Angiogenic gene therapy. A leg to stand on?
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Animals↗
Biomedical subjects
J C Fox
Publications and source records attributed to J C Fox.
Antisense inhibition of basic fibroblast growth factor induces apoptosis in vascular smooth muscle cells.
Basic fibroblast growth factor (bFGF), a potent mitogen for many cell types, is expressed by vascular smooth muscle cells and plays a prominent role in the proliferative response to vascular injury. Basic FGF has also been implicated as a survival factor for a variety of quiescent or terminally differentiated cells. Autocrine mechanisms could potentially mediate both proliferation and cell survival. To probe such autocrine pathways, endogenous bFGF production was inhibited in cultured rat vascular smooth muscle cells by the expression of antisense bFGF RNA. Inhibition of endogenous bFGF production induced apoptosis in these cells independent of proliferation, and apoptosis could be prevented by exogenous bFGF but not serum or epidermal growth factor. The induction of apoptosis was associated with an inappropriate entry into S phase. These data demonstrate that interruption of autocrine bFGF signaling results in apoptosis of vascular smooth muscle cells, and that the mechanism involves disruption of normal cell cycle regulation.
Animals↗
Case manager follow-up to failed appointments and subsequent service utilization.
Case manager responses to failed appointments were monitored for 83 seriously mentally ill persons in a rural community mental health center. Case manager actions taken were grouped into four categories of follow-up from most intensive to least intensive: home visit, phone call, letter, and no follow-up. On the whole, case managers most frequently did not follow-up missed appointments (56.7%), followed up by letters (21.3%), and telephone calls (18.7%), and home visits (3.3%). Analyses revealed that home visits were most intensive and all clients who were visited following failed appointments did not fail the subsequent appointment. Clients who received telephone calls or letters were about equally likely to fail the subsequent appointment, but were much more likely to attend the subsequent appointment than were clients who received no follow-up to the failed appointment. Interestingly, clients who failed appointments and received no follow-up were much more likely to need emergency services rather than a regular appointment as their next contact with the clinic.
Appointments and Schedules↗
Cardiovascular gene therapy: current concepts.
Gene therapy techniques are under development for many areas of medicine, including cardiovascular disease. Identifying appropriate gene targets will require more detailed knowledge of the molecular pathophysiology of these disorders, and choosing appropriate vectors and delivery systems will contribute significantly to the challenge of developing this approach for clinical use. The concepts of toxicology and therapeutic drug monitoring will need to be broadened to account for the unique chemical, biological, and genetic characteristics of gene therapeutic agents. This review will provide an overview of strategy development, currently available vectors, and examples of their application to cardiovascular gene transfer. Considerations of the potential toxicities associated with particular vectors and delivery systems, as well as the types of genetic modifications possible, will provide some guidelines regarding appropriate monitoring of their clinical application.
Adenoviridae↗
Serum stimulation, cell-cell interactions, and extracellular matrix independently influence smooth muscle cell phenotype in vitro.
Vascular injury profoundly alters the vessel wall microenvironment, and smooth muscle cells respond with cell cycle re-entry, loss of contractile elements, extracellular matrix remodeling, and altered signaling by endogenous growth factors and their receptors. Environmental cues include stimulation by exogenous mitogens and both cell-cell and cell-matrix interactions. Modeling this process in smooth muscle cells in vitro, these environmental determinants were varied independently and the phenotypic consequences assessed. Mitogenic stimulation with serum promoted the synthesis of collagen and fibronectin and the expression of fibroblast growth factor receptor-1 and suppressed the content of smooth muscle alpha-actin, myosin heavy chain, and basic fibroblast growth factor. Low cell density (reduced cell-cell contact) was also associated with enhanced extracellular matrix protein production, increased fibroblast growth factor receptor-1 expression, and reduced contractile protein and basic fibroblast growth factor content. The influence of serum stimulation and reduced cell-cell contact were independent and additive. Provision of a type I collagen matrix blunted the influence of serum and cell-cell contact on collagen synthesis but had minor effects on other measures of phenotype. Environmental factors thus independently influence smooth muscle cell phenotype, including endogenous growth factor expression and responsiveness, which can in turn influence the microenvironment of the vessel wall after injury.
Actins↗
Attempted transmission of Ehrlichia canis by Rhipicephalus sanguineus after passage in cell culture.
