Biomedical subjects
Publications and source records attributed to M Goldstein.
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Modern therapy for stage III ovarian carcinoma patients usually involves one or more laparotomies with maximal resection of tumor, and intensive multi-agent chemotherapy. However, with long-term follow-up only 10-15% of patients remain free of disease. In the hope of improving outcome, we have treated 17 women with sequential multimodality therapy, including initial surgical resection (if possible), cyclophosphamide-adriamycin +/- cis-platinum, second-look surgery, and whole abdominal irradiation. Seven patients are currently alive without disease, with median follow-up of 52 months since initiation of radiation and 60 months since initiation of chemotherapy. Disease-free survival correlated with residual tumor at the start of radiotherapy: none (4/4); microscopic, less than or equal to 5 mm (3/4); greater than 5 mm or no surgery (0/9). Survival also correlated with tumor grade: grade 1 (2/2); grade 2 (2/3); grade 3 (3/11). Hematological tolerance of radiotherapy was dependent upon the number of chemotherapy cycles: ten of 11 patients receiving less than or equal to eight cycles completed radiotherapy without excessive delay, compared with only one of five receiving greater than eight cycles. There were no treatment-related deaths and only one patient required laparotomy for bowel obstruction. We conclude that intensive multimodal treatment may be tolerated moderately well if the amount of chemotherapy is limited, and that further studies are justified.
Cis-dichlorodiammine platinum (II), or cisplatin, has emerged as a principal chemotherapeutic agent in the treatment of otherwise resistant solid tumors and is currently among the most widely used agents in the chemotherapy of cancer. The chief limit to its greater efficacy is its nephrotoxicity, which has made it necessary both to lower its dosage and actively hydrate patients to reduce it. The vulnerability of the kidney to cisplatin is almost certainly related to its primary role in the excretion of cisplatin. Cisplatin enters renal cells by a process that depends on normal oxygen utilization and is specifically inhibited by organic bases. Greater localization of platinum to the S3 segment of the proximal tubules suggests that the vulnerability of this segment may depend on its specific uptake of the drug. The majority of intracellular platinum is bound to macromolecules, including protein and DNA, yet a significant portion of cell platinum is biotransformed to a nonmutagenic and possibly nontoxic compound. Polyuria and hypomagnesemia, which are commonly associated with cisplatin nephrotoxicity, may be due to defects in deep nephron or collecting duct fluid and solute transport. Low single nephron glomerular filtration rates (SNGFR) during early cisplatinum-induced acute renal failure is accompanied by reduced renal blood flow and transglomerular hydrostatic pressure without elevated intratubular hydrostatic pressure, suggesting preglomerular vasoconstriction as an important determinant of renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Rat brain and adrenal gland were analyzed by hybridization histochemistry using an RNA probe complementary to mRNA for tyrosine 3-hydroxylase (TyrOHase; tyrosine 3-monooxygenase, EC 1.14.16.2), by immunohistochemistry using TyrOHase antiserum, and by retrograde tracing using the fluorescent compound Fast blue. Cell bodies in the ventral mesencephalon contained mRNA for TyrOHase, and these cells were also TyrOHase immunoreactive. After injection of Fast blue into the striatum, such double-labeled cells in addition contained the retrograde tracer, showing that these cells send axonal projections to the injection site. These results show that hybridization histochemistry can be used to identify transmitter-specific neuron populations and that their projections can be established.
A monoclonal antibody against the rat liver glucocorticoid receptor was used in combination with rabbit antibodies against tyrosine hydroxylase, phenylethanolamine N-methyltransferase, and 5-hydroxytryptamine to demonstrate strong glucocorticoid receptor immunoreactivity in large numbers of central monoaminergic nerve cell bodies of the male rat. The receptor immunoreactivity was predominantly located in the nucleus, whereas the tyrosine hydroxylase, phenylethanolamine N-methyltransferase, and 5-hydroxytryptamine were detected mainly in the cytoplasm. The vast majority of the noradrenergic nerve cell bodies of groups A1-A7 and of the 5-hydroxytryptaminergic cell bodies of groups B1-B9 were found to contain strong glucocorticoid receptor immunoreactivity. The majority of the phenylethanolamine N-methyltransferase-immunoreactive nerve cells of the adrenergic cell groups C1-C3 and of the dorsal subnuclei of the nucleus tractus solitarius in the medulla oblongata were also strongly immunoreactive for glucocorticoid receptor. In the midbrain dopaminergic groups A8-A10, moderately (A8, A9) to strongly (A10) glucocorticoid receptor-immunoreactive cells were found, ranging from 40 to 75% of the total population. In the hypothalamic dopaminergic cell groups, all the cells of groups A12 and A14, as well as the majority of the dopaminergic cells of the zona incerta (A13), were found to contain moderate to strong glucocorticoid receptor immunoreactivity, but none of the large dopaminergic cells of the posterior hypothalamus (A11) showed such immunoreactivity.
