Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms.

BACKGROUND AND PURPOSE: Myeloproliferative neoplasms (MPNs) - polycythemia vera, essential thrombocythemia and primary myelofibrosis - are associated with increased risk for ischaemic cerebrovascular events (ICVEs). Due to their low prevalence, MPNs often remain undiagnosed as the cause of ICVEs. METHODS: Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN-related ICVEs. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. RESULTS: In all, 3318 patients with ICVEs were identified, and amongst them 17 patients with MPN-related ICVEs were included in a retrospective study. In 58% of these patients, ICVEs were the first manifestation of the underlying MPN; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK2 V617F mutation, whilst in 29% recurrent ICVEs (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence (P < 0.001). DISCUSSION: Evidence is provided that, although rare, MPNs represent an underdiagnosed cause of recurrent ICVEs. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN-associated ICVEs.

Nerve ultrasound as follow-up tool in treated multifocal motor neuropathy.

BACKGROUND AND PURPOSE: High-resolution ultrasound is a valuable tool in supporting the diagnosis of multifocal motor neuropathy (MMN) but longitudinal data under therapy are lacking. METHODS: The change in peripheral nerve ultrasound pattern in patients with MMN was assessed over time. Patients with MMN received a thorough initial examination and follow-up over a period of 6-12 months using high-resolution ultrasound of the cervical roots and the nerves of the arms and legs, nerve conduction studies, Medical Research Council Sum Score (MRCSS) and Rotterdam Inflammatory Neuropathy Cause and Treatment Group (INCAT) score to evaluate changes under treatment. The Ultrasound Pattern Sum Score (UPSS) was used as standardized peripheral nerve ultrasound protocol. RESULTS: Seventeen patients with MMN received initial examinations of whom 12 were successfully followed up. All patients with MMN showed at least localized but often multifocal peripheral nerve enlargement. An enlarged overall cross-sectional area as well as enlarged single fascicles (>3 mm²) in clinically and electrophysiologically affected (>90%) and unaffected (>70%) nerves were found. The UPSS did not correlate with clinical disability at both visits. However, the change in clinical disability (evaluated as difference in MRCSS) and the change in UPSS correlated significantly inversely (P = 0.004). CONCLUSIONS: High-resolution sonography of peripheral nerves revealed multifocal nerve enlargement in MMN. Distinct enlargement patterns may support the diagnosis. Ultrasound findings did not correlate well with clinical severity or electrophysiological findings at initial presentation. As changes in UPSS correlated significantly with the clinical course in terms of muscle strength (MRCSS), sonographic assessment may represent a useful tool for therapeutic monitoring.

Insertable cardiac monitors after cryptogenic stroke--a risk factor based approach to enhance the detection rate for paroxysmal atrial fibrillation.

BACKGROUND AND PURPOSE: Recently, the CRYSTAL AF trial detected paroxysmal atrial fibrillation (AF) in 12.4% of patients after cryptogenic ischaemic stroke (IS) or cryptogenic transient ischaemic attack (TIA) by an insertable cardiac monitor (ICM) within 1 year of monitoring. Our aim was (i) to assess if an AF risk factor based pre-selection of ICM candidates would enhance the rate of AF detection and (ii) to determine AF risk factors with significant predictive value for AF detection. METHODS: Seventy-five patients with cryptogenic IS/TIA were consecutively enrolled if at least one of the following AF risk factors was present: a CHA2DS2-VASc score ≥4, atrial runs, left atrium (LA) size >45 mm, left atrial appendage (LAA) flow ≤0.2 m/s, or spontaneous echo contrast in the LAA. The electrocardiographic and echocardiographic criteria were chosen as they have been repeatedly reported to predict AF; the same applies for four of the six items of the CHA2DS2-VASc score. The study end-point was the detection of one or more episodes of AF (≥2 min). RESULTS: Seventy-four patients underwent implantation of an ICM; one patient had AF at the date of implantation. After 6 months, AF was detected in 21/75 patients (28%), after 12 months in 25/75 patients (33.3%). 92% of AF episodes were asymptomatic. LA size >45 mm and the presence of atrial runs were independently associated with AF detection [hazard ratio 3.6 (95% confidence interval 1.6-8.4), P = 0.002, and 2.7 (1.2-6.7), P = 0.023, respectively]. CONCLUSIONS: The detection rate of AF is one-third after 1 year if candidates for an ICM after cryptogenic IS/TIA are selected by AF risk factors. LA dilation and atrial runs independently predict AF.

