Minimally invasive lateral plating for diaphyseal fractures with extension into the proximal humerus and its implications for the deltoid muscle and its distal insertion: functional analysis and MR-imaging.

BACKGROUND: In minimally invasive lateral plate osteosynthesis of the humerus (MILPOH) the plate is introduced through a deltoid split proximally and advanced through the central portion of the deltoid insertion and between bone and brachial muscle to the distal aspect of the humerus. The fracture is then indirectly reduced and bridged by the plate. Whereas it has been shown that the strong anterior and posterior parts of the distal deltoid insertion remain intact with this maneuver, its impact on deltoid muscle strength and muscular morphology remains unclear. It was the aim of this study to evaluate deltoid muscle function and MR-morphology of the deltoid muscle and its distal insertion after MILPOH. METHODS: Six patients (median age 63 years, range 52-69 years, f/m 5/1) who had undergone MILPOH for diaphyseal humeral fractures extending into the proximal metaphysis and head (AO 12B/C(i)) between 08/2017 and 08/2020 were included. Functional testing was performed for the injured and uninjured extremity including strength measurements for 30/60/90° shoulder abduction and flexion at least one year postoperatively. Constant-Murley-Score (CMS) including an age-and gender-adjusted version, were obtained and compared to the uninjured side. Oxford Shoulder Score (OSS) and the Disability of the Arm, Shoulder and Hand (DASH) questionnaire were acquired for the affected extremity. Quality of life was measured using the EQ visual analogue scale (EQ-5D-5 L VAS). MR imaging was performed for both shoulders accordingly at the time of follow-up to assess the integrity of the distal insertion, muscle mass and fatty degeneration of the deltoid muscle. Muscle mass was determined by measuring the area of the deltoid muscle on the axial MR image at the height of the center of the humeral head. RESULTS: Median follow-up was 29 months (range 12-48 months). Median difference of abduction strength after MILPOH was + 13% for 30°, 0% for 60° and - 22% for 90°. For flexion, the difference to the uninjured side was measured 5% for 30°, -7% for 60° and - 12% for 90°. Median CMS was 75 (66-82) for the operated extremity compared to 82 (77-90) for the uninjured side. Age- and gender-adapted CMS was calculated 88 (79-99) vs. 96 (89-107). Median OSS was 47 (40-48). DASH was 26 (15-36). EQ-5D-5 L VAS ranged from 81 to 95 with a median of 90. The median difference of the deltoid muscle area on MRI was 2% (-21% to + 53%) compared to the uninjured side. No fatty degeneration of the deltoid muscle was observed. The weaker central part of the distal deltoid insertion was exclusively perforated by the plate, leaving the strong anterior and posterior parts of the insertion intact in all patients. CONCLUSIONS: MILPOH was associated with good functional and subjective outcome. Minor impairment of abduction strength was observed with increasing abduction angles. The reason for this impairment is unclear since MILPOH did not affect the structural quality of the deltoid muscle and the integrity of the strong anterior and posterior parts of its insertion remained intact. TRIAL REGISTRATION: 26/05/2023: ISRCTN51786146.

A European-Japanese study on peach allergy: IgE to Pru p 7 associates with severity.

BACKGROUND: Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity. METHODS: In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity. RESULTS: Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only. CONCLUSIONS: Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone.

Imaging through extreme scattering in extended dynamic media.

Critical to navigation, situational awareness, and object identification is the ability to image through turbid water and fog. To date, the longest imaging ranges in such environments rely on active illumination and selection of ballistic photons by means of time gating. Here we show that the imaging range can be extended by using time-gated holography in combination with multi-frame processing. Instead of simply summing the intensity of the frames, we use the complex fields retrieved through digital holographic processing and coherently add the frames. We demonstrate imaging through extended bodies of turbid water and fog at one-way attenuation lengths of 13 and 13.6, respectively. Compared to equivalent traditional time-gated systems, gated holography and coherent processing require 20× less laser illumination power for the same imaging range.

