Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides

Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) stimulates major histocompatibility complex class I-restricted cytotoxic T cells (CTLs), which normally resolve the infection. Three peptide epitopes derived from LCMV have been shown to bind the mouse class I molecule H-2 Db and to stimulate CTL responses in LCMV-infected mice. This report describes the identity and abundance of each CTL epitope after their elution from LCMV-infected cells. Based on this information, peptide abundance was found to correlate with the magnitude of each CTL response generated after infection with LCMV. Subsequent experiments, performed to determine the antiviral capacity of each CTL specificity, indicate that the quantitative hierarchy of CTL activity does not correlate with the ability to protect against LCMV infection. This report, therefore, indicates that immunodominant epitopes should be defined, not only by the strength of the CTL response that they stimulate, but also by the ability of the CTLs to protect against infection.     

Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats: evidence for their protection against cerebral vasospasm

The Ca2+-sensitive K+ channel (K(Ca) channel) plays a key role in buffering pressure-induced constriction of small cerebral arteries. An amplified current through this channel has been reported in vascular smooth muscle cells obtained from hypertensive animals, implying that the expression or properties of K(Ca) channels may be regulated by in vivo blood pressure levels. In this study, we investigated this hypothesis and its functional relevance by comparing the properties, expression levels, and physiological role of K(Ca) channels in cerebral resistance arteries from normotensive and genetically hypertensive rats. Whole-cell patch-clamp experiments revealed a 4.7-fold higher density of iberiotoxin-sensitive K(Ca) channel current at physiological membrane potentials in spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto (WKY) rat cerebrovascular smooth muscle cells (n = 18 and 21, respectively). However, additional single-channel analysis in detached patches showed similar levels of unitary conductance, voltage, and Ca2+ sensitivity in K(Ca) channels from WKY and from SHR membranes. In contrast, Western analysis using an antibody directed against the K(Ca) channel alpha-subunit revealed a 4.1-fold increase in the corresponding 125-kD immunoreactive signal in cerebrovascular membranes from SHR compared with WKY rats. The functional impact of this enhanced K(Ca) channel expression was assessed in SHR and WKY rat pial arterioles, which were monitored by intravital microscopy through in situ cranial windows. Progressive pharmacological block of K(Ca) channels by iberiotoxin (0.1 to 100 nmol/L) dose-dependently constricted pial arterioles from SHR and WKY rats (n = 6 to 8). The arterioles in SHR constricted 2- to 4-fold more intensely, and vasospasm occurred in some vessels. These data provide the first direct evidence that elevated levels of in situ blood pressure induce K(Ca) channel expression in cerebrovascular smooth muscle membranes. This homeostatic mechanism may critically regulate the resting tone of cerebral arterioles during chronic hypertension. Furthermore, the overexpression of distinct K+ channel types during specific cardiovascular pathologies may provide for the upregulation of novel disease-specific membrane targets for vasodilator therapies.     

Osteonecrosis of the knee following arthroscopic laser meniscectomy

An unusual case of osteonecrosis of the knee following an arthroscopic laser meniscectomy is presented. The unusual presentation of the osteonecrosis and the chronology suggest that the osteonecrosis of the knee resulted from damage to the articular cartilage and subchondral bone at the time of the arthroscopic laser meniscectomy.     

Low-dose computerized tomography of the jaw bone in pre-implantation diagnosis. Limits of dose reduction and accuracy of distance measurements

This commentary on the issues and challenges related to the provision of sex education in US schools opens by using a 1997 action of the Franklin County, North Carolina, school board as an example of the controversy. In this case, the school board ordered the removal of chapters on sex behavior, contraception, AIDS, and sexually transmitted diseases from its 9th grade health text book to comply with a new state law requiring public schools to teach sexual abstinence until marriage. While most US adults approve of sex education in schools, the abstinence-only movement has orchestrated a highly organized, successful campaign to remove information from schools and has garnered a $250 million commitment from the federal government to promote abstinence until marriage as part of welfare reform efforts. The commentary continues with a review of efforts to undermine sexuality education starting in the 1960s and sketches the current state of sex education efforts. The next section looks at the new strategy used by sex education opponents, which led them to refocus efforts on local school boards and state legislatures instead of national policies. Remaining topics include the other tactics used by sex education opponents, the heightened fear of teachers to discuss controversial subjects, the lack of teacher training to discuss sexuality, and the consequences of this situation in the classroom. Recommendations to redress this situation include improving professional training, forming local advisory committees, encouraging parental involvement, and promoting the benefits of comprehensive programs.     

