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Biomedical subjects

J D Green

Publications and source records attributed to J D Green.

At least 55 records · Page 3Linked to original sources
PubMed1993

Pathology of recombinant human transforming growth factor-beta 1 in rats and rabbits.

The systemic administration of high doses of rHuTGF-beta 1 to rats produced a spectrum of lesions in multiple target tissues, including liver, bone, kidney, heart, thymus, pancreas, stomach, cecum, at the injection vein, and in skeletal muscle at the site of anesthetic injection. The majority of these lesions can be attributed to known biological activities of TGF-beta 1. High-dose dermal application resulted in local effects at the wound sites without systemic toxicity.

Animals↗
PubMed1993

Comparative pathology of recombinant murine interferon-gamma in mice and recombinant human interferon-gamma in cynomolgus monkeys.

Interferon-gamma is a highly species-specific cytokine and has the most restricted host range of activity of the interferons. Recombinant human IFN-gamma was one of the first species-specific recombinant proteins to be thoroughly assessed in conventional safety models used for xenobiotics. Acute single-dose intravenous toxicity studies with rHuIFN-gamma were performed in rats, marmosets, and squirrel monkeys with no indications of toxicity. A complete series of subchronic toxicity studies and segment I and II reproductive studies in the rat revealed no evidence of toxicity at any of the doses tested. These results suggested that studies conducted in pharmacologically nonresponsive species may not be predictive of clinical toxicity. Human IFN-gamma is active on nonhuman primate cells, though not at the same level as on human cells. Multidose studies in cynomolgus monkeys with rHuIFN-gamma for 28 or 90 days were predictive of many of the dose-limiting clinical toxicities. Qualitative similarity was observed between toxicity studies employing rHuIFN-gamma in the cynomolgus monkey and rMuIFN-gamma in the mouse. The adverse effects seen in toxicity studies with cytokines and growth factors are often exaggerated pharmacological effects of the molecules, and therefore can only be studied in a responsive species. In situations in which a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment.

Abnormalities, Drug-Induced↗
PubMed1992

Conformational studies of the interdomain linker peptides in the dihydrolipoyl acetyltransferase component of the pyruvate dehydrogenase multienzyme complex of Escherichia coli.

Two peptides (PEP1, 26 residues, and PEP2, 22 residues) were synthesized with amino acid sequences identical to two of the long segments of polypeptide chain rich in alanine, proline, and charged amino acids that link the lipoyl domains together in the dihydrolipoyl acetyltransferase component of the pyruvate dehydrogenase multienzyme complex of Escherichia coli. The circular dichroism and 400-MHz 1H NMR spectra of the peptides indicated that they lacked regular secondary structure. Even in the presence of 45% (v/v) hexafluoroisopropanol, they appeared to acquire a helical content of only 23-25%. However, 13C NMR spectroscopy revealed that the Ala-Pro peptide bonds were all (> 95%) in the trans configuration, compared with a value of 87% for the Ala-Pro bond in the model peptide AAPA, which is a recurrent sequence motif in PEP1 and PEP2. Likewise in peptides representing the N- and C-terminal halves of peptide PEP2, the Ala-Pro bonds were again all (> 95%)-trans, suggesting that peptide length is the essential determinant of the cis:trans ratio. Antisera were raised against peptides PEP2 and PEP3, the latter representing a third interdomain segment of polypeptide chain (Radford, S. E., Laue, E. D., Perham, R. N., Martin, S. R., and Appella, E. (1989a) J. Biol. Chem. 264, 767-775). Despite extensive sequence similarity among peptides PEP1, PEP2, and PEP3, only limited immunological cross-reactivity was observed, which suggests that the antigenic epitope(s) in the peptides are different and distinct. It is likely that these peptides are representative of a class of inter-domain linkers or spacers found in a wide variety of proteins and endowed with varying degrees of flexibility and stiffness to match their particular biological purpose.

Acetyltransferases↗
PubMed1992

Middle fossa vestibular neurectomy in retrolabyrinthine neurectomy failures.

