Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts

Introduction: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments.

Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, for example, extracellular vesicles and microRNA, and novel players in pathogenesis, for example, neutrophils and neutrophil extracellular traps (NETs).

Expert commentary: It is evident that aPL induce a proinflammatory and procoagulant state and recent data suggest that different aPL species activate different signaling pathways which sometimes converge into a common cellular response. This implies that presence of more than one aPL species may disproportionally increase the risk for the major manifestations of APS, that is, thrombosis and fetal loss. Further delineation of the pathogenic mechanisms will hopefully provide clues to causal rather than symptomatic treatments of APS.     

Impaired sodium excretion, decreased glomerular filtration rate and elevated blood pressure in endothelin receptor type B deficient rats

The renal endothelin (ET) system, particularly the ET type B receptor, has been implicated in the regulation of sodium excretion and glomerular filtration rate (GFR). We analyzed kidney morphology and function in a rat strain characterized by complete absence of a functional ETB receptor. Due to Hirschsprung's disease limiting lifetime in these rats, studies were performed in 23-day-old rats. Kidney size and morphology (glomerular and interstitial matrix content, glomerular size and cell density and intrarenal vascular morphology) were normal in ETB-deficient rats. There were also no evidence of altered kidney cell cycle regulation in these rats. GFR was significantly lower, by 72% (P<0.001), in homozygous ETB-deficient rats than in wild-type rats. Fractional sodium excretion was likewise markedly reduced by 84% in homozygous ETB-deficient rats (P<0.001 versus wild-type rats). Treatment with the specific epithelial sodium channel blocker amiloride led to a much higher increase in fractional sodium excretion in ETB-deficient rats (934.2+/-73% in ETB-deficient rats versus 297+/-20% in wild-type rats, expressed as percentage of corresponding placebo treated control; P<0.001). Mean arterial blood pressure was elevated by 7.9 mmHg in homozygous ETB-deficient rats (P<0.05 versus wild-type rats). Our study demonstrates that ETB-deficiency causes early onset kidney dysfunction characterized by a markedly reduced sodium excretion, decreased GFR, and slightly elevated blood pressure. The complete absence of the ETB receptor causes in the kidney--in contrast to the colon--a functional rather than a developmental, neural crest cell dependent disease, since kidney morphology was normal in ETB-deficient rats. The much higher increase in the fractional sodium excretion in ETB-deficient rats after pharmacological blockade of the epithelial sodium channel indicates that the decreased fractional sodium excretion in ETB-deficient rats is most probably due to a lack of the inhibitory property of the ETB receptor on the epithelial sodium channel activity.     

Pneumonien bei akuten Leukämien

Summary Acute leukaemia was complicated by pneumonia in 38 (34.8%) of 109 patients treated between 1979 and 1983; in 39.5% of the patients pneumonia occurred more than once. In 23 patients (60.5%) pneumonia occurred during cytostatic therapy, and 25 patients (65.8%) had less than 1000 mm² granulocytes. Antibiotic therapy had no or only little effect in 70%. A total of 21 patients (55.3%) died of pneumonia. In 15 patients a direct relationship could be seen between pneumonia and the bacterial spectrum in the sputum. A prevalence of gram-negative bacteria was found (24 of 40 bacteria isolated, especially Enterobacteriaceae (19). Fungi were cultivated in 10 cases. Each of the typical pneumonia bacteria was only seen once respectively. It is most important that therapy begin immediately, even before the bacteria have been identified. Only then is there hope that the survival time of patients with acute leukaemia can be influenced.

     

Analytical technique for quantification of selected resorbable calcium phosphate bone void fillers with the use of polarized-light microscopy

Synthetic calcium phosphate bone void fillers promote varying rates of bone formation and material resorption depending on chemistry, porosity, pore structure, and implant site. The objective of this study was to quantify the resorption of a novel ultraporous beta-tricalcium phosphate cancellous bone void filler with simultaneous quantification of bone formation in a canine humerus model. Potential measurement error involved in conventional histomorphometry using Von Kossa stains inspired the development of a new technique. This technique utilizes bright-field and polarized-light microscopy in conjunction with image analysis software, allowing more accurate histomorphometry. This technique was validated with two separate controlled experiments. Scanning electron microscopy further supported the results. The findings suggest that the use of polarized-light microscopy combined with image analysis software can be an effective tool in simultaneously quantifying calcium phosphate resorption and bone formation.     

Selective inhibition of the transmembrane Ca conductivity of mammalian myocardial fibres by Ni,Co and Mn ions

Pflügers Archiv - European Journal of Physiology - According to earlier studies on mammalian papillary muscles, Ni and Co ions reduce the Ca dependent mechanical response whilst the action...     

Effects of sorbent suspension dialysis on plasma amino acid levels in cirrhotic patients with refractory hepatic encephalopathy

In cirrhotic patients, plasma amino acid levels are severely deranged. A decreased ratio of branched-chain to aromatic amino acids (Fischer ratio) has been implicated in the pathogenesis of hepatic encephalopathy. In this prospective study, we investigated the effects of extracorporeal detoxification on amino acid levels using a sorbent suspension dialysis system. Twenty patients with documented cirrhosis and hepatic encephalopathy grade II-III not responding to standard treatment were randomized to receive either six hours of sorbent dialysis and standardized conventional medical treatment or ongoing medical treatment alone. In contrast to previous uncontrolled studies, no significant effect on amino acid levels, Fischer ratio or clinical grade of hepatic encephalopathy was detected in either treatment group. In conclusion, a 6-hour treatment with sorbent dialysis did not significantly influence plasma levels of amino acids and did not ameliorate the clinical grade of hepatic encephalopathy.     

On-line compensation for perturbations of a reaching movement is cerebellar dependent: support for the task dependency hypothesis

Although the cerebellum has been shown to be critical for the acquisition and retention of adaptive modifications in certain reflex behaviors, this structures role in the learning of motor skills required to execute complex voluntary goal-directed movements still is unclear. This study explores this issue by analyzing the effects of inactivating the interposed and dentate cerebellar nuclei on the adaptation required to compensate for an external elastic load applied during a reaching movement. We show that cats with these nuclei inactivated can adapt to predictable perturbations of the forelimb during a goal-directed reach by including a compensatory component in the motor plan prior to movement initiation. In contrast, when comparable compensatory modifications must be triggered on-line because the perturbations are applied in randomized trials (i.e., unpredictably), such adaptive responses cannot be executed or reacquired after the interposed and dentate nuclei are inactivated. These findings provide the first demonstration of the condition-dependent nature of the cerebellums contribution to the learning of a specific volitional task.     

Transgenic rat model of Huntington's disease

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.