Clearance of Theiler's virus infection depends on the ability to generate a CD8+ T cell response against a single immunodominant viral peptide

Theiler's murine encephalomyelitis virus (TMEV) induces a chronic demyelinating disease in the central nervous system of susceptible mice. Resistance to persistent TMEV infection maps to he D locus of the major histocompatibility complex suggesting a prominent role of antiviral CTL in the protective immune response. Introduction of the D(b) gene into the FVB strain confers resistance to this otherwise susceptible mouse line. Infection of the FVB/D(b) mouse with TMEV provides a model where antiviral resistance is determined by a response elicited by a single class I molecule. Resistant mice of the H-2(b) haplotype mount a vigorous H-2D(b)-restricted immunodominant response to the VP2 capsid protein. To investigate the extent of the contribution of the immunodominant T cell population in resistance to TMEV, FVB/D(b) mice were depleted of VP2-specific CD8(+) T cells by peptide treatment prior to virus infection. Peptide-treated mice were not able to clear the virus and developed extensive demyelination. These findings demonstrate that the D(b)-restricted CD8(+) T cells specific for a single viral peptide can confer resistance to TMEV infection. Our ability to manipulate this cellular response provides a model for investigating the mechanisms mediating protection against virus infection by CD8(+) T cells.     

HIV-1 seroconversion during pregnancy resulting in vertical transmission.

The uptake of antenatal HIV testing in England and Scotland improved from 33% in 1998 to 92% in 2004 after implementing an opt-out policy. However, there is the potential for missing HIV seroconversion during pregnancy unless a further test is carried out between antenatal booking, which mostly occurs between 12-14 weeks, and delivery. We report a 32-year old Caucasian woman who developed a primary symptomatic HIV infection late in pregnancy. Unfortunately, despite antiretroviral treatment, caesarean section and formula feeding to reduce the risk of mother to child transmission (MCT), the baby was found to be infected by 12 weeks of age. Despite a 95% uptake rate at King's College Hospital, another HIV seroconversion during late pregnancy was detected after the partner was admitted with AIDS defining diagnoses. In the absence of national data on HIV seroconversion rates in pregnancy, further maternal HIV testing later in pregnancy, especially for women at-risk in an ethnically diverse area such as London, should be considered.     

The yeast VPS genes affect telomere length regulation

Eukaryotic cells invest a large proportion of their genome in maintaining telomere length homeostasis. Among the 173 non-essential yeast genes found to affect telomere length, a large proportion is involved in vacuolar traffic. When mutated, these vacuolar protein-sorting (VPS) genes lead to telomeres shorter than those observed in the wild type. Using genetic analysis, we characterized the pathway by which VPS15, VPS34, VPS22, VPS23 and VPS28 affect the telomeres. Our results indicate that these VPS genes affect telomere length through a single pathway and that this effect requires the activity of telomerase and the Ku heterodimer, but not the activity of Tel1p or Rif2p. We present models to explain the link between vacuolar traffic and telomere length homeostasis.     

Activated status of tumour-infiltrating lymphocytes and apoptosis in testicular seminoma.