Retrolabyrinthine vestibular nerve section is an important treatment option in patients with refractory, incapacitating vertigo. However, an indistinct cleavage plane between the cochlear and vestibular portions of the eighth cranial nerve may result in incomplete sectioning of the superior and inferior vestibular nerve fibers. We describe 11 patients in whom middle fossa vestibular neurectomy was performed following failure of a retrolabyrinthine vestibular neurectomy. A successful postoperative outcome from this revision surgery was obtained in six of 11 patients on follow-up evaluation. Patients in whom infrared video electronystagmography showed persistent function of the inferior vestibular nerve following retrolabyrinthine vestibular nerve section had a better response to middle fossa vestibular neurectomy than those with no measurable residual vestibular function. Because it provides access to the vestibular nerves where there is separation from the cochlear nerves distal to the previous section, we feel that the middle fossa vestibular neurectomy is the procedure of choice in selected patients who fail retrolabyrinthine neurectomy.

Adult↗
PubMed1992

Utilization of homologous proteins to evaluate the safety of recombinant human proteins--case study: recombinant human interferon-gamma (rhIFN-gamma).

Interferon-gamma is an immunomodulatory cytokine that has an extremely restricted host range of activities. RhIFN-gamma was one of the first species-specific recombinant proteins to be assessed in conventional safety models typically utilized for xenobiotics. Acute, subchronic and Segment I and II reproductive studies in rats revealed no evidence of toxicity at any of the doses tested; these results were not predictive of clinical toxicity, which is not unexpected since rodents are known to be pharmacologically nonresponsive to rhIFN-gamma. In contrast, 4- and 13-week multidose toxicity studies in cynomolgus monkeys with rhIFN- were predictive of many of the dose-limiting clinical toxicities. RhIFN- is active on non-human primate cells, though not at the same level as on human cells. In addition, qualitative similarities were observed between toxicity studies employing rhIFN-gamma in the cynomolgus monkey and recombinant murine interferon-gamma (rmuIFN-gamma) in the mouse. These results suggest that in situations where a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment. This information should be evaluated in conjunction with data from studies conducted with the human protein in pharmacologically responsive animal models when possible.

Animals↗
PubMed1992

Binaural cochlear implants.

With the success of monaural cochlear implantation, patients frequently ask about having a second implant. We have performed binaural cochlear implants in 12 adult patients. Desire not to disrupt a functioning implant was the primary consideration in implanting the contralateral ear. Seven patients received a second 3M/House single-channel implant to upgrade to a magnetic external receiver. Four patients with a 3M/House device in one ear elected to place a Nucleus multichannel implant in the opposite ear. One patient with a poorly functioning Nucleus device elected to have a second Nucleus device. Four patients with a Nucleus and a 3M/House implant, one with binaural 3M/House implants, and one with binaural Nucleus implants were tested for auditory discrimination in order to quantify monaural versus binaural differences. The functional benefit of the second implant was mixed, but all patients showed some degree of objective improvement on one or more tests. Five of the six are regular users of both devices; the patient with binaural Nucleus implants wears only one. Despite the differing processing schemes, patients with a Nucleus device in one ear and a 3M/House device in the other ear are able to combine the two signals to advantage. We feel that cochlear implantation in the contralateral ear is an acceptable option in selected patients desiring an upgraded implant without placing a functioning implant at risk.

Aged↗
PubMed1992

Translabyrinthine approach for acoustic tumor removal.

The translabyrinthine approach is the most direct route to the cerebellopontine angle. It is the preferred approach for removal of all tumors in patients with poor hearing and for large tumors when the likelihood of hearing preservation is slight. This approach offers the advantages of minimum cerebellar retraction, identification of the facial nerve proximally and medially, and the ability to repair immediately the facial nerve if it is severed during acoustic tumor removal. This approach has the lowest morbidity with regard to spinal fluid leaks and also postoperative headaches.

Contraindications↗
PubMed1991

Prevention of HIV-1 IIIB infection in chimpanzees by CD4 immunoadhesin.

