Trisomy 9 mosaicism in two girls with multiple congenital malformations and mental retardation.

Two girls with mosaicism for an extra chromosome 9 are reported. Clinical findings included growth and mental retardation, facial dysmorphism, delayed ossification, single flexion crease, gastro-oesophageal reflux in one girl, and ventricular and atrial septal defects in the other patient. These findings are compared to the other previously reported cases of trisomy 9 mosaicism.     

Serum 27E10 antigen: a new potential marker for staging HIV disease.

MRP8 and MRP14 are myeloic related proteins expressed by most circulating and emigrated neutrophils and monocytes. Their composite molecule MRP8/14 (27E10 antigen) was shown to exhibit striking antimicrobial properties. The aim of the present study was to assess the value of MRPs as markers for detection of the different stages of HIV infection (Centres for Disease Control and Prevention, 1993). By employing the ELISA technique we measured serum concentrations of these proteins in samples from 122 HIV patients at the various stages of disease, and the results were compared with those for healthy controls. Serum levels of the heterodimeric molecule 27E10 were significantly increased (P < 0.001) in patients with CDC stages II and III, with the highest levels being in patients with stage III and acute ongoing opportunistic infections. For the single component MRP14, significantly raised levels (P < 0.05) were only found in HIV stage III individuals with acute clinical events. Similar associations were not found for MRP8 alone. Increase was not related to CD4+ cell count. There was a significant correlation between 27E10 antigen serum concentrations and levels of neopterin in patients with HIV stages II and III without acute concurrent illness. Patients being treated with Zidovudine showed no statistically significant variation in levels of 27E10 and its single components MRP8 and MRP14 compared with untreated patients. These findings suggest that elevation of MRP14 levels occurs in HIV+ individuals at later stages post-HIV infection, after the onset of opportunistic infections. 27E10 antigen is concluded to be a potential marker for the different stages of HIV disease.     

Diminished interleukin 2 production and receptor generation characterize the acquired immunodeficiency syndrome

The Acquired Immunodeficiency Syndrome (AIDS) is a disease found primarily in homosexual men, consisting of opportunistic infections and tumors, and is due to an acquired T-cell defect. In the present report, we studied various T-cell functions which might serve to distinguish homosexuals with a symptom complex including lymphadenopathy from those with AIDS. T lymphocytes from the lymphadenopathy and AIDS patients had markedly depressed proliferative responses in the autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR) compared to healthy homosexuals or heterosexual controls (P less than 0.001). Since proliferation in the MLR depends upon interleukin 2 (IL-2), a T-cell growth factor, we studied the production of and response to IL-2 in various groups of homosexuals and heterosexual controls. IL-2 production was markedly depressed in the lymphadenopathy and AIDS patients, 1.0 and 0.1 U/ml, respectively, compared to the healthy homosexual or heterosexual controls, both 5.0 U/ml (P less than 0.05 and P less than 0.01, respectively). Although the auto MLR of the lymphadenopathy patients rose to control values with the addition of exogenous IL-2, the auto MLR of the AIDS patients did not (P less than 0.01). This lack of responsiveness to IL-2 in the AIDS group was due to their inability to generate IL-2 receptors as shown by the absence of IL-2 absorption by activated cells and the absence of the Tac antigen (IL-2 receptor) on these same cells. The T4+ and T8+ T-cell subsets from the AIDS patients each demonstrated depressed IL-2 production and responsiveness following activation with autologous cells or mitogen, as well as the absence of Tac antigen. The diminished T-cell proliferation in the auto MLR in the lymphadenopathy group is associated with one defect, low IL-2 production, while the depressed proliferation in the AIDS group is associated with two defects, low IL-2 production and a lack of IL-2 receptor generation. These studies demonstrate that IL-2 receptor generation helps distinguish homosexuals with lymphadenopathy from those with AIDS, and that in addition to T-cell defects in the OKT4+ T-cell subset there are significant abnormalities in the OKT8+ T-cell subset in AIDS patients.     

The use of computer-assisted video image analysis in the enumeration of immuno-stained cells in tissue sections.

A novel method of computer-assisted video image analysis (VIA) was used to determine the number of immunostained cells in tissue sections. This method permitted an accurate and objective quantification of cells of a particular phenotype. This enumeration was achieved by measuring the area stained by a test monoclonal antibody (such as the T cell marker, CD3) and comparing it with the area stained by a leukocyte common (LCA) monoclonal antibody (CD45). The proportion of T cells within the total leukocyte population in a particular tissue was then calculated. The differentiation of positive (stained) and negative (unstained) cells was uniformly maintained by setting the computer to detect a threshold for staining intensity. This enabled consistency to be maintained within a tissue section as well as between sections stained with the same antibody. In the present study, we determined the phenotype of leukocytes in colonic carcinomas by VIA and compared this with results obtained by normal visual analysis. The VIA method showed distinct advantages over normal visual analysis especially in sections which contained moderate numbers of stained cells.     

