Type-specific Serum Research Articles

Prediction of tissue-of-origin of early stage cancers using serum miRNomes.

Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. A serum miRNA profile (miRNomes)-based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type-specific serum miRNomes. This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.

Safety and Immunogenicity of a Shigella Bivalent Conjugate Vaccine (ZF0901) in 3-Month- to 5-Year-Old Children in China.

No licensed Shigella vaccine is presently available globally. A double-blinded, randomized, placebo-controlled, age descending phase II clinical trial of a bivalent conjugate vaccine was studied in China. The vaccine ZF0901 consisted of O-specific polysaccharides purified and detoxified from lipopolysaccharide (LPS) of S. flexneri 2a and S. sonnei and covalently bonded to tetanus toxoid. A total of 224, 310, and 434 children, consented by parents or guardians, aged 3 to 6 and 6 to 12 months and 1 to 5 years old, respectively, were injected with half or full doses, with or without adjuvant or control Hib vaccine. There were no serious adverse reactions in all recipients of ZF0901 vaccine independent of age, dosage, number of injections, or the adjuvant status. Thirty days after the last injection, ZF0901 induced robust immune responses with significantly higher levels of type-specific serum antibodies (geometric mean concentrations (GMCs) of IgG anti-LPS) against both serotypes in all age groups compared with the pre-immune or the Hib control (p < 0.0001). Here, we demonstrated that ZF0901 bivalent Shigella conjugate vaccine is safe and immunogenic in infants and young children and is likely suitable for routine immunization.

Lack of Opsonic Antibody Responses to Invasive Infections With Streptococcus dysgalactiae.

IntroductionStreptococcus dysgalactiae can cause severe recurrent infections. This study aimed to investigate antibody responses following S. dysgalactiae bacteraemia and possible development of protective immunity.Materials and MethodsPatients with S. dysgalactiae bacteraemia in the county of Skåne between 2017 and 2018 were prospectively included. Acute and convalescent sera were obtained. All isolates were emm typed and enzyme-linked immunosorbent assay (ELISA) was utilised to analyse specific antibody responses to bacteria and antigens. Bactericidal- and phagocytosis assays were applied to further establish antibody function.ResultsSixteen patients with S. dysgalactiae bacteraemia were included of whom one had recurrent episodes of bacteraemia. Using ELISA with S. dysgalactiae isolates and mutants, development of IgG antibodies was demonstrated in few patients. Type-specific antibodies were demonstrated in one patient when recombinant M proteins as antigens, were applied. The type-specific serum mediated a small increase in phagocytosis but did not facilitate increased killing of the S. dysgalactiae isolate, carrying that M protein, in blood or by phagocytic cells.ConclusionS. dysgalactiae bacteraemia sometimes results in increased levels of antibodies to the infecting pathogen. We did not find evidence that these antibodies are effectively opsonising. Apparent failure to produce opsonising antibodies might partially explain why S. dysgalactiae can cause recurrent invasive infections in the same host.

Effect of naturally acquired type-specific serum antibodies against human papillomavirus type 16 infection

BackgroundWhile vaccine-induced antibodies are known to confer protection against incident human papillomavirus (HPV) infection, there is inconsistent data regarding the protective effect of naturally acquired anti-HPV antibodies. ObjectivesTo estimate the protective effect of naturally acquired anti-HPV16 serum antibodies against incident anogenital infection with HPV16 in females aged 20–64 years and to assess whether antibodies influence the persistence/clearance of anogenital HPV16 infection. Study design4432 women attending the organized national cervical cancer screening program in Slovenia were initially enrolled. 2199 and 1848 women had valid HPV DNA results obtained using PCR-based assays and HPV antibody serotyping results obtained using pseudovirion-based serological assay, at baseline and at three-year follow-up, respectively. ResultsBaseline HPV16 seroprevalence was 2.4-fold higher among HPV16 DNA-positive women (55.7% vs. 23.2%; p<0.01). Baseline HPV16 DNA-positive/seronegative women frequently acquired anti-HPV16 antibodies during follow-up (OR=8.2; 95% CI: 3.8–17.8). Baseline anti-HPV16 antibodies persisted at follow-up, irrespective of baseline HPV16 DNA status (OR=40.6; 95% CI: 30.3–54.5). Baseline HPV16 DNA-negative/seropositive women were less likely to acquire HPV16 infection at follow-up (unadjusted OR=0.2; 0.1–0.9). However, the age-adjusted association was non-significant (adjusted OR=0.3; 0.1–1.2). The tendency for protective effect was stronger among women older than 25 years (OR=0.2; 0.03–1.8). Baseline anti-HPV16 antibodies were not associated with persistence/clearance of HPV16 infection at follow-up (OR=0.8; 0.3–1.9). ConclusionsNaturally acquired anti-HPV16 serum antibodies appeared to protect against anogenital HPV16 infection, but this association was at least partially confounded by age. Baseline anti-HPV16 serum antibodies did not influence persistence/clearance of HPV16 infection at follow-up.

Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose of vaccine

ObjectiveAlthough HIV-infected children are recommended to receive quadrivalent human papillomavirus vaccine (QHPV) there is limited information on their response to QHPV. This study in HIV-infected children, evaluated the magnitude and duration of immune responses to QHPV. This report describes type-specific serum antibody responses over a 4-to-5year period after either 3 or 4 doses of QHPV. Design/methodsHIV-infected children, ages 7-to-11years, received 3 doses of QHPV (n=96) or placebo (n=30). At 72weeks QHPV recipients received a fourth dose (n=84), while placebo recipients began the 3-dose QHPV schedule (n=27). HPV serotype-specific antibody was determined, by competitive Luminex immunoassay (cLIA) and IgG Luminex immunoassay, at 2, 3.5, and 4-to-5years after the last dose of QHPV in each treatment arm. ResultsAt 4-to-5years after the last dose of QHPV, antibody titers were significantly higher in 4-dose than in 3-dose group. However, the proportion of vaccinees with a seroresponse in the cLIA assay was not different between the two groups (86–93% for HPV types 6, 11, and 16, and 64% for HPV type 18). These results were very similar to the seroresponse rate in these HIV-infected children at 1month after completing vaccination. ConclusionsChildren with well-controlled HIV infection who receive 3 doses of the QHPV vaccine maintain seropositivity and antibody levels that are generally similar to children of the same age who are not HIV-infected. Antibody titer correlated strongly with low log HIV RNA, low CD8%, and high CD4%. Additionally, a fourth dose of vaccine in HIV-infected children produces a marked rise in antibody characteristic of an anamnestic response and persistence of high antibody levels.Study identification: IMPAACT P1085 (V501-021). CLINICALTRIALS.GOV identifier: NCT01206556.

Genotype considerations for virus-like particle-based bivalent norovirus vaccine composition.

Norovirus (NoV) genogroup I (GI) and GII are responsible for most human infections with NoV. Because of the high genetic variability of NoV, natural infection does not induce sufficient protective immunity to different genotypes or to variants of the same genotype and there is little or no cross-protection against different genogroups. NoV-derived virus-like particles (VLPs) are promising vaccine candidates that induce high levels of NoV-specific humoral and cellular immune responses. It is believed that a bivalent NoV vaccine consisting of a representative VLP from GI and GII is a minimum requirement for an effective vaccine. Here, we compared the abilities of monovalent immunizations with NoV GI.1-2001, GI.3-2002, GII.4-1999, and GII.4-2010 New Orleans VLPs to induce NoV type-specific and cross-reactive immune responses and protective blocking antibody responses in BALB/c mice. All of the VLPs induced comparable levels of type-specific serum IgG antibodies, as well as blocking antibodies to the VLPs used for immunization. However, the abilities of different VLP genotypes to induce cross-reactive IgG and cross-blocking antibodies varied remarkably. Our results confirm previous findings of a lack of cross-protective immune responses between GI and GII NoVs. These data support the rationale for including NoV GI.3 and GII.4-1999 VLPs in the bivalent vaccine formulation, which could be sufficient to induce protective immune responses across NoV genotypes in the two common genogroups in humans.

