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Biomedical subjects

A D Miller

Publications and source records attributed to A D Miller.

At least 91 records · Page 5Linked to original sources
PubMed1997

Role of pre-inspiratory neurons in vestibular and laryngeal reflexes and in swallowing and vomiting.

Fifteen pre-inspiratory (Pre-I) neurons were extracellularly recorded in the pre-Bötzinger complex and their involvements in vestibular (VN) and superior laryngeal (SLN) nerve reflexes and in fictive swallowing and vomiting were tested in decerebrated and artificially ventilated cats. Both type I (1 of 9) and type II (1 of 6) pre-I neurons could project to the contralateral ventral respiratory group region. Pre-I neurons changed their firing during VN and SLN respiratory reflexes and fictive swallowing and vomiting; different response properties were observed among individual pre-I neurons. These results suggest that pre-I neurons are a population of heterogeneous and multi-functional propriobulbar neurons.

Animals↗
PubMed1997

Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors.

We previously found that gene transduction by adeno-associated virus (AAV) vectors in cell culture can be stimulated over 100-fold by treatment of the target cells with agents that affect DNA metabolism, such as irradiation or topoisomerase inhibitors. Here we show that previous gamma-irradiation increased the transduction rate in mouse liver by up to 900-fold, and the topoisomerase inhibitor etoposide increased transduction by about 20-fold. Similar rates of hepatic transduction were obtained by direct injection of the liver or by systemic delivery via tail vein injection. Hepatocytes were much more efficiently transduced than other cells after systemic delivery, and up to 3% of all hepatocytes could be transduced after one vector injection. The presence of wild-type AAV, which contaminates many AAV vector preparations, was required to observe a full response to gamma-irradiation. Injection of mice with AAV vectors encoding human clotting factor IX after gamma-irradiation resulted in synthesis of low levels of human clotting factor IX for the 5-month period of observation. These studies show the potential of targeted gene transduction of the liver by AAV vectors for treatment of various hematological or metabolic diseases.

Animals↗
PubMed1997

The nucleus retroambigualis controls laryngeal muscle activity during vocalization in the cat.

The purpose of this study was to determine (1) whether the nucleus retroambigualis (NRA) plays an essential role in periaqueductal gray (PAG)-induced vocalization and (2) which NRA neurons are involved in the projection from the PAG to laryngeal motoneurons. Bilateral injections of the neurotoxin kainic acid into the NRA in decerebrate cats abolished PAG-induced vocalization; PAG stimulation after the injections no longer modulated vocal fold adductor or tensor activity, and only tonically, but no longer phasically, activated the abdominal muscles. In contrast, PAG-induced inspiratory excitation remained even after the injections. These results suggest that the NRA is essential for the vocal activation of the laryngeal adductor and abdominal muscles, and that an additional pathway from the PAG to respiratory motoneurons other than through the NRA is important for mediating PAG-induced inspiratory activation. Secondly, axonal projections of NRA neurons to the contralateral nucleus ambiguus (NA) were studied electrophysiologically. Five expiratory neurons, which had decrementing (n=4) or constant (n=1) firing patterns, were identified as both having axonal projections to the NA and receiving inputs from the PAG. Furthermore, following NA stimulation many constant-latency action potentials of silent cells were recorded in the vicinity of the NRA, where many silent cells were also orthodromically activated by PAG stimulation. No NRA augmenting expiratory neurons could be antidromically activated from the NA. It is suggested that the NRA and adjacent reticular formation integrate inputs from the PAG and send outputs to laryngeal motoneurons for vocalization.

Action Potentials↗
PubMed1997

Substance use disorder and the early course of illness in schizophrenia and affective psychosis.

The relationship between a history of substance use disorder and the early course of psychotic illness was examined in 96 subjects with schizophrenia and 106 subjects with affective psychosis followed in the Suffolk County Mental Health Project, a longitudinal study of first-admission psychosis. Subjects received a structured diagnostic interview and clinical ratings at baseline assessment and again 6 months later. The 6-month assessment included information about treatment received during the interval. A lifetime history of substance use disorder was associated with worse clinical functioning at 6 months for schizophrenia subjects, but not for those with affective psychosis. There were no significant associations of substance use disorder with type of treatment during the interval or with self-reported compliance with medication. Schizophrenia subjects were more likely than subjects with affective psychosis to report cannabis use during the interval and to meet criteria for cannabis use disorder.

