[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.

BACKGROUND: Current treatment of bullous pemphigoid (BP) is based on the long-term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality. OBJECTIVES: To study the corticosteroid-sparing potential of azathioprine and dapsone. METHODS: This was a prospective, multicentre, randomized, nonblinded clinical trial that compared the efficacy and safety of two parallel groups of patients with BP treated with oral methylprednisolone 0·5 mg kg-1 per day in combination with either azathioprine 1·5-2·5 mg kg-1 per day or dapsone 1·5 mg kg-1 per day. Nine German and Austrian departments of dermatology included 54 patients based on clinical lesions, positive direct immunofluorescence (IF) microscopy and detection of serum autoantibodies by indirect IF microscopy, immunoblotting or enzyme-linked immunosorbent assay. The primary end point was the time until complete tapering of methylprednisolone, and the most important secondary end point was the cumulative corticosteroid dose. RESULTS: In eight patients (five azathioprine, three dapsone), methylprednisolone could be discontinued after a median time of 251 days in the azathioprine group and 81 days in the dapsone group. The median cumulative corticosteroid dose was 2·65 g for azathioprine compared with 1·92 g for dapsone (P = 0·06). The median numbers of days when corticosteroids were applied were 148 and 51, respectively (P = 0·24). No significant difference in the number of adverse events was seen between the treatment arms. Four patients (8%) died within the observation period of 12 months. CONCLUSIONS: Due to the lower than intended number of patients, the results of the primary and secondary end points were not or only barely significant. Dapsone appeared to have a moderately higher corticosteroid-sparing potential than azathioprine. The combination regimen of either drug with oral methylprednisolone is associated with a relatively low 1-year mortality in this vulnerable patient population.

The Good Clinical Practice guideline and its interpretation - perceptions of clinical trial teams in sub-Saharan Africa.

OBJECTIVES: To explore the advantages and challenges of working with the Good Clinical Practice (GCP)-International Conference of Harmonization (ICH) E6 guideline and its interpretation from the perspective of clinical trial teams based in sub-Saharan Africa. METHODS: We conducted 60 key informant interviews with clinical trial staff at different levels in clinical research centres in Kenya, Ghana, Burkina Faso and Senegal and thematically analysed the responses. RESULTS: Clinical trial teams perceived working with ICH-GCP as highly advantageous and regarded ICH-GCP as applicable to their setting and efficiently applied. Only for informed consent did some clinical trial staff (one-third) perceive the guideline as insufficiently applicable. Specific challenges included meeting the requirements for written and individual consent, conditions for impartial witnesses for illiterates or legally acceptable representatives for children, guaranteeing voluntary participation and ensuring full understanding of the consent given. It was deemed important to have ICH-GCP compliance monitored by relevant ethics committees and regulatory authorities, without having guidelines applied overcautiously. CONCLUSION: Clinical trial teams in sub-Saharan Africa perceived GCP as a helpful guideline, despite having been developed by northern organisations and despite the high administrative burden of implementing it. To mitigate consent challenges, we suggest adapting GCP and making use of the flexibility it offers.

Short communication: Genetic relationships between functional longevity and direct health traits in Austrian Fleckvieh cattle.

The aim of this study was to conduct a multitrait 2-step approach applied to yield deviations and deregressed breeding values to get genetic parameters of functional longevity, clinical mastitis, early fertility disorders, cystic ovaries, and milk fever of Austrian Fleckvieh cattle. An approximate multitrait approach allows the combination of information from pseudo-phenotypes derived from different statistical models in routine genetic evaluation, which cannot be estimated easily in a full multitrait model. A total of 66,890 Fleckvieh cows were included in this study. For estimating genetic parameters, a simple linear animal model with year of birth as a fixed effect and animal as a random genetic effect was fitted. The joint analysis of yield deviations and deregressed breeding values was feasible. As expected, heritabilities were low, ranging from 0.03 (early fertility disorders) to 0.15 (functional longevity). Genetic correlations between functional longevity and clinical mastitis, early fertility disorders, cystic ovaries, and milk fever were 0.63, 0.29, 0.20, and 0.20, respectively. Within direct health traits genetic correlations were between 0.14 and 0.45. Results suggest that selecting for more robust disease-resistant cows would imply an improvement of functional longevity.

Complications and postoperative non-steroidal anti-inflammatory use of three extracapsular cruciate ligament repair techniques performed in a general practice clinic environment.

