CD8 memory T cells: cross-reactivity and heterologous immunity

Virus-specific memory T cell populations demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. The degeneracy of T cell antigen recognition and the flexibility of diverse antigen-specific repertoires allow the host to respond to a multitude of pathogens while accommodating these numerous large memory pools in a finite immune system. These cross-reactive memory T cells can be employed in immune responses and mediate protective immunity, but they can also induce life-threatening immunopathology or impede transplantation tolerance and graft survival. Here we discuss examples of altered viral pathogenesis occurring as a consequence of heterologous T cell immunity and propose models for the maintenance of a dynamic pool of memory cells.     

Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors

In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.     

Less severe retinopathy of prematurity induced by surfactant replacement therapy

To assess the effect of surfactant replacement therapy (SRT) on the prevalence and severity of retinopathy of prematurity (ROP), we compared data from 160 SRT-treated preterm infants with data from 230 historic controls. The prevalence of ROP was 30.6% in the treatment group and 23.4% in the control group. Severe ROP (stages 3-4) was seen in 6.1% of the infants with ROP in the treatment group and 20.3% of the ROP patients in the control group. Surfactant therapy had no influence on the prevalence of ROP (odds ratio 1.4, 95% confidence interval 0.797-2.459, p = 0.242). However, SRT was associated with a decreased risk for severe ROP, compared to mild ROP (odds ratio 0.226, 95% confidence interval 0.056-0.905, p = 0.036). These data suggest that SRT is associated with a decreased risk for severe ROP.     

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 ± 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow‐up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow‐up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow‐up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.     

Modulation of the beta-adrenergic receptor system of vascular smooth muscle cells in vitro and in vivo by chronically elevated endothelin-1 levels

Endothelin-1 (ET-1) levels are chronically elevated in several cardiovascular diseases and correlate with an increased mortality. However, in contrast to acute biological activities such as vasoconstriction, little is known about long-term effects of ET-1. In this study we determined the effects of ET-1 on the beta(2)-adrenergic receptor (AR) system. Incubation of smooth muscle cells with ET-1 for 72 hr led to increased beta(2)AR density as determined by radioligand binding. Experiments with inhibitors of protein and RNA synthesis as well as RT-PCR revealed that beta(2)AR upregulation required de novo synthesis. In addition, protein kinase C but neither NO nor prostaglandin metabolism were involved in this effect. The enhanced expression of beta(2)AR was associated with an increased expression of its stimulatory G-protein and the receptor's ability to stimulate adenylyl cyclase. To study chronic effects of ET-1 in vivo, rats were infused with ET-1 for 3 weeks. Similarly as in cultured cells, prolonged ET-1 exposure led to increased betaAR expression in vivo. As a consequence, beta(2)AR-induced vasodilatation was increased in aortic rings from ET-1-treated animals. Our results therefore suggest that chronically elevated ET-1 levels in vitro and in vivo induce counterregulatory mechanisms by increasing betaARs that attenuate the vasoconstrictive effects of ET-1.     

Enhancing didactic education through participation in a clinical research project.

The purpose of this study was to assess self-evaluation of knowledge and skills (e.g., counseling, education, interviewing, and assessment skills) of students participating as research assistants. Fifteen students enrolled in the Dietetics Program (n = 10) or the Graduate Program in Nutrition (n = 5) were recruited as research assistants via flyers and announcements in nutrition courses. These students assisted faculty researchers with their clinical study called "Weight Loss Effects on Bone Mass in Adolescent Females." The clinical study included a comprehensive 6-month weight-loss program. Surveys asking students to evaluate their experience as research assistants were mailed with a self-addressed, stamped envelope to all 15 student research assistants, followed by a reminder telephone call. Thirteen surveys (87%) were returned. On a Likert scale (1 = poor, 5 = excellent) student research assistants scored 63% of the knowledge-based and skill-based requirements of their research participation as "good" (mean score > or = 4.0) and 27% as "adequate" (4.0 > or = mean > or = 3.5). Open-ended questions reported the research experience to be beneficial in developing knowledge and skills and in identifying knowledge deficits (e.g., behavior modification). According to our findings, it seems that participation in clinical research enhances students' knowledge and skills and, thus, is valuable in preparing dietetics students for future practice.