Demography-environment relationships improve mechanistic understanding of range dynamics under climate change.

Species respond to climate change with range and abundance dynamics. To better explain and predict them, we need a mechanistic understanding of how the underlying demographic processes are shaped by climatic conditions. Here, we aim to infer demography-climate relationships from distribution and abundance data. For this, we developed spatially explicit, process-based models for eight Swiss breeding bird populations. These jointly consider dispersal, population dynamics and the climate-dependence of three demographic processes-juvenile survival, adult survival and fecundity. The models were calibrated to 267 nationwide abundance time series in a Bayesian framework. The fitted models showed moderate to excellent goodness-of-fit and discriminatory power. The most influential climatic predictors for population performance were the mean breeding-season temperature and the total winter precipitation. Contemporary climate change benefitted the population trends of typical mountain birds leading to lower population losses or even slight increases, whereas lowland birds were adversely affected. Our results emphasize that generic process-based models embedded in a robust statistical framework can improve our predictions of range dynamics and may allow disentangling of the underlying processes. For future research, we advocate a stronger integration of experimental and empirical studies in order to gain more precise insights into the mechanisms by which climate affects populations. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Effects of FLIRT on bubble growth in man.

Recompression during decompression has been suggested to possibly reduce the risk of decompression sickness (DCS). The main objective of the current study was to investigate the effects of FLIRT (First Line Intermittent Recompression Technique) on bubble detection in man. 29 divers underwent 2 simulated dives in a dry recompression chamber to a depth of 40 msw (500 kPa ambient pressure) in random order. A Buehlmann-based decompression profile served as control and was compared to an experimental profile with intermittent recompression during decompression (FLIRT). Circulating bubbles in the right ventricular outflow tract (RVOT) were monitored by Doppler ultrasound and quantified using the Spencer scoring algorithm. Heat shock protein 70 (HSP70), thrombocytes, D-Dimers and serum osmolarity were analyzed before and 120 min after the dive. Both dive profiles elicited bubbles in most subjects (range Spencer 0-4). However, no statistically significant difference was found in bubble scores between the control and the experimental dive procedure. There was no significant change in either HSP70, thrombocytes, and D-Dimers. None of the divers had clinical signs or symptoms suggestive of DCS. We conclude that FLIRT did not significantly alter the number of microbubbles and thus may not be considered superior to classical decompression in regards of preventing DCS.

Contrast-enhanced ultrasonography for the detection of joint vascularity in arthritis--subjective grading versus computer-aided objective quantification.

PURPOSE: To compare joint inflammation assessment using subjective grading of power Doppler ultrasonography (PDUS) and contrast-enhanced ultrasonography (CEUS) versus computer-aided objective CEUS quantification. MATERIALS AND METHODS: 37 joints of 28 patients with arthritis of different etiologies underwent B-mode ultrasonography, PDUS, and CEUS using a second-generation contrast agent. Synovial thickness, extent of vascularized pannus and intensity of vascularization were included in a 4-point PDUS and CEUS grading system. Subjective CEUS and PDUS scores were compared to computer-aided objective CEUS quantification using Qontrast® software for the calculation of the signal intensity (SI) and the ratio of SI for contrast enhancement. RESULTS: The interobserver agreement for subjective scoring was good to excellent (κ = 0.8 - 1.0; P < 0.0001). Computer-aided objective CEUS quantification correlated statistically significantly with subjective CEUS (P < 0.001) and PDUS grading (P < 0.05). The Qontrast® SI ratio correlated with subjective CEUS (P < 0.02) and PDUS grading (P < 0.03). Clinical activity did not correlate with vascularity or synovial thickening (P = N. S.) and no correlation between synovial thickening and vascularity extent could be found, neither using PDUS nor CEUS (P = N. S.). CONCLUSION: Both subjective CEUS grading and objective CEUS quantification are valuable for assessing joint vascularity in arthritis and computer-aided CEUS quantification may be a suitable objective tool for therapy follow-up in arthritis.

