Parkinson’s disease is a complex,progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons in the substantia nigra,leading to motor and non-motor symptoms.While sympto...Parkinson’s disease is a complex,progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons in the substantia nigra,leading to motor and non-motor symptoms.While symptomatic treatments such as levodopa and monoamine oxidase-B inhibitors offer short-term relief,they do not halt disease progression.In recent years,significant advances have been made in understanding the molecular mechanisms underlying Parkinson’s disease,including alpha-synuclein aggregation,mitochondrial dysfunction,neuroinflammation,and lysosomal impairment.These insights have spurred the development of targeted therapeutic strategies aimed at modifying disease progression.This review comprehensively explores emerging approaches such as gene and cell therapies,LRRK2 inhibitors,alpha-synuclein immunotherapy,and gut microbiota modulation.We also discuss the therapeutic potential of mitophagy activators,digital biomarkers,and neuromodulation techniques.Each therapeutic strategy is critically evaluated in the context of underlying pathophysiological mechanisms.Special attention is given to recent clinical trials(2023–2025),translational gaps,and the potential of personalized medicine in Parkinson’s disease management.Furthermore,we examine the integration of multi-omics data and digital tools in advancing precision therapeutics.Overall,this review highlights current challenges and future prospects in the journey toward disease-modifying interventions that move beyond symptomatic relief.展开更多
BACKGROUND Equations for estimation glomerular filtration rate(eGFR)have been associated with poor clinical performance and their clinical accuracy and reliability have been called into question.AIM To assess the long...BACKGROUND Equations for estimation glomerular filtration rate(eGFR)have been associated with poor clinical performance and their clinical accuracy and reliability have been called into question.AIM To assess the longitudinal changes in measured glomerular filtration rate(mGFR)in patients with autosomal dominant polycystic kidney disease(ADPKD).METHODS Analysis of an ambispective data base conducted on consecutive patients diagnosed with ADPKD.The mGFR was assessed by iohexol clearance;while eGFR was calculated by three different formulas:(1)The chronic kidney disease epidemiology collaboration(CKD-EPI);(2)Modification of diet in renal disease(MDRD);and(3)The 24-hour urine creatinine clearance(CrCl).The primary end-points were the mean change in mGFR between the baseline and final visit,as well as the comparison of the mean change in mGFR with the change estimated by the different formulas.RESULTS Thirty-seven patients were included in the study.As compared to baseline,month-6 mGFR was significantly decrease by-4.4 mL/minute±10.3 mL/minute(P=0.0132).However,the CKD-EPI,MDRD,and CrCl formulas underestimated this change by 48.3%,89.0%,and 45.8%respectively,though none of these differences reached statistical significance(P=0.3647;P=0.0505;and P=0.736,respectively).The discrepancies between measured and estimated glomerular filtration rate values,as evaluated by CKD-EPI(r=0.29,P=0.086);MDRD(r=0.19,P=0.272);and CrCl(r=0.09,P=0.683),were not correlated with baseline mGFR values.CONCLUSION This study indicated that eGFR inaccurately reflects the decline in mGFR and cannot reliably track changes over time.This poses significant challenges for clinical decision-making,particularly in treatment strategies.展开更多
Aging is an inevitable process that is usually measured by chronological age,with people aged 65 and over being defined as"older individuals".There is disagreement in the current scientific literature regard...Aging is an inevitable process that is usually measured by chronological age,with people aged 65 and over being defined as"older individuals".There is disagreement in the current scientific literature regarding the best methods to estimate glomerular filtration rate(eGFR)in older adults.Several studies suggest the use of an age-adjusted definition to improve accuracy and avoid overdiagnosis.In contrast,some researchers argue that such changes could complicate the classification of chronic kidney disease(CKD).Several formulas,including the Modification of Diet in Renal Disease,CKD-Epidemiology Collaboration,and Cockcroft-Gault equations,are used to estimate eGFR.However,each of these formulas