Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes"

We have identified at least 2 highly promiscuous major histocompatibility complex class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating CD4(+)CD25(Hi)FoxP3(+) natural regulatory T cells (nT(Regs)). Coincubation of these regulatory T-cell epitopes or "Tregitopes" and antigens with peripheral blood mononuclear cells led to a suppression of effector cytokine secretion, reduced proliferation of effector T cells, and caused an increase in cell surface markers associated with T(Regs) such as FoxP3. In vivo administration of the murine homologue of the Fc region Tregitope resulted in suppression of immune response to a known immunogen. These data suggest that one mechanism for the immunosuppressive activity of IgG, such as with IVIG, may be related to the activity of regulatory T cells. In this model, regulatory T-cell epitopes in IgG activate a subset of nT(Regs) that tips the resulting immune response toward tolerance rather than immunogenicity.     

Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe

OBJECTIVE: The aetiopathogenesis of the primary systemic vasculitides (PSV) is unknown but includes both environmental and genetic factors. The development of classification criteria/definitions for PSV allows comparison of the epidemiology between different regions. METHODS: The same methods and the American College of Rheumatology (1990) criteria or Chapel Hill definitions were used to compare the epidemiology of Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa in Norwich (east England population 413 500) and Lugo (northwest Spain population 204 100). Patients with PSV were identified between 1 January 1988 and 31 December 1998. RESULTS: Overall, the incidence of PSV in adults was almost equal in Norwich (18.9/million) and Spain (18.3/million). The incidence of Wegener's granulomatosis in Norwich (10.6/million) was greater than in Spain (4.9/million). There was a marked age-specific increase in incidence in Norwich with a peak age 65-74 years (52.9/million), but a virtually equal age distribution between ages 45 and 74 in Lugo (34.1/million). There was no significant increase with time in either population, or evidence of cyclical changes in incidence. CONCLUSION: These data support the suggestion that environmental factors may be important in the pathogenesis of PSV.     

Noninvasive Methods for Determining Pulmonary Vascular Function in Children with Pulmonary Arterial Hypertension: Application of a Mechanical Oscillator Model

Objective. Noninvasive diagnostics for pulmonary arterial hypertension (PAH) have traditionally sought to predict main pulmonary artery pressure from qualitative or direct quantitative measures of the flow velocity pattern obtained from spectral Doppler ultrasound examination of the main pulmonary artery. A more detailed quantification of flow velocity patterns in the systemic circuit has been obtained by parameterizing the flow trace with a simple dynamic system model. Here, we investigate such a model's utility as a noninvasive predictor of total right heart afterload and right heart function. Design. Flow velocity and pressure was measured within the main pulmonary artery during right heart catheterization of patients with normal hemodynamics (19 subjects, 20 conditions) and those with PAH undergoing reactivity evaluation (34 patients, 69 conditions). Our model parameters were obtained by least‐squares fitting the model velocity to the measured flow velocity. Results. Five parameter means displayed significant (P < .05) differences between normotensive and hypertensive groups. The model stiffness parameter correlated to actual pulmonary vascular resistance (r = 0.4924), pulmonary vascular stiffness (r = 0.6811), pulmonary flow (r = 0.6963), and stroke work (r = 0.7017), while the model initial displacement parameter had good correlation to stiffness (r = 0.6943) and flow (r = 0.6958). Conclusions. As predictors of total right heart afterload (resistance and stiffness) and right ventricle work, the model parameters of stiffness and initial displacement offer more comprehensive measures of the disease state than previous noninvasive methods and may be useful in routine diagnostic monitoring of patients with PAH.     

Adrenoceptors and Colocolonic Inhibitory Reflex

The colocolonic inhibitory reflex ischaracterized by inhibition of proximal colonic motilityinduced by distal colonic distension. The aim of thisstudy was to investigate the underlying neuralmechanisms of this reflex, in vivo , using an isolatedloop of canine colon. In five beagle dogs, motility wasrecorded from an exteriorized colonic loop via a serosalstrain gauge connected to a digital data logger and chart recorder. Inflation of a balloon inthe distal colon resulted in inhibition of motility inthe isolated loop. Inhibition of motor activitypersisted following injection of propranolol (100g/kg intravenously), a -adrenoceptorantagonist, but was abolished following administrationof the ₂-adrenoceptor antagonistyohimbine (200 g/kg intravenously). This studyconfirms that the colocolonic inhibitory reflex is mediatedvia the extrinsic nerves to the colon. As the reflex wasabolished by ₂-, but not-adrenoceptor blockade, this indicates that thereflex pathway involves₂-adrenoceptors.     

Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: a randomized controlled trial

Megestrol acetate (MA) (Bristol-Myers Squibb Co., Princeton, NJ) increases weight gain in AIDS and cancer patients and in age-related cachexia; however, the weight gain is predominately fat. We determined if adding resistance exercise and/or testosterone (T) replacement to MA administration would result in a more favorable body composition change than MA alone. Thirty older men (aged 67.0 +/- 5.8) completed this 12-wk study. All subjects received MA and were randomly assigned to one of the following groups: placebo (P) injections, resistance training (RT) and P (RT + P), weekly injections of T (100 mg/wk) or, RT and T (RT + T). The mean increase in body weight for all groups combined was 3.8 kg (P < 0.0001), but this increase was not different between groups. There was a significant interaction for the change in thigh muscle cross-sectional area (P = 0.0006). Thigh muscle cross-sectional area was significantly reduced from baseline by 5.20 [1.62] cm(2) (P = 0.05) in P which was not prevented in T [-4.44 (1.66) cm(2) from baseline; P = 0.04]. RT prevented this decline [+0.61 (1.41) cm(2) from baseline]. Muscle cross-sectional area increased 4.51 (1.69) cm(2) from baseline in RT + T (P = 0.002 vs. P and P = 0.002 vs. T). Despite significant weight gain, MA appears to have an antianabolic effect on muscle size even when combined with T replacement. Resistance exercise attenuated this reduction in muscle mass and when combined with T had an anabolic effect on muscle mass.     

Identification of CD8+ T cell epitopes in the immediate early 62 protein (IE62) of varicella-zoster virus,and evaluation of frequency of CD8+ T cell response to IE62, by use of IE62 peptides after varicella vaccination

Varicella-zoster virus (VZV) causes varicella, establishes neuronal latency, and can reactivate, resulting in herpes zoster. VZV-specific T cells are important for controlling infection. VZV immediate early protein 62 (IE62) is recognized by cytotoxic T cells from immune individuals, but no CD8(+) T cell epitopes have been defined for any VZV protein. CD8(+) T cell frequencies were assessed by cytokine flow cytometry (CFC), by use of synthetic-peptide pools corresponding to the IE62 sequence. IE62 peptide-specific CD8(+) T cells were below the threshold of detection, by direct CFC of either whole blood or peripheral blood mononuclear cells (PBMCs). Activated CD8(+)CD69(+) T cells that produced interferon-gamma were detectable after in vitro restimulation of PBMCs, and restricted epitopes were identified for HLA-A*0201-positive subjects. Varicella vaccination of 3 VZV-immune subjects was associated with increases in IE62 peptide-specific CD8(+) T cells, a finding indicating that in vivo re-exposure boosts memory immunity to this important viral protein.     

Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men

Circulating testosterone (T) levels have behavioral and neurological effects in both human and nonhuman species. Both T concentrations and neuropsychological function decrease substantially with age in men. The purpose of this prospective, longitudinal study was to investigate the relationships between age-associated decreases in endogenous serum T and free T concentrations and declines in neuropsychological performance. Participants were volunteers from the Baltimore Longitudinal Study of Aging, aged 50-91 yr at baseline T assessment. Four hundred seven men were followed for an average of 10 yr, with assessments of multiple cognitive domains and contemporaneous determination of serum total T, SHBG, and a free T index (FTI). We administered neuropsychological tests of verbal and visual memory, mental status, visuomotor scanning and attention, verbal knowledge/language, visuospatial ability, and depressive symptomatology. Higher FTI was associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning and a reduced rate of longitudinal decline in visual memory. Men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster rate of decline in visual memory. No relations between total T or the FTI and measures of verbal knowledge, mental status, or depressive symptoms were observed. These results suggest a possible beneficial relationship between circulating free T concentrations and specific domains of cognitive performance in older men.     

Captopril versus perindopril: a double blind study in essential hypertension

This was a double blind, parallel group, multicentre comparison of the therapeutic efficacy and acceptability of perindopril and captopril in essential hypertension. After one month of placebo, 165 patients with supine diastolic blood pressure (DBP) between 95 and 125 mmHg were randomised to perindopril 4 mg once daily or captopril 25 mg twice daily orally. The perindopril group (n = 82) had significantly higher pretreatment DBP (105.4 +/- 0.8 mmHg vs 102.3 +/- 0.6 mmHg) but other demographic variables were similar. Assessment was monthly for three months: 'uncontrolled' patients (DBP greater than 90 mmHg) had the dose doubled and then hydrochlorothiazide added. Two of the six withdrawals were attributed to drug side effects and were in the captopril group. There was no significant difference in the number of withdrawals or incidence of side effects between the drugs. The final titrated treatments were similar and monotherapy normalised DBP in 49% of each group. The final 'control' rate was higher with perindopril than captopril: 75% vs 57%, P = 0.016. The overall fall in DBP was greater in the perindopril group: 26.5 +/- 1.9 mmHg vs 18.9 +/- 1.9 mmHg, P = 0.005. The doses of diuretic were similar in the two groups. The DBP of patients who received only monotherapy for three months also fell more in the perindopril group (-17.5 +/- 1.4 mmHg vs -13.9 +/- 1.0 mmHg, P less than 0.01). At the doses studied, perindopril was more effective than captopril in lowering DBP, either as monotherapy or in combination with a diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)