Biomedical subjects

F C Schmalstieg

Publications and source records attributed to F C Schmalstieg.

At least 19 recordsLinked to original sources

PubMed2006

The role of the bronchial circulation in the acute lung injury resulting from burn and smoke inhalation.

Smoke inhalation in burn patients is a serious medical problem around the world. Inhalation injury increases mortality in addition to increasing infections, ventilator-days, and hospital stays. There are also large numbers of patients subjected to smoke inhalation without burns from cooking fires, burning crops and forest fires. The injury results in a fall in arterial oxygenation as a result of airway blockade, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated at least in part by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). NO combines with superoxide to form reactive nitrogen species such as peroxynitrite. These reactive nitrogen species can be detected by measuring their reaction products such as 3-nitrotyrosine. The latter is elevated in the airway following smoke/burn injury. The control of NO formation involves poly (ADP ribose) polymerase (PARP) and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. Present data also support a major role for the bronchial circulation in the injury since blockade of bronchial blood flow will also minimize the pulmonary injury. The data suggest that cytotoxins or activated cells are formed in the airway and carried to the parenchyma. These materials cause the formation of oedema and a reduction of PaO(2).

Acute Disease↗

PubMed2001

Trisomy 4 pter-q12 and monosomy of chromosome 13 pter-q12 in a male with deficiency of all blood lymphocyte populations.

A six-year-old male presented with multiple congenital anomalies, mental retardation, developmental delay, and an increased frequency of upper and lower respiratory infections and deficiency of all blood lymphocyte populations. Chromosome analysis showed an unbalanced translocation involving chromosomes 4 and 13, leading to partial trisomy for 4pter-q12 and partial monosomy for 13pter-q13 [karyotype, 46,XY,+der(4)t(4;13)(q12;q12),-13)]. The mother is the carrier of a balanced translocation involving chromosomes 4 and 13. The translocation is known to be segregating for three generations in this family. The child was found to have deficiency of all blood lymphocyte populations, but other hemopoietic lineages appeared to be normal. In addition, his fresh T cells were principally CD45RA+, CD62L+, and deficient in the Fas receptor. This deficiency of all blood lymphocyte populations may be due to an overdose of a gene or genes located in the region of chromosome 4 or a partial deficiency of a gene or genes in the region of chromosome 13 that regulate the development of the lymphocyte lineage. Since the mother contributed two copies of chromosomal region 4pter-q12 and no copy of 13pter-q12, the deficiency of all blood lymphocyte populations in our patient may be the result of either uniparental disomy or imprinting. A maternal granduncle with dissimilar dysmorphic features was not lymphopenic but was neutropenic.

Child↗

PubMed2001

Role of nitric oxide in myocardial dysfunction after combined burn and smoke inhalation injury.

This study tested the hypothesis that nitric oxide (NO) synthesized from inducible NO synthase (iNOS) is responsible for the cardiac dysfunction observed after burn and smoke inhalation injury. Twelve sheep received 40% third-degree burn and smoke inhalation under halothane anesthesia. The animals were divided into two groups: a MEG group [iNOS was inhibited with mercaptoethylguanidine (MEG), a selective inhibitor of iNOS, n=6] and a control group (n=6). The control group showed a significant increase in NO(2)(-)/NO(3)(-) (NO(x)) concentration, metabolite of NO, in plasma after 24 h, whereas the MEG group did not. In the control group, cardiac depression was observed immediately after injury associated with hemoconcentration. Cardiac function returned to a normal level within 6 h following injury. In the control group cardiac dysfunction was observed again after 24 h although the hemoconcentration peaked at 24 h after injury and then began to resolve. In the MEG group, cardiac depression and hemoconcentration were not observed. The present data suggest that cardiac depression seen with this combination injury consists of two phases and that the later phase is mediated by iNOS-NO.

Analysis of Variance↗

PubMed2001

Genesis of progressive T-cell deficiency owing to a single missense mutation in the common gamma chain gene.

