MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas

The endothelium is one of the largest cellular compartments of the human body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradiction, data on growth and angiogenesis control mechanisms of angiosarcomas are scarce. In this study of 19 angiosarcomas and 10 benign vascular control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2 proto-oncogene, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factors, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exhibited clear nuclear p53 protein accumulation. Two of these cases revealed mutations in the sequence-specific DNA binding domain of the p53 gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 protein. Elevated expression of p53 and MDM-2 protein correlated with increased VEGF expression, which was found in nearly 80% of the angiosarcoma cases. Negative or clearly lower immunostaining was obtained in cases from the benign control collective. Only one case of a juvenile hemangioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression. Our data suggest that the p53/ MDM-2 pathway is impaired in about two-thirds (14/ 19) of the angiosarcomas. This may be a key event in the pathogenesis of human angiosarcomas. The increased VEGF expression observed supports this hypothesis.     

Magnetic resonance imaging of articular cartilage in the knee. An evaluation with use of fast-spin-echo imaging

The purpose of this study was to demonstrate that specialized magnetic resonance imaging provides an accurate assessment of lesions of the articular cartilage of the knee. Arthroscopy was used as the comparative standard. Eighty-eight patients who had an average age of thirty-eight years were evaluated with magnetic resonance imaging and subsequent arthroscopy because of a suspected meniscal or ligamentous injury. The magnetic resonance imaging was performed with a specialized sequence in the sagittal, coronal, and axial planes. Seven articular surfaces (the patellar facets, the trochlea, the femoral condyles, and the tibial plateaus) were graded prospectively on the magnetic resonance images by two independent readers with use of the 5-point classification system of Outerbridge, which was also used at arthroscopy. Six hundred and sixteen articular surfaces were assessed, and 248 lesions were identified at arthroscopy. Eighty-two surfaces had chondral softening; seventy-five, mild ulceration; fifty-three, deep ulceration, fibrillation, or a flap without exposure of subchondral bone; and thirty-eight, full-thickness wear. To simplify the statistical analysis, grades 0 and 1 were regarded as disease-negative status and grades 2, 3, and 4 were regarded as disease-positive status. When the grades that had been assigned by reader 1 were used for the analysis, magnetic resonance imaging had a sensitivity of 87 per cent (144 of 166), a specificity of 94 per cent (424 of 450), an accuracy of 92 per cent (568 of 616), a positive predictive value of 85 per cent (144 of 170), and a negative predictive value of 95 per cent (424 of 446) for the detection of a chondral lesion. Interobserver variability was minimum, as indicated by a weighted kappa statistic of 0.93 (almost perfect agreement). With use of this readily available modified magnetic resonance imaging sequence, it is possible to assess all articular surfaces of the knee accurately and thereby identify lesions that are amenable to arthroscopic treatment.     

Manifestations of scleroderma pulmonary disease

Scleroderma is a multisystem disease of unknown cause characterized by synthesis and deposition of excessive extracellular matrix and vascular anti-GBM antibodies, leading to pulmonary hemorrhage and glomerulonephritis with rapidly progressive renal insufficiency. Recent advances in the understanding of disease pathogenesis and diagnosis and treatment have significantly improved our ability to recognize the syndrome, distinguish it from other similar disorders, and offer successful treatment. This article focuses on the pathogenetic features, clinical manifestations, diagnostic strategies, and therapeutic principles of anti-GBM disease.     

Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine in acute uncomplicated falciparum malaria in Nigerian children

A 47-year-old woman on long-term hemodialysis due to a chronic isolated abdominal aortic dissection was admitted to our department with severe abdominal pain. She had not suffered any hematemesis or melena. An emergency laparotomy revealed an abdominal aortic aneurysm with a diameter of 60mm, densely adhered to the ileum. An aortoenteric fistula manifesting as intramural rupture into the ileum was found after infrarenal abdominal aortic and bilateral common iliac cross-clamping. The fistula on the ileac side was nontransmural, but that on the aortic side communicated with the pseudolumen of the abdominal aorta, and contained mural thrombus. The infrarenal abdominal aorta and bilateral common iliac arteries were replaced with a collagen-sealed woven Dacron bifurcated graft. Histological examination of the ileum in this portion showed intramural bleeding and xanthomatous granulation with foam cell infiltration in the thickened subserosa. While it is difficult to diagnose nonpenetrating aortoenteric fistula preoperatively, such a fistula must be considered in a patient with severe abdominal pain, for whom previous abdominal aortic surgery has been performed or when an abdominal aneurysm is observed. To our knowledge, no other case of an aortoenteric fistula presenting as an intramural rupture into the ileum in an isolated abdominal aortic dissection has ever been reported.     

