Endogenous anandamide and self-reported pain are significantly reduced after a 2-week multimodal treatment with and without radon therapy in patients with knee osteoarthritis: a pilot study.

Multimodal therapies comprising spa applications are widely used as non-pharmaceutical treatment options for musculoskeletal diseases. The purpose of this randomized, controlled, open pilot study was to elucidate the involvement of the endocannabinoid system in a multimodal therapy approach. Twenty-five elderly patients with knee osteoarthritis (OA) received a 2-week spa therapy with or without combination of low-dose radon therapy in the Bad Gastein radon gallery. A 10-point numerical rating scale (pain in motion and at rest), WOMAC questionnaire, and the EuroQol-5D (EQ-5D) questionnaire were recorded at baseline, and during treatment period at weeks one and two, and at 3-month and 6-month follow-ups. Plasma levels of the endocannabinoid anandamide (AEA) were determined at baseline and at 2 weeks, and serum levels of several cartilage metabolism markers at all five time-points. A significant and sustained reduction of self-reported knee pain was observed in the study population, but no further significant effect of the additional radon therapy up and above base therapy. This pain reduction was accompanied by a significant reduction of AEA plasma levels during treatment in both groups. No significant differences were seen in serum marker concentrations between the groups treated with or without radon, but a small reduction of serum cartilage degradation markers was observed during treatment in both groups. This is the first study investigating AEA levels in the context of a non-pharmacological OA treatment. Since the endocannabinoid system represents a potential target for the development of new therapeutics, further studies will have to elucidate its involvement in OA pain.

Systemic safety analysis of mycophenolate in Graves' orbitopathy.

PURPOSE: The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves' orbitopathy (GO). METHODS: Safety data from the two published mycophenolate trials and the original database of the European Group on Graves' Orbitopathy (EUGOGO) trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of activity and severity were compared. RESULTS: A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenous glucocorticoid (MPS + GC) group of the EUGOGO trial recorded significantly more AE (55.4% versus 4.6% of patients affected) and serious adverse events (SAE) (12.5% versus 0%) than mycophenolate mofetil (MMF) group of the Chinese trial. None of those SAE was side effect (SE). Most SE in MPS + GC group were mild. Gastrointestinal disorders, infection and liver dysfunction affected 8.8%, 7.1% and 1.2% of all mycophenolate-treated patients (versus 5.4%, 5.4% and 1.2% of all patients on GC monotherapy, respectively). MPS + GC did not significantly increase the risk of infection or liver dysfunction when compared to GC monotherapy. No cytopenia, serious infection or treatment-related mortality was reported. The much higher AE rates of mycophenolate trials in other autoimmune diseases or transplantations suggested that major mycophenolate toxicities were mostly dose- and duration dependent. Mycophenolate, either as monotherapy or as combination, achieved better overall response than GC monotherapy. CONCLUSION: The risk-benefit ratio of low-dose mycophenolate treatment in active moderate-to-severe GO is highly favorable given its reassuring safety profile with low rate of mild-to-moderate SE and promising efficacy.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Prospective, systematically recorded mycophenolate safety data in Graves' orbitopathy.

CONTEXT: The antiproliferative mechanism of mycophenolate acid (MPA) suggests a beneficial effect in patients with Graves' orbitopathy (GO). OBJECTIVE: To systematically analyze for the first time adverse events (AEs) during MPA treatment in GO. DESIGN: Prospective longitudinal study. SETTING: Academic tertiary referral center with a joint thyroid-eye clinic. PATIENTS: Fifty-three consecutive, unselected patients with clinically active and moderate-to-severe GO. METHODS: MPA 0.720 g was given once daily for 24-weeks in GO patients. AEs were documented and coded according to the standardized medical dictionary for regulatory activities (MedDRA). AE were followed up and seriousness as defined by ICH-guideline E6 was documented. All AEs were analyzed regarding a possible underlying cause and if not, graded as side effect (SE). RESULTS: Fifty GO patients (93 %) had Graves' disease, 37 (70 %) and 29 (54.7 %) were female and smoker, respectively. Thirty-six patients (68 %) reported at least one AE. A total of 88 AEs were documented, most frequent AEs were insomnia (N = 6), fatigue (N = 5) and optic neuropathy (N = 5), while other AEs occurred in up to three patients (5.6 %), only. In 12 (23 %) patients, at least one SE occurred. All 17 reported SE, i.e. mild infections and gastrointestinal intolerance were within the known safety profile of MPA. No patient dropped MPA medication because of drug-induced SE. Most AEs showed a recovered (76 %) or recovering (16 %) outcome. Seven (13 %) patients were hospitalized, five (62 %) due to optic neuropathy, none of these events was graded as SE. CONCLUSIONS: MedDRA-coded data documented the good tolerance of a moderate MPA dose in GO patients.

