Induction of major histocompatibility complex class II glycoproteins by interferon-gamma: attenuation of the effects of restraint stress.

The effect of restraint on the activation of macrophages was evaluated based on the induction of I-A expression following injection of viable Mycobacterium bovis (strain BCG) or treatment in vitro with recombinant interferon-gamma (rIFN-gamma). We found that restraint suppressed the induction of I-A expression when applied just prior to or at the same time as the injection of the microorganisms but had no effect if applied after the injection of the Mycobacteria. The effect of stress was attenuated by increasing the number of microorganisms or by incubating macrophages from stressed mice with higher doses of rIFN-gamma. The suppressive effect of restraint does not appear to be associated with uptake, processing or presentation of antigen but rather to an alteration in the response of the macrophages to rIFN-gamma.     

Effects of inotropes on human leucocyte numbers, neutrophil function and lymphocyte subtypes

We have investigated the effects of inotropes with different adrenergic receptor specificity on differential white cell count, lymphocyte subtypes and neutrophil function in healthy volunteers. Six healthy, male volunteers were enrolled into this randomized, placebo-controlled pilot study. Each volunteer was studied on four separate occasions during a 2-h infusion of various agents, and for 2 h after stopping the infusion. The agents investigated were adrenaline 0.1 microgram kg-1 min-1, dobutamine 5 micrograms kg-1 min-1, dopexamine 2 micrograms kg-1 min-1 and 5% glucose 0.5 ml kg-1 h-1. Venous blood was sampled at 0, 30, 120 and 240 min. Haemodynamic monitoring was continued throughout the study. Full blood count, white cell differential count and enumeration of lymphocyte subtypes were performed. Neutrophil function tests included chemoluminescence, and assessment of neutrophil chemotaxis, phagocytosis and adhesion. The Wilcoxon signed rank test was used to compare differences between placebo and active drugs at each time compared with baseline. There was a significant increase in white cell count, lymphocyte count and neutrophil count with adrenaline, and a small but significant decrease in these variables with dobutamine and dopexamine. These changes were also apparent for absolute CD3+, CD4+ and CD8+ lymphocyte counts. Neutrophil respiratory burst in response to f-methionyl-leucyl-phenylalanine increased significantly only with adrenaline at 30 min (P = 0.046). There were no other significant changes in tests of neutrophil function. Infusion of inotropes was associated with changes in white cell numbers, lymphocyte subtypes and neutrophil respiratory burst. In healthy volunteers, adrenaline had effects different from those of dobutamine and dopexamine. The clinical relevance of such effects requires further investigation in critically ill patients.      

Delayed acute measles inclusion body encephalitis in a 9-year-old girl: ultrastructural, immunohistochemical, and in situ hybridization studies.

A 9-yr-old girl developed delayed acute measles inclusion body encephalitis, which was different from subacute sclerosing panencephalitis (SSPE) in clinical course. Measles virus was demonstrated by electron microscopy, immunohistochemistry, and in situ hybridization. Contrary to the most previous reports, matrix (M) protein was present in the brain, cerebrospinal fluid, and serum and was demonstrated by Western blot analysis and in situ hybridization. The hybridization was performed by a nonradioactive digoxigenin method.     

Thyroid growth immunoglobulins in feline hyperthyroidism.

Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general.     

An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics.

Clinical diabetic nephropathy in man is the consequence of the development of a specific constellation of glomerular, tubular, vascular, and interstitial structural abnormalities accompanied by highly characteristic immunohistochemical alterations that, together, are unique to diabetes. Because changes resembling the specific pathology of diabetes do not develop in patients with conditions that lead to long-standing glomerular hyperfunction (such as unilateral nephrectomy), it is unlikely that glomerular hemodynamic abnormalities per se can be the cause of diabetic nephropathy. Whether hemodynamic abnormalities represent a risk factor that, in the presence of the diabetic state, can accelerate the rate of development of the basic lesions of diabetic nephropathy is currently unclear. However, there is considerable evidence that when the renal lesions of diabetes are far advanced, factors such as systemic hypertension can determine the rate of renal functional deterioration in diabetes as in other disorders. Although the diabetic rat may be a useful model for the study of aspects of the pathogenesis of diabetic nephropathy, much confusion has resulted from the inclusion of focal segmental glomerular sclerosis as a diabetic lesion. Similarly, the acceptance of all increases in urinary protein excretions in this model as resulting from or reflecting of diabetic nephropathology can be misleading. It is concluded that treatment aimed at manipulating renal hemodynamics in diabetic patients without evidence of renal disease should remain in the realm of clinical research.     

