a disease in an animal that does not naturally have such a disease.These differences are likely the reason for the failures of drug candidates in human trials but,until recently,human models of neurodegenerative diseases were lacking.The development of the human cerebral organoid model,by differentiating three-dimensional human neuronal tissue from pluripotent stem cells,represents a significant advance in studying human brain diseases.Cerebral organoids have been used to model Alzheimer’s disease,Parkinson’s disease,Down’s syndrome dementia and we have now shown they can be infected with human prions creating a new model of human prion diseases.展开更多
Fulminant myocarditis is a rare form of severe myocarditis that is most commonly caused by viral infection.Fulminant myocarditis is often pathophysiologically indistinguishable from milder forms of acute myocarditis b...Fulminant myocarditis is a rare form of severe myocarditis that is most commonly caused by viral infection.Fulminant myocarditis is often pathophysiologically indistinguishable from milder forms of acute myocarditis but is categorically defined based on clinical disease progression.Patients may initially present with mild symptoms,such as fever,shortness of breath or heart palpitations,but rapidly progress to severe respiratory distress,arrhythmias,and cardiogenic shock.展开更多
Background: Parkinson’s disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and hear...Background: Parkinson’s disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and heart. Accumulation of α-syn in sympathetic noradrenergic nerves may provide a useful PD biomarker;however, whether α-syn buildup is pathophysiological has been unclear. If it were, one would expect associations of intra-neuronal α-syn deposition with catecholaminergic denervation and with decreased NE contents in the same samples. Methods: We assayed immunoreactive α-syn and tyrosine hydroxylase (TH, a marker of catecholaminergic innerva-tion) concurrently with catecholamines in coded post-mortem scalp skin, submandibular gland (SMG), and apical left ventricular myocardial tissue samples from 14 patients with autopsy-proven PD and 12 age-matched control subjects who did not have a neurodegenerative disease. Results: The PD group had increased α-syn in sympathetic noradrenergically innervated arrector pili muscles (5.7 times control, P < 0.0001), SMG (35 times control, P = 0.0011), and myocardium (11 times control, P = 0.0011). Myocar-dial TH in the PD group was decreased by 65% compared to the control group (P = 0.0008), whereas the groups did not differ in TH in either arrector pili muscles or SMG. Similarly, myocardial NE was decreased by 92% in the PD group (P < 0.0001), but the groups did not differ in NE in either scalp skin or SMG. Conclusions: PD entails increased α-syn in skin, SMG, and myocardial tissues. In skin and SMG, augmented α-syn deposition in sympathetic nerves does not seem to be pathogenic. The pathophysiological significance of intra-neuronal α-syn deposition appears to be organ-selective and prominent in the heart.展开更多
Objective:Patient-reported health-related quality-of-life(HRQOL)measures can provide guidance for treatment decision making,symptom management,and discharge planning.HRQOL is often influenced by the distress experienc...Objective:Patient-reported health-related quality-of-life(HRQOL)measures can provide guidance for treatment decision making,symptom management,and discharge planning.HRQOL is often influenced by the distress experienced by patients from disease or treatment-related symp-toms.This study aimed to identify symptoms that can predict changes in HRQOL in men undergo-ing external beam radiation therapy(EBRT)for nonmetastatic prostate cancer(NMPC).Methods:Fifty-one men with NMPC scheduled for EBRT were assessed at the baseline,at the midpoint of EBRT,and at the end of EBRT.All participants received 38-42 daily doses of EBRT(five times a week),depending on the stage of their disease.Validated questionnaires were administered to evaluate depressive symptoms,urinary and sexual functions,bowel issues,symp-tom-related distress,fatigue,and HRQOL.Pearson correlations,repeated-measures ANOVA,and multiple regressions examined the relationships among variables.Results:Intensification of symptoms and increased symptom-related distress,with a corre-sponding decline in HRQOL,were observed during EBRT in men with NMPC.Changes in symp-toms and symptom distress were associated with changes in HRQOL at the midpoint of EBRT(r=-0.37 to-0.6,P=0.05)and at the end of EBRT(r=-0.3 to-0.47,P=0.01)compared with the baseline.The regression model comprising age,body mass index,Gleason score,T category,androgen-deprivation therapy use,radiation dose received,symptoms(urinary/sexual/bowel prob-lems,fatigue),and overall symptom distress explained 70%of the variance in predicting HRQOL.Urinary problems and fatigue significantly predicted the decline in HRQOL during EBRT.Conclusion:Identifying specific symptoms that can influence HRQOL during EBRT for NMPC can provide feasible interventional targets to improve treatment outcomes.展开更多
Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has ...Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4 + regulatory T cells (Tregs) in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of ILIO, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4+ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs (CD4+ and CD8+), effector CD8+ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II + neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface.展开更多
Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats.The site of closest c...Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats.The site of closest contact between the mother and fetus is the decidua,which represents the maternal–fetal interface.Many of the immune cell subsets present at the maternal–fetal interface have been well described;however,the importance of the maternal T cells in this compartment during late gestation and its complications,such as preterm labor and birth,has only recently been established.Moreover,pioneer and recent studies have indicated that fetal T cells are activated in different subsets of preterm labor and may elicit distinct inflammatory responses in the amniotic cavity,leading to preterm birth.In this review,we describe the established and proposed roles for maternal T cells at the maternal–fetal interface in normal term parturition,as well as the demonstrated contributions of such cells to the pathological process of preterm labor and birth.We also summarize the current knowledge of and proposed roles for fetal T cells in the pathophysiology of the preterm labor syndrome.It is our hope that this review provides a solid conceptual framework highlighting the importance of maternal and fetal T cells in late gestation and catalyzes new research questions that can further scientific understanding of these cells and their role in preterm labor and birth,the leading cause of neonatal mortality and morbidity worldwide.展开更多
基金Supported by National Institutes of Health grant,No.NS045614the Ruth L.Kirschstein National Research Service Award,No.1F31 DK083165-01A1 from the National Institute of Diabetes and Digestive and Kidney DiseasesDivision of Intramural Research,National Institute of Nursing Research,No.1ZIANR000018-01-05 to Henderson WA and Intramural Training Award to Del Valle-Pinero AY and Sherwin LB
文摘AIM: To investigate the vasoactive intestinal peptides(VIP) expression in irritable bowel syndrome(IBS) and trinitrobenzene sulfonic acid(TNBS) induced colitis.METHODS: The VIP gene expression and protein plasma levels were measured in adult participants(45.8% male) who met Rome Ⅲ criteria for IBS for longer than 6 mo and in a rat model of colitis as induced by TNBS.Plasma and colons were collected from naive and inflamed rats.Markers assessing inflammation(i.e.,weight changes and myeloperoxidase levels) were assessed on days 2,7,14 and 28 and compared to controls.Visceral hypersensitivity of the rats was assessed with colo-rectal distension and mechanical threshold testing on hind paws.IBS patients(n = 12) were age,gender,race,and BMI-matched with healthy controls(n = 12).Peripheral whole blood and plasma from fasting participants was collected and VIP plasma levels were assayed using a VIP peptide-enzyme immunoassay.Human gene expression of VIP was analyzed using a custom PCR array.RESULTS: TNBS induced colitis in the rats was confirmed with weight loss(13.7 ± 3.2 g) and increased myeloperoxidase activity.Visceral hypersensitivity tocolo-rectal distension was increased in TNBS treated rats up to 21 d and resolved by day 28.Somatic hypersensitivity was also increased up to 14 d post TNBS induction of colitis.The expression of an inflammatory marker myeloperoxidase was significantly elevated in the intracellular granules of neutrophils in rat models following TNBS treatment compared to naive rats.This confirmed the induction of inflammation in rats following TNBS treatment.VIP plasma concentration was significantly increased in rats following TNBS treatment as compared to naive animals(P < 0.05).Likewise,the VIP gene expression from peripheral whole blood was significantly upregulated by 2.91-fold in IBS patients when compared to controls(P < 0.00001; 95%CI).VIP plasma protein was not significantly different when compared with controls(P = 0.193).CONCLUSION: Alterations in VIP expression may play a role in IBS.Therefore,a better understanding of the physiology of VIP could lead to new therapeutics.
