Radiographic score was not found to be closely associated with function. Amongst patients with the same radiographic score there was considerable variation in function, pain and power.
Cortico-striato-thalamic (CST) systems are anatomical substrates for many motor and executive functions and are implicated in diverse neuropsychiatric disorders. Electrophysiological studies in rats, monkeys and patients with Parkinson's disease have shown that power and coherence of low frequency oscillations in CST systems can be profoundly modulated by dopaminergic drugs. We combined functional MRI with correlational and path analyses to investigate functional and effective connectivity, respectively, of a prefronto-striato-thalamic system activated by object location learning in healthy elderly human subjects (n = 23; mean age = 72 years). Participants were scanned in a repeated measures, randomized, placebo-controlled design to measure modulation of physiological connectivity between CST regions following treatment with drugs which served both to decrease (sulpiride) and increase (methylphenidate) dopaminergic transmission, as well as non-dopaminergic treatments (diazepam and scopolamine) to examine non-specific effects. Functional connectivity of caudate nucleus was modulated specifically by dopaminergic drugs, with opposing effects of sulpiride and methylphenidate. The more salient effect of sulpiride was to increase functional connectivity between caudate and both thalamus and ventral midbrain. A path diagram based on prior knowledge of unidirectional anatomical projections between CST components was fitted satisfactorily to the observed inter-regional covariance matrix. The effect of sulpiride was defined more specifically in the context of this model as increased strength of effective connection from ventral midbrain to caudate nucleus. In short, we have demonstrated enhanced functional and effective connectivity of human caudate nucleus following sulpiride treatment, which is compatible both with the anatomy of ascending dopaminergic projections and with electrophysiological studies indicating abnormal coherent oscillations of CST neurons in parkinsonian states.
Background
Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear.
Methods
We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided.
Results
Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers.
Conclusions
Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
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