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C Langston

Publications and source records attributed to C Langston.

At least 19 recordsLinked to original sources
PubMed2002

Challenges associated with the evaluation of veterinary product bioequivalence: an AAVPT perspective.

The Generic Animal Drug Patent Term Restoration Act (GADPTRA) enacted in 1988 provided the same benefits to animal drug products that were granted to human generic products. It has been over 13 years since the GADPTRA was enacted, and veterinary drug sponsors and regulators have gained enormous insight and experience into some of the unique challenges associated with the determination of product bioequivalence for veterinary dosage forms. Moreover, advances in information and technology have opened both new issues that must be addressed and new mechanisms for demonstrating product bioequivalence. While many aspects of the existing Center for Veterinary Medicine Bioequivalence Guidance continue to provide invaluable guidance to the animal drug industry, there are also aspects of this guidance that are being called into question. Therefore, during the 2001 annual meeting of the American Academy of Veterinary Pharmacology and Therapeutics, participants were asked to address issues and concerns associated with the evaluation of veterinary product bioequivalence. This manuscript provides a summary of the concerns and discussions that transpired.

Animals↗
PubMed2001

Lymphocytic interstitial pneumonitis, elevated IgM concentration, and hepatosplenomegaly in ataxia-telangiectasia.

An 8-year-old girl developed ataxia-telangiectasia. Western blotting of lysate revealed absence of the ATM protein, and 2 mutations in the ATM gene were found. Subsequently, the patient developed increased respiratory symptoms. Open lung biopsy revealed lymphocytic interstitial pneumonitis, which is not characteristic of ataxia-telangiectasia. There was a therapeutic response to glucocorticosteroid treatment.

Ataxia Telangiectasia↗
PubMed2001

Human immunodeficiency virus-related mortality in infants and children: data from the pediatric pulmonary and cardiovascular complications of vertically transmitted HIV (P(2)C(2)) Study.

OBJECTIVES: To identify the causes of mortality in children with vertically transmitted human immunodeficiency virus (HIV) infection and to study age-related mortality trends. METHODS: In the multicenter P(2)C(2) HIV Study, 816 children born to HIV-infected mothers were followed for a median of 3.6 years. Two hundred five study participants with HIV infection were enrolled at a median age of 23 months; 611 were enrolled either prenatally or in the neonatal period before their HIV infection status was known. There were 121 deaths in study patients. The cause of death for all patients, its relationship to HIV infection, and pulmonary or cardiac involvement were determined. Age trends in disease-specific mortality were summarized for the HIV-related deaths. RESULTS: Ninety-three children died of HIV-related conditions. Infection was the most prevalent cause of death for children under 6 years of age with 32.3% caused by pulmonary infection and another 16.9% caused by nonpulmonary infection. The frequency of pulmonary disease as the underlying cause of death decreased significantly with increasing age: 5/9 (55.6%) by age 1, 1/12 (8.3%) after age 10 years. The frequency of chronic cardiac disease as the underlying cause increased with age-0% by age 1 year, 3/12 (25.0%) after age 10 years, as did the frequency of wasting syndrome with disseminated Mycobacterium avium complex-0% by age 1 year, 6/12 (50.0%) after age 10 years. CONCLUSIONS: Children with HIV who survive longer are less likely to die of pulmonary disease or infection and more likely to die of cardiac causes or with wasting syndrome.pediatric acquired immunodeficiency syndrome, mortality, human immunodeficiency virus.

AIDS Dementia Complex↗
PubMed2000

Multiple advantages of alpha-fetoprotein as a marker for in vivo gene transfer.

The development of improved gene transfer vectors has been hampered by the lack of a nonimmunogenic reporter gene that can be serially quantified in the serum or from other sites. In response to the need to develop a new reporter protein, we have evaluated alpha-fetoprotein (AFP) as a potential candidate. A first-generation E1/E3-deleted adenoviral vector expressing human AFP (hAFP) was generated as a preliminary tool to evaluate AFP as a reporter. Using both mouse and baboon models, hAFP expression was evaluated in serum after intravenous delivery and in serum and bronchioalveolar lavage (BAL) fluid after delivery to the lung. In immunocompetent animals, intravenous delivery of the hAFP adenoviral vector resulted in hAFP expression in the serum early after injection, which declined rapidly over time. Disappearance of hAFP from the serum was complete by 3-4 weeks after administration and was accompanied by robust antibody responses to hAFP and loss of infected cells. After lung delivery, hAFP could be detected in both serum and BAL. This allowed the analysis of the kinetics of gene expression in the lung without sacrificing the animals. In both liver and lung, immunohistochemical analysis correlated well with hAFP levels as detected in serum or BAL, indicating that serum levels were a reliable marker of tissue expression. Preliminary results with a mouse AFP expressed in a helper-dependent adenoviral vector indicate that use of a species-specific version of AFP will eliminate the complication of antibody development. These initial evaluations suggest that AFP is useful as a reporter gene to evaluate gene expression of therapeutic cassettes in multiple tissues, and it should be considered for use in human subjects.

Animals↗
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↗
PubMed2000

Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector.

BACKGROUND: Certain gene therapy protocols may require multiple administrations of vectors to achieve therapeutic benefit to the patient. This may be especially relevant for vectors such as adenoviral vectors that do not integrate into the host chromosome. Because immunocompetent animal models used for gene transfer studies develop neutralizing antibodies to adenoviral vectors after a single administration, little is known about how repeat administrations of vectors might affect transgene expression and vector toxicity. MATERIALS AND METHODS: We used mice deficient in the membrane spanning region of immunoglobulin (IgM), which do not develop antibodies, to evaluate the effect of repeated intravenous administration of first-generation and helper-dependent adenoviral vectors expressing human alpha 1-antitrypsin (hAAT). The duration and levels of transgene expression were evaluated after repeated administration of vectors. Toxicity was assessed by measuring the level of liver enzymes in the serum and the degrees of hepatocyte hypertrophy and proliferation. RESULTS: We found that previous administration of first-generation adenoviral vectors can alter the response to subsequent doses. These alterations included an increase in transgene expression early (within 1 and 3 days), followed by a rapid drop in expression by day 7. In addition, previous administrations of first-generation vectors led to an increase in toxicity of subsequent doses, as indicated by a rise in liver enzymes and an increase in hepatocyte proliferation. In contrast to first-generation vectors, use of the helper-dependent adenovirus vector, Ad-STK109, which contained no viral coding regions, did not lead to increased toxicity after multiple administrations. CONCLUSIONS: We conclude that the response of the host to adenoviral vectors can be altered after repeated administration, compared with the response after the initial vector dose. In addition, these experiments provide further evidence for the relative safety of helper-dependent adenoviral vectors for gene therapy, compared with first-generation vectors.

Adenoviridae↗
PubMed1999

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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↗