[From stroke to reperfusion : How can we be faster?] / Vom Schlaganfall zur Reperfusion : Wie geht es schneller?

BACKGROUND: During the last two decades major efforts in clinical research have led to the establishment of intravenous thrombolysis as the first line acute therapy for ischemic stroke. More recently, data from successful phase III trials have provided proof of the efficiency of mechanical recanalization in acute stroke. The fact that the efficiency of the available therapies can be increased through faster delivery is well documented; however, many institutions dealing with the emergency care of stroke patients lack organizational or infrastructural arrangements to optimize time efficiency in the diagnostic and therapeutic workup. CONCLUSION: Many of these arrangements have been well evaluated, can be implemented at reasonable costs and have been proven to increase the beneficial effects of thrombolytic therapy.

The short- and long-term effects of bezafibrate in the rat.

Bezafibrate is a potent hypolipidemic agent, which causes marked proliferation of peroxisomes in rat liver. At the same dosage, bezafibrate is more effective in male than in female rats. This is probably related to divergent pharmacokinetics, which cause differences in drug level in serum and liver. The volume density of peroxisomes and several of their enzymes such as carnitine acetyl transferase and acyl-COA oxidase increase in a dose-related fashion. The hypolipidemic effect of bezafibrate, however, does not correlate with the used dosage. This implies that peroxisomal proliferation may play only a minor role in the hypolipidemic action of bezafibrate. In animals treated for 26 months with 300, 750, or 1500 ppm bezafibrate, the relative liver weight and serum triglycerides did not differ significantly from controls. Peroxisomal proliferation varied in different cells, being most prominent in single hepatocytes. The liver catalase activity was significantly reduced, but carnitine acetyl transferase was increased. Abnormal peroxisomes and mitochondria with longitudinal cristae were quite frequent. In one focus, catalase activity was severely diminished ahd peroxisomes were markedly reduced. The incidence of liver tumors was the same (1-3%) in treated animals as in controls.

Sephadex induced bronchial hyperreactivity in the rat: hematology, histology, histochemistry and immunohistology of the lung.

24 hours after an i.v. injection of 2 mg Sephadex G 200 particles ovalbumin sensitized Sprague Dawley rats show an antigen specific bronchial hyperreactivity and an unspecific hyperreactivity against serotonin. The aim of this study was to investigate the effects of Sephadex on blood parameters and lung pathology to find the morphological substrate of bronchial hyperreactivity in this animal model. In the blood neutrophilia (p < 0.01) but no eosinophilia was present. We conclude that a blood eosinophilia needs not to be necessarily correlated with hyperreactivity of the airways like claimed by other investigators for this animal model. Histologically we found that Sephadex particles are trapped in smaller-diameter arteries of the lung and lead to a granulomatous arteritis consisting mainly of ED1 positive and widely ED2 negative macrophages interspersed with eosinophils and neutrophils. Larger vessels not occluded by particles showed perivascular oedema with infiltration of eosinophils. We report here for the first time a significant hypertrophy of PAS positive goblet cells (p < 0.01) accompanied by a peribronchial infiltration with eosinophils (p < 0.01) and macrophages positive for ED1, ED2 and Ox-6 (p < 0.01) but not Ox-19 positive T-lymphocytes. The authors suggest that the peribronchial inflammation contributes importantly to the onset of bronchial hyperreactivity in this animal model and that the hypertrophy of goblet cells indicates the pathophysiological importance of peribronchial leukocytes.

[Quality assurance in the teaching of medical students illustrated by the example of spa therapy for rheumatic diseases]. / Qualitätssicherung in der Lehre von Medizinstudenten illustriert am Beispiel der Kurorttherapie bei rheumatischen Erkrankungen.

