Extreme ecchymoses in a migraine patient using concomitant treatment with calcitonin gene-related peptide receptor antibodies and fish oil supplements: a case report.

BACKGROUND: Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, is registered for migraine prevention. Compared to other conventional migraine prevention medicines (i.e. topiramate, betablockers and amitriptyline) erenumab has better tolerability. Impaired hemostasis has not been reported previously. Here, we report the first case of an increased tendency to bruise in a migraine patient treated with erenumab. CASE PRESENTATION: A 41-year old female migraine patient was treated with erenumab for 12 months, which led to a significant reduction of headache and migraine days. Three months after treatment start, she experienced increased tendency to bruise leading to extreme ecchymosis after 4 months treatment. Platelet counts and aggregation, thromboelastography, activated partial thromboplastin time (APTT) and international normalized ratio (INR) were all normal. Thorough interview revealed intake of fish oil supplements for many years prior to treatment. The increased tendency to bruise subsided after discontinuation of fish oil supplements. CONCLUSION: The combination of fish oil supplements and erenumab may cause increased tendency to bruise. Erenumab has no effect on the platelets per se but may cause impaired wound healing by suppression of CGRP. Thus, small and unnoticeable bruises may be aggravated instead in patients with tendency to bruise caused by for instance fish oil supplements.

Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients.

OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS containing whey (LNS/w), an LNS containing soy (LNS/s) or no LNS. Trough plasma concentrations of efavirenz and nevirapine were measured at 1 and 2 months. Genotyping for 516 G>T and 983 T>C polymorphisms of the cytochrome P450 (CYP) 2B6 locus was performed. Multilevel linear mixed-effects models were used to assess the associations between LNS and plasma efavirenz and nevirapine concentrations. RESULTS: In patients with BMI > 17 kg/m(2), nevirapine concentrations were lower in the LNS/w and LNS/s groups by a median of -2.3 µg/mL [interquartile range (IQR) -3.9; -0.9 µg/mL; P = 0.002] and -2.1 µg/mL (IQR -3.9; -0.9 µg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 µg/mL higher plasma efavirenz concentration compared with the wild type (P < 0.0001), while it was not associated with plasma nevirapine concentrations. CONCLUSIONS: Intake of an LNS was associated with lower plasma nevirapine trough concentrations, indicating possible drug-LNS interactions. The clinical relevance of such reductions in nevirapine exposure is not clear. Plasma efavirenz concentration was not affected by the LNS.

Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Chest physiotherapy and breathing exercises for cardiac surgery patients in Sweden--a national survey of practice.

BACKGROUND: Various chest physiotherapy techniques are recommended after cardiac surgery around the world. There is limited published data on what breathing exercises actually are recommended to patients after surgery in Europe. The aim of this national survey was to establish the current practice of chest physiotherapy and breathing exercises for adult patients following cardiac surgery in Sweden. METHODS: A postal questionnaire was sent to a total population sample of 33 Swedish physiotherapists working at the departments of cardiothoracic surgery in December 2007 and January 2008. RESULTS: In total, 29 replies (88%) were received. Seven male and twenty two female physiotherapists completed the questionnaire. All physiotherapists instructed, on a regular basis, the cardiac surgery patients to perform post-operative breathing exercises. Positive expiratory pressure (PEP) breathing was routinely used as the first choice for treatment by 22 (83%) of the physiotherapists. Expiratory pressures used varied between 2 and 20 cm H2O. Recommended frequency and duration of the exercises varied from 4 to 30 breaths hourly during the daytime in the first post-operative days. All physiotherapists provided coughing support to the patients. Recommendations to continue breathing exercises after discharge varied from not at all up to 3 months after surgery. CONCLUSIONS: Breathing exercises are regularly prescribed during the initial post-operative days after cardiac surgery in Sweden. Hourly deep breathing exercises performed with or without a PEP device were reported to be first choice treatments during the hospital stay. Instructions concerning how long patients should continue the exercises after discharge varied notably.

Acupuncture as an adjunct to standard treatment for pelvic girdle pain in pregnant women: randomised double-blinded controlled trial comparing acupuncture with non-penetrating sham acupuncture.

