Biomedical subjects

C Langston

Publications and source records attributed to C Langston.

At least 19 recordsLinked to original sources

PubMed2000

Pulmonary infiltrates with eosinophilia syndromes in children.

Pulmonary infiltrates with eosinophilia (PIE) are a group of heterogeneous disorders having the common findings of lung disease and eosinophilia in the peripheral blood, bronchoalveolar lavage fluid, or pulmonary interstitium. Eleven cases of PIE syndromes were identified through a retrospective and prospective chart review: drug-induced (2), acute eosinophilic pneumonia (3), infant pulmonary eosinophilia (2), parasite-induced (2), Churg-Strauss syndrome (1), and atypical chronic PIE (1). Patient demographics, clinical presentation, and disease severity varied considerably among groups. Therapeutic interventions included bronchodilators (10), oxygen (7), corticosteroids (9), and mechanical ventilation (3). A single patient with acute eosinophilic pneumonia died. Our experience suggests that PIE syndromes are rare in childhood and that clinical presentation can vary widely. Because of the potential for significant morbidity and mortality, aggressive diagnostic evaluations are warranted, particularly in children with respiratory failure of unknown etiology.

Adolescent↗

PubMed1999

Reply.

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Journal Article↗

PubMed1999

Unexpected non-HIV causes of death in children born to HIV-infected mothers. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group.

INTRODUCTION: A high incidence of sudden, unexplained deaths in infants born to HIV-infected mothers has been noted in several epidemiologic studies. During the course of a prospective study of heart and lung disease in children born to HIV-infected mothers, we noted that of 5 unexpected non-HIV-related deaths, 4 were attributed to traumatic events. METHODS: The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2) study is a multicenter, prospective investigation of the incidence of heart and lung disease in HIV-infected children. A total of 805 children were enrolled and followed for 5 to 7 years with serial immunologic, pulmonary and cardiac function studies. During the study, a multidisciplinary committee was formed to review the cause of death for those patients who died. The committee used results of pulmonary, cardiac, and laboratory tests, hospital summaries, as well as autopsy and coroners' reports. The committee formed a consensus about the underlying and contributing causes of death for each subject using the definitions from the 1989 US Standard Certificate of Death. RESULTS: A total of 121 deaths occurred during the course of the P2C2 study. Of the 121 deaths, 5 were traumatic or sudden and unexpected and judged by the Mortality Review Committee to be unrelated to HIV infection. The median age at the time of death was 1.3 months and ranged from 1.2 to 37.8 months. Two infants died of trauma: a skull fracture and subdural hematoma in 1 infant and multiple skeletal fractures consistent with battered child syndrome in the other infant. The third infant died of accidental suffocation at home at 1.2 months of age. The fourth infant died suddenly and unexpectedly at home at 1.3 months of age. The autopsy showed no sign of HIV or other infection and was consistent with sudden unexpected death or SIDS. One non-HIV-related death occurred when a 38-month-old child died together with the mother in an unwitnessed drowning. The cumulative mortality rate attributable to trauma and sudden death at 4 months of age was 0.95% (95% CI: 0.02-1. 87%) and the infant mortality rate was 9.5/1000 live births. Three children were born prematurely at 30, 33, and 36 weeks' gestational age, respectively, and 3 mothers admitted using recreational drugs before or during pregnancy. DISCUSSION: These traumatic and sudden non-HIV-related deaths accounted for 4.1% (5/121) of the deaths during the entire P2C2 study period and for 20% (4/20) of the deaths in the first year of life. Four deaths were attributable to accidental and nonaccidental trauma rather than to other common causes of infant death. One death was a sudden unexpected death, similar to SIDS, a leading cause of infant death in the United States. The majority of previously reported non-HIV-related deaths in infants born to HIV-infected mothers have been attributed to SIDS or to unexplained sudden death. In contrast with other reports, 4 of the 5 children in our series died of accidental or nonaccidental trauma and only 1 was a sudden unexplained death. It is unlikely that HIV exposure is related directly to the deaths described in this report; however, maternal HIV infection may be a marker for factors that place the child at risk for sudden or traumatic death. SUMMARY: This report suggests that children born to HIV-infected mothers may be at increased risk for traumatic or sudden, unexplained, non-HIV-related death. These children seem to be at risk regardless of their own HIV infection status. Furthermore, 4 of the deaths in our study occurred within the first few months of life, suggesting that this is a period of increased vulnerability. Studies to identify associated risk factors for non-HIV-related deaths are needed to identify these high-risk infants. Children born to HIV-infected mothers may be more vulnerable than was recognized previously and may be in need of increased social services, especially in early infancy.

