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Background Xylaria nigripes (Koltz.) Cooke, also known as Wuling Shen, is a high-value medicinal mushroom. It is a herbal medicine traditionally used for treating insomnia, trauma and depression. However, its toxicity has never been systematically evaluated. This study aimed to evaluate the safety of a standardized aqueous extract (XNE), an ingredient of commercial products, prepared from solid-state cultured X. nigripes in rats. Methods A 90-day subchronic toxicity study was conducted by oral administration of XNE at daily doses of 20, 1000 and 2000 mg/kg body weight to Sprague-Dawley rats of both sexes, and the control group was given distilled water (vehicle). All animals were checked daily for general behavior, body weight changes and signs of toxicity. At the end of the treatment period, hematological analysis, biochemical analysis and histopathological examination of organs were conducted. Results At tested concentrations, oral XNE administration caused no treatment-induced adverse effects on general health, body weight gain, relative organ weights, and hematological and biochemical parameters. Histopathological results also showed no significant structural changes in organs even in high-dose XNE-treated animals. Conclusion This study suggests that treatment with XNE for 90 days does not produce significant toxicity, even up to 100 fold (2000 mg/kg body weight/day) of the recommended daily intakes. Therefore, the use of XNE as herbal medicines is considered to be relatively safe.

β-Linked polysaccharides including β-glucans are well known to be important functional ingredients, and are known to possess immunomodulatory and anti-tumor activities. This study aimed to investigate the anti-inflammatory properties and participating receptor of water soluble and insoluble bioactive polysaccharides from Grifola frondosa (GFP, non-digestible water soluble polysaccharides), Laminaria digitata (laminarin, a water soluble β-glucan) and Saccharomyces cerevisiae (zymosan, a water insoluble β-glucan) in lipopolysaccharide (LPS)-stimulated parental and Dectin-1 highly expressing RAW264.7 macrophages. Results showed that GFP and laminarin significantly inhibited nitric oxide and prostaglandin E2 production, but only the GFP with high molecular weight exhibited strong inhibition on pro-inflammatory cytokine (TNF-α and IL-6) secretion in a concentration-dependent manner. The activation of NF-κB was also significantly down-regulated by GFP treatment as compared with cells treated with LPS alone. Although GFP and laminarin were able to bind to β-glucan receptor Dectin-1, there was no relationship between the inhibitory potency and the content of β-glucans in GFP, and these inhibitory effects were not affected by the expression level of Dectin-1 in macrophage cells. In contrast, zymosan significantly intensified LPS-induced inflammatory responses through Dectin-1. In conclusion, these results suggest that the inhibitory effects of water soluble polysaccharides on LPS-induced pro-inflammatory mediator production in murine macrophages may not involve β-glucan receptor Dectin-1.

Mushroom polysaccharides including β-glucans possess various health-promoting properties and are known to be the major bioactive constituents of Grifola frondosa (GF), which is a popular edible and medicinal mushroom. Dectin-1, a pattern-recognition receptor, is responsible for recognizing β-glucans. In this study, parental RAW264.7 macrophages and Dectin-1-expressing RAW264.7 macrophages were used to investigate the anti-inflammatory activity and receptor involvement of the water-soluble polysaccharides from GF. Results indicated that the high molecular weight fraction of GF (GF70-F1; 1260 kDa) inhibited TNF-α and IL-6 production as well as NF-κB activation in lipopolysaccharide-induced macrophages. Chemical and enzymatic linkage analyses indicated that GF70-F1 mainly contained the known (1→3),(1→6)-β-d-glucan and a polysaccharide not previously isolated from GF, a nondigestible glucan with a β-(1→4)-linked backbone and β-(1→6)-linked branches. The ability of GF70-F1 to inhibit cytokine production was not affected by the expression level of Dectin-1 in cells, and a similar inhibitory activity was observed after removing the (1→3),(1→6)-β-d-glucan from GF70-F1. Blockade of Toll-like receptor 2 (TLR2) but not Dectin-1 or complement receptor 3 (CR3) attenuated the inhibitory activity of GF70-F1. The nondigestible (1→6)-branched (1→4)-β-d-glucan in GF70-F1 may contribute to the anti-inflammatory activity via interacting with TLR2 rather than Dectin-1 or CR3 receptors.