Sublingual immunization of trivalent human papillomavirus DNA vaccine in baculovirus nanovector for protection against vaginal challenge.

Here, we report the immunogenicity of a sublingually delivered, trivalent human papillomavirus (HPV) DNA vaccine encapsidated in a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus nanovector. The HERV envelope-coated, nonreplicable, baculovirus-based DNA vaccine, encoding HPV16L1, -18L1 and -58L1 (AcHERV-triHPV), was constructed and sublingually administered to mice without adjuvant. Following sublingual (SL) administration, AcHERV-triHPV was absorbed and distributed throughout the body. At 15 minutes and 1 day post-dose, the distribution of AcHERV-triHPV to the lung was higher than that to other tissues. At 30 days post-dose, the levels of AcHERV-triHPV had diminished throughout the body. Six weeks after the first of three doses, 1×108 copies of SL AcHERV-triHPV induced HPV type-specific serum IgG and neutralizing antibodies to a degree comparable to that of IM immunization with 1×109 copies. AcHERV-triHPV induced HPV type-specific vaginal IgA titers in a dose-dependent manner. SL immunization with 1×1010 copies of AcHERV-triHPV induced Th1 and Th2 cellular responses comparable to IM immunization with 1×109 copies. Molecular imaging revealed that SL AcHERV-triHPV in mice provided complete protection against vaginal challenge with HPV16, HPV18, and HPV58 pseudoviruses. These results support the potential of SL immunization using multivalent DNA vaccine in baculovirus nanovector for induction of mucosal, systemic, and cellular immune responses.

Serum and mucosal antibody responses to inactivated polio vaccine after sublingual immunization using a thermoresponsive gel delivery system

Administering vaccines directly to mucosal surfaces can induce both serum and mucosal immune responses. Mucosal responses may prevent establishment of initial infection at the port of entry and subsequent dissemination to other sites. The sublingual route is attractive for mucosal vaccination, but both a safe, potent adjuvant and a novel formulation are needed to achieve an adequate immune response. We report the use of a thermoresponsive gel (TRG) combined with a double mutant of a bacterial heat-labile toxin (dmLT) for sublingual immunization with a trivalent inactivated poliovirus vaccine (IPV) in mice. This TRG delivery system, which changes from aqueous solution to viscous gel upon contact with the mucosa at body temperature, helps to retain the formulation at the site of delivery and has functional adjuvant activity from the inclusion of dmLT. IPV was administered to mice either sublingually in the TRG delivery system or intramuscularly in phosphate-buffered saline. We measured poliovirus type-specific serum neutralizing antibodies as well as polio-specific serum Ig and IgA antibodies in serum, saliva, and fecal samples using enzyme-linked immunosorbent assays. Mice receiving sublingual vaccination via the TRG delivery system produced both mucosal and serum antibodies, including IgA. Intramuscularly immunized animals produced only serum neutralizing and binding Ig but no detectable IgA. This study provides proof of concept for sublingual immunization using the TRG delivery system, comprising a thermoresponsive gel and dmLT adjuvant.

Septic Arthritis Caused by Streptococcus suis Serotype 5 in Pig Farmer

Septic Arthritis Caused by Streptococcus suis Serotype 5 in Pig Farmer

Trivalent Combination Vaccine Induces Broad Heterologous Immune Responses to Norovirus and Rotavirus in Mice

Rotavirus (RV) and norovirus (NoV) are the two major causes of viral gastroenteritis (GE) in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1) derived virus-like particles (VLPs) of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6), the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50%) as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs) and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes.

