Therapeutic Effect of Dimethyl Dimethoxy Biphenyl Dicarboxylate on Collagen-Induced Arthritis in Rats

Objective:To study the effect of oral administration of dimethyl dimethoxy biphenyl dicarboxylate(DDB) on adjusting angiogeneic/inflammatory mediators and ameliorating the pathology of bones in rats with collagen-induced arthritis(CIA).Methods:Wistar rat model of CIA was set up using bovine collagen type Ⅱ.Fifty rats were divided into five groups randomly:normal,CIA model,DDB treatment,methotrexate(MTX) treatment,and combined DDB+MTX treatment.Ankle joints of rats were imaged with digital X-ray machine to show the destruction of joints.Fore and hind paw and knee joints were removed above the ankle joint then processed for haematoxylin and eosin staining.Plasma levels of vascular endothelial growth factor(VEGF),platelet derived growth factor,interleukin-8(IL-8),IL-4,tumor necrosis factor α(TNF-α),and cyclooxygenase-2(COX-2) were quantified by enzyme-linked immunosorbent assay.Nitric oxide levels were detected by Griess reagent.Results:Compared with the CIA model group,a remarkable reduction in various angiogenic(VEGF and IL-8) and inflammatory mediators(TNF-α,IL-4 and COX-2) after treatment with DDB either alone or combined with MTX(P0.05 or P0.01).Histopathological and X-ray findings were confirmatory to the observed DDB anti-arthritic effect.The DDB-treated group showed amelioration in signs of arthritis which appeared essentially similar to normal.Conclusion:Our data shed light on the therapeutic efficacy of DDB in experimental rheumatoid arthritis(RA) compared with a choice drug(MTX) and it may be offered as a second-line drug in the treatment of RA.     

Extracorporeal membrane oxygenation for the circulatory support of children after repair of congenital heart disease

We have treated 39 infants and children with congenital heart disease with extracorporeal membrane oxygenation during the past 5 years. Thirty-six were treated for low cardiac output or pulmonary vasoreactive crisis after repair of congenital heart defects. Twenty-two (61%) survived. Most patients were cannulated from the neck via the right internal jugular vein and the right common carotid artery. Six patients were cannulated from the chest, including three who had separate drainage of the left side of the heart with a left atrial cannula. Two of these patients survived and were the only survivors of the nine patients cannulated in the operating room because they could not be weaned from cardiopulmonary bypass after open cardiac operations. We also reviewed 312 patients (the predictor study series) having open cardiac operations before the availability of extracorporeal membrane oxygenation; 27 of these patients died. Data were collected at 1 and 8 hours postoperatively to determine if any parameters might predict early mortality. With these parameters used as criteria, patients who went on extracorporeal membrane oxygenation were as sick as those who died before extracorporeal membrane oxygenation was available. The most common complication was bleeding related to heparinization. The mean transfusion requirement in survivors was 1.50 +/- 1.13 ml/kg/hr, 5.63 +/- 7.0 ml/kg/hr in the nonsurvivors, and 7.46 +/- 8.29 ml/kg/hr in those cannulated in the operating room because they could not be weaned from bypass. Four children had intracranial hemorrhage, and two of them died. There was one late death. Nine of the 22 survivors are entirely normal. All survivors who do not have Down's syndrome are considered to have normal central nervous system function. We conclude that extracorporeal membrane oxygenation can improve survival in patients with both pulmonary artery hypertension and low cardiac output after operations for congenital heart disease.     

Our experience in intraocular foreign-body removal.

Foreign bodies embedded in the retina and choroid that cannot be extracted by a magnet and require vitreous surgery for their removal comprise a separate group. A retrospective review of 40 consecutive cases (between 1977-1990) showed that this type of trauma frequently accompanied extensive ocular damage, including corneal and or scleral perforation, disruption of the lens, significant vitreous hemorrhage, retinal and choroid hemorrhage, and retinal detachment. Intraoperative and late complications occurred frequently, making the visual and structural outcomes of such eyes uncertain; therefore, another alternative must be sought that might improve the prognosis of these eyes. In this review, we emphasize (1) the time elapsed between the accident and the removal of the foreign body and (2) the final visual acuity and the time before the surgery.     

