Factors associated with the initiation of alpha-interferon treatment in Medicaid patients diagnosed with hepatitis C.

We aimed to determine rates of treatment with alpha-interferon medication in patients diagnosed with hepatitis C virus (HCV), to ascertain the prevalence of selected conditions that could influence initiation of interferon treatment, and to examine the association between the presence of these conditions and interferon treatment. A nested case-control design was used in California Medicaid (Medi-Cal) claims data covering the period from 1 January 1996 to 30 June 2002. Interferon-treated cases and non-treated controls were selected in a 1 : 2 ratio that matched the length of the observation period and year of index HCV diagnosis. Predictor variables examined in bivariate and multivariate analyses included demographics, substance abuse and dependence, psychotropic drug use, selected chronic conditions and medical utilization. The proportion of eligible subjects diagnosed with HCV and treated with interferon ranged from 10.7 to 13.9%. There were 529 treated cases that met the eligibility criteria and 1058 non-treated HCV patients selected as controls. Multivariate factors that increased the likelihood of treatment were a liver biopsy, a diagnosis of mild liver disease, a diagnosis of psoriasis, antidepressant use and classification of race/ethnicity as 'other'. A decreased likelihood of treatment was linked to age > or =65 years, a diagnosis of kidney disease, one to four emergency visits and five or more emergency visits. The proportion of patients receiving interferon treatment in the Medi-Cal-insured population was low compared with published rates in HCV patients in other general medical settings. The diverse factors linked to initiation of HCV therapy raise compelling questions for further research.

Drug glucuronidation in clinical psychopharmacology.

Glucuronidation is a phase II metabolic process and one of the most common pathways in the formation of hydrophilic drug metabolites. At least 33 families of uridine diphosphate-glucuronosyltransferases have been identified in vitro, and specific nomenclature similar to that used to classify the cytochrome (CYP) P450 system has been established. The UGT1 and UGT2 subfamilies represent the most important of these enzymes in human drug metabolism. Factors affecting glucuronidation include the following: cigarette smoking, obesity, age, and gender. In addition, several drugs have been found in vitro to be substrates, inhibitors, or inducers of UGT enzymes. Induction or inhibition of both UGT and CYP isoforms may occur simultaneously. Some important drug interactions involving glucuronidation have been documented and others can be postulated. This review summarizes the relevant literature pertaining to drug glucuronidation and its implications for clinical psychopharmacology.

Is valproate pharmacotherapy associated with polycystic ovaries?

OBJECTIVE: To review and evaluate the published data associating the use of valproate with the development of polycystic ovaries. DATA SOURCES: A computerized search of MEDLINE (1966-May 1999) and Current Contents was performed. Also, bibliographies were cross-referenced to yield additional pertinent publications. All articles written in English were considered for review. STUDY SELECTION AND DATA EXTRACTION: All pertinent clinical studies and review articles associating valproate with polycystic ovaries and other endocrinologic disorders were evaluated. DATA SYNTHESIS: Valproate is among the most commonly used medications today effective in the treatment of a variety of neurologic and psychiatric disorders. An accumulating body of literature has suggested an increase in the incidence of polycystic ovarian syndrome among women treated with valproate. The syndrome is characterized as hyperandrogenism and chronic anovulation in the absence of identifiable adrenal or pituitary pathology. It is a highly prevalent syndrome, affecting 2-22% of women in the general population. CONCLUSIONS: Although a number of studies have found clear evidence of neuroendocrine perturbations in patients treated with valproate, there are presently limited data from large controlled studies involving valproate monotherapy. Nonetheless, there appears to be a greater incidence of polycystic ovaries associated with valproate use in comparison with other anticonvulsants. The mechanism by which valproate may induce polycystic ovarian syndrome is unknown, but could possibly be secondary to valproate-induced weight gain or direct interference with steroid metabolism. Further study of the potential association of valproate treatment with the development of polycystic ovarian syndrome is warranted. Until the issue is clarified, clinicians should at least be aware of the possibility of valproate-induced polycystic ovarian syndrome and monitor patients accordingly.

Atypical antipsychotics: Part II: Adverse effects, drug interactions, and costs.

