Low molecular weight heparin plus dihydroergotamine for prophylaxis of postoperative deep vein thrombosis

In a prospective, double-blind investigation of the prophylaxis of deep vein thrombosis (DVT) in patients undergoing elective major abdominal surgery, 269 patients were randomized into two groups. One hundred and thirty-two patients received a fixed combination of heparin sodium 5000 units plus dihydroergotamine mesylate 0.5 mg (H/DHE) twice a day and 137 patients received a fixed combination of low molecular weight heparin 1500 units plus dihydroergotamine mesylate 0.5 mg (LMWH/DHE) once a day as well as one injection of placebo per day. Treatment was initiated 2 h pre-operatively in both groups and continued for 7-10 days. The frequency of DVT determined by the 125I-labelled fibrinogen uptake test and phlebography was 10.3 per cent in patients receiving H/DHE and 10.4 per cent in those receiving LMWH/DHE. DVT of the femoral vein was detected in four patients of the H/DHE group and in none of the LMWH/DHE group. Intra- and postoperative blood loss did not differ significantly between both groups. Also no difference in the development of wound haematoma and injection site haematoma was found. While intra-operative volume substitution was comparable in both groups, significantly more patients under H/DHE prophylaxis received volume substitution during the postoperative phase. These results show that once-daily prophylaxis with the combination of low molecular weight heparin and dihydroergotamine is equally as effective and as safe as the twice-daily regimen using a combination of unfractionated heparin and dihydroergotamine in patients undergoing elective, major abdominal surgery. The advantages of the once-daily regimen of LMWH/DHE include greater patient acceptance, less nursing time and greater cost effectiveness, provided the new combination can be sold at a cost which maintains this advantage.     

Effects of endothelial-cell-derived growth factors on cultured astrocytes.

To clarify the participation of endothelial-cell-derived growth factors (ECDGFs) in astrocytosis, the effects of endothelial-cell-conditioned medium (ECCM) derived either from normotensive rats or spontaneously hypertensive, stroke-prone rats (SHRSPs) on proliferation of C6 cells of an established rat glioma cell line were bioassayed. The ECCM from both strains stimulated proliferation of astrocytes, but the ECCM from SHRSPs showed a higher mitogenic activity for astrocytes than that from normotensive rats. Growth-promoting activity of the ECCM derived from SHRSPs showed an increase that was linear to the conditioning time. These results seem to indicate that endothelial cells produce and release factors that promote the growth of astrocytes. It seems also probable that chronic hypertension causes an increase in production and release of such ECDGFs that correlated with astrocytic proliferation.     

Evaluation of an aortic stent graft for use in surgery on esophageal cancer involving the thoracic aorta

Objective: The purpose of this experimental study was to investigate whether aortic stent grafting can be applied to the treatment of an esophageal cancer involving the thoracic aorta. Methods: The canine thoracic aorta was partially resected without aorta being clamped after emplacement of an endovascular stent graft. Study I; The aortic whole layer of 1 cm in length and 1/4 of the circumference was resected and was covered by a free fascia patch of the abdominal rectal muscle immediately after stent graft placement. Study II; The aortic adventitia and the outer half of the media of the same size was resected on day 3, 7,14, 21, and on day 28, after the stent graft placement. The resected portion was covered by the free fascia patch in half experimental dogs, and was uncovered in the others. Study III; The aortic adventitia and the outer half of the media of 1 cm in length and 1/2 of the circumference was resected and was uncovered on day 7 after stent graft placement. Histological examinations were performed on day 28 and at one year after aortic resection. Results: The aortic wall could be resected in all cases with no complication, except in resection of 1/2 the circumference where the aorta had become narrow. There was no difference in healing of the resected portion of the aorta between with and without fascia covering. Conclusion: An aortic endovascular stent graft could be applied to surgery for an esophageal cancer involving the aorta.     

Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; Is its efficacy permanent?

BACKGROUND: Angiographic regression of luminal narrowing occurs 6 months to 3 years poststenting. However, after 4 years lesions progressed gradually and late restenosis was observed in 28% of 179 Palmaz-Schatz-stented lesions during the past 10 years. Elucidating its pathogenesis is pivotal to developing preventive strategies. METHODS AND RESULTS: Histopathological and immunohistochemical studies were performed in 19 stented coronary arteries obtained from 19 patients autopsied after noncardiac death 2-7 years poststenting. The quality/severity of chronic inflammatory cells (T lymphocytes, macrophages and multinucleated giant cells) infiltration around the stent struts that is observed even in the absence of restenosis depended on the time elapsed from stenting: a) 2 years postprocedure, in spite of angiographic regression during the first year and pathologically expressed as maturation of the neointimal scar, there was chronic inflammatory response evidence: neovascularization and lymphocyte infiltration, b) > or = 3 years: the neointimal smooth muscle cells were sparse with abundant proliferation of collagen fibers. Presence of slight helper/inducer T lymphocytes and mild macrophage infiltration around the stent struts was evident immunohistochemically, c) > or = 4 years: prominent infiltration by lipid-laden macrophages with strong collagen-degrading matrix metalloproteinase immunoreactivity was observed around the struts. In two of these arteries, the surface contacting the stent was focally disrupted and covered by nonocclusive mural thrombi. CONCLUSIONS: Stainless steel stents evoke a remarkable foreign-body inflammatory reaction to the metal. These persistent peri-strut chronic inflammatory cells may accelerate new indolent atherosclerotic changes and consequent plaque vulnerability.     

Dynamic alteration of human β-defensin 2 localization from cytoplasm to intercellular space in psoriatic skin

Defensins are cationic antimicrobial peptides with a broad spectrum. Recently human beta-defensin 2 (hBD-2) has been isolated from psoriatic skin; however, its exact localization and fate have not been fully understood. We studied the distribution pattern of hBD-2 in skin tissues of psoriasis and other inflammatory skin diseases. In the upper spinous and granular layer of psoriasis vulgaris hBD-2 was present in the cytoplasm. In the horny layer the positive signals were in a basket-weave pattern, indicating possible accumulation of hBD-2 in the intercellular space. The similar pattern of hBD-2 distribution was observed in the lesions of nummular eczema and atopic dermatitis. hBD-2 was not detected in the section of normal elbow and knee skin. When isolated psoriatic scales were stained, hBD-2 was detected in a wrapping paper-like distribution pattern surrounding the corneocytes. In horny layer of psoriatic skin hBD-2 was closely associated or colocalized with elafin, which is known to be in extracellular space, as demonstrated by double staining. Western blot analysis using cultured human keratinocytes detected hBD-2 with an expected size in the conditioned medium and in the cell lysates when stimulated with 5% FCS or IL-alpha. These results indicate that hBD-2 was synthesized and remained in cytoplasm in the upper spinous and granular layer, and then secreted into intercellular space in the horny layer. This dynamic change in hBD-2 distribution in epidermis is certainly relevant to function as an innate host defense mechanism against invading micro-organisms.     

Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up

Summary Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was >97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CL_tot,p=50.6 W^0.957; Bd, ss=1.29 W^1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CL^u _tot,p and Vd,^u _ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CL^u _tot,p=71.7 W^0.891; Bd,^u _ss=1.82 W^0.966) were also high (r0.991). The extrapolated values vs those observed in a 70-kg human were the following: CL^u _tot,p, 3,160 vs 2,290 ml/min; Vd,^u _ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.