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Biomedical subjects

D L Black

Publications and source records attributed to D L Black.

At least 19 recordsLinked to original sources
PubMed1992

Activation of c-src neuron-specific splicing by an unusual RNA element in vivo and in vitro.

A conserved positive-acting RNA sequence was found to be required for the neuron-specific splicing of the mouse c-src N1 exon. The sequence lies in the intron between exons N1 and 4, close to the N1 donor site. Normally, only the neural-specific splicing of exon N1 required this sequence. When the intron downstream of N1 was shortened, splicing at the constitutive exon 4 acceptor also became dependent on the activating sequence. The neuronal and nonneuronal patterns of src splicing were reconstituted in vitro. HeLa cell extracts spliced exon 4 to exon 3, skipping exon N1. Weri-1 retinoblastoma cell extracts spliced exon 4 to exon N1 as well as to exon 3. Both patterns of splicing were dependent on the activating sequence. A 123 nt RNA containing just the activating sequence specifically inhibited both patterns of src splicing, indicating that factors bound to the activator were required for its effects.

Animals↗
PubMed1992

Role of maternal toxicity in assessing developmental toxicity in animals: a discussion.

The belief that any drug or chemical, when administered at a high enough dose, can be expected to produce fetal malformations is not consistent with the facts. However, the stress associated with maternally toxic doses can be expected to result in associated, often transient, fetal abnormalities that may not be the result of deviant organogenesis. Sometimes the toxicity toward the pregnant animal, including her embryos/fetuses since they are hardly in a sanctuary, is severe enough to result in resorption of the embryo or abortion of the fetus. Thus, it is possible that the embryolethality and other indications of developmental toxicity, produced by some drugs and chemicals, may be the result of a mechanism(s) other than selective toxicity toward the embryo. Also, some test materials have been shown to affect maternal homeostasis, thereby disrupting support to the embryo, without causing significant overt toxicity to the embryo or dam; e.g., the endocrine system of the dam is altered. Routine testing has thus far revealed a relatively limited number of true teratogens, although a large number of drugs and chemicals have resulted in fetal effects such as developmental variations when administered at doses that approach lethal levels. Such effects on the fetus should be expected when the maternal animals are stressed by the high dosages usually employed. A better understanding of the etiology and biological relevance of the embryo/fetal deviations often seen in developmental toxicology studies might help to avoid the sometimes unjustified withholding of potentially useful drugs and chemicals from the marketplace.

Abnormalities, Drug-Induced↗
PubMed1992

Cholestasis in transplant patients--what is the role of cyclosporin?

The use of the drug cyclosporin is limited by toxicity. It would be advantageous to develop therapeutic monitoring of cyclosporin which would predict the development of clinical toxicity. In the present study, alternative methods of measuring cyclosporin levels were evaluated in a heterogenous population of transplant patients, comparing a fluorescent polarization immunoassay using a non-specific polyclonal antibody, which measures both cyclosporin and its main metabolites, and a specific high-performance liquid chromatography assay for unchanged cyclosporin in blood. Neither measured variable alone correlated with laboratory evidence of renal toxicity (serum creatinine) or liver toxicity (serum glutamate transaminase, lactic dehydrogenase, alkaline phosphatase, or serum bilirubin). The relationship between metabolites and parent cyclosporin was quantitated using the ratio of cyclosporin levels determined by fluorescent polarization immunoassay over levels determined by high-performance liquid chromatography. A cohort of patients with markedly elevated ratios of cyclosporin were identified. When patients' data were reviewed collectively and individually there was a correlation between an elevated ratio and the serum bilirubin (r = 0.41, P less than 0.001). This association could be either due to cyclosporin as a cause of cholestasis or to cholestasis from any cause resulting in metabolite accumulation. Further studies are needed to clarify the role of cyclosporin in hepatic dysfunction and develop early, specific markers for this cyclosporin-associated toxicity.

