Effects of Azimilide Dihydrochloride on Circus Movement Atrial Flutter in the Canine Sterile Pericarditis Model

Azimilide and Atrial Flutter. Introduction: The effects of a Class III agent, azimilide di-hydrochloride, on atrial flutter circuits were studied in a functional model of single loop reentrant atrial flutter using dogs, 3 to 5 days after production of sterile pericarditis. Methods and Results: A computerized mapping system was used to construct activation maps from 138 to 222 epicardial sites in the right atrium. Doses of 3, 10, and 30 mg/kg IV azimilide dihydrochloride were analyzed in 8 dogs in which sustained atrial flutter lasting more than 30 minutes was induced by burst pacing. Atrial flutter was always due to a single loop circus movement reentry in the lower right atrium. At 3 mg/kg, azimilide dihydrochloride terminated atrial flutter in 2 dogs; however, atrial flutter was reinduced. At 10 mg/kg, atrial flutter was terminated in all 8 dogs but was reinduced in 4 dogs with slower rate. At 30 mg/kg, atrial flutter was terminated in the remaining 4 dogs and could not be reinduced. Atrial flutter cycle length always increased prior to termination. Isochronal activation maps showed that the increase in cycle length was due to additional conduction delays in the slow zone of the reentrant circuit. The site of termination was always located within the slow conduction zone situated in the lower right atrium between the line of functional conduction block and the AV ring. effective refractory periods (ERPs) were measured at selected sites in the slow zone and normal zone at twice diastolic threshold for the 10 mg/kg dose. Azimilide preferentially prolonged ERP in the slow zone (42.4 ± 20.l msec, mean ± SD) compared with (he normal zone (23.3 ± 15.4 msec, P < 0.0001). The increase in cycle length corresponded with the increase in ERP in the slow zone. Conclusions: In a functional model of circus movement atrial flutter, azimilide dihydrochloride terminates and prevents reinduction of atrial flutter by a preferential increase in refractoriness leading to further conduction delay and conduction block in the slow zone of the functional reentrant circuit.     

Homing of transplanted bone marrow cells in livers of Schistosoma mansoni‐infected mice

Elkhafif N, Voss B, Hammam O, Yehia H, Mansy S, Akl M, Boehm S, Mahmoud S, El Bendary O, El Fandy G. Homing of transplanted bone marrow cells in livers of Schistosoma mansoni‐infected mice. APMIS 2010; 118: 277–87. The efficiency of differentiation of bone marrow cells (BMCs) into hepatocytes in vivo and its importance in physiopathological processes is still debated. Murine schistosomiasis was used as a liver injury model and unfractionated male mice BMCs were transplanted through intrahepatic injection into non‐irradiated Schistosoma mansoni‐infected female mice on their 16th week post‐infection. Two weeks after bone marrow transplantation, mice were sacrificed on a weekly basis until 10 weeks. Tracing of male donor‐derived cells in female recipient mice livers was carried out by the detection of Y chromosome expression by fluorescent in situ hybridization (FISH) and also of chromodomain Y‐linked (CDYL) protein by indirect immunofluorescence (IF). Their transformation into hepatocytes was studied by double labelling indirect IF using antibodies directed against CDYL and mouse albumin. Histopathological and electron microscopic examinations revealed the presence of small hepatocyte‐like cells in the periportal tracts and in between the hepatocytes facing the sinusoids. Donor‐derived cells showing Y chromosome by FISH and expressing CDYL protein by IF were recovered in the infected transplanted livers. The initial number of these cells increased with increased post‐transplantation time. Cells were mainly localized in the periphery of schistosoma granuloma. Few donor‐derived cells appeared within the hepatic parenchymal tissue and showed positivity for albumin secretion by double labelling with IF. We suggest that transplanted bone marrow stem cells can repopulate the Schistosoma‐infected liver of immunocompetent mice. Their differentiation is a complex event controlled by many factors and needs to be further characterized extensively. The extent and type of liver injury and the number of transplanted cells are important variables in the process of stem cell engraftment and differentiation into functioning hepatic cells that still need to be defined.     

Giant Condyloma Acuminatum in an Infant

Abstract:   We report a 10-month-old boy who presented with a giant perianal condyloma acuminatum, and a similar lesion on the neck. These lesions were treated by surgical excision with satisfactory results. This size, extent, and early age of appearance make this case highly unusual.     