基金Supported by Division of Intramural ResearchNational Institute of Nursing Research to W.A.H.No.1ZIANR000018-01-05
文摘AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus and Embase in February 2015.Date filters were applied from the year2009 and onward,and studies were limited to those written in the English language and those performed upon human subjects.The initial search yielded 797articles,out of which 38 were pulled for full text review and 27 were included for study analysis.Investigations were reviewed to determine study design,methodology and results,and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.RESULTS:Analysis of study data resulted in the abstraction of four key themes:Neurohormonal differences,anatomic measurements of brain structure and connectivity,differences in functional responsiveness of the brain during rectal distention,and confounding/correlating patient factors.Studies in this review noted alterations of glutamate in the left hippocampus(HIPP),commonalities across IBS subjects in terms of brain oscillation patterns,cortical thickness/gray matter volume differences,and neuroanatomical regions withincreased activation in patients with IBS:Anterio cingulate cortex,mid cingulate cortex,amygdala anterior insula,posterior insula and prefrontal cortex.A striking finding among interventions was the substantia influence that patient variables(e.g.,sex,psychologica and disease related factors)had upon the identification of neuroanatomical differences in structure and con nectivity.CONCLUSION:The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.
基金supported in part by the Intramural Research Program of the NIH,NIAID(to CLH)
文摘Neurodegenerative diseases are an ever-increasing burden in an aging society.Currently no cure is available for any of these diseases and treatment is based on managing symptoms.Despite many candidate therapeutics demonstrating promise in animal models,none has yet shown efficacy in human trials.It is self-evident that humans are different from the animals used to model our diseases,especially models that have been highly manipulated to generate a disease in an animal that does not naturally have such a disease.These differences are likely the reason for the failures of drug candidates in human trials but,until recently,human models of neurodegenerative diseases were lacking.The development of the human cerebral organoid model,by differentiating three-dimensional human neuronal tissue from pluripotent stem cells,represents a significant advance in studying human brain diseases.Cerebral organoids have been used to model Alzheimer’s disease,Parkinson’s disease,Down’s syndrome dementia and we have now shown they can be infected with human prions creating a new model of human prion diseases.
基金supported, in part, by the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH (Z01 ES025034 to D.C.Z.)
文摘Fulminant myocarditis is a rare form of severe myocarditis that is most commonly caused by viral infection.Fulminant myocarditis is often pathophysiologically indistinguishable from milder forms of acute myocarditis but is categorically defined based on clinical disease progression.Patients may initially present with mild symptoms,such as fever,shortness of breath or heart palpitations,but rapidly progress to severe respiratory distress,arrhythmias,and cardiogenic shock.
基金the National Institutes of Health(NIH)the Intramural Research Program of the NIH,NINDS.
文摘Background: Parkinson’s disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and heart. Accumulation of α-syn in sympathetic noradrenergic nerves may provide a useful PD biomarker;however, whether α-syn buildup is pathophysiological has been unclear. If it were, one would expect associations of intra-neuronal α-syn deposition with catecholaminergic denervation and with decreased NE contents in the same samples. Methods: We assayed immunoreactive α-syn and tyrosine hydroxylase (TH, a marker of catecholaminergic innerva-tion) concurrently with catecholamines in coded post-mortem scalp skin, submandibular gland (SMG), and apical left ventricular myocardial tissue samples from 14 patients with autopsy-proven PD and 12 age-matched control subjects who did not have a neurodegenerative disease. Results: The PD group had increased α-syn in sympathetic noradrenergically innervated arrector pili muscles (5.7 times control, P < 0.0001), SMG (35 times control, P = 0.0011), and myocardium (11 times control, P = 0.0011). Myocar-dial TH in the PD group was decreased by 65% compared to the control group (P = 0.0008), whereas the groups did not differ in TH in either arrector pili muscles or SMG. Similarly, myocardial NE was decreased by 92% in the PD group (P < 0.0001), but the groups did not differ in NE in either scalp skin or SMG. Conclusions: PD entails increased α-syn in skin, SMG, and myocardial tissues. In skin and SMG, augmented α-syn deposition in sympathetic nerves does not seem to be pathogenic. The pathophysiological significance of intra-neuronal α-syn deposition appears to be organ-selective and prominent in the heart.