OBJECTIVE: To investigate whether acupuncture has a greater treatment effect than non-penetrating sham acupuncture in women with pelvic girdle pain (PGP) during pregnancy. DESIGN: Randomised double-blinded controlled trial. SETTING: East Hospital, Gothenburg, and 25 antenatal primary care units in the region of Västra Götaland, Sweden. POPULATION: A total of 115 pregnant women with a clinical diagnosis of PGP who scored > or =50 on a 100-mm visual analogue scale (VAS). METHOD: Women were randomly allocated to standard treatment plus acupuncture or to standard treatment plus non-penetrating sham acupuncture for 8 weeks. MAIN OUTCOME MEASURES: Main outcome measure was pain. Secondary outcomes were frequency of sick leave, functional status, discomfort of PGP, health-related quality of life and recovery of severity of PGP as assessed by the independent examiner. RESULTS: After treatment, median pain decreased from 66 to 36 in the acupuncture group and from 69 to 41 in the non-penetrating sham group (P = 0.493) as assessed on a VAS. Women in the acupuncture group were in regular work to a higher extent than women in the sham group (n = 28/57 versus 16/57, P = 0.041). The acupuncture group had superior ability to perform daily activities measured with the disability rating index (DRI) (44 versus 55, P = 0.001). There were no significant differences in quality of life, discomfort of PGP and recovery from severity of PGP between the groups. CONCLUSIONS: Acupuncture had no significant effect on pain or on the degree of sick leave compared with non-penetrating sham acupuncture. There was some improvement in performing daily activities according to DRI. The data imply that needle penetration contributes to a limited extent to the previously reported beneficial effects of acupuncture.

Regression of pelvic girdle pain after delivery: follow-up of a randomised single blind controlled trial with different treatment modalities.

OBJECTIVE: An earlier publication showed that acupuncture and stabilising exercises as an adjunct to standard treatment was effective for pelvic girdle pain during pregnancy, but the post-pregnancy effects of these treatment modalities are unknown. The aim of this follow-up study was to describe regression of pelvic girdle pain after delivery in these women. DESIGN: A randomised, single blind, controlled trial. SETTING: East Hospital and 27 maternity care centres in Göteborg, Sweden. POPULATION: Some 386 pregnant women with pelvic girdle pain. METHODS: Participants were randomly assigned to standard treatment plus acupuncture (n=125), standard treatment plus specific stabilising exercises (n=131) or to standard treatment alone (n=130). PRIMARY OUTCOME MEASURES: pain intensity (Visual Analogue Scale). SECONDARY OUTCOME MEASURE: assessment of the severity of pelvic girdle pain by an independent examiner 12 weeks after delivery. RESULTS: Approximately three-quarters of all the women were free of pain 3 weeks after delivery. There were no differences in recovery between the 3 treatment groups. According to the detailed physical examination, pelvic girdle pain had resolved in 99% of the women 12 weeks after delivery. CONCLUSIONS: This study shows that irrespective of treatment modality, regression of pelvic girdle pain occurs in the great majority of women within 12 weeks after delivery.

Effects of abdominal binding on breathing patterns during breathing exercises in persons with tetraplegia.

STUDY DESIGN: Cross-sectional, experimental. OBJECTIVES: To investigate and compare static lung volumes and breathing patterns in persons with a cervical spinal cord lesion during breathing at rest, ordinary deep breathing, positive expiratory pressure (PEP) and inspiratory resistance-positive expiratory pressure (IR-PEP) with and without an abdominal binder (AB). SETTING: The outpatient clinic at the Spinal Unit at Sahlgrenska University Hospital, Goteborg, Sweden. METHOD: The study group consisted of 20 persons with complete cervical cord lesion at C5-C8 level. Breathing patterns and static lung volumes with and without an AB were measured using a body plethysmograph. RESULTS: : With an AB, static lung volumes decreased, vital capacity increased, breathing patterns changed only marginally and functional residual capacity remained unchanged during PEP and IR-PEP. CONCLUSION: Evidence supporting the general use of an AB to prevent respiratory complications by means of respiratory training is questionable. However, the interindividual variation in our results indicates that we cannot rule out that some patients may benefit from the treatment.

Breathing patterns during breathing exercises in persons with tetraplegia.

STUDY DESIGN: Cross-sectional, observational, controlled study. OBJECTIVES: To survey breathing patterns during breathing at rest, ordinary deep breathing (DB), positive expiratory pressure (PEP) and inspiratory resistance-positive expiratory pressure (IR-PEP) among individuals with a cervical spinal cord lesion (SCL) compared with able-bodied controls. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. METHOD: Participants consisted of 20 persons with a complete SCL at the C5-C8 level (at least 1 year postinjury) and 20 matched, able-bodied controls. Breathing patterns and static lung volumes were measured using a body plethysmograph. RESULTS: Compared to the controls, breathing patterns at rest among the people with tetraplegia were characterised by a decreased tidal volume, stable respiratory rate and total cycle duration resulting in decreased mean inspiratory and expiratory flow, and alveolar ventilation. All volume and flow parameters increased except respiratory rate, which decreased during DB and PEP. During IR-PEP, tidal volume increased less compared to PEP, and combined with a decreased respiratory rate the alveolar ventilation was lower than during breathing at rest. The functional residual capacity increased during PEP and IR-PEP in people with tetraplegia. CONCLUSION: DB exercises with or without resistance during expiration or the whole breathing cycle affect the breathing pattern in persons with tetraplegia. DB was superior in increasing volumes and flow. PEP and IR-PEP increased FRC but IR-PEP decreased volumes and flows. However, large interindividual differences in the SCL group indicate the need for caution in generalising the results. SPONSORSHIP: This work was supported in part by grants from the Memorial Foundation of the Swedish Association of registered Physiotherapists and the Association of Cancer and Road Accident Victims.

