Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy

The presenting symptoms, hormonal regimens, treatment modalities, tumor pathology, and follow-up of 25 women developing endometrial cancer while receiving postmenopausal estrogen and progestin therapy were investigated retrospectively. Patients were interviewed and hormone therapies were confirmed through medical records. Pathology specimens were reviewed. Patients received conjugated estrogens (n = 20) or another estrogen (n = 5). For those on conjugated estrogens, the mean daily dose was 0.68 mg, monthly duration was 24.9 days, and monthly dose was 17.0 mg. Women also received medroxyprogesterone acetate (n = 23) or norethindrone acetate (n = 2). The most common regimen was sequential medroxyprogesterone acetate, at a mean daily dose of 7.5 mg, monthly duration of 9.3 days, and monthly dose of 68 mg (mean duration = 5.7 years). Most tumors were low stage and grade, with few demonstrating grade 3 disease (n = 2) or greater than 50% myometrial invasion (n = 2). Twenty-three (92%) had disease limited to the uterus, while two had stage IIIA disease. All are alive and disease-free after a median follow-up of 26 months. Estrogen and progestin therapy does not prevent endometrial cancer in all patients. Women who developed this tumor on sequential therapy in general received less than the recommended guidelines for daily dosage and monthly duration of progestin. Most patients had early-stage and low-grade disease. Continued vigilance in the care of women on hormone replacement therapy is necessary even when combination therapy is prescribed.     

Bcl-xL functions downstream of caspase-8 to inhibit Fas- and tumor necrosis factor receptor 1-induced apoptosis of MCF7 breast carcinoma cells

Stimulation of the Fas or tumor necrosis factor receptor 1 (TNFR1) cell surface receptors leads to the activation of the death effector protease, caspase-8, and subsequent apoptosis. In some cells, Bcl-xL overexpression can inhibit anti-Fas- and tumor necrosis factor (TNF)-alpha-induced apoptosis. To address the effect of Bcl-xL on caspase-8 processing, Fas- and TNFR1-mediated apoptosis were studied in the MCF7 breast carcinoma cell line stably transfected with human Fas cDNA (MCF7/F) or double transfected with Fas and human Bcl-xL cDNAs (MCF7/FB). Bcl-xL strongly inhibited apoptosis induced by either anti-Fas or TNF-alpha. In addition, Bcl-xL prevented the change in cytochrome c immunolocalization induced by anti-Fas or TNF-alpha treatment. Using antibodies that recognize the p20 and p10 subunits of active caspase-8, proteolytic processing of caspase-8 was detected in MCF7/F cells following anti-Fas or TNF-alpha, but not during UV-induced apoptosis. In MCF7/FB cells, caspase-8 was processed normally while processing of the downstream caspase-7 was markedly attenuated. Moreover, apoptosis induced by direct microinjection of recombinant, active caspase-8 was completely inhibited by Bcl-xL. These data demonstrate that Bcl-xL can exert an anti-apoptotic function in cells in which caspase-8 is activated. Thus, at least in some cells, caspase-8 signaling in response to Fas or TNFR1 stimulation is regulated by a Bcl-xL-inhibitable step.     

Immunoglobulins to group A streptococcal surface molecules decrease adherence to and invasion of human pharyngeal cells

The M protein is one of the most important virulence factors of group A streptococci (Streptococcus pyogenes) and may play an important role in the first steps of streptococcal infection. Since acute pharyngitis is a frequently occurring infectious disease caused by these bacteria, we wished to know whether antibodies to the M protein or other surface components inhibit adherence and internalization of streptococci to pharyngeal cells. We investigated the role of whole human secretory immunoglobulin A (sIgA), M6 protein-specific sIgA, and M6 protein-specific serum IgG in the inhibition of streptococcal adherence and internalization to cultured human pharyngeal cells. S. pyogenes D471, which produces a type 6 M protein (M+), and its isogenic M-negative (M-) derivative JRS75 were tested. Purified whole sIgA, M protein-specific sIgA, and sIgA preabsorbed with M protein were able to decrease significantly the adherence of streptococci to pharyngeal cells. Purified IgG against the M6 protein did not diminish the attachment of streptococci to the pharyngeal cells but did reduce internalization. Thus, our data suggest that secretory IgA may play a key role in preventing streptococcal infection at mucosal surfaces by blocking adherence while affinity-purified anti-M protein-specific IgG blocks epitopes responsible for invasion.     

