Immunoglobulin G responses against human papillomavirus type 16 virus-like particles in a prospective nonintervention cohort study of women with cervical intraepithelial neoplasia

BACKGROUND: Infection with cancer-linked human papillomavirus (HPV) types such as HPV type 16 (HPV16) is the most important risk factor in the development of cervical cancer. It has been shown that immunoglobulin G (IgG) antibody responses against HPV16 virus-like particles (VLPs) are specifically associated with genital HPV16 infection. PURPOSE: The aim of this study was to determine the temporal relationships between the presence of HPV16 VLP-specific IgGs, HPV16 infection patterns, and the course of premalignant cervical disease. METHODS: Plasma samples from 133 women who had been diagnosed originally with mild to moderate cervical dyskaryosis and enrolled in a prospective non-intervention cohort study conducted in Amsterdam, The Netherlands, from 1991 through 1996 were analyzed for the presence of HPV16 VLP-specific IgGs by use of an enzyme-linked immunosorbent assay. A detailed analysis was performed on 43 women with different HPV16 infection patterns during a follow-up period of 10-34 months. Progression or regression of cervical intraepithelial neoplasia (CIN) lesions was monitored by cytologic and colposcopic testing at intervals of 3-4 months. HPV typing in cervical smears was performed by use of a polymerase chain reaction-based assay. Statistical analysis of the serologic data was performed by use of the Mann-Whitney U test or 2 x 2 table analyses. RESULTS: The presence of HPV16 VLP-specific IgGs in the plasma of the patients was found to be associated with the presence of HPV16 DNA in the cervical smear. Significantly higher proportions of patients with persistent HPV16 infections (i.e., who were polymerase chain reaction positive in three to 11 consecutive tests) than of patients with cleared HPV16 infections were found to be positive for the presence of HPV16 VLP-specific IgGs (18 [69.2%] of 26 versus nine [28.1%] of 32, respectively; P = .003). HPV16 VLP-specific IgGs were consistently detected in all women (n = 11) who were persistently HPV16 DNA positive during follow-up and whose disease ultimately progressed to CIN III (histologically diagnosed severe dysplasia or carcinoma in situ). CONCLUSION: HPV16 VLP-specific IgG responses are present in the plasma of a majority of patients with persistent HPV16 infections and histologically confirmed high-grade lesions but only in a smaller subset of patients with cleared HPV16 infections and either normal cervical histology or low-grade CIN lesions. IMPLICATIONS: These results suggest that HPV16 VLP-specific antibodies are not responsible for the clearance of virally induced CIN lesions but that they might, in patients with persistent HPV16 infections, be indicative of an increased cervical cancer risk.     

Meniscal regeneration in the long-term after total meniscectomy?

A cohort of 39 patients (28 male, 11 female) that had undergone total meniscectomy as adolescents (mean age 16 years) underwent FISP 3D Magnetic Resonance Imaging at a mean follow up of 30 years. The presence of meniscal tissue was assessed by two independent observers blinded to the operation details. The volume of any meniscal tissue present was calculated. A posterior horn remnant was seen in 57% of medial and 45% of lateral meniscectomy cases. The mean volume of an operated medial meniscal remnant was 0.29 mL compared with a mean volume of 1.15 mL for an intact medial meniscus. The mean volume of an operated lateral meniscal remnant was 0.30 mL compared with 1.07 mL for an intact lateral meniscus. We have shown that the incidence of incomplete excision of the posterior horn is more common after total medial meniscectomy, and that at a mean follow up of 30 years there is no convincing in vivo MRI evidence of long-term meniscal regeneration.     