Background: We investigated the association between taking herbal medicine (HM) containing aristolochic acid (AA) and the risk of primary liver cancer (PLC) among patients with hepatitis C virus (HCV) infection. Methods: This is a prospective study for the long-term follow-up of a nationwide population-based cohort of patients ages 18 years or older diagnosed with HCV infection during 1997 to 2010. A total of 223,467 HCV-infected patients were identified using the National Health Insurance Research Database in Taiwan. The use of HM containing AA was evaluated among patients who had visited traditional Chinese medicine clinics beginning from 1997 to 1 year prior to the diagnosis of PLC or dates censored (2003). We tracked each individual patient from 1997 to 2013 to identify incident cases of PLC since 1999. Results: During the follow-up period of 3,052,132 person-years, we identified 25,502 PLC cases; this corresponded to an overall incidence rate of 835.5 PLCs per 100,000 person-years. The adjusted HRs were 1.21 [95% confidence interval (CI), 1.18–1.24], 1.48 (95% CI, 1.37–1.59), 1.50 (95% CI, 1.34–1.68), and 1.88 (95% CI, 1.61–2.19) for estimated AA usage groups: 1 to 250, 251 to 500, 501 to 1,000, and more than 1,000 mg, respectively, relative to no AA exposure (reference group). Conclusions: The current findings suggest that among HCV-positive patients, increasing exposure to AA poses an increased risk of acquiring PLC. Impact: AA may increase the risk of PLC in HCV-positive populations.

Nondigestible polysaccharides are essential nutrients, which are also important bioactive constituents of mushrooms. This study aimed to investigate the physicochemical properties and anti-inflammatory effects of different polysaccharide components of Xylaria nigripes in lipopolysaccharides (LPS)-induced RAW264.7 macrophages. Results showed that X. nigripes nondigestible polysaccharide (XN) possessed a molecular weight of 910.7 kDa and mainly composed of glucose; it effectively suppressed NO, TNF-α, and IL-6 production. Based on molecular weight, two bioactive polysaccharide components (F1 and F2) were isolated from XN. F1 was a glucan with high molecular weight (885.2 kDa), whereas F2 was a low molecular weight heteropolysaccharide (24.5 kDa) composing of glucose, mannose, and galactose. F1 showed stronger inhibitory effects on NO, TNF-α, and IL-6 production than F2, however, its inhibitory effects were weaker than XN. Further analysis demonstrated that the combined treatment of F1 and F2 exhibited anti-inflammatory activity as good as XN, and they possessed synergistic effects on inhibiting pro-inflammatory mediator production. PRACTICAL APPLICATIONS: Polysaccharides are essential nutrients, and are major bioactive constituents of mushrooms. This study isolated two bioactive polysaccharide components from Xylaria nigripes, namely F1 and F2. F1 was a high molecular weight glucan, whereas F2 was a low molecular weight heteropolysaccharide. F1 showed stronger anti-inflammatory activity than F2, but was weaker than their combined treatment (F1 + F2). Different polysaccharide components were shown to possess synergistic anti-inflammatory effects, suggesting their importance in the formulation of polysaccharide-based products.

Polysaccharides including β-glucans are important bioactive components of mushroom. Xylaria nigripes is a popular medicinal fungus that has been used for treating trauma, insomnia and mental illness. This study examined the physicochemical characteristics and anti-inflammatory activities of water soluble non-digestible polysaccharides (TXNP and CXNP) from fruiting bodies of two cultivated X. nigripes strains (TXN and CXN). Results showed that both TXNP and CXNP possessed relatively similar FT-IR spectra. TXNP had a triple helix conformation and molecular weight of 853.8 kDa, whereas the molecular weight of CXNP was 14.7 kDa. The monosaccharide composition of TXNP was predominantly glucose, whereas CXNP contained xylose, mannose and glucose. Although both TXNP and CXNP dose-dependently suppressed the production of NO, IL-1β, TNF-α and PGE2, as well as the expression of iNOS, COX-2 and NF-κB in the lipopolysaccharide-induced RAW264.7 macrophages, the potency of TXNP was stronger. This study reveals that under similar conditions of cultivation and extraction procedures, the different physicochemical characteristics of polysaccharides from TXN and CXN may have contributed to the differences in their anti-inflammatory potency.

