MHC associations with clinical and autoantibody manifestations in European SLE.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.

European population substructure correlates with systemic lupus erythematosus endophenotypes in North Americans of European descent.

Previous work has demonstrated that Northern and Southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. In this study, 1855 SLE cases of European descent were genotyped for 4965 single-nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished Northern from Southern European ancestry, PC2 differentiated Eastern from Western European ancestry and PC3 delineated Ashkenazi Jewish ancestry. Compared with Northern European ancestry, Southern European ancestry was associated with autoantibody production (odds ratio (OR)=1.40, 95% confidence interval (CI) 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.

Vagal control of fasting somatostatin levels.

UNLABELLED: The relationship between fasting intestinal motility, plasma concentration of somatostatin and vagal integrity was examined in four conscious dogs. Small intestinal motility was recorded using subserosally implanted bipolar electrodes. The cervical vagosympathetic trunks, previously isolated in skin loops, were blocked by cooling. In the fasted state, peaks in somatostatin concentration were observed during phase III of the migrating myoelectric complex (MMC). During vagal blockade, small intestinal MMCs persisted but with phase II being absent or decreased in duration in the duodenum and upper jejunum. Somatostatin levels significantly decreased to below the basal levels observed prior to blockade. No cycling of somatostatin levels was evident during the period of vagal blockade. Upon termination of vagal cooling, normal motility returned and somatostatin levels returned to their pre-blockade levels. IN CONCLUSION: (1) plasma somatostatin levels cycle with phase III of the MMC in the upper small intestine; (2) the cycling of fasting somatostatin concentrations is primarily dependent upon intact vagal pathways; and (3) basal plasma somatostatin levels are in part vagally dependent.

Impact of laser refractive surgery on ocular alignment in myopic patients.

PURPOSE: To evaluate the impact of myopic keratorefractive surgery on ocular alignment. METHODS: This prospective study included 194 eyes of 97 myopic patients undergoing laser refractive surgery. All patients received a complete ophthalmic examination with particular attention to ocular alignment before and 3 months after surgery. RESULTS: Patients with a mean age of 26.6 years and a mean refractive error of -4.83 diopters (D) myopia were treated. Asymptomatic ocular misalignment was present preoperatively in 46 (47%) patients: a small-angle heterophoria (1-8 prism diopters, PD) in 36%; and a large-angle heterophoria (>8 PD)/heterotropia in 11%. Postoperatively, the change in angles of 10 PD or greater occurred in 3% for distance and 6% for near fixation: in 7% of the patients with orthophoria, in 3% of those with a small-angle heterophoria, and in 18% of those with a large-angle heterophoria/heterotropia. No patient developed diplopia. The preoperative magnitude of myopia or postoperative refractive status was not related to the change in ocular alignment. The higher anisometropia was associated with a decrease in deviation (P=0.041 for distance and P=0.002 for near fixation), whereas the further near point of convergence tended to be related with an increase in near deviation (P=0.055). CONCLUSIONS: Myopic refractive surgery may cause a change in ocular alignment, especially in cases with a large-angle heterophoria/heterotropia. There is also a chance of improvement of misalignment in patients with anisometropia.

The efficacy of intravenous ketorolac for pain relief in single-stage adjustable strabismus surgery: a prospective, randomized, placebo-controlled trial.

PURPOSE: To determine the efficacy of preoperative intravenous ketorolac in reducing intraoperative and postoperative pain and improving patient satisfaction in patients undergoing single-stage adjustable strabismus surgery. METHODS: A prospective, randomized, placebo-controlled clinical trial was performed with 67 patients who underwent horizontal recti muscle surgery with adjustable sutures. The test group received intravenous ketorolac (60 mg) before surgery, and the control group received intravenous normal saline. Topical 0.5% proparacaine was administered to both groups during surgery. Vital signs including heart rate and blood pressure were recorded every 10 min throughout the surgery. The patients were asked to rate their maximum intraoperative and postoperative pain scores using a numerical pain rating scale. Patient satisfaction was also assessed using a five-point analogue scale. RESULTS: The ketorolac-premedicated patients had less pain both during and after surgery (P = 0.033 and P = 0.024, respectively). There were no differences in vital signs during surgery and patient satisfaction between the two groups. CONCLUSIONS: Intravenous ketorolac, when administered preoperatively for single-stage adjustable strabismus surgery under topical anaesthesia, was effective in reducing pain during and after surgery.