After repeated, successful extradural injections in a parturient, the extradural catheter migrated into the subdural space. The injection of 3% chloroprocaine 10 ml resulted in an extensive block, which extended to the cranial nerves and paralysed the respiratory muscles. The position of the catheter tip was confirmed by fluoroscopy. Subdural injection should always be suspected when tests for subarachnoid injection are negative, but an extensive block occurs gradually within 15-20 min. Respiration and circulation should be supported until the block regresses.
A combined morphological and physiological analysis of the properties of the adrenergic vasoconstrictor innervation was carried out in the splanchnic vasculature in the rat. Three generations of vessels were studied: (1) the abdominal aorta and the caval vein; (2) the superior mesenteric artery and vein; (3) 200 microns branches of the superior mesenteric artery and their parallelling veins. The adrenergic innervation was visualized by the Hillarp-Falck fluorescence technique, and by the immunohistochemical localization of immunoreactivity to tyrosine hydroxylase and dopamine-beta-hydroxylase. Determination of responses to applied noradrenaline, to transmural nerve stimulation and to direct activation of the muscle was made on ring preparations mounted in a myograph. All vessels were found to be innervated at the adventitio-medial border by noradrenergic nerves with varying density; the small arteries had the highest nerve density, the abdominal aorta was least innervated. When related to the maximal isometric response to applied noradrenaline, the maximal neurogenic response parallelled the density of the adrenergic innervation. Variations in frequency for half-maximal response among the vessels could not, however, be ascribed to innervation properties only. The constriction under isotonic conditions amounted to 20% of the initial circumference in the aorta, and to 30% in the small arteries and veins. The relation between response to applied noradrenaline and to nerve stimulation was similar for isometric and isotonic responses. In the smaller veins, a beta-receptor-mediated decline in the response to applied noradrenaline was seen. This decline was much less pronounced in neurogenic responses. The results indicate a gradation from proximal to peripheral arteries towards denser innervation and greater neurogenic responses. On the venous side only minor differences were found.
By means of quantitative receptor autoradiography using 125I-neuropeptide Y (125I-NPY) as a radioligand, the distribution of 125I-NPY binding sites has been evaluated in coronal sections at various rostrocaudal levels of the medulla oblongata of the male rat. High densities of neuropeptide Y (NPY) binding sites were demonstrated in the nucleus tractus solitarius (nTS), in the nucleus paratrigeminalis, in the area postrema, in the medial nuclei of the inferior olive and in the substantia gelatinosa of the caudal part of the spinal trigeminal nucleus. Low densities were present in the dorsal motor nucleus of the vagus (dmnX) and in the hypoglossal nucleus. Other regions of the medulla oblongata showed only a very low density or no specific binding of 125I-NPY. These results indicate that the central cardiovascular actions of NPY at least in part may be mediated via an action in the nTS, in this way controlling the baroreceptor reflex activity. Neuropeptide Y mechanisms may also play a role in the regulation of other visceral afferents such as those involved in gastrointestinal control (dmnX) and of cerebellar function (inferior olive). Finally, the results indicate that a high density of NPY immunoreactive terminals in some regions of the medulla oblongata is associated with a low density of high affinity 125I-neuropeptide Y binding sites and vice versa.
The distribution of growth hormone-releasing factor (GRF) and tyrosine hydroxylase (TH), a marker for dopamine neurons in this region, was analyzed in the mediobasal hypothalamus with indirect immunofluorescence histochemistry and an elution-restaining procedure. TH-like immunoreactivity was present in most GRF-immunoreactive cells in the ventral part of the arcuate nucleus (ventral A12 dopamine cell group). Dopamine cells in the dorsal A12 group and, for example, in the hypothalamic A14 cell group seemed to lack GRF peptide. Partly overlapping GRF- and TH-immunoreactive fibers in the median eminence were observed, indicating possible coexistence of the two compounds also in nerve endings close to portal vessels. These findings suggest that a subpopulation of A12 dopamine neurons produces, stores and releases a GRF-like peptide. Possible interactions of GRF and dopamine in the control of growth hormone secretion are discussed.