Adolescent↗
PubMed1991

Reversal of bropirimine developmental toxicity with progesterone.

Bropirimine is an immunomodulator with experimental antiviral and antitumor activities. This pyrimidinone has been found to be embryolethal at doses (200 and 400 mg/kg) that produce only transient maternal toxicity, when administered to pregnant Upj:TUC(SD)spf rats on specific days of gestation. Serum analyses carried out in previous studies have shown marked decreases in progesterone levels in the 24 hr following bropirimine administration. In the present study, each of four groups of 5 bred rats and four groups of 10 bred rats was given bropirimine (gastric intubation) on Day 10 of gestation. Also, on Day 10 of gestation, progesterone (0.25, 0.50, or 1.00 mg/rat) was administered (im) twice (12-hr interval) a day to three of the groups of 5 dams each that had received bropirimine. In addition, three of the groups of 10 dams each received progesterone (0.25, 0.50, or 1.00 mg/rat) twice a day on Days 10-19 of gestation. Another group of 5 dams received progesterone only (0.50 mg/rat, b.i.d.) on Day 10 while a group of 10 dams received this same dose of progesterone on Days 10-19 of gestation. The groups containing 5 dams each were killed 24 hr postdosing while the groups containing 10 dams each were killed on Day 20 of gestation. The uteri were removed from the dams and examined. Administration of bropirimine alone resulted in the death of 100% of the embryos, at both the 24-hr and the Gestation Day 20 terminations. Exogenous administration of progesterone protected against bropirimine-mediated embryolethality; however, maternal effects were not alleviated. Thus, it appears likely that the embryolethality of bropirimine is the result of interruption of progesterone release from, or synthesis by, the corpora lutea, rather than direct toxicity toward the embryo, or lethal defects during organogenesis (terata).

Adjuvants, Immunologic↗
PubMed1991

Case report 695: Cementifying fibroma of the proximal end of the tibia.

A case of a cementifying fibroma in the proximal end of the tibia in a 31-year-old woman is presented. The lesion was expanding but well-defined with amorphous central calcification. The unique, calcified, cementum-like particles in a fibrous stroma have been reported in only four previous cases in long bones. The histological and radiographic differences between a cementifying fibroma, bone cysts with cementum, and a true cementoma are discussed. The radiological differential diagnosis of fibrous dysplasia, giant cell tumor, and low grade central osteosarcoma was considered.

Adult↗
PubMed1991

Does steric interference between splice sites block the splicing of a short c-src neuron-specific exon in non-neuronal cells?

The neuron-specific splicing of the mouse c-src N1 exon was analyzed. Model src genes, transiently expressed in HeLa and LA-N-5 neuroblastoma cells, were assayed for the insertion of the 18-nucleotide neuron-specific N1 exon into their product mRNA. The normal clone fails to use this exon in HeLa cells but inserts the exon into 50% of the mature mRNA in LA-N-5 cells. When the exon and flanking intron sequences are placed between two adenovirus exons, the N1 exon is still only inserted in the neural cells. Thus, the neural specificity is a property of the exon itself and its immediate flanking sequences. Simply extending the length of the N1 exon to 109 nucleotides allows its efficient use in HeLa cells, implying that the exon is normally skipped because it is too short to allow spliceosomes to assemble at both ends simultaneously. This model predicts that exclusion of the exon should be sensitive to proteins or mutations that alter the relative strength of the flanking splice sites. Mutations that change these splice sites support this hypothesis.

Animals↗
PubMed1991

'Ecstasy' psychosis and flashbacks.

We report three cases of flashbacks and one case of recurrent psychosis experienced by three MDMA users. We draw the attention of clinicians to the combination of adverse effects observed with this drug of abuse and to the advisability of prolonged treatment should they occur.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Somatosensory-evoked potential monitored during total hip arthroplasty.