Reliability and validity of a health-related quality of life battery for evaluating outpatient antidepressant treatment

This study was designed to evaluate the reproducibility, validity and responsiveness of a health-related quality of life (HRQOL) battery that was assembled for the evaluation of antidepressant therapy. The Montgomery-Asberg Depression Rating Scale was used to measure severity of depression. The HRQOL battery contained measures of energy and fatigue, social behaviour, cognitive function, home and work role function, and general well-being (i.e., health perceptions, life satisfaction) selected from previously developed and validated instruments. The clinical investigators and research nurses reported on difficulty in using the HRQOL battery. Most patients were able to complete the questionnaire without problems within 10 min. Reproducibility was very good with intraclass correlation coefficients ranging from 0.74 to 0.97. The HRQOL scales showed evidence of good concurrent validity. The scales were moderately correlated with MADRS scores (r=0.30–0.62). The magnitude of these correlations indicate that HRQOL scales are related to depression measures, but they are not alternative measures of depression. Changes in MADRS scores were associated with changes in all scales, except for work behaviour, indicating that improvements in depression ratings also resulted in improvements in health status and well-being. The HRQOL scales included in this study were found to be reliable, reproducible, and valid and no appreciable burden was placed on patients or investigators participating in the study. With the exception of the Work Behaviour scale, the HRQOL scales were very responsive to changes in depression severity. This brief HRQOL instrument can provide a comprehensive assessment of the outcomes of antidepressant treatment.This research was supported by a grant from Pfizer International.     

Outcomes in patients with interrupted aortic arch and associated anomalies: a 20-year experience.

OBJECTIVE: The surgical results for the repair of interrupted aortic arch (IAA) have evolved in recent years. We report our results for staged repair of this complex congenital malformation. METHODS: Sixty-five patients (mean age, 16.9+/-41.7 days) were diagnosed with IAA and referred for surgical therapy. The surgical management strategy at our institution between 1982 and 2005 has been one-stage complete repair (n=13) or staged repair (n=52) in selected patients. Non-complex patients (group I, n=51) had a ventricular septal defect (87%), aortopulmonary window (8%), and left ventricular outflow tract obstruction (27%). Group II (n=14) were patients with Taussig-Bing double outlet right ventricle (n=6) or truncus arteriosus (n=8). Method of staged repair of IAA was to transect and turn down the left carotid artery and anastomosis it to the descending aorta (n=41) or graft interposition (n=2) combined with a pulmonary artery (PA) banding followed in a few months by delayed ventricular septal defect (VSD) closure and PA de-banding. RESULTS: There were 5 early and 10 late deaths. The actuarial survival including early mortality was 92% at 1 year, 81% at 5 years, and 76% at 10 and 15 years. There was an 81% 15-year survival for children in group I compared with a 54% for children in group II (p<0.001). Risk factors for increased mortality by univariate analysis were as follows: (1) primary aortic anastomosis (p=0.03), (2) presence of complex anomalies (p=0.05), and (3) initial IAA repair performed before 1994 (p=0.05). Actuarial freedom from any type of aortic reoperation or intervention was 86% at 1 year, 69% at 5 years, and 60% at 10 and 15 years. Univariate and multivariate analyses identified no tested variables as risk factors for reoperation. The majority (86%) was in New York Heart Association (NYHA) class I, and 14% remained in NYHA class II. During the postoperative course there were no neurologic deficits, seizures, and growth disturbances in any patient. CONCLUSION: Staged repair of IAA using a left carotid artery turn down can be safely applied in IAA patients with and without other intracardiac anomalies with good results. Use of the left carotid artery for arch reconstruction did not result in any detectable neurological events or growth disturbances later in life. Associated anomalies played an important role in outcomes. The long-term probability for reoperation and/or reintervention remains high regardless of operative technique.     

Cerebellar toxicity with high-dose cytosine arabinoside

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.