The impact of metastatic sites on survival Rates and predictors of extended survival in patients with metastatic pancreatic cancer.

BACKGROUND OBJECTIVES: The aim of this study was to determine the role of site-specific metastatic patterns over time and assess factors associated with extended survival in metastatic PDAC. Half of all patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. The site of metastasis plays a crucial role in clinical decision making due to its prognostic value. METHODS: We examined 56,757 stage-IV PDAC patients from the National Cancer Database (2016-2019), categorizing them by metastatic site: multiple, liver, lung, brain, bone, carcinomatosis, or other. The site-specific prognostic value was assessed using log-rank tests while time-varying effects were assessed by Aalen's linear hazards model. Factors associated with extended survival (>3years) were assessed with logistic regression. RESULTS: Median overall survival (mOS) in patients with distant lymph node-only metastases (9.0 months) and lung-only metastases (8.1 months) was significantly longer than in patients with liver-only metastases (4.6 months, p < 0.001). However, after six months, the metastatic site lost prognostic value. Logistic regression identified extended survivors (3.6 %) as more likely to be younger, Hispanic, privately insured, Charlson-index <2, having received chemotherapy, or having undergone primary or distant site surgery (all p < 0.001). CONCLUSION: While synchronous liver metastases are associated with worse outcomes than lung-only and lymph node-only metastases, this predictive value is diminished after six months. Therefore, treatment decisions beyond this time should not primarily depend on the metastatic site. Extended survival is possible in a small subset of patients with favorable tumor biology and good conditional status, who are more likely to undergo aggressive therapies.

Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

Endothelial Cell Autophagy Maintains Shear Stress-Induced Nitric Oxide Generation via Glycolysis-Dependent Purinergic Signaling to Endothelial Nitric Oxide Synthase.

OBJECTIVE: Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS: On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOSS1177) and NO generation. Maneuvers that restore glucose transport and glycolysis (eg, overexpression of GLUT1 [glucose transporter 1]) or purinergic signaling (eg, addition of exogenous ADP) rescue shear-induced p-eNOSS1177 and NO production in ECs with impaired autophagy. Conversely, inhibiting glucose transport via GLUT1 small interfering RNA, blocking purinergic signaling via ectonucleotidase-mediated ATP/ADP degradation (eg, apyrase), or inhibiting P2Y1 receptors using pharmacological (eg, MRS2179 [2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium salt]) or genetic (eg, P2Y1-receptor small interfering RNA) procedures inhibit shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Supporting a central role for PKCδT505 (protein kinase C delta T505) in relaying the autophagy-dependent purinergic-mediated signal to eNOS, we find that (1) shear stress-induced activating phosphorylation of PKCδT505 is negated by inhibiting autophagy, (2) shear-induced p-eNOSS1177 and NO generation are restored in autophagy-impaired ECs via pharmacological (eg, bryostatin) or genetic (eg, constitutively active PKCδ) activation of PKCδT505, and (3) pharmacological (eg, rottlerin) and genetic (eg, PKCδ small interfering RNA) PKCδ inhibition prevents shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Key nodes of dysregulation in this pathway on autophagy compromise were revealed in human arterial ECs. CONCLUSIONS: Targeted reactivation of purinergic signaling and PKCδ has strategic potential to restore compromised NO generation in pathologies associated with suppressed EC autophagy.

Acinar Cell Carcinoma of the Pancreas: A Case Report.

Acinar cell carcinoma (ACC) of the pancreas is a very rare neoplasm. We report a case of pancreatic acinar cell carcinoma involving the uncinate process of the pancreas. A 45 year old man presented with a painful upper abdominal mass without any jaundice or weight loss. Computed Tomography (CT) and Magnetic Resonance Cholangio-Pancreatography (MRCP) indicated a mass lesion in the uncinate process of the pancreas. He underwent Whipple's procedure (Pancreaticoduodenectomy). Histological slides revealed features of Acinar cell carcinoma (ACC) in the uncinate process of the pancreas and a lymph node.

Risky sex in rural America: longitudinal changes in a community-based cohort of methamphetamine and cocaine users.