Small intestinal motility in fasted and postprandial states: effect of transient vagosympathetic blockade.

We investigated vagal control of the migrating myoelectric complex (MMC) and postprandial pattern of the canine small intestine. Gastric and small intestinal motility were monitored in six conscious dogs. The vagosympathetic nerves, previously isolated in bilateral skin loops, were blocked by cooling. To feed, a meat-based liquid food was infused by tube into the gastric fundus. MMC phases I, II, III, and IV were observed in the fasted state. On feeding, the fed pattern appeared quickly in the proximal small bowel but was delayed distally. Vagal blockade abolished all gastric contractions and spiking activity as well as the small bowel fed pattern. During vagal blockade, the small bowel exhibited MMC-like migrating bursts of spikes in both the fasted and fed states. The migration and cycling of these bursts were not significantly different from the MMC, but the duodenal and jejunal phase II was absent or shortened. On termination of vagal blockade, normal fasting or fed activity reappeared but with a delay in the fed pattern distally. We conclude: the ileum is the least sensitive to vagal blockade; the fasting vagal influence is exerted primarily on phases I and II of the duodenal and jejunal MMC; the fed pattern throughout the entire small bowel is normally dependent upon vagal integrity; the phase III-like bursts of activity seen during vagal blockade likely represents the intrinsic small bowel MMC, which is vagally independent.

Adrenergic blockage does not restore the canine gastric migrating motor complex during vagal blockade.

Bilateral cervical cooling blockade of the vagi abolishes the gastric migrating motility complex (MMC), except for the pylorus. The present study investigated if this finding is caused by adrenergic inhibition of the stomach via sympathetic nerves entering the vagi below the level of the blockade. Stomach and upper small bowel motor activity was monitored in five chronic dogs whose vagosympathetic nerve trunks were previously isolated in bilateral, cervical skin loops to permit blockade by cooling. Adrenergic blockade was performed by an initial bolus injection of phentolamine (0.3 mg/kg) and propranolol (0.3 mg/kg) followed by a continuous intravenous infusion of the combined drugs at a rate of 1.5 mg.kg-1.h-1 for phentolamine and 0.3 mg.kg-1.h-1 for propranolol. Bilateral cervical vagal blockade abolished the gastric MMC, with persistence of phase III of the MMC in the upper small bowel. During combined vagal and adrenergic blockade, gastric contractions were absent in 4 of the 22 duodenal complexes observed. In the other duodenal complexes, intermittent gastric contractions were associated with all phases of the intestinal MMC, including phase I. At times, this contractile activity was accentuated during phase III but never reached the intensity of activity or showed the typical coordination features of the gastric MMC seen with the vagi intact. Therefore, unopposed adrenergic inhibition of the stomach does not explain the absence of the gastric MMC during vagal cooling blockade. Under normal circumstances, the vagus nerve is the most important pathway for central control of the appearance of the gastric MMC.

Relationship of postprandial motilin, gastrin, and pancreatic polypeptide release to intestinal motility during vagal interruption.

Experiments were performed to determine how postprandial motilin, gastrin, and pancreatic polypeptide plasma concentrations measured during vagal blockade relate to coincident small intestinal motility patterns. Feeding produced a postprandial pattern of intestinal motility coincident with a sustained increase in gastrin and pancreatic polypeptide and a decline in motilin plasma concentrations. Vagal blockade replaced the fed pattern with one similar to migrating motor complex (MMC) activity. Highest motilin plasma concentrations were observed during phase III of this MMC-like activity, as occurs in the fasted state. Vagal blockade reduced but did not abolish the postprandial increase in plasma gastrin and pancreatic polypeptide concentrations. Termination of vagal cooling produced a decline in motilin and an elevation in gastrin and pancreatic polypeptide concentrations, coincident with the return of the fed pattern. In conclusion, during vagal blockade in the fed state (i) motilin, but not gastrin or pancreatic polypeptide plasma concentrations, fluctuate with the MMC-like activity, and any measurement of motilin concentration under these circumstances must be interpreted on the basis of gut motility patterns, and (ii) gastrin and pancreatic polypeptide concentrations are marginally elevated, but these changes are not enough to disrupt the MMC or have any motor effect. Lastly, the fed pattern and the postprandial changes in motilin, gastrin, and pancreatic polypeptide concentrations are in part dependent upon intact vagal pathways.