OBJECTIVE: To report complications and postoperative non-steroidal anti-inflammatory use associated with fabellotibial suture, Tightrope and Ligafiba Isotoggle procedures performed on dogs of varying weights within a general practice setting. MATERIALS AND METHODS: Clinical records of eligible patients from 2009 to 2018 were retrospectively extracted from five general practice clinics. Data for signalment, patient weight, surgery performed, complications, postoperative use of non-steroidal anti-inflammatory drugs, and timing thereof were extracted and analysed using multinomial logistic regression. Predicted probability tables were generated for complications and non-steroidal anti-inflammatory drug use. RESULTS: The study included 370 surgeries, with 97 fabellotibial suture, 158 Tightrope and 42 Ligafiba Isotoggle procedures in patients less than 15 kg, and 43 fabellotibial suture, 16 Tightrope and 30 Ligafiba Isotoggle procedures in patients at least 15 kg. The proportion of patients that can be expected to have no complications was greatest for older dogs (9 years) weighing less than 15 kg (fabellotibial suture, 91%; Tightrope/Ligafiba Isotoggle, 88%), and the highest major medical and surgical complication risks were expected in young dogs (1 year) weighing over 15 kg (fabellotibial suture, 28%; Tightrope/Ligafiba Isotoggle, 59%). The predicted risk of requiring repeated non-steroidal anti-inflammatory drug prescriptions in the 18-month postoperative period for an 15 kg patient was 37% to 39%. CONCLUSION: Weight and age were significant factors influencing complications and postoperative non-steroidal anti-inflammatory drug use in fabellotibial suture, Tightrope and Ligafiba Isotoggle surgical patients in a general practice setting. CLINICAL SIGNIFICANCE: Clinicians should consider the possibility of complications and requirement for ongoing non-steroidal anti-inflammatory drug use before performing extracapsular procedures in patients weighing more than 15 kg.

Disseminated Mycobacterium immunogenum infection presenting with septic shock and skin lesions in a renal transplant recipient.

Mycobacterium immunogenum is a relatively new species within the Mycobacterium chelonae-Mycobacterium abscessus group of rapidly growing mycobacteria (RGM). M. immunogenum was first characterized in 2001 and, similar to other RGM, is an ubiquitous environmental organism. This organism has most commonly been implicated in cutaneous infection in both healthy and immunosuppressed patients. To our knowledge, this is the first reported case of septic shock in the setting of disseminated M. immunogenum infection. Definitive identification of this organism requires gene sequencing at specialized centers, which may limit its detection. M. immunogenum is resistant to many anti-mycobacterial agents, and treatment can be especially challenging in transplant patients, given potential drug interactions and added toxicities. It is important to distinguish M. immunogenum from other RGM and determine the susceptibility profile to devise a successful treatment plan, particularly in the transplant population in which it can potentially cause severe, disseminated disease.

Perilymph Fistula as a Complication of Eustachian Tube Dilation and Tympanoplasty.

Eustachian tube dilation (ETD) is an established, minimally invasive therapeutic approach for chronic eustachian tube dysfunction. The complications associated with performing a ETD are rare. A 22-year-old female patient presented with chronic otitis media on the right side and chronic obstructive tube dilation disorder on both sides. A type I tympanoplasty was performed on the right side because of a tympanic membrane perforation after a ETD on both sides without apparent complications. On the 5th postoperative day, she presented with headache, dizziness and hearing loss on the right side. There was a decrease of hearing threshold on the right side in the pure-tone audiogram and vHIT, cVEMP, and SVV were irregular. The ß-2-transferrin test was positive. Since a right-sided perilymph fistula was suspected, an emergency tympanotomy was performed with a round window membrane cover with fascia on the right side. Intraoperatively, a regular, intact ossicular chain was found with a slightly moist middle ear mucosa. The round window membrane was covered by the promontorial lip. Under these measures, the patient's dizziness regressed. The right ear pure-tone threshold vHIT, cVEMP, and SVV normalized.

The black summer bushfires: impacts and risk factors for livestock bushfire injury in south-eastern Australia.