It was suspected that aristolochic acid-induced mutations may be associated with hepatitis B virus (HBV), playing an important role in liver carcinogenesis. The purpose of this study was to investigate the association between the use of Chinese herbs containing aristolochic acid and the risk of hepatocellular carcinoma (HCC) among HBV-infected patients. We conducted a retrospective, population-based, cohort study on patients older than 18 years who had a diagnosis of HBV infection between January 1, 1997 and December 31, 2010 and had visited traditional Chinese medicine clinics before one year before the diagnosis of HCC or the censor dates. A total of 802,642 HBV-infected patients were identified by using the National Health Insurance Research Database in Taiwan. The use of Chinese herbal products containing aristolochic acid was identified between 1997 and 2003. Each patient was individually tracked from 1997 to 2013 to identify incident cases of HCC since 1999. There were 33,982 HCCs during the follow-up period of 11,643,790 person-years and the overall incidence rate was 291.8 HCCs per 100,000 person-years. The adjusted hazard ratios (HRs) were 1.13 (95% confidence interval [CI], 1.11-1.16), 1.21 (95% CI, 1.13-1.29), 1.37 (95% CI, 1.24-1.50) and 1.61 (95% CI, 1.40-1.84) for estimated aristolochic acid of 1-250, 251-500, 501-1,000 and more than 1,000 mg, respectively, relative to no aristolochic acid exposure. Our study found a significant dose-response relationship between the consumption of aristolochic acid and HCC in patients with HBV infection, suggesting that aristolochic acid which may be associated with HBV plays an important role in the pathogenesis of HCC.

Mushroom polysaccharides including β-glucans possess various health-promoting properties and are known to be the major bioactive constituents of

Xylaria nigripes, also known as Wu Ling Shen, is popular for treating insomnia and trauma in traditional Chinese medicine. This study aimed to examine the anti-inflammatory activity and bioactive constituents of cultivated X. nigripes fruiting bodies in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Results showed that among the different extracts, the hexane fraction exhibited the best protection against cell toxicity induced by 1 μg/mL LPS and the strongest inhibitory effect on nitric oxide (NO) production. This fraction led to the isolation of 2 bioactive compounds (namely, XN-CP1 and XN-CP2), which were confirmed to be ergostarien-3β-ol and ergosterol peroxide, respectively. Although both XN-CP1 and XN-CP2 showed good inhibitory effects on NO, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and prostaglandin E2 production in LPS-stimulated macrophages, XN-CP2 was shown to have a stronger anti-inflammatory activity; this was further supported by its strong suppressive effects on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and nuclear factor (NF)-κB activation. These results conclude that ergosterol peroxide (XN-CP2) could be the main bioactive compound contributing to the potent anti-inflammatory activity of X. nigripes, and its mechanism of action is mediated through inhibition of iNOS and COX-2 expression via the NF-κB signaling pathway.

Background Taiwan has a remarkably high incidence of end-stage renal disease (ESRD). The objective of this study is to determine the association between prescribed herbal products containing aristolochic acid and ESRD. Study Design Population-based case-control study. Setting & Participants All new ESRD cases in Taiwan and a simple random sample (200,000 people) drawn from the national health insurance reimbursement database in 1997-2002. Predictor Age; sex; hypertension; diabetes; cumulative doses of nonsteroidal anti-inflammatory drugs, acetaminophen, and adulterated herbal supplements potentially containing aristolochic acid before the development of chronic kidney disease; and indications for prescribing such herbs, including chronic hepatitis, chronic urinary tract infection, chronic neuralgia, or chronic musculoskeletal diseases. Outcomes & Measurements Occurrence of ESRD through construction of multiple logistic regression models. Results There were 36,620 new ESRD cases from 1998 through 2002. After exclusion of cases with chronic kidney disease diagnosed before July 1, 1997, there were 25,843 new cases of ESRD and 184,851 controls in the final analysis. Women, older age, hypertension, and diabetes were significantly associated with increased risks of the development of ESRD. After adjustment for known risk factors, cumulative doses >60 g of Mu Tong (OR, 1.47 [95% CI, 1.01-2.14] for 61-100 g; OR, 5.82 [95% CI, 3.89-8.71] for >200 g) or Fangchi (OR, 1.60 [95% CI, 1.20-2.14] for 61-100 g; OR, 1.94 [95% CI, 1.29-2.92] for >200 g) were associated with increased risk of the development of ESRD with a dose-response relationship. This relationship persisted when analyses were limited to participants who consumed Limitations No measurement of renal function, no contact with patients, over-the-counter sales were not recorded, and potential underestimation of exposure dose for cases and ORs. Conclusions Consumption of >60 g of Mu Tong or Fangchi from herbal supplements was associated with an increased risk of developing kidney failure.