Effects of breathing exercises on breathing patterns in obese and non-obese subjects.

Chest physiotherapy in connection with abdominal surgery includes different deep-breathing exercises to prevent post-operative pulmonary complications. The therapy is effective in preventing pulmonary complications, especially in high-risk patients such as obese persons. The mechanisms behind the effect is unclear, but part of the effect may be explained by the changes in breathing patterns. The aim of this study was therefore to describe and to analyse the breathing patterns in obese and non-obese subjects during three different breathing techniques frequently used in the treatment of post-operative patients. Twenty-one severely obese [body mass index (BMI) > 40] and 21 non-obese (BMI 19-25) subjects were studied. All persons denied having any lung disease and were non-smokers. The breathing techniques investigated were: deep breaths without any resistance (DB), positive expiratory pressure (PEP) with an airway resistance of approximately +15 cmH2O (1.5 kPa) during expiration, inspiratory resistance positive expiratory pressure (IR-PEP) with a pressure of approximately -10 cmH2O (-1.0 kPa) during inspiration. Expiratory resistance as for PEP. Volume against time was monitored while the subjects were sitting in a body plethysmograph. Variables for volume and flow during the breathing cycle were determined. Tidal volume and alveolar ventilation were highest during DB, and peak inspiratory volume was significantly higher than during PEP and IR-PEP in the group of obese subjects. The breathing cycles were prolonged in all techniques but were most prolonged in PEP and IR-PEP. The functional residual capacity (FRC) was significantly lower during DB than during PEP and IR-PEP in the group of obese subjects. FRC as determined within 2 min of finishing each breathing technique was identical to before the breathing manoeuvres.

Hemodynamic and renal effects of indomethacin in losartan-treated hypertensive individuals.

This study was undertaken to examine whether prostaglandin (PG) inhibition with indomethacin interferes with angiotensin II receptor blockade (losartan) during treatment for arterial hypertension. In a double-blind crossover design 10 patients with essential arterial hypertension and treated with losartan were randomized to supplementary treatment with indomethacin or placebo for 1 week, with a 2-week washout period interposed. At the end of each treatment period the following examinations were performed, preceded by 4 days on sodium-fixed diet: 24-h blood pressure (BP), 24-h sodium excretion (UNaV), supine BP, glomerular filtration rate (GFR), renal resistive index (RRI), extracellular fluid volume (ECV), sodium clearance (Cl(Na)), body weight, peripheral blood flow (PBF), and plasma concentrations of aldosterone, renin (PRC), and atrial natriuretic peptide (ANP). Indomethacin did not change BP. Indomethacin increased weight (P < .05) and ECV (P < .05). A nonsignificant decrease in UNaV was seen after indomethacin, as in 24-h Cl(Na). Conversely, in the laboratory in the supine position Cl(Na) increased after indomethacin (P = .05). Indomethacin increased plasma ANP (P < .01). No changes were observed in GFR, RRI, PBF, PRC, or plasma aldosterone. Thus indomethacin did not attenuate the antihypertensive effect of losartan, neither was peripheral blood flow affected. Indomethacin caused sodium retention in the nonresting situation, which was not counterbalanced by the increased Cl(Na) in the resting supine position. The observed changes during prostaglandin (PG) inhibition seem most likely due to lack of PG "protection" of renal function, when the sympathetic nervous system is activated throughout the day.

Chest physiotherapy does not improve the outcome in laparoscopic fundoplication and vertical-banded gastroplasty.

BACKGROUND: Chest physiotherapy is a common practice after open reflux and obesity surgery. It is now possible to perform fundoplication and vertical banded gastroplasty (VBG) by the laparoscopic technique. The aim of this study was to evaluate in a prospective, randomized, controlled trial whether chest physiotherapy affects the postoperative course. METHOD: A series of 40 patients underwent laparoscopic fundoplication; another 40 underwent laparoscopic VBG. Twenty patients in each series received prophylactic chest physiotherapy; the other 20 served as control patients and were not given any information or training. RESULTS: Postoperatively, all patients had a significant reduction in respiratory function, measured as oxygen saturation, forced vital capacity, and peak expiratory flow, but the differences between the groups within each series were not significant. Postoperatively, one patient in the VBG treatment group had hypoxemia (SaO2 <92%) versus two control patients. One control patient developed postoperative pneumonia. CONCLUSIONS: This study indicates that routine chest physiotherapy is not necessary in patients undergoing laparoscopic upper gastrointestinal surgery, such as fundoplication and VBG.

