Inflammatory bowel diseases(IBD),including ulcerative colitis(UC) and Crohn's disease(CD),are chronic,progressive and disabling disorders.Over the last few decades,new therapeutic approaches have been introduced w...Inflammatory bowel diseases(IBD),including ulcerative colitis(UC) and Crohn's disease(CD),are chronic,progressive and disabling disorders.Over the last few decades,new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD.The identification of clinical,genetic and serological prognostic factors has permitted a better stratification of the disease,thus allowing the opportunity to indicate the most appropriate therapy.Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change,at least in the short term,the course of the disease by reducing,in a subset of patients with IBD,hospitalization and the need for surgery.In this review,the crucial steps in the natural history of both UC and CD will be discussed,as well as the factors that may change their clinical course.The methodological requirements for high quality studies on the course and prognosis of IBD,the true impact of environmental and dietary factors on the clinical course of IBD,the clinical,serological and genetic predictors of the IBD course(in particular,which of these are rel-evant and appropriate for use in clinical practice),the impact of the various forms of medical treatment on the IBD complication rate,the role of surgery for IBD in the biologic era,the true magnitude of risk of colorectal cancer associated with IBD,as well as the mortality rate related to IBD will be stressed;all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.展开更多
Objective We aimed to evaluate the combined effect of a family history of cardiovascular disease(CVD) and high serum C‐reactive protein(CRP) on the stroke incidence in an Inner Mongolian population in China. Meth...Objective We aimed to evaluate the combined effect of a family history of cardiovascular disease(CVD) and high serum C‐reactive protein(CRP) on the stroke incidence in an Inner Mongolian population in China. Methods A prospective cohort study was conducted from June 2002 to July 2012, with 2,544 participants aged 20 years and over from Inner Mongolia, China. We categorized participants into four groups based on the family history of CVD and CRP levels. Results We adjusted for age; sex; smoking; drinking; hypertension; body mass index; waist circumference; and blood glucose, triglycerides, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol levels. Compared with the group with no family history of CVD/low CRP levels, the group with family history of CVD/high CRP levels had a hazard ratio(HR) of 1.78 [95% confidence interval(CI), 1.03‐3.07; P = 0.039] of stroke, and an HR of 2.14(95% CI, 1.09‐4.20; P = 0.027) of ischemic stroke. The HRs of hemorrhagic stroke for the other three groups were not statistically significant(all P 〉 0.05). Conclusion Participants with both a family history of CVD and high CRP levels had the highest stroke incidence, suggesting that high CRP levels may increase stroke risk, especially of ischemic stroke, among individuals with a family history of CVD.展开更多
Crohn’s disease (CD) is a multifactorial potentially debilitating disease. It has a variable disease course, but the majority of patients eventually develop penetrating or stricturing complications leading...Crohn’s disease (CD) is a multifactorial potentially debilitating disease. It has a variable disease course, but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability. Studies on the natural history of CD provide invaluable data on its course and clinical predictors, and may help to identify patient subsets based on clinical phenotype. Most data are available from referral centers, however these outcomes may be different from those in population-based cohorts. New data suggest the possibility of a change in the natural history in Crohn’s disease, with an increasing percentage of patients diagnosed with inflammatory disease behavior. Hospitalization rates remain high, while surgery rates seem to have decreased in the last decade. In addition, mortality rates still exceed that of the general population. The impact of changes in treatment strategy, including increased, earlier use of immunosuppressives, biological therapy, and patient monitoring on the natural history of the disease are still conflictive. In this review article, the authors summarize the available evidence on the natural history, current trends, and predictive factors for evaluating the disease course of CD.展开更多
Patients with extensive or complicated Crohn's disease(CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines.In patients with localized and uncompli...Patients with extensive or complicated Crohn's disease(CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines.In patients with localized and uncomplicated CD at diagnosis,early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact.In this context,there is a need for predictors of benign or unfavourable subsequent clinical course,in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions.At diagnosis,an age below 40 years,the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course.The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts.Consequently,the use of these predictors can be integrated into the elements that influence individual decisions.In the CD postoperative context,keeping smoking and history of prior resection are the stron-gest predictors of disease symptomatic recurrence.However,these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice.In ulcerative colitis(UC),extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease,and also with long-term colectomy and colorectal inflammation-associated colorectal cancer.In patients with extensive UC at diagnosis,a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered.At the moment,no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.展开更多