Cause of Death↗

PubMed1998

High doses of a helper-dependent adenoviral vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity.

Optimal gene therapy for many disorders will require efficient transfer to cells in vivo, high-level and long-term expression, and tissue-specific regulation, all in the absence of significant toxicity or inflammatory responses. While recombinant adenoviral vectors are efficient for gene transfer to hepatocytes, their usefulness is limited by short duration of expression related, at least in part, to immune responses to viral proteins and by a low capacity for foreign DNA. A number of systems have been developed for producing adenoviral vectors devoid of all viral coding sequences. Using AdSTK109, a vector lacking all viral coding sequences and carrying the complete human alpha1-antitrypsin (hAAT) genomic DNA locus, we have demonstrated sustained expression for longer than 10 months in mice. Utilizing high doses of this vector for hepatic gene transfer in mice, we find that supraphysiological levels of hAAT can be achieved without hepatotoxicity.

Adenoviridae↗

PubMed1998

Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1.

Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia characterized by incomplete ossification of cartilage anlagen. Histologically, the cartilage contains irregular clusters that occasionally include giant chondrocytes. Pulmonary hypoplasia is a characteristic finding that has been presumed to be the cause of neonatal lethality. We report on a male fetus with AO1 and document the early ultrasonographic/ radiologic progression of this disorder from 15 weeks gestation until delivery at 41 weeks. While the radiological findings we describe are typical of AO1 by the lack of proximal and middle phalangeal ossification, the complete radiological picture showed considerable overlap with boomerang dysplasia. Although pulmonary hypoplasia was present, it was moderate and considered unlikely to be the sole cause of death. Detailed neonatal and postmortem examination showed severe subglottic hypoplasia and tracheomalacia. The tracheal walls were supported by thin and pliable cartilaginous plates that allowed luminal collapse with minimal pressure. The marked luminal narrowing, tracheomalacia, and temporal proximity of extubation to demise support tracheal collapse as a major contributor to the death in AO1. The detailed description of this patient should contribute to earlier diagnosis of this condition; anticipation of the poor prognosis in AO1 is essential for appropriate genetic counseling of the parents and for determining postnatal treatment options.

Abnormalities, Multiple↗

PubMed1998

Toxicological comparison of E2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery.

Second-generation adenoviral vectors, mutated in E2a, have been proposed to decrease host immune responses against transduced cells, reduce toxicity, and increase duration of expression as compared with first-generation vectors deleted only in E1. To test these hypotheses further, we have developed an E2a-deleted adenoviral vector expressing human alpha1-antitrypsin (hAAT). Toxicity of first-generation and E2a-deleted vectors, as determined by hematological indices, liver function tests, and histological analyses, was evaluated in C3H mice for 21 days after vector administration at increasing doses starting at 1 x 10(12) particles/kg. Both vectors induced dose-dependent abnormalities including transient thrombocytopenia, elevated ALT levels in serum, and increased hepatocyte proliferation followed by inflammation and then hypertrophy. Differences in the ratio of particles to plaque-forming units among vector preparations led to differences in hAAT expression at similar particle doses. There were no differences in toxicity between the two vectors when measured at matching levels of hAAT expression. However, the E2a-deleted vector was demonstrated to have slightly reduced hepatocyte toxicity at an intermediate particle dose. This suggests that hepatocyte toxicity is related primarily to viral entry and expression, rather than to the presence of noninfectious particles, and implies that vectors with complete elimination of viral gene expression, such as vectors with all viral coding sequences deleted, are likely to have substantial advantages in terms of safety and toxicity.