The first step in infection by the human immunodeficiency virus (HIV) is the specific binding of gp120, the envelope glycoprotein of HIV, to its cellular receptor, CD4. To inhibit this interaction, soluble CD4 analogues that compete for gp120 binding and block HIV infection in vitro have been developed. To determine whether these analogues can protect an uninfected individual from challenge with HIV, we used the chimpanzee model system of cell-free HIV infection. Chimpanzees are readily infected with the IIIB strain of HIV-1, becoming viraemic within about 4-6 weeks of challenge, although they do not develop the profound CD4+ T-cell depletion and immunodeficiency characteristic of HIV infection in humans. CD4 immunoadhesin (CD4-IgG), a chimaeric molecule consisting of the N-terminal two immunoglobulin-like regions of CD4 joined to the Fc region of human IgG1, was selected as the CD4 analogue for testing because it has a longer half-life than CD4, contributed by the IgG Fc portion of the molecule. In humans, this difference results in a 25-fold increased concentration of CD4-IgG in the blood compared with recombinant CD4. Here we report that pretreatment with CD4-IgG can prevent the infection of chimpanzees with HIV-1. The need for a preventative agent is particularly acute in perinatal HIV transmission. As recombinant CD4-IgG, like the parent IgG molecule, efficiently crosses the primate placenta, it may be possible to set up an immune state in a fetus before HIV transfer occurs, thus preventing infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins.

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the preclinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.

Animals↗
PubMed1991

Labyrinthitis ossificans: histopathologic consideration for cochlear implantation.

Labyrinthitis ossificans may be a hindrance to cochlear implantation by making electrode insertion difficult. We performed a histopathologic study of 24 temporal bones with labyrinthitis ossificans from multiple causes. The organ of Corti was graphically reconstructed and the degree of obstruction was estimated for each millimeter of the cochlea. Correlations were calculated between the degree of new bone formation and the cause, patient's age and sex, and time from the original temporal bone insult. Our results demonstrate that complete cochlear ossification is rare. The scala tympani in the basal turn of the cochlea is the most frequent area of ossification, regardless of the cause of the labyrinthitis ossificans. Meningogenic labyrinthitis, usually a childhood disease, was associated with the greatest amount of ossification. When ossification resulted from tympanogenic labyrinthitis, the scala tympani was completely ossified near the round window niche in all temporal bones. Neo-ossification of the basal turn associated with otosclerosis was limited to the proximal 6 mm of the scala tympani in all cases. Three temporal bones had a patent round window niche and basal turn, but significant apical and middle-turn ossification. Peripheral sensorineural elements were severely degenerated in the region of the ossification in all specimens, and spiral ganglion cell counts were decreased.

Adolescent↗
PubMed1991

Longitudinal followup of patients with Menière's disease.

The etiology, pathophysiology, and natural history of Menière's syndrome are poorly understood. The reported studies have had inadequate followup or insufficient numbers of patients to allow conclusions about the natural history. Our study group was 119 patients who had the classic symptom complex of episodic vertigo, tinnitus, and hearing loss in the year 1970. After initial review of these charts, follow-up information was obtained by questionnaire, telephone interview, chart review, or repeat examination, when possible, both in 1983 and in 1988, for a total followup of 18 years. In the patients with followups of at least 14 years, vertiginous episodes had disappeared completely in 50% of patients and somewhat resolved in 28%; hearing was absent in 48% and worse in 21%. Surprisingly, 43% of patients underwent surgery at some point for control of vertigo. Bilateral disease was present initially in 13% and developed subsequently in 45% of patients. Other areas reviewed included the efficacy of long-term medical treatment, frequency and severity of vertiginous attacks, and contralateral ear symptoms.

Adult↗
PubMed1991

Ganglion cell populations in labyrinthitis ossificans.

Ossification of the perilymphatic spaces of the inner ear is frequently found in patients with profound deafness who may be candidates for cochlear implantation. The ossification may be a hindrance in electrode insertion and has previously been considered a relative contraindication to implantation. The quantity of peripheral auditory elements remaining in a series of patients with labyrinthitis ossificans has not been reviewed. We performed a histopathologic study of 16 temporal bones with partial cochlear ossification of multiple etiologies. The organ of Corti and spiral ganglion were graphically reconstructed. The degree of obstruction was estimated for each millimeter of the scala tympani and scala vestibuli. A quantitative evaluation of the sensorineural elements of the inner ear (spiral ganglion cells, inner and outer hair cells, and peripheral auditory axons) was performed. The results were compared with 16 control patients with normal hearing and no evidence of cochlear ossification. Our results show that the greatest amount of damage is found in the organ of Corti with preservation of a significant number of spiral ganglion cells in most cases. A wide range of ganglion cells (6,310 to 28,196) was found in patients with labyrinthitis ossificans with the mean number of ganglion cells being 17,152. A profound sensorineural hearing loss was noted in all patients except one. Meningogenic labyrinthitis and otosclerosis were associated with the greatest loss of ganglion cells. The location of ossification could be correlated with the region showing loss of the organ of Corti. In the majority of patients, the location of ossification and fibrosis could not be correlated with the region of the spiral ganglion showing loss of ganglion cells. The implications of these findings for cochlear implantation is discussed.