Cell mediated immune response in chronic liver diseases: schistosomal, viral and neoplastic

Cell mediated immune response (CMIR) was studies in 120 patients having chronic liver diseases. Patients were divided into 6 groups, (20 each). (1) Early hepatosplenic Schistosomiasis. (EHSS), (2) Late hepatosplenic Schistosomiasis. (LHSS), (3) Hepatosplenic Schistosomiasis with hepatitis B and/or C infections, (4) Hepatitis B virus cases. (HBV), (5) Hepatitis C virus cases (HCV), (6) Hepatocellular carcinoma cases. (HCC). Twenty within normal subjects taken as controls. Laboratory investigations revealed significant esinophilia in patients of group (1), haemoglobin level was significantly reduced in patients of group (1, 2, 3, & 6), serum albumin was significantly reduced in group (2). The percentage of positivity of skin testing using purified protein derivative, ranged between 10% of patients with LHSS, HBV, HCC and HSS with HBV and/or HCV, 20% of patients with HCV and 25% of patients with EHSS. Percentage of positivity in control group was 100%. The mean diameter of delayed intradermal reaction (2.2 +/- 0.5-6.1 +/- 2.1 mms.) was significantly lower in patients than controls. The response of lymphocyte transformation test to phytohaemmagglutinin was significantly lower in patients when compared to controls. The association of HBV and/or HCV with hepatosplenomegaly was accompanied with a marked depression in cell mediated immune response. Anaemia, hypoalbuminemia and nutritional status of the patients with chronic liver diseases play a major role in the suppression of cell mediated immune response.     

A virulent nonencapsulated Haemophilus influenzae

Nontypeable Haemophilus influenzae strain INT1 was isolated from the blood of a young child with clinical signs of meningitis following acute otitis media. No immunologic or anatomic predisposition of this child for invasive bacterial infection with an unusual organism was documented. Sensitive ELISA proved the absence of intra- or extracellular capsular polysaccharide production by INT1 and Southern blot analysis confirmed the lack of an intact capsulation (cap) gene locus within the chromosome. Nevertheless, INT1 established bacteremia and meningitis in infant and weanling rat models of invasive H. influenzae infection. High-molecular-weight DNA isolated from INT1 was shown to confer an invasive phenotype on transformation of a nonencapsulated, avirulent laboratory strain of H. influenzae. Together these findings imply the presence of one or more as-yet-undiscovered, noncapsular virulence factors of H. influenzae that are capable of mediating invasive disease and resistance to immunologic clearance.     

A new method for in vivo evaluation of biofilms on surface-modified silicone rubber voice prostheses

A new method is presented that permits a rapid and accurate in vivo evaluation of biofilm formation on surface-modified silicone rubber voice prostheses. The method is based on partial modification of a Groningen button voice prosthesis by exposing half of the prosthesis to an argon plasma. This results in one side of the prosthesis becoming hydrophilic while leaving the unmodified side hydrophobic as a control. Modified prostheses were placed in patients for an evaluation period of approximately 4 weeks. Despite making the silicone rubber surface hydrophilic, biofilm formation was stimulated when compared to unmodified, hydrophobic silicone rubber. Findings show that biofilm formation on voice prostheses is influenced by hydrophobicity of a silicone rubber surface. The method of partial surface modification used was seen to be suitable for demonstrating such influences regardless of nutrition and other variations in the patient's lifestyle. Microbiological analysis of the biofilms on both sides of the prosthesis valve did not show any changes in microbial composition, with Candida albicans, streptococci and staphylococci being the most commonly isolated strains.