OBJECTIVES: To compare the transmissibility by the brown dog tick, Rhipicephalus sanguineus, of a recent isolate of Ehrlichia canis (Ebony) with that of another isolate (Oklahoma) that had been passaged in cell culture, and to assess the genetic similarity of the 2 isolates as reflected in the nucleotide (NT) sequence of 16S rDNA. ANIMALS: 13 healthy dogs of various ages and breeds. PROCEDURE: Larval and nymphal ticks were acquisition fed on acutely infected dogs, and, after molting, they were transmission fed as nymphs and adults, respectively, on Ehrlichia-naive dogs. All dogs were monitored daily by blood smear evaluation for evidence of parasitized leukocytes and by physical examination for clinical signs of ehrlichiosis. Serologic and hematologic values were measured weekly. Using a nested polymerase chain reaction, the 16S rDNA was amplified, and the NT sequence of the template DNA was determined. RESULTS: The Ebony isolate of E canis was successfully transmitted to dogs by nymphal and adult ticks. In contrast, no ticks that fed on dogs harboring the cell-cultured isolate (Oklahoma) transmitted it to dogs. On the basis of 16S rDNA sequence, the 2 isolates were 99.9% similar, with only 1 NT difference. CONCLUSIONS: These results reconfirm the vector potential of R sanguineus for E canis. Passage of the Oklahoma isolate of E canis in cell culture apparently adversely affected its transmissibility by ticks, raising the possibility that cell-cultured isolates of this rickettsia may lose their affinity for ticks. Determination of 16S rDNA sequence suggests minor strain variation within the species E canis.
Animals↗
Critical issues in reforming rural mental health service delivery.
Critical issues in reforming rural mental health service delivery systems under health care reform are outlined. It is argued that the exclusive focus on health care financing reform fails to include obstacles to effective mental health service delivery in rural area, which should focus on issues of availability, accessibility, and acceptability, as well as financing and accountability. Characteristics of rural areas are delineated and three assumptions about the structure of rural communities which are shaping the dialogue on rural health and mental health service delivery are examined. These assumptions include the notion that rural communities are more closely knit than urban ones, that rural services can be effectively delivered through urban hubs, and that rural dwellers represent a low risk population which can be effectively served through existing facilities and by extending existing services.
Community Mental Health Services↗
Biomechanical analysis of the pharyngeal swallow in postsurgical patients with anterior tongue and floor of mouth resection and distal flap reconstruction.
The purpose of this study was to examine changes in the biomechanics of pharyngeal swallow after surgery in eight patients (six men and two women) with anterior tongue and floor of mouth resections with distal flap reconstruction. Eight normal age-matched subjects were also studied. Swallowing performance was assessed following a standardized protocol with videofluoroscopy preoperatively and at 1 and 3 months postoperatively for the oral cancer patients. The normal subjects received a single videofluoroscopic study. Computer-assisted biomechanical analysis was used to mark the movements of specific oropharyngeal structures over time throughout the swallow of calibrated boluses. Statistical analyses revealed that tongue base, pharyngeal wall, hyoid, laryngeal, and cricopharyngeal movements during the swallow were altered significantly after surgery for the cancer patients. Some oropharyngeal structural movements differed from those of normal control subjects before surgery. In this study, biomechanical measures indicated that there was recovery in some aspects of the pharyngeal swallow in this patient group. The duration of tongue base to pharyngeal wall contact, which was significantly reduced preoperatively and at 1 month after surgery, increased significantly to within normal levels by the 3-month postoperative evaluation. Duration of laryngeal closure and the onset of laryngeal closure relative to cricopharyngeal opening also improved significantly to within normal levels by the 3-month postoperative evaluation.
Adult↗
Experimental transmission of Ehrlichia chaffeensis (Rickettsiales: Ehrlichieae) among white-tailed deer by Amblyomma americanum (Acari: Ixodidae).
Ehrlichia chaffeensis Anderson, Dawson & Wilson, causative agent of human (predominantly monocytic) ehrlichiosis, was successfully transmitted experimentally by Amblyomma americanum (L.) to white-tailed deer, Odocoileus virginianus (Zimmerman). Deer were needle-exposed intravenously to E. chaffeensis in tissue-culture canine macrophage (DH82) cells, and 11 d later were exposed to laboratory-reared A. americanum larvae, nymphs, and adults for acquisition feeding. Three months after this feeding, naive deer and dogs were exposed to recently molted nymphs and adults. Attempted reisolation of the pathogen by way of tissue culture was successful from one needle-exposed deer but not from the tick-exposed deer or dogs. Based on serologic evidence and polymerase chain reaction data, both nymphal and adult ticks transmitted E. chaffeensis to naive deer but not to dogs.
Animals↗
Longitudinal analysis of cytomegalovirus load in renal transplant recipients using a quantitative polymerase chain reaction: correlation with disease.