Adolescent↗
PubMed1990

Fertilization envelope assembly in sea urchin eggs inseminated in chloride-deficient sea water: II. Biochemical effects.

Eggs of the sea urchin Strongylocentrotus purpuratus were fertilized in normal and in several chloride-deficient sea waters ([ Cl-]: normal greater than isethionate greater than methyl sulfonate greater than bromide). The fertilization envelopes (FE) were thinner and failed to harden, and the characteristic I-T transition did not occur. The permeability of the experimental FEs, as determined by release of protein from the perivitelline space, increased in the order of decreasing [Cl-]. Release of the enzymes beta-1,3-glucanase and cortical granule protease were not significantly altered. On the other hand, release of ovoperoxidase was increased three to four times in bromide sea water. Furthermore, a dose-response was observed in varying concentrations of bromide-normal sea water. With decreasing chloride (increasing bromide) concentration, more ovoperoxidase activity was observed. Cytochemical localization of ovoperoxidase activity with diaminobenzidine revealed almost a total lack of staining of FEs from bromide-substituted sea water. The results suggest that in chloride-deficient sea waters protein incorporation into the nascent FE is impaired. At least in the case of bromide, the incorporation of ovoperoxidase into the nascent FE was also inhibited.

Animals↗
PubMed1990

Increased morbidity in surgical patients undergoing secondary (incidental) cholecystectomy.

Using computerized hospital discharge abstracts for all Vermont residents hospitalized during 1983 and 1984, we examined the question of whether increased morbidity occurs in patients undergoing secondary (incidental) cholecystectomy. Among a cohort of 4183 patients undergoing a primary surgical procedure in which secondary cholecystectomy might have been considered. 69 patients had a secondary cholecystectomy. The surgical wound infection rate was 8.7% in the secondary cholecystectomy group compared to 2.4% in the rest of the cohort (relative risk, 3.7, 95% C.I. 1.7, 8.1). Other postoperative complications occurred in 10.1% of those undergoing secondary cholecystectomy compared to 4.1% in those who did not (relative risk, 2.5, 95% C.I. 1.2, 5.1). The adjusted relative risk for wound infection was 3.3 (95% C.I. 1.4,8.0) and for other surgical complications was 1.7 (95% C.I. 0.8, 3.8). Postoperative length of hospital stay was longer for the secondary cholecystectomy group (mean, 13.8 days) than in the comparison group (mean 8.9 days, p = 0.001). These data suggest that patients undergoing a secondary cholecystectomy may have an increased risk of surgical wound infection and possibly other surgical complications.

Adolescent↗
PubMed1990

Three-dimensional reconstruction of the temporal bone.

Study of the complex anatomy and pathology of the temporal bone has traditionally used microscopy which permits analysis in only two dimensions. Recent advances in bioimaging technology have permitted visualization and reconstruction of computed tomography images in three dimensions. We have developed a technique that applies this technology in the imaging and reconstruction of human temporal bones. Data taken from serial histologic sections of the temporal bone are entered into a computer. The sections are edited and, through the use of specially developed software, a realistic three-dimensional reconstruction is produced. The reconstructed image can be rotated along any of three axes, and structures within the temporal bone can be isolated for more detailed analysis. Applications for the study of pathologic conditions of the temporal bone will be discussed.

Adult↗
PubMed1989

Unsuspected foreign body in the frontal sinus and anterior cranial fossa.

We present the case of a 46-year-old man who was involved in a motor vehicle accident in which his forehead struck the dashboard of his semi-tractor trailer. A toggle switch penetrated the anterior and posterior tables of his frontal sinus and lodged in the frontal lobe. The foreign body was not found on physical examination at an emergency care facility. The wound was closed, and the patient was sent home. Severe headaches prompted his return the next day. Skull roentgenograms showed the toggle switch, and the patient was referred to our institution for definitive care. This unusual case serves to emphasize the potential for a foreign body to penetrate the frontal sinus with few physical findings.

Accidents, Traffic↗