Seroprevalence of Human Papillomavirus (HPV) Type 6 and 16 Vary by Anatomic Site of HPV Infection in Men

It is largely unknown if antihuman papillomavirus (HPV) serum antibody responses vary by anatomic site of infection in men. This study assessed type-specific anti-HPV serum antibody prevalence associated with corresponding HPV DNA detection in the external genitalia and the anal canal of 1,587 heterosexual men and 199 men who have sex with men (MSM). We observed that HPV 6 and 16 seroprevalence was higher in the presence of same HPV-type infection in the anal canal compared with same HPV-type infection in the external genitalia only, and among MSM compared with the heterosexual men. Seropositivity to HPV 6 was strongly associated with HPV 6 DNA detection in the anal canal but not in the external genitalia alone among both heterosexual men [adjusted prevalence ratio (APR), anal+/genital+ vs. anal-/genital-: 4.2, 95% confidence interval (CI), 11.7-10.5; anal+/genital- vs. anal-/genital-: 7.9 (95% CI, 3.7-17.0)] and MSM [APR, anal+/genital+ vs. anal-/genital-: 5.6 (95% CI, 2.7-11.9); anal+/genital- vs. anal-/genital-: 3.2 (95% CI, 2.1-4.9)]. Similar associations between seropositivity to HPV 16 and anal HPV 16 DNA detection were only observed in MSM [anal+/genital+ vs. anal-/genital-: 3.1 (95% CI, 2.0-5.0); anal+/genital- vs. anal-/genital-: 2.2 (95% CI, 1.3-3.5)]. Our data showed that seroprevalence varied by anatomic site of HPV infection, suggesting differences in epithelium type present at these anatomic sites may be relevant. Our finding is instrumental in advancing our understanding of immune mechanism involved in anatomic site-specific antibody response.

Type-Specific Seroprevalence of Herpes Simplex Virus Type 2 and Associated Risk Factors in Middle-Aged Women From 6 Countries: The IARC Multicentric Study

To determine type-specific seroprevalence of herpes simplex viruses (HSV-1 and HSV-2) and HSV-2 risk factors. Six-hundred fifty eight middle-aged control women (hospital-based in 4 of 6 countries) from a multicenter cervical cancer case-control study participated from 1985 to 1997. Type-specific serum IgG antibodies against HSV-1 and HSV-2 were detected with Western Blot. HSV-1 seroprevalence was 89% to 100% everywhere except Thailand (51%). HSV-2 seroprevalence ranged from 9% (Spain) to 57% (Colombia), and was independently associated with having >or=2 lifetime sexual partners overall [Odds ratio (OR), 2.1; 95% confidence interval (CI) 2.5-3.1], and in Morocco (OR, 2.7; 95% CI, 1.2-6.1) and Thailand (OR, 4.4; 95% CI, 1.3-15.4), and with being unmarried in Colombia, Peru, Spain, but not significantly in Mali. Women whose male partner's sexual debut was <or=17 years had a higher HSV-2 risk (OR, 4.3 95% CI, 1.3-13.7). HSV-2 seroprevalence in middle-aged women varied over 4-fold and was associated with riskier sexual behaviors in women and their male partners.

Pneumonia before antibiotics Therapeutic evolution and evaluation in twentieth-century America

