Reached Control Levels Research Articles

Increased GABAergic transmission aggravates nucleus basalis magnocellularis lesion-induced behavioral deficits

Quisqualic acid NBM lesions had no effect on water maze performance, but slightly impaired passive avoidance acquisition. GammavinylGABA treatment alone had no effect on the passive avoidance and water maze performance, but aggravated acquisition deficit in rats subjected to NBM lesioning. However, gammavinylGABA-treated NBM-lesioned rats reached control level of performance.

Toxic neurofilamentous axonopathies and fast anterograde axonal transport: III. Recovery from single injections and multiple dosing effects of acrylamide and 2,5-hexanedione

Fast anterograde axonal transport has been advanced as a potential site of action of acrylamide (ACR) and the neurotoxic γ-diketones in producing nerve degeneration. The segmental analysis method of axonal transport was used to measure the rate and quantity of protein transport in the rat sciatic nerve from 1 to 24 hr after a single injection of 50 mg/kg (0.7 mmol/kg) ACR or 4 mmol/kg 2,5-hexanedione (2,5-HD). The single injection of ACR or 2,5-HD resulted in an immediate reduction in transport quantity of 48 and 43%, respectively. Transport remained depressed for 16 hr; recovery occurred from 16 to 24 hr reaching control levels at 24 hr postinjection for both toxicants. Protein transport, measured immediately after the 2nd, 4th, 7th, and 10th injections, was reduced 36–38% by 50 mg/kg ACR and 30–43% by 4 mmol/kg 2,5-HD. Therefore, both ACR and 2,5-HD produce a transient and repeated compromise of fast anterograde transport during the dosing regimen which results in distal nerve degeneration. Assuming a rate of recovery after each subsequent dose similar to the first, the protein delivery to the axon was calculated to be reduced 29% by ACR and 22% by 2,5-HD. Current evidence supports the hypothesis that a toxicant-induced reduction in protein delivery to the axon by ACR and 2,5-HD contributes to development of axonal degeneration.

Castration affects brain iodomelatonin binding in hamsters maintained in long but not short days

The effects of castration on 2-[ 125I]iodomelatonin ([ 125I]melatonin) binding sites in discrete brain areas were investigated in male Syrian hamsters exposed to long and short days. In hamsters maintained in long days (14 h light: 10 h darkness), castration produced a marked decrease in [ 125I]melatonin binding in the brain, particularly in the medulla-pons hypothalamus and hippocampus. Maximal response in the medulla-pons and hypothalamus was observed at 3 days; specific [ 125I]melatonin binding subsequently increased to reach control levels within 30 days after castration. In the hippocampus, the decrease in [ 125I]melatonin binding was still evident at 90 days after castration and could be reversed by testosterone. Exposure to short days (8 h light: 16 h darkness) did not affect [ 125I]melatonin binding in the various brain areas of the intact hamsters; even after 90 days when circulating testosterone decreased to castrated levels, the binding remained as in intact, long-day-housed controls. Moreover, [ 125I]melatonin binding in the various brain areas of hamsters exposed to short, days was unaffected by castration. The results clearly indicate that the regulation by testosterone of melatonin receptors in the medullapons, hypothalamus and hippocampus of the male hamster depends on the prevailing photoperiod.

Migration inhibition