Animal models of compulsive eating behavior

In industrialized nations, overeating is a significant problem leading to overweight, obesity, and a host of related disorders; the increase in these disorders has prompted a significant amount of research aimed at understanding their etiology. Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Considering that compulsive eating in the face of adverse consequences characterizes some eating disorders, similar to the way in which compulsive drug intake characterizes drug-addiction, it might be considered an addiction in its own right. Moreover, numerous review articles have recently drawn a connection between the neural circuits activated in the seeking/intake of palatable food and drugs of abuse. Based on this observation, “food addiction” has emerged as an area of intense scientific research and accumulating evidence suggests it is possible to model some aspects of food addiction in animals. The development of well-characterized animal models would advance our understanding of the etiologic neural factors involved in eating disorders, such as compulsive overeating, and it would permit to propose targeted pharmacological therapies. However, to date, little evidence has been reported of continued food seeking and intake despite its harmful consequences in rats and mice

Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials

Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Methods: We searched MEDLINE and Embase from Jan 1, 1950, to Dec 31, 2015, to identify unconfounded, randomised trials of a gastroprotectant drug (defined as a PPI, prostaglandin analogue, or H2RA) versus control, or versus another gastroprotectant. Two independent researchers reviewed the search results and extracted the prespecified outcomes and key characteristics for each trial. We did meta-analyses of the effects of gastroprotectant drugs on ulcer development, bleeding, and mortality overall, according to the class of gastroprotectant, and according to the individual drug within a gastroprotectant class. Findings: We identified comparisons of gastroprotectant versus control in 849 trials (142 485 participants): 580 prevention trials (110 626 participants), 233 healing trials (24 033 participants), and 36 trials for the treatment of acute upper gastrointestinal bleeding (7826 participants). Comparisons of one gastroprotectant drug versus another were available in 345 trials (64 905 participants), comprising 160 prevention trials (32 959 participants), 167 healing trials (28 306 participants), and 18 trials for treatment of acute upper gastrointestinal bleeding (3640 participants). The median number of patients in each trial was 78 (IQR 44·0–210·5) and the median duration was 1·4 months (0·9–2·8). In prevention trials, gastroprotectant drugs reduced development of endoscopic ulcers (odds ratio [OR] 0·27, 95% CI 0·25–0·29; p<0·0001), symptomatic ulcers (0·25, 0·22–0·29; p<0·0001), and upper gastrointestinal bleeding (0·40, 0·32–0·50; p<0·0001), but did not significantly reduce mortality (0·85, 0·69–1·04; p=0·11). Larger proportional reductions in upper gastrointestinal bleeding were observed for PPIs than for other gastroprotectant drugs (PPIs 0·21, 99% CI 0·12–0·36; prostaglandin analogues 0·63, 0·35–1·12; H2RAs 0·49, 0·30–0·80; phet=0·0005). Gastroprotectant drugs were effective in preventing bleeding irrespective of the use of non-steroidal anti-inflammatory drugs (phet=0·56). In healing trials, gastroprotectants increased endoscopic ulcer healing (3·49, 95% CI 3·28–3·72; p<0·0001), with PPIs more effective (5·22, 99% CI 4·00–6·80) than prostaglandin analogues (2·27, 1·91–2·70) and H2RAs (3·80, 3·44–4·20; phet<0·0001). In trials among patients with acute bleeding, gastroprotectants reduced further bleeding (OR 0·68, 95% CI 0·60–0·78; p<0·0001), blood transfusion (0·75, 0·65–0·88; p=0·0003), further endoscopic intervention (0·56, 0·45–0·70; p<0·0001), and surgery (0·72, 0·61–0·84; p<0·0001), but did not significantly reduce mortality (OR 0·90, 0·72–1·11; p=0·31). PPIs had larger protective effects than did H2RAs for further bleeding (phet=0·0107) and blood transfusion (phet=0·0130). Interpretation: Gastroprotectants, in particular PPIs, reduce the risk of peptic ulcer disease and its complications and promote healing of peptic ulcers in a wide range of clinical circumstances. However, this meta-analysis might have overestimated the benefits owing to small study bias

