Facilitation of discrimination transfers under amphetamine: the relative control by S+ and S− and general transfer effects

Rats were trained in a Y-maze on a two-choice simultaneous black-white discrimination with either black or white as S⁺. Animals were then transferred to one of three discrimination tasks. In task 1 (New S^–), a new stimulus, either vertical or horizontal stripes, was substituted for the original S^–. In task 2 (New S⁺), a new stimulus, either vertical or horizontal stripes as in task 1, was substituted for the original S⁺. In task 3 (New S⁺/S^–) animals were trained on horizontal-vertical discrimination. The pre-trial administration of 1 mg/kg d-amphetamine facilitated the acquisition of the original black-white discrimination with both black as S⁺ and white as S⁺. Likewise, the drug improved performance in all three transfer conditions. However, the course of learning in the three transfer tasks was different in the placebo- and amphetamine-treated animals. Amphetamine-treated animals were disrupted more by a change in S⁺ than by a change in S^–, whereas the opposite pattern was evident in the placebo controls. When both discriminative stimuli were changed, placebo animals exhibited pronounced decrement in performance, whereas amphetamine animals exhibited excellent learning. The implications of these findings for the effects of amphetamine on discrimination learning are discussed.     

Comparison of action of the anti-neoplastic drug lonidamine on drug-sensitive and drug-resistant human breast cancer cells:31 P and 13C nuclear magnetic resonance studies

Lonidamine (LND) is a relatively new anti-cancer drug,and several clinical trials have indicated that it may be effectivein combinations with other therapeutic modalities. LND isclassified within the metabolic inhibitor agents. Multidrugresistance (MDR) phenomenon is often associated with increasedenergy requirements, and enhanced glycolysis rate. These studieswere performed to delineate the mechanism of action of LNDon MDR human breast cancer cells, and to investigate whetherLND as a single agent, or in combination with anotheranti-metabolism drug, 2-deoxyglucose (2-DG), may be usefulagainst MDR tumors. The effects of LND on intact perfuseddrug-sensitive (WT) and 33-fold resistant to Adriamycin(Adr) MCF-7 cells, embedded in alginate micro capsules, were continuouslymonitored by ³¹P and ¹³C nuclearmagnetic resonance (NMR) spectroscopy. ³¹PNMR studies showed that LND induced intracellular acidificationand depletion of NTP in both WT and Adr cells. However, pH and NTPlevels decreased less in the Adr cells than in the WT cells(p < 0.05 for both parameters). ¹³CNMR demonstrated that LND inhibited lactate transport,and lactate signals were elevated in both cell lines. However, theintracellular lactate levels increased to a greater extentin the WT than in the Adr cells (p < 0.05).There were major differences in the effects of LND onmetabolism between sensitive and resistant cells.While LND enhanced glucose uptake in the WT cells, and itsadministration was followed by continuous increase oflactate signal, both processes were not affected by LNDin the Adr cells. 2-DG is a glucose analogue that inhibitsboth cellular uptake and utilization of glucose, leading to cell starvation. Combined treatment with LND and2-DG yielded at best additive, but not synergistic,cellular toxicity, and the metabolic effects of LNDwere attenuated by 2-DG. These results showed that the principalmechanism of action of LND is inhibition of lactate transportleading to intracellular lactate accumulation and acidificationin both WT and Adr cells. The Adr cells were only 2-fold resistantto LND (compared to the WT cells), and since cellular uptakeof alkaloid chemotherapy is improved in acidic environment,LND may have a role in the treatment protocols of MDR tumors,especially when given as the initial means for inductionof intracellular acidification.     

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn’s disease

Background and aims

Distinguishing between fibrotic and inflammatory strictures in Crohn’s disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD.

Methods

Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation.

Results

A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (< 1 × 10⁻³ mm²/s) was significantly associated with the risk of treatment failure (AUC = 0.81, 66% vs. 0%, p = 0.015).

Conclusions

Our results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

     

Localized pericardial inflammation in systemic lupus erythematosus

Regional or localized pericarditis has been infrequently reported. We report a patient with systemic lupus erythematosus (SLE), who presented with retrosternal pleuritic-type chest pain without audible friction rub, electrocardiographic changes or detectable pericardial effusion on echocardiography. Computed tomography, however, revealed a circumscribed area of pericardial inflammation, suggesting a diagnosis of localized lupus-associated pericarditis. This case demonstrates that localized pericarditis may occur in SLE and that chest CT may be required as part of the work-up in the diagnosis of lupus pericarditis.     

The risk of advanced histology in small-sized colonic polyps: are non-invasive colonic imaging modalities good enough?

Purpose

The study aims to evaluate the risk of advanced histology within small colonic polyps and assess whether this risk warrants different recommendation for surveillance and treatment of such polyps.

Methods

A retrospective study of all patients undergoing their first ever colonoscopy and polypectomy in a tertiary hospital for one of three indications: screening, positive family history, and positive occult blood in stool. The histological reports of all resected polyps were retrieved and stratified according to the various polyps’ sizes. Advanced neoplasia was defined as tubular adenoma ≥10?mm or any size polyp with advanced histology, i.e., villous or tubulovillous adenoma, high-grade dysplasia, intramucosal carcinoma, or invasive cancer.

Results

Seven hundred forty-one patients who had a total of 1,192 resected polyps were included. Of polyps ≤5?mm in size, 1.6% harbored invasive cancer or high-grade dysplasia, and additional 4.1% contained villous component. The rate of advanced histology for polyps sized 6–9?mm was over 15%. The rate of advanced histology in polyps ≤5?mm was not significantly different when employing sensitivity analysis accounting for possible under or overestimation of polyp sizes by 1 and 2?mm. However, 4.6% of polyps sized 6–9?mm were found to harbor an invasive or high-grade dysplasia component when taken into account a 2-mm overestimation.

Conclusions

A non-negligible fraction of small polyps harbor advanced histology. This finding suggests that expectant follow-up by non-invasive colonic imaging modalities for small polyps or not reporting them may put more than 5% of patients at risk of dysplasia progression.     

Cholesterol crystal embolization to the digestive system: characterization of a common,yet overlooked presentation of atheroembolism

In the 1359 published patients with multiorgan cholesterol crystal embolism (CCE), the digestive system seems to be the third most frequently affected system. Yet, this system received hitherto only little attention in the medical literature. Therefore, the aim of the present study was to clinically characterize the subset of patients with CCE involving the digestive system, based on our institutional experience and a review of the literature. Cases with CCE in a 7-yr period (1995-2001) were sought in the computerized records of our medical center. Of the CCE patients, those with digestive system involvement that could be related to CCE were included in this study. The clinical features of CCE were determined and compared with those found in published series. Fourteen cases with CCE were identified, giving an annual incidence of 0.8 per 10(5). Digestive system involvement was found in five (36%) of the 14 patients. All five patients had established atherosclerosis. Precipitating factors were vascular manipulations or anticoagulation treatment in four of these five patients. Two patterns of disease appeared: acute catastrophic multiorgan disorder with poor prognosis and chronic and more indolent GI disease. Abdominal pain, GI bleeding, fever, and diarrhea were the most common manifestations, resulting from bowel infarction, mucosal ulcerations, hepatocellular liver disorder, and/or pancreatitis. CCE is a systemic disorder with a frequent involvement of the digestive system and protean clinical manifestations. It should, therefore, be considered in any gastroenterological patient with atherosclerosis and recent vascular manipulations or systemic anticoagulation.