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID).

OBJECTIVE: The objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. METHODS: The GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. RESULTS: Data from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.6 ± 7.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. CONCLUSION: With the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE.

A physiologically based pharmacokinetic model for capreomycin.

The emergence of multidrug-resistant tuberculosis (MDR-TB) has led to a renewed interest in the use of second-line antibiotic agents. Unfortunately, there are currently dearths of information, data, and computational models that can be used to help design rational regimens for administration of these drugs. To help fill this knowledge gap, an exploratory physiologically based pharmacokinetic (PBPK) model, supported by targeted experimental data, was developed to predict the absorption, distribution, metabolism, and excretion (ADME) of the second-line agent capreomycin, a cyclic peptide antibiotic often grouped with the aminoglycoside antibiotics. To account for interindividual variability, Bayesian inference and Monte Carlo methods were used for model calibration, validation, and testing. Along with the predictive PBPK model, the first for an antituberculosis agent, this study provides estimates of various key pharmacokinetic parameter distributions and supports a hypothesized mechanism for capreomycin transport into the kidney.

The EuroPrevall surveys on the prevalence of food allergies in children and adults: background and study methodology.

BACKGROUND: The epidemiological surveys in children and adults of the EU-funded multidisciplinary Integrated Project EuroPrevall, launched in June 2005, were designed to estimate the currently unknown prevalence of food allergy and exposure to known or suspected risk factors for food allergy across Europe. We describe the protocol for the epidemiological surveys in children and adults. This protocol provides specific instructions on the sampling strategy, the use of questionnaires, and collection of blood samples for immunological analyses. METHODS: The surveys were performed as multi-centre, cross-sectional studies in general populations. Case-control studies were nested within these surveys. The studies in children aged 7-10 years and adults aged 20-54 years were undertaken in eight centres representing different social and climatic regions in Europe. RESULTS: After a community-based survey collecting basic information on adverse reactions to foods, all those stating they had experienced such reactions, as well as of a random sample of those stating 'no reactions' to foods, completed a detailed questionnaire on potential risks and exposures. Also a blood sample was taken to allow serological analysis to establish patterns of food and aeroallergen sensitization. We also included a questionnaire to schools on their preparedness for dealing with food allergy amongst pupils. Subjects reporting adverse reactions to foods and sensitized to the same food(s) were called in for a full clinical evaluation that included a double blind placebo controlled food challenge (DBPCFC), following a protocol which is described in detail elsewhere. CONCLUSIONS: The outcome of these studies will help to improve our understanding of several important aspects of food allergies in the European Community, providing for more well-informed policies and effective measures of disease prevention, diagnosis and management.

A phase II study of interferon-alpha for the treatment of refractory Churg-Strauss syndrome.

OBJECTIVE: Uncontrolled vasculitis is the major cause of early death in Churg-Strauss syndrome and standard therapy is not always effective. This study was carried out to examine the safety and efficacy of interferon-alpha for induction of remission in patients with refractory Churg-Strauss syndrome. METHODS: In a prospective open-label trial, seven patients with Churg-Strauss syndrome refractory to cyclophosphamide or methotrexate received interferon-alpha (3 million. I.U. 3 times weekly s.c.) for induction of remission. Primary end point was the successful induction of remission. Prednisolone was tapered according to the study protocol. RESULTS: All seven patients entered remission after 3 months of treatment. Five patients reached complete remission while in two patients, residual asthmatic complaints persisted. The mean Birmingham Vasculitis Activity Score (BVAS) decreased from 6.4 (+/-2.8) to 0 (+/-0) (p=0.017). Clinical improvement in response to interferon-alpha allowed to taper concomitant prednisolone according to the protocol from a mean dose of 20.4 mg/d (+/-13.3) to 6.9 mg/d (+/-1.9) (p=0.068). During a follow up of 6 months all patients remained in remission. In one patient, leukencephalopathy without clinical symptoms was seen on MRI after 61 months of treatment, as previously reported. In this cohort, no other cases of leukencephalopathy were observed during long-term follow-up. Constitutional symptoms related to the injection of interferon-alpha responded well to paracetamol. A transient leukopenia was found in two patients. CONCLUSION: Interferon-alpha appears to be an effective and well-tolerated treatment for induction of remission in patients with refractory Churg-Strauss syndrome.

