Haemorrhagic complications during pulmonary resection. A retrospective review of 1428 resections with 113 haemorrhagic episodes

A series of 1428 standard pulmonary resections (pneumonectomy 30%, lobectomy 66%, segmentectomy 4%) performed over a 13-year period was reviewed with regard to haemorrhagic complications. The incidence of intra-operative vascular injuries was 5%. The pulmonary artery was damaged in 50 of these 73 injuries, the pulmonary vein in 21, and the superior vena cava and the subclavian vein in one case each. Two deaths were associated with the intra-operative bleeding. The vascular lesions could be repaired without extensive resection of pulmonary tissue in all but 3 of the other patients, in whom two, three and five pulmonary segments, respectively, had to be sacrificed. Postoperative bleeding necessitated emergency thoracotomy in 37 patients (2.6% of the series), and in 3 patients autopsy disclosed such haemorrhage. The cause of the bleeding in 12 cases was slipping or cutting through of ligatures applied to divided major vessels (pulmonary artery in 8 cases, pulmonary vein in 3 and azygos vein in 1 case). Systemic arterial haemorrhage occurred in 15 patients and diffuse bleeding in 12, while one patient had a coagulation disorder causing bleeding. Nine of the 40 patients died, 7 of the haemorrhage and 2 of bronchopleural fistula. The death rate was significantly higher in postoperative than in intra-operative bleeding. The study demonstrated that the widely used and recommended transfixion suture is not absolutely safe to prevent slipping of ligatures from divided major intrathoracic vessels. A purse-string suture has proved to be a safer alternative.     

p27(Kip1) Knockout mice are protected from diabetic nephropathy: evidence for p27(Kip1) haplotype insufficiency

BACKGROUND: High glucose up-regulates the mesangial cell expression of p27(Kip1), an inhibitor of cyclin-dependent kinases/cyclin complexes. Previous in vitro studies using cultured mesangial cells from p27(Kip1-/-) mice demonstrated that these cells do not undergo high glucose-mediated cellular hypertrophy. Since glomerular hypertrophy is an early feature of diabetic nephropathy and may precede the development of glomerulosclerosis, interference with p27(Kip1) expression may attenuate diabetic nephropathy. However, it is unclear whether deletion of p27(Kip1) protects the kidneys of diabetic nephropathy in vivo. METHODS: Type 1 diabetes mellitus was induced in p27(Kip1+/+), p27(Kip1+/-), and p27(Kip1-/-) mice by injection of streptozotocin (STZ). Mice were studied for 6 weeks. Animals injected with citrate buffer only served as controls. At the end of the experiments, urine was collected, albuminuria was determined with an enzyme-linked immunosorbent assay (ELISA), and blood glucose concentrations were measured. Kidneys were perfusion-fixed for quantitative morphologic analysis with glutaraldehyde and for immunohistochemical studies with formaldehyde. Glomerular cell number and volume were analyzed. Glomerulosclerosis, tubulointerstitial, and vascular damage indices were semiquantitatively assessed according to standard methodology. Quantitative glomerular parameters (cell numbers and volumes of endothelial, mesangial, and epithelial cells) were measured on semithin sections. Expression of transforming growth factor-beta1 (TGF-beta1), laminin, and collagen type IV were determined by immunohistochemical staining. RESULTS: In contrast to animals only injected with citrate buffer, mice that received STZ developed hyperglycemia. There was no significant difference in the degree of hyperglycemia among p27(Kip1+/+), p27(Kip1+/-), and p27(Kip1-/-) mice. Diabetic p27(Kip1+/+), but not control p27(Kip1+/+) animals, developed albuminuria. Albuminuria was significantly reduced in diabetic p27(Kip1+/-) and more profoundly in p27(Kip1-/-) animals. Diabetic p27(Kip1+/+) mice revealed a significant increase in mean glomerular volume at 6 weeks. The volumes of mesangial and endothelial cells and podocytes all increased, whereas cell numbers were reduced, consistent with cell hypertrophy. Glomerular, endothelial, mesangial and podocyte hypertrophy were reduced in diabetic p27(Kip1+/-) and p27(Kip1-/-) animals. Diabetic p27(Kip1) (+/+) animals had significantly increased glomerulosclerosis, tubulointerstium, and vascular damage indices compared to nondiabetic p27(Kip1+/+) controls. Diabetic p27(Kip1-/-) mice exhibited significantly less structural damage than diabetic wild-type animals. Diabetic p27(Kip1+/-) animals revealed intermediate glomerulosclerosis, tubulointerstium, and vascular damage values. Immunohistological stainings demonstrated increases in TGF-beta1, collagen type IV, and laminin expression in kidneys of diabetic p27(Kip1+/+) animals compared to nondiabetic p27(Kip1+/+) controls. Staining intensity for type IV collagen and laminin, but not for TGF-beta1, was significantly lower in diabetic p27(Kip1-/-) mice. CONCLUSION: Deletion of p27(Kip1) attenuates the functional and morphologic features of diabetic nephropathy. Although deletion of p27(Kip1) abolished some parameters of diabetic glomerular hypertrophy, the significant reduction of TGF-beta1 expression in the tubulointerstitium indicates that other protective mechanisms could be operative. The p27(Kip1) gene is haplo-insufficient because diabetic p27(Kip1)+/- mice exhibited an intermediate degree of functional and structural renal injury. Our data shows that p27(Kip1) plays an important role in diabetic nephropathy.     