Intimal thickening involves transdifferentiation of embryonic endothelial cells

Morphological studies have hypothesized different origins for the precursors of the vascular smooth muscle cells (SMCs). The intriguing possibility that intimal SMCs may arise from the endothelium has newly emerged. As a first step towards understanding of the possible mechanisms involved in the transdifferentiation of endothelium into smooth muscle cells, we characterized the in vivo phenotype of the cells located in the aortic wall (distal to the aortic arches). This was accomplished using advanced stages of chicken embryo development. Furthermore, we investigated whether the cells present at the intimal thickening derive from the endothelial cell transdifferentiation. Immunolabeling of serial cryosections suggested that mesenchymal cells observed in the intimal thickening may arise from the endothelium. These cells may persist either as non-muscle throughout the development or possibly convert to cells expressing smooth muscle alpha-actin (SM alpha-actin). To determine whether endothelial cells may actually transdifferentiate into mesenchymal cells, aortic explants from 14-day-old chicken embryos (stage 40) were used. We found that explanted endothelial cells lose their cobblestone-appearance and migrate toward cell-free area. Some of these cells maintain the vWf immunoreactivity, whereas other cells coordinately lose vWf and gain SM alpha-actin expression (transitional cells). Taken together these findings strongly support the possibility that embryonic aortic endothelial transdifferentiate into mesenchymal cells, some of which express SM alpha-actin. Since TGFbeta-3 is considered an essential factor during epithelial to mesenchymal transitions in earlier chicken heart development, we also investigated the distribution of this growth factor at day 14. Our observations indicated that the immunoreactivity for TGFbeta-3 in this stage may be associated with migrating mesenchymal cells and that this immunoreactivity appears to decrease as cell differentiation advances. Therefore, the present study provides evidence that could help to explain 1) the presence of cells displaying a phenotype reminiscent of fetal-like cells in the normal chicken aorta and in the intimal region of the human aorta; 2) the SM lineage diversity in the chicken embryo reported by others; 3) a subpopulation of immature cells in the subendothelial region of the main pulmonary arteries of fetal, neonatal and adult bovines; and 4) the presence of intimal cushions, intimal pads, eccentric and diffuse intimal thickening that are observed in mammalian and avian vessels at birth.     

Interlaboratory validation of a CD71-based flow cytometric method (Microflow) for the scoring of micronucleated reticulocytes in mouse peripheral blood

An interlaboratory study was performed to validate an anti-CD71/flow cytometry-based technique for enumerating micronucleated reticulocytes (MN-RETs) in mouse peripheral blood. These experiments were designed to address International Workshop on Genotoxicity Test Procedures validation criteria by evaluating the degree of correspondence between MN-RET measurements generated by flow cytometry (FCM) with those obtained using traditional microscopy-based methods. In addition to these cross-methods data, flow cytometric MN-RET measurements for each blood sample were performed at two separate sites in order to evaluate the reproducibility of data between laboratories. In these studies, groups of male CD-1 mice were treated with vehicle (saline or vegetable oil), a negative control (saline or vegetable oil), or four dose levels of five known genotoxicants (clastogens: cyclophosphamide, benzo[a]pyrene, 5-fluorouracil, methotrexate; aneugen: vincristine sulfate). Exposure occurred on 3 consecutive days via intraperitoneal injection, and blood samples were obtained approximately 24 hr after the final treatment. MN-RET frequencies were determined for each sample based on the analysis of 2,000 (microscopy) and 20,000 (FCM) reticulocytes. Regardless of the method utilized, each genotoxic agent was observed to cause statistically significant increases in the frequency of MN-RETs, and each response occurred in a dose-dependent manner. Spearman's correlation coefficient (rs) for FCM versus microscopy-based MN-RET measurements (nine experiments, 252 paired measurements) was 0.740, indicating a high degree of correspondence between methods. The rs value for all flow cytometric MN-RET measurements performed at the two independent sites was 0.857 (n = 248), suggesting that the automated method is highly transferable between laboratories. Additionally, the flow cytometric system offered advantages relative to microscopy-based scoring, including a greater number of cells analyzed, much faster analysis times, and a greater degree of objectivity. Collectively, data presented in this report suggest that the overall performance of mouse peripheral blood micronucleus tests is enhanced by the use of the flow cytometric scoring procedure.     