has significant limitations when applied to older adults,primarily due to sarcopenia and malnutrition,which greatly affect both muscle mass and creatinine levels.Alternative formulas,such as the Berlin Initiative Study and the Full Age Spectrum equations,provide more accurate estimates of values for older adults by accounting for age-related physiological changes.In frail older adults,the use of cystatin C leads to better eGFR calculations to assess renal function.Accurate eGFR measurements improve the health of older patients by enabling better medication dosing.A thorough approach that includes multiple calibrated diagnostic methods and a detailed geriatric assessment is necessary for the effective management of kidney disease and other age-related conditions in older adults.展开更多
Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.De...Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs.展开更多
Parkinson＇s disease （PD） is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neur...Parkinson＇s disease （PD） is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have dif- ferent rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.展开更多
Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis...Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.展开更多
AIM: To incorporate estimated glomerular filtration rate (eGFR) into the model for end-stage liver disease (MELD) score to evaluate the predictive value. METHODS: From January 2004 to October 2008, the records of 4127...AIM: To incorporate estimated glomerular filtration rate (eGFR) into the model for end-stage liver disease (MELD) score to evaluate the predictive value. METHODS: From January 2004 to October 2008, the records of 4127 admitted cirrhotic patients were reviewed. Patients who survived and were followed up as outpatients were defined as survivors and their most recent available laboratory data were collected. Patients whose records indicated death at any time during the hospital stay were defined as non-survivors (in-hospital mortality). Patients with incomplete data or with cirrhosis due to a congenital abnormality such as primary biliary cirrhosis were excluded; thus, a total of 3857 patients were enrolled in the present study. The eGFR, which was calculated by using either the modification of diet in renal disease (MDRD) equation or the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, was incorporated into the MELD score after adjustment with the original MELD equation by logistic regression analysis [bilirubin and international normalized ratio (INR) were set at 1.0 for values less than 1.0]. RESULTS: Patients defined as survivors were significantly younger, had a lower incidence of hepatoma, lower Child-Pugh and MELD scores, and better renal function. The underlying causes of cirrhosis were very different from those in Western countries. In Taiwan, most cirrhotic patients were associated with the hepatitis virus, especially hepatitis B. There were 16 parameters included in univariate logistic regression analysis to predict in-hospital mortality and those with significant predicting values were included in further multivariate analysis. Both 4-variable MDRD eGFR and 6-variable MDRD eGFR, rather than creatinine, were significant predictors of in-hospital mortality. Three new equations were constructed (MELD-MDRD-4, MELD-MDRD-6, MELD-CKD-EPI). As expected, original MELD score was a significant predictor of in-hospital mortality (odds ratio = 1.25, P < 0.001). MELD-MDRD-4 excluded serum creatinine, with the coefficients refit among the remaining 3 variables, i.e., total bilirubin, INR and 4-variable MDRD eGFR. This model represented an exacerbated outcome over MELD score, as suggested by a decrease in chi-square (2161.45 vs 2198.32) and an increase in -2 log (likelihood) (2810.77 vs 2773.90). MELD-MDRD-6 included 6-variable MDRD eGFR as one of the variables and showed an improvement over MELD score, as suggested by an increase in chi-square (2293.82 vs 2198.32) and a decrease in -2 log (likelihood) (2810.77 vs 2664.79). Finally, when serum creatinine was replaced by CKD-EPI eGFR, it showed a slight improvement compared to the original MELD score (chi-square: 2199.16, -2 log (likelihood): 2773.07). In the receiver-operating characteristic curve, the MELD-MDRD-6 score showed a marginal improvement in area under the curve (0.909 vs 0.902), sensitivity (0.854 vs 0.819) and specificity (0.818 vs 0.839) compared to the original MELD equation. In patients with a different eGFR, the MELD-MDRD-6 equation showed a better predictive value in patients with eGFR ≥ 90, 60-89, 30-59 and 15-29. CONCLUSION: Incorporating eGFR obtained by the 6-variable MDRD equation into the MELD score showed an equal predictive performance in in-hospital mortality compared to a creatinine-based MELD score.展开更多