The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study.

BACKGROUND: There has been some concern that leucotriene receptor antagonists might precipitate the onset of Churg-Strauss syndrome (CSS). A study was undertaken to investigate the relationship between the leucotriene receptor antagonist montelukast and the onset of CSS. METHODS: Medication histories of 78 patients with CSS from France and Germany were retraced by questioning the patients, treating physicians and dispensing pharmacists, and from medical records. Using a case-crossover research design, exposures to montelukast and other asthma medications during the 3-month "index" period immediately preceding the onset of CSS were compared with those of four previous 3-month "control" periods. Odds ratios (ORs) were computed by conditional logistic regression. RESULTS: The ORs for CSS onset were 4.5 (95% CI 1.5 to 13.9) for montelukast, 3.0 (95% CI 0.8 to 10.5) for inhaled long-acting beta(2) agonists, 1.7 (95% CI 0.5 to 5.4) for inhaled corticosteroids and 4.0 (95% CI 1.3 to 12.5) for oral corticosteroids. Montelukast exposure during control periods increased temporally over three consecutive calendar periods of CSS onset from 1999 to 2003 (p(trend) <0.0001). CONCLUSION: Montelukast use was associated with a 4.5-fold higher risk of CSS onset within 3 months. However, the positive estimates obtained for other long-term asthma control medications suggest that this link might be confounded by a general escalation of asthma therapy before CSS onset. The association between montelukast and CSS observed in this study is probably also explained by the increasing use of this medication over time.

Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis.

OBJECTIVES: Results from open-label trials suggest that methotrexate (MTX) and leflunomide (LEF) are effective for maintenance of remission in Wegener's granulomatosis (WG), but data from randomized controlled clinical trails are not yet available. METHODS: In this multicentre, prospective randomized controlled clinical trial, patients with generalized WG were treated either with oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with cyclophosphamide. The primary endpoint was the incidence of relapses. Secondary outcome parameters were DEI, BVAS, SF-36, cANCA-titre, ESR and CRP. RESULTS: Fifty-four patients were included in the study, 26 in the LEF-limb, 28 in the MTX-limb. In the LEF-group, six patients relapsed after a median time of 7 months, thereof one major relapse with a new pulmonary manifestation. In the MTX-group, 13 relapses occurred in 6 months, of which seven were major: rapidly progressive glomerulonephritis (n = 4), pulmonary haemorrhage (n = 2) and one cerebral granuloma. The significantly higher incidence of major relapses in the MTX-limb (P = 0.037) led to premature termination of the study. In the LEF-limb, four patients were withdrawn due to hypertension (n = 2), peripheral neuropathy (n = 1) and leucopenia (n = 1). CONCLUSION: LEF at a dosage of 30 mg/day appears to be effective in the prevention of major relapses in WG, however, this is associated with an increased frequency of adverse events. Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patients cohorts.

[New therapeutic concepts for vasculitis and collagenosis]. / Neue Therapiekonzepte bei Vaskulitiden und Kollagenosen.

After improvement of the prognosis of the primary systemic vasculitides and systemic lupus erythematosus from a desperate diagnosis with hardly a one year survival after diagnosis to a 5-year-survival-rate of more than 90% actual therapeutic regimes aim at those patients refractory to standard therapeutic regimes, not achieving a remission by standard approaches or having organ damage or contraindications. Furthermore less toxic regimes are looked for with the aim to avoid secondary complications of the standard therapy. New drugs used successfully in rheumatology, transplantation medicine and haematology are used for these purposes in the last years. Recent experiences with Infliximab, Mycophenolate Mofetil, Rituximab und Deoxyspergualin for the treatment of the small vessel vasculitides and systemic lupus erythematosus are reviewed.