The catecholaminergic neurons of the nervous system have been studied histochemically with fluorescent derivatives of catecholamines and immunocytochemically using antibodies against their biosynthetic enzymes. The immunocytochemical techniques yield permanent preparations and make possible ultrastructural studies and combined applications with other procedures. In this report, we describe the production and application of a high-affinity mouse monoclonal antibody against the rate-limiting enzyme in the biosynthetic pathway of the catecholamines, tyrosine hydroxylase. This antibody, coded TOHA1.1, has been used successfully to stain tyrosine hydroxylase immunoreactive sites in the known catecholaminergic neurons and fiber systems of rat brain in both light and electron microscopy. It has also been demonstrated that TOH A1.1 will immunoprecipitate phosphorylated tyrosine hydroxylase.
Neurologists in the United States were enumerated for each year from 1935 to 1984 on two bases: board certification (including Child Neurology and Psychiatry and Neurology) and completion of PG4 neurology residency training. The annual incidence of new neurologists was calculated at less than 200 until 1970; then it rose steadily to 380 in 1980, and plateaued thereafter at 385. The estimated number of neurologists present at one time (prevalence) was 1,500 in 1950, 2,400 in 1970, 4,600 in 1980, 8,100 in 1990, and 11,000 in 2000. These numbers for total neurologists will plateau at 12,200 by about 2010, at which time the number of certified neurologists will also plateau at 9,900. Both numbers are notably less than our prior estimate of needs: 16,500 neurologists by 1990, 19,100 in 2010.
Estimates of the number of neurologists needed in the United States have been widely divergent. For direct patient care needs alone in a US population of 243.5 million, the Joint Commission on Neurology (ANA-AAN) estimate was 14,000 neurologist, the Delphi Panel median (Battelle/GMENAC) 11,200, and the Advisory Panel (Battelle/GMENAC) 6,200; our review suggests a need for 12,600. Total needs for clinical neurologists including faculty were 8,400 (Advisory Panel), 14,500 (Delphi Panel), and 16,500 (ours) for respective rates of 3.44, 5.96, and 6.76 neurologists per 100,000 population.
No validated criteria exist for assigning patients to the creative arts therapies. This paper reports on a pilot study attempting to identify predictors of benefit from art, movement, and poetry therapy. Based on a priori hypotheses, selected psychological tests were administered to 31 patients who each received all three modalities of treatment. The relationships of these test scores and therapist prediction of benefit ratings to outcome were then evaluated statistically; outcome was measured by patient ratings and figure drawings. Results showed few significant predictors, though several findings requiring confirmation may provide a framework for future research. Implications and possible explanations of these results, as well as design and other research issues relevant to further work in this area, are discussed.
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The coexistence of galanin (GAL)-like immunoreactivity (LI) with markers for catecholamines, 5-hydroxytryptamine (5-HT), GABA, or some neuropeptides was mapped in the rat CNS by using adjacent sections, as well as by elution-restaining and double-labeling immunocytochemistry. Many instances of coexistence were observed, but there were also numerous GAL-positive cell body populations displaying distributions similar to those of these markers but without apparent coexistence. In the hypothalamic arcuate nucleus GAL-LI was found in a large proportion of tyrosine hydroxylase (TH)-positive cell bodies (A12 cells), both in the dorsomedial and ventrolateral subdivisions, with a higher number in the latter. GAL-LI coexisted in glutamic acid decarboxylase (GAD)-positive somata in the posterior aspects of the arcuate nucleus and at all rostrocaudal levels in fibers in the external layer of the median eminence. In the anterior hypothalamus, a large population of the cells of the parvocellular and magnocellular paraventricular nuclei contained both GAL-LI and vasopressin-LI. Moreover, somata containing both GAD- and GAL-LI were seen lateral to the mammillary recess in the tuberal and caudal magnocellular nuclei. Some of the neurons of the caudal group were shown to project to the occipital cortex using combined retrograde tracing and immunofluorescence. With regard to mesencephalic and medullary catecholamine neurons, GAL-LI coexisted in a large proportion of the noradrenergic locus coeruleus somata (A6 cell group) and in the A4 group dorsolateral to the fourth ventricle, as well as in the caudal parts of the A2 group in the dorsal vagal complex. However, in more rostral parts of the latter, especially in the medial subdivision of the solitary tract nucleus, a very large population of GAL-IR small cell bodies was seen intermingling with catecholamine neurons, but they did not contain TH-LI. Furthermore, GAL-IR cell bodies coextensive with, but not coexisting in, TH-IR somata were seen in the C1 (epinephrine) horea in the ventrolateral medulla at the level of area postrema and in the most rostral aspects of the C1 group. Finally, 5-HT-positive cell bodies of the mesencephalic and medullary raphe nuclei and a subpopulation of coarse 5-HT nerve fibers in the hippocampus co-contained GAL-LI. The present results demonstrate that a GAL-like peptide is present in many systems containing other neuroactive compounds, including dopamine, norepinephrine, 5-HT, GABA, and vasopressin.(ABSTRACT TRUNCATED AT 400 WORDS)
The topography of the peptidergic neuronal subpopulations in the guinea pig celiac-superior mesenteric ganglion was studied analyzing the distribution of immunoreactivity to neuropeptide Y (NPY), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP)/polypeptide HI (PHI). For comparison, the ganglion was also studied using antisera against the 2 catecholamine-synthesizing enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Approximately 65% of the neuronal cell bodies contained NPY-like immunoreactivity (NPY-LI), whereas 25% of the principal ganglion cells contained SOM-like immunoreactivity (SOM-LI). Though occasional cells were found to contain both NPY-LI and SOM-LI, these peptides had a complementary distribution in the ganglion, with NPY cells in the celiac poles and SOM cells in the superior mesenteric pole. The vast majority of both the NPY- and SOM-positive cells also contained TH-like immunoreactivity (TH-LI), confirming their catecholaminergic, presumably noradrenergic, nature. Some noradrenergic neurons seemed to lack NPY- and SOM-LI. Small numbers of VIP/PHI-containing cell bodies were found in areas where the NPY-immunoreactive neurons predominated. Many of the VIP/PHI-positive cells contained NPY-LI and occasionally also TH-LI. The immunohistochemical markers were also observed in fibers. Thus, a comparatively weak NPY-LI was seen in smooth fibers, probably representing axons and axon bundles. SOM-LI was seen in a similar type of fiber but also in more strongly fluorescent fibers with a varicose appearance. The latter fibers were observed only in the SOM-dominated part of the ganglion, often surrounding the ganglion cells. Varicose fibers with a similar distribution containing DBH-like immunoreactivity (DBH-LI) were also seen. In addition, DBH- and TH-LI were seen in smooth axonlike processes. VIP-positive fibers exhibited a very dense fiber network, almost exclusively related to the SOM cell-dominated part of the ganglion. The projection of the postganglionic sympathetic neurons was studied with special reference to the pylorus using a combination of retrograde axonal tracing and indirect immunofluorescence techniques. Seventy-two hours after injection of the fluorescent tracer Fast Blue into the pyloric sphincter, labeled neurons were found in the ganglion. By comparing the Fast Blue-labeled cells with the immunoreactive cell bodies, neurons containing both dye and NPY- or SOM-LI were observed. In elution-restaining experiments, it was established that the majority of these cells were also immunoreactive to TH, indicating that they produce noradrenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
The axonal transport of adrenergic and cholinergic axonal organelles in rat sciatic nerve has been studied using a cytofluorimetric scanning (CFS) technique. This technique gives quantitative data on material which accumulates in a nerve relative to a crush, as well as morphological and morphometrical information about the accumulated axons in the nerve. One important advantage is that several substances can be measured in the same nerve segment, thus reducing the number of animals needed. The substances must be made fluorescent, and in this study we have investigated noradrenaline (NA), using formaldehyde induced fluorescence, and dopamine beta-hydroxylase (DBH), tyrosine hydroxylase (TH), neuropeptide Y (NPY) and two cholinergic vesicle components (a transmembrane glycoprotein and synapsin I) using indirect immunofluorescence. The antisera used for labelling immunoreactive material (IR) were produced in rabbit or goat (DBH). In adrenergic axons NA, DBH-IR and TH-IR accumulated with time after crushing the nerve as described earlier with biochemical techniques. After reserpine, the amounts of amine granules transported distally in the sciatic nerve initially fell, but recovered during day 2 after reserpine. At day 4 the amount of NA and DBH-IR which was transported distally in the axons was supranormal, 160% and 140% of control, respectively, but the level of NPY-IR was not increased, even falling to subnormal at day 4, indicating different mechanisms for regulating the synthesis of DBH and NPY which are suggested to co-exist in axonal adrenergic large dense core vesicles. In cholinergic motor axons organelles, recognized by rabbit-anti-cholinergic synaptic vesicles-antiserum (RASVA) and by anti-synapsin I-antiserum, are transported distally at a rapid rate.(ABSTRACT TRUNCATED AT 250 WORDS)