Lymphocyte-mediated cytotoxicity in humans during revaccination with vaccinia virus.

Fifteen healthy human volunteers were revaccinated with vaccinia virus. Blood samples (4 to 7) were obtained during the 3 weeks after revaccination. Peripheral blood lymphocytes were washed extensively and tested for cytotoxicity against vaccinia-infected autologous and/or homologous skin fibroblasts. Without addition of antibodies, peak levels of killing were observed on days 7 to 9. The killing did not depend on common HLA markers. On days with peak activity, extensively washed lymphocytes showed higher levels of killing than normally washed lymphocytes. By cell separation experiments, the cell most active in killing proved to be a nonadherent, non-phagocytizing lymphocyte with Fc receptors. Serum antibodies tested in two sensitive serological assays peaked on days 14 to 17. The question of whether the killing observed is dependent on or independent of antibodies is not clarified in the present study.     

Exercises may be as efficient as subacromial decompression in patients with subacromial stage II impingement: 4-8-years' follow-up in a prospective, randomized study

OBJECTIVES: To compare the prognosis of subacromial impingement (SAI) stage II treated conservatively or with subacromial decompression. METHODS: A follow-up study after 4-8 years in a randomized controlled trial (RCT) with 90 adult cases with SAI treated in a Danish hospital from 1996 to 2000 with graded physiotherapy and exercises or arthroscopic subacromial decompression. Outcomes were proportion of time per year with income transfers (indexed 0-1), including total transfers (marginalization), sick leave and disability pension obtained from the registry at the Ministry of Work. Self-reported function, working capability, employment status and global improvement were obtained by questionnaire in September 2004. The main outcomes are given as differences in development from baseline. RESULTS: Seventy-nine (88%) responded to the questionnaire and registry data were obtained from 81. After 1 year the marginalization index increased by 0.45 [95% confidence interval (CI) 0.35-0.56] for surgery and 0.25 (0.16-0.34) for physiotherapy. Cases undergoing surgery also tended to have more sick payments during the first year, but the difference was not significant. Four years after inclusion, changes in indices did not differ between treatment groups. Self-reported outcomes after 4-8 years did not differ between treatment groups. CONCLUSION: The results of surgical decompression were equal to those of conservative treatment, and the surgery group had more income transferrals during the first year of follow-up.     

Inhibition of calpain prevents NMDA-induced cell death and β-amyloid-induced synaptic dysfunction in hippocampal slice cultures

Background and purpose:

Alzheimer''s disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid-β (Aβ). While the Aβ pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Aβ-induced synaptic deficits, as well as NMDA receptor-mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments.

Experimental approach:

Application of the specific, water-soluble calpain inhibitor A-705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Aβ-induced deficits in neurotransmission in CA1, as well as NMDA-induced neuronal cell death.

Key results:

A-705253 dose-dependently prevented excitotoxicity-induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A-705253 also fully prevented Aβ oligomer-induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model.

Conclusions and implications:

We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.     

Integrative care and bridge building among health care providers in Norway and Denmark

BACKGROUND: Patients in Norway and Demmark with the medical diagnoses of cancer, multiple sclerosis (MS), and HIV/AIDS use complementary and alternative treatment (CAT) in growing numbers, most often in addition to receiving conventional treatment. At the same time, the interest and demand from patients for more holistic-oriented care is strongly increasing. Following this, there is a desire and need for better communication and cooperation among the conventional medical establishment, CAT practitioners, and patients. This development raises new demands on research designs to incorporate complexity and diversity concerning the intervention, effect mechanisms, and outcomes. DISCUSSION: This article outlines different models used to combine conventional, complementary, and alternative treatment (CCAT), describing various degrees of integration among therapies. The authors are closely involved in three current and planned research projects in Norway and Denmark focusing on cancer, MS, and HIV/AIDS. These research projects are briefly introduced as examples of bridge-building efforts dealing with integrative care. Despite explicit political good will in Norway and Denmark, initiatives to enhance integration face challenges connected to lack of knowledge; resistance toward CCAT; lack of time, space, and economic resources; and patients left without any claim on insurance in the case of treatment failure. These challenges are outlined based on the researchers' experience from being involved in the research projects. CONCLUSIONS: To optimize treatment outcomes in the future, it is argued that the need for closer cooperation among conventional and alternative therapists across professional boundaries in an interactive partnership with patients is evident. Researchers have to rethink research design and methods in meeting the new trend toward bridge building based on integrative health care.     

Lack of association between prior depressive episodes and cerebral [11C]PiB binding

Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-β (Aβ) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [(11)C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.     

Mass dose effects and in vivo affinity in brain PET receptor studies--a study of cerebral 5-HT4 receptor binding with [11C]SB207145

Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity.

Methods

The approach was used for [¹¹C]SB207145, a new PET radioligand for imaging the cerebral 5-HT₄ receptors in humans. Test–retest PET studies with varying specific activities of [¹¹C]SB207145 were conducted in seven healthy subjects, and the output parameter regional BP_ND was modeled. Individual occupancy plots were first computed to estimate the mass dose that saturates 50% of receptors (ID₅₀), and subsequently, the maximal mass dose that can be injected (arbitrarily set at an occupancy <5%) was calculated. Scatchard plots were computed to estimate the in vivo K_D.

Results

Increasing the mass dose resulted in a decrease in BP_ND, whilst the relative cerebellar uptake was unchanged. The ID₅₀ was 85.4±30.2 μg, and the upper mass dose limit was 4.5±1.6 μg, which does not require ultrahigh specific activity. The estimated in vivo K_D was 2.8 nM (range 1.0–4.8), without any regional differences.

Conclusion

The presented method for estimating the upper mass dose limit is suggested as part of validation of PET radioligands.     

Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats

The present study was undertaken to study the growth hormone-releasing properties and growth-promoting effect of a GH secretagogue ipamorelin (IPA) in rats given the synthetic glucocorticoid methylprednisolone (MP).In a first experiment, rats received either saline or MP (5.0 mg/kg) for 8 days. Treatment with MP significantly (P< 0.001) decreased body weight gain, but the acute response to either IPA or growth hormone releasing hormone (GHRH) in terms of plasma GH was not changed.In a second experiment, venous catheters were surgically implanted. On the next day, rats were randomly allocated to receive saline alone, MP alone (5.0 mg/kg) or MP plus IPA in doses of 0.4 or 1.6 mg/kg/day for 10 days. IPA was administered intravenously four times a day.MP treatment significantly (P< 0.05) retarded recovery from surgery in terms of body weight. Thus, saline treated animals lost 4.0 +/- 3.5 g over the entire experimental period, whereas animals receiving MP lost 13. 6 +/- 2.9 g. When IPA was given together with MP, losses in body weight were significantly (P< 0.05) reduced to 2.3 +/- 2.0 and 1.6 +/- 2.0 g in animals given the high and low dose of IPA, respectively. In parallel with this IGF-I levels increased.In conclusion, this work shows that MP does not disrupt the response of the GH-IGF-I axis to an exogenous stimulus like IPA, and repeated stimulation leads to increases in IGF-I and of body weight gain.