Poly I:C accelerates development of diabetes mellitus in diabetes-prone BB rat.

We developed a new experimental model of accelerated diabetes mellitus in the genetically susceptible diabetes-prone BB rat with the administration of the IFN-alpha inducer poly I:C. With this model, there was both an increased incidence and accelerated onset of insulin-dependent-diabetes in poly I:C-treated animals compared with saline-treated controls. All twelve rats administered poly I:C (5 micrograms/gm body weight 3 times/wk) developed diabetes by 57 days of age (100%) compared with 1 of 27 (3.7%) saline-treated controls. Furthermore, the development of diabetes was accelerated in the poly I:C-treated group (mean age +/- SE at onset 52.8 +/- 0.58 days) compared with saline-treated controls (89.3 +/- 2.4 days, P less than 0.01). Additionally, poly I:C-treated rats had higher mean serum IFN-alpha levels than saline-treated rats at weeks 2 and 3 of treatment (210 vs. 27 and 183 vs. 25 U/ml, respectively, P less than 0.001). Poly I:C treatment of 5 Wistar rats, the parental strain, which is not susceptible to diabetes, did not result in insulitis, diabetes, or hyperglycemia. The histopathologic findings of insulitis and decreased immunoreactive islet insulin in poly I:C-accelerated diabetic BB rats and in BB rats with spontaneous diabetes suggest a similar pathophysiology.

Poly I:C induces development of diabetes mellitus in BB rat.

Polyinosinic polycytidilic acid (poly I:C), an inducer of alpha-interferon, accelerates the development of diabetes in diabetes-prone (DP) BioBreeding (BB) rats. This study investigates the effect of administering poly I:C to a diabetes-resistant (DR) strain of BB rats. We compared the incidence of diabetes, the degree of insulitis, the number of NK cells, helper-inducer cells, cytotoxic-suppressor cells, Ia+ T cells, RT6.1+ T cells, and NK cell bioactivity in DR rats treated with saline and with a 5 micrograms/g body wt (poly-5) dose and a 10 micrograms/g body wt (poly-10) dose of poly I:C. The incidence of diabetes was also compared with that of DP rats receiving poly-5. We found that both doses of poly I:C significantly induce the development of diabetes in the DR BB rat. However, treatment of DR rats with the higher dose induces a greater rate of development of diabetes and earlier onset of diabetes than the lower poly-5 dose. The rate of diabetes development and the mean age of onset were similar in poly-10-treated DR and poly-5-treated DP rats. A significant degree of insulitis occurred in all the poly I:C-treated DR rats, even those not developing diabetes. Peripheral blood NK cell number was greater in poly I:C than in saline-treated rats, after 2 wk of treatment and when killed. The percentage of OX19+ peripheral blood mononuclear cells expressing RT6.1 allotype or Ia antigen were similar in poly I:C- and saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Poly I:C induction of alpha-interferon in the diabetes-prone BB and normal Wistar rats. Dose-response relationships.

Although the administration of a fixed dose of the alpha-interferon (alpha-IFN) inducer, polyinosinic polycytidilic acid (poly I:C), accelerates the development of diabetes in DP-BB rats, no reports have characterized the dose-response relationship of poly I:C with serum alpha-IFN levels and the development of diabetes. This study examines the dose-response relationships of poly I:C with the induction of serum alpha-IFN and the development of diabetes in DP-BB and normal Wistar rats. Also tested in this study is the hypothesis that the lack of development of diabetes in poly I:C-treated normal Wistar rats is attributable to a deficient alpha-IFN response. Using poly I:C doses of 0.5, 1.5, 5, and 10 micrograms/g body weight, a direct dose-response relationship was observed in DP-BB rats with the serum alpha-IFN response. Moreover, all doses of poly I:C accelerated the onset of diabetes in BB rats. Serum alpha-IFN levels inversely correlated with time of onset of diabetes (P < 0.01). Also, BB rats with higher levels of serum alpha-IFN were associated with earlier onset of diabetes (P < 0.001). Poly I:C-induced serum alpha-IFN levels were significantly lower in diabetic than in nondiabetic BB rats. In normal Wistar rats, although all doses of poly I:C significantly increased serum alpha-IFN levels, diabetes was not induced. The results of this study indicate that poly I:C administration elevates serum alpha-IFN and accelerates the development of diabetes in BB rats at even very low doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Gender-related variations and interaction of human neutrophil cyclooxygenase and oxidative burst metabolites.