Adenoviridae↗

PubMed1998

Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity.

Many applications for human gene therapy would be facilitated by high levels and long duration of physiologic gene expression. Adenoviral vectors are frequently used for gene transfer because of their high cellular transduction efficiency in vitro and in vivo. Expression of viral proteins and the low capacity for foreign DNA limits the clinical application of first- and second-generation adenoviral vectors. Adenoviral vectors with all viral coding sequences deleted offer the prospect of decreased host immune responses to viral proteins, decreased cellular toxicity of viral proteins and increased capacity to accommodate large regulatory DNA regions. Currently most vectors used in vivo for preclinical and clinical studies express cDNAs under the control of heterologous eukaryotic or viral promoters. Using an adenoviral vector with all viral coding sequences deleted and containing the complete human alpha1-antitrypsin (PI) locus, we observed tissue-specific transcriptional regulation in cell culture and in vivo; intravenous injection in mice resulted in high levels of very stable expression for more than ten months and decreased acute and chronic toxicity. These results indicate significant advantages of regulated gene expression using genomic DNA for gene transfer and of adenoviral gene transfer vectors devoid of all viral coding sequences.

Adenoviridae↗

PubMed1998

Congenital varicella-zoster virus infection and Barrett's esophagus.

Congenital varicella syndrome is a rare complication of varicella-zoster virus (VZV) infection during pregnancy. An infant was exposed to VZV at 18.5 weeks of gestation and had eye and skin abnormalities at birth and persistent feeding difficulties, prompting esophageal biopsies at 12 days and 20 and 20.5 months of age. Esophageal tissues demonstrated specialized intestinal metaplasia (Barrett's esophagus). VZV DNA (in situ hybridization) and proteins (immunohistochemistry and polymerase chain reaction) were found in esophageal epithelial cells adjacent to the Barrett's lesion. Immediate-early 63 protein (IE63) of VZV was demonstrated in the day 12 specimen, and IE62 and the late VZV glycoprotein E (gE) were found in the 20-month specimen. Clinical and endoscopic improvement followed fundoplication and acyclovir therapy, but VZV DNA and IE62 persisted in esophageal tissue. These findings associate VZV with specialized intestinal metaplasia within the esophagus and suggest a novel site for either latent or active VZV infection.

Barrett Esophagus↗

PubMed1998

Histochemical analysis of mucous cells of congenital adenomatoid malformation of the lung: insights into the carcinogenesis of pulmonary adenocarcinoma expressing gastric mucins.

Adenocarcinomas expressing gastric mucins often are accompanied by ectopic gastric mucosa or pyloric metaplasia. We have previously described mucinous bronchioloalveolar carcinoma (mucinous BAC) producing gastric mucins. In the lung tissue, mucous cells seemingly similar to gastric mucous cells are present in congenital adenomatoid malformation (CAM). We assessed 26 cases of CAM morphologically and histochemically. Mucous cells were detected in 12 of 26 cases. These mucous cells displayed papillary growth in cystic spaces and proliferated along alveolar walls. Mucous cells in the papillary, configuration stained with galactose oxidase cold thionine Schiff reaction, and those in indented portions stained with paradoxical concanavalin A stain in all 8 cases and with pepsinogen II in 5 of 8 cases, which were available for histochemical analysis. Pepsinogen I was negative. Mucous cells in CAM were identical to those of pyloric mucosa and could be considered candidates for the origin of mucinous BAC producing gastric mucins.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1997

Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors.