Nephropathy associated with aristolochic acid (AA) has been documented by human and animal studies. Ancient Chinese herbology claimed to reduce toxicity in their mixtures. It was the objective of this study to determine the risk of chronic kidney disease (CKD) associated with AA-related Chinese herbal products (CHP) or mixtures of herbs in a national cohort.A retrospective follow-up study was conducted, using a systematic random sample (200 000 people) in the National Health Insurance reimbursement database during 1997-2002. The incidence rates of CKD and end-stage renal disease (ESRD) were calculated for the whole sample and those that had used CHP suspected to contain AA. Cox regression models were constructed to control potential confounders, including age, sex, hypertension, diabetes mellitus, and use of non-steroidal anti-inflammatory drugs and acetaminophen.A total of 199 843 persons were included in the final analysis, 102 464 (51.3%) men and 97 379 (48.7%) women, with an average incidence rate of 1964/10(6) person-years for CKD and 279/10(6) person-years for ESRD. After controlling other risk factors, the hazard ratios for development of CKD seemed to increase for patients that had consumed more than 30 g Mu-Tong, and more than 60 g Fangchi.Prescription of more than 30 g Mu-Tong or more than 60 g Fangchi CHP was associated with an increased risk of developing CKD. In addition to prohibiting the use of Guan-Mu-Tong and Guang-Fangchi, patients who have used these CHP should continue to be followed up.

Background In many parts of the world, diabetic nephropathy is the principal cause of patients requiring renal replacement therapy. The survival rate of diabetic patients on maintenance dialysis, either hemodialysis (HD) or peritoneal dialysis (PD), is lower than that of non-diabetic patients on either modality. However, studies analyzing the rates of survival between the methods have reported conflicting results. Methods We used a retrospective analysis of data obtained from the China Medical University Hospital in Taiwan. All new end-stage renal disease (ESRD) patients who were undergoing initial dialysis, either HD or PD, for more than 3 months at our hospital from January 2000 through December 2003, and were followed-up through June 2004, were included. We compared survival rates between diabetic and non-diabetic patients, and between the 2 modalities. Results Of the 445 patients studied, 219 patients (49.2%) received HD and 226 patients (50.8%) received PD as their initial therapy. One hundred two HD patients (46.6%) and 96 PD patients (42.5%) were diabetic. The average age was 60 ± 13 years for the HD patient group and 57 ± 16 years for the PD patient group. The hemoglobin level for the HD group was 9.5 ± 1.4 g/dL and 9.4 ± 1.3 g/dL for the PD group. The serum albumin level was 3.0 ± 0.6 g/dL for the HD group and 2.9 ± 0.6 g/dL for the PD group. There was no significant difference in the number of co-morbidities between the HD and PD patients. Kaplan-Meier survival curve and Cox-regression analysis were used to compare the relative ratio (RR) of mortality between the HD and PD patient groups. Among these 445 patients, PD patients were associated with a significantly lower risk of death (RR: 0.382) compared with the HD patients. Older age (≥65 years), diabetes mellitus as the cause of ESRD, co-morbidity of ischemic heart disease, congestive heart failure, cerebral vascular accident, peripheral artery occlusive disease, or liver cirrhosis, and Hb levels

Background/Aims: To compare dialysance and ultrafiltration (UF) of peritoneum in diabetes mellitus (DM) and non-DM patients on continuous ambulatory peritoneal dialysis. Methods: A total of 162 adult patients on continuous ambulatory peritoneal dialysis (40 DM and 122 non-DM patients) were studied with the peritoneal equilibration test (PET) using 2.5% glucose dialysis solution retained for 4 h. Patients using 2,000 or 1,500 ml of infusion volume were classified into groups A (23 DM and 63 non-DM patients) and B (16 DM and 41 non-DM patients), respectively. PET results were compared between DM and non-DM patients by unpaired t test. Using Pearson’s correlation and least-square multiple regression, the most powerful predictors of UF rate were also evaluated in DM and non-DM patients. Results: There were no differences between PET parameters and UF rate between DM and non-DM patients in the whole group (WG) and group A. The only significant difference (p < 0.05) was an increased D4/D0 value in DM patients in group B. The most simple but powerful method to predict UF rate was (100 – GAP)/(D4/D0), where GAP corresponds to the glucose absorption percentage and D4/D0 is the PET 4-hour dialysate glucose level/PET 0-hour dialysate glucose level. GAP and D4/D0 were two major determinants of UF rate in the DM group, non-DM group and WG. Conclusions: Peritoneal permeability did not differ between DM and non-DM patients, and GAP and D4/D0 were two major factors predicting UF rate.