BACKGROUND: The currently employed methods for quality assurance in student education are frequently considered as being inadequate. In the present study the request to plan a budget for the treatment of patients with ankylosing spondylitis is presented as an additional method to assess the influence of a teaching course on the student's attitude towards certain interventions. How would medical students distribute financial resources for the treatment of patients with ankylosing spondylitis? Does a course 'Excursion to a Spa' lead to changes in budgeting by the student? MATERIAL AND METHODS: Before and after a 4-day excursion to Bad Gastein (health resort primarily for patients with rheumatic diseases) to become better acquainted with the local treatment modalities medical students in semester 8.4 +/- 3.8 (5th year in medical school) were asked how they would distribute a fixed sum of EUR 5,000.- (= 100%) for a prospective period of 5 years over 9 given forms of treatment in a patient with ankylosing spondylitis in order to provide optimal improvement of the disease and quality of life. RESULTS: Before the excursion the students distributed the budget as follows: drug therapy 15%, spa therapy 17%, physical therapy 14%, exercise therapy 19%, massage therapy 11%, unconventional therapies 5%, psychological therapy 7%, changes in the household environment 8%, private pleasure 4%. After the excursion to the spa the medical students assigned more financial means on spa therapy (p = 0.024, Wilcoxon test) and unconventional therapies (p = 0.015). CONCLUSION: Creating a budget for a defined disease appears to be a useful instrument for assessing the influence of a teaching course on medical students' attitude towards certain interventions and for detecting imbalances in the presentation of therapy procedures or discrepancies between the presentation and the aims of teaching.

[Influence of reflex zone therapy of the feet on intestinal blood flow measured by color Doppler sonography]. / Beeinflussung der Darmdurchblutung durch Fussreflexzonenmassage, gemessen mittels farbkodierter Dopplersonographie.

OBJECTIVE: An influence on organ-associated blood flow is considered as a possible mechanism of action of reflex zone massage of the feet (FRZM) therapy. In the present study we investigated whether changes in intestinal blood flow can be achieved by FRZM. MATERIAL AND METHODS: 32 healthy adults (19 women and 13 men) were randomly assigned to the treatment or the placebo group. Subjects of the treatment group received foot massage on the zones assigned to the intestines and those of the placebo group received massage on zones unrelated to the intestines. Before, during and after FRZM, the blood flow velocity, the peak systolic and the end diastolic velocities in the superior mesenteric artery as well as the resistive index as a parameter of vascular resistance were calculated. RESULTS: During FRZM, in the subjects of the treatment group there was a significant reduction in the resistive index (p = 0.021), suggesting an increase in the blood flow in the superior mesenteric artery and the subordinate vascular system. In contrast, there were no significant changes in the resistive index in the subjects of the placebo group. CONCLUSION: The reduction in the resistive index observed in the treatment group supports the assumption that FRZM improves blood flow in the organs considered to be associated with the specific foot zones, at least during the therapy process.

Glomerular lipidosis in the dog.

With both light-microscopy and electron-microscopy, glomerular lipidosis in the dog appears in two forms which can freely pass into each other: 1. A nodular non-compressing form, and 2. and expansive compressing form. The focal areas are completely surrounded by a basal membrane. The covering podocytes are basically unchanged. The primary site of lipid deposition is the mesangial cell, not the endothelial cell.

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: the hypolipidemic effect and the induction of peroxisomal enzymes.

The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal beta-oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid beta-oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.

Effects of daltroban, a thromboxane (TX) A2 receptor antagonist, on lipid metabolism and atherosclerosis.

In rat hepatocyte cultures daltroban reduced 14C-acetate incorporation stronger into cholesterol (CH) esters than into free CH. Further data suggest that the reduction of cellular sterols by daltroban is independent from its TXA2 receptor antagonistic activity and caused by reduced capacity of ACAT depending CH esterification. In rabbits fed CH-enriched diet treatment with daltroban led to an inhibition of platelet aggregation and to a significant reduction of progression of atherosclerosis. Both reduced CH esterification and TXA2 receptor antagonism may contribute to the diminution of progression of atherosclerosis by daltroban.

Hyperfibrinolysis and hypercholesterolaemia in salt-intoxication in pigs.

Non-acute salt-intoxication in pigs leads to hyperfibrinolysis and a continuous rise in cholesterol due to an increase in the LDL fraction. Morphologically, spherical microthrombi, vascular wall infiltration and changes to organs have been found, as have also been described in shock or stress situations.

The influence of epsilon-aminocaproic acid on the mineralocorticoid hypertension of the rat.