Adult↗
PubMed1997

Effect of small focal errors on vision.

PURPOSE: The aim of this study was to quantify the effects of small plus focal errors on the quality of vision of wearers who habitually wear either no correction, or a low powered, distance only correction. METHODS: Patients wore spectacles with small errors deliberately included for a 2-day trial wear period; a short subjective questionnaire, and some laboratory measures of visual function were also used to assess the effects of these focus errors. RESULTS: A significant number of wearers notice, and are dissatisfied with, focal errors in distance vision as small as +0.25 D, in both sphere and cylinder. CONCLUSION: This finding supports clinical practice in refining the refraction to the nearest 0.25 D. It suggests that for critical applications and for critical patients, the practice of slightly undercorrecting hypermetropes should be applied, so that patients can use a little of their own accommodation for optimal distance vision.

Adult↗
PubMed1997

Murine retroviruses use at least six different receptors for entry into Mus dunni cells.

Murine retroviruses have been divided into six interference groups that use different receptors for cell entry: the ecotropic, xenotropic, polytropic, amphotropic, 10A1, and Mus dunni endogenous virus groups. Some interference is observed between xenotropic and polytropic viruses and between amphotropic and 10A1 viruses, indicating some overlap in receptor specificity between these groups, but otherwise these interference groups appear completely independent. In contrast, one study found interference among many of these groups when Mus dunni wild mouse cells were examined with an immunofluorescence assay to detect infection by the challenge virus. Here we have used a more direct assay for cell entry by using pseudotyped retroviral vectors to measure interference in M. dunni cells, and we find no evidence for extensive interference between members of different murine retrovirus groups. Indeed, our results in M. dunni cells are consistent with interference results observed in other cell types and indicate that the anomalous interference results previously observed in M. dunni cells with the immunofluorescence assay were most likely due to factors other than those that affect receptor-mediated virus entry. In summary, our results show that murine retroviruses use at least six different receptors for entry into M. dunni cells.

Animals↗
PubMed1997

Molecular cloning of Mus dunni endogenous virus: an unusual retrovirus in a new murine viral interference group with a wide host range.

Mus dunni endogenous virus (MDEV) is activated from cells of the Asian wild mouse M. dunni (also known as Mus terricolor) in response to treatment with either 5-iodo-2'-deoxyuridine or hydrocortisone. MDEV represents a new murine retrovirus interference group and thus appears to use a different receptor for entry into cells than do other murine retroviruses. Here we show that MDEV is also not in the gibbon ape leukemia virus or RD114 virus interference groups. A retroviral vector with an MDEV pseudotype was capable of efficiently infecting a wide variety of cells from different species, indicating that the MDEV receptor is widely expressed. We isolated a molecular clone of this virus which exhibited no hybridization to any cloned retrovirus examined, suggesting that MDEV has an unusual genome. One copy of a possible retrovirus element that weakly hybridized with MDEV was present in the genomes of laboratory strains of mice, while no such elements were present in other species examined. A virus activated by 5-iodo-2'-deoxyuridine from cells of a BALB/c mouse, however, was not related to MDEV by either hybridization or interference analyses.

Animals↗
PubMed1997

Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration.

The ability of recombinant adeno-associated virus (AAV) vectors to integrate into the host genome and to transduce nondividing cells makes them attractive as vehicles for gene delivery. In this study, we assessed the ability of several AAV vectors to transduce airway cells in rabbits by measuring marker gene expression. AAV vectors that transferred either a beta-galactosidase (beta-gal) or a human placental alkaline phosphatase (AP) gene were delivered to one lobe of the rabbit lung by use of a balloon catheter placed under fluoroscopic guidance. We observed vector-encoded beta-gal or AP staining almost exclusively in the epithelial and smooth muscle cells in the bronchus at the region of balloon placement. The overall efficiency of transduction in the balloon-treated bronchial epithelium was low but reached 20% in some areas. The majority of the staining was in ciliated cells but was also observed in basal cells and airway smooth muscle cells. We observed an 80-fold decrease in marker-positive epithelial cells during the 60-day period after vector infusion, whereas the number of marker-positive smooth muscle cells stayed constant. Although treatment with the topoisomerase inhibitor etoposide dramatically enhanced AAV transduction in primary airway epithelial cells in culture, treatment of rabbits did not improve transduction rates in the airway. Vector readministration failed to produce additional transduction events, which correlated with the appearance of neutralizing antibodies. These results indicate that both readministration and immune modulation will be required in the use of AAV vectors for gene therapy to the airway epithelium.