OBJECTIVE: To compare the adverse effects, drug interactions, and costs of conventional and atypical agents, and to provide a summary of therapeutic guidelines. Part I compared the pharmacology, pharmacokinetics, and efficacy of atypical and conventional agents. DATA SOURCES: Information was retrieved from a MEDLINE English-language literature search from June 1986 to June 1998 and by review of references. Indexing terms included atypical antipsychotics, neuroleptics, clozapine, risperidone, olanzapine, sertindole, quetiapine, and ziprasidone. STUDY SELECTION: Comparative studies were selected when possible; placebo-controlled studies were included when data were limited on newer atypical antipsychotics. DATA EXTRACTION: Emphasis was placed on properly designed clinical trials that assessed dosage, expanded efficacy, enhanced adverse effect profile, and cost. DATA SYNTHESIS: Significant adverse effects are agranulocytosis with clozapine, dose-dependent extrapyramidal side effects (EPS) with risperidone, and neuroleptic malignant syndrome with clozapine and risperidone. Clinically relevant drug interactions may occur with clozapine-lorazepam, clozapine-fluvoxamine, and sertindole-quinidine. Newer atypical agents have high acquisition costs but may reduce noncompliance and rehospitalization rates. CONCLUSIONS: Risperidone or olanzapine are recommended as first-line agents for schizophrenia due to accumulating controlled trials and clinical experience. Quetiapine should be considered with partial response or if EPS develop, and clozapine is an option with treatment-refractory patients. Atypical agents may contribute to a better quality of life, but conventional neuroleptics are the first choice for strictly cost considerations.

A simple model to estimate survival after retransplantation of the liver.

To formulate a model predicting survival after liver retransplantation, we analyzed in detail the last 150 cases of hepatic retransplantation at UCLA. Cox proportional hazards regression analysis identified five variables that demonstrated independent simultaneous prognostic value in estimating patient survival after retransplantation: (1) age group (pediatric or adult), (2) recipient requiring preoperative mechanical ventilation, (3) donor organ cold ischemia > or =12 hr, (4) preoperative serum creatinine, and (5) preoperative serum total bilirubin. The Cox regression equation that predicts survival based on these covariates was simplified by assigning individual patients a risk classification based on a 5-point scoring system. We demonstrate that this system can be employed to identify a subgroup of patients in which the expected outcome is too poor to justify retransplantation. These findings may assist in the rational selection of patients suitable for retransplantation.

Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management.

BACKGROUND: Although jejunoileal bypass results in end-stage liver disease in up to 100% of patients, little is known about outcome after liver transplantation. METHODS: The clinical courses of six patients who underwent liver transplantation at UCLA for decompensated cirrhosis owing to a jejunoileal bypass were reviewed. Liver function, allograft pathology, renal function, and nutritional status were assessed. RESULTS: Of the four patients with an intact jejunoileal bypass, two of the three who were biopsied had recurrent steatotic liver disease. The two patients whose jejunoileal bypass was reversed at the time of liver transplantation had lower alkaline phosphatase, lower creatinine, higher albumin, and higher cholesterol, and were more obese than their counterparts with intact bypasses. CONCLUSIONS: Patients undergoing liver transplantation for jejunoileal bypass-associated liver disease should, if possible, have their bypass reversed at the time of transplantation; otherwise, they must be followed closely and be biopsied routinely. Recurrent liver disease should prompt reversal of the jejunoileal bypass.

Fas ligand gene transfer to renal allografts in rats: effects on allograft survival.

BACKGROUND: Fas ligand (FasL) induces apoptosis of cells bearing its receptor Fas, and has been shown to be important in T-cell development and regulation and in immune privilege. We hypothesized that FasL expression by renal allografts might provide protection from rejection. METHODS: The murine FasL cDNA was cloned into a replication-defective adenovirus (AdV-FasL). Protein expression was confirmed by immunostaining of AdV-FasL-transduced HeLa cells. Allogeneic kidney transplants were performed between WF (RT1u) donors and Lewis (RT1) recipients. Donor kidneys were perfused in situ with saline alone (control), or 9 x 10(9) plaque-forming units of AdV-FasL. One native kidney was removed at the time of transplant and the other at 6 or 7 days. Uremic death was the endpoint, and deaths within 7 days of transplant were excluded. Transduced allografts were stained for FasL expression using a monoclonal antibody and tested for FasL mRNA production by reverse transcriptase-polymerase chain reaction and Northern blotting. RESULTS: Immunostaining of AdV-FasL-transduced allografts demonstrated efficient gene transfer lasting approximately 2 weeks, and FasL mRNA production in the AdV-FasL-transduced allografts was confirmed by Northern blotting and reverse transcriptase-polymerase chain reaction. Mean survival of animals with AdV-FasL-transduced renal allografts was 27.8 days vs. 11.6 days in control animals (P < 0.05). CONCLUSIONS: (1) Adenoviral vectors can successfully transduce rat kidneys with the FasL cDNA. (2) FasL gene transfer prolongs rat renal allograft survival.