Human leukocyte derived interferon-alpha in a hydrophilic gel for the treatment of intravaginal warts in women: a placebo-controlled, double-blind study

Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.     

The role of the nurse manager in ambulatory care: results of a national survey

Increasing complexity in ambulatory care settings requires nurse managers who can function at higher levels. Little agreement currently exists regarding the role expectations and academic preparation needed for nurse managers in ambulatory care settings. The majority of surveyed ambulatory care nurse managers (40%) have an AD or diploma as their highest level of academic preparation, and have thus acquired the majority of their management skills in the practice setting. The authors express concern that there are pressures to employ non-nurses as managers in ambulatory health care settings and that ambulatory nurse managers are often seen as not needing advanced academic preparation. A wide variety of settings including university and community hospitals, outpatient departments, physician group practices and HMOs, currently employ nurse managers in their multidisciplinary ambulatory care sites. The majority of ambulatory care nurse managers describe their model of care as either the medical model or the functional model.     

Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection

This study elucidates a basically new mechanism of function of a virus-modified tumor cell vaccine which has been successful in mouse tumor models (metastatic ESb lymphoma and B16-F10 melanoma) in preventing or delaying metastatic spread and improving survival and which is being tested in clinical studies. Modification of tumor cells by a low dose of Newcastle disease virus (NDV), which caused this therapy effect, led to an augmentation of the tumor-specific cytotoxic CD8 T-cell (CTL) response and to increased CD4 T-helper activity in the absence of an antiviral T-cell response. When various noninfectious NDV preparations, which, according to newly established quantitative tests, had lost one or several of the viral functions, were tested, noninfectious virus particles with inactive fusion proteins and virus inactivated by UV light, which could fuse but could not replicate, were as active as infectious NDV in the tumor-specific CTL response. In contrast, NDV inactivated by heat treatment (NDV-HI) had no effect on the CTL response. NDV-HI, even when added to the cultures in excess, did not modulate the antitumor CTL response, which argues against a nonspecific adjuvant effect. There was no mitogenic effect of NDV. Because NDV-HI was not able to bind to the tumor cell surface and because hemagglutinin-neuraminidase c-DNA transfectants increased antigen-presenting function as virus-modified cells do, we propose that the NDV effect in the CTL response is caused by the introduction of functional viral hemagglutinin-neuraminidase molecules (1000 per virus particle) into the tumor cell surface, thereby facilitating cell-cell interactions through their cell-binding and neuraminidase activity.     

Treatment of pre-invasive conditions during opportunistic screening and its effectiveness on cervical cancer incidence in one Norwegian county

OBJECTIVE: To identify a correlation between dialysis treatment duration and severity of acquired cystic disease of the end-stage kidney measured by cyst sizes; and assess its effect on spontaneous improvement of anemia. MATERIALS AND METHODS: Ten patients, 6 males and 4 females were selected, who have been on hemodialytic treatment for more than 5 years. There was no patient selected with autosomal dominant polycystic kidney disease. The renal evaluation has been made through ultrasonographic studies. Acquired cystic disease of the end-stage kidney was characterized by finding four or more cysts in both kidneys. The largest cysts were measured for correlation effect. The diagnosis of anemia was established by hematocrit and hemoglobin serum values. It has also been analyzed serum urea, creatinine, albumin, iron, total iron-binding capacity and the per cent saturation of serum transferrin were tested. RESULTS: The patients were properly dialysed (serum urea and creatinine = 98.7 +/- 35 mg/dL e 9.7 +/- 2.7 mg/dL, respectively). There were in good nutritional shape (serum albumin = 4.5 +/- 0.5 g/dL) and had normal serum iron level (serum iron = 80 +/- 34 mg/dL). The prevalence of acquired renal cystic disease was 80%. No finding of malignancy has been detected in these cysts. There was a significant correlation between time on dialysis treatment and hematocrit values (R = 0.70; p < 0.05). Cyst sizes had a direct and significant correlation with hematocrit levels (R = 0.74; p < 0.05). CONCLUSION: These results show that spontaneous improvement on anemia seen in patients on chronic dialysis has a significant correlation with the severity of acquired cystic disease of the end-stage kidney. Our data suggest a functional role of acquired kidney cysts on endogenous erythropoietin production.