One hundred consecutive patients were monitored using somatosensory-evoked potential (SEP) monitoring to detect intraoperative sciatic nerve compromise during total hip arthroplasty. The peroneal nerve was stimulated using the contralateral extremity to rule out systemic influences on the SEP tracings. Loss of amplitude or an increase in latency of greater than 10% was considered significant. Of the 18 patients who exhibited changes that met these criteria, 16 were female. Two patients had loss of amplitude of the tracings at the time of closure, and both of these patients exhibited postoperative sciatic nerve palsies. There were no false negatives. Femoral reaming and reduction are the surgical events most commonly associated with nerve reactions. Patients who have had prior hip procedures appear to be at higher risk. There was no correlation with intraoperative SEP changes and age, weight, surgical approach, or leg lengthening. Compared with unmonitored patients, there was no reduction in the incidence of sciatic palsy.

Evoked Potentials, Somatosensory↗
PubMed1990

Variability in the developmental toxicity of bropirimine with the day of administration.

The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.

Animals↗
PubMed1989

Drug testing.

Explore the source record for details and available documents.

Humans↗
PubMed1989

Intraoperative cortical somatosensory evoked potentials for detection of sciatic neuropathy during total hip arthroplasty.

Approximately 3% of patients undergoing hip arthroplasty develop postoperative sciatic neuropathy. The factors associated with changes in somatosensory evoked potentials (SSEP) and sciatic neuropathy were examined in patients undergoing hip arthroplasty, to evaluate whether the use of intraoperative SSEP could help reduce the incidence of postoperative sciatic neuropathy. Eighty-eight patients were assigned to either monitored or unmonitored groups. SSEP were recorded following peroneal nerve stimulation, using contralateral stimulation to detect systemic influences on SSEP. Amplitude reduction of less than 50% of control and/or latency increase of greater than 10% of control was considered significant, and surgical intervention was attempted to restore SSEP. Previous surgery and a lateral incision approach tended to be associated with sciatic neuropathy (p less than 0.053). The incidence of sciatic neuropathy in the monitored group (4.3%) was not different from the unmonitored group (2.4%). Isolated reduction in amplitude or prolongation in latency of the SSEP was not predictive of postoperative neurologic function of the sciatic nerve. Six patients, two of whom developed sciatic neuropathy, demonstrated complete flattening of the SSEP. Both of these patients had flattened SSEP for two or more surgical events (p less than 0.01) and flattened SSEP were present at the end of the surgical procedure. There were no false-negative SSEP changes. Simultaneous amplitude and latency changes appear to be predictive of sciatic nerve function following hip arthroplasty.

Evoked Potentials, Somatosensory↗
PubMed1989

U5 small nuclear ribonucleoprotein: RNA structure analysis and ATP-dependent interaction with U4/U6.

To understand how the U5 small nuclear ribonucleoprotein (snRNP) interacts with other spliceosome components, its structure and binding to the U4/U6 snRNP were analyzed. The interaction of the U5 snRNP with the U4/U6 snRNP was studied by separating the snRNPs in HeLa cell nuclear extracts on glycerol gradients. A complex running at 25S and containing U4, U5, and U6 but not U1 or U2 snRNAs was identified. In contrast to results with native gel electrophoresis to separate snRNPs, this U4/U5/U6 snRNP complex requires ATP to assemble from the individual snRNPs. The structure of the U5 RNA within the U5 snRNP and the U4/5/6 snRNP complexes was then compared. Oligonucleotide-targeted RNase H digestion identified one RNA sequence in the U5 snRNP capable of base pairing to other nucleic acid sequences. Chemical modification experiments identified this sequence as well as two other U5 RNA sequences as accessible to modification within the U5 RNP. One of these regions is a large loop in the U5 RNA secondary structure whose sequence is conserved from Saccharomyces cerevisiae to humans. Interestingly, no differences in modification of free U5 snRNP as compared to U5 in the U4/U5/U6 snRNP complex were observed, suggesting that recognition of specific RNA sequences in the U5 snRNP is not required for U4/U5/U6 snRNP assembly.