In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-amyloid precursor protein（APP） gene were found in patients with Alzheimer＇s disease（AD） compared wit...In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-amyloid precursor protein（APP） gene were found in patients with Alzheimer＇s disease（AD） compared with the normal population. Moreover, the expression of SIRT1 was significantly decreased while that of APP was increased in AD patients. These results indicated a correlation of DNA methylation with gene expression levels in AD patients. To further investigate the epigenetic mechanism of gene modulation in AD, we used two epigenetic drugs, the DNA methylation inhibitor 5-aza-20-deoxycytidine（DAC） and the histone deacetylase inhibitor trichostatin A（TSA）, to treat human neuroblastoma SK-N-SH cells in the presence of amyloid b-peptide Ab25-35（Ab25-35）. We found that DAC and TSA had different effects on the expression trends of SIRT1 and APP in the cell model of amyloid toxicity. Although other genes, such as microtubule-associated protein s, presenilin 1, presenilin 2, and apolipoprotein E, were up-regulated after Ab25-35treatment, no significant differences were found after DAC and/or TSA treatment. These results support the evidence in AD patients and reveal a strong correlation of SIRT1/APP expression with DNA methylation and/or histone modification, which may help understand the pathogenesis of AD.展开更多
AIM:To evaluate the difference between the performance of the (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations in cirrhotic patients. METHODS: From Jan 2004 to Oct 2008, 4127 cirrhotic patients wer...AIM:To evaluate the difference between the performance of the (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations in cirrhotic patients. METHODS: From Jan 2004 to Oct 2008, 4127 cirrhotic patients were reviewed. Patients with incomplete data with respect to renal function were excluded; thus, a total of 3791 patients were included in the study. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD (MDRD-4), 6-variable MDRD (MDRD-6), and CKD-EPI equations.RESULTS:When serum creatinine was 0.7-6.8 mg/dL and 0.6-5.3 mg/dL in men and women, respectively, a significantly lower GFR was estimated by the MDRD-6 than by the CKD-EPI. Similar GFRs were calculated by both equations when creatinine was > 6.9 mg/dL and > 5.4 mg/dL in men and women, respectively. In predicting in-hospital mortality, estimated GFR obtained by the MDRD-6 showed better accuracy [81.72%; 95% confidence interval (CI), 0.94-0.95] than that obtained by the MDRD-4 (80.22%; 95%CI, 0.96-0.97), CKD-EPI (79.93%; 95%CI, 0.96-0.96), and creatinine (77.50%; 95%CI, 2.27-2.63). CONCLUSION: GFR calculated by the 6-variable MDRD equation may be closer to the true GFR than that calculated by the CKD-EPI equation.展开更多
The diagnosis of small renal masses(SRMs) continues to increase likely attributable to widespread use of axial cross-sectional imaging. Many of these SRMs present in elderly patients with abnormal baseline renal funct...The diagnosis of small renal masses(SRMs) continues to increase likely attributable to widespread use of axial cross-sectional imaging. Many of these SRMs present in elderly patients with abnormal baseline renal function. Such patients are at risk for further decline following therapeutic intervention. Renal thermal ablation presents one approach for management of SRMs whereby tumors are treated in situ without need for global renal ischemia. These treatment characteristics contribute to favorable renal function outcomes following kidney tumor ablation particularly in patients with an anatomic or functional solitary renal unit.展开更多