Curli, fibrous surface proteins of Escherichia coli, interact with major histocompatibility complex class I molecules

Curli are thin, coiled fibers expressed on the surface of Escherichia coli that bind several matrix and plasma proteins such as fibronectin, laminin, plasminogen, tissue plasminogen activator, and H-kininogen. In this work, we examined the interactions between curli-expressing E. coli and human major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Curliated E. coli was found to interact with an MHC-I-expressing lymphoma cell line as shown by scanning electron microscopy, whereas the binding to a mutant variant of this cell line expressing small amounts of MHC-I molecules was significantly lower. Moreover, curli-expressing E. coli bound purified radiolabeled MHC-I but not MHC-II molecules, whereas an isogenic curli-deficient mutant strain showed no affinity for either MHC-I or MHC-II. Purified insoluble curli could also bind 125I-labeled MHC-I molecules, and in Western blot experiments the 15-kDa curlin subunit protein bound intact MHC-I molecules as well as beta2-microglobulin, the light chain of MHC-I molecules. A direct interaction between monomeric MHC-I molecules and a bacterial surface protein has previously not been reported. The binding of curli to MHC-I molecules, which are present on virtually all cells in higher vertebrates, will provide curliated E. coli with ample opportunities to interact with a great variety of hosts and host cells. This should facilitate the adaptation of E. coli to different ecological niches, and in human infections the interaction between curli and MHC-I molecules could contribute to adherence and colonization.     

Nephrotic syndrome. What is new since the 1988 study?

Hormone-refractory prostate cancer (HRPC) patients often have nonmeasurable disease. In such patients, predictive biomarkers other than tumor response may be required to compare therapeutic effects. We examined the predictive value for survival of various clinical and laboratory parameters, including prostate-specific antigen (PSA), in HRPC patients treated with suramin. Data from 103 HRPC patients were analyzed using various survival analyses, the likelihood ratio approach, and logistic regression analyses. When pretreatment factors, percentage decrease in PSA at 4 weeks from start of treatment (deltaPSA), and updated survival data were fit by a multivariate Cox proportional hazards model, acid phosphatase, lactate dehydrogenase, and deltaPSA were significant, with risk ratios close to 1. There was a decrease in likelihood ratio with increasing APSA. A logistic regression model was developed to predict the probability of <1 year of survival from the start of treatment. Hemoglobin and deltaPSA were found to be significant variables. However, in view of the complexities involving the relationship between PSA expression and prostate cancer growth and possible selective effect of treatment on PSA, further prospective testing is necessary. Therefore, deltaPSA cannot necessarily be used as a biomarker for survival response in individual patients during the evaluation of the therapeutic response of HRPC to new antineoplastic drugs.     

Fluorescence quenching and time-resolved fluorescence studies on Momordica charantia (bitter gourd) seed lectin

Chemical modification studies implicated tryptophan (Trp) residues in the sugar binding activity of Momordica charantia lectin (MCL) [Mazumdar, T., Gaur, N. & Surolia, A. (1981) Eur. J. Biochem. 113, 463-470]. In the present study, the accessibility and environment of Trp residues in MCL were investigated by intrinsic fluorescence quenching and time-resolved fluorescence. The emission lamda max of native MCL in the absence as well as in the presence of 0.1 M lactose was around 335 nm, which shifted to 365 nm in the presence of 8 M urea, suggesting that the Trp residues which are predominantly buried in the hydrophobic core of the native lectin get exposed to the aqueous environment upon denaturation. At a quencher concentration of 0.5 M, the extent of quenching observed for the native MCL with acrylamide, I- and Cs+ was 46%, 17% and 12%, respectively. In the presence of 0.1 M lactose this quenching was smaller, suggesting that the sugar ligand provides a partial protection to the Trp residues. In time-resolved fluorescence measurements, the decay curves could be fitted well to a biexponential function with the estimated life times 0.92 ns and 4.64 ns for the native protein and 1.15 ns and 5.1 ns in the presence of 0.1 M lactose. All these results are consistent with the involvement of Trp residues in the sugar-binding activity of MCL.     

