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.     

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.     

High energy phosphate compounds and mitochondrial function in ischemic myocardium of swine with advanced coronary atherosclerosis

High energy compounds (adenosine triphosphate and creatine phosphate), lactate and mitochondrial function and morphology were investigated in swine suffering from persistent myocardial ischemia. The myocardial ischemia was secondary to severe diffuse coronary artery atherosclerosis induced by hypercholesterolemia enhanced by X-irradiation to the heart.In the ischemic myocardia, the high energy phosphate compounds were decreased up to 50% and lactate was increased threefold. The ischemia apparently had also damaged myocardial mitochondria; QO₂ and ACR were lower in mitochondrial preparations from the ischemic tissue. In addition, electron microscopy showed more swollen and broken forms in mitochondria preparations from the ischemic myocardium. Hypercholesterolemia alone or irradiation alone to other groups of swine did not induce alterations in QO₂ or ACR, although the percentage recovery of mitochondria was decreased by X-irradiation to the heart.We cannot yet relate the findings in this study to the ventricular fibrillation and sudden death that these swine are prone to develop. A possibility that might be investigated is that the decrease in high energy compounds impairs function of ion transport systems (e.g. Na-K-ATPase). The resultant disturbances in ion transport may enhance the development of fibrillation. Despite the abnormalities of mitochondria in the myocardia of the ischemic swine, there were no manifestations of congestive heart failure in this group.     

Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method

PRL exists in different forms in human serum. The predominant form is little PRL (molecular mass 23 kDa) with smaller amounts of big PRL (molecular mass 50--60 kDa) and at times big big or macroprolactin (molecular mass 150--170 kDa). The frequency and clinical consequences of macroprolactinemia have not been clearly established, mainly because of difficulty in identifying these patients biochemically. This previously required the use of gel filtration chromatography, which could not be used routinely. Recently, a screening test using polyethylene glycol (PEG) has been used to identify macroprolactin in serum. Consequently, this study was designed to examine the use of PEG precipitation in the identification of patients with a predominance of macroprolactin and to establish the clinical characteristics of such a cohort. Over 12 months, 18,258 requests for serum PRL were received and of these 1225 patients had a serum PRL more than 700 mU/L. A total of 322 of these patients (26%) had a percentage recovery after PEG precipitation of less than 40%, thus indicating the presence of a predominance of macroprolactin. Fifty-five of these patients were referred for detailed clinical assessment. Symptoms typical of hyperprolactinemia were not common in this cohort. None had sustained amenorrhea and eight have had oligomenorrhea at age less than 40 yr. One had galactorrhea. All had pituitary imaging, and four had a microadenoma with none having a macroadenoma. PEG precipitation allows easy identification of macroprolactin in routine clinical practice. As the clinical consequences of this entity at this stage seem relatively benign, referral and intensive investigation of these patients may not be necessary. However, follow-up of a large cohort is required to ensure that the long-term outlook is likewise benign. This would have important implications for both patients and healthcare systems.     

Diagnostic and prognostic factors in acute monocytic leukaemia: an analysis of 51 cases

Diagnostic features (cytochemistry, immunophenotyping and serum biochemistry) were examined in 51 cases of acute monocytic leukaemia (AMoL). Peroxidase, Sudan black B and alpha naphthyl acetate esterase (ANAE) cytochemical reactions were unrelated to morphological (FAB groups M5a and M5b) or immunological subtype. ANAE cytochemistry, however, indicated that AMoL cases could be subdivided into those with typical (M-type) reactions and those with insignificant staining or monocytic ANAE isoenzymes (defined by IEF). All cases were phenotypically CD13/CD33 positive and, with one exception, had greater than 30% HLA-DR positive cells. Membrane CD14 expression was insignificant or variable in 33% of M5a cases in contrast to 23/24 M5b cases which showed high proportions of CD14-staining cells with at least two monoclonal antibodies. Serum lysozyme, LDH and beta-2 microglobulin (beta 2m) were increased in 88%, 68% and 81% of cases respectively but, with the exception of statistically higher lysozyme levels in CD14+ cases, were unrelated to the morphological, cytochemical or immunological diagnostic subgroups. Clinical and diagnostic features were also examined as possible prognostic indicators. The morphological, cytochemical and immunological subgroups of AMoL were not found to be of prognostic relevance but age (P = 0.004), renal failure (P = 0.005) and serum beta 2m levels (P = 0.002) were related to patient survival. Moreover, renal failure and serum beta 2m remained significant (P = 0.012 respectively) when age was taken into account and were shown to be independent prognostic variables.     

Morphologic significance of left atrial involvement

Left atrial involvement, defined as the terminal negativity of the P wave in Lead V₁ of 1 mm. or more in depth and a duration of 0.04 second or more, was evaluated in 270 autopsied cases with the use of a chamber dissection technique for the determination of atrial and ventricular hypertrophy. Left atrial involvement was present in the following: 35 (44.3 per cent) of 79 hearts with left atrial hypertrophy, 31 (34.8 per cent) of 89 hearts with right atrial hypertrophy, 32 (22.4 per cent) of 143 hearts without atrial hypertrophy, 52 (44.4 per cent) of 117 hearts with left ventricular hypertrophy, 17 (34.7 per cent) of 49 hearts with right ventricular hypertrophy, 9 (11.5 per cent) of 78 hearts without anatomic evidence of atrial or ventricular hypertrophy, and 3 (3.8 per cent) of 78 hearts without anatomic evidence of atrial or ventricular hypertrophy or any clinical or postmortem findings of cardiopulmonary disease. Left atrial involvement has a significant correlation with left atrial hypertrophy (p < 0.01) and left ventricular hypertrophy (p < 0.001). Left atrial involvement was frequently noted to be transient. The presence of left atrial involvement on the ECG appears to be the result of many factors including left-sided heart disease, left atrial hypertrophy, left ventricular hypertrophy, increases in left atrial volume or pressure, and possibly intra-atrial conduction delays.     

Serial lung function testing in patients treated with amiodarone: a prospective study

PURPOSE: Amiodarone has proven to be effective in many cases of cardiac arrhythmias, refractory ventricular tachycardia, and ventricular fibrillation. Pulmonary toxicity is a possible side effect of the drug, with a reported incidence of 2 to 15 percent per year. To determine the effect of amiodarone on lung function, we prospectively studied serial lung function tests in a cohort of 91 patients with refractory cardiac arrhythmias treated with this agent. PATIENTS AND METHODS: Spirometry and carbon monoxide diffusing capacity (DLCO) were measured at zero, three, six, 12, 18, and 24 months, with a mean follow-up of 351 days. RESULTS: For the whole population taking a mean dose of amiodarone of 367 mg daily (range: 136 to 512 mg), there was no accelerated rate of decline in spirometric indices or DLCO. Analysis of lung function changes by multivariate analysis demonstrated that an accelerated decline in DLCO values occurred in elderly patients (p less than 0.05) but not in patients with pre-existing lung disease or cigarette smokers. In four patients (4.5 percent), clinical evidence of amiodarone pulmonary toxicity developed that was associated with a fall in DLCO of greater than 20 percent. All four patients recovered after the drug was stopped. Another 15 patients, without clinical evidence of pulmonary toxicity, had a sustained decline in DLCO of greater than 20 percent. These 15 patients remained asymptomatic over the next 11 months without interruption of therapy. A greater than 20 percent fall in DLCO was a sensitive test for clinically evident amiodarone pulmonary toxicity, but had a positive predictive value of only 21 percent. CONCLUSION: An isolated fall in DLCO, in the absence of clinical evidence of toxicity, does not necessitate stopping amiodarone. An unchanged DLCO value appears to be a reliable negative predictor of pulmonary toxicity.