Maintenance of remission with leflunomide in Wegener's granulomatosis.

OBJECTIVE: To investigate the safety and efficacy of leflunomide plus low-dose prednisolone for the maintenance of remission in Wegener's granulomatosis (WG). METHODS: This was a Phase II, single-centre, open-label clinical investigation of patients with generalized WG treated with leflunomide after the induction of complete (n = 4) or partial (n = 16) remission by cyclophosphamide/prednisolone combination therapy. Leflunomide treatment was initiated at 20 mg/day and increased to 30 mg/day after 12 weeks and, in patients with partial remission, to 40 mg/day after 24 weeks. Concomitant low-dose prednisolone (< or =10 mg/day) was allowed during the study. In addition to the frequency of relapse, treatment efficacy was assessed by the standard measures of disease activity/extent. RESULTS: A total of 20 patients were enrolled in the trial. During a treatment period of up to 2.5 yr (median 1.75 yr, range 1-2.5 yr), one patient had a major relapse and required retreatment with cyclophosphamide/prednisolone. Eight patients had minor relapses that were successfully treated by dose increases to 40 mg/day leflunomide. Disease activity remained unchanged for the duration of the study. The most frequently reported adverse events were mild respiratory infection (40%), arthralgia (35%) and hypertension (35%); dry skin, nail disorder and diarrhoea were each reported by 30% of patients. Despite the aggressive pretreatment with cyclophosphamide, adverse events with leflunomide treatment at the higher dose (30-40 mg/day) were comparable with those seen with the standard dose (20 mg/day) for rheumatoid arthritis patients. CONCLUSION: Leflunomide appears to be safe and well tolerated for the maintenance of complete or partial remission of WG. The results of this pilot study encourage further controlled trials comparing leflunomide with alternative remission maintenance therapies.

Disposition of a novel and potent alpha(v)beta3 antagonist in animals, and extrapolation to man.

1. The disposition of 3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) propyl]-imidazolidin-1-yl]-3(S)-(6-methoxy-pyridin-3-yl)propionic acid (compound A), a potent and selective alpha(v)beta(3) antagonist, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 2. Compound A exhibited marked species differences in pharmacokinetics; the plasma clearances and bioavailabilities ranged from 33-47 ml min(-1) kg(-1) in rats and mice to 4-9 ml min(-1) kg(-1) in dogs and monkeys, and about 20% in rats to 70-80% in dogs and monkeys, respectively. Both the intravenous (i.v.) and oral kinetics of compound A were linear over the dose range studied in dogs (0.1-5 mg kg(-1) i.v. and 0.25-20 mg kg(-1) orally [p.o.]) and rats (1-30 mg kg(-1) i.v. and 4-160 mg kg(-1) p.o.). 3. Compound A was eliminated substantially by urinary excretion; the urinary recovery of the unchanged drug was 67% in rhesus, 48% in dogs and about 30% in rats. In these animal species, biotransformation was modest. 4. Following i.v. administration of [(14)C]-compound A to rats, the radioactivity rapidly distributed to all tissues investigated, with high levels of the radioactivity detected in liver, kidney and intestine soon after the drug administration. The radioactivity declined rapidly, with less than 1% of the i.v. dose remaining at 30-h post-dose. 5. Compound A was moderately bound to plasma proteins, with unbound fractions of 26, 20, 14 and 5% for rats, dogs, monkeys and humans, respectively. It was bound primarily to human alpha(1)-acid glycoprotein (about 85% binding at 0.1% concentration), as compared with human albumin (< 50% binding at 4% concentration). 6. Using simple allometry, compound A was predicted to exhibit relatively low clearance (1-3 ml min(-1) kg(-1)) and low volume of distribution (0.1-0.3 l kg(-1)) in humans. Based on the predicted values, compound A was projected to exhibit a favourable oral pharmacokinetic profile in humans, with good bioavailability (50-80%). These predicted values provided a basis for compound selection for further development.