Serial surveillance samples of urine collected from 103 renal transplant recipients were analysed by polymerase chain reaction (PCR) for the presence of human cytomegalovirus (HCMV) DNA. The PCR results were consistently negative in 70 patients, none of whom developed HCMV disease, and PCR positive in 33 patients of whom 10 developed HCMV disease (P < 0.001). In 12 patients, PCR results were positive in three or more consecutive samples indicating extensive HCMV replication. HCMV load in 104 samples from these patients was analysed using a quantitative co-amplification PCR system. The maximal viral burden in the symptomatic patients ranged from 10(5.9) to 10(7.12) genomes/ml urine (median 10(6.5)) and in the asymptomatic patients from 10(4) to 10(5.7) genomes/ml urine (median 10(5.2)). The 10(1.3) difference between these median values was significant (P < 0.01). Individual kinetic profiles of viral burden showed that high levels of HCMV correlated with clinically apparent disease. In the majority of the asymptomatic individuals HCMV load remained between 10(4) and 10(5.1) genomes/ml urine; however, in two patients fluctuations in viral load were observed involving higher viral levels (up to 10(5.7) genomes/ml urine) suggesting that immune responses able to modulate viral replication could be studied in individual patients. Analysis of the temporal appearance and quantity of HCMV in the urine with alterations in white cell numbers showed that leukopenia occurred following the appearance of HCMV in the urine of symptomatic patients but preceded HCMV in the urine of asymptomatic patients (P = 0.01). Overall, these results show that longitudinal analysis using fully quantitative PCR methods for HCMV can provide insight into the natural history of HCMV disease in renal transplant recipients.
Adolescent↗
The pig as a potential organ donor for man. A study of potentially transferable disease from donor pig to recipient man.
Ten pigs, reared in an unmodified laboratory animal house environment, have been investigated to ascertain the incidence of diseases or disorders, including infection, neoplasia, or metabolic abnormalities, that might preclude the transplantation of major organs from the pig to man. Noninvasive studies were performed in the second month of life (study 1) and repeated after an interval that varied between 3 and 5 1/2 months (study 2). Necropsy was then performed as a means of assessing the accuracy of the 2 screening examinations. A total of 150 tests were performed on each pig. At both studies the feces contained cysts and/or trophozoites of several parasites, all of which were considered commensals. No other organisms potentially infective for man were identified either at study or at necropsy. Neither congenital anomalies nor malignant neoplasia was found at necropsy. However, in 2 pigs a vasculitis of uncertain etiology was present in the kidneys on microscopic examination, and in one of these the same condition affected the heart. This pathology was suspected neither from the screening examinations nor from the macroscopic appearance of these organs. Biopsy and microscopic examination would therefore appear to be essential before any organ is transplanted into a human.
Animal Feed↗
Western immunoblot analysis of Ehrlichia chaffeensis, E. canis, or E. ewingii infections in dogs and humans.
Ehrlichia chaffeensis, E. canis, and E. ewingii are genetically closely related, as determined by 16S rRNA gene base sequence comparison, but they exhibit biologic differences. E. chaffeensis is the etiologic agent of human ehrlichiosis. E. canis and E. ewingii cause two distinctly different forms of canine ehrlichiosis and infect different types of leukocytes, monocytes and granulocytes, respectively. E. chaffeensis can also infect dogs. In the study, Western immunoblot analysis of sera from dogs inoculated with E. chaffeensis, E. canis, or E. ewingii was performed to determine antigenic specificity and the intensities of the reactions to purified E. chaffeensis and E. canis antigens. At 2 to 3 weeks postexposure, antisera from four dogs inoculated with E. chaffeensis reacted with 64-, 47-, 31-, and 29-kDa proteins of E. chaffeensis but reacted poorly with E. canis antigen. In contrast, at 2 to 3 weeks postexposure, antisera from four E. canis-inoculated dogs reacted strongly with the 30-kDa major antigen of E. canis but reacted poorly with proteins from E. chaffeensis. At 4 weeks postexposure, the sera from three E. ewingii-inoculated dogs showed weak binding to 64- and 47-kDa proteins of both E. chaffeensis and E. canis. Convalescent-phase sera from human ehrlichiosis patients and sera from dogs chronically infected with E. ewingii strongly reacted with similar sets of proteins of E. chaffeensis and E. canis with similar intensities. However, sera from dogs chronically infected with E. canis reacted more strongly with a greater number of E. canis proteins than with E. chaffeensis proteins. The protein specificity described in the report suggests that dogs with E. canis infections can be distinguished from E. chaffeensis-infected animals by Western immunoblot analysis with both E. canis and E. chaffeensis antigens.
Animals↗
Myogenic differentiation triggered by antisense acidic fibroblast growth factor RNA.
Acidic fibroblast growth factor (FGF) and related family members regulate differentiation in organisms as diverse as Xenopus laevis and mammals. We utilized a well-characterized model of myogenic development to directly assess the importance of endogenously produced FGF in controlling differentiation. A role for endogenous FGF is suggested by the previous finding that acidic and basic FGF abundance in cultured myocytes decreases during differentiation. In this study we inhibited the endogenous production of FGF in murine Sol 8 myoblasts by using antisense RNA and observed precocious myogenic differentiation. Exogenously supplied acidic FGF rescues this phenotype. Further results suggest that the effect of FGF on myogenic differentiation is mediated in part through inhibition of myogenin expression. These results demonstrate a direct role for endogenously synthesized growth factors in regulating myogenesis and provide support for a general role for related proteins in mammalian development.