Background The new Chronic Kidney Disease Epidemiology Collaboration （CKD-EPI） equation was developed to address the systematic underestimation of glomerular filtration rate （GFR） by the Modification of Diet in Re...Background The new Chronic Kidney Disease Epidemiology Collaboration （CKD-EPI） equation was developed to address the systematic underestimation of glomerular filtration rate （GFR） by the Modification of Diet in Renal Disease （MDRD） Study equation in patients with relatively well-preserved kidney function.Performance of the new equation in the Chinese population is unknown.The goal of the present study was to compare performance of these two equations in Chinese patients with chronic kidney disease （CKD）.Methods We enrolled 450 Chinese patients （239 women and 211 men） with CKD in the present study.The renal dynamic imaging method was used to measure the referenced standard GFR （rGFR） for comparison with estimations using the two equations.Their overall performance was assessed with the Bland-Altman method and receiver-operating characteristics （ROC） analysis.Performance of the two equations in lower and higher estimated GFR （eGFR） subgroups was further investigated.Results Both eGFRs correlated well with rGFR （r=0.88,0.81,P〈0.05）.In overall performance,the CKD-EPI equation showed less bias,higher precision and improved accuracy,and was better for detecting CKD.In the higher-eGFR subgroup,the CKD-EPI equation corrected the underestimation of GFR by the abbreviated MDRD equation.Conclusions The CKD-EPI equation outperformed the abbreviated MDRD equation not only in overall performance but also in the subgroups studied.For the present,the CKD-EPI equation appears to be the first-choice prediction equation for estimating GFR.展开更多
Background Recently, it has been suggested that the serum uric acid （SUA） level decreased in diabetic patients. The aim of this study was to explore the association between SUA level and different state of glucose m...Background Recently, it has been suggested that the serum uric acid （SUA） level decreased in diabetic patients. The aim of this study was to explore the association between SUA level and different state of glucose metabolism and glomerular filtration rate （GFR） reflected by the simplified Modification of Diet in Renal Disease （MDRD） equation and to test the hypothesis that high MDRD is one of the determinants of SUA level.Methods This cross-sectional study included 2373 subjects in Beijing who underwent a 75 g oral glucose tolerance test （OGTT） for screening of diabetes. According to the states of glucose metabolism, they were divided into normal glucose tolerance, impaired glucose regulation and diabetes.Results Multiple stepwise linear regression analysis showed that adjusted by gender, SUA was positively correlated with body mass index （BMI）, waist/hippo ratio, systolic blood pressure （SBP） and triglyceride, meanwhile negatively correlated with age, hemoglobin A1c, fasting insulin and MDRD. There was an increasing trend in SUA concentration and a decreasing trend in MDRD when the levels of fasting plasma glucose （FPG） increased from low to high up to the FPG level of 8.0 mmol/L; thereafter, the SUA concentration started to decrease with further increases in FPG levels, and the MDRD started to increase with further increases in FPG levels.Conclusion This study confirmed the previous finding that SUA decreased in diabetes and provided the supporting evidence that the increased MDRD might contribute to the fall of SUA.展开更多
文摘Parkinson’s disease is a complex,progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons in the substantia nigra,leading to motor and non-motor symptoms.While symptomatic treatments such as levodopa and monoamine oxidase-B inhibitors offer short-term relief,they do not halt disease progression.In recent years,significant advances have been made in understanding the molecular mechanisms underlying Parkinson’s disease,including alpha-synuclein aggregation,mitochondrial dysfunction,neuroinflammation,and lysosomal impairment.These insights have spurred the development of targeted therapeutic strategies aimed at modifying disease progression.This review comprehensively explores emerging approaches such as gene and cell therapies,LRRK2 inhibitors,alpha-synuclein immunotherapy,and gut microbiota modulation.We also discuss the therapeutic potential of mitophagy activators,digital biomarkers,and neuromodulation techniques.Each therapeutic strategy is critically evaluated in the context of underlying pathophysiological mechanisms.Special attention is given to recent clinical trials(2023–2025),translational gaps,and the potential of personalized medicine in Parkinson’s disease management.Furthermore,we examine the integration of multi-omics data and digital tools in advancing precision therapeutics.Overall,this review highlights current challenges and future prospects in the journey toward disease-modifying interventions that move beyond symptomatic relief.
文摘BACKGROUND Equations for estimation glomerular filtration rate(eGFR)have been associated with poor clinical performance and their clinical accuracy and reliability have been called into question.AIM To assess the longitudinal changes in measured glomerular filtration rate(mGFR)in patients with autosomal dominant polycystic kidney disease(ADPKD).METHODS Analysis of an ambispective data base conducted on consecutive patients diagnosed with ADPKD.The mGFR was assessed by iohexol clearance;while eGFR was calculated by three different formulas:(1)The chronic kidney disease epidemiology collaboration(CKD-EPI);(2)Modification of diet in renal disease(MDRD);and(3)The 24-hour urine creatinine clearance(CrCl).The primary end-points were the mean change in mGFR between the baseline and final visit,as well as the comparison of the mean change in mGFR with the change estimated by the different formulas.RESULTS Thirty-seven patients were included in the study.As compared to baseline,month-6 mGFR was significantly decrease by-4.4 mL/minute±10.3 mL/minute(P=0.0132).However,the CKD-EPI,MDRD,and CrCl formulas underestimated this change by 48.3%,89.0%,and 45.8%respectively,though none of these differences reached statistical significance(P=0.3647;P=0.0505;and P=0.736,respectively).The discrepancies between measured and estimated glomerular filtration rate values,as evaluated by CKD-EPI(r=0.29,P=0.086);MDRD(r=0.19,P=0.272);and CrCl(r=0.09,P=0.683),were not correlated with baseline mGFR values.CONCLUSION This study indicated that eGFR inaccurately reflects the decline in mGFR and cannot reliably track changes over time.This poses significant challenges for clinical decision-making,particularly in treatment strategies.
文摘Aging is an inevitable process that is usually measured by chronological age,with people aged 65 and over being defined as"older individuals".There is disagreement in the current scientific literature regarding the best methods to estimate glomerular filtration rate(eGFR)in older adults.Several studies suggest the use of an age-adjusted definition to improve accuracy and avoid overdiagnosis.In contrast,some researchers argue that such changes could complicate the classification of chronic kidney disease(CKD).Several formulas,including the Modification of Diet in Renal Disease,CKD-Epidemiology Collaboration,and Cockcroft-Gault equations,are used to estimate eGFR.However,each of these formulas has significant limitations when applied to older adults,primarily due to sarcopenia and malnutrition,which greatly affect both muscle mass and creatinine levels.Alternative formulas,such as the Berlin Initiative Study and the Full Age Spectrum equations,provide more accurate estimates of values for older adults by accounting for age-related physiological changes.In frail older adults,the use of cystatin C leads to better eGFR calculations to assess renal function.Accurate eGFR measurements improve the health of older patients by enabling better medication dosing.A thorough approach that includes multiple calibrated diagnostic methods and a detailed geriatric assessment is necessary for the effective management of kidney disease and other age-related conditions in older adults.
基金JC acknowledges funding from the National Institute of General Medical Sciences(Grant:P20GM109025)and support from Keep Memory Alive.
文摘Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs.
基金supported by the National Institutes of Health (R15-HD061022 and R15-HD061022-S1)the Faculty Development Fund of the School of Pharmacy and Health Professions,Creighton University in Omaha Nebraska,USA
文摘Parkinson＇s disease （PD） is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have dif- ferent rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.
文摘Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.