Streptococcus pneumoniae (the pneumococcus) was first isolated by Pasteur and Sternberg in 1880 and shortly thereafter was recognized as the most common cause of bacterial pneumonia. Between then and now, the implication of a diagnosis of pneumococcal pneumonia has undergone a monumental change in the minds of physicians. In the early 20th century, when William Osler gave pneumonia its oft-cited appellation “captain of the men of death,” its case fatality rate was estimated to be between 30% and 40%. The subsequent decades saw a gathering storm of interest in the biology and treatment of pneumococcal infection. Neufeld and Haendel demonstrated that pneumococci could be divided into immunologic types, later distinguishable in a matter of hours in a clinical specimen. In the 1930s, sulfonamide therapy for pneumonia reduced the case fatality rate substantially, and with the introduction of penicillin, the respect and fear accorded to pneumonia among physicians was diminished (perhaps to the point of excess), the focus shifting to strategies for prevention of pneumococcal disease by vaccination. Scott Podolsky, an internist and lecturer in the Department of Social Medicine at Harvard Medical School, focuses on a sometimes untold story in the evolution of therapy for pneumococcal pneumonia, the development and implementation of type-specific serum therapy. Serum therapy, when it is discussed, is often presented as a footnote in this historical parade, a brief stop between the hopelessness of Osler’s time and the triumph of the antibiotic era. Podolsky tells a story that is much richer, full of scientific and medical giants, such as Oswald Avery, Rufus Cole, and Maxwell Finland. Before the coming of the antibiotic era, which marks the end of the narrative, a massive public health system will have been mobilized and subsequently dismantled, pharmaceutical companies will have devoted massive resources to serum production, and debates will have simmered throughout the medical community as to how and when serum might best be used. The three parts of the book trace the development, wide implementation, and subsequent decline of serotherapy over a period of more than 40 years. Podolsky is at his best when he illustrates the many instances in which debates over serotherapy foreshadowed questions that the medical community continues to face today. The role of the public health system vis-a-vis local practitioners was hotly debated, with individual doctors resentful of intrusions into their practices. Serious concerns were raised about the role of pharmaceutical companies in the investigation, marketing, and distribution of a product (serum) from which they profited. Finally, students of clinical investigation will recognize the seeds of controlled trials in this book, with disagreements over the proper handling of control groups, the need to convince practitioners of the value of statistical analysis, and the generalizability of studies performed at academic centers to the “real world.” As an additional parallel to today, it is striking in the telling of this story how consistently medicine has underestimated the diversity and adaptability of the pneumococcus. As the number of known serotypes expanded from 2 to 4 to more than 30 (of the 90 that are currently recognized), there was the gradual realization that type-specific therapy would become logistically challenging. Likewise, antibiotics such as penicillin, hailed as the final blow against the pneumococcus, would prove ultimately to select antibiotic-resistant mutants. Today, we face similar issues as we use polysaccharide vaccines against a limited number of serotypes, a strategy that ultimately may require revision or addition of serotypes currently not represented in the vaccine. It is somewhat unfortunate that, despite the timeliness of this book, it is written in large part in a manner not easily accessible to the general reader. A great deal of the text is devoted to specific local reactions to larger scale policies. The writing is turgid, and much of the story resides in the voluminous footnotes, which constitute roughly 40% of the book’s length. The result is a volume that is likely to be of greater interest to medical historians and sociologists than to clinicians or basic scientists.

Specificity of serum neutralizing antibodies induced by transient immune suppression of inapparent carrier ponies infected with a neutralization-resistant equine infectious anemia virus envelope strain

It has been previously reported that transient corticosteroid immune suppression of ponies experimentally infected with a highly neutralization resistant envelope variant of equine infectious anemia virus (EIAV), designated EIAV(DeltaPND), resulted in the appearance of type-specific serum antibodies to the infecting EIAV(DeltaPND) virus. The current study was designed to determine if this induction of serum neutralizing antibodies was associated with changes in the specificity of envelope determinants targeted by serum antibodies or caused by changes in the nature of the antibodies targeted to previously defined surface envelope gp90 V3 and V4 neutralization determinants. To address this question, the envelope determinants of neutralization by post-immune suppression serum were mapped. The results demonstrated that the neutralization sensitivity to post-immune suppression serum antibodies mapped specifically to the surface envelope gp90 V3 and V4 domains, individually or in combination. Thus, these data indicate that the development of serum neutralizing antibodies to the resistant EIAV(DeltaPND) was due to an enhancement of host antibody responses caused by transient immune suppression and the associated increase in virus replication.

ERK1/2-dependent contractile protein expression in vascular smooth muscle cells.