Long-term survival after retransplantation of the liver.

OBJECTIVE: The authors determined the long-term outcome of patients undergoing hepatic retransplantation at their institution. Donor, operative, and recipient factors impacting on outcome as well as parameters of patient resource utilization were examined. SUMMARY BACKGROUND DATA: Hepatic retransplantation provides the only available option for liver transplant recipients in whom an existing graft has failed. However, such patients are known to exhibit patient and graft survival after retransplantation that is inferior to that expected using the same organs in naiive recipients. The critical shortage of donor organs and resultant prolonged patient waiting periods before transplantation prompted the authors to evaluate the results of a liberal policy of retransplantation and to examine the factors contributing to the inferior outcome observed in retransplanted patients. METHODS: A total of 2053 liver transplants were performed at the UCLA Medical Center during a 13-year period from February 1, 1984, to October 1, 1996. A total of 356 retransplants were performed in 299 patients (retransplant rate = 17%). Multivariate regression analysis was performed to identify variables associated with survival. Additionally, a case-control comparison was performed between the last 150 retransplanted patients and 150 primarily transplanted patients who were matched for age and United Network of Organ Sharing (UNOS) status. Differences between these groups in donor, operative, and recipient variables were studied for their correlation with patient survival. Days of hospital and intensive care unit stay, and hospital charges incurred during the transplant admissions were compared for retransplanted patients and control patients. RESULTS: Survival of retransplanted patients at 1, 5, and 10 years was 62%, 47%, and 45%, respectively. This survival is significantly less than that seen in patients undergoing primary hepatic transplantation at the authors' center during the same period (83%, 74%, and 68%). A number of variables proved to have a significant impact on outcome including recipient age group, interval to retransplantation, total number of grafts, and recipient UNOS status. Recipient primary diagnosis, cause for retransplantation, and whether the patient was retransplanted before or after June 1, 1992, did not reach statistical significance as factors influencing survival. In the case-control comparison, the authors found that of the more than 25 variables studied, only preoperative ventilator status showed both a significant difference between control patients and retransplanted patients and also was a factor predictive of survival in retransplanted patients. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated total hospitalization charges more than 170% of those by control patients. CONCLUSIONS: Hepatic retransplantation, although life-saving in almost 50% of patients with a failing liver allograft, is costly and uses scarce donor organs inefficiently. The data presented define patient characteristics and preoperative variables that impact patient outcome and should assist in the rational application of retransplantation.

The impact of microsurgical hepatic arterial reconstruction on the outcome of liver transplantation for congenital biliary atresia.

BACKGROUND: Hepatic artery thrombosis (HAT) after liver transplantation for biliary atresia (BA) is a serious complication that most often leads to retransplantation (re-OLT). The purpose of the present study was: (1) to identify risk factors associated with HAT and (2) to analyze the impact of recently introduced microsurgical hepatic arterial reconstruction (MHR) on the incidence of HAT, subsequent need for re-OLT, and patient survival. METHODS: A retrospective review of 194 patients transplanted for BA was performed. One hundred and sixty-six patients (group 1) underwent conventional arterial reconstruction and 28 (group 2) had MHR. RESULTS: Actuarial survival for patients with HAT was significantly worse than for patients without HAT at 1, 2, and 5 years (71%, 61%, and 57% versus 85%, 85%, and 85%, P = 0.0007). Stepwise logistic regression analysis revealed that the risk of HAT correlated best with the type of arterial reconstruction (P = 0.007) followed by pretransplant bilirubin concentration (P = 0.04) and the number of acute rejection episodes (P = 0.03). In group 1, 32 patients developed HAT (19%), and of these, 18 underwent re-OLT for HAT. No patient in group 2 developed HAT (P = 0.006 versus group 1). One-year actuarial patient survival was 81% in group 1 and 100% in group 2 (P = 0.02). CONCLUSIONS: In OLT for BA, (1) the predominant risk factor for HAT is the technique of arterial reconstruction, and (2) MHR markedly reduces the incidence of HAT and the need for re-OLT while improving patient survival.

Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.

OBJECTIVE: The purpose of this study was to analyze a single center's 12-year experience with 127 orthotopic liver transplantations (OLT) for primary sclerosing cholangitis (PSC). SUMMARY BACKGROUND DATA: Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown origin that occurs most commonly in young men and is associated frequently (70-80%) with inflammatory bowel disease (IBD). Patients with PSC also are at risk for the development of cholangiocarcinoma (CCA) and those with IBD for colon carcinoma. Although the course of PSC is variable, it frequently is progressive, leading to cirrhosis and requirement for OLT. METHODS: The medical records of 127 consecutive patients undergoing OLT for PSC from July 1, 1984, to May 30, 1996, were reviewed. Actuarial patient and graft survival was determined at 1,2, and 5 years. The incidence and outcome of patients with CCA, recurrent sclerosing cholangitis, and post-transplant colon carcinoma was determined. Results were analyzed by way of stepwise Cox regression to determine the statistical strength of independent associations between pretransplant covariates and patient survival. The median follow-up period was 3.01 years. Incidental cholangiocarcinoma (ICCA) was defined as a tumor < 1 cm in size that was discovered at the time of pathologic sectioning of the explanted liver. RESULTS: Ninety-two patients (72%) had associated IBD. Seventy-nine (62%) had undergone previous biliary tract surgery. One hundred seven patients (84%) received a single graft, whereas 20 patients (16%) required 22 retransplants. Patients received either cyclosporine- (n = 76) or tacrolimus- (n = 51) based immunosuppression. The 1-, 2-, and 5-year actuarial patient survivals were 90%, 86%, and 85%, respectively, whereas graft survival was 82%, 77%, and 72%, respectively. The presence of previous biliary surgery had no effect on patient survival. Ten patients (8%) had ICCA and their survival was not significantly different from patients without ICCA (100%, 83%, and 83% at 1, 2, and 5 years, respectively). Four patients were known to have CCA at the time of OLT, all recurred within 6 months, and had a significantly worse outcome (p < 0.0001). Recurrent sclerosing cholangitis developed in 11 patients (8.6%). The patient and graft survival in this group was not different from those in whom recurrence did not develop (patient; 100%, 90%, and 90%; graft: 80%, 70%, and 52%). Thirty patients (23%) underwent colectomy after liver transplantation for dysplasia-carcinoma or symptomatic colitis. Of the nine covariates entered into the Cox multivariate regression analysis, only common bile duct frozen section biopsy specimen showing CCA was predictive of a survival disadvantage. CONCLUSIONS: Liver transplantation provides excellent patient and graft survival rates for patients affected with PSC independent of pretransplant biliary tract surgery. Incidental cholangiocarcinoma does not affect patient survival significantly. However, known CCA or common duct frozen section biopsy specimen or both showing CCA are associated with poor recipient survival, and OLT should be proscribed in these cases. Recurrent PSC occurs in approximately 9% of cases but does not affect patient survival. Post-transplant colectomy does not affect patient survival adversely.

Orthotopic liver transplantation for congenital biliary atresia. An 11-year, single-center experience.