BACKGROUND AND OBJECTIVES: This study examined the longitudinal associations between stimulant use and sexual behaviors. METHODS: Data are from a 3-year community-based study of 710 rural stimulant users. Past 30-day crack cocaine, powder cocaine, and methamphetamine use and sexual behaviors (any sex, inconsistent condom use, and multiple sexual partners) were assessed through in-person interviews every 6 months. RESULTS: GEE analyses revealed that the odds of having sex remained steady over time, with crack cocaine and methamphetamine use positively associated with having sex. The odds of multiple sexual partners declined, but the odds of inconsistent condom use remained steady over time. Crack cocaine use was positively associated with multiple sexual partners, whereas powder cocaine use was negatively associated with inconsistent condom use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Many rural stimulant users could potentially benefit from safe sex educational programs. Such efforts could reduce the incidence of HIV and other STIs in rural America.

The use of coupled HSQC spectra to aid in stereochemical assignments of molecules with severe proton spectral overlap.

INTRODUCTION: A simple glycoside with only 13 carbons exhibited extensive overlapping of four of the glycosidic protons, causing extreme difficulty in the determination of the stereochemistry of the pyranose unit. However, acquisition of a high-resolution coupled heteronuclear single-quantum coherence (HSQC) spectrum overcame this problem. This spectrum provides a useful method for determining vicinal proton coupling constants between strongly coupled protons. OBJECTIVE: To show the potential of high-resolution coupled HSQC spectra in overcoming spectral overlap. METHODOLOGY: The sample was obtained by methanol extraction, followed by fractionation and column chromatography of the dried leaves of Montrichardia arborescens (Araceae). NMR spectra were obtained on 1.5 mg of sample dissolved in 120 µL of CD3OD containing 0.1% trimethylsilyl (TMS) as internal standard. A gradient-selected HSQC spectrum was obtained using standard Varian library pulse sequences in phase sensitive mode. The high-resolution coupled HSQC spectrum focused on the saccharide region with a 1025 Hz ¹H spectral window, a 6300 Hz ¹³C spectral window, 1024 data points, a 0.3 Hz relaxation delay, 384 time increments (linear predicted to 4096), and 80 scans per time increment. RESULTS: The use of a high-resolution coupled HSQC spectrum allowed determination of the coupling patterns of the various pyranose protons with sufficient accuracy. This enabled completion of the assignments and identification of the pyranose unit as glucose. CONCLUSION: The study has shown the effectiveness of the use of a high-resolution coupled HSQC spectrum in the assignment of molecules with severe spectral overlap.

Variable-temperature ¹H-NMR studies on two C-glycosylflavones.

Two known C-glycosylflavones, swertisin and embinoidin, were isolated from the leaves of Anthurium aripoense, and characterized by room temperature 1D and 2D NMR experiments. At this temperature, the ¹H- and ¹³C-NMR spectra of these C-glycosylflavones revealed doubling of signals, which suggested the presence of two rotamers in solution. Variable-temperature (VT) ¹H-NMR studies supported this hypothesis. The T-ROESY data, in addition to the theoretical (MM2) calculations utilizing the Chem3D Pro software, confirmed the hypothesis that the two rotamers interchange via rotation about the C-glycosidic bond.

Physical victimization of rural methamphetamine and cocaine users.

Substance use and physical violence often coincide, but little has been published on the correlates associated with receipt of partner versus nonpartner physical violence for rural users of methamphetamine and/or cocaine. In this study, participants' substance use, depression and past-year physical victimization were assessed. In separate logistic regression models, received partner violence in females was associated with age; alcohol, cocaine, and methamphetamine abuse/dependence; and number of drugs used in the past 6 months. In males, received nonpartner violence was associated with age, cocaine abuse/dependence, and being Caucasian. Findings suggest a relationship between stimulant use and received violence among rural substance users and a need for victimization screenings in settings where such individuals seek health care.

Toxicity-structure activity evaluation of limonoids from Swietenia species on Artemia salina.

