Immunization with glycosylated Kb-binding peptides generates carbohydrate-specific,unrestricted cytotoxic T cells

Cytotoxic T cells (CTL) recognize target proteins as short peptides presented by major histocompatibility complex (MHC) class I restriction elements. However, there is also evidence for peptide-independent T cell receptor (TCR) recognition of target proteins and non-protein structures. How such T cell responses are generated is presently unclear. We generated carbohydrate (CHO)-specific, MHC-unrestricted CTL responses by coupling di- and trisaccharides to K^b- or D^b-binding peptides for direct immunization in mice. Four peptides and three CHO have been analyzed with the CHO either in terminal or central positions on the carrier peptide. With two of these glycopeptides, with galabiose (Galα1-4Gal; Gal₂) bound to a homocysteine (via an ethylene spacer arm) in position 4 or 6 in a vesicular stomatitis virus nucleoprotein-derived peptide (RGYVYQGL binding to K^b), CTL were generated which preferentially killed target cells treated with glycopeptide compared to those treated with the core peptide. Polyclonal CTL were also found to kill target cells expressing the same Gal₂ epitope in a glycolipid. By fractionation of CTL, preliminary data indicate that glycopeptide-specific K^b-restricted CTL and unrestricted CHO-specific CTL belong to different T cell populations with regard to TCR expression. The results demonstrate that hapten-specific unrestricted CTL responses can be generated with MHC class I-binding carrier peptides. Different models that might explain the generation of such responses are discussed.     

Antibody against the carboxyl terminus of intimin alpha reduces enteropathogenic Escherichia coli adherence to tissue culture cells and subsequent induction of actin polymerization

The C-terminal third of intimin binds to its translocated receptor (Tir) to promote attaching and effacing lesion formation during infection with enteropathogenic Escherichia coli (EPEC). We observed that the adherence of EPEC strains to HEp-2 cells was reduced and that actin polymerization was blocked by antibody raised against the C-terminal third of intimin alpha.     

The University of Missouri-Kansas City School of Medicine: thirty-five years of experience with a nontraditional approach to medical education.

The University of Missouri-Kansas City (UMKC) School of Medicine is a public medical school that opened in 1971 in response to a need to train more physicians in Missouri. As a six-year, integrated, combined-degree program leading to the baccalaureate and medical degrees, the school offers an innovative, nontraditional approach to medical education. In the past 35 years, UMKC has graduated over 2,400 physicians who are successful according to outcomes measures used at other medical schools. With recent interest in reforming medical education to prepare physicians for a changing world, a review of alternative models may be especially instructive.UMKC's academic plan offers a blueprint for the curriculum plan and governance of the school. The plan is built on four hallmarks: (1) a combined baccalaureate/MD program, (2) early exposure to clinical medicine, (3) small-group learning through the docent system, and (4) a continuing ambulatory care clinic experience for four years.This article catalogs the results of this plan including student, faculty, and graduates' perceptions of and satisfaction with the school's educational approach, students' achievement on licensing examinations and in the residency match, graduates' performance in residency programs, and their subsequent career patterns. The authors also discuss lessons learned and adjustments made in response to local needs in the context of a changing environment in education, health care, and health care delivery while continually improving the school's nontraditional approach to medical education. These include changes in basic and clinical science instruction, student assessment, faculty development, and funding and governance.     

Upper and lower body functional asymmetries in the newborn: Do they have the same lateral biases?

It is still an open question as to whether functional asymmetries in the human newborn derive from a single lateralized system or multiple subsystems based on different neural mechanisms. In the present study, asymmetries in head turning were compared to those in leg movements during stepping and placing, with the latter also being related to differences in leg mass. The effects of an active versus an inactive state or condition were examined for all three behaviors. No overall lateral biases were found for head turning or for the first foot to move in stepping and placing, and there were no concordances among them; however, there was an asymmetry in that the left foot had a shorter onset latency when compared to the right foot for both stepping and placing. Findings are discussed in terms of what they imply about underlying neural systems that have a bearing on expressions of newborn laterality, and also with regard to the impact of methodological differences in this area of study.     