OBJECTIVE: The authors analyze a single center's 11-year experience with 190 orthotopic liver transplants for congenital biliary atresia. SUMMARY BACKGROUND DATA: Hepatic portoenterostomy generally is the initial treatment for children with congenital biliary atresia. Despite multiple modifications of the hepatic portoenterostomy, two thirds of treated patients still develop recurrent cholestasis, portal hypertension, cholangitis, and cirrhosis. Therefore, the only hope of long-term survival in the majority of children with congenital biliary atresia is definitive correction with orthotopic liver transplantation. METHODS: The medical records of 190 consecutive patients undergoing orthotopic liver transplantation for congenital biliary atresia from July 1, 1984 to February 29, 1996 were reviewed. Results were analyzed via Cox multivariate regression analysis to determine the statistical strength of independent associations between pretransplant covariates and patient and graft survival. Actuarial patient and graft survival was determined at 1, 2, and 5 years. The type and incidence of post-transplant complications were determined, as was the quality of long-term graft function. The median follow-up period was 3.21 years. RESULTS: The liver grafts were comprised on 155 whole-organ, 24 reduced-size, and 11 living donor organs. Median pretransplant values for recipient age, weight, and total bilirubin were 1.4 years, 12.3 kg, and 13.8 mg/dL, respectively. One hundred sixty-four patients (86%) had undergone prior hepatic portoenterostomy. Eighty-seven patients (46%) were United Network for Organ Sharing (UNOS) status 1 or 2 at the time of liver transplantation. The majority (15/24, 62%) of reduced-size graft recipients were UNOS status I at the time of transplantation. One hundred fifty-nine patients (84%) received a single graft, whereas 31 patients required 37 retransplants. The 1, 2, and 5 year actuarial patient survival rates were 83%, 80% and 78% respectively, whereas graft survival rates were 81%, 77%, and 76%, respectively. Cox multivariate regression analysis demonstrated that pretransplant total bilirubin, UNOS status, and graft type significantly predicted patient survival, whereas recipient age, weight, and previous hepatic portoenterostomy did not. Current median follow-up values for total bilirubin and aspartate aminotransferase levels in the 154 surviving patients were 0.5 mg/dL and 34 international units/L, respectively. CONCLUSION: Long-term patient survival after orthotopic liver transplantation for congenital biliary atresia is excellent and is independent of recipient age, weight, or previous hepatic portoenterostomy. Optimal results are obtained in this patient population when liver transplantation is performed before marked hyperbilirubinemia, and when possible, using a living-donor graft.

Thermal degradation of clozapine-N-oxide to clozapine during gas chromatographic analysis.

Studies were undertaken to determine if clozapine-N-oxide, the principal urinary metabolite of the antipsychotic agent clozapine, may interfere with the gas chromatographic-mass spectrometric bioanalysis of clozapine. Following injection of clozapine-N-oxide onto a (5% phenyl)methylpolysiloxane capillary column operated at 250 degrees C, significant on-column reduction of clozapine-N-oxide to the parent drug occurred. Accordingly, preparation of biological samples for clozapine determination by gas chromatography should avoid conditions which reportedly co-extract the N-oxide to assure no artifactual contribution of this metabolite in the detection of clozapine.

Failure of symptomatic relief after pancreaticojejunal decompression for chronic pancreatitis. Strategies for salvage.

OBJECTIVE: To evaluate causes of intractable recurrent pain following pancreaticojejunostomy for chronic pancreatitis and to evaluate treatment strategies aimed at lasting pain relief. DESIGN: Case series. SETTING: Tertiary care referral center. PATIENTS: Fifteen selected patients having severe pain associated with chronic pancreatitis with onset 0 to 60 months (median, 5 months) following pancreaticojejunostomy. Each patient underwent computed tomography and endoscopic retrograde cholangiopancreatography. Two patients (13%) were found to have pancreatic cancer, two (13%) had inadequate pancreatic duct decompression, two (13%) had biliary stenosis, and 10 (67%) had presumed neuropathy in the pancreatic head. INTERVENTIONS: Fourteen (93%) of the 15 patients underwent the following reoperations: distal pancreatectomy and splenectomy (one patient), extension of the pancreaticojejunostomy and choledochojejunostomy (one patient), biliary stenting followed by choledochojejunostomy (one patient), and Whipple-type resection of the pancreatic head (14 patients). Two patients subsequently underwent a completion pancreatectomy. MAIN OUTCOME MEASURES: Pain relief, functional capacity, and pancreatic exocrine and endocrine status were determined. The median follow-up after reoperation was 39 months. RESULTS: Of the 14 patients who underwent reoperation, 13 were long-term survivors. One died of pancreatic cancer. Ten of the other 13 have had satisfactory-to-excellent relief of pain, with resumption of a normal level of function. Of the 10 previously euglycemic patients who underwent pancreatic head resection, eight remain free of diabetes mellitus to date. CONCLUSIONS: The causes of recurrent or persistent pain following pancreaticojejunal decompression for chronic pancreatitis are complex and include neuropathic changes, residual or evolving pancreatic and biliary duct obstruction, and unrecognized pancreatic cancer. Acceptable outcomes can usually be achieved by following a treatment strategy aimed at addressing identified residual disease while maximally preserving pancreatic tissue.

Class II-positive hematopoietic cells cannot mediate positive selection of CD4+ T lymphocytes in class II-deficient mice.