CONTEXT: Many plant extracts and compounds are being investigated for their cytotoxicity and hence their medicinal or therapeutic properties. Reports of toxicity studies with limonoid analogs have been sparse and have involved mainly crude extracts. In this study, individual natural limonoids have been isolated and their toxicity manipulated via semisynthesis. OBJECTIVE: The lethality of limonoid analogs from Swietenia macrophylla King and Swietenia aubrevilleana Stehlé & Cusin (Meliaceae) against Artemia salina Leach was determined. MATERIALS AND METHODS: Four known natural limonoids were isolated from the dry ground seeds of S. macrophylla and S. aubrevilleana, modified using acylation and hydrolysis reactions and tested in A. salina lethality assays at 1-400 ppm. A 50% lethal concentration (LC(50)) was determined by probit analysis. RESULTS: Higher levels of toxicity were achieved in most of the prepared analogs compared with the parent natural limonoids. The compound showing the highest toxicity with LC(50) 3.9 ppm was 3-O-benzoyl-3-detigloylisoswietenine (20). Other analogs with high toxicity were 6-O-benzoylswietenolide (7), 6-O-benzoylswietenine (17), and 3,6-O,O-dipropionylswietenolide (9), which showed LC(50) values of 4.3, 7.5, and 28.5 ppm, respectively. DISCUSSION AND CONCLUSIONS: Toxicity can be improved via semisynthesis. The compounds exhibiting high toxicity (low LC(50)) may be good candidates for cytotoxicity studies.

Characteristics of rural crack and powder cocaine use: gender and other correlates.

BACKGROUND: Little is known about the relationship of gender with cocaine use in rural areas. This study describes these relationships among stimulant users residing in rural areas of Arkansas, Kentucky, and Ohio. OBJECTIVES: Understanding the characteristics of crack and powder cocaine users in rural areas may help inform prevention, education, and treatment efforts to address rural stimulant use. METHODS: Participants were 690 stimulant users, including 274 (38.6%) females, residing in nine rural counties. Cocaine use was measured by self-report of cocaine use, frequency of use, age of first use, and cocaine abuse/dependence. Powder cocaine use was reported by 49% of this sample of stimulant users and 59% reported using crack cocaine. FINDINGS: Differing use patterns emerged for female and male cocaine users in this rural sample; females began using alcohol, marijuana, and cocaine at later ages than males but there were no gender differences in current powder cocaine use. Females reported more frequent use of crack cocaine and more cocaine abuse/dependence than males, and in regression analyses, female crack cocaine users had 1.8 times greater odds of reporting frequent crack use than male crack users. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings suggest differing profiles and patterns of cocaine use for male and female users in rural areas, supporting previous findings in urban areas of gender-based vulnerability to negative consequences of cocaine use. Further research on cocaine use in rural areas can provide insights into gender differences that can inform development and refinement of effective interventions in rural communities.

One-arm maximal strength training improves work economy and endurance capacity but not skeletal muscle blood flow.

Maximal strength training with a focus on maximal mobilization of force in the concentric phase improves endurance performance that employs a large muscle mass. However, this has not been studied during work with a small muscle mass, which does not challenge convective oxygen supply. We therefore randomized 23 adult females with no arm-training history to either one-arm maximal strength training or a control group. The training group performed five sets of five repetitions of dynamic arm curls against a near-maximal load, 3 days a week for 8 weeks. This training increased maximal strength by 75% and improved rate of force development during both strength and endurance exercise, suggesting that each arm curl became more efficient. This coincided with a 17-18% reduction in oxygen cost at standardized submaximal workloads (work economy), and a 21% higher peak oxygen uptake and 30% higher peak load during maximal arm endurance exercise. Blood flow assessed by Doppler ultrasound in the axillary artery supplying the working biceps brachii and brachialis muscles could not explain the training-induced adaptations. These data suggest that maximal strength training improved work economy and endurance performance in the skeletal muscle, and that these effects are independent of convective oxygen supply.

Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis.

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

The evolving biology and treatment of prostate cancer.

Since the effectiveness of androgen deprivation for treatment of advanced prostate cancer was first demonstrated, prevention strategies and medical therapies for prostate cancer have been based on understanding the biologic underpinnings of the disease. Prostate cancer treatment is one of the best examples of a systematic therapeutic approach to target not only the cancer cells themselves, but the microenvironment in which they are proliferating. As the population ages and prostate cancer prevalence increases, challenges remain in the diagnosis of clinically relevant prostate cancer as well as the management of the metastatic and androgen-independent metastatic disease states.

Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.

A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism.

TanGeoMS: tangible geospatial modeling system.