BACKGROUND: The 2019/2020 Australian bushfires were the largest bushfire event in modern Australian history. While actions to mitigate risk to homes from bushfires are well reported, there is very little research reported on the impacts of bushfires on livestock. With an increasing incidence of bushfires predicted, there is an urgent need to identify how farmers can best protect their livestock. OBJECTIVES: Compare bushfire affected farms with and without injured livestock to identify associations between risk factors and bushfire injury. Infer management approaches that can be used to reduce bushfire injury in livestock. METHOD: A case-control study using a structured interview questionnaire, delivered in late 2020 to cattle and sheep farmers in south-eastern Australia (New South Wales and Victoria) whose farmland was burnt in the 2019/2020 Australian bushfires. Case farms were farms with bushfires injured or killed livestock. Control farms were farms that had no bushfire injured livestock but that still had fire present on the farm. Interview responses were summarised and information theoretical approaches were used to identify potential risk factors for livestock bushfire injury and protective actions that could inform future fire-preparation recommendations. RESULTS AND DISCUSSION: Of 46 farms in the case-control study, 21 (46%) reported bushfire injured or killed livestock. Apparent protective factors identified included: preparation (having a bushfire plan and more than two farm bushfire fighting units), backburning and receiving assistance from fire authorities. Combined beef and sheep grazing enterprises appeared to have an increased risk of bushfire injury to livestock.

Surgical management of superficial digital flexor tendon luxation in dogs: 48 cases (2005-2020).

OBJECTIVES: To report the outcome, frequency of complications and potential prognostic factors associated with surgical repair of superficial digital flexor tendon (SDFT) luxation in dogs. MATERIALS AND METHODS: Medical records from 10 referral hospitals were reviewed retrospectively for cases of SDFT luxation in dogs that underwent surgical stabilisation. Signalment, clinical presentation, diagnostic imaging, surgical method, type and length of post-operative limb immobilisation, nature of and length of exercise restriction, presence of post-operative complications and outcomes were recorded. Data were summarised descriptively and prognostic risk factors assessed for association with surgical outcome using risk ratios. RESULTS: Forty-eight cases were included. A successful surgical outcome was recorded in 35 of 48 (73%) cases. Re-luxation of the SDFT occurred in seven of 48 (15%). Six out of 48 (13%) had a persistent lameness despite a stable non-luxating SDFT. A high frequency of post-operative complications occurred (71%), with the majority resolved medically. The risk of surgical failure was 60% higher (risk ratio 1.6, 95% confidence interval 1.1 to 2.4) where absorbable suture material was used compared to non-absorbable suture material. Surgical failure was more common in cases managed with non-rigid immobilisation post-operatively (57% failure) compared to cases managed with rigid immobilisation (19% failure), although this result was not statistically significant. Limb immobilisation of 6 weeks or longer did not significantly affect surgical outcome, compared to shorter periods of exercise restriction or limb immobilisation. CLINICAL SIGNIFICANCE: A good outcome can be expected following surgical stabilisation of SDFT luxation. The use of non-absorbable suture was associated with a more successful surgical outcome.

A general synthetic approach for obtaining cationic and anionic inorganic nanoparticles via encapsulation in amphiphilic copolymers.

A series of amphiphilic copolymers with variable charge densities on their backbone is synthesized. Positively charged N,N,N-trimethylammonium-2-ethyl methacrylate iodide or negatively charged 2-(methacryloyloxy)ethylphosphonic acid and lauryl methacrylate are used as building blocks. When wrapped around hydrophobically capped inorganic nanoparticles (NPs), the latter are able to disperse in aqueous solutions. Using this method, positively as well as negatively charged colloidal NPs can be synthesized in a reliable way. The method presented herein allows the charge on the NPs to be adjusted to different negative and positive values by using polymers with a variable ratio of charged monomers and lauryl methacrylate. Virtually all kinds of hydrophobic inorganic NPs could be coated with these amphiphilic polymers. The coating procedure is demonstrated for Au particles as well as for CdSe/ZnS quantum dots. To date, wrapping amphiphilic polymers around NPs has led only to anionic NPs. The polymers synthesized in this work allow for positively charged NPs with a high colloidal stability.

Up-regulation of CCL11 and CCL26 is associated with activated eosinophils in bullous pemphigoid.

Eosinophils contribute to the pathogenesis of bullous pemphigoid (BP) by secretion of proinflammatory cytokines and proteases. Trafficking of eosinophils into tissue in animal models and asthma depends on interleukin-5 and a family of chemokines named eotaxins, comprising CCL11, CCL24 and CCL26. Up-regulation of CCL11 has been described in BP, but the expression of the other two members of the eotaxin-family, CCL24 and CCL26, has not been investigated. In addition to these chemokines, expression of adhesion molecules associated with eosinophil migration to the skin should be analysed. We demonstrate that similar to CCL11, the concentration of CCL26 was up-regulated in serum and blister fluid of BP patients. In contrast, the concentration of CCL24 was not elevated in sera and blister fluid of the same BP patients. In lesional skin, CCL11 and CCL26 were detected in epidermis and dermis by immunohistochemistry. In contrast to CCL11, CCL26 was expressed strongly by endothelial cells. In line with these findings, eosinophils represented the dominating cell population in BP lesional skin outnumbering other leucocytes. The percentage of eosinophils expressing very late antigen (VLA): VLA-4 (CD49d) and CD11c correlated with their quantity in tissue. Macrophage antigen (MAC)-1 (CD11b/CD18) was expressed constitutively by tissue eosinophils. In conclusion, these data link the up-regulation of the eosinophil chemotactic factor CCL26 in BP to the lesional accumulation of activated eosinophils in the skin. Thereby they broaden the understanding of BP pathogenesis and might indicate new options for therapeutic intervention.