Actins↗
Q&A: 'Reasonable accommodation' under disability law includes a 'right of transfer'.
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Career Mobility↗
Social environments of adult homes.
The purpose of this study was to examine the social environments of adult homes in the community to determine if different types of adult homes existed and which environmental variables best described each home type. Three hundred and two adult home staff rated 10 social environment variables of 49 adult homes using Moos' Community Oriented Programs Environment Scale. Using cluster analysis, 4 distinct environmental home types were identified. Discriminant analysis suggested that homes in each cluster differed primarily in their degree of staff involvement, staff support and expression of anger.
Adult↗
Auto and transactivation of FGF expression: potential mechanism for regulation of myogenic differentiation.
Fibroblast growth factors (FGFs) are potent inhibitors of myogenic differentiation. The recent observation that the endogenous expression of acidic and basic FGF by myogenic cells decreases coordinately with differentiation suggests a regulatory role for these growth factors in myogenesis. Inasmuch as other proteins known to influence myogenesis (e.g., MyoD1 and myogenin) activate their own expression as well as the expression of other members of their family, we hypothesized that the FGFs might be capable of similar autoregulation. We examined the effect of exogenously supplied FGF on the abundance of the mRNAs encoding acidic and basic FGF in Sol 8 myoblasts, and demonstrate that either acidic or basic FGF stimulate, through paracrine mechanisms, the accumulation of the mRNAs encoding both of these FGFs. Thus FGFs can auto- and transregulate their own expression in a manner analogous to that observed for the myogenic determination proteins. In addition, similar to that previously observed for MyoD1, both acidic and basic FGF suppress myogenin expression in myoblasts. These results suggest two mechanisms whereby endogenously produced FGFs participate in the maintenance of the undifferentiated state of myogenic cells. These data provide support for paracrine, and suggest potential autocrine, roles for FGFs in the regulation of myogenic differentiation.
Animals↗
Provision of prognostic information in immunocompromised patients by routine application of the polymerase chain reaction for cytomegalovirus.
A polymerase chain reaction (PCR) assay that amplifies a 149 base pair fragment of the cytomegalovirus glycoprotein B gene was used in the routine screening of 548 urine and 248 blood specimens from immunocompromised patients. The PCR results were compared with those obtained for the same specimens tested by the methods of conventional cell culture (CCC) and detection of CMV-specific immediate-early antigen fluorescent foci (DEAFF). For both urine and blood, PCR positivity correlated with a positive result in CCC (urine 93.2%; blood 86%). As expected for a more sensitive assay, PCR also identified CMV in samples that were negative by CCC and DEAFF such that there was no concordance between tests (Kappa test P > 0.05). The sensitivity, specificity, positive predictive value, and negative predictive values of PCR positivity in blood with respect to CMV disease were 0.8, 0.86, 0.62, and 0.94, respectively, with an associated relative risk of 5.84 (95% CI; 3.2-10.8). PCR detection of CMV in urine was more sensitive than either DEAFF or CCC (0.6 vs. 0.35 and 0.5, respectively) and had a high negative predictive value (0.89) but the positive predictive value was lower than either CCC or DEAFF (0.32 vs. 0.41 and 0.37, respectively) with respect to disease. Longitudinal data on patients with disease showed that CMV in blood was detected at a median of 5 days (range; -20 to +3 days) before disease onset whereas CMV was detected by CCC at a median of 13 days (range -4 to +20 days) after disease onset. In addition, the PCR assay was integrated into the battery of tests routinely performed on transplant patients in the diagnostic laboratory at this institution.
AIDS-Related Opportunistic Infections↗
Equine protozoal myeloencephalitis: antigen analysis of cultured Sarcocystis neurona merozoites.
Antigens of cultured Sarcocystis neurona merozoites were examined using immunoblot analysis. Blotted proteins were probed with S. cruzi, S. muris, and S. neurona antisera produced in rabbits, S. fayeri (pre- and post-infection) and S. neurona (pre- and post-inoculation) sera produced in horses, immune sera from 7 histologically confirmed cases of equine protozoal myeloencephalitis (EPM), and pre-suckle serum from a newborn foal. Eight proteins, 70, 24, 23.5, 22.5, 13, 11, 10.5, and 10 Kd, were detected only by S. neurona antiserum and/or immune serum from EPM-affected horses. Equine sera were titered by the indirect immunofluorescent antibody (IFA) method using air-dried, cultured S. neurona merozoites. Anti-Sarcocystis IFA titers were found in horses with or without EPM. Serum titers did not correspond to the number of specific bands recognized on immunoblots.
Animals↗