Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists

Triptans are 5HT(1B/1D) receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT(1B/1D) receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.     

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.

     

The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy

BackgroundType 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.MethodsC57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.ResultsTreatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.ConclusionsOur data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.     

Application of the American College of Cardiology (ACC/AHA) 2017 Guideline for the Management of Hypertension in Adults and Comparison with the 2014 Eighth Joint National Committee Guideline

ObjectivesThis study aims to compare the 2017-ACC/AHA hypertension guideline with 2014-JNC-8 guideline in regard to the number of patients who are eligible for treatment and to determine the physicians’ adherence and the financial impact of implementing the new guideline.MethodsA cross-sectional observational study was conducted on adult patients who attended the hospital outpatient setting in UAE during January 1, 2018 till February 28, 2018. Adults who are diagnosed with hypertension and those with blood pressure (BP) levels based on two or more readings obtained on two or more different occasions were screened for inclusion into this study and cardiovascular diseases (CVD) risk was calculated. The two guidelines were compared with respect to the number of patients diagnosed with hypertension and eligible for treatment. Results were extrapolated to the UAE population. Financial impact of applying the 2017-ACC/AHA guideline was also evaluated.ResultsIn comparison with the JNC-8, the 2017-ACC/AHA guideline would increase the proportion of patients diagnosed with hypertension among UAE adults from 40.8% to 76.3% and the number of UAE adults recommended for antihypertensive medications would rise from 2.42 million (32.1%) to 4.71 million (62.5%). Among UAE adults, almost 4.42 million (58.6%) and 0.76 million (10.1%) would have BP above the target according to the 2017-ACC/AHA and JNC-8 guidelines, respectively. The expected increase in the cost of anti-hypertension medications prescribed for the new labeled cases according to 2017-ACC/AHA but not JNC-8 would reach 1.8 billion AED/year. For those who were recommended for antihypertensive medications, who had BP above target, the additional cost would reach 3.5 billion AED/year.ConclusionsThe current study reveals marked increase in the proportion of patients diagnosed with hypertension in concordance with the 2017-ACC/AHA guideline. This is also will be associated with almost double the number of UAE adults recommended for antihypertensive medications. The poor compliance with the 2017-ACC/AHA reflects the concern regarding the increase risk of adverse events.     

Single-Domain Antibodies or Nanobodies: A Class of Next-Generation Antibodies

Nanobodies for the first time were identified in the sera of Camelidae. Single-domain antibodies or nanobodies are a class of next-generation antibodies that have specific features: small size (in nanoscale), high penetration in various tissues, high stability in hard situations and ease production process in microbial systems. In fact single-domain antibodies are the smallest fragment of the antibody with binding ability. Unique characteristics and features of nanobodies make them an appropriate candidate for further evaluation as the development of novel antibody-based therapeutics. In this regard single-domain antibodies are in the interest of many researchers as well as biopharmaceutical companies for diagnostic and therapeutic applications. Nowadays several single domain antibodies have been developed and evaluated in different clinical trials. Because of many advantages of single-domain antibodies over other formats of antibodies, they could be good replacement for other formats of antibodies in near future. Here, we review the biology, engineering platforms and application of nanobodies.