Acute Moderate Hypoxia in Conscious Rabbits: Effect on Hepatic Cytochrome P450 and on Reactive Oxygen Species

This study aimed to document whether acute moderate hypoxia modifies the amount and activity of hepatic cytochrome P450 and in addition, induces changes in the production or the ability to neutralize oxygen reactive species (ORS). Rabbits were exposed to a low partial pressure of oxygen (12%) for 8 or 24 h, killed, and the amount and activity of cytochrome P450, lipid peroxidation, microsomal chemiluminescence and enzymatic scavenger activity were assessed in the liver. After 8 h of hypoxia, total amount but not the activity of cytochrome P450 was decreased, although after 24 h of hypoxia, both the amount and the activity of cytochrome P450 were decreased. Hypoxia for 8 h increased the activity of glutathione peroxidase. However, after 24 h of hypoxia, lipid peroxidation, microsomal chemiluminescence and superoxide dismutase activity were increased, while hepatic glutathione and glutathione peroxidase activity were reduced, modifications that suggest an enhanced presence of ORS. In in-vitro studies, an ORS generating system reduced the activity of cytochrome P450 and enhanced lipid peroxidation of hepatic microsomal membranes, supporting the view that ORS can impair cytochrome P450. The results of the present study show that hypoxia induces changes in the amount and activity of cytochrome P450, as well as in the production or the ability to neutralize ORS, and that these changes are time-dependent.     

Electrotonic Inhibition and Active Facilitation of Excitability in Ventricular Muscle

Inhibition and Facilitation in Cardiac Muscle. Introduction: The effects of subthreshold electrical pulses on the response to subsequent stimulation have been described previously in experimental animal studies as well as in the human heart. In addition, previous studies in cardiac Purkinje fibers have shown that diastolic excitability may decrease after activity (active inhibition) and, to a lesser extent, following subthreshold responses (electrotonic inhibition). However, such dynamic changes in excitability have not been explored in isolated ventricular muscle, and it is uncertain whether similar phenomena may play any role in the activation pal-terns associated with propagation abnormalities in the myocardium. Methods and Results: Experiments were performed in isolated sheep Purkinje fibers and papillary muscles, and in enzymatically dissociated guinea pig ventricular myocytes. In all types of preparations introduction of a conditioning subthreshold pulse between two subthreshold pulses was followed by a transient decay in excitability (electrotonic inhibition). The degree of inhibition was directly related to the amplitude and duration of the conditioning pulse and inversely related to the postconditioning interval. Yet, inhibition could be demonstrated long after (> 1 sec) the end of the conditioning pulse. Electrotonic inhibition was found at all diastolic intervals and did not depend on the presence of a previous action potential. In Purkinje fibers, conditioning action potentials led to active inhibition of subsequent responses. In contrast, in muscle cells, such action potentials had a facilitating effect (active facilitation). Electrotonic inhibition and active facilitation were observed in both sheep ventricular muscle and guinea pig ventricular myocytes. Accordingly, during repetitive stimulation with pulses of barely threshold intensity, we observed: (1) bistability (i.e., with the same stimulating parameters, stimulus: response patterns were either 1:1 or 1:0, depending on previous history), and (2) abrupt transitions between 1:1 and 1:0 (absence of intermediate wenckebach-like patterns). Simulations utilizing an ionic model of cardiac myocytes support the hypothesis that electrotonic inhibition in well-polarized ventricular muscle is the result of partial activation of I_k following subthreshold pulses. On the other hand, active facilitation may be the result of an activity-induced decrease in the conductance of I_K1. Conclusion: Diastolic excitability of well-polarized ventricular myocardium may be transiently depressed following local responses and transiently enhanced following action potentials. On the other hand, diastolic excitability decreases during quiescence. Active facilitation and electrotonic inhibition may have an important role in determining the dynamics of excitation of the myocardium in the presence of propagation abnormalities.     

Frequency and prognostic value of HLA antigens in osteosarcoma patients

A homogeneous group of 53 Caucasian subjects with high-grade osteosarcoma (OS) was typed for HLA-A and B locus antigens. Although no significant differences in the distribution of these antigens were found in comparison with 425 local controls, a trend towards an increase of HLA-B18 and decrease of HLA-B21 was observed. All the patients underwent amputation plus adjuvant chemotherapy and among the 29 patients with a follow-up longer than one year, 9 out of 10 subjects with HLA-A3 antigens developed metastases within a few months. None of the OS patients had the HLA-A3, B7 haplotype which is present in linkage-disequilibrium in the control population.     

Prognostic relevance of serum thymidine kinase in primary myelodysplastic syndromes: relationship to development of acute myeloid leukaemia

The aim of this study was to evaluate the possible prognostic relevance of thymidine kinase serum levels (s-TK), an indirect marker of proliferative activity, in myelodysplastic syndromes (MDS). S-TK levels were monitored by means of a radioenzyme assay in 90 patients affected by MDS (22 refractory anaemia, RA; 17 RA with ring sideroblasts, RARS; 21 RA with blast excess, RAEB; 15 RAEB in transformation, RAEB-T; 15 chronic myelomono-cytic leukaemia, CMMoL). Mean s-TK levels (U//tl) measured at diagnosis were 11–9 –12–6 for RA, 11–4–13'6 for RARS, 19–9 – 28–4 for RAEB, 39–6 – 34–3 for RAEB-T and 77–7 – 69–7 for CMMoL (normal values <5U//LI1). With the only exception of a weak relationship with lactate dehydrogenase, no correlation was found between initial s-TK values and other clinical or laboratory parameters, such as age, haemoglobin, white blood cell or platelet count, percentage of bone marrow blasts. MDS patients with s-TK >38 V/fA , a cut-off level selected by means of ROC statistical analysis, showed a significantly shorter survival than those with s-TK <38U//xl (8–2 v 37–4 months, respectively; P < 0–0001). In particular, transformation in acute myeloid leukaemia (AML) occurred in 17/21 (81%) of patients with s-TK >38U//d and 9/69 (13%) of those with lower levels at diagnosis (P < 00001), independently of FAB subtype. High s-TK levels were also useful to predict evolution in AML during the course of the disease in patients with normal initial values. Multivariate analysis confirmed the independent prognostic value of s-TK on both overall survival and risk of acute transformation. We conclude that s-TK may be an important prognostic factor in MDS, strongly correlated with development of AML.     