Alkaline Phosphatase↗
PubMed1997

Identification and elimination of replication-competent adeno-associated virus (AAV) that can arise by nonhomologous recombination during AAV vector production.

Adeno-associated virus (AAV) vector preparations are often contaminated with variable amounts of replication-competent AAV (rcAAV), which may influence the behavior of these vectors both in cultured cells and in animals. A packaging plasmid/vector plasmid system containing no significant homology and lacking the wild-type AAV p5 promoter was constructed to eliminate the production of wild-type AAV by recombination. Still, rcAAV was detected in vector produced by cotransfection of these plasmids at large scale. Sequence analysis revealed that nonhomologous recombination was responsible for the generation of these novel rcAAVs. A new AAV packaging plasmid carrying separate rep and cap expression cassettes in opposite transcriptional orientations was constructed. AAV vector preparations produced by using this packaging construct did not contain rcAAV.

Animals↗
PubMed1997

Differential tropism of pseudorabies virus for sensory neurons in the cat.

The permissiveness of cat motor and sensory systems to infection by pseudorabies virus (PRV) was examined. Eight adult cats of both sexes received injections of a virulent strain of PRV (PRV-Becker) into either the diaphragm or neck musculature. Temporal analysis of the replication and transynaptic passage of virus in each experimental paradigm revealed that sensory neurons in the dorsal root ganglia were more susceptible to infection than motor neurons. Only scattered motor neurons displayed productive replication of virus at postinoculation intervals extending to 192 h whereas robust replication of virus in neurons in the dorsal root ganglia and dorsal horn of the spinal cord was apparent as early as 96 h post inoculation. The data demonstrate that functionally distinct populations of neurons in the cat are differentially permissive to infection and transneuronal transport of PRV.

Animals↗
PubMed1996

Transduction of hematopoietic cells by foamy virus vectors.

Foamy viruses are retroviruses of the spumavirus family that are often isolated from primary cultures of primate cells. We previously constructed vectors based on human foamy virus (HFV) and found that they were able to transduce a wide variety of vertebrate cells by integration of the vector genome. Here we show that several types of hematopoietic cells are efficiently transduced by an HFV vector that encodes alkaline phosphatase (AP). These cell types include transformed cell lines and primary hematopoietic progenitors from mice, baboons, and humans. The transduction rates of HFV vectors compare favorably with those obtained by murine leukemia virus vectors, which suggests that HFV vectors may be effective in the treatment of hematologic diseases by gene therapy.

Animals↗
PubMed1996

Modulation of vomiting by the medullary midline.

Studies were conducted to investigate the possible role of the brainstem midline region as a source of facilitatory input for the vomiting process. Experiments were conducted using the "fictive vomiting' model in decerebrate, paralysed cats. Dysfunction of the medullary midline region produced by localized injections of the neurotoxin kainic acid abolished or greatly attenuated fictive vomiting. In addition, some respiratory-related midline neurons were found to fire in synchrony with co-active phrenic and abdominal nerve discharge during fictive vomiting. These experiments demonstrate the importance of the medullary midline for the normal occurrence of the vomiting process. An explanation for the post-lesion elimination of vomiting is that the lesions remove an important source of facilitatory input to spinal respiratory motoneurons and/or to the brainstem circuitry that mediates vomiting.

Animals↗
PubMed1996

Cell-surface receptors for retroviruses and implications for gene transfer.