Molecular identification of pathogenetic IdLNF+1 autoantibody idiotypes derived from the NZBxSWR F1 model for systemic lupus erythematosus

The acceleration of nephritis in SNF(1) mice by CD4(+) T-cell clones reactive with a nephritogenic idiotype, Id(LN)F(1) [1], as well as the ability of anti-Id(LN)F(1) antisera to down-regulate the production of Id(LN)F(+)(1) immunoglobulin (Ig) in vivo and delay nephritis [2], suggests that dysregulation of this idiotype may contribute to the development of SNF(1) nephritis. Herein, we show that a monoclonal Id(LN)F(1)-expressing antibody, 540, significantly (P< or = 0.01) stimulated Id(LN)F(1)-reactive T-cell clones B6 and D2 to proliferate, while other Id(LN)F+1 antibodies did not. Further, injection of 540-producing hybridoma cells into nonautoimmune (SWRxBalb/c)F(1) mice resulted in the deposition of Id(LN)F(+)(1) Ig in the kidneys, in a pattern indicative of early nephritis. To identify the pathogenetic Id(LN)F(1) epitope(s) at the molecular level, we compared the deduced amino acid sequences of the heavy and light chain variable regions of pathogenetic and non-pathogenetic Id(LN)F(1)-expressing Igs 540, 317, and 533. Two overlapping peptides derived from the V(H) sequence of 540 (aa 54-66 and 62-73), which both contain the triple basic amino acid motif K(X)K(X)K, stimulated SNF(1) T cells and T-cell clones B6 and D2. These results further support the involvement of a subset of Id(LN)F(1)-expressing Ig in SNF(1) nephritis.     

Isolation of Campylobacter fetus subsp. jejuni from Bangladeshi children.

To determine the prevalence of infection with Campylobacter fetus subsp. jejuni in Bangladesh, culture surveys were conducted among three populations. In Dacca, Campylobacter was isolated from 5.2% of 97 individuals with clinical dysentery and from 12.3% of 204 patients with only diarrhea. This difference may have resulted from a greater representation of young children in the second group. Campylobacter was isolated from 17.7% of the 141 healthy village children aged 1 to 5.5 years and from 38.8% of the 1-year-old children. More infected children (48%) had a history of recent diarrheal illness than did a group of matched controls (20%; P = 0.016). These findings suggest that campylobacter infection is common for Bangladeshi children. However, this organism may not cause diarrheal illness in all instances in which it is isolated.     

Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity

Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells. Recent results revealed a direct interaction of MIA and epitopes within extracellular matrix proteins including fibronectin. The aim of this study was to analyze functional consequences mediated by this interaction. Here we show that MIA interferes specifically with attachment of melanoma cells to fibronectin, a phenomenon we refer to as active detachment. Antibodies inhibiting binding of alpha4beta1 and alpha5beta1 integrins to fibronectin cross-react specifically with MIA, suggesting that MIA shares significant structural homology with the binding pockets of these integrins and thereby masks the respective epitopes on extracellular matrix molecules. Several peptides derived from fibronectin and from a phage display screening were tested with respect to a potential MIA-inhibitory effect. In vitro tests identified two peptides affecting MIA function; both inhibited growth of melanoma metastases in vivo. In summary, we conclude that MIA may play a role in tumor progression and spread of malignant melanomas via mediating active detachment of cells from extracellular matrix molecules within their local milieu. Further, our results suggest that inhibiting MIA functions in vivo may provide a novel therapeutic strategy for metastatic melanoma disease.     

Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network

BACKGROUND: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known. METHODS: We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age. RESULTS: The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age. CONCLUSIONS: In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth.     

Differential recruitment of CD8+ macrophages during Wallerian degeneration in the peripheral and central nervous system

The strong macrophage response occurring during Wallerian degeneration in the peripheral but not central nervous system has been implicated in tissue remodeling and growth factor production as key requirements for successful axonal regeneration. We have previously identified a population of CD8+ phagocytes in ischemic brain lesions that differed in its recruitment pattern from CD4+ macrophages/microglia found in other lesion paradigms. In the present study we show that crush injury to the sciatic nerve induced strong infiltration by CD8+ macrophages both at the crush site and into the degenerating distal nerve stump. At the crush site, CD8+ macrophages appeared within 24 hours whereas infiltration of the distal nerve parenchyma was delayed to the second week. CD8+ macrophages were ED1+ and CD11b+ but always MHC class II-. Most CD8+ macrophages coexpressed CD4 while a significant number of CD4+/CD8-macrophages was also present. Expression of the resident tissue macrophage marker ED2 was largely restricted to the CD4+/CD8- population. Following intraorbital crush injury to the optic nerve, infiltration of CD8+ macrophages was strictly confined to the crush site. Taken together, our study demonstrates considerable spatiotemporal diversity of CD8+ macrophage responses to axotomy in the peripheral and central nervous system that may have implications for the different extent of axonal regeneration observed in both systems.