Testicular seminoma is characterized by a prominent lymphoid infiltrate and an excellent prognosis. Cytotoxic T-lymphocytes (CTLs) infiltrating seminoma tumour nests constitute a major subset of the lymphoid infiltrate. The objective of this study was to determine whether CTLs express markers of cytotoxic potential and activity and whether the number of activated CTLs correlates with the extent of apoptosis in testicular seminomas, as opposed to non-seminomatous testicular germ cell tumours (NSTGCTs). Twenty cases of pure seminoma as well as 20 cases of NSTGCTs including 16 mixed germ cell tumours (MGCTs) were studied. Immunohistochemistry for the cytotoxic markers TIA-1 (cytotoxic potential) and granzyme B (cytotoxic activity) and the T-cell markers CD3 and CD8 was performed on formalin-fixed, paraffin-embedded sections. The apoptotic index (AI) was determined by the TUNEL method. The number of CD3(+), CD8(+), TIA-1(+), and granzyme B(+) cells in tumour cell nests was markedly increased in testicular seminomas, compared with NSTGCTs (p<0.01). Activated granzyme B(+) cells numbered 25.6+/-5.2 per high power field in seminomas and 8.9+/-3.2, 8.1+/-3.9, and 0.4+/-0.2 for embryonal carcinomas, yolk sac tumours, and immature teratomas, respectively. Double immunohistochemical staining for granzyme B and CD8 revealed that 82.6+/-8.5% of granzyme B-expressing cells were CD8(+). The tumour cell AI was significantly increased in embryonal carcinoma, compared with the seminoma, yolk sac tumour, and immature teratoma subgroups (6.7+/-1.3, 2.3+/-0.3, 3.0+/-1.1, and 2.3+/-1.1, respectively, p<0.001). TUNEL/CD3 double immunostaining revealed that a significant proportion of the apoptotic seminomatous tumour cells were in direct contact with one or more CD3(+) lymphocytes (47.2+/-6.2%). The number of activated granzyme B(+) CTLs showed a strong linear correlation with the AI in the seminoma group (r=0.71, p<0.0001) but not in other subgroups. TUNEL/granzyme B double immunolabelling revealed that a proportion of activated granzyme B(+) lymphocytes (20%) were often seen in close contact with apoptotic tumour cells. The presence of increased numbers of activated cytotoxic lymphocytes in testicular seminomas suggests that apoptotic tumour cell death in this neoplasm may be triggered by cytotoxic granule effectors. This phenomenon may be one of the key host immune mechanisms leading to the excellent prognosis in this tumour.     

The effect of crosslinking in elastomers investigated by NMR analysis of 13C edited transverse 1H NMR relaxation

The transverse nuclear ¹H magnetization decay in poly(styrene-co-butadiene) (SBR) is investigated by editing ¹³C NMR spectra. This technique allows for the assignment of localized ¹H dynamical information by discriminating the chemical sites based on their chemical shift in the ¹³C dimension. Here, the homo- and heteronuclear dipolar couplings contribute to the ¹H NMR relaxation giving additional information to a homonuclear experiment. In this heteronuclear 2D experiment two prominent peaks are observed in the ¹³C dimension, which correspond to CH and CH₂ groups, respectively. The decay rate in the ¹H dimension is found for both groups to scale with the crosslink density. An additional ultra-fast magnetization decay is reported. The effect of the carbon black filler is investigated for this component. The analysis of the ¹³C NMR edited transverse ¹H magnetization relaxation is a useful tool in combining high resolution NMR spectra with information on molecular dynamics, providing insight into crosslink density and filler effects.     

Risk factors,clinical course and outcomes of pregnancy-related group A streptococcal infections: retrospective 13-year cohort study

Objectives

To investigate the incidence, risk factors, clinical course and outcomes of pregnancy-related group A streptococcus (GAS) infection.

Differences in professional activities, perceptions of professional problems, and practice patterns between men and women graduates of Jefferson Medical College

Differences between men and women graduates of one medical school in practice patterns, professional activities, and problems were investigated. A questionnaire was mailed in 1986 to 600 physicians, randomly selected from 1,102 who had graduated from Jefferson Medical College of Thomas Jefferson University between 1977 and 1981. Four hundred fifty (364 men and 86 women) responded (75%). The women were less likely than the men to be employed full-time; however, proportionately more women than men held full-time academic appointments, treated patients from low-income families, and served in underserved areas in inner cities. The women reported working fewer hours per week and having fewer patients than did the men. The women published scientific articles as often as did the men but were less likely to serve on professional committees, receive professional awards, or develop medical procedures. The women were less concerned about the oversupply of physicians and malpractice litigation. Implications of the findings for health manpower planning and practice pattern expectations are discussed.