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would...AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.展开更多
BACKGROUND Type 1 diabetes(T1D)contributes to altered lipid profiles and increases the risk of cardiovascular disease(CVD).Youth with T1D may have additional CVD risk factors within the first decade of diagnosis.AIM T...BACKGROUND Type 1 diabetes(T1D)contributes to altered lipid profiles and increases the risk of cardiovascular disease(CVD).Youth with T1D may have additional CVD risk factors within the first decade of diagnosis.AIM To examine risk factors for dyslipidemia in young subjects with T1D.METHODS Longitudinal and cross-sectional retrospective study of 170 young subjects with T1D(86 males;baseline mean age 12.2±5.6 years and hemoglobin A1c 8.4%±1.4%)were followed in a single tertiary diabetes center for a median duration of 15 years.Predictors for outcomes of lipid profiles at last visit(total cholesterol[TC],triglycerides[TGs],low-density lipoprotein-cholesterol[LDL-c],and highdensity lipoprotein-cholesterol[HDL-c])were analyzed by stepwise linear regression models.RESULTS At baseline,79.5%of the patients had at least one additional CVD risk factor(borderline dyslipidemia/dyslipidemia[37.5%],pre-hypertension/hypertension[27.6%],and overweight/obesity[16.5%])and 41.6%had multiple(≥2)CVD risk factors.A positive family history of at least one CVD risk factor in a first-degree relative was reported in 54.1%of the cohort.Predictors of elevated TC:family history of CVD(β[SE]=23.1[8.3],P=0.006);of elevated LDL-c:baseline diastolic blood pressure(DBP)(β[SE]=11.4[4.7],P=0.003)and family history of CVD(β[SE]=20.7[6.8],P=0.017);of elevated TGs:baseline DBP(β[SE]=23.8[9.1],P=0.010)and family history of CVD(β[SE]=31.0[13.1],P=0.020);and of low HDL-c levels:baseline DBP(β[SE]=4.8[2.1],P=0.022]).CONCLUSION Our findings suggest that elevated lipid profiles are associated with DBP and a positive family history of CVD.It is of utmost importance to prevent and control modifiable risk factors such as these,as early as childhood,given that inadequate glycemic control and elevation in blood pressure intensify the risk of dyslipidemia.展开更多
Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with CO...Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with COVID-19 vaccination is side effects after vaccination. In this report, we identify the relationship between side effects and elevation of antibodies as determined by monitoring several kinds of antibodies against COVID-19. Objective: We investigated whether the antibody level changed depending on side effects after COVID-19 vaccination. Methods: Healthy volunteers, who received two vaccinations between 10 March and 7 May 2021, were collected for this study. Information including age, gender, smoking history, medical history including allergies and side reactions after vaccination was obtained by questionnaire. Serum levels of antibodies of IgG and IgM against each S1, SP, and NP antigens of COVID-19 were evaluated frequently for 3 - 4 months after the first vaccination. Result: Ten employees working at Iwate Medical University were evaluated in this study. Side effects were observed in 7 of 10 patients, and grade 2 side effects in all 3 patients with a history of allergic disease. Serum S1 and SP IgG were elevated sufficiently in all patients. In all patients, IgG antibody titers fell below the cutoff point in approximately 3 months. No cases had elevated NP antibodies. SP IgM was elevated in three cases;all three cases with elevated IgM had allergic disease and the degree of side effects was relatively higher. Subjects with long-lasting elevated SPIgM were observed. Conclusion: S1 IgG and SP IgG exceeded the cutoff in all subjects after vaccination but decreased below the cutoff in all subjects within 4 months, regardless of side effects or allergic history. On the other hand, elevated SPIgM was suspected to be related to side effects and history of allergies, and cases with persistent elevation of SPIgM were observed.展开更多
BACKGROUND Timely and accurate identification of subgroup at risk for major adverse cardiovascular events among patients presenting with acute chest pain remains a challenge.Currently available risk stratification sco...BACKGROUND Timely and accurate identification of subgroup at risk for major adverse cardiovascular events among patients presenting with acute chest pain remains a challenge.Currently available risk stratification scores are suboptimal.Recently,a new scoring system called the Symptoms,history of Vascular disease,Electrocardiography,Age,and Troponin(SVEAT)score has been shown to outperform the History,Electrocardiography,Age,Risk factors and Troponin(HEART)score,one of the most used risk scores in the United States.AIM To assess the potential usefulness of the SVEAT score as a risk stratification tool by comparing its performance to HEART score in chest pain patients with low suspicion for acute coronary syndrome and admitted for overnight observation.METHODS We retrospectively reviewed medical records of 330 consecutive patients admitted to our clinical decision unit for acute chest pain between January 1st to April 17th,2019.To avoid potential biases,investigators assigned to calculate the SVEAT,and HEART scores were blinded to the results of 30-d combined endpoint of death,acute myocardial infarction or confirmed coronary artery disease requiring revascularization or medical therapy[30-d major adverse cardiovascular event(MACE)].An area under receiving-operator characteristic curve(AUC)for each score was then calculated.C-statistic and logistic model were used to compare RESULTS A 30-d MACE was observed in 11 patients(3.33%of the subjects).The AUC of SVEAT score(0.8876,95%CI:0.82-0.96)was significantly higher than the AUC of HEART score(0.7962,95%CI:0.71-0.88),P=0.03.Using logistic model,SVEAT score with cut-off of 4 or less significantly predicts 30-d MACE(odd ratio 1.52,95%CI:1.19-1.95,P=0.001)but not the HEART score(odd ratio 1.29,95%CI:0.78-2.14,P=0.32).CONCLUSION The SVEAT score is superior to the HEART score as a risk stratification tool for acute chest pain in low to intermediate risk patients.展开更多
