Use of the discriminant index in dynamic treatment to reduce recurrence of calcium oxalate kidney stones

Treatment with phosphates, thiazides and allopurinol was undertaken in 54 idiopathic calcium oxalate stone formers, 38 of whom were recurrent stone formers. The patients were followed up for 1 1/2 to 4 years (mean 2.6). During the same period at the pre-treatment stage the patients formed 80 stones, but during therapy only one stone was formed. A dynamic scheme of therapy was used. Each patient was tested before the start of drug treatment by the discriminant index (DI) method, which measures the overall inhibitory potential to calcium oxalate crystallisation. About 10 days after the start of treatment the DI was tested again. If the response was positive, therapy was continued; if not, the patient was given another drug. Adjustments were made as required. The stopping of stone formation correlated well with the DI prediction but less well with the hypocalciuric effect of the drugs.     

Protective effect of lisinopril against ischemia-reperfusion injury in isolated guinea pig hearts

BACKGROUND: In order to determine whether angiotensin-converting enzyme inhibitors (ACEI s) attenuate ischemia-reperfusion injury, we investigated and compared the effects of lisinopril via different routes of administration in an isolated guinea pig heart model of ischaemia reperfusion. METHODS: The effect of lisinopril cardioplegia, oral pretreatment with lisinopril and lisinopril enriched reperfusion solution on myocardium after a normothermic global ischemia of 90 minutes and 30 minutes of reperfusion in the modified Langendorff model was randomly studied in 4 groups (n=8 in each). In all groups, cardioplegic arrest was achieved by administering St. Thomas Hospital Cardioplegic Solution (STHCS). The first group was utilized as the control. In the second group, hearts were arrested with lisinopril (1 micromol/L) enriched STHCS. In the third group, animals were pretreated with oral lisinopril (0.2 mg/kg/twice a day) for ten days. In the last group hearts were again pretreated with oral lisinopril (like in Group 3) and the heart were reperfused with lisinopril enriched (1 micromol/L) Krebs-Henseleit solution during the reperfusion period. RESULTS: Contractility, which was expressed as contractile force (g contractility/g heart weight), was preserved better in the study groups. In the last group, the hearts had the best left ventricular contractile function, where contractile force was 58.4%+/-4.82% of the preischaemic values. In Group I, Group II and Group III they achieved 29.5%+/-5.6%, 41.9%+/-4.9%, and 55.3%+/-5.8% of their preischaemic contractile force values respectively. Creatine kinase leakage was significantly lower and also post- ischaemic coronary flows were significantly higher in the 4th group. Coronary flow after reperfusion increased from 48.0+/-6.2 to 68.0+/-4.51 ml/min.g.heart, in Group IV (p<0.05). CONCLUSIONS: Myocardial MDA and GSH contents showed that there was a correlation between the depletion of myocardial GSH content and increased lipid peroxidation. The myocardial GSH content indicates that the best results were obtained in the last group as compared to the other groups. These preliminary results showed that oral preconditioning improved postischaemic myocardial function and decreased myocardial injury. Because the best results were achieved in the last group, it can be suggested that lisinopril may also play a protective role against reperfusion injury.     

Orthostatic hypercoagulability: a novel physiological mechanism to activate the coagulation system

Orthostatic stress causes significant plasma shift and raises transmural pressure in lower extremities, resulting in an increase in endothelial activation and plasma proteins concentrations, possibly including coagulation factors. This may lead to activation of the coagulation system during standing. To test this hypothesis, we recruited 18 healthy volunteers (9 females and 9 males; mean age: 25+/-1.2 years; body mass index: 21.7+/-0.5 kg/m(2)). Hemodynamics, plasma shift (extrapolated from sequential hematocrit concentration), plasma proteins, and coagulation tests, including procoagulants; fibrinogen, factor V, and factor VIII activity; prothrombin fragments 1 and 2; and endothelial activation-related factors (tissue factor and von Willebrand factor), as well as protein C global pathway, were determined at rest supine and at 15 minutes, 30 minutes, and 60 minutes of still standing. Thirty minutes of standing caused a decrease in plasma volume by 12.0+/-0.5% and an increase in plasma protein by 13.0+/-0.7%. Fibrinogen, factor V, and factor VIII activity rose by 12.0+/-1.2%, 13.0+/-1.0%, and 40.0+/-6.0% (P<0.002 for all), respectively. Prothrombin fragments 1 and 2 were elevated by 150.0+/-30.0%. Tissue factor and von Willebrand factor increased by 30.0+/-9.0% and 17.4+/-51.0% (P<0.02 for both), respectively. However, protein C assay results decreased from 0.95+/-0.20 to 0.83+/-0.16 (P<0.001). We hereby introduce a novel physiological mechanism, "orthostatic procoagulation," that should be considered during coagulation tests. Furthermore, it could be extrapolated to the pathophysiology of stasis and venous thromboembolism.     

Thick Acellular Heart Extracellular Matrix with Inherent Vasculature: A Potential Platform for Myocardial Tissue Regeneration

The decellularization of porcine heart tissue offers many opportunities for the production of physiologically relevant myocardial mimetic scaffolds. Earlier, we reported the successful isolation of a thin porcine cardiac extracellular matrix (pcECM) exhibiting relevant bio-mechanical properties for myocardial tissue engineering. Nevertheless, since native cardiac tissue is much thicker, such thin scaffolds may offer limited regeneration capacity. However, generation of thicker myocardial mimetic tissue constructs is hindered by diffusion limitations (～100?μm), and the lack of a proper vascular-like network within these constructs. In our present work, we focused on optimizing the decellularization procedure for thicker tissue slabs (10-15?mm), while retaining their inherent vasculature, and on characterizing the resulting pcECM. The trypsin/Triton-based perfusion procedure that resulted in a nonimmunogenic and cell-supportive pcECM was found to be more effective in cell removal and in the preservation of fiber morphology and structural characteristics than stirring, sonication, or sodium dodecyl sulfate/Triton-based procedures. Mass spectroscopy revealed that the pcECM is mainly composed of ECM proteins with no apparent cellular protein remains. Mechanical testing indicated that the obtained pcECM is viscoelastic in nature and possesses the typical stress-strain profile of biological materials. It is stiffer than native tissue yet exhibits matched mechanical properties in terms of energy dissipation, toughness, and ultimate stress behavior. Vascular network functionality was maintained to the first three-four branches from the main coronary vessels. Taken together, these results reaffirm the efficiency of the decellularization procedure reported herein for yielding thick nonimmunogenic cell-supportive pcECM scaffolds, preserving both native tissue ultra-structural properties and an inherent vascular network. When reseeded with the appropriate progenitor cells, these scaffolds can potentially serve as ex vivo screening platforms for new therapeutics, as models for human cardiac ECM, or as biomedical constructs for patch or transmural transplantation strategies.     

Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti-epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case-control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals.