Biomedical subjects
Publications and source records attributed to H M Lederman.
The authors report on a patient with tetrasomy 9p and 9qh due a karyotype 47,XY,+dic(9)(q12) in lymphocytes and a normal karyotype in fibroblasts. Clinical and complementary investigation revealed a malformation syndrome with many anomalies like those of trisomy 9p as well as Dandy-Walker cyst and Hirschsprung disease not previously described in tetrasomy 9p.
To better understand the factors involved in chronic sinusitis in childhood, we cultured the sinuses, middle meatus, and nasopharynx in 39 children requiring surgical intervention. Sixty-nine percent of these patients had other medical problems, including asthma (49%) and immunologic compromise (18%). We cultured coagulase-negative staphylococcus in 18 patients, Streptococcus viridans in 14 patients, normal flora in 10 patients, Staphylococcus aureus in nine patients, group D streptococcus in five patients, Corynebacterium in five patients, Haemophilus influenzae in three patients, Neisseria in three patients, and Streptococcus pneumoniae, group A streptococcus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella oxytoca, Propionibacterium acnes, Actinomyces, and an anaerobic gram-negative bacillus in one patient each. Cultures yielded no growth in nine patients. A strong association between cultures of the middle meatus obtained ipsilaterally and cultures of the maxillary (83%) and ethmoid sinuses (80%) occurred. A poor correlation was found between cultures of the nasopharynx and maxillary (45%) and ethmoid sinuses (49%). All seven patients who had both maxillary and ethmoid sinus cultures showed the same organisms in both sinuses. Only 41% of organisms were found on both sides when procedures were performed bilaterally. Cultures of the middle meatus appear to be sensitive and specific for organisms within sinuses. The presence of predominantly nonvirulent organisms in low titers suggests that additional factors other than bacterial overgrowth contribute to the pathogenesis of chronic sinusitis in children.
Pulmonary Aspergillus infection in patients with chronic granulomatous disease tends to involve the chest wall and consequently carries a high mortality rate. We report the findings of computed tomography (CT) and magnetic resonance imaging (MRI) in three such cases. One patient underwent both CT and MRI, one, CT only, and one, MRI only. In all three, both CT and MRI demonstrated pulmonary consolidations with direct extension to the adjacent chest wall. In both patients who were examined by CT, scans revealed permeative osteolytic changes of adjacent rib or spine compatible with osteomyelitis. In both patients who were examined by MRI, adjacent chest wall involvement was depicted on T1-weighted images and showed increased signal intensity on T2-weighted images. In one of these patients, the chest wall lesion was well defined on T2-weighted images, an appearance compatible with abscess. Epidural extension was demonstrated on MRI in the other patient, who later developed paraparesis. We suggest that CT and MRI have a complementary role in evaluating chest wall invasion by pulmonary Aspergillus infection in chronic granulomatous disease.
Elevated temperature has profound effects on the immune system, particularly by increasing T-cell proliferation rates, interleukin 1 (IL-1)-driven secretion of IL-2, and primary antibody responses to T-dependent antigens. Therefore, this study shows, in detail, the effects of incubation temperature (29 degrees C to 41 degrees C) on proliferation, IL-2 secretion, and IL-2 mRNA expression in both a murine thymoma cell line (EL4-6.1) and in nontransformed murine splenocytes. Temperature was found to be a positive regulator of IL-2 secretion whether or not IL-1 was part of the activation signal. Parallel effects were observed at the level of IL-2 gene expression. Messenger RNA was quantitated with a novel system, using solution hybridization followed by detection of RNA-DNA complexes by enzyme immunoassay. The time to onset of IL-2 mRNA expression was inversely related to temperature, and mRNA levels increased 20- to 50-fold with increases in average incubation temperature from 29 degrees C to 39 degrees C. This effect was observed whether cells were incubated at constant temperature or exposed intermittently to elevated temperature. Over the same intervals of time and temperature, mRNA levels for tau-actin and beta-tubulin remained relatively constant. Taken together, these findings suggest that temperature-mediated augmentation of IL-2 secretion does not require the presence of IL-1, and that the effect occurs at a pretranslational level.
The hallmark of chronic granulomatous disease (CGD) is defective killing of ingested microorganisms by phagocytic cells. Invasive aspergillosis in CGD patients is particularly virulent and has a mortality rate of approximately 50%. A patient with autosomal recessive CGD was identified who had progressive pulmonary aspergillosis that was unresponsive to conventional antifungal therapy. She was treated with recombinant human interferon-gamma (rHuIFN-gamma) and had a dramatic improvement in clinical symptoms, sedimentation rate, and radiographic scans. No consistent improvement in bactericidal function or neutrophil oxidative capacity could be demonstrated. However, serum neopterin levels, a measure of macrophage activation, increased in a dose-dependent manner with rHuIFN-gamma therapy; increased levels mirrored the improved clinical parameters. This patient's treatment illustrates the usefulness of the single-photon emission computed tomography (SPECT) gallium scan for following pulmonary inflammatory lesions in the presence of fibrosis and indicates that rHuIFN-gamma may be of benefit to CGD patients with serious infections unresponsive to conventional therapy.
A novel nucleic acid detection technique is described for the quantitative measurement of eukaryotic mRNA in biological samples. The procedure involves two steps: a hybridization reaction in solution with a biotinylated cDNA probe, and a conventional enzyme immunoassay that uses a monoclonal antibody for DNA.RNA hybrids to detect the specific mRNA.cDNA complexes. The method has comparable sensitivity to 32P-based methods and yields results that are quantitative and highly reproducible. Furthermore, the test can be performed using unfractionated cytoplasm without the need for extraction with organic solvents. This technique provides a rapid and quantitative method for studying changes in cellular mRNA levels, and it is suitable for testing large numbers of samples.
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The purified human immunodeficiency virus type-l (HIV-l) Tat protein inhibited lymphocyte proliferation induced by tetanus toxoid or Candida antigens by 66 to 97% at nanomolar concentrations of Tat. In contrast, Tat did not cause a significant reduction of lymphocyte proliferation in response to mitogens such as phytohemagglutinin or pokeweed mitogen. Inhibition was blocked by oxidation of the cysteine-rich region of Tat or by incubation with an antibody to Tat before the assay. A synthetic Tat peptide (residues 1 to 58) also inhibited antigen-stimulated proliferation. Experiments with H9 and U937 cell lines showed that Tat can easily enter both lymphocytes and monocytes. The specific inhibition of antigen-induced lymphocyte proliferation by Tat mimics the effect seen with lymphocytes from HIV-infected individuals and suggests that Tat might directly contribute to the immunosuppression associated with HIV infection.
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Humoral immunity was evaluated in seven children undergoing continuous ambulatory peritoneal dialysis (CAPD). Five children (71%) had serum immunoglobulin levels which were more than 2 SD below the mean for age. One mechanism contributing to hypogammaglobulinemia was loss via the peritoneal membrane. Daily losses of IgG into peritoneal dialysis effluents represented 7%-29% of normal daily IgG synthesis, and losses increased with duration of CAPD therapy. Despite the observed hypogammaglobulinemia, all children had protective antibody responses to immunization.
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The records of 102 hospitalized preschool-age children were reviewed to determine their immunization status. Nineteen children (19%) had a documented delay in immunizations. None of these children were immunized prior to hospital discharge, although no contraindications to immunization had been identified. Two to five months after hospital discharge, ten patients (53%) were still deficient. Compliance with recommended immunization schedules is not adequately addressed during hospital admissions.
To investigate the temperature dependence of T lymphocyte activation, we have examined the IL 1-induced secretion of IL 2 by the murine T lymphoma cell line LBRM-33-1A5. During 24-hr incubations, there are modest increases in IL 2 secretion as culture temperatures are increased from 33 degrees to 37 degrees C, but IL 2 secretion declines at higher temperatures. However, the kinetics of IL 2 release during the first 8 hr of culture are highly temperature-dependent. The rate of IL 2 release increases linearly with temperature over the range from 33 degrees to 41 degrees C, demonstrating temperature coefficients (Q10) greater than 70. In contrast, IL 2-promoted proliferation of a continuous T cell line is much less temperature-dependent with Q10 values of less than 4.0.
A case of thoracic pedicle aplasia of T12 coincident with pedicle hypoplasia at T11 is reported. The authors review the literature on thoracic pedicle deficiency and discuss the computed tomography (CT) findings in the thoracic pedicle aplasia/hypoplasia spectrum.
Severe adverse reactions to intravenous immune serum globulin occurred repeatedly in four of 10 hypogammaglobulinemic patients. Treatment-limiting symptoms included fever, chills, headache, hypertension, and chest pain. Pretreatment of patients with hydrocortisone immediately prior to infusion prevented subsequent adverse reactions and permitted these patients to receive immune serum globulin intravenously.
The incidence and morbidity of Mycoplasma infections were examined in a group of 23 patients with hypogammaglobulinemia. Among this group of patients, 18 had one or more episodes of acute respiratory illness during which Ureaplasma urealyticum, Mycoplasma orale, or Mycoplasma pneumoniae were isolated from sputum. Resolution only followed institution of specific antibiotic therapy and elimination of the Mycoplasma. In addition to respiratory illness, U. urealyticum was isolated from the urine of two patients with urinary tract infection and from an area of cellulitis in another patient. M. pneumoniae was isolated from the joint of a patient with arthritis. In six patients with chronic lung disease, Mycoplasma was frequently isolated and clinical improvement, albeit transient, coincided with negative Mycoplasma culture results. These findings emphasize the unique susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.
Rotaviruses are common causes of diarrhea in animals and humans. Little is known, however, about the components of the host response to these viruses. Rotavirus infection was studied in athymic mice experimentally infected with murine rotavirus. Neonatal T-cell-deficient mice experienced a self-limited gastrointestinal infection which was identical to that observed in age-matched immunocompetent mice. Adult T-cell-deficient seronegative mice and age-matched normal mice showed a similar extent of resistance to symptomatic rotavirus infection. In both cases, the infection was resolved without the generation of antirotavirus antibody. These studies indicate that host defense against murine rotavirus requires neither functional T-lymphocytes nor specific antiviral antibody.