♦ BackgroundPeritoneal fibrosis is a long-term complication following continuous ambulatory peritoneal dialysis (CAPD). Peritoneal fibroblasts may play an important role in peritoneal fibrosis. Up to now, the treatment of peritoneal fibrosis in patients with CAPD remains unsatisfactory. Pentoxifylline (PTX) is a xanthine derivative and is used in the treatment of peripheral vascular and cerebrovascular diseases. Several studies have demonstrated that PTX can ameliorate fibrosis of the skin, liver, and kidney.♦ ObjectiveTo investigate the effect of PTX on in vitro growth and collagen synthesis of human peritoneal fibroblasts (HPFBs), and to evaluate the effects of PTX on silica-induced peritoneal fibrosis in vivo.♦ Design and MeasurementsIn the in vitro study, HPFBs were cultured from human omentum. The effect of PTX on the growth of serum-stimulated HPFBs was evaluated by MTT assay. The effect of PTX on the collagen synthesis of HPFB was measured by [3H]-proline incorporation. Expression of type I and type III collagen mRNA was evaluated by Northern blotting. The effects of PTX on matrix metalloproteinase (MMP) activity and cAMP level in HPFBs were measured by immunoassays. In the in vivo study, Wistar rats were randomly divided into five groups. All rats received intraperitoneal (IP) injection of silica suspension (250 mg/100 g body weight) on day 0. The rats of group 1 (control group) were injected with vehicle IP every day for 14 days. The rats of groups 2, 3, and 4 were injected with PTX (4 mg/100 g body weight) IP every day for 3, 7, and 14 days, respectively. The rats in group 5 received an intravenous infusion of PTX (8 mg/100 g body weight) every day for 7 days. On the 15th day after silica injection, all rats were sacrificed. Their parietal and visceral peritoneums were removed and processed for pathology, and the severity of fibrosis was measured and scored. ♦ Results: In vitro, PTX inhibited serum-stimulated HPFB growth (maximum was 93% at 1 mg PTX/mL) in a dose-dependent manner. Collagen synthesis by HPFB was reduced (47% at 1 mg PTX/mL), and collagen I and III mRNA expression in HPFBs was suppressed by PTX. The PTX did not affect the MMP (including MMP-1, MMP-8, and MMP-13) activities of HPFBs. The mechanism of PTX was through increasing cAMP by its phosphodiesterase inhibiting activity. In vivo, the severity of fibrosis was significantly reduced in groups 4 and 5 compared to group 1 ( p < 0.05).♦ ConclusionThese results suggest that PTX can inhibit growth of and collagen synthesis by HPFBs in vitro. The fibrosis derived from silica-induced peritonitis in vivo was also ameliorated by PTX. Therefore, pentoxifylline may have the potential to be used to treat peritoneal fibrosis in patients on CAPD.

Renal failure with severe uremia is still an important cause of mortality, despite effective renal replacement therapy. Cardiopulmonary arrest (CPA) is the most severe complication during hemodialysis (HD). To acquire more information about cardiopulmonary resuscitation (CPR) during HD, we retrospectively enrolled 24 patients (11 males and 13 females) who had CPR during HD in a medical center during a 3-year period. Their mean age was 66.8 ± 16.8 years. The CPR rate of the patients from our outpatient department (0.02%) was significantly lower than that from general wards (0.11%), the intensive care unit (ICU, 0.16%), or the emergency room (ER, 0.38%). Eighteen patients (75%) were initially resuscitated successfully. Only 11 patients (45.8%) survived more than 24 h after CPR, and 2 patients (8.3%) survived more than 1 month, but none survived until discharge. The rates of surviving 24 h and surviving to discharge during HD were lower than those in the general wards, the ICU or the ER. Sepsis (33.3%) and cardiogenic shock (25%) were the two leading causes of death. For analyzing factors affecting the outcome of CPR, we divided the patients into 2 groups by survival time (≦24 vs. >24 h). Patients with heart disease or with prolonged CPR durations (>30 min) had shorter survival. No significant survival difference between the 2 groups was found due to factors of age, sex, diabetic nephropathy, pre-arrest morbidity scores, pre-arrest laboratory data, renal failure pattern, HD duration, the preceding HD time and ultrafiltrated volume.