The Yellow Emperor's Classic of Internal Medicine (黄帝内经素问Huangdi Neijing Suwen), created in the Warring States period (475 to 221 BC) described a phenomenon whereby the eastern, western, northern, southern, ...The Yellow Emperor's Classic of Internal Medicine (黄帝内经素问Huangdi Neijing Suwen), created in the Warring States period (475 to 221 BC) described a phenomenon whereby the eastern, western, northern, southern, and central regions were liable to different diseases. It brought forward the principle of treatment in accordance with local conditions. Lv's Spring and Autumn Annals, Huai Nan Tzu (Huainanzi), and the Regiment of Health (Yangshenglun) in the Qin, Han, Wei, Jin, and Southern and Northern Dynasties all describe regional diseases such as goiter (endemic goiter) and yellowish teeth (dental fluorosis) as being caused by geologic and climatic factors. Zhang (miasma), first mentioned in the Han Dynasty, was considered related to the summer heat and dampness particular to the geographical environment of the south. Zhang was further associated with malaria in the Jin Dynasty. General Treatise on the Etiology and Symptomology of Diseases (Zhubingyuanhou Lun), in the Sui Dynasty, held that as a type of poisonous gas, Zhang was the predisposing cause of malaria, seasonal disease, and barbiers, among other conditions. General Guide (Zhinan Zonglun), in the Southern Song Dynasty, regarded Zhang malaria as a separate disease. Healthy Prescription in the Southern Wuling District (Lingnan Weisheng Fang), in the late Song and early Yuan Dynasties, explicitly put forward the concepts of cold Zhang, hot Zhang, and lockjaw Zhang. Guidelines for Treatment of Zhang Malaria (Zhangnue Zhinan), in the Ming Dynasty, maintained that cold Zhang was equivalent to malaria, while hot Zhang and lockjaw Zhang were equivalent to cold damage, the latter of which can be treated by prescriptions for cold damage. Records on Zhang gas and Zhang disease decreased during the Ming and Qing Dynasties.展开更多
文摘Inflammatory bowel diseases(IBD),including ulcerative colitis(UC) and Crohn's disease(CD),are chronic,progressive and disabling disorders.Over the last few decades,new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD.The identification of clinical,genetic and serological prognostic factors has permitted a better stratification of the disease,thus allowing the opportunity to indicate the most appropriate therapy.Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change,at least in the short term,the course of the disease by reducing,in a subset of patients with IBD,hospitalization and the need for surgery.In this review,the crucial steps in the natural history of both UC and CD will be discussed,as well as the factors that may change their clinical course.The methodological requirements for high quality studies on the course and prognosis of IBD,the true impact of environmental and dietary factors on the clinical course of IBD,the clinical,serological and genetic predictors of the IBD course(in particular,which of these are rel-evant and appropriate for use in clinical practice),the impact of the various forms of medical treatment on the IBD complication rate,the role of surgery for IBD in the biologic era,the true magnitude of risk of colorectal cancer associated with IBD,as well as the mortality rate related to IBD will be stressed;all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.
基金supported by the National Natural Science Foundation of China(grants:30972531 and 81320108026)a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Objective We aimed to evaluate the combined effect of a family history of cardiovascular disease(CVD) and high serum C‐reactive protein(CRP) on the stroke incidence in an Inner Mongolian population in China. Methods A prospective cohort study was conducted from June 2002 to July 2012, with 2,544 participants aged 20 years and over from Inner Mongolia, China. We categorized participants into four groups based on the family history of CVD and CRP levels. Results We adjusted for age; sex; smoking; drinking; hypertension; body mass index; waist circumference; and blood glucose, triglycerides, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol levels. Compared with the group with no family history of CVD/low CRP levels, the group with family history of CVD/high CRP levels had a hazard ratio(HR) of 1.78 [95% confidence interval(CI), 1.03‐3.07; P = 0.039] of stroke, and an HR of 2.14(95% CI, 1.09‐4.20; P = 0.027) of ischemic stroke. The HRs of hemorrhagic stroke for the other three groups were not statistically significant(all P 〉 0.05). Conclusion Participants with both a family history of CVD and high CRP levels had the highest stroke incidence, suggesting that high CRP levels may increase stroke risk, especially of ischemic stroke, among individuals with a family history of CVD.