Influence of the time of day on physical performance in patients with coronary artery disease

The exercise training workload for cardiac patients is determined from the peak heart rate achieved safely during a stress test. Circadian rhythms may play a key role in changing physiological responses to the stress test. Therefore, the purpose of this study was to evaluate the influence of the time of day on cardiopulmonary and metabolic responses in highly trained men with coronary artery disease. A group of 15 patients with coronary artery disease [53.5 (SD 6) years] performed two sessions of graded tests to exhaustion: one session was performed at 10 a.m. and the second at 5 p.m. in randomized order. Treadmill velocity was kept constant at a speed of 4.8 km · h^–1 starting with an elevation of 0% which was increased thereafter by 2.5% every 3 min. At rest the results revealed that only oxygen uptake was significantly lower (P < 0.05) in the morning compared to that observed in the evening [2.9 (SD 0.4) compared to 3.5 (SD 0.5) ml O₂ · kg^–1 · min^–1, respectively]. During exercise, differences due to time of day were found in the variables of maximal oxygen uptake which were significantly higher (P < 0.05) in the evening than in the morning [34.2 (SD 2.6) and 40.8 (SD 2.5) ml O₂ · kg^–1 · min^–1, respectively]. These data indicated that in these well-trained coronary artery disease patients there was a significant time of day effect associated with metabolic responses following stress-testing.     

Exercise- and insulin-stimulated muscle glucose transport: distinct mechanisms of regulation.

In mammals, skeletal muscle is the primary target for the stimulation of glucose transport by a variety of activators. These include the hormone insulin and stimuli which increase energy demand such as exercise, hypoxia, and challenges to the oxidative chain. While it is known that both stimuli rapidly elevate glucose uptake into muscle by signalling the translocation of glucose transporters from intracellular stores to the plasma membrane, there are numerous contrasts between energy stressors and insulin in their mechanisms of glucose transport activation. Exercise and insulin recruit distinct intracellular pools of glucose transporters in skeletal muscle and the maximal effects of contraction and insulin are additive. Activation of phosphatidylinositol 3-kinase (PI3-K) is utilized by insulin to induce glucose transporter translocation, but does not participate in the responses to exercise or hypoxia. These findings suggest that energy stressors utilize different mechanisms from insulin to increase glucose influx; however, how these factors elicit their response is not clear. This review will summarize our current knowledge of these alternative pathways of glucose transport regulation. Emphasis is placed on the use of the mitochondrial uncoupler dinitrophenol to investigate mediators of this alternative signalling pathway in L6 muscle cells, a line used to characterize physiological responses in muscle such as glucose transport.     

Progressive tubulointerstitial nephritis and chronic cholestatic liver disease

We report the clinical and morphological features of a distinctive hepatorenal disorder in four patients and review the five similar patients in the literature. The main clinical characteristics were early onset of cholestatic liver disease and progressive tubulointerstitial nephritis leading to renal death in early childhood. Liver histology showed disturbed architecture with nodular and acinar formations and portal fibrosis and bile duct proliferation. Histological abnormalities in the kidney were severe interstitial fibrosis and tubular atrophy and dilatation, while the typical features of nephronophthisis were lacking. These clinical and morphological characteristics distinguish our patients from the majority described, as having nephronophthisis and congenital hepatic fibrosis or any other known syndrome with concomitant hepatorenel involvement. We suggest that the association of cholestatic liver disease and progressive tubulointerstitial nephritis represents a new syndrome.     

The septal arteries in the differential diagnosis of constrictive pericarditis

Angiographic study of the motion of the septal and left marginal arteries was performed in patients with restriction in ventricular diastolic filling in order to separate patients with constrictive pericarditis from those with restrictive cardiomyopathy. Twelve patients with constrictive pericarditis (group I) and 10 patients with restrictive cardiomyopathy (group II) were evaluated and compared with 21 patients with normal coronary angiograms (group III). The displacement of the septal arteries (23 +/- 2.04 mm) was abnormally exaggerated in group I and normal (9 +/- 0.81 mm) in groups II and III. The displacement of the left marginal arteries as seen by the "corrugating index" was similar in all groups. We conclude that study of the displacement of the septal arteries is a useful angiographic sign that helps to separate constrictive pericarditis from restrictive cardiomyopathy and normals.