文摘AIM: To incorporate estimated glomerular filtration rate (eGFR) into the model for end-stage liver disease (MELD) score to evaluate the predictive value. METHODS: From January 2004 to October 2008, the records of 4127 admitted cirrhotic patients were reviewed. Patients who survived and were followed up as outpatients were defined as survivors and their most recent available laboratory data were collected. Patients whose records indicated death at any time during the hospital stay were defined as non-survivors (in-hospital mortality). Patients with incomplete data or with cirrhosis due to a congenital abnormality such as primary biliary cirrhosis were excluded; thus, a total of 3857 patients were enrolled in the present study. The eGFR, which was calculated by using either the modification of diet in renal disease (MDRD) equation or the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, was incorporated into the MELD score after adjustment with the original MELD equation by logistic regression analysis [bilirubin and international normalized ratio (INR) were set at 1.0 for values less than 1.0]. RESULTS: Patients defined as survivors were significantly younger, had a lower incidence of hepatoma, lower Child-Pugh and MELD scores, and better renal function. The underlying causes of cirrhosis were very different from those in Western countries. In Taiwan, most cirrhotic patients were associated with the hepatitis virus, especially hepatitis B. There were 16 parameters included in univariate logistic regression analysis to predict in-hospital mortality and those with significant predicting values were included in further multivariate analysis. Both 4-variable MDRD eGFR and 6-variable MDRD eGFR, rather than creatinine, were significant predictors of in-hospital mortality. Three new equations were constructed (MELD-MDRD-4, MELD-MDRD-6, MELD-CKD-EPI). As expected, original MELD score was a significant predictor of in-hospital mortality (odds ratio = 1.25, P < 0.001). MELD-MDRD-4 excluded serum creatinine, with the coefficients refit among the remaining 3 variables, i.e., total bilirubin, INR and 4-variable MDRD eGFR. This model represented an exacerbated outcome over MELD score, as suggested by a decrease in chi-square (2161.45 vs 2198.32) and an increase in -2 log (likelihood) (2810.77 vs 2773.90). MELD-MDRD-6 included 6-variable MDRD eGFR as one of the variables and showed an improvement over MELD score, as suggested by an increase in chi-square (2293.82 vs 2198.32) and a decrease in -2 log (likelihood) (2810.77 vs 2664.79). Finally, when serum creatinine was replaced by CKD-EPI eGFR, it showed a slight improvement compared to the original MELD score (chi-square: 2199.16, -2 log (likelihood): 2773.07). In the receiver-operating characteristic curve, the MELD-MDRD-6 score showed a marginal improvement in area under the curve (0.909 vs 0.902), sensitivity (0.854 vs 0.819) and specificity (0.818 vs 0.839) compared to the original MELD equation. In patients with a different eGFR, the MELD-MDRD-6 equation showed a better predictive value in patients with eGFR ≥ 90, 60-89, 30-59 and 15-29. CONCLUSION: Incorporating eGFR obtained by the 6-variable MDRD equation into the MELD score showed an equal predictive performance in in-hospital mortality compared to a creatinine-based MELD score.
基金supported by the National Basic Research Development Program of China (2006cb500700)the National Natural Science Foundation of China (30470904 and 31401627)+3 种基金Guangdong Provincial Natural Science Foundation of China (2010B031600070 and 2015A030313066)Science and Technology Social Development Project of Guangdong Province (2008B030301320 and 2012B031800053)a Guangdong Provincial Science and Technology Project (2013B051000009)a Guangzhou Science and Technology Plan Application Basic Research Project (2012J410076)
文摘In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-amyloid precursor protein（APP） gene were found in patients with Alzheimer＇s disease（AD） compared with the normal population. Moreover, the expression of SIRT1 was significantly decreased while that of APP was increased in AD patients. These results indicated a correlation of DNA methylation with gene expression levels in AD patients. To further investigate the epigenetic mechanism of gene modulation in AD, we used two epigenetic drugs, the DNA methylation inhibitor 5-aza-20-deoxycytidine（DAC） and the histone deacetylase inhibitor trichostatin A（TSA）, to treat human neuroblastoma SK-N-SH cells in the presence of amyloid b-peptide Ab25-35（Ab25-35）. We found that DAC and TSA had different effects on the expression trends of SIRT1 and APP in the cell model of amyloid toxicity. Although other genes, such as microtubule-associated protein s, presenilin 1, presenilin 2, and apolipoprotein E, were up-regulated after Ab25-35treatment, no significant differences were found after DAC and/or TSA treatment. These results support the evidence in AD patients and reveal a strong correlation of SIRT1/APP expression with DNA methylation and/or histone modification, which may help understand the pathogenesis of AD.