文摘Crohn’s disease (CD) is a multifactorial potentially debilitating disease. It has a variable disease course, but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability. Studies on the natural history of CD provide invaluable data on its course and clinical predictors, and may help to identify patient subsets based on clinical phenotype. Most data are available from referral centers, however these outcomes may be different from those in population-based cohorts. New data suggest the possibility of a change in the natural history in Crohn’s disease, with an increasing percentage of patients diagnosed with inflammatory disease behavior. Hospitalization rates remain high, while surgery rates seem to have decreased in the last decade. In addition, mortality rates still exceed that of the general population. The impact of changes in treatment strategy, including increased, earlier use of immunosuppressives, biological therapy, and patient monitoring on the natural history of the disease are still conflictive. In this review article, the authors summarize the available evidence on the natural history, current trends, and predictive factors for evaluating the disease course of CD.
文摘Patients with extensive or complicated Crohn's disease(CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines.In patients with localized and uncomplicated CD at diagnosis,early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact.In this context,there is a need for predictors of benign or unfavourable subsequent clinical course,in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions.At diagnosis,an age below 40 years,the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course.The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts.Consequently,the use of these predictors can be integrated into the elements that influence individual decisions.In the CD postoperative context,keeping smoking and history of prior resection are the stron-gest predictors of disease symptomatic recurrence.However,these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice.In ulcerative colitis(UC),extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease,and also with long-term colectomy and colorectal inflammation-associated colorectal cancer.In patients with extensive UC at diagnosis,a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered.At the moment,no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.
文摘AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
基金The study was reviewed and approved by the Institutional Review Board at Rabin Medical Center,approval No.0075-17-RMC.
文摘BACKGROUND Type 1 diabetes(T1D)contributes to altered lipid profiles and increases the risk of cardiovascular disease(CVD).Youth with T1D may have additional CVD risk factors within the first decade of diagnosis.AIM To examine risk factors for dyslipidemia in young subjects with T1D.METHODS Longitudinal and cross-sectional retrospective study of 170 young subjects with T1D(86 males;baseline mean age 12.2±5.6 years and hemoglobin A1c 8.4%±1.4%)were followed in a single tertiary diabetes center for a median duration of 15 years.Predictors for outcomes of lipid profiles at last visit(total cholesterol[TC],triglycerides[TGs],low-density lipoprotein-cholesterol[LDL-c],and highdensity lipoprotein-cholesterol[HDL-c])were analyzed by stepwise linear regression models.RESULTS At baseline,79.5%of the patients had at least one additional CVD risk factor(borderline dyslipidemia/dyslipidemia[37.5%],pre-hypertension/hypertension[27.6%],and overweight/obesity[16.5%])and 41.6%had multiple(≥2)CVD risk factors.A positive family history of at least one CVD risk factor in a first-degree relative was reported in 54.1%of the cohort.Predictors of elevated TC:family history of CVD(β[SE]=23.1[8.3],P=0.006);of elevated LDL-c:baseline diastolic blood pressure(DBP)(β[SE]=11.4[4.7],P=0.003)and family history of CVD(β[SE]=20.7[6.8],P=0.017);of elevated TGs:baseline DBP(β[SE]=23.8[9.1],P=0.010)and family history of CVD(β[SE]=31.0[13.1],P=0.020);and of low HDL-c levels:baseline DBP(β[SE]=4.8[2.1],P=0.022]).CONCLUSION Our findings suggest that elevated lipid profiles are associated with DBP and a positive family history of CVD.It is of utmost importance to prevent and control modifiable risk factors such as these,as early as childhood,given that inadequate glycemic control and elevation in blood pressure intensify the risk of dyslipidemia.