Patients with a moderate X-linked combined immunodeficiency (XCID) owing to a single missense mutation in the common gamma chain (gammac) gene (L-->Q271) were found to have a progressive T-cell deficiency. Blood T cells from four older subjects with XCIDL-->Q271 were studied to ascertain the basis of that progression. Few CD4+ T cells displayed the phenotype (CD45RA+ CD62L+) or deletion circles from T-cell receptor (TCR) Vbeta-gene rearrangements found in recent thymic emigrants. These deficiencies were more severe in older males with XCIDL-->Q271. Relative frequencies of fresh CD4+ and CD8+ T cells that bound annexin V, an early indicator of programmed cell death, or propidium iodide, an indicator of cell necrosis, were greater in XCIDL-->Q271 T cells than in normal fresh T cells. The binding of annexin V and propidium iodide to XCIDL-Q271 T cells increased marginally after stimulation with anti-CD3, but binding by fresh or stimulated XCIDL-Q271 T cells exceeded that found in normal stimulated T cells. Also, telomeres from XCIDL-->Q271 CD4+ T cells were shortened in these patients compared to normal young adults. It therefore appears that the thymus is dysfunctional and that mature T cells are not effectively rescued from apoptosis or replication senescence via gamma-mediated pathways in XCIDL-->Q271.

Adolescent↗

PubMed2001

Blood gammadelta T cells and gammadelta TCR V gene specificities in a single missense mutation (L-->Q271) in the common gamma chain gene.

The numbers of blood CD4+, CD8+, and CD4-CD8- T cells bearing alphabeta T-cell receptor (TCR) or gammadelta TCR molecules in males with a single missense mutation (L-->Q271) in the common gamma chain gene (gamma(c)) were investigated by flow cytometry. Virtually all XCIDL-->Q271 blood T cells that were CD4+ or CD8+ displayed alphabeta TCR but no gammadelta TCR. In contrast, CD4-CD8- T cells from affected males usually displayed gammadelta TCR, but no alphabeta TCR. The gammadelta TCR specificities were also studied. Except for the oldest subject, there was a direct relationship between blood CD3+ T cells that displayed gammadelta TCR and Vgamma9 and Vdelta2a specificities. Relative frequencies of CD3+ blood T cells that were Vgamma9+ or Vdelta2a+ were inversely related to age. In the oldest patient, the only detected gammadelta TCR specificity was Vdelta1. Thus, in contrast to mice with no gamma(c), XCIDL-Q271 blood T cells that bear gammadelta TCR with Vgamma9/Vdelta2a specificities develop but then decline in late childhood and thereafter. TCR with the Vdelta1 specificity then appear in older survivors with XCIDL-->Q271.

CD4-Positive T-Lymphocytes↗

PubMed2001

Pathophysiological analysis of combined burn and smoke inhalation injuries in sheep.

We investigated the pathophysiological alterations seen with combined burn and smoke inhalation injuries by focusing on pulmonary vascular permeability and cardiopulmonary function compared with those seen with either burn or smoke inhalation injury alone. To estimate the effect of factors other than injury, the experiments were also performed with no injury in the same experimental setting. Lung edema was most severe in the combined injury group. Our study revealed that burn injury does not affect protein leakage from the pulmonary microvasculature, even when burn is associated with smoke inhalation injury. The severity of lung edema seen with the combined injury is mainly due to augmentation of pulmonary microvascular permeability to fluid, not to protein. Cardiac dysfunction after the combined injury consisted of at least two phases. An initial depression was mostly related to hypovolemia due to burn injury. It was improved by a large amount of fluid resuscitation. The later phase, which was indicated to be a myocardial contractile dysfunction independent of the Starling equation, seemed to be correlated with smoke inhalation injury.

Animals↗

PubMed2001

Role of nitric oxide in vascular permeability after combined burns and smoke inhalation injury.