Experiments designed to evaluate the effect of deletion of E2a on duration of expression using adenoviral vectors led to a series of observations regarding host responses to adenoviral vectors and reporter proteins. In studies using human alpha1-antitrypsin (hAAT) as a reporter gene, we found that the duration of expression is very brief for C3H/J and CBA/J mice but is prolonged for C57BL/6J mice, that disappearance of hAAT from the blood is correlated with the appearance of antibodies, and that immunization against hAAT can prevent appearance of the protein in the blood after administration of an adenoviral vector. Deletion of E2a in hAAT vectors did not prolong expession in C3H/J or CBA/J mice and did not shorten duration of expression in C57BL/6J mice. Using similar vectors expressing Escherichia coli beta-galactosidase (beta-Gal) in immunocompetent mice, short duration of expression with a beta-Gal reporter was remarkably different from the long expression with an identical vector expressing hAAT in C57BL/6J. In the case of vectors expressing hAAT, adenoviral sequences persisted in the liver, and inflammatory responses were minimal compared to vectors expressing beta-Gal, where adenoviral sequences disappeared from the liver concomitant with a prominent inflammatory response. The duration of expression of beta-Gal in hepatocytes was increased in transgenic mice expressing the reporter in keratinocytes, indicating that host immune responses to the reporter can limit duration of expression. Dosage studies indicated that persistence of expression of hAAT can be markedly decreased by administration of high doses of vector in a manner consistent with a nonimmune-mediated toxicity following injection. These experiments indicate that host responses to reporter genes rather than host responses to adenoviral proteins can be the primary determinant of duration of expression under many experimental conditions.

Adenoviridae↗

PubMed1997

Exogenous surfactant enhances the delivery of recombinant adenoviral vectors to the lung.

Somatic gene therapy for pulmonary diseases must be accomplished in vivo, requiring the spread of a gene transfer vector across a vast expanse of respiratory epithelium. Surfactant, a naturally occurring protein and lipid mixture used to treat the respiratory distress syndrome of prematurity, disperses rapidly and evenly throughout the lung. We employed exogenous bovine surfactant (Survanta beractant) as a carrier vehicle for pulmonary delivery of a recombinant adenovirus expressing beta-galactosidase (beta-Gal). Rats treated with an adenovirus-beractant mixture demonstrated more uniform lobar distribution of transgene expression than rats treated with the same amount of virus in saline. Tissue homogenates were examined for quantitative beta-Gal expression by reaction with o-nitrophenol beta-n-galactopyranoside (ONPG). The degree of beta-Gal activity was affected by both the volume and type of carrier used to deliver the virus. At low volumes (0.5 ml, 1.3 ml/kg), beractant-treated animals demonstrated significantly greater pulmonary beta-Gal activity than saline-treated animals (p < 0.002) and untreated controls. At high volume (1.2 ml, 4 ml/kg), average beta-Gal activity was similar between groups treated with beractant or saline, but was more variable within the saline treated group. Higher volumes of delivery medium were associated with increased levels of beta-Gal expression regardless of the carrier used. Survanta was well tolerated by the animals and did not affect the duration of transgene expression. Exogenous beractant provides a useful medium for delivering recombinant adenoviruses to the lung when diffuse distribution of transgene expression is desired.

Adenoviridae↗

PubMed1997

Severe necrotizing pneumonitis in a child with Mycoplasma pneumoniae infection.

Lower respiratory tract illness due to Mycoplasma pneumoniae is typically mild and self-limited. There are, however, numerous reports of serious and life-threatening cases of mycoplasma pneumonia in adults. We present a case involving a 4-year-old girl with severe mycoplasma infection and necrotizing pneumonitis requiring lobectomy. A detailed pathological report is provided.

Child, Preschool↗

PubMed1997

Role of placental cytokines and inflammation in vertical transmission of HIV infection.