Mechanisms coordinating gastric and small intestinal MMC: role of extrinsic innervation rather than motilin.

We have investigated the role of vagal and efferent adrenergic innervation coordinating the gastric and small intestinal migrating motor complexes (MMCs) after removal of the pylorus, duodenum, and upper jejunum in three dogs. The cervical vagus nerves were previously isolated in bilateral skin loops to permit reversible cooling blockade of the vagi. Pharmacological alpha- and beta-receptor blockade was accomplished by bolus intravenous injection of phentolamine and propranolol followed by intravenous infusion of the combined drugs. Gastric and upper jejunal MMC-like activity was initially absent after bowel resection but reappeared after 1-4 mo with the gastric and jejunal MMC-like activities coordinated as if the jejunum were the duodenum. Motilin peaks were absent. All gastric contractions were abolished by vagal blockade. Pharmacological adrenergic blockade immediately induced an intense burst of contractile and electrical activity in the stomach, which propagated to the distal ileum. This phase III-like burst was followed by ongoing intermittent bursts of contractile and electrical activity in the stomach and small intestine, lasting throughout the blockade, without further MMC-like activity. Vagal cooling blockade in combination with adrenergic blockade did not restore gastric MMC-like activity but abolished or decreased the number of gastric contractions, with the reappearance of the small intestinal MMC. Atropine boluses abolished all control and adrenergic blockade-induced stomach and small intestinal contractile and electrical activity. In conclusion, after duodenectomy, the gastric MMC-like activity that is reestablished and is coordinated with the small intestinal MMC is vagally dependent and cholinergic, but its cyclical nature requires adrenergic efferent pathways. Under these circumstances, coordination of the gastric and jejunal MMCs appears to require extrinsic innervation.

Knowledge of sleep apnea in a sample grouping of primary care physicians.

UNLABELLED: The purpose of this pilot study was to examine four groups of primary care physicians' knowledge of sleep apnea. METHODS: Using a 36-item questionnaire, we investigated how cognizant primary care physicians in Ontario, Canada, were of sleep apnea and its different symptoms. The questions covered incidence, diagnosis, treatment, and medical and social ramifications of sleep apnea. Sleep apnea surveys were administered to small groups of primary care physicians attending educational conferences or were distributed by mail to physicians who had previously referred patients to the sleep clinic. RESULTS: A total of 151 physicians responded to the survey. An overall average score of 69% was obtained on the questionnaire. CONCLUSIONS: This score suggests that the physicians sampled in this pilot study are relatively under-informed about the clinical features and medical and social ramifications associated with sleep apnea.

The ventilatory response to carbon dioxide in hyperoxic exercise.

The sensitivity of the ventilatory response to carbon dioxide in hyperoxia during light (25 W) exercise was compared to that at rest in 14 volunteers. The method used was that of rebreathing. Two factors were found to produce artefactual changes in the slope of the response during exercise. First, breath-by-breath response lines showed that the maximum limit of ventilation was reached in 3 volunteers before the end of rebreathing, despite the low exercise load. The inclusion of such breaths in the calculation of the slope of the response could produce an artefactual decrease in slope. Second, most of the response lines showed an increase in their slope during exercise. However, a model of rebreathing in exercise showed that an increase in sensitivity could be the result of variation in the difference between end-tidal and central chemoreceptor carbon dioxide levels during exercise. A criterion derived from the model, proportional to the variation in this difference, was found to be correlated with the increase in sensitivity from rest to exercise. It was therefore concluded that the sensitivity of the ventilatory response to carbon dioxide during light exercise is unchanged from that at rest.