Liver transplantation as last-resort treatment for patients with bile duct injuries following cholecystectomy: A multicenter analysis

Background Liver transplantation (LT) has been used as a last resort in patients with end-stage liver disease due to bile duct injuries (BDI) following cholecystectomy. Our study aimed to identify and evaluate factors that cause or contribute to an extended liver disease that requires LT as ultimate solution, after BDI during cholecystectomy. Methods Data from 8 high-volume LT centers relating to patients who underwent LT after suffering BDI during cholecystectomy were prospectively collected and retrospectively analyzed. Results Thirty-four patients (16 men, 18 women) with a median age of 45 (range 22-69) years were included in this study. Thirty of them (88.2%) underwent LT because of liver failure, most commonly as a result of secondary biliary cirrhosis. The median time interval between BDI and LT was 63 (range 0-336) months. There were 23 cases (67.6%) of postoperative morbidity, 6 cases (17.6%) of post-transplant 30-day mortality, and 10 deaths (29.4%) in total after LT. There was a higher probability that patients with concomitant vascular injury (hazard ratio 10.69, P=0.039) would be referred sooner for LT. Overall survival following LT at 1, 3, 5 and 10 years was 82.4%, 76.5%, 73.5% and 70.6%, respectively. Conclusion LT for selected patients with otherwise unmanageable BDI following cholecystectomy yields acceptable long-term outcomes

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

The treatment of polycythaemia vera: an update in the JAK2 era

The clinical course of polycythaemia vera is marked by a high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of transformation into acute leukaemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin. Cytotoxic therapy is indicated in high-risk patients, with the drug of choice being hydroxyurea because its leukaemogenicity is low. The recent discovery of JAK2 V617F mutation in the vast majority of polycythaemia vera patients opens new avenues for the treatment of this disease. Novel therapeutic options theoretically devoid of leukaemic risk, such as alpha-interferon and imatinib, affect JAK2 expression in some patients. Nevertheless, these drugs require further clinical experience and, for the time being, should be reserved for selected cases

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

<p>Abstract</p> <p>Background</p> <p>Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the <it>SPAST </it>(<it>SPG4</it>) and <it>ATL1 </it>(<it>SPG3A</it>) genes would account for about 50% of the ADHSP cases.</p> <p>Methods</p> <p>We defined the <it>SPAST </it>and <it>ATL1 </it>mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).</p> <p>Results</p> <p>We found 50 <it>SPAST </it>mutations (including two large deletions) in 54 patients and 7 <it>ATL1 </it>mutations in 11 patients. A total of 33 of the <it>SPAST </it>and 3 of the <it>ATL1 </it>were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the <it>SPAST </it>mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.</p> <p>Conclusions</p> <p>In a large cohort of Spanish patients with spastic paraplegia, <it>SPAST </it>and <it>ATL1 </it>mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.</p

Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI

Platelet inhibition remains the core pharmacotherapy component in patients under-going emergency or primary percutaneous coronary interventions (PCI). This can be achieved using a number of intravenous and oral preparations. Intravenous (iv) antiplatelets include various glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors and the only available intravenous P2Y12 inhibitor, cangrelor. Available oral agents include aspirin and various P2Y12 inhibitors or their analogues. These are usually used in combination with the intention to maintain dual antiplatelet therapy (DAPT) for a period of time (generally up to 12 months) after the index PCI procedure.Understanding and appropriate use of antiplatelet agents are vital in optimizing clinical outcomes of patients with acute coronary syndromes, particularly in the emergency setting where the patient may be naïve to all pharmacological agents. In this review, an overview on antiplatelet therapy for patient needing emergency PCI is described, including evidence from important clinical trials and suggested anti-platelet therapy regimens by published clinical practice guidelines