We present TanGeoMS, a tangible geospatial modeling visualization system that couples a laser scanner, projector, and a flexible physical three-dimensional model with a standard geospatial information system (GIS) to create a tangible user interface for terrain data. TanGeoMS projects an image of real-world data onto a physical terrain model. Users can alter the topography of the model by modifying the clay surface or placing additional objects on the surface. The modified model is captured by an overhead laser scanner then imported into a GIS for analysis and simulation of real-world processes. The results are projected back onto the surface of the model providing feedback on the impact of the modifications on terrain parameters and simulated processes. Interaction with a physical model is highly intuitive, allowing users to base initial design decisions on geospatial data, test the impact of these decisions in GIS simulations, and use the feedback to improve their design. We demonstrate the system on three applications: investigating runoff management within a watershed, assessing the impact of storm surge on barrier islands, and exploring landscape rehabilitation in military training areas.

[Surgical treatment of infective endocarditis: Surgical indications, complications, intrahospital and long-term mortality]. / Endocardites infectieuses opérées : indications chirurgicales, complications, mortalité intrahospitalière et à long terme.

BACKGROUND: In addition to medical treatment, half of the patients with infective endocarditis (IE) receive surgical treatment. Despite clear recommendations on the indications and the operating delays, the decision remains difficult and must take into consideration several factors. METHODS: A retrospective study was performed at Foch Hospital. All patients operated for IE between 2005 and 2018 were included. Patient characteristics, indications and operating delays, as well as intrahospital mortality, were noted. Patient follow-up was provided by phone calls. RESULTS: Fifty-two patients were operated on for IE between 2005 and 2018. The most frequent surgical indications were the presence of a massive symptomatic regurgitation, an uncontrolled infection and large vegetations with embolism. The average operative delay was 13.2 days with 56.5% of patients operated within the first 10 days. The most common postoperative complications were acute kidney injury (AKI) in 57.7% of cases, with 9.6% of dialysis, shock in 50% of cases, rhythm disorders in 40.4% of cases, infectious complications in 19.2% of cases, conductive disorders in 25% of cases, of which 17.3% require a definitive pacemaker implementation. The intrahospital mortality was 7.7% and the average length of hospital stay was 35 days. Survival at one year and 5 years was 95% and 85%, respectively. CONCLUSION: The indications and the operating delays were conformed to international recommendations. Intrahospital and long-term mortality rate was low.

[Infective prosthetic endocarditis following percutaneous edge-to-edge mitral valve repair - A Case-report of a successfully medically-treated Staphylococcus epidermidis endocarditis and a literature review]. / Endocardite infectieuse sur prothèse après implantation de Mitra-Clip ­ Cas d'un succès du traitement médical sur une endocardite à Staphylococcus epidermidis et revue de littérature.

During the last decade there has been a craze for the percutaneous edge-to-edge mitral valve repair technique with the Mitra-Clip device. This is an alternative treatment to mitral valve surgery for severe mitral regurgitation. In France, this device is aimed at poor candidates for mitral valve surgery. It involves intra-cardiac prosthetic material, which exposes them to the risk of bacterial endocarditis. The consequences of this infective disease can be dramatic, especially for these old patients who suffer from multiple comorbidities. It appears to be a rare but relatively unknown and potentially underestimated complication. The relative data remain scarce and consist of rare case-reports. We report an original case of a Methicilline-sensitive Staphylococcus epidermidis mitral endocarditis following the implantation of clips two months earlier. The patient was then successfully treated with antibiotics. Since the first Mitra-Clip implantation in 2003, only 19 cases of endocarditis have previously been reported. This article proposes a review of theses case-reports and a collection of their relevant clinical, echocardiographic and microbiological characteristics, the delivered therapies and their outcomes. These data contribute to a humble discussion around the main stakes of the disease, which are the prevention, the diagnosis, the involved bacteria's type, the prognosis and the treatments with a focus on the question of the recourse to surgical management.

Hair depigmentation during chemotherapy with dasatinib, a dual Bcr-Abl/Src family tyrosine kinase inhibitor.