Patients with severe burn and/or smoke inhalation injury suffer both systemic and pulmonary vascular hyperpermeability. We hypothesized that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) plays a role in the changes in microvascular permeability seen with this injury. To test the hypothesis, we administered mercaptoethylguanidine (MEG), a selective iNOS inhibitor, to conscious sheep subjected to a combined smoke inhalation and third-degree burn injury to 40% of total body surface area. The sheep were surgically prepared for chronic study with lung and prefemoral lymph fistulas in order to estimate microvascular permeability. Both the groups and a control group of animals showed an increase in iNOS protein and message in their lungs. The control animals showed significant increases in either plasma or lymph NO2-/NO3- (NOx) concentration at 24 h after injury, with associated cardiac depression and hemoconcentration. The airway epithelium stained for nitrotyrosine. In the treatment group, NOx did not increase significantly in plasma or lymph throughout the experiment, there was no nitrotyrosine staining, hemodynamic depression was not observed, and the fluid requirement was significantly less than in the control group. Changes in pulmonary microvascular permeability were significantly suppressed by inhibition of iNOS. However, there was no significant difference between the two study groups in the microvascular permeability of burned tissue. These data suggest that NO produced by iNOS plays an important role in the changes in systemic and pulmonary microvascular permeability in combined smoke inhalation/third-degree burn injury, but does not affect the vascular permeability of third-degree-burned tissue in this type of injury.

Animals↗

PubMed2000

Successful bone marrow transplantation in a patient with Schimke immuno-osseous dysplasia.

Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Antigens, CD↗

PubMed1999

Immunodeficiency due to a unique protracted developmental delay in the B-cell lineage.

A unique immune deficiency in a 24-month-old male characterized by a transient but protracted developmental delay in the B-cell lineage is reported. Significant deficiencies in the number of B cells in the blood, the concentrations of immunoglobulins in the serum, and the titers of antibodies to T-dependent and T-independent antigens resolved spontaneously by the age of 39 months in a sequence that duplicated the normal development of the B-cell lineage: blood B cells followed by immunoglobulin M (IgM), IgG, IgA, and specific IgG antibodies to T-independent antigens (pneumococcal polysaccharides). Because of the sequence of recovery, the disorder could have been confused with other defects in humoral immunity, depending on when in the course of disease immunologic studies were conducted. Investigations of X-chromosome polymorphisms suggested that the disorder was not X linked in that the mother appeared to have identical X chromosomes. An autosomal recessive disorder involving a gene that controls B-cell development and maturation seems more likely. In summary, this case appears to be a novel protracted delay in the development of the B-cell lineage, possibly due to an autosomal recessive genetic defect.

B-Lymphocytes↗

PubMed1999

Role of L-selectin in physiological manifestations after burn and smoke inhalation injury in sheep.

The effects of a monoclonal antibody against L-selectin [leukocyte adhesion molecule (LAM)1-3] on microvascular fluid flux were determined in conscious sheep subjected to a combined injury of 40% third-degree burn and smoke inhalation. This combined injury induced a rapid increase in systemic prefemoral lymph flow (sQlymph) from the burned area and a delayed-onset increase in lung lymph flow. The initial increase in sQlymph was associated with an elevation of the lymph-to-plasma oncotic pressure ratio; consequently, it leads to a predominant increase in the systemic soft tissue permeability index (sPI). In an untreated control group, the increased sPI was sustained beyond 24 h after injury. Pretreatment with LAM1-3 resulted in earlier recovery from the increased sPI, although the initial responses in sQlymph and sPI were identical to those in the nontreatment group. The delayed-onset lung permeability changes were significantly attenuated by pretreatment with LAM1-3. These findings indicate that both leukocyte-dependent and -independent mechanisms are involved in the pathogenesis that occurs after combined injury with burn and smoke inhalation.

Animals↗

PubMed1998

CD45 partially mediates heterotypic adhesion between murine leukemia/lymphoma cell line L5178Y and marrow stromal cells.

We raised mAbs to whole L5178Y leukemia/lymphoma (LL) cells to identify adhesion proteins involved in adherence between LL cells and marrow stromal cells. One mAb, 4C, and its subclones 4C.1 and 4C.2 inhibited adherence of L5178Y LL cells to MLT. a nontransformed murine marrow stromal cell line. These MoAbs are directed against CD45RA. Control anti-CD45 mAbs and isotype mAbs were non-inhibitory. Other anti-CD45 mAbs, M1/9.3, RA3-3A1/6.1 and RA3-2C2/1 do not compete with mAb 4C.1 for binding to the L5178Y cell surface, but mAb 4C.1 competes for binding of mAb RA3-2C2/1. Effects of mAb 4C on tyrosine-phosphatase activity of CD45 in L5178Y cells are minimal, suggesting direct involvement of CD45 as an adhesion protein.

Animals↗

PubMed1996

Cytokines in human milk: properties and potential effects upon the mammary gland and the neonate.