Monocyte procoagulant activity induced by adherence to an artificial surface is reduced by end-point immobilized heparin-coating of the surface

Heparin-coating improves the biocompatibility of blood contacting artificial surfaces. This led us to investigate the impact of heparin-coating (Carmeda AB, Stockholm) of polymetylmetacrylate on the expression of monocyte tissue factor procoagulant activity (TF-PCA) by surface adhesion. Also, the anticoagulant effect of heparin-coating in the presence or absence of adherent procoagulant monocytes was assessed. This is of particular interest, since activation of extrinsic coagulation by adherent monocyte TF-PCA may play a significant role in thrombin generation during extracorporeal circulation. Monocytes exposed to heparin-coated or non-coated polymetylmetacrylate expressed TF-PCA. The heparin coat did not affect the rate of monocyte adhesion. However, heparin-coating reduced the induction of TF-PCA of non-adherent and adherent monocytes by 17 and 33% (p <0.001 and p <0.0003), respectively. Heparin-coating in the absence of monocytes, totally inhibited the clotting of recalcified plasma (p <0.003). In contrast, in the presence of adherent monocytes expressing TF-PCA, surface-bound heparin did not inhibit clotting. However, inclusion of heparin in a plasma concentration of 8.9 IU/ml totally inhibited the activation of coagulation. It is apparent that heparin-coating of an artificial surface is an efficient means to inhibit coagulation of recalcified plasma, but much less so when procoagulant monocytes are adherent to the coated surface. The present findings are of clinical relevance, since monocytes will adhere to blood contacting surfaces of extracorporeal circuits or to implanted vascular prostheses and subsequently express TF-PCA, and this may promote thromboembolism.     

Lack of familial clustering of hepatitis C virus infection

BACKGROUND: Although transmission of hepatitis C virus (HCV) through parental exposure is well documented, it is still controversial whether familial clustering of HCV occurs. METHODS: To investigate risk factors for HCV infection, 109 cases and 84 non-infected controls were studied. In addition, 250 family members (104 men, 146 women) of cases and 170 family members of controls (64 men, 106 women) were tested for HCV infection using an anti-HCV antibody, alanine aminotransferase (ALT), and reverse transcribed polymerase chain reaction (RT-PCR). RESULTS: In the case-control analysis, people aged > or =60 were almost three times more likely to be infected by HCV than those aged <40. Risk of HCV infection was most strongly related to a history of blood transfusion (OR = 12.6, 95% CI: 4.3-36.5) followed by a history of jaundice (OR = 4.1, 95% CI: 1.3-12.6). Only one family member of cases and no-one related to the controls had HCV infection. CONCLUSIONS: These results suggest that, in Korea, age and parenteral exposure, such as a blood transfusion, are risk factors for HCV infection and familial clustering of HCV infection, if it occurs, is rare.     

Gamma 3 gene-disrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides undergo normal isotype switching after immunization with polysaccharide-protein conjugate vaccines

Bacterial polysaccharides (PS) are T-independent type 2 Ags that elicit restricted Ab responses of IgM and IgG3 in mice and IgM and predominantly IgG2 in humans. Immunodeficiency in the dominant IgG subclass made to PS is associated with chronic sinus and pulmonary infections with PS-encapsulated bacteria. To elucidate the biologic role of the dominant IgG subclass in the immune response to PS and to make an animal model of human IgG subclass deficiency, we generated mice with a targeted disruption of the exon encoding the CH1 domain of the gamma 3 heavy-chain constant region gene. Homozygotes had no detectable serum IgG3, and their splenocytes did not produce IgG3 after LPS stimulation. IgG3(-/-) mice immunized with PS from Pseudomonas aeruginosa LPS O-side chain or Streptococcus pneumoniae type 19F capsule did not produce any IgG3 anti-PS Abs, in contrast to wild-type mice in which IgG3 was the major IgG subclass. Immunizing both wild-type and IgG3(-/-) mice with 19F PS-protein conjugate elicited IgG1 Abs. We conclude that IgG3(-/-) mice have a selective deficiency in the dominant murine IgG subclass made to T-independent type 2 Ags and may be a useful animal model of IgG subclass deficiency. In addition, we show that the anti-PS Ab class switching to IgG1 that occurs when mice are immunized with a PS-protein conjugate vaccine does not require sequential Ig expression or an intact, upstream gamma 3 heavy-chain gene.