Adenosine Triphosphate↗
PubMed1989

Differential regulation of progestin receptor immunoreactivity in the rabbit oviduct.

Cellular distribution of progestin receptor immunoreactivity (PR-IR) in paraffin-embedded rabbit oviduct tissue was determined using a monoclonal antibody and the indirect immunoperoxidase method. Ampullar and isthmic tissue from ovariectomized animals primed with 17 beta-estradiol or vehicle alone was examined. As expected, in the absence of estradiol, PR-IR was rarely observed in the ampulla. Estradiol treatment increased PR-IR in cell nuclei of the stroma and muscularis of the ampulla, but not of the epithelium. In contrast, PR-IR was seen in epithelial cell nuclei of the isthmus in the absence of estradiol. Surprisingly, while estradiol treatment increased PR-IR in cell nuclei of the stroma and muscularis of the isthmus, it decreased PR-IR in the epithelium. These results suggest for the first time a differential regulation of progestin receptors in the ampulla and isthmus of the oviduct. In particular, while estradiol treatment increased PR-IR in the stroma and muscularis and was without effect on PR-IR in the epithelium of the ampulla, it decreased PR-IR in the epithelium of the isthmus.

Animals↗
PubMed1987

Reproductive and developmental effects on rats after prenatal, postnatal, or pre- and postnatal exposure to the hypotensive agent losulazine.

Losulazine was administered orally to 21 bred Sprague-Dawley rats per group at 0, 4, and 8 mg/kg/day by three dosing schedules: gestation day 15 until term (prenatal section); postnatal days 1 to 21 (postnatal section); and gestation day 15 until postnatal day 21 (pre- and postnatal section). Dams were allowed to deliver and the number of live and dead pups recorded. Each pup was sexed and weighed on days 0, 4, and 21. Also, pinna detachment and eye opening were monitored. Randomly selected offspring were allowed to mature and then cohabited for assessment of reproductive performance. Dam body weight gain during dosing was reduced in the high dose group of the pre- and postnatal section. Treated dams in the postnatal and pre- and postnatal sections had litters with reduced body weight, delayed development, and decreased survival. In the F1 mating portion of the postnatal and pre- and postnatal sections, F1 offspring from losulazine-treated dams had reduced body weights over the entire study. A dose-related decrease was found for both the percentage of F1 males that bred and the conception rate of bred F1 females. All F1 females entered estrus at least once, and those that conceived delivered normal litters. Neither microscopic examination of F1 male reproductive organs nor analyses of serum prolactin, luteinizing hormone (LH), and testosterone levels indicated the cause of impaired fertility. Thus, although prenatal exposure only did not result in adverse effects, postnatal exposure to losulazine via lactation affected offspring growth, development, and reproductive capacity.

Administration, Oral↗
PubMed1987

Relationship between progesterone suppression and pregnancy in rats.

Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.

Animals↗
PubMed1987

Enzyme immunoassay method for comprehensive drug screening in micro-samples of urine.

We adapted the reagents from 11 different enzyme-multiplied immunoassay technique (EMIT; Syva Co., Palo Alto, CA 94304) drug-detection kits for use in a centrifugal analyzer. The antibody reagents were mixed into a single dilute solution, and the enzyme-labeled drug derivatives were combined similarly (Mixed EMIT reagents), for use in testing urine samples for the presence of multiple drugs. The assay, a rapid comprehensive drug-screening technique, requires 100 microL of sample and is capable of testing seven samples, in duplicate, simultaneously, in less than 10 min. Clinical evaluation (n = 325) by comparison with thin-layer chromatography (TLC) had the following results: 230 samples were negative by TLC and Mixed EMIT, 77 samples were positive by TLC and Mixed EMIT, 16 samples were negative by TLC and positive by Mixed EMIT, and two samples were positive by TLC and negative by Mixed EMIT.

Autoanalysis↗