Epidemiologic and immunologic studies of breastfed and nonbreastfed infants and investigations of certain biologic activities in human milk led to the identification of immunomodulating agents in human milk. Among them were the cytokines interleukin-1 beta (IL-1 beta); IL-6, IL-8, IL-10, granulocyte-colony stimulating factor, macrophage-colony stimulating factor (M-CSF), tumor necrosis factor-alpha, interferon-gamma, epithelial growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and TGF-beta 2. Interferon-gamma may originate from T cells in milk; EGF, TGF-alpha, TGF-beta, M-CSF, IL-6, and IL-8 may be produced by mammary gland epithelium. Based upon their known functions, we hypothesize that cytokines influence the development and immunologic function of the mammary gland and the neonate. Those in vivo functions remain to be defined by future investigations.

Adjuvants, Immunologic↗

PubMed1995

Heterotypic adherence between human B-lymphoblastic and pre-B-lymphoblastic cells and marrow stromal cells is a biphasic event: integrin very late antigen-4 alpha mediates only the early phase of the heterotypic adhesion.

Heterotypic adherence between marrow stromal cells (MSC) and lymphoblastic cells is essential for normal lymphopoiesis and malignant lymphoblastic development. However, the detailed molecular mechanisms by which this heterotypic adherence occurs are poorly understood. The cell-cell interactions between a B-lymphoblastic cell line (UTMB-460) and a pre-B-cell line (NALM-6) with MSC were chosen as models to investigate potential mechanisms and adhesion molecules involved in the apposition between normal and malignant lymphoblastic cells and MSC. A parallel-flow detachment assay (PFDA) and a 51Cr detachment assay, coupled with monoclonal antibody (MoAb) blocking experiments, were used to quantify the attachment of lymphoblastic cells to confluent monolayers of MSC. The apposition between MSC and B-lymphoblastic cells (UTMB-460 cells) was investigated for variable time periods, ranging from 1 minute to 4 hours. Results from the temporal study suggest that the heterotypic adherence of the B-lymphoblastic cells to MSC is a biphasic event and the interactions occur rapidly (< or = 1 minute) after the two cells come into contact. More specifically, the early phase of adherence (< or = 15 minutes) solely involves very late antigen-4 alpha (VLA-4 alpha)/vascular cell adhesion molecule 1 (VCAM-1) interactions, as evidenced by the nearly complete inhibition (93%) of UTMB-460 cell adherence in the presence of anti-VLA-4 alpha. The late phase (> or = 30 minutes) proceeds despite the continuous presence of anti-VLA-4 alpha. In addition, the late-phase adherence is not affected by MoAbs to LFA-1, CD44, VCAM-1, E-selectin, or L-selectin, which suggests the possible involvement of other adhesion molecules. Adherence of pre-B-lymphoblastic cells (NALM-6) to MSC is also biphasic. Integrin VLA-4 is again a major player in the early phase of pre-B-lymphoblastic cell/MSC interactions. The early phase of adherence may be important in homing of the malignant lymphoblastic cells to the MSC and the late phase in retention of malignant lymphoblastic cells in the bone marrow.

Antibodies, Monoclonal↗

PubMed1995

Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (CAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma c gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.

Amino Acid Sequence↗

PubMed1995

Interleukin-10 in human milk.

The concentrations of immunoreactive IL-10 in the aqueous fraction of 20 specimens of human milk obtained during the first 80 h of lactation and stored at -60 degrees C ranged from 66 to 9301 pg/mL (mean +/- SD, 3304 +/- 3127 pg/mL). IL-10 was present also in the lipid layer of milk. Gel filtration revealed that IL-10 was located in a high molecular weight fraction, where certain other cytokines in human milk have been found. In addition, immunoreactive IL-10 in milk increased after treatment with sodium taurocholate. Bioactive IL-10 was demonstrated by the finding that human milk inhibited [3H]thymidine uptake by human blood lymphocytes and that inhibition was partly overcome by concomitant incubation with antibodies to human IL-10. IL-10 mRNA but no protein product was found in cultured human mammary epithelial cells. Some IL-10 was associated with preparations of human milk leukocytes, but the data did not suggest that the cells were producing the cytokine. Bioactive IL-10 in a possible protected compartment suggests that IL-10 in human milk may have immunomodulating, antiinflammatory effects on the alimentary tract of the recipient infant.

