A Case-Based Approach to Constipation in Primary Care.

Primary care physicians frequently evaluate patients with constipation. The history is crucial in uncovering warning symptoms and signs that warrant colonoscopy. Particular elements in the history and rectal examination also can provide clues regarding the underlying etiology. Regardless of etiology, lifestyle modifications, fiber, and laxatives are first-line therapies. Patients who fail first-line therapies can be offered second-line treatments and/or referred for testing of defecatory function. In those with severely refractory symptoms, referrals to a gastroenterologist and a surgeon should be considered.

Gastric food retention at endoscopy is associated with severity of liver cirrhosis.

BACKGROUND: Gastrointestinal symptoms are prevalent in patients with cirrhosis. Cirrhotic patients have a known predilection to delayed gastric emptying compared to those without cirrhosis. However, the contributing factors have not been fully elucidated. Retained gastric food on esophagogastroduodenoscopy (EGD) has been used as a surrogate marker for delayed gastric emptying with reasonably high specificity. Therefore, we hypothesize that the frequency of retained gastric food contents at EGD will be higher in a cirrhotic population compared to a control population without liver disease. Additionally, we hypothesize that increased frequency of gastric food contents will be associated with increased severity of cirrhosis. AIM: To determine the relative frequency of delayed gastric emptying among cirrhotics as compared to non-cirrhotics and to identify associated factors. METHODS: We performed a retrospective case-control study of cirrhotic subjects who underwent EGD at an academic medical center between 2000 and 2015. Three hundred sixty-four patients with confirmed cirrhosis, who underwent a total of 1044 EGDs for the indication of esophageal variceal screening or surveillance, were identified. During the same period, 519 control patients without liver disease, who underwent a total of 881 EGDs for the indication of anemia, were identified. The presence of retained food on EGD was used as a surrogate for delayed gastric emptying. The relative frequency of delayed gastric emptying among cirrhotics was compared to non-cirrhotics. Characteristics of patients with and without retained food on EGD were compared using univariable and multivariable logistic regression analysis to identify associated factors. RESULTS: Overall, 40 (4.5%) patients had evidence of retained food on EGD. Cirrhotics were more likely to have retained food on EGD than non-cirrhotics (9.1% vs 1.4%, P < 0.001). Characteristics associated with retained food on univariable analysis included age less than 60 years (12.6% vs 5.2%, P = 0.015), opioid use (P = 0.004), Child-Pugh class C (24.1% Child-Pugh class C vs 6.4% Child-Pugh class A, P = 0.007), and lower platelet count (P = 0.027). On multivariate logistic regression analysis, in addition to the presence of cirrhosis (adjusted OR = 5.83; 95%CI: 2.32-14.7, P < 0.001), diabetes mellitus (types 1 and 2 combined) (OR = 2.34; 95%CI: 1.08-5.06, P = 0.031), opioid use (OR = 3.08; 95%CI: 1.29-7.34, P = 0.011), and Child-Pugh class C (OR = 4.29; 95%CI: 1.43-12.9, P = 0.01) were also associated with a higher likelihood of food retention on EGD. CONCLUSION: Cirrhotics have a higher frequency of retained food at EGD than non-cirrhotics. Decompensated cirrhosis, defined by Child-Pugh class C, is associated with a higher likelihood of delayed gastric emptying.

Dopamine Transporter Dynamics of N-Substituted Benztropine Analogs with Atypical Behavioral Effects.

Atypical dopamine transporter (DAT) inhibitors, despite high DAT affinity, do not produce the psychomotor stimulant and abuse profile of standard DAT inhibitors such as cocaine. Proposed contributing features for those differences include off-target actions, slow onsets of action, and ligand bias regarding DAT conformation. Several 3α-(4',4''-difluoro-diphenylmethoxy)tropanes were examined, including those with the following substitutions: N-(indole-3''-ethyl)- (GA1-69), N-(R)-2''-amino-3''-methyl-n-butyl- (GA2-50), N-2''aminoethyl- (GA2-99), and N-(cyclopropylmethyl)- (JHW013). These compounds were previously reported to have rapid onset of behavioral effects and were presently evaluated pharmacologically alone or in combination with cocaine. DAT conformational mode was assessed by substituted-cysteine accessibility and molecular dynamics (MD) simulations. As determined by substituted-cysteine alkylation, all BZT analogs except GA2-99 showed bias for a cytoplasmic-facing DAT conformation, whereas cocaine stabilized the extracellular-facing conformation. MD simulations suggested that several analog-DAT complexes formed stable R85-D476 "outer gate" bonds that close the DAT to extracellular space. GA2-99 diverged from this pattern, yet had effects similar to those of other atypical DAT inhibitors. Apparent DAT association rates of the BZT analogs in vivo were slower than that for cocaine. None of the compounds was self-administered or stimulated locomotion, and each blocked those effects of cocaine. The present findings provide more detail on ligand-induced DAT conformations and indicate that aspects of DAT conformation other than "open" versus "closed" may facilitate predictions of the actions of DAT inhibitors and may promote rational design of potential treatments for psychomotor-stimulant abuse.