Learning to use novel objects: a training study on the acquisition of novel action representations.

Many studies have suggested that the motor system is organized in a hierarchical fashion, around the prototypical end location associated with using objects. However, most studies supporting the hierarchical view have used well-known actions and objects that are highly over-learned. Accordingly, at present it is unclear if the hierarchical principle applies to learning the use of novel objects as well. In the present study we found that when learning to use a novel object subjects acquired an action representation of the end location associated with using the object, as evidenced by slower responses in an action observation task, when the object was presented at an incorrect end location. By showing the importance of knowledge about end locations when learning to use a novel object, the present study suggests that end locations are a fundamental organizing feature of the human motor system.

Rapid detection of multidrug resistant Gram-negative bacilli by Cica-Beta-Test strips.

AIM OF THE STUDY: This study aimed to evaluate the sensitivity and specificity of a new system (Cica-Beta-Test, Kanto Chemical, Japan) for rapid detection of AmpC-derepressed, extended-spectrum ß-lactamases (ESßL) and metallo-ß-lactamases (MßL). METHODS: Two hundred Multi-Drug Resistant (MDR)-Gram-negative bacilli were studied: 170 Enterobacteriaceae and 30 Gram-negative non-fermentative bacteria. One hundred and eighteen strains produced an ESßL, seven MßL and 75 derepressed cephalosporinases. One drop of substrate was dispensed onto the filter pad of the Cica-Beta-Test strip. The bacterial colonies were spread on the filter pad of strip. The reading was performed after 2 to 15 min: turning chromogenic indicated the positive test. Three tests were used: Cica-Beta I for detection of MDR bacteria; Cica-Beta MßL for detection of MßL-producing bacteria and Cica-Beta CVA, which distinguish ESßL and AmpC-derepressed producers. Results were compared with molecular assays. RESULTS: Cica-Beta-Test I has detected 194 MDR (sensitivity 97%), Cica-Beta-Test MßL has shown the presence of six MßL tested (sensitivity 85.7%). Five strains were non-MßL false positive (specificity 97.3%). Cica-Beta-Test CVA allowed the differentiation of ESßL-producing strains (109/115) and AmpC-derepressed strains (56/67) (sensitivity 94.8%, specificity 83.8%). CONCLUSIONS: Because of their epidemic nature, the MDR strains are screened and require strict hygienic measures patients. The simultaneous use of three strips can quickly determine the presence of MDR including ESßL and MßL. Rapid screening of MDR avoids transmission and limits the use of broad-spectrum antibiotics.

Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells.

Naive CD4+ T cells can differentiate into cells predominantly involved in humoral immunity, known as T helper type 2 cells (Th2), or cells involved in cell-mediated immunity, known as Th1 cells. In this report, we show that priming of CD4+ T cells bearing a transgene-encoded T cell receptor can lead to differentiation into Th1-like cells producing abundant interferon gamma when the cells are exposed to high antigen doses, while low doses of the same peptide induce cells with the same T cell receptor to differentiate into Th2-like cells producing abundant interleukin 4. Thus antigen dose is one factor that can control the differentiation fate of a naive CD4+ T cell.

Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo.

Antigen priming of naive CD4 T cells can generate effector CD4 T cells that produce interleukin 4 (T helper [Th]2-like) or interferon-gamma (Th1-like). Using a system in which priming leads to responses dominated by one or the other of these cell types, we show that varying either the antigenic peptide or the major histocompatibility complex class II molecule can determine whether Th1-like or Th2-like responses are obtained. Our results show that peptide/major histocompatibility complex class II complexes that interact strongly with the T cell receptor favor generation of Th1-like cells, while those that bind weakly favor priming of Th2-like T cells. Thus, signals from the T cell receptor can influence the differentiation of CD4 T cells into specific types of effector cells.