In light of new evidence suggesting that maternal human immunodeficiency virus (HIV) infection produces at least a three-fold increase in the number of early spontaneous abortions, it is important to search for factors that may predispose to fetal wastage. Immunological factors are thought to play an important role in permitting the HLA-disparate fetus to continue to term, despite powerful maternal immune forces capable of rejection. In the context of a heightened incidence of spontaneous abortion in HIV infection, evidence is now accumulating that implicates an imbalance in immune factors in contributing to this fetal loss. Soluble immune factors, such as cytokines, have been suggested as contributing agents to recurrent spontaneous abortions. Inflammatory cytokines-interleukin 1beta, interleukin 6 and tumor necrosis factor alpha-have been measured in isolated placental trophoblastic cells in HIV-infected and non-infected pregnant women in an attempt to explore this hypothesis. These inflammatory cytokines and their messenger RNAs were significantly elevated before and after stimulation in HIV-infected women, supporting the belief that HIV-infected women present their fetuses a milieu of imbalanced immune factors capable of contributing to immunological rejection. In addition, these elevated inflammatory cytokine levels may contribute to HIV disease progression in fetuses by virtue of activation of HIV gene transcription factors similar to what has been demonstrated in in vitro systems. We therefore propose that HIV infection in pregnant women produces an altered state of certain soluble immune factors, which in concert with other immune factor abnormalities, such as loss of immune selection in the fetal thymus, predisposes the fetus to advanced HIV infection and possible spontaneous abortion.

Abortion, Spontaneous↗

PubMed1997

Early spontaneous abortions and fetal thymic abnormalities in maternal-to-fetal HIV infection.

The thymus is thought to play a major role in the immunopathogenesis of human immunodeficiency virus (HIV) infection, particularly in maternal-to-fetal HIV transmission. Characteristic lesions of the HIV-infected thymus include a prominent CD4+ CD8+ T lymphocyte depletion at the corticomedullary junction, the region of the thymus where immune selection occurs. At least threefold excess early spontaneous abortions were noted in a cohort of 124 HIV-infected pregnant women. In these 13 abortuses a very high rate (54%) of HIV vertical transmission was documented, with the thymus gland particularly affected. It is possible that the thymic insult in HIV-infected fetuses contributes to immune rejection of the fetus, possibly by an imbalance of maternal and fetal T1- and T2-type cytokines, known to be important in HIV disease progression. We propose, therefore, that the early spontaneous abortions occurring in HIV-infected pregnant women are due, at least in part, to abnormal immune forces created by HIV infection of the thymus.

Abortion, Spontaneous↗

PubMed1997

Inflammatory cytokine expression is correlated with the level of human immunodeficiency virus (HIV) transcripts in HIV-infected placental trophoblastic cells.

The inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) have been associated with increased human immunodeficiency virus (HIV) expression and enhanced lymphocyte adhesion to trophoblastic cells in experimental systems. To determine if there is a correlation between the expression of these cytokines and the levels of HIV transcripts in trophoblasts of term placentas from HIV-infected women, we studied the placentae of 30 HIV-positive and 13 control gravidae. Twenty-three of the HIV-positive women received zidovudine (ZDV) as prophylaxis against HIV vertical transmission; only one of the seven women who did not receive ZDV was a transmitter, for an overall vertical transmission rate of 3.8%. Cytokine production was measured by enzyme-linked immunosorbent assay in the supernatants of trophoblastic cell cultures. Additionally, cytokine transcripts and HIV gag sequences were determined by a quantitative reverse transcription-PCR assay. In general, trophoblastic cells of HIV-positive placentas expressed significantly higher levels of IL-1beta, IL-6, and TNF-alpha than those of control placentas. All placentas from HIV-positive women expressed HIV gag transcripts at either a low (<156 copies per microg of total RNA) or a high (>156 copies per microg of total RNA) level. There was a statistically significant positive association between the basal level of TNF-alpha production and the level of HIV gag transcripts of HIV-positive placental trophoblastic cells. Nevertheless, these data, coupled with a low transmission rate, would indicate that some other factors, perhaps working in concert with cytokines, are necessary for vertical transmission of HIV from mother to infant.