Introduction Both end-stage renal disease (ESRD) and urothelial cancer (UC) are associated with the consumption of Chinese herbal products containing aristolochic acid (AA) by the general population. The objective of this study was to determine the risk of UC associated with AA-related Chinese herbal products among ESRD patients. Methods We conducted a cohort study using the National Health Insurance reimbursement database to enroll all ESRD patients in Taiwan from 1998–2002. Cox regression models were constructed and hazard ratios and confidence intervals were estimated after controlling for potential confounders, including age, sex, residence in region with endemic black foot disease, urinary tract infection, and use of non-steroidal anti-inflammatory drugs and acetaminophen. Results A total of 38,995 ESRD patients were included in the final analysis, and 320 patients developed UC after ESRD. Having been prescribed Mu Tong that was adulterated with Guan Mu Tong (Aristolochia manshuriensis) before 2004, or an estimated consumption of more than 1–100 mg of aristolochic acid, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC, although there was little correlation between the two risk factors. Conclusion Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. Regular follow-up screening for UC in ESRD patients who have consumed Chinese herbal products is thus necessary.

Background/Purpose End-stage renal disease (ESRD) may increase the likelihood of malignancy. The aim of this study is to evaluate the characteristics of increased urothelial cancer (UC) risk in patients with ESRD in Taiwan by a population-based study. Methods The standardized incidence ratios (SIRs) for UC among a registered cohort of ESRD in Taiwan during 1997–2002 were calculated using reimbursement data obtained from the Bureau of National Health Insurance (NHI), with the incidence rates of UC in the general population as the reference. Results During the study period we identified 58,739 patients with ESRD, 20,939 patients with UC, and 1305 patients with ERSD and UC. Among the 1305 patients with both diseases, 687 developed UC after ESRD had been diagnosed. Using the general population as the reference group, SIRs were 12.9 [95% confidence interval (CI)]: 12.0–13.9) for all UC cases, 13.9 (95% CI: 12.4–15.0) for bladder cancer, 11.9 (95% CI: 8.6–16.0) for renal cell carcinoma, and 11.6 (95% CI: 10.1–13.1) for upper tract urothelial cancer. Conclusion Patients with ESRD are at increased risk for UC in Taiwan, especially women age 50 years and younger. Early and lifelong surveillance of UC is recommended after diagnosis of ESRD.

Background Consumption of Chinese herbs that contain aristolochic acid (eg, Mu Tong) has been associated with an increased risk of urinary tract cancer. Methods We conducted a population-based case–control study in Taiwan to examine the association between prescribed Chinese herbal products that contain aristolochic acid and urinary tract cancer. All patients newly diagnosed with urinary tract cancer (case subjects) from January 1, 2001, to December 31, 2002, and a random sample of the entire insured population from January 1, 1997, to December 31, 2002 (control subjects), were selected from the National Health Insurance reimbursement database. Subjects who were ever prescribed more than 500 pills of nonsteroidal anti-inflammatory drugs and/or acetaminophen were excluded, leaving 4594 case patients and 174 701 control subjects in the final analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multivariable logistic regression models for the association between prescribed Chinese herbs containing aristolochic acid and the occurrence of urinary tract cancer. Models were adjusted for age, sex, residence in a township where black foot disease was endemic (an indicator of chronic arsenic exposure from drinking water [a risk factor for urinary tract cancer]), and history of chronic urinary tract infection. Statistical tests were two-sided. Results Having been prescribed more than 60 g of Mu Tong and an estimated consumption of more than 150 mg of aristolochic acid were independently associated with an increased risk for urinary tract cancer in multivariable analyses (Mu Tong: at 61–100 g, OR = 1.6, 95% CI = 1.3 to 2.1, and at >200 g, OR = 2.1, 95% CI = 1.3 to 3.4; aristolochic acid: at 151–250 mg, OR = 1.4, 95% CI = 1.1 to 1.8, and at >500 mg, OR = 2.0, 95% CI = 1.4 to 2.9). A statistically significant linear dose–response relationship was observed between the prescribed dose of Mu Tong or the estimated cumulative dose of aristolochic acid and the risk of urinary tract cancer (P < .001 for both). Conclusions Consumption of aristolochic acid–containing Chinese herbal products is associated with an increased risk of cancer of the urinary tract in a dose-dependent manner that is independent of arsenic exposure.