Tocotrienols: constitutional effects in aging and disease

Tocotrienols, a class of vitamin E analogs, modulate several mechanisms associated with the aging process and aging-related diseases. Most studies compare the activities of tocotrienols with those of tocopherols ("classical vitamin E"). However, some biological effects were found to be unique for tocotrienols. Although the absorption mechanisms are essentially the same for all vitamin E analogs, tocotrienols are degraded to a greater extent than tocopherols. The levels of tocotrienols in the plasma of animals and humans were estimated to reach low micromolar concentrations. One hallmark in the origin of disease and aging is the overproduction of reactive oxygen species (ROS). Tocotrienols possess excellent antioxidant activity in vitro and have been suggested to suppress ROS production more efficiently than tocopherols. In addition, tocotrienols show promising nonantioxidant activities in various in vitro and in vivo models. Most notable are the interactions of tocotrienols with the mevalonate pathway leading to the lowering of cholesterol levels, the prevention of cell adhesion to endothelial cells, and the suppression of tumor cell growth. Furthermore, glutamate-induced neurotoxicity is suppressed in the presence of tocotrienols. This review summarizes the main antioxidant and nonantioxidant effects of tocotrienols and assesses their potential as health-maintaining compounds.     

Preoperative (neoadjuvant) systemic treatment of breast cancer

Preoperative systemic treatment (PST) is a valid option not only for advanced breast cancer stages but also for operable breast cancer. We know that disease-free and overall survival after PST are equivalent to those after adjuvant therapy. Furthermore, PST is able to improve surgical treatment by increasing the rate of breast conservation surgery, which minimises psychological distress for patients fearing mastectomy. Response to PST is a predictor of long-term outcome and gives prognostic information after a short-term interval in contrast to adjuvant trials, which do not show their results until after a 5- to 10-year follow-up. More often, endocrine non-responsive tumours demonstrate a pathological complete response (pCR). Thus, PST can change the formerly bad prognostic marker into one that indicates a favourable prognosis if pCR is achieved by PST. If PST is performed outside clinical trials, anthracycline/taxane-based regimens should be used, especially in sequential prolonged schedules. The use of aromatase inhibitors in preoperative endocrine therapy in elderly postmenopausal patients with endocrine-responsive breast cancer yields a larger proportion of local response than tamoxifen. The duration of PST is not well established, but at least four cycles of chemotherapy should be administered and endocrine therapy needs a minimal time to show greatest benefit when given for at least 3-4 months . The concurrent use of chemotherapy and endocrine drugs did not show any benefit, even in endocrine-responsive tumours and should therefore be avoided. Sentinel node biopsy is a reasonable approach, but this technique should be reserved for experienced surgeons. PCR is the most important surrogate marker of PST, demonstrating an improved disease-free and overall survival. But even if pCR of the primary tumour is achieved, the detection of lymph node metastases is the most important prognostic factor, indicating a substantial risk of cancer recurrence. PST will lead to individualised (tailored) treatment in patients with primary breast cancer.     

From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy

Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.     

Implications of terminal deoxynucleotidyl transferase activity in various forms of childhood leukemia (author's transl)

Terminal deoxynucleotidyl transferase (TdT) was examined in mononuclear peripheral blood cells (pB) and bone marrow (BM) specimens of 63 children with acute leukemia (AL). The enzyme activity in normal specimens (pB, BM) was below 0.2 U/10(8) cells; whereas, 49 of the 52 children with acute lymphoblastic leukemia (ALL) at diagnosis showed an activity in the range 1.2--60 U/10(8) cells. 2 of the remaining 3, devoid of TdT activity, were found to be B-cell leukemia. Patients with acute non-lymphoblastic leukemia (ANLL) were generally TdT-negative. Elevated level of TdT activity was detected in only one of 11 children with ANLL. In one patient with acute leukemia two distinct populations of cells with lymphoblastic (87%) and myeloblastic characteristics were evident. The clinical course and cell marker studies were consistent with the interpretation of a defect at the level of the common stem cell giving rise to a TdT-positive lymphoblastic cell population at diagnosis and, following the initial ALL-therapy (4 weeks), a predominant TdT-negative myeloblastic population. TdT as a marker for the modulation of chemotherapy was examined in the remission phase of the disease. Of the nine patients in the first 3 months of remission, one was found to have elevated level of TdT activity (2.5 U/10(8) cells). These data define the usefulness of TdT in the classification of acute leukemia.