Pilot study of MK-462 in migraine

MK-462 is a potent, selective 5HT_1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg ( n = 8) and 40 mg ( n =36) vs placebo ( n =21), administered to 65 male and post-menopausal female migraine patients aged 22–51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly ( p <0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (10 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.     

Reduced lysosomal clearance of autophagosomes promotes survival and colonization of Helicobacter pylori

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori‐infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose‐6‐phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro‐survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Load transfer in tilted implants with varying cantilever lengths in an all‐on‐four situation

Background: The aim of this study was to evaluate if tilting of the distal implant at different angulations (30° and 40°) with different cantilever lengths (4 mm and 12 mm) affects the stress and strain distribution in an ‘all‐on‐four’ situation. Methods: A completely edentulous mandible was modelled with four tapered implants placed within the interforaminal region to receive an all acrylic fixed prosthesis. The two posterior implants were tilted at an angle of 30° and 40°. The prosthesis cantilever was given two different variables of 4 mm and 12 mm. For all models, the equivalent von Mises stress and strain was analysed using three‐dimensional finite element analysis. Results: Statistical significance (p < 0.05) was seen when a comparison was made for the stress developed on the implant and cortical bone between the 30° and 40° distally tilted posterior implants in both situations. No significance was seen in the trabecular bone and on the strain developed in these situations. Conclusions: The study shows that increasing the tilt of the distal implants does not increase the stress significantly. It also shows that the architecture of the mandible plays a major role during treatment planning of a completely edentulous patient.     

Carotid artery stump pressure and associated neurological changes in predominantly symptomatic carotid artery disease patients undergoing awake carotid endarterectomy

Aim

To determine the mean carotid artery stump pressure (SP) at which patients develop neurological changes while undergoing awake carotid artery endarterectomy (CEA) under cervical block anaesthesia (CBA).

Methods

A prospective analysis was carried out of patients undergoing awake CEA under CBA between February 2004 and April 2007. All patients had mean SP measured, with selective shunting on those who developed neurological symptoms on carotid artery clamping regardless of stump pressure. A ball connected to a pressure sensor was put in the patient’s contra-lateral hand.

Results

Fifty-nine patients had awake CEA, 40 were males with a mean age of 64 years. Indications for CEA were asymptomatic high-grade stenosis in 12 (20%) patients and symptomatic stenosis in 47 (80%). Seven (12%) patients required shunting, one for transient ischaemic attack (TIA) and six for loss of consciousness. Six of these patients had presented with symptomatic disease.Taking the threshold of mean carotid SP of 50 mmHg as an indication for shunting, 22% (6/27) of patients with a mean SP of < 50 mmHg required shunting and only 3% (1/32) with a mean carotid SP of > 50 mmHg needed a shunt. This was not statistically significant. Using a mean carotid SP of ≤ 40 mmHg as the threshold for shunting, 40% (4/10) of patients required shunting and 3% (1/31) with a mean carotid SP of > 40 mmHg required shunting. This was statistically significant. Thirteen (22%) patients were complicated by transient hoarseness of voice. One (2%) had a haematoma that required re-exploration. None of these patients had any major postoperative neurological or cardiological complications.

Conclusion

Even though the sample in this study was small, awake CEA under local anaesthesia was seen as a safe procedure. It would appear to be safe to use the mean SP of 40 mmHg as a threshold for selective shunting in CEA under general anaesthesia.     

Identification of Novel ROR2 Gene Mutations in Indian Children with Robinow Syndrome

Ob­jec­ti­ve: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder.Methods: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient’s mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster.Results: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. Conclusion: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.     

PROTEIN KINASE C AND TRANSMITTER RELEASE

1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca²⁺entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca²⁺ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.