Generation of immunocompetent alpha/beta T-cell receptor-positive T cells from CD4+CD8+ thymocytes depends upon their interaction with thymic major histocompatibility complex (MHC) molecules. This process of positive selection provides mature T cells that can recognize antigens in the context of self-MHC proteins. Previous studies investigating haplotype restriction in thymic and bone-marrow chimeras concluded that radioresistant thymic cortical epithelium directs the positive selection of thymocytes. There is controversy, however, as to whether intra- or extrathymic radiosensitive bone marrow-derived macrophage and dendritic cells also can mediate positive selection. To determine whether CD4+ T cells can be positively selected by hematopoietic cells, we generated chimeric animals expressing MHC class II molecules on either bone marrow-derived or thymic stromal cells by using a recently produced strain of MHC class II-deficient mice. CD4+ T cells developed only when class II MHC molecules were expressed on radioresistant thymic cells. In contrast to what recently has been observed for the selection of CD8+ T lymphocytes, MHC class II-positive bone marrow-derived cells were unable to mediate the selection of CD4+ T cells when the thymic epithelium lacked MHC class II expression. These data suggest that CD4+ and CD8+ T cells may be generated by overlapping, but not identical, mechanisms.

Prognosis after initial recurrence of cutaneous melanoma.

We reviewed 231 patients who developed recurrent disease 1 to 218 months after surgical therapy for clinical stage I cutaneous melanoma. Metastatic lesions amenable to surgery, including visceral recurrences, were resected. Adjuvant systemic chemotherapy/immunotherapy or regional hyperthermic perfusion was added in patients with unresected disease. Local irradiation was employed for nonresectable brain or other isolated symptomatic metastases. The overall 5-year survival rate after initial recurrence was 36%. In patients with soft tissue or nodal recurrence, the 5-year survival rates were 49% and 38%, respectively; six (11%) of 53 patients whose initial recurrence was in a visceral organ achieved prolonged remission. Primary lesion anatomic site, thickness, pathologic type, and interval from initial therapy to recurrence were unrelated to survival. Significant prognostic factors included the site of initial metastasis, stage of primary disease, and the successful complete eradication of gross disease by surgical excision or intensive chemotherapy.

Self-reported short- and long-term respiratory effects among PVC-exposed firefighters.

Firefighters exposed to burning polyvinyl chloride (PVC) were studied to assess respiratory effects at 5-6 wk post-incident and again 22 mo following the fire. Exposed subjects reported significantly more frequent and severe respiratory symptoms at both time points than did firefighter controls. In longitudinal analyses, a number of symptoms persisted over time, and acute symptom scores were significantly correlated with chronic scores. At Time 2, approximately 18% of exposed firefighters, compared with none of the controls, reported that since the time of the PVC exposure, a physician had told them that they had either asthma and/or bronchitis.

Gas chromatographic-mass spectrometric analysis of plasma oxybutynin using a deuterated internal standard.

A gas chromatographic-mass spectrometric method is described for the quantitative analysis of plasma oxybutynin. Deuterated oxybutynin served as the internal standard and its synthesis is described. Chromatographic separation on a methylsilicone capillary column avoided the thermal decomposition observed using a packed column. Electron-impact ionization and selected-ion monitoring of the alpha-cleavage fragments of drug and internal standard permitted quantitation of oxybutynin down to 0.25 ng/ml of plasma. At the 2 ng/ml level the accuracy and precision are 4 and 10%, respectively, and improved at higher drug concentrations. Application of the method to the pharmacokinetics of oral oxybutynin in man demonstrated rapid absorption and elimination of the drug.

Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed daughters.

In utero exposure to diethylstilbestrol (DES) was initially linked to vaginal-cervical cancer and subsequently to reproductive difficulties. These unanticipated and ongoing health risks to female offspring may constitute a chronic source of stress for DES mothers. We interviewed 60 mothers of exposed daughters and 30 acquaintance controls. Two hypotheses were tested in regard to DES mothers: DES discovery and its aftermath have a direct, long-term, negative effect on psychological health and the DES experience intensifies the negative psychological effects of other adverse life circumstances. To operationalize psychological health, we measured symptoms of "demoralization" and positive health practices--the latter as a behavioral indicator of mastery and personal control. We also measured adversities that may mediate the threat posed by DES, including stressful events, medical problems, and chronic burdens. We found DES history to be associated with poorer psychological health only when mothers encountered other losses and threats to themselves and their families. We concluded that DES mothers may manifest increased vulnerability to subsequent stresses in their lives.