Retroviruses can utilize a variety of cell-surface proteins for binding and entry into cells, and the cloning of several of these viral receptors has allowed refinement of models to explain retrovirus tropism. A single receptor appears to be necessary and sufficient for entry of many retroviruses, but exceptions to this simple model are accumulating. For example, HIV requires two proteins for cell entry, neither of which alone is sufficient; 10A1 murine leukemia virus can enter cells by using either of two distinct receptors; two retroviruses can use different receptors in some cells but use the same receptor for entry into other cells; and posttranslational protein modifications and secreted factors can dramatically influence virus entry. These findings greatly complicate the rules governing retrovirus tropism. The mechanism underlying retrovirus evolution to use many receptors for cell entry is not clear, although some evidence supports a mutational model for the evolution of new receptor specificities. Further study of factors that govern retrovirus entry into cells are important for achieving high-efficiency gene transduction to specific cells and for the design of retroviral vectors to target additional receptors for cell entry.

Amino Acid Sequence↗
PubMed1996

Vestibular effects on upper airway musculature.

The vestibular system produces a variety of compensatory responses to accelerations of the head, which include reflex responses recorded from respiratory muscle nerves of the thorax and abdomen. In order to better understand the functional significance of vestibulo-respiratory reflexes, we investigated the extent to which such responses are also present on muscle nerves of the upper airway. Experiments were conducted on adult cats that were decerebrated, paralyzed, and artificially ventilated. Electrical stimulation of the vestibular nerve using short trains of current pulses evoked reflex responses on the following nerves: recurrent laryngeal, superior laryngeal, pharyngeal branch of the vagus, glossopharyngeal, and hypoglossal. The responses were bilateral and occurred on average within about 15 ms after stimulus onset. The medial and inferior vestibular nuclei were shown to be essential for the reflex, since the responses were abolished by injections of the neurotoxin kainic acid into these nuclei. The widespread presence of vestibular-evoked responses recorded from respiratory muscle nerves of the upper airway. as well as from those of the thorax and abdomen, suggests that one function of vestibulo-respiratory reflexes is to provide adjustments in breathing and airway patency during movements and changes in posture.

Animals↗
PubMed1996

Retroviral vectors efficiently transduce basal and secretory airway epithelial cells in vitro resulting in persistent gene expression in organotypic culture.

Gene therapy of the lung requires the introduction and expression of a therapeutic gene in airway cells. Although retroviral vectors may be useful in this context, the ability of retroviruses to infect specific cell types in the airway is not known. In this study, we examined the ability of amphotropic recombinant retroviral vectors to transduce primary cultures of rabbit airway epithelial cell populations purified for basal or secretory cells. Transduction efficiencies in basal and secretory cell populations were found to be similar; about 27% after a single exposure to vector, and up to 77% after multiple exposures. The fate of genetically modified cells from the different populations was followed through terminal differentiation using organotypic cultures. The epithelium of the organotypic cultures generated from each population exhibited both pseudostratified and stratified morphology, produced mucin, and stained positively with antibodies specific for basal and ciliated cells. The mucociliary epithelium also showed co-localization of these phenotypic markers with the expression of the vector-encoded beta-galactosidase gene. We conclude that retroviruses can efficiently transduce primary cultures of basal and secretory cells, and that both of these cell types can be progenitor cells of the airway epithelium. In vivo delivery of a retroviral vector containing a human placental alkaline phosphatase gene resulted in expression of the heterologous gene in rabbit tracheal epithelial cells. However, transduction efficiency was low and occurred only in the wounded trachea.

Animals↗
PubMed1996

Fictive vocalization in the cat.

A new animal model is described for the study of fictive vocalization, evoked by electrical stimulation of the periaqueductal grey (PAG) in decerebrate, paralyzed and artificially ventilated cats. Changes in activities of the phrenic, abdominal, recurrent and superior laryngeal nerves induced by PAG stimulation after induction of paralysis were compared with the activities of these nerves or the muscles innervated by them during actual vocalization induced before paralysis. The PAG-induced respiratory and laryngeal motor pattern in paralyzed cats is similar to that of PAG-induced vocalization. Furthermore, the switch from inspiration to vocal-like activity is usually synchronized with lung inflation in both paradigms. It is concluded that fictive vocalization can be induced by PAG stimulation in paralyzed cats.

Animals↗