In vivo, vascular smooth muscle (VSM) cells change their contractile phenotype toward a more proliferative phenotype during the pathogenesis of vascular diseases. Because these dedifferentiated VSM cells may gradually regain contractile functions, we aimed to identify signaling pathways that result in an increased expression of contractile proteins in VSM cells. In vitro, serum and thrombin induced a reversible upregulation of smooth muscle myosin heavy-chain (SM-MHC) in cultured neonatal rat VSM cells. Cotransfection of a SM-MHC-promoter chloramphenicol acetyltransferase-construct with dominant-negative N17Ras or N17Raf or treatment with the mitogen-activated/ERK-activating kinase (MEK) inhibitor PD 98059 concentration dependently decreased the serum- or thrombin-induced SM-MHC promoter activity. Consistently, the serum- or thrombin-induced phosphorylation of MEK and extracellular signal-regulated kinase 1/2 (ERK1/2) coincided with a MEK-dependent nuclear accumulation of phosphorylated ERK1/2 and subsequent nuclear phosphorylation of the transcription factors c-myc and Elk-1. A 5'-deletion analysis of cis-elements within the SM-MHC promoter demonstrated that a conserved region (nucleotide -1346 to -1102) was required for both cell type-specific expression and serum- or thrombin-induced upregulation of the SM-MHC promoter in VSM cells. Within this region, 2 CArG-boxes, a GC-rich element, and a CTF/NF-1 site are critical positively acting cis-elements for the serum- or thrombin-induced upregulation of SM-MHC. We conclude that the serum- or thrombin-induced differentiation requires an intact Ras/Raf/MEK/ERK signaling cascade, nuclear translocation of activated ERK1/2, phosphorylation of transcription factors, and several cis-elements within the SM-MHC promoter.

Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer.

Human papillomavirus (HPV) infection is the main cause of invasive cervical cancer, but cofactors may act in conjunction with HPV. We performed a pooled analysis of seven case-control studies to examine the effect of one possible HPV cofactor, herpes simplex virus-2 (HSV-2) infection, in the etiology of invasive cervical cancer. Blood and exfoliated cervical specimens were obtained from 1263 case patients with invasive cervical cancer (1158 with squamous-cell carcinomas and 105 with adeno- or adenosquamous-cell carcinomas) and 1117 age-matched control subjects. Western blot analysis and/or an enzyme-linked immunosorbent assay were used to detect type-specific serum antibodies to HSV-2 and HSV-1, and Chlamydia trachomatis serum antibodies were detected using a micro-immunofluorescence assay. HPV DNA was detected using a polymerase chain reaction assay. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were computed from unconditional logistic regression models. Overall, HSV-2 seropositivity was higher among case patients with squamous-cell carcinoma (44.4%, 95% CI = 41.5% to 47.3%) or adeno- or adenosquamous-cell carcinoma (43.8%, 95% CI = 34.2% to 53.5%) than among control subjects (25.6%, 95% CI = 23.0% to 28.2%). Cervical specimens from 1098 (94.8%) squamous-cell carcinoma case patients, 95 (90.5%) adeno- or adenosquamous carcinoma case patients, and 164 (14.7%) control subjects were positive for HPV DNA. Among the HPV DNA-positive women, HSV-2 seropositivity was associated with increased risks of squamous-cell carcinoma (OR = 2.19, 95% CI = 1.41 to 3.40) and adeno- or adenosquamous-cell carcinoma (OR = 3.37, 95% CI = 1.47 to 7.74) after adjustment for potential confounders. A similar association between HSV-2 seropositivity and squamous-cell carcinoma risk was observed after further controlling for markers of sexual behavior (OR = 1.96, 95% CI = 1.24 to 3.09). Among control subjects, HSV-2 seropositivity was associated with markers of sexual behavior, but not with cervical HPV DNA positivity. HSV-2 infection may act in conjunction with HPV infection to increase the risk of invasive cervical carcinoma.

Prevalence and association between herpes simplex virus types 1 and 2-specific antibodies in attendees at a sexually transmitted disease clinic.

