Inhibition of granulocyte migration by tiotropium bromide

<p>Abstract</p> <p>Study objectives</p> <p>Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS).</p> <p>Method</p> <p>AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M_1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors.</p> <p>Results</p> <p>Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition.</p> <p>Conclusion</p> <p>Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation.</p

Tracheobronchopathia osteochondroplastica: A rare cause of chronic cough with haemoptysis

A case of tracheobronchopathia osteochondroplastic (TPO) was diagnosed in a 69-year old male with prolonged cough. TPO is a rare condition of unknown cause and only sporadic cases have been reported. The condition is benign, characterized by submucosal nodules growing from the submucosal layer of the airways, protruding into the bronchial lumen. The bronchscopic view together with bronchial cartilage with abnormal distributed mineralization of the histologic examination of theses nodules leads to the correct diagnosis. Mild cases are treated symptomatically, whereas we tried an inhaled corticosteroid. Prominent protrusions in the trachea or the bronchi must be removed. In most cases the disease is stable over years but progressive forms have been reported. TPO may cause chronic refractory cough, which eventually is the only prominent symptom of this disease

Development of an enzyme-linked immunosorbent assay for the detection of human calretinin in plasma and serum of mesothelioma patients

<p>Abstract</p> <p>Background</p> <p>Calretinin is one of the well-established immunohistochemical markers in the diagnostics of malignant mesothelioma (MM). Its utility as a diagnostic tool in human blood, however, is scarcely investigated. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for human calretinin in blood and to assess its usefulness as a potential minimally invasive diagnostic marker for MM.</p> <p>Methods</p> <p>Initially, attempts were made to establish an assay using commercially available antibodies and to optimize it by including a biotin-streptavidin complex into the assay protocol. Subsequently, a novel ELISA based on polyclonal antibodies raised in rabbit immunized with human recombinant calretinin was developed. The assay performance in human serum and plasma (EDTA/heparin) and the influence of calcium concentrations on antibody recognition were studied. Stability of spiked-in calretinin in EDTA plasma under different storage conditions was also examined. In preliminary studies serum and plasma samples from 97 healthy volunteers, 35 asbestos-exposed workers, and 42 MM patients were analyzed.</p> <p>Results</p> <p>The mean detection range of the new ELISA was 0.12 to 8.97 ng/ml calretinin. The assay demonstrated markedly lower background and significantly higher sensitivity compared to the initially contrived assay that used commercial antibodies. Recovery rate experiments confirmed dependence of calretinin antibody recognition on calcium concentration. Calcium adjustment is necessary for calretinin measurement in EDTA plasma. Spiked-in calretinin revealed high stability in EDTA plasma when stored at room temperature, 4°C, or after repeated freeze/thaw cycles. Median calretinin values in healthy volunteers, asbestos workers, and MM patients were 0.20, 0.33, and 0.84 ng/ml, respectively (p < 0.0001 for healthy vs. MM, p = 0.0036 for healthy vs. asbestos-exposed, p < 0.0001 for asbestos-exposed vs. MM). Median values in patients with epithelioid and biphasic MM were similar. No influence of age, gender, smoking status, or type of medium (plasma/serum) on calretinin values was found.</p> <p>Conclusions</p> <p>The novel assay is highly sensitive and applicable to human serum and plasma. Calretinin appears to be a promising marker for the blood-based detection of MM and might complement other markers. However, further studies are required to prove its usefulness in the diagnosis of MM patients.</p

Acute Rhabdomyolysis Associated with Coadministration of Levofloxacin and Simvastatin in a Patient with Normal Renal Function