Adjuvant regional chemotherapy in advanced pancreatic cancer: results of a prospective study

BACKGROUND/AIMS: In order to improve the dismal prognosis of patients suffering from advanced pancreatic cancer we treated 20 patients with adjuvant regional chemotherapy following resection of the tumor. METHODOLOGY: All tumors were classified UICC stage III (TxN1M0). Regional chemotherapy consisted of Mitoxantrone 10 mg/m2 day 1, Folinic Acid 170 mg/m2 and 5-FU 600 mg/m2 days 2-4, and cis-Platinum 60 mg/m2 day 5 for up to 6 cycles. In a total of 101 cycles toxicities WHO III occurred in 6%, WHO IV in 0%. RESULTS: The median survival times, compared to institutional historical controls (treated vs. controls) were 18.5 vs. 9.3 months (p < 0.0006). Hepatic disease progression seemed to be suppressed. CONCLUSION: In conclusion regional chemotherapy seems to be effective for adjuvant treatment in resected pancreatic cancer.     

Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor alpha, and phospholipase C gamma

The epidermal growth factor (EGF) receptor is a transmembrane protein that binds EGF and transforming growth factor alpha (TGF alpha), and that stimulates phospholipase C gamma 1 (PLC gamma 1) activity. In this study the role of the EGF receptor in chronic pancreatitis was studied. By immunohistochemistry, the EGF receptor, TGF alpha, and PLC gamma 1 were found to be expressed at high concentrations in pancreatic ductal and acinar cells from chronic pancreatitis patients. Northern blot analysis showed that, by comparison with normal controls, 19 of 27 chronic pancreatitis tissues exhibited a 5.7-fold increase in EGF receptor mRNA concentrations, and 20 of 27 chronic pancreatitis tissues exhibited a sixfold increase in TGF alpha mRNA concentrations. In situ hybridisation confirmed that overexpression occurred in ductal and acinar cells, and showed that both mRNA moieties colocalised with their respective proteins. These findings suggest that TGF alpha may act through autocrine and paracrine mechanisms to excessively activate the overexpressed EGF receptor in the two major cell types of the exocrine pancreas, thereby contributing to the pathobiology of this disorder.     

Radiosynoviorthesis with rhenium-186 in rheumatoid arthritis: a prospective study of three treatment regimens

Four strains isolated from patients with hemorrhagic fever with the renal syndrome and from field mice, natural hosts of Hantavirus, were examined in order to choose a functionally active strain fit for the development of inactivated Hantavirus brain vaccine. Virulent strain PM-10508/89 isolated from mouse lungs was chosen. The strain was highly virulent for newborn mice and rats: 100% of infected mice aged up to 24 h and 75% of rats developed an acute lethal infection upon challenge. The incubation period of Hantavirus adapted to mouse brain was decreased from 19 to 7 days. The infective titer of the virus in brain suspension was 0.1 to 6.5 lg LD50/ml. The strain was highly immunogenic and possessed a high hemagglutinating activity.     

Higher-level snake phylogeny inferred from mitochondrial DNA sequences of 12S rRNA and 16S rRNA genes

N-Nitrosomethylbenzylamine (NMBA) is a potent esophagus-specific carcinogen that has been utilized extensively in the study of esophageal carcinogenesis in rats. While many studies have focused on the pathogenesis of NMBA-induced esophageal tumors, the tumorigenicity of NMBA itself has not been thoroughly investigated in any single, systematic dose-response study. Therefore, in this study we evaluated NMBA tumorigenicity in rats following various short-term s.c. treatment regimens with the aim of developing an abbreviated treatment protocol which could be used in future studies. To assess the possible correlation of basal cell proliferation with NMBA tumorigenicity, we evaluated the expression of proliferating cell nuclear antigen (PCNA) in both control and NMBA-treated rats. In rats which received a cumulative NMBA dosage of 7.5 mg/kg over the course of 5 weeks, tumor incidence and multiplicity were as follows: 40% with 0.4 +/- 0.3 tumors/rat at week 10; 100% with 2.2 +/- 1.0 tumors/rat at week 20; and 100% with 2.3 +/- 1.0 tumors/rat at week 30. These rats exhibited marked increases in basal cell labeling, with indices that were 1.5- to 1.8-fold higher than controls. NMBA treatment regimens of shorter duration with equivalent or higher cumulative dosages were generally ineffective in producing esophageal tumors, even though significantly elevated levels of basal cell proliferation occurred. Together, these findings indicate that the duration of NMBA treatment is of critical importance in the tumorigenic potential of the carcinogen.