[Which factors have an impact on levetiracetam serum concentrations? An analysis in 163 patients with epilepsy]. / Welche Faktoren beeinflussen die Serumkonzentration von Levetiracetam? Eine Analyse bei 163 Patienten mit Epilepsie.

We evaluated factors possibly influencing serum concentrations of levetiracetam (LEV-SC). The study included 163 patients with epilepsy (91 men, 72 women; mean age 39.6 years). The duration of treatment on first analysis was 226 days; the mean daily dose amounted to 2,434 mg. In each patient between one and seven measurements were carried out (mean 2.2). LEV-SC significantly depended on daily dosage and the interval between the time the medication was taken and the time of blood extraction. A marked drop in LEV-SC was observed 4-5 h following ingestion. Carbamazepine, oxcarbazepine and clobazam reduced LEV-SC, whereas valproate elevated LEV-SC significantly. When assessing evaluation of compliance these factors have to be taken into consideration when comparing intraindividual LEV-SC.

Large Variability of Frequency and Type of Physical Therapy in Patients in the German Network for Systemic Sclerosis.

OBJECTIVE: To determine the type and frequency of physical therapy (PT) prescribed by physicians for patients in the registry of the German Network for Systemic Sclerosis. METHODS: The data for 4,252 patients were analyzed using descriptive statistics, chi-square tests, and odds ratios (ORs). RESULTS: Overall, 37.4% of patients (1,590 of 4,252) received PT at the end of a yearly follow-up. The most frequently used type of PT was lymphatic drainage (n = 1,061, 36.8%), followed by exercise therapy (n = 1,047, 36.3%) and heat therapy (n = 689, 23.9%). More than three-fourths of treated patients (82%) received 1 or 2 different forms of PT simultaneously. The prescription of PT was associated with the extent of skin fibrosis as measured by the modified Rodnan skin thickness score (<10 [41.8% of patients], 11-20 [55.8% of patients], and >21 [63.9% of patients]; P < 0.001). Patients with musculoskeletal involvement (e.g., arthritis, muscle weakness, joint contractures, tendon friction rubs) had a higher chance of receiving PT than patients without these symptoms, with corresponding ORs ranging from 1.96 (95% confidence interval [95% CI] 1.69-2.28) for joint contractures to 3.83 (95% CI 2.89-5.08) for arthritis. When comparing the type of PT prescription across the initial and all follow-up visits from 2003 to 2017, significant alterations with a decreasing frequency of patients receiving PT could be observed (P = 0.001). CONCLUSION: To our knowledge, this is the first study reporting the use of PT in patients with systemic sclerosis (SSc) in a large cohort. Although SSc is characterized by considerable disability and restriction of motion, <40% of patients received PT.

CCL18 is expressed in patients with bullous pemphigoid and parallels disease course.

BACKGROUND: The autoimmune skin disease bullous pemphigoid (BP) is characterized by subepidermal blister formation and a strong dermal infiltrate of mononuclear cells and eosinophils as well as a T-helper (Th) 2-dominated cytokine milieu. CCL18 is a chemokine, with unknown receptor counterpart, frequently associated with inflammatory Th2-type responses. OBJECTIVES: The study was performed to investigate an association of CCL18 with BP. METHODS: CCL18 was determined by enzyme-linked immunosorbent assay in serum and blister fluid of patients with BP, pemphigus vulgaris and healthy individuals. In vitro chemotaxis assays were performed to demonstrate migration of peripheral blood mononuclear cells to BP blister fluid. Immunohistology and immunofluorescence staining were used to evaluate CCL18 expression in skin. RESULTS: We have found that the levels of CCL18 in sera from patients with BP are 84% higher than those normally observed in healthy individuals. In addition, blister fluid of patients with BP is extremely rich in CCL18, reaching concentrations which are fivefold and sevenfold higher than those found in the sera of patients with BP and healthy individuals, respectively. Using immunofluorescence techniques we identified Langerhans cells, antigen-presenting cells of the dermis and eosinophils as producers of CCL18 in BP skin. We studied the possibility of using CCL18 expression as a biomarker linked to BP by monitoring the serum levels of CCL18 and the disease course of nine patients with BP over a maximum period of 54 months. In this study, CCL18 levels correlated with the disease course in most of the patients. CONCLUSIONS: Our data implicate CCL18 as a functionally relevant chemokine in BP, mediating recruitment of blood mononuclear cells into the hallmark infiltrated skin lesion. The high correlation of CCL18 expression and BP disease suggests that blood levels of this chemokine can be used as an easy method to monitor disease progression and/or efficacy of therapeutic interventions.