Prospectively recorded and MedDRA-coded safety data of intravenous methylprednisolone therapy in Graves' orbitopathy.

CONTEXT: Safety of intravenous (IV) steroid pulses in patients with Graves' orbitopathy (GO) is still controversial while steroid dose and treatment application have not been finalized. Frequency, severity and characterization of adverse events (AE) were prospectively analyzed. SETTING: Academic referral orbital center with a joint thyroid-eye clinic. PATIENTS: Eighty consecutive and unselected patients with active and severe GO. METHODS: During an established treatment with IV methylprednisolone (cumulative dose 4.5 g) occurring AE were prospectively coded according to the standardized and recognized medical dictionary for regulatory activities (MedDRA). Outcome and severity of AE were documented. AEs judged as at least possibly related to drug treatment were graded as side effect (SE). AEs matching a seriousness criteria as defined by the ICH guideline E6 (good clinical practice) were graded as serious. RESULTS: A total of 38.75% (31/80) of the treated GO patients reported at least one AE while 18 patients (22.5%) reported at least one SE. All SE were within the safety profile of IV methylprednisolone; 31/32 SE (96.87%) were mild-moderate and reversible and only 1/80 patient (1.25%) stopped steroid treatment due to exacerbation of her depression. Most AE were accessory symptoms of the underlying disease and a few only were directly related to IV steroids. Most AEs (90.6%) were graded as mild. Only six patients (7.5%) were hospitalized, three of them due to a dysthyroid optic neuropathy. CONCLUSIONS: Prospective and standardized evaluation with MedDRA and the ICH guideline demonstrated the good pharmacological tolerance and low morbidity of this moderate steroid regimen.

Multiscale recurrence analysis of spatio-temporal data.

The description and analysis of spatio-temporal dynamics is a crucial task in many scientific disciplines. In this work, we propose a method which uses the mapogram as a similarity measure between spatially distributed data instances at different time points. The resulting similarity values of the pairwise comparison are used to construct a recurrence plot in order to benefit from established tools of recurrence quantification analysis and recurrence network analysis. In contrast to other recurrence tools for this purpose, the mapogram approach allows the specific focus on different spatial scales that can be used in a multi-scale analysis of spatio-temporal dynamics. We illustrate this approach by application on mixed dynamics, such as traveling parallel wave fronts with additive noise, as well as more complicate examples, pseudo-random numbers and coupled map lattices with a semi-logistic mapping rule. Especially the complicate examples show the usefulness of the multi-scale consideration in order to take spatial pattern of different scales and with different rhythms into account. So, this mapogram approach promises new insights in problems of climatology, ecology, or medicine.

Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial.

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.

Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

Sexual function and quality of life after surgical treatment for anal fistulas in Crohn's disease.

BACKGROUND: The aim of this study was to assess sexual function and quality of life (QoL) in patients after surgery for perianal Crohn's disease. METHODS: Eighty-eight consecutive patients with perianal Crohn's disease, operated on at the Medical University of Vienna, completed a self-administered questionnaire including the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), Short Form-12 Health Survey (SF-12), and the Inflammatory Bowel Disease Questionnaire (IBDQ). Patients with a current stoma were excluded from further analysis. The median follow-up time was 104 months (range 3-186 months). Healthy subjects served as controls for each case and were matched by age (±6 years) and gender. Forty-seven (68 %) female and 22 male patients with a median age of 46.5 years (range 18-64 years) were analyzed. Eleven (16 %) patients had simple and 58 (84 %) complex anal fistulas. RESULTS: The median SF-12 physical health score of the patients was significantly lower (47.9 (range 25.5-57.2)) than that of the controls (54.3 (range 34.6-61.8); p = 0.03). Not surprisingly, the median total sore of the IBDQ of the controls was significantly better than that of the patients (controls: 188.5 (range 125-206.5), patients: 157 (range 60-199.5); p < 0.0001). Analysis with the multiple logistic regression test showed that type of operation, >1 perianal fistula opening, and active Crohn's disease were independent risk factors for a worse IBDQ (p = 0.03, p = 0.015 and p < 0.0001). Interestingly, the median FSFI and IIEF score were not found to be significant different in any domain. CONCLUSIONS: QoL but not sexual function is significantly influenced by surgery for perianal Crohn's disease.