EVALUATION OF COLCHICINE WITH OR WITHOUT PRAZIQUANTEL THERAPY IN THE CONTROL OF HEPATIC FIBROSIS IN MURINE SCHISTOSOMIASIS

Colchicine alone or following praziquantel was given to mice infected withSchistosoma mansonieither 6 or 10 weeks post infection. Praziquantel increased body weight gain, histologically reduced number, diameter and cellularity of granuloma and improved liver function parameters. Early praziquantel therapy decreased hepatic collagen content as detected by the colorimetric method and the serum procollagen propeptide (PIIIP), while later treatment at the 10th week of infection increased hepatic collagen content and serum PIIIP. Colchicine therapy significantly decreased body weight gain with significant weight loss after early treatment. Colchicine did not change the histologic picture of schistosomal liver fibrosis; it induced a detectable hepatocytic injury recorded ultrastructurally and histologically with excitation of the inflammatory reaction in the granuloma and in portal tracts after early treatment. Excess pigmentation in macrophages and Kupffer cells, binucleation and large sized hepatocytic nuclei were evident after colchicine therapy. Colchicine increased hepatic collagen content μg/mg protein, raised globulin and total serum protein and normalized the raised serum PIIIP of infected mice, but had no effect on PIIIP of normal mice. Early cessation of schistosomal infection evidently minimized the adverse effects of colchicine.     

The effect of the photodecomposition of chlorpromazine on lecithin monolayers

Chlorpromazine hydrochloride (cpz) is decomposed when irradiated with ultraviolet light, forming H⁺, hydrochloric acid, chlorpromazine sulphoxide and 2-hydroxypromazine. The order of the reaction (as measured by the expansion that is produced in a lecithin/cpz monolayer) varies between zero and about 3/4. The results have been used to explain some of the adverse side effects that are observed when patients are treated with cpz.     

ANXIOGENIC RESPONSES OF RATS ON WITHDRAWAL FROM CHRONIC ETHANOL TREATMENT: EFFECTS OF TIANEPTINE

Rats were fed a liquid diet with Concentrations of ethanol increasingover 2 weeks and then maintained for 4 weeks to give a meanethanol intake of 11.6 g/kg/day. They were withdrawn from ethanolfor 12 hr and tested in two tests of anxiety, the social interactionand elevated plus-maze tests, and in the holeboard. which providesmeasures of exploration and motor activity. Compared with controlanimals that had received the liquid diet without ethanol, therats withdrawn from ethanol showed significant reductions insocial interaction, in the percentage of entries onto, and timespent on, the open arms of the plus-maze, and in measures ofgeneral activity in all three tests. Tianeptine, a tricyclicantidepressant which increases 5-HT uptake. reversed the anxiogenicresponses and the hypoactivity detected in the social interactiontest, but was without significant effect in the other tests.     

Biological and molecular studies on specific immune cells treated with checkpoint inhibitors for the thera-personal approach of breast cancer patients (<i>ex-vivo</i> study)

Immunotherapy becomes a promising line of treatment for breast cancer (BC) however, its success rate is still limited. Methods: The study was designed to optimize the condition for producing an effective dendritic cell (DCs) based immunotherapy by using DCs and T lymphocytes together with tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating DCs (TIDCs), treated with anti-PD1 and anti-CTLA4 monoclonal antibodies. This mixture of immune cells was co-cultured with autologous breast cancer cells (BCCs) isolated from 26 BC females. Results: There was a significant upregulation of CD86 and CD83 on DCs (P = 0.001 and 0.017, respectively), similarly upregulation of CD8, CD4 and CD103 on T cells (P = 0.031, 0.027, and 0.011, respectively). While there was a significant downregulation of FOXP3 and combined CD25.CD8 expression on regulatory T cells (P = 0.014 for both). Increased CD8/Foxp3 ratio (P < 0.001) was also observed. CD133, CD34 and CD44 were downregulated on BCCs (P = 0.01, 0.021, and 0.015, respectively). There was a significant increase in interferon-γ (IFN-γ, P < 0.001), lactate dehydrogenase (LDH, P = 0.02), and a significant decrease in vascular endothelial growth factor (VEGF, P < 0.001) protein levels. Gene expression of FOXP3 and Programmed cell death ligand 1 (PDL-1) were downregulated in BCCs (P < 0.001, for both), similarly cytotoxic T lymphocyte antigen-4 (CTLA4, P = 0.02), Programmed cell death 1 (PD-1, P < 0.001) and FOXP3 (P < 0.001) were significantly downregulated in T cells. Conclusion: Ex-vivo activation of immune cells (DCs, T cells, TIDCs, and TILs) with immune checkpoint inhibitors could produce a potent and effective BC immunotherapy. However, these data should be validated on an experimental animal model to be transferred to the clinical setting.