Seroprevalence of herpes simplex virus type 1 (HSV-1) and HSV-2 was determined in 1993 and 1998 in a randomly selected study group of 1024 and 654 attendees, respectively, at the sexually transmitted disease (STD) clinic of the University Hospital Rotterdam-Dijkzigt, The Netherlands. Correlations of HSV-1 and HSV-2 seropositivity were investigated. The relationship between HSV-1 and HSV-2 antibodies was also studied. Data were collected in a cross-sectional study from February 1993 until February 1994 and from January 1998 until December 1998. Glycoprotein G (gG) HSV type specific serum IgG was determined. Seroprevalence of HSV-1 was 68% versus 59% (1993 versus 1998, chi(2)-test P < 0.001), of HSV-2 it was 30% versus 22% (1993 versus 1998, chi(2)-test P < 0.001). Using logistic regression analyses, HSV-1 and HSV-2 seropositivity were significantly associated with age and ethnicity in both groups. In 1993, HSV-1 seropositivity also correlated with lower level of education and female gender, whereas in 1998 it correlated with 'number of sexual partners in the past 6 months' and 'present diagnosis of STD'. In both groups, HSV-2 seropositivity was also more prevalent in females and related to sexual lifestyle variables. In an exposure-disease model, HSV-1 seropositivity was not correlated with HSV-2 seropositivity (odds ratio 1993 = 1.1, 95% CI : 0.8--1.7; odds ratio in 1998 = 1.0, 95% CI : 0.5--1.8). Seroprevalence of HSV-1 and HSV-2 is falling among STD clinic attendees in Rotterdam. A changing pattern of risk factors for HSV-1 seropositivity indicates increasing sexual transmission of HSV-1. Seropositivity for HSV-2 correlated with known risk factors. A previous HSV-1 infection does not reduce susceptibility to subsequent genital HSV-2 infections.

Typing of Streptococcus pneumoniae: past, present, and future

Early works leading to the detection of the pneumococcus and eventually to the appreciation that isolates differed in agglutination and that antisera differed in their capacity to protect against pneumococcal infection in the mouse protection test are reviewed. Studies by researchers from Europe, South Africa, and the United States over nearly five decades led to the introduction of serum therapy. Rapid typing methods thus became very important, and type-specific serum therapy generated a dramatic decrease in the number of deaths from pneumococcal pneumonia. Just before the introduction of sulfonamides and, shortly thereafter, penicillin, the use of horse sera was replaced by the use of rabbit sera for a number of reasons. The present methods of typing comprise the capsular reaction test, latex- and coagglutination, and capillary precipitation, to name the most important; these use a large variety of antisera. Newer methods include the use of DNA probes and DNA sequence-based subtyping.

Clinical Virology of Rhinoviruses

This chapter discusses the various aspects of the clinical virology of rhinoviruses. Some attributes of the virus and epidemiology of disease that have clinical relevance, the efficiency of methods for detecting the presence of the virus in the human respiratory tract, and the means by which symptomatic illness is produced by rhinovirus infection of the respiratory tract are described Rhinoviruses cause more infections in humans than any other microorganism. The chapter also discusses the attributes of virus and the epidemiology of disease. These acid-sensitive picornaviruses infect epithelial cells following inoculation onto the nasal mucosa and are detected reliably in nasopharyngeal secretions. Rhinovirus colds occur year round, with a peak of illness in the fall. Type-specific serum antibody correlates with protection against infection. The fact that there are at least 100 different immunotypes makes development of an effective vaccine unlikely. The chapter presents various techniques for the detection of rhinovirus, such as sampling and cell culture, and polymerase chain reaction.

The Role of C3 in Mediating Binding and Ingestion of Group B Streptococcus Serotype III by Murine Macrophages

To understand how complement effects phagocytosis of type III group B streptococcus, we assessed the specific role of C3 in mediating binding and ingestion of these bacteria by macrophages. Phagocytosis of bacteria by resident mouse peritoneal macrophages was measured under conditions in which C3 deposition on bacteria was inhibited or after blockade of C3-ligands or of complement receptor type three (CR3) with specific antibodies. C3 depletion, incubation with F(ab')2 fragments of antibody to C3, or blockade of CR3 completely inhibited the binding of bacteria that was seen in the presence of nonimmune serum. Immune serum increased the number of associated organisms 6-fold compared to that seen with nonimmune serum. With this serum, 82% of organisms were ingested. C3 depletion or CR3 blockage had a modest effect, but this interaction could be ablated completely only after Fc receptors were blocked. Using varied concentrations of an IgG2a MAb against type III capsular antigen, it was possible to show that small amounts of antibody incapable of mediating bacterial binding by itself directed an interaction that also depended upon C3. Phagocytosis of group B streptococci by macrophages in the presence of little or no antibody requires complement and C3 opsonization specifically. C3-dependent binding may be important in determining mononuclear phagocyte-dependent clearance of these pathogens from blood, particularly in patients with little or no type-specific serum antibody.