Churg Strauss syndrome--successful induction of remission with methotrexate and unexpected high cardiac and pulmonary relapse ratio during maintenance treatment.

OBJECTIVE: To examine the safety and efficacy of methotrexate (MTX) plus low-dose prednisolone for induction of remission in non life- or organ-threatening courses and for remission maintenance in Churg-Strauss syndrome (CSS). METHODS: In an open-label study 11 patients were treated with MTXfor induction of remission at initial diagnosis and relapse. Twenty-five patients received MTX for maintenance of remission. Primary endpoints were the achievement of remission and the incidence of relapses, respectively. Doses of concomitant prednisolone (PRD) and side effects were secondary endpoints. RESULTS: Induction of remission was achieved in 8/11 patients with MTX/PRD. Median time to remission was 5 months (range 2-9). Remission was maintained in 12 of 23 with available long-term follow-up (median 48 months). Eleven patients experienced 8 major and 3 minor relapses with a median time from remission to first relapse of 9 months. With MTX, the median cumulative PRD dose during the induction phase was 6.2 g. In the maintenance phase PRD could be reduced by 53% in responders. Apart from one case of MTX-induced pneumonitis, adverse events were confined to mild/moderate episodes of infection and leucopenia. No opportunistic infections occurred, neither did steroid-specific adverse events. CONCLUSIONS: MTX is safe and effective for the induction of remission in non-life-threatening CSS. It allows a considerable reduction of PRD and thus avoidance of PRD-related adverse events. However, the ability of MTX to prevent relapses in CSS appears limited. The identification of an optimal maintenance regimen and prognostic factors for treatment response requires trials with larger patient numbers.

Renal elimination of a novel and potent alphavbeta3 integrin antagonist in animals.

Compound A (3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid), a hydrophilic zwitter-ion, is a potent and selective alphavbeta3 integrin antagonist currently under clinical development for the treatment of osteoporosis. The mechanism of renal excretion of compound A was investigated using a combination of in vivo and in vitro approaches. In rats, renal excretion of compound A involved tubular secretion; ratios between renal clearance, corrected for unbound fraction in plasma (CLr,u) and glomerular filtration rate (GFR) were greater than unity (2-5). The tubular secretion of compound A was saturable at high plasma levels (> 26 microM), and was inhibited significantly, although modestly (about twofold) by relatively high plasma concentrations of the organic anion PAH (160 microM) and the cation cimetidine (about 400 microM), but not by the P-gp inhibitor quinidine (about 50 microM). However, compound A (about 100 microM) had a minimal effect on CLr/GFRs for cimetidine and PAH. In rhesus monkeys, renal elimination of compound A also involved tubular secretion, with a CLr,u/GFR ratio of about 30. The renal secretion of compound A was not affected by either cimetidine (about 120 microM) or PAH (about 80 microM). Similarly, compound A (about 40 microM) had a minimal effect on the renal tubular secretion of both cimetidine and PAH. At the doses studied, neither rat nor monkey plasma protein binding of compound A, cimetidine or PAH was affected in the presence of each other. In vitro transport studies showed that compound A was not a substrate for P-gp in the Caco-2, human MDR1 and mouse mdr1a transfected LLC-PK1 cell lines. In an uptake study using rOAT1 and rOAT3 transfected HEK cell lines, compound A was shown to be a substrate for rat OAT3 (Km= 15 microM), but not rat OAT1. The results suggest that the tubular secretion of compound A is not mediated by P-gp, but rather is mediated, at least in part, via the organic anion transporter OAT3, the renal transporter shown to be capable of transporting both the organic anion PAH and the organic cation cimetidine. Although there is a possibility for pharmacokinetic interactions between compound A and substrates or inhibitors of OAT3, at the renal excretion level, the magnitude of interaction would likely be modest in humans at clinically relevant doses.