Interleukin (IL)-10, IL-12, and interferon-gamma production in primary and memory immune responses to varicella-zoster virus

Varicella immunization provided the opportunity to examine the kinetics of interleukin (IL)-10, IL-12 and interferon (IFN)-gamma production elicited during primary in vivo sensitization with proteins of varicella-zoster virus (VZV), a common human herpesvirus. VZV-specific IFN-gamma release and T cell proliferation were elicited by immunization and persisted through 15 months of follow-up. The induction of VZV-specific T cells and IgG antibodies was accompanied by transient increases in IL-10 and IL-12 production. T cell proliferation to VZV was significantly lower in adults at 15 months than in vaccinated children or naturally immune subjects and correlated with lower IFN-gamma responses in individual vaccinees. After primary immunity was induced, continued IL-12 production was not necessary to maintain the predominant Th1-type response elicited by VZV. Cytokine profiles observed during primary in vivo sensitization to VZV suggest that parallel increases in IFN-gamma and IL-10 may be important in the induction of immunity to some viral pathogens.     

Striatal dopamine dynamics are altered following an intranigral infusion of iron in adult rats

Exercise has a noted effect on skin blood flow and temperature. We aimed to characterize the normal skin temperature response to exercise by thermographic imaging. A study was conducted on ten healthy and active subjects (age=25.8+/-0.7 years) who were exposed to graded exercise for determination of maximal oxygen consumption (VO2 max), and subsequently to constant loads corresponding to 50%, 70%, and 90% of VO2 max. The skin temperature response during 20 min of constant load exercise is characterized by an initial descending limb, an ascending limb and a quasi-steady-state period. For 50% VO2 max, the temperature decrease rate was - 0.0075+/-0.001 degrees C/s during a time interval of 390+/-47 s and the temperature increase rate was 0.0055+/-0.0031 degrees C/s during a time interval of 484+/-99 s. The level of load did not influence the temperature decrease and increase rates. In contrast, during graded load exercise, a continuous temperature decrease of -0.0049+/-0.0032 degrees C/s was observed throughout the test. In summary, the thermographic skin response to exercise is characterized by a specific pattern which reflects the dynamic balance between hemodynamic and thermoregulatory processes.     

Exposure effects on music preference and recognition

In three experiments, the effects of exposure to melodies on their subsequent liking and recognition were explored. In each experiment, the subjects first listened to a set of familiar and unfamiliar melodies in a study phase. In the subsequent test phase, the melodies were repeated, along with a set of distractors matched in familiarity. Half the subjects were required to rate their liking of each melody, and half had to identify the melodies they had heard earlier in the study phase. Repetition of the studied melodies was found to increase liking of the unfamiliar melodies in the affect task and to be best for detection of familiar melodies in the recognition task (Experiments 1, 2, and 3). These memory effects were found to fade at different time delays between study and test in the affect and recognition tasks, with the latter leading to the most persistent effects (Experiment 2). Both study-to-test changes in melody timbre and manipulation of study tasks had a marked impact on recognition and little influence on liking judgments (Experiment 3). Thus, all manipulated variables were found to dissociate the memory effects in the two tasks. The results are consistent with the view that memory effects in the affect and recognition tasks pertain to the implicit and explicit forms of memory, respectively. Part of the results are, however, at variance with the literature on implicit and explicit memory in the auditory domain. Attribution of these differences to the use of musical material is discussed.     

Leprosy (Hansen''s Disease): Summary notes

This article takes three different approaches to the question of whether the failing heart is in an energy-starved state. A brief historical overview introduces the issue and points out problems in both models and methods. Second, current information regarding the energetic state of the failing heart is examined. Finally, the mechanistic and therapeutic implications of a defect in energy production are described.     

Structural features of thyroid hormone response elements that increase susceptibility to inhibition by an RTH mutant thyroid hormone receptor

The chicken lysozyme silencer F2 (F2) thyroid hormone response element (TRE) contains an unusual everted palindromic arrangement, has a high affinity for thyroid hormone receptor (TR) homodimers, and is especially sensitive to dominant negative inhibition by, the T3 resistance (RTH) mutant TR beta P453H. We used various TREs and TR mutations to determine the mechanisms for this sensitivity. Changing the F2 orientation from an everted palindrome to a direct repeat with a 4-bp gap (DR+4) (F2-DR) decreased the sensitivity to inhibition at high T3 concentrations, while a loss of this sensitivity occurred with a palindromic arrangement of these same half-sites. F2 contains the dinucleotide TG 5' to each consensus half-site conforming to the optimal TR-binding octamer, YRRGGTCA. A T to A change in position 1 of both F2 half-sites markedly reduced T3-induction, yet only slightly reduced TR homodimer or TR-retinoid X receptor (RXR) heterodimer binding. The TR beta ninth heptad mutation, L428R, prevents TR heterodimerization with RXR and eliminates the inhibitory effect of the P453H mutant TR on the F2-DR, but not the F2 element. Structural features of a TRE that favor strong TR binding of both TR homodimers and TR-RXR heterodimers containing the mutant TR, such as the everted palindromic conformation or the optimal TR-binding consensus octamer, enhance the sensitivity of a TRE to inhibition by the mutant TR. Thus, both half-site orientation and sequence contribute to the sensitivity of a given TRE to dominant negative inhibition by a mutant TR.     

The efficacy of drugs in the management of endometriosis

STUDY OBJECTIVE: To establish the crude effects of danazol and gonadotropin-releasing hormone (GnRH) analogs in the management of endometriosis. DESIGN: Prospective case-control study. SETTING: Unit of the Pathophysiology of Reproduction outpatient department. PATIENTS: Two groups of 110 women each with endometriosis (American Fertility Society score 1-3) who received danazol and GnRH analogs, and a control group who did not receive any drugs. INTERVENTIONS: Women in the treatment groups received danazol 200 mg every 8 hours for 6 months, or a different GnRH agonist at standard dosages for 6 months. Laparoscopy was performed twice, at the time of diagnosis and just before the end of treatment (or no therapy for controls). Surgical treatment of the implants was performed at the second laparoscopy. MEASUREMENTS AND MAIN RESULTS: Samples of both eutopic and ectopic endometrium were collected during both laparoscopies. Both danazol and GnRH agonists were useful in reducing the AFS scores to inactive endometriotic implants, and there were no significant differences between the effects (p <0.001). Fibrosis was found after 6 months of observation in the implants in one control woman (0.9%), in 20 patients (18.2%) treated with danazol (p <0.001 vs controls), and in 4 patients (3.6%) treated with GnRH agonists (NS vs controls). A correlation between a clinical diagnosis of AFS score zero and histologic features of fibrosis in the ectopic specimens after therapies was observed in 28% of women, with poor agreement (k = 0.07). CONCLUSIONS: Fibrosis, which represent the absence of endometrial cells within the specimens of endometriotic lesions or eutopic endometrium, did not appear in eutopic endometria but it was found in some endometriotic implants. Danazol and GnRH agonists reduced the clinical AFS scores of endometriosis, but their histologic effects in completely and permanently eliminating endometriotic implants were unacceptable.     

The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep

The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied. We therefore examined the influence of the injection rate of i.v. bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received i.v. propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. Implications: Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly.     

Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.     

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.     

New endeavors and innovative programs in end of life care

This paper presents summaries of initiatives and demonstration programs developed by professional and patient care organizations to improve care at the end of life.