Cells, Cultured↗

PubMed1997

Practice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists.

The Placental Pathology Practice Guideline Development Task Force, a multidisciplinary group, has prepared this guideline to assist those involved with placental examination. It provides recommendations related to indications and methods for placental examination as well as sample worksheets. An algorithm for the handling of placentas summarizes the recommendations of the guideline. A summary of specific findings of placental examination together with their pathogenesis and clinical associations is also provided. Recommendations related to reporting with sample reporting formats are included. The guideline is intended as an educational tool, and its use should be guided by the individual circumstances and care setting of specific cases.

Humans↗

PubMed1996

PCR diagnosis of viral pneumonitis from fixed-lung tissue in children.

Viral infection in children commonly causes acute lung disease leading to respiratory decompensation requiring intensive supportive therapy. Definitive diagnosis of the causative virus may be difficult, relying on serologic data since viral cultures are frequently negative; lung biopsy may be necessary to increase the diagnostic yield. The objective of this study was to develop a rapid and sensitive diagnostic method using the polymerase chain reaction (PCR). Analyzing Formalin-fixed lung tissue from autopsies of 32 patients with pneumonitis in whom cultures, serology, and histopathology results were blinded to the investigators, and 10 negative control samples, PCR was performed for cytomegalovirus, adenovirus, enteroviruses, herpes simplex virus, and Epstein-Barr virus. Among the 32 affected specimens, 7 were culture-positive for a specific virus in the lung; 6/7 of these were PCR-positive for the identical virus. In the culture-positive specimen not PCR amplified, influenza B was the cultured agent, but this virus was not evaluated by PCR. In the remaining 25 samples which were culture-negative, 11 were PCR-positive. All 10 negative controls were negative by PCR. Three specimens with CMV inclusions but culture-negative were also negative by PCR. We conclude that PCR is sensitive and accurate in the evaluation of lung tissue for viral pneumonitis.

Adolescent↗

PubMed1996

P-selectin is upregulated early in the course of hyperoxic lung injury in mice.

While treatment with supplemental oxygen is often essential in patients with lung disease, prolonged therapy may cause lung injury by itself. Although the mechanisms responsible for initiating hyperoxic lung damage almost certainly involve primary oxidative transformations, the possible contributions of inflammation to the tissue injury have been attracting increasing research activity. Increases in intercellular adhesion molecule-1 (ICAM-1) coincide with the inflammation, but in other models of inflammation transient adhesion mediated by members of the Selectin gene family was found to be essential before ICAM-1/beta 2 interactions could occur. We, therefore, wondered whether a similar sequence of initial transient adhesion followed by subsequent responses would be observed in hyperoxic lung inflammation. We, therefore, determined the effects of hyperoxia exposure on lung mRNA for P- and E-Selectin in mouse lungs. We found that there was no detectable mRNA for E-Selectin through 72 h of hyperoxia exposure by Northern blotting, but that mRNA for P-Selectin was detectable as early as 48 h after initiation of hyperoxia. To determine the location of P-Selectin upregulation we examined hyperoxia-exposed mouse lungs by in situ hybridization and found that the upregulation of P-Selectin at 48 h was localized to large muscularized vessels, at 72 h expression was detected in some medium size muscularized vessels, and at 96 h abundant expression was observed also on nonmuscularized small vessels. In conclusion, increases in mRNA for P-Selectin early in the course of hyperoxia exposure suggest that P-Selectin expression in hyperoxic lungs increases in parallel with upregulation of ICAM-1, leading to the accumulation of neutrophils in hyperoxic lungs, and that interventions targeting these two adhesion molecules may lead to a diminution in hyperoxic lung inflammation and lung injury.

Animals↗