文摘Objective:Patient-reported health-related quality-of-life(HRQOL)measures can provide guidance for treatment decision making,symptom management,and discharge planning.HRQOL is often influenced by the distress experienced by patients from disease or treatment-related symp-toms.This study aimed to identify symptoms that can predict changes in HRQOL in men undergo-ing external beam radiation therapy(EBRT)for nonmetastatic prostate cancer(NMPC).Methods:Fifty-one men with NMPC scheduled for EBRT were assessed at the baseline,at the midpoint of EBRT,and at the end of EBRT.All participants received 38-42 daily doses of EBRT(five times a week),depending on the stage of their disease.Validated questionnaires were administered to evaluate depressive symptoms,urinary and sexual functions,bowel issues,symp-tom-related distress,fatigue,and HRQOL.Pearson correlations,repeated-measures ANOVA,and multiple regressions examined the relationships among variables.Results:Intensification of symptoms and increased symptom-related distress,with a corre-sponding decline in HRQOL,were observed during EBRT in men with NMPC.Changes in symp-toms and symptom distress were associated with changes in HRQOL at the midpoint of EBRT(r=-0.37 to-0.6,P=0.05)and at the end of EBRT(r=-0.3 to-0.47,P=0.01)compared with the baseline.The regression model comprising age,body mass index,Gleason score,T category,androgen-deprivation therapy use,radiation dose received,symptoms(urinary/sexual/bowel prob-lems,fatigue),and overall symptom distress explained 70%of the variance in predicting HRQOL.Urinary problems and fatigue significantly predicted the decline in HRQOL during EBRT.Conclusion:Identifying specific symptoms that can influence HRQOL during EBRT for NMPC can provide feasible interventional targets to improve treatment outcomes.
文摘Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4 + regulatory T cells (Tregs) in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of ILIO, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4+ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs (CD4+ and CD8+), effector CD8+ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II + neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface.
基金This research was supported by the Wayne State University Perinatal Initiative in Maternal,Perinatal and Child Health and the Perinatology Research Branch,Division of Obstetrics and Maternal–Fetal Medicine,Division of Intramural Research,Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health,U.S.Department of Health and Human Services(NICHD/NIH/DHHS)in part,with federal funds from NICHD/NIH/DHHS under Contract no.HHSN275201300006C.Dr.Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.
文摘Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats.The site of closest contact between the mother and fetus is the decidua,which represents the maternal–fetal interface.Many of the immune cell subsets present at the maternal–fetal interface have been well described;however,the importance of the maternal T cells in this compartment during late gestation and its complications,such as preterm labor and birth,has only recently been established.Moreover,pioneer and recent studies have indicated that fetal T cells are activated in different subsets of preterm labor and may elicit distinct inflammatory responses in the amniotic cavity,leading to preterm birth.In this review,we describe the established and proposed roles for maternal T cells at the maternal–fetal interface in normal term parturition,as well as the demonstrated contributions of such cells to the pathological process of preterm labor and birth.We also summarize the current knowledge of and proposed roles for fetal T cells in the pathophysiology of the preterm labor syndrome.It is our hope that this review provides a solid conceptual framework highlighting the importance of maternal and fetal T cells in late gestation and catalyzes new research questions that can further scientific understanding of these cells and their role in preterm labor and birth,the leading cause of neonatal mortality and morbidity worldwide.