Safety and Effectiveness of Transvenous Lead Extraction in Octogenarians

Transvenous Lead Extraction . Introduction: As the population ages, the number of elderly patients with implantable cardiac devices referred for transvenous lead extraction will dramatically increase in Western countries. The safety and effectiveness of lead extraction in elderly patients has not been well evaluated. We report the safety and effectiveness of transvenous lead extraction in octogenarians. Methods and Results: From January 2005 to January 2011, we reviewed data from consecutive patients ≥ 80 years referred to our institutions for transvenous lead extraction because of cardiac device infection or lead malfunction. Clinical characteristics, procedural features, and periprocedural major and minor complications were compared between octogenarians and younger patients. Out of 849 patients undergoing lead extraction in the participating institutions during the study period, 150 (18%) patients were octogenarians (mean age 84 years; range 80–96; 64% males). A significantly higher percentage of octogenarians presented with chronic renal failure (55% vs 26%; P < 0.001), history of malignancy (22% vs 6%; P < 0.001), and chronic obstructive pulmonary disease (46% vs 19%; P < 0.001). Complete lead extraction rates were similar in the 2 age groups (97% in octogenarians vs 96% in patients <80 years; P = 0.39). Periprocedural death occurred in 2 (1.3%) patients ≥80 years and in 5 (0.72%) patients <80 years (P = 0.45 for comparison). No differences in terms of other periprocedural major and minor complications were found between the 2 age groups. Conclusion: Despite presenting with a significantly higher rate of comorbidities, transvenous lead extraction can be performed safely and successfully in octogenarians. (J Cardiovasc Electrophysiol, Vol. 23 pp. 1103‐1108, October 2012)     

Megakaryocytopoiesis in Experimentally Induced Immune Thrombocytopenia

The hypothesis that in immune thrombocytopenia, platelet antibody maynot only cause destruction of the circulating platelets but also depress plateletproduction by injuring the megakaryocytes of the bone marrow, was testedexperimentally.

Sustained thrombocytopenia was produced in rats by titrated injections ofa potent heteroimmune antiplatelet serum and megakaryocytopoiesis wasthen studied by the use of tritiated thymidine and bone marrow autoradiography. Rats in which the platelet count was maintained at a lower thannormal level by repeated thrombocytophereses, and other rats injected withplatelet antiserum previously absorbed with rat platelets, served as controls.

Profoundly altered patterns of megakaryocytopoiesis were found in the ratsin which thrombocytopenia was produced by the antiplatelet serum. The dataindicated a severely impaired and depressed megakaryocyte maturation and,possibly, destruction of some of the megakaryocytes during their maturationprocess. In the rats in which the platelet level was maintained low by repeatedthrombocytophereses, the pattern of megakaryocytopoiesis indicated accelerated maturation and there was also an increased megakaryocyte mass. Nodifference from normal was found in the rats receiving the platelet-adsorbed antiserum. It was concluded that the platelet antibody produced aninjurious effect on the megakaryocytes in the bone marrow, thereby depressing platelet production, and that the immune thrombocytopenia was theresult of both increased platelet destruction and defective platelet production.

Submitted on November 22, 1968 Accepted on October 3, 1969     

Psoriasis vs allergic contact dermatitis in palms and soles: a quantitative histologic and immunohistochemical study

Cesinaro AM, Nannini N, Migaldi M, Pepe P, Maiorana A. Psoriasis vs allergic contact dermatitis in palms and soles: a quantitative histologic and immunohistochemical study. APMIS 2009; 117: 629–34. A systematic histologic and immunohistochemical study of cases of psoriasis (PSO) and allergic contact dermatitis (ACD) in palmo‐plantar skin was performed to find differences between these two diseases that usually show overlapping features in these specific sites. Skin biopsies from 42 (22 female, 20 male) patients were evaluated for several histopathologic parameters and immunohistochemistry was applied to quantify keratinocytic proliferation, the number of dendritic cells (DCs) and the phenotype of the mononuclear cell infiltrate. Regular epidermal hyperplasia and marked parakeratosis were found to be more frequent in PSO than in ACD cases, but only the first parameter reached the level of significance (p = 0.03). The number of S100 protein‐positive DCs was significantly higher in ACD (p = 0.006), whereas keratinocytic proliferation, studied with Mib‐1, was found to be higher in PSO than in ACD, but the difference was not statistically significant. No significant difference was detected in the number of CD4⁺, CD8⁺ and bcl2⁺ lymphocytes in PSO and ACD cases. In the palms and soles, the finding of irregular epidermal hyperplasia and the detection of a higher number of S100 protein‐positive DCs favor the diagnosis of ACD over PSO. The differential diagnosis between PSO and ACD can be practically approached using a histopathologic parameter and a commercially available antibody.