Comparison of shear bond strength and surface structure between conventional acid etching and air-abrasion of human enamel.

Recently, air-abrasion technology has been examined for potential applications within dentistry, including the field of orthodontics. The purpose of this study was to compare the traditional acid-etch technique with an air-abrasion surface preparation technique, with two different sizes of abrading particles. The following parameters were evaluated: (a) shear bond strength, (b) bond failure location, and (c) enamel surface preparation, as viewed through a scanning electron microscope. Sixty extracted human third molars were pumiced and divided into three groups of 20. The first group was etched with a 37% phosphoric acid gel for 30 seconds, rinsed for 30 seconds, and dried for 20 seconds. The second and third groups were air-abraded with (a) a 50 microm particle and (b) a 90 microm particle of aluminum oxide, with the Micro-etcher microabrasion machine (Danville Engineering Inc.). All three groups had molar stainless steel orthodontic brackets bonded to the buccal surface of each tooth with Transbond XT bonding system (3M Unitek). A Zwick Universal Testing Machine (Calitek Corp.) was used to determine shear bond strengths. The analysis of variance was used to compare the three groups. The Adhesive Remnant Index (ARI) was used to evaluate the residual adhesive on the enamel after bracket removal. The chi square test was used to evaluate differences in the ARI scores among the groups. The significance for all tests was predetermined at p < or = 0.05. The results indicated that there was a significant difference in shear bond strength among the three groups (p = 0.0001). The Duncan Multiple Range test showed a significant decrease in shear bond strength in the air-abraded groups. The chi square test revealed significant differences among the ARI scores of the acid-etched group and the air-abraded groups (chi(2) = 0.0001), indicating no adhesive remained on the enamel surface after debonding when air-abrasion was used. In conclusion, the current findings indicate that enamel surface preparation using air-abrasion results in a significant lower bond strength and should not be advocated for routine clinical use as an enamel conditioner at this time.

The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants.

Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable.

Casual blood pressure in a general Danish population. Relation to age, sex, weight, height, diabetes, serum lipids and consumption of coffee, tobacco and alcohol.

A population survey was conducted on 3608 randomly selected Danes aged 30, 40, 50 and 60 years respectively. Of these, 3400 were not in medical treatment for arterial hypertension. The following parameters were investigated: sex, age, serum lipid levels (total cholesterol, HDL cholesterol, triglycerides), presence of diabetes mellitus, height, body mass index (BMI), and average daily consumption of coffee, tobacco and alcohol. Analysis with multiple linear regression showed that all variables with the exception of triglycerides, HDL cholesterol and height were significantly associated with systolic blood pressure. Likewise all factors except diabetes, triglycerides and height were significantly associated with diastolic blood pressure. Further analysis in which the effect of each parameter was corrected for by the effects of the remaining variables, demonstrated that apart from age and sex only BMI and high alcohol consumption were positively associated with differences in blood pressure greater than a few mmHg. However, the variation in both systolic and diastolic blood pressures was only partly accounted for by the parameters studied--in the covariates analysis R2 for systolic blood pressure was 0.28 and R2 for diastolic blood pressure was 0.30. In conclusion, this investigation demonstrated that blood pressure is relatively independent of other factors important in the development of cardiovascular disease. Of the above-mentioned factors with some influence on blood pressure only age, BMI and high alcohol consumption have potential clinical importance.

Effects of cold stress on rats fed different levels of docosenoic acids.

Male Sprague-Dawley rats, 4 weeks old, were subjected to an ambient temperature of 4 C for periods up to 24 days and fed a synthetic diet containing one of the following oils: peanut oil (PO), rapeseed oil (RO), low erucic acid rapeseed oil (LO), and partially hydrogenated marine oil (HO), each at 20% w/w. A parallel experiment using the same oils was performed at room temperature (23 C). During cold stress, animals on the RO diet showed higher mortality than all other groups; all 20 animals in this group died within 5 days. At room temperature, however, all animals survived. The lipid accumulation in the heart reached its peak in all groups after 3 days and then gradually declined. The accumulation was most pronounced in the RO animals and coincided with the high mortality at 4 C. The fatty acid composition of the cardiac triglycerides reflected that of the diet, while the composition of the cardiac lecithin was only marginally modified.