Effects of dexamethasone and transient malnutrition on rabbits infected with aerosolized Mycobacterium tuberculosis CDC1551

Malnutrition is common in the developing world, where tuberculosis is often endemic. Rabbits infected with aerosolized Mycobacterium tuberculosis that subsequently became inadvertently and transiently malnourished had compromised cell-mediated immunity comparable to that of the rabbits immunosuppressed with dexamethasone. They had significant leukopenia and reduced delayed-type hypersensitivity responses. Malnutrition dampened cell-mediated immunity and would interfere with diagnostic tests that rely on intact CD4 T-cell responses.     

Prevalence of transmitted HIV-1 drug resistance and the role of resistance algorithms: data from seroconverters in the CASCADE collaboration from 1987 to 2003

OBJECTIVES: To examine factors influencing the rate of transmitted drug resistance (TDR) among seroconverters, with particular emphasis on 3 widely used genotypic drug resistance algorithms. METHODS: The study used data from CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe), a collaboration of seroconverter cohorts in Europe and Canada. Genotypic resistance data were derived within 18 months of the last seronegative test or date of laboratory evidence of acute infection and before the initiation of antiretroviral therapy. The Stanford algorithm was used to analyze each individual's nucleotide sequence. A multivariate logistic model was used to assess independent relationships between the presence of TDR and exposure category, sex, age at seroconversion, and year of seroconversion. The paper also describes 3 alternative definitions of resistance: the Stanford algorithm, the key resistance mutations defined by the International AIDS Society, and the Agence Nationale de Recherches sur le Sida (ANRS) algorithm. RESULTS: Forty-five of 438 patients (10.3%) seroconverting between 1987 and 2003 were infected with a drug-resistant HIV-1 variant. Forty patients (9.1%) showed resistance mutations to only 1 class of antiretroviral drugs, 2 (0.5%) to 2 classes, and 3 (0.7%) to 3 classes of antiretroviral therapy. It was suggested that individuals seroconverting later in calendar time were more likely to have TDR (relative risk 3.89 and 95% CI: 0.84 to 18.02, and relative risk 4.69 and 95% CI: 1.03 to 21.31, for 1996-1999 and 2000-2003, respectively, compared with pre-1996; P trend = 0.08). This trend was apparent regardless of the definition of TDR used. The total estimated proportion of individuals with TDR varied between 10.3% and 15.5% according to which definition was used. CONCLUSIONS: Evidence was found for the rise of TDR over time. A specific definition of what constitutes TDR rather than a simple list of mutations is needed.     

Lack of interchangeability between visual analogue and verbal rating pain scales: a cross sectional description of pain etiology groups

Background:  

Rating scales like the visual analogue scale, VAS, and the verbal rating scale, VRS, are often used for pain assessments both in clinical work and in research, despite the lack of a gold standard. Interchangeability of recorded pain intensity captured in the two scales has been discussed earlier, but not in conjunction with taking the influence of pain etiology into consideration.     

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.     

Comparative efficacy,speed, and adverse effects of three PTSD treatments: exposure therapy,EMDR, and relaxation training

The authors examined the efficacy, speed, and incidence of symptom worsening for 3 treatments of posttraumatic stress disorder (PTSD): prolonged exposure, relaxation training, or eye movement desensitization and reprocessing (EMDR; N = 60). Treaments did not differ in attrition, in the incidence of symptom worsening, or in their effects on numbing and hyperarousal symptoms. Compared with EMDR and relaxation training, exposure therapy (a) produced significantly larger reductions in avoidance and reexperiencing symptoms, (b) tended to be faster at reducing avoidance, and (c) tended to yield a greater proportion of participants who no longer met criteria for PTSD after treatment. EMDR and relaxation did not differ from one another in speed or efficacy.