文摘Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with COVID-19 vaccination is side effects after vaccination. In this report, we identify the relationship between side effects and elevation of antibodies as determined by monitoring several kinds of antibodies against COVID-19. Objective: We investigated whether the antibody level changed depending on side effects after COVID-19 vaccination. Methods: Healthy volunteers, who received two vaccinations between 10 March and 7 May 2021, were collected for this study. Information including age, gender, smoking history, medical history including allergies and side reactions after vaccination was obtained by questionnaire. Serum levels of antibodies of IgG and IgM against each S1, SP, and NP antigens of COVID-19 were evaluated frequently for 3 - 4 months after the first vaccination. Result: Ten employees working at Iwate Medical University were evaluated in this study. Side effects were observed in 7 of 10 patients, and grade 2 side effects in all 3 patients with a history of allergic disease. Serum S1 and SP IgG were elevated sufficiently in all patients. In all patients, IgG antibody titers fell below the cutoff point in approximately 3 months. No cases had elevated NP antibodies. SP IgM was elevated in three cases;all three cases with elevated IgM had allergic disease and the degree of side effects was relatively higher. Subjects with long-lasting elevated SPIgM were observed. Conclusion: S1 IgG and SP IgG exceeded the cutoff in all subjects after vaccination but decreased below the cutoff in all subjects within 4 months, regardless of side effects or allergic history. On the other hand, elevated SPIgM was suspected to be related to side effects and history of allergies, and cases with persistent elevation of SPIgM were observed.
文摘BACKGROUND Timely and accurate identification of subgroup at risk for major adverse cardiovascular events among patients presenting with acute chest pain remains a challenge.Currently available risk stratification scores are suboptimal.Recently,a new scoring system called the Symptoms,history of Vascular disease,Electrocardiography,Age,and Troponin(SVEAT)score has been shown to outperform the History,Electrocardiography,Age,Risk factors and Troponin(HEART)score,one of the most used risk scores in the United States.AIM To assess the potential usefulness of the SVEAT score as a risk stratification tool by comparing its performance to HEART score in chest pain patients with low suspicion for acute coronary syndrome and admitted for overnight observation.METHODS We retrospectively reviewed medical records of 330 consecutive patients admitted to our clinical decision unit for acute chest pain between January 1st to April 17th,2019.To avoid potential biases,investigators assigned to calculate the SVEAT,and HEART scores were blinded to the results of 30-d combined endpoint of death,acute myocardial infarction or confirmed coronary artery disease requiring revascularization or medical therapy[30-d major adverse cardiovascular event(MACE)].An area under receiving-operator characteristic curve(AUC)for each score was then calculated.C-statistic and logistic model were used to compare RESULTS A 30-d MACE was observed in 11 patients(3.33%of the subjects).The AUC of SVEAT score(0.8876,95%CI:0.82-0.96)was significantly higher than the AUC of HEART score(0.7962,95%CI:0.71-0.88),P=0.03.Using logistic model,SVEAT score with cut-off of 4 or less significantly predicts 30-d MACE(odd ratio 1.52,95%CI:1.19-1.95,P=0.001)but not the HEART score(odd ratio 1.29,95%CI:0.78-2.14,P=0.32).CONCLUSION The SVEAT score is superior to the HEART score as a risk stratification tool for acute chest pain in low to intermediate risk patients.
文摘The Yellow Emperor's Classic of Internal Medicine (黄帝内经素问Huangdi Neijing Suwen), created in the Warring States period (475 to 221 BC) described a phenomenon whereby the eastern, western, northern, southern, and central regions were liable to different diseases. It brought forward the principle of treatment in accordance with local conditions. Lv's Spring and Autumn Annals, Huai Nan Tzu (Huainanzi), and the Regiment of Health (Yangshenglun) in the Qin, Han, Wei, Jin, and Southern and Northern Dynasties all describe regional diseases such as goiter (endemic goiter) and yellowish teeth (dental fluorosis) as being caused by geologic and climatic factors. Zhang (miasma), first mentioned in the Han Dynasty, was considered related to the summer heat and dampness particular to the geographical environment of the south. Zhang was further associated with malaria in the Jin Dynasty. General Treatise on the Etiology and Symptomology of Diseases (Zhubingyuanhou Lun), in the Sui Dynasty, held that as a type of poisonous gas, Zhang was the predisposing cause of malaria, seasonal disease, and barbiers, among other conditions. General Guide (Zhinan Zonglun), in the Southern Song Dynasty, regarded Zhang malaria as a separate disease. Healthy Prescription in the Southern Wuling District (Lingnan Weisheng Fang), in the late Song and early Yuan Dynasties, explicitly put forward the concepts of cold Zhang, hot Zhang, and lockjaw Zhang. Guidelines for Treatment of Zhang Malaria (Zhangnue Zhinan), in the Ming Dynasty, maintained that cold Zhang was equivalent to malaria, while hot Zhang and lockjaw Zhang were equivalent to cold damage, the latter of which can be treated by prescriptions for cold damage. Records on Zhang gas and Zhang disease decreased during the Ming and Qing Dynasties.