B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled cross-over study in healthy men.

AIMS/HYPOTHESIS: B-type natriuretic peptide (BNP) is a hormone released from cardiomyocytes in response to cell stretching and elevated in heart failure. Recent observations indicate a distinct connection between chronic heart failure and diabetes mellitus. This study investigated the role of BNP on glucose metabolism. METHODS: Ten healthy volunteers (25 ± 1 years; BMI 23 ± 1 kg/m(2); fasting glucose 4.6 ± 0.1 mmol/l) were recruited to a participant-blinded investigator-open placebo-controlled cross-over study, performed at a university medical centre. They were randomly assigned (sequentially numbered opaque sealed envelopes) to receive either placebo or 3 pmol kg(-1) min(-1) BNP-32 intravenously during 4 h on study day 1 or 2. One hour after beginning the BNP/placebo infusion, a 3 h intravenous glucose tolerance test (0.33 g/kg glucose + 0.03 U/kg insulin at 20 min) was performed. Plasma glucose, insulin and C-peptide were frequently measured. RESULTS: Ten volunteers per group were analysed. BNP increased the initial glucose distribution volume (13 ± 1% body weight vs 11 ± 1%, p < 0.002), leading to an overall reduction in glucose concentration (p < 0.001), particularly during the initial 20 min of the test (p = 0.001), accompanied by a reduction in the initial C-peptide levels (1.42 ± 0.13 vs 1.62 ± 0.10 nmol/l, p = 0.015). BNP had no impact on beta cell function, insulin clearance or insulin sensitivity and induced no adverse effects. CONCLUSIONS/INTERPRETATION: Intravenous administration of BNP increases glucose initial distribution volume and lowers plasma glucose concentrations following a glucose load, without affecting beta cell function or insulin sensitivity. These data support the theory that BNP has no diabetogenic properties, but improves metabolic status in men, and suggest new questions regarding BNP-induced differences in glucose availability and signalling in various organs/tissues. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01324739 FUNDING: The study was funded by Jubilée Fonds of the Austrian National Bank (OeNB-Fonds).

Serum uric acid is related to cardiovascular events and correlates with N-terminal pro-B-type natriuretic peptide and albuminuria in patients with diabetes mellitus.

BACKGROUND: Hyperuricemia is a risk factor for cardiovascular events and renal insufficiency. It correlates to intima-media thickness and microalbuminuria. In this study we evaluated uric acid as an independent marker for cardiac events in patients with diabetes. METHODS: In a prospective observational study we recruited 494 patients with diabetes. Patients were then followed for 12.8 months (mean follow-up) and hospitalizations as a result of cardiac events (ischaemic heart disease, arrhythmias, heart failure) were recorded. RESULTS: The median duration of diabetes was 11 ± 10.35 years. Patients were in the mean 60 ± 13 years old and mean HbA(1c) was 62 ± 13 mmol/mol (7.8 ± 3.3%). At baseline, mean uric acid was 321.2 ± 101.1 µmol/l (range 101.1-743.5 µmol/l), median N-terminal pro-B-type natriuretic peptide was 92 ± 412 pg/ml and median urinary albumin to creatinine ratio was 8 ± 361 mg/g; Uric acid significantly correlated to N-terminal pro-B-type natriuretic peptide (r = 0.237, P < 0.001) and urinary albumin:creatinine ratio (r = 0.198, P < 0.001). In a Cox regression model, including age, estimated glomerular filtration rate, gender, systolic blood pressure, smoking and alcohol consumption, uric acid was the best predictor of cardiac events (hazard ratio 1.331, confidence interval 1.095-1.616, P = 0.04). However, uric acid lost its prognostic value when the natural logarithm of N-terminal pro-B-type natriuretic peptide was added to the model. CONCLUSION: Serum uric acid is a predictor of cardiac events and correlates to N-terminal pro-B-type natriuretic peptide and albuminuria, underscoring the importance of uric acid as a cardiovascular risk marker in patients with diabetes.

Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.

BACKGROUND: New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment. METHODS: Mice conditionally knocked out for HIF-1ß were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1α levels were also measured in endobronchial biopsies and bronchial fluid of patients with asthma and nasal fluid of patients with rhinitis after challenge. RESULTS: Deletion of HIF-1ß resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG(1) . EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of vascular endothelial growth factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1α and VEGF increased in lung tissue and bronchial fluid of patients with asthma and in the nasal fluid of patients with rhinitis after challenge. CONCLUSIONS: Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1α is increased after challenge in patients with asthma and rhinitis. Therefore, we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.

Cardiovascular regulation during sleep quantified by symbolic coupling traces.

Sleep is a complex regulated process with short periods of wakefulness and different sleep stages. These sleep stages modulate autonomous functions such as blood pressure and heart rate. The method of symbolic coupling traces (SCT) is used to analyze and quantify time-delayed coupling of these measurements during different sleep stages. The symbolic coupling traces, defined as the symmetric and diametric traces of the bivariate word distribution matrix, allow the quantification of time-delayed coupling. In this paper, the method is applied to heart rate and systolic blood pressure time series during different sleep stages for healthy controls as well as for normotensive and hypertensive patients with sleep apneas. Using the SCT, significant different cardiovascular mechanisms not only between the deep sleep and the other sleep stages but also between healthy subjects and patients can be revealed. The SCT method is applied to model systems, compared with established methods, such as cross correlation, mutual information, and cross recurrence analysis and demonstrates its advantages especially for nonstationary physiological data. As a result, SCT proves to be more specific in detecting delays of directional interactions than standard coupling analysis methods and yields additional information which cannot be measured by standard parameters of heart rate and blood pressure variability. The proposed method may help to indicate the pathological changes in cardiovascular regulation and also the effects of continuous positive airway pressure therapy on the cardiovascular system.

Modeling the cardiovascular system using a nonlinear additive autoregressive model with exogenous input.

The parameters of heart rate variability and blood pressure variability have proved to be useful analytical tools in cardiovascular physics and medicine. Model-based analysis of these variabilities additionally leads to new prognostic information about mechanisms behind regulations in the cardiovascular system. In this paper, we analyze the complex interaction between heart rate, systolic blood pressure, and respiration by nonparametric fitted nonlinear additive autoregressive models with external inputs. Therefore, we consider measurements of healthy persons and patients suffering from obstructive sleep apnea syndrome (OSAS), with and without hypertension. It is shown that the proposed nonlinear models are capable of describing short-term fluctuations in heart rate as well as systolic blood pressure significantly better than similar linear ones, which confirms the assumption of nonlinear controlled heart rate and blood pressure. Furthermore, the comparison of the nonlinear and linear approaches reveals that the heart rate and blood pressure variability in healthy subjects is caused by a higher level of noise as well as nonlinearity than in patients suffering from OSAS. The residue analysis points at a further source of heart rate and blood pressure variability in healthy subjects, in addition to heart rate, systolic blood pressure, and respiration. Comparison of the nonlinear models within and among the different groups of subjects suggests the ability to discriminate the cohorts that could lead to a stratification of hypertension risk in OSAS patients.

HbA1c values calculated from blood glucose levels using truncated Fourier series and implementation in standard SQL database language.

OBJECTIVES: This article presents a mathematical model to calculate HbA1c values based on self-measured blood glucose and past HbA1c levels, thereby enabling patients to monitor diabetes therapy between scheduled checkups. This method could help physicians to make treatment decisions if implemented in a system where glucose data are transferred to a remote server. The method, however, cannot replace HbA1c measurements; past HbA1c values are needed to gauge the method. METHODS: The mathematical model of HbA1c formation was developed based on biochemical principles. Unlike an existing HbA1c formula, the new model respects the decreasing contribution of older glucose levels to current HbA1c values. About 12 standard SQL statements embedded in a php program were used to perform Fourier transform. Regression analysis was used to gauge results with previous HbA1c values. The method can be readily implemented in any SQL database. RESULTS: The predicted HbA1c values thus obtained were in accordance with measured values. They also matched the results of the HbA1c formula in the elevated range. By contrast, the formula was too "optimistic" in the range of better glycemic control. Individual analysis of two subjects improved the accuracy of values and reflected the bias introduced by different glucometers and individual measurement habits.