Gender-related variations in human neutrophil membrane bound oxidative metabolism were evaluated employing the calcium ionophore A23187. These included the measurement of cyclooxygenase metabolites of arachidonate by specific RIA determination of thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-Keto PGF1 (6KPGF) as well as the initiation of the oxidative burst by the quantitative evaluation of superoxide (O-2) reduction of nitroblue tetrazolium (NBT). Neutrophils from women generated 30% less TxB2 and PGE2 than those obtained from men. In contrast, the neutrophils from women demonstrated relatively higher O-2 production with a cyclic pattern of both TxB2 and O-2 which correlated with their menstrual cycle. The elevated O-2 generation appeared to inversely correlate with TxB2 production. Further, introduction of an intracellular oxygen centered radical (OCR) scavenger, sodium benzoate, for the hydroxyl (.OH) radical was observed to affect cyclooxygenase metabolism in a dose-response manner. At higher concentrations of sodium benzoate, i.e., 10(-2) M, TxB2 production was inhibited; in contrast, 10(-3) M sodium benzoate enhanced neutrophil TxB2 generation which was particularly marked during times of increased oxidative burst activity, i.e. O-2 production. We conclude that the decreased production of cyclooxygenase metabolites observed in neutrophils from women in part derive from an increased oxidative burst activity. This suggests that a regulatory mechanism may exist between the neutrophil membrane bound oxidative system(s) involving oxygen centered radicals generated during both the oxidative burst and prostaglandin cyclic endoperoxide reduction. Further, these gender-related differences may be partially attributable to variations in circulating endogenous sex steroids.

Idiopathic pulmonary hemosiderosis: ultrastructural studies and responses to azathioprine.

Two boys are presented who fulfilled criteria for a diagnosis of idiopathic pulmonary hemosiderosis. A lung biopsy specimen from the first patient showed alveolar-capillary basement membrane abnormalities, together with abnormalities of capillary endothelial cells and hemosiderin-laden macrophages. A lung biopsy specimen from the second patient showed mainly capillary endothelial abnnormalities and interestitial fibrosis. Both patients had a noticeable improvement in symptoms and relative stabilization of their roentgenographic and pulmonary function abnormalities following azathioprine therapy.

Improvement of gene transduction efficiency in T lymphocytes using retroviral vectors.

Successful gene transfer into T lymphocytes would provide a useful therapeutic modality for the treatment of various diseases and a valuable way to study T cell functions. Currently, most protocols involving gene transfer into T lymphocytes utilize amphotropic retroviral vectors. However, transduction efficiency using these vectors is relatively low because of the high proportion of resting cells, the concentration-dependent growth manner of T lymphocytes, and the low titer of retroviral vectors. In this article we define conditions that provide high levels of transduction by using IL-2 prestimulation and LipofectAMINE for both mouse and human T lymphocytes. We compared the effects of IL-2 prestimulation on transduction efficiencies at different time points and achieved maximum transfer levels at 72 hr after the incubation. By combining the best prestimulation time and cationic lipids-LipofectAMINE at a dose of 0.8 microM, the transduction efficiencies were increased to 45-75% (62.3 +/- 4.3%) in human T lymphocytes and to 21-33% (27 +/- 1.42%) in murine T lymphocytes as determine by FDG staining and X-Gal visualization, compared with 5% with conventional methods. These results indicate that transduction efficiencies in T lymphocytes can be significantly improved by a prolonged preincubation with IL-2 and by the addition of LipofectAMINE.

Regulation and characterization of the interferon-alpha present in patients with advanced human immunodeficiency virus type 1 disease.

To examine a possible association between plasma viremia and interferon-alpha (IFN-alpha) in patients with the acquired immunodeficiency syndrome (AIDS), we performed IFN plasma immunoadsorption by apheresis (IFN-alpha apheresis) in four volunteers with AIDS who had sustained levels of endogenous plasma IFN-alpha. IFN-alpha apheresis with two plasma volume exchanges was performed daily for 5 days. Clinical signs and symptoms and hematologic, virologic, and immunologic parameters were monitored. Two subjects developed anemia from phlebotomy, and one had a catheter++-associated bacteremia. The IFN-alpha apheresis was effective only in transiently removing IFN-alpha: depletion of IFN-alpha led only to its rapid reconstitution. Cell-associated HIV-1 was unchanged, but three of four subjects had a modest decrease in culturable plasma virus burden following the procedures. The recovery of in vivo HIV-1-related IFN-alpha by apheresis allowed its biologic and biochemical characterization. The HIV-1 IFN-alpha showed characteristics on ELISA, western blot, and biologic assays similar to two subspecies of the natural protein. The natural, recombinant, and HIV-1-induced IFN-alpha s demonstrated nearly identical antiviral activities. The HIV-1 IFN-alpha eluted from the column was not acid labile. The inability of large amounts of plasma IFN-alpha found in some patients with AIDS to affect viral burden likely reflects properties of the virus or of host factors independent of IFN-alpha.

A modified technique for the radioallergosorbent test.

A modification of the radioallergosorbent test (RAST) is described utilizing a multiple automated sample harvester. The technique increases the efficiency of the procedure by shortening the time required for its performance. A study is reported in which this method is compared to that recommended by the manufacturer.

Unusual eye abnormalities associated with congenital cytomegalovirus infection.

Seven children with congenital cytomegalovirus infection demonstrated a higher than expected incidence of "rare" ophthalmological abnormalities, including anophthalmia and Peters' anomaly. These data suggest that appropriate investigation for evidence of cytomegalovirus infection should be instituted in any child with congenital ocular defects.

Lack of transmission of human immunodeficiency virus from infected children to their household contacts.

The possibility of transmission of the human immunodeficiency virus (HIV) from infected children to their contacts has been confronted in households, schools, day-care centers, and other child care settings. Cases reported to the Centers for Disease Control and several studies of close contacts of HIV-infected patients suggested that the risk of transmission in these settings is extremely low. However, most of these studies involved infected adults or older children. Younger children, who drool, bite, mouth toys, and are incontinent, may be more likely to transmit HIV in these settings. To assess this possibility, the authors tested 89 members of households in which 25 children with HIV infection, most of whom were preschool-aged, resided. Household members had close personal contact with the infected children. They shared many items likely to be soiled with blood and body fluids, such as toys, toothbrushes, eating utensils, toilets, and bathtubs. Hugging, kissing, sharing a bed, and bathing together were common. Household members were tested no sooner than 4 months after initial contact with the infected child, to allow adequate time for sero-conversion. All 89 participating household members were anti-HIV seronegative, and 78 who were tested were serum p24 antigen negative. It was concluded from this study and other evidence that the risk of transmission from children to their contacts is extremely low and has not been clearly documented in the household setting.

Antiviral chemotherapy and neonatal herpes simplex virus infecition: a pilot study--experience with adenine arabinoside (ARA-A).

Among 13 neonates with herpes simplex virus (HSV) infection, eight had disseminated disease, one localized CNS disease, and in four the infection was confined to the skin and eyes. Ara-A, a purine nucleoside with anti-viral activity against DNA-VIRUSES, WAS GIVEN (10 TO 20 MG/MG/DAY) BY A CONTINUOUS 12-HOUR INTRAVENOUS DRIP FOR 10 TO 15 DAYS. In all, ara-A administration was begun within three to eight days after the appearance of skin vesicles which represented the hallmark of the disease. Both diagnosis and ara-A treatment were much delayed in one infant without skin vesicles and four infants whose skin vesicles appeared late, long after the occurrence of CNS damage. In this group of infants with disseminated disease, four died and one infant was left with severe neurological deficits. Eight infants (four with disseminated and four with localized skin disease) with skin vesicles as the earliest sign of infection received ara-A early, within three days after the onset of neurologic signs. All survived with no neurologic deficit at 6 months to 1 year of age. There was no apparent toxicity of ara-A to the bonemarrow, liver, or kidney.

Recurrent respiratory tract infections in paediatric patients.