We report a rare case of severe acute rhabdomyolysis in association with coadministration of levofloxacin and simvastatin in a patient with normal renal function. A 70-year-old Caucasian male was treated due to community acquired pneumonia with levofloxacin in a dosage of 500 mg once and then twice a day. On the 8th day of hospitalization the patient presented with acute severe rhabdomyolysis requiring an intensive care support. After discontinuation of levofloxacin and concomitant medication with simvastatin 80 mg/day, clinical and laboratory effects were totally reversible. Up to now, levofloxacin has been reported to induce rhabdomyolysis mainly in patients with impaired renal function, as the medication has a predominant renal elimination. In our case renal function remained normal during the severe clinical course. According to a recent case report rhabdomyolysis was observed due to interaction of simvastatin and ciprofloxacin. To our best knowledge this is the first case of interaction between simvastatin and levofloxacin to be reported. This case emphasizes the need of close monitoring of creatine kinase in patients under more than one potentially myotoxic medication especially when patients develop muscle weakness

Patient and Physician Factors Contributing to Poor Outcomes in Patients with Asthma and COPD

Poor adherence with medical regimens by patients with asthma and chronic obstructive pulmonary disease (COPD) is a major problem facing medical practitioners, with patients typically taking approximately half the prescribed doses of self-administered medications. Poor adherence with medication regimens results in inadequate disease control and is assumed to be associated with poor long-term outcomes and high medical and social costs. Efforts to assist patients with treatment adherence are thought to improve the benefits of prescribed medications; however, even the most effective interventions do not necessarily lead to significant improvements in adherence and treatment outcomes. Simple interventions (such as re-calling patients who miss appointments, making every effort to keep patients in care, and simplifying treatment regimens) and complex strategies (including combinations of more thorough patient instructions and counseling, reminders, close follow-up, supervised self-monitoring, family therapy, crisis intervention, and telephone follow-up) may improve adherence and treatment outcomes for both short- and long-term treatments. All these measures are highly dependent on a good physician-patient relationship, and the willingness and ability of caregivers to closely follow guidelines and recommendations. The diversity and complexity of interventions, and uncertainty about their effects, make it difficult to assess which interventions are effective and which are not. The literature regarding interventions remains surprisingly limited. There is little evidence to show that medication adherence can be improved consistently, or that interventions will inevitably lead to improvements in treatment outcomes, especially considering the resources usually available in outpatient settings. Most studies assessing successful complex interventions have not assessed the effect on clinical endpoints. Studies in COPD are sparse compared with those in asthma, leaving room for further research efforts. As all self-administered treatments are affected by low adherence, and as the number of efficacious, self-administered treatments continues to grow, detailed knowledge about this complex issue may help to ensure better management in patients with obstructive pulmonary diseases.Asthma, Chronic-obstructive-pulmonary-disease, Patient-compliance

Medical Students’ Perceptions towards Digitization and Artificial Intelligence: A Mixed-Methods Study

Digital technologies in health care, including artificial intelligence (AI) and robotics, constantly increase. The aim of this study was to explore attitudes of 2020 medical students’ generation towards various aspects of eHealth technologies with the focus on AI using an exploratory sequential mixed-method analysis. Data from semi-structured interviews with 28 students from five medical faculties were used to construct an online survey send to about 80,000 medical students in Germany. Most students expressed positive attitudes towards digital applications in medicine. Students with a problem-based curriculum (PBC) in contrast to those with a science-based curriculum (SBC) and male undergraduate students think that AI solutions result in better diagnosis than those from physicians (p p < 0.002). Around 38% of the students felt ill-prepared and could not answer AI-related questions because digitization in medicine and AI are not a formal part of the medical curriculum. AI rating regarding the usefulness in diagnostics differed significantly between groups. Higher emphasis in medical curriculum of digital solutions in patient care is postulated

Histologically proven isoniazid hepatoxicity in complicated tuberculous salpingitis

Isoniazid (INH) hepatic injury is histologically indistinguishable from viral hepatitis and is related to individual susceptibility of patients who hydrolyze the drug to isonicotinic acid at different rates. We here present a case initially involving a complaint of lower abdominal pain, which was diagnosed after a long diagnostic work-up as tuberculous salpingitis and which is rare in women in developed countries. A lack of pulmonary effects further delayed correct diagnosis of the underlying tuberculosis infection. Based on the clinical follow up and liver histology, INH-induced severe hepatoxicity, which further contributed to the abdominal symptoms, could be confirmed. After adaptation of the standard therapeutic regimen no further complications occurred