Adult↗

PubMed1995

Comparison of pulmonary neutrophils in the adult and neonatal rat after hyperoxia.

The mechanisms of the increased tolerance to hyperoxia of neonatal animals of many species is incompletely understood. To investigate the etiology of this difference we compared neutrophil entry into the lungs of neonatal and adult rats after hyperoxic exposure. Adult rats were studied after exposure to > or = 98% O2 for 60 h and neonatal rats after 3 and 7 d. Neonatal survival was prolonged compared with that reported for adult rats (77% after 7 d of exposure). In adult rats, there were significant increases in pulmonary neutrophils after 60 h of O2 exposure. In neonatal rats, these changes were not evident after 72 h of exposure, but pulmonary neutrophils increased after 7 d of hyperoxia. Before mortality, pulmonary neutrophils were distributed differently in the age groups. After 7 d of O2 exposure in the neonates, total neutrophil counts in lung tissue (21.92 +/- 7.29 per cm2 grid) and lung myeloperoxidase (0.085 +/- 0.02 U/mg protein) remained significantly lower than in adults after 60 h of O2 exposure (41.44 +/- 9.08 per cm2 grid and 0.411 +/- 0.085 U/mg protein, respectively). However, in histologic specimens, O2-exposed neonates had higher percentages of neutrophils free in the alveolar air space than did adults, corresponding to a trend toward higher neutrophil counts in bronchoalveolar lavage fluid in the neonates. It appears that, in addition to delay in neutrophil influx into the lung, neonatal rats have lowered retention of neutrophils to the alveolar tissue.

Aging↗

PubMed1994

Thymic hypoplasia and T-cell deficiency in ectodermal dysplasia: case report and review of the literature.

Ectodermal dysplasia is a heterogeneous disorder that includes a constellation of congenital malformations occasionally associated with mild to moderate immune dysfunction. In this report, we describe a female infant with ectodermal dysplasia who was found to have thymic hypoplasia but no other phenotypic features of the DiGeorge anomalad. She experienced Candida parapsilosis sepsis at 1 week of age and a skin infection with Mycobacterium chelonii at 6 months. The numbers of blood B cells were normal and serum immunoglobulins normal to slightly reduced, but serum antibody responses of all immunoglobulin isotypes to protein immunogens were absent. Blood T cells were profoundly reduced and proliferative responses of T cells to mitogens were blunted. In contrast, there was an increased number of natural killer (NK) cells and increased NK activity in the blood. Over the first year of life, some of the immunodeficiencies resolved. Although the numbers of blood T cells (17% of total lymphocytes) remained low, proliferative responses to mitogens normalized and specific antibody responses improved. It seems likely that the thymic hypoplasia in this case was due to a paucity of ectodermal elements in the developing thymus, and that the immune defects were largely secondary to that event. In that respect, this human model of ectodermal dysplasia and thymic hypoplasia resembled the ectodermal/thymic defects found in the nude mouse.

Cell Line↗

PubMed1994

Production of interleukin-6 and interleukin-8 by human mammary gland epithelial cells.

The production of transforming growth factor-beta 2 (TGF-beta 2), interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) by spontaneously immortalized human mammary gland epithelial cells of non-malignant origin and the effect of prolactin upon the production of those cytokines were investigated. Cells were cultured on plastic with epithelial growth factor, insulin, and hydrocortisone. Cytokines were quantified by enzyme-immunoassays. The cells produced IL-6 and IL-8, but no detectable TGF-beta 2, IL-1 beta, or TNF-alpha. Although prolactin enhanced the uptake of [3H]thymidine, it did not alter the production of cytokines/interleukins. Because of the marked production of IL-8 by mammary epithelium and a past report of TGF activity in human milk, those agents were quantified in human milk. The mean +/- S.D. concentrations of IL-8 and TGF-beta 2 in human milk obtained in the first 3 days of lactation were 3684 +/- 2910 and 130 +/- 108 pg/ml, respectively. Thus, IL-8 and TGF-beta 2 are normal constituents in human milk, and human mammary gland epithelium may be responsible for producing some of the IL-6 and IL-8 in human milk.

Adult↗