Paediatric respiratory tract infections are one of the most common reasons for physician visits and hospitalisation, and are associated with significant morbidity and mortality. The role of physicians and other healthcare professionals has expanded from merely treating disease to implementing measures aimed at health maintenance and disease prevention. Therefore, children with recurrent respiratory tract infections represent a great challenge for the paediatrician, from both therapeutic and preventive standpoints. The paediatrician must first determine whether these recurrent infections are because of host-derived factors or are the result of increased environmental exposure. Host-derived factors may be nonimmunological or related to host immunodeficiency. The leading cause of recurrent respiratory tract infections throughout the world is increased environmental exposure in children attending nursery school or daycare centres. Acute otitis media in children is of particular concern because of its high incidence, frequent recurrence, and serious long term sequelae, e.g. hearing loss. The socioeconomic impact of these recurrent infections is staggering, and there remains much scope for devising methods for their treatment and prevention. Recent approaches have included the encouragement of breastfeeding, the use of intravenous immunoglobulin and respiratory syncytical virus immune globulin, as well as methods of stimulating immunity, such as ribosomal immunotherapy.

Meta-analysis of published clinical trials of a ribosomal vaccine (ribomunyl) in prevention of respiratory infections.

OBJECTIVE: To perform a meta-analysis using data from all clinical trials and studies of a ribosomal vaccine (Ribomunyl((R))) in order to estimate its overall effect on the number of infections and antibacterial courses used per person. DESIGN AND SETTING: Meta-analysis of studies performed between 1985 and 1999 in 7 European countries and also in Kazakhstan, Tunisia, Morocco and Argentina. PATIENTS AND PARTICIPANTS: Information from 14 213 adults and children. RESULTS: There were 9 randomised, double-blind, placebo-controlled studies, 3 randomised nonblind studies and 16 nonblind studies with no placebo arm in which the response to ribosomal vaccine was compared with historical information. The mean number of infections per person in a study period of 3 months using placebo was found to be 2.39 (standard error +/- 0.50), and in a study period of 6 months was 3.35 (+/-0.41) infections. In both study periods, ribosomal vaccine use was associated with a reduction in the number of infections per person of 1.43 (+/-0.26). In the study period, patients on placebo reported 3.02 (+/-0.44) antibacterial courses, whereas ribosomal vaccine was associated with a reduction of 1.32 (+/-0.42) antibacterial courses. CONCLUSIONS: In spite of variability in data quality, and the small sample size in some of the studies, we conclude that in patients with recurrent respiratory infections ribosomal vaccine significantly reduces both the number of infections and the number of antibacterial courses compared with placebo. This study is a strong and objective demonstration of the efficacy of ribosomal vaccine in limiting the number of otorhinolaryngological infections in children and adults.

Basic immunologic principles underlying vaccination procedures.

Mass immunization programs and routine immunization of infants and children have significantly reduced the incidence of several serious diseases. This article describes the immunologic principles that guide the use of vaccines and explains the mechanisms of protective immunity, adverse side reactions associated with immunization, and new molecular approaches for producing vaccines.

The diagnosis of immune deficiency diseases.

The functions of the immune system, divided into three types, are conceived as the basis for classification of immune deficiency disorders, and useful laboratory procedures are reviewed.

Cytokines and the immune response.

The recent massive growth and development of clinical immunology has been enriched by the discovery of a new family of molecules, the cytokines, which consist of various groups of polypeptide mediators involved in the communication network of the cells of the immune system. This article provides an overview of the immune system and the current status of the cytokines and their clinical application.

You Can Control Asthma: evaluation of an asthma education program for hospitalized inner-city children.

A self-management education program was designed for staff nurses to offer children while they received medical care for asthma in the hospital. The program uses videotapes, written activity books and nurse discussion with the patient. Evaluation was conducted to assess program feasibility and impact. Pre- and post-tests of 40 children age 6-12 years revealed that the children had statistically significant increases in knowledge of and expected response to early warning signs of acute asthma, and in their sense of personal control (Health Locus of Control). Parents reported an increased use of asthma self-management techniques for acute episodes of asthma. Medical record review for a 15 month pre- and post-period indicated reductions in emergency room use. Inpatient hospital based education offers a critical opportunity to introduce asthma management skills, especially to children not reached by more traditional programs.