Hair depigmentation has been shown to occur with disruption of the interaction between the ligand stem cell factor (SCF) with its class III receptor tyrosine kinase c-kit, also called the stem cell factor receptor. This article reports the case of a patient who experienced depigmentation of her eyelashes, eyebrows, and temporal scalp hair six-to-eight weeks after initiating treatment with dasatinib (BMS-354825 or Sprycel), a novel dual Bcr-Abl/Src family tyrosine kinase inhibitor for chronic myeloid leukemia (CML). This case illustrates a previously unreported side-effect of dasatinib that is most likely due to the drug's inhibition of the c-kit, Src family, and platelet-derived growth factor receptor beta (PDGFRbeta) tyrosine kinases. Further study of hair depigmentation as a side effect of multi-kinase inhibitors can provide useful information on hair and melanocyte physiology.

Clinical epidemiology and outcomes of ventilator-associated pneumonia in critically ill adult patients: protocol for a large-scale systematic review and planned meta-analysis.

BACKGROUND: An increasing number of studies have investigated the clinical epidemiology and outcomes of ventilator-associated pneumonia (VAP) in intensive care units. However, these findings have not been clearly defined in broad subgroups of mechanically ventilated adults. Hence, this protocol for a systematic review and meta-analysis is designed to better understand the clinical and epidemiological features of VAP in these patient populations by establishing its overall prognosis of and risk factors for morbidity and mortality and to determine the differences in clinical and economic outcomes between VAP and non-VAP patients. METHODS: This present review will systematically search available full-text articles without date and language restrictions and indexed in PubMed, CENTRAL, CINAHL, Web of Science, and EMBASE databases. In addition, reference lists and citations of retrieved articles and relevant medical and nursing journals will be manually reviewed. Supplementary search in other databases involving trials, reviews, and grey literatures, including conference proceedings, theses, and dissertations, will be performed. Study investigators will be contacted to clarify missing or unpublished data. All prognostic studies meeting the pre-defined eligibility criteria will be included. The study selection, risk of bias assessment, data extraction, and grading of the quality of evidence will be carried out in duplicate, involving independent evaluation by two investigators with consensus or a third-party adjudication. The degree of inter-rater agreement will be calculated using the kappa statistic. For meta-analysis, dichotomous and continuous outcome measures will be pooled using odds ratios and standardized mean differences with 95% confidence intervals, respectively. The Mantel-Haenszel or inverse variance methods with random effects model will be used as a guide for analysis. The heterogeneity of each outcome measure will be assessed using both X2 and I2 statistics. In addition, sensitivity and subgroup analyses will be performed to ensure consistency of pooled results. The review protocol described herein is in accordance with the PRISMA-P standards. DISCUSSION: The investigation of the epidemiological profiles, prognostic factors, and outcomes associated with VAP is critical for the identification of high-risk groups of mechanically ventilated patients and evaluation of possible clinical endpoints. This may provide substantial links for improved VAP prevention practices targeting modifiable risk factors. Implications for future research directions are discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017048158.

Longitudinal changes in methamphetamine and cocaine use in untreated rural stimulant users: racial differences and the impact of methamphetamine legislation.

AIMS: To examine how race and methamphetamine legislation are associated with changes in cocaine and methamphetamine use among untreated rural stimulant users. DESIGN: A longitudinal study of stimulant users identified through respondent-driven sampling. SETTING: Rural areas of three US states. PARTICIPANTS: Participants at baseline were current users of methamphetamine and/or cocaine. MEASURES: Self-reports of methamphetamine, crack cocaine and powder cocaine use were assessed at 6-month intervals over a 2-year period. Generalized estimating equations were performed to account for correlations between the repeated measurements. FINDINGS: Compared to whites, African Americans were much more likely to use crack cocaine, equally likely to use powder cocaine and much less likely to use methamphetamine. Both whites and African Americans reduced their consumption of methamphetamine and both forms of cocaine over 2 years. Exposure to laws restricting the purchase of over-the-counter cold medications containing methamphetamine precursors was not associated with methamphetamine use, but associated with a slight rise in powder and crack cocaine use. CONCLUSIONS: The study yielded disconcerting as well as promising findings regarding the natural history of stimulant use in rural areas. Of some concern is that methamphetamine precursor laws were correlated with increased cocaine consumption, diminishing their net public health benefits. However, despite its insurgence in rural areas of the United States, very few African Americans have initiated methamphetamine use. Regardless of race, many stimulant users stopped using cocaine and methamphetamine without formal substance abuse treatment over 24 months.