The development of hypertension induced by DOCA/salt in rats can be reduced by epsilon-aminocaproic acid. Analogously to the clinical finding, glomerulopathy is also less marked. Recognising on the one hand the interaction between the coagulation system and the vessel wall and on the other hand the fibrinolysis-blocking properties of EACA, it can be assumed that derangements of the coagulation system are aetiologically involved i hypertension induced by salt/DOCA. As a secondary finding, it was observed that the course of an existing lung infection is deleteriously affected by fibrinolysis-blockade with EACA.

Incidence of spontaneous tumors in laboratory rats.

The Caw-Hoe-Wiga strain of the Sprague-Dawley rat was observed for a period of ten years (1974--1983). In toxicity studies, a gradual increase of food intake could be noted in 12- to 13-week-old rats. The food intake of males was 21 g in 1974 and 27 g in 1983; in females 16 g in 1974 and 19 g in 1984. Correspondingly, a gradual increase of body weight was measured. The body weight of males was 400 g in 1974 and 470 g in 1983; of females 240 g in 1974 and 285 g in 1983. The gradual increase of food intake and body weight was followed by a gradual increase in the incidence of spontaneous tumors, 1974: 5% and 1983: 13%. Our experiments support the opinion of a causal connection between food intake, body weight and incidence of spontaneous tumors. Tumors can appear in any age group, but tumors. occur more often in older animals. In our studies, the increase in the incidence of spontaneous tumors was proportional to the increase in age: At 15 months only 6%, at 32 months 86%. 32% of the tumors were located in the mammary glands, 27% in the hypophysis, 12% in skin and appendages, and 9% in other endocrine organs. The comparison of toxicity and carcinogenicity studies revealed no change in the tumor spectrum, but strain-related tumors appeared earlier in life, more frequently and more often multifocally towards the end of the 10-year observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

[Elevation of 7-dehydrocholesterol concentrations in serum and liver and pericentral peroxisome proliferation in hepatocytes of rats after inhibition of cholesterol biosynthesis by BM 15,766]. / Erhöhung der 7-Dehydrocholesterol-Konzentrationen in Serum und Leber und perizentrale Peroxisomenproliferation in Hepatozyten von Ratten nach Hemmung der Cholesterin-Biosynthese durch BM 15.766.

Sprague-Dawley rats of both sexes were treated for three months with BM 15,766, an inhibitor of cholesterol biosynthesis in conjunction with standard or high-fat and high-cholesterol diets. In serum and livers of all drug-treated rats lowered cholesterol concentration associated with an increase of 7-dehydrocholesterol (7-DHC) was found. Electron microscopy of the liver showed a distinct proliferation of peroxisomes and an increase of dumb-bell shaped mitochondria in the pericentral zone 3. Abnormal-shaped peroxisomes with DAB-negative loops attached to their membranes were found in the intermediate zone 2. These alterations were more accentuated in drug-treated rats fed standard diet, then in treated rats receiving a high-fat and high-cholesterol diet. The observations demonstrate, that the increase of 7-DHC is due to the inhibition of 7-DHC-delta 7-reductase by BM 15.766 and emphasize the zonal heterogeneity of hepatocytes. The relevance of these observations for the investigation of the human Smith-Lemli-Opitz syndrome, in which also decreased plasma-cholesterol levels and an increase of 7-DHC were reported, is discussed.

Investigations on the exogenous influencing of the spontaneous tumour rate in rats.

72 male and 72 female rats of the strain Can-Hoe-Wiga received standard diet in a long-term study (24 months). A group of equal size received the beta-blocker BM 51.052 administered at a dose of 900 ppm in the feed. The animals in the drug group showed a 20 to 30% delay in body weight gain in comparison with the control animals. These drug-treated animals showed, similarly to experiments with a restrictive diet, a lower death rate, fewer glomerulopathies, and lower creatinine and protein levels in the serum. In addition, there were fewer tumour bearers, the total number of tumours was less, and the malignancy and formation of metastases was reduced. This experiment shows the importance which should be attached to the course of body weight gain during a long-term study. Only if these parameters are taken into consideration, an interpretation of the experimental results is possible.