文摘AIM:To evaluate the difference between the performance of the (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations in cirrhotic patients. METHODS: From Jan 2004 to Oct 2008, 4127 cirrhotic patients were reviewed. Patients with incomplete data with respect to renal function were excluded; thus, a total of 3791 patients were included in the study. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD (MDRD-4), 6-variable MDRD (MDRD-6), and CKD-EPI equations.RESULTS:When serum creatinine was 0.7-6.8 mg/dL and 0.6-5.3 mg/dL in men and women, respectively, a significantly lower GFR was estimated by the MDRD-6 than by the CKD-EPI. Similar GFRs were calculated by both equations when creatinine was > 6.9 mg/dL and > 5.4 mg/dL in men and women, respectively. In predicting in-hospital mortality, estimated GFR obtained by the MDRD-6 showed better accuracy [81.72%; 95% confidence interval (CI), 0.94-0.95] than that obtained by the MDRD-4 (80.22%; 95%CI, 0.96-0.97), CKD-EPI (79.93%; 95%CI, 0.96-0.96), and creatinine (77.50%; 95%CI, 2.27-2.63). CONCLUSION: GFR calculated by the 6-variable MDRD equation may be closer to the true GFR than that calculated by the CKD-EPI equation.
文摘The diagnosis of small renal masses(SRMs) continues to increase likely attributable to widespread use of axial cross-sectional imaging. Many of these SRMs present in elderly patients with abnormal baseline renal function. Such patients are at risk for further decline following therapeutic intervention. Renal thermal ablation presents one approach for management of SRMs whereby tumors are treated in situ without need for global renal ischemia. These treatment characteristics contribute to favorable renal function outcomes following kidney tumor ablation particularly in patients with an anatomic or functional solitary renal unit.
文摘Background The new Chronic Kidney Disease Epidemiology Collaboration （CKD-EPI） equation was developed to address the systematic underestimation of glomerular filtration rate （GFR） by the Modification of Diet in Renal Disease （MDRD） Study equation in patients with relatively well-preserved kidney function.Performance of the new equation in the Chinese population is unknown.The goal of the present study was to compare performance of these two equations in Chinese patients with chronic kidney disease （CKD）.Methods We enrolled 450 Chinese patients （239 women and 211 men） with CKD in the present study.The renal dynamic imaging method was used to measure the referenced standard GFR （rGFR） for comparison with estimations using the two equations.Their overall performance was assessed with the Bland-Altman method and receiver-operating characteristics （ROC） analysis.Performance of the two equations in lower and higher estimated GFR （eGFR） subgroups was further investigated.Results Both eGFRs correlated well with rGFR （r=0.88,0.81,P〈0.05）.In overall performance,the CKD-EPI equation showed less bias,higher precision and improved accuracy,and was better for detecting CKD.In the higher-eGFR subgroup,the CKD-EPI equation corrected the underestimation of GFR by the abbreviated MDRD equation.Conclusions The CKD-EPI equation outperformed the abbreviated MDRD equation not only in overall performance but also in the subgroups studied.For the present,the CKD-EPI equation appears to be the first-choice prediction equation for estimating GFR.
文摘Background Recently, it has been suggested that the serum uric acid （SUA） level decreased in diabetic patients. The aim of this study was to explore the association between SUA level and different state of glucose metabolism and glomerular filtration rate （GFR） reflected by the simplified Modification of Diet in Renal Disease （MDRD） equation and to test the hypothesis that high MDRD is one of the determinants of SUA level.Methods This cross-sectional study included 2373 subjects in Beijing who underwent a 75 g oral glucose tolerance test （OGTT） for screening of diabetes. According to the states of glucose metabolism, they were divided into normal glucose tolerance, impaired glucose regulation and diabetes.Results Multiple stepwise linear regression analysis showed that adjusted by gender, SUA was positively correlated with body mass index （BMI）, waist/hippo ratio, systolic blood pressure （SBP） and triglyceride, meanwhile negatively correlated with age, hemoglobin A1c, fasting insulin and MDRD. There was an increasing trend in SUA concentration and a decreasing trend in MDRD when the levels of fasting plasma glucose （FPG） increased from low to high up to the FPG level of 8.0 mmol/L; thereafter, the SUA concentration started to decrease with further increases in FPG levels, and the MDRD started to increase with further increases in FPG levels.Conclusion This study confirmed the previous finding that SUA decreased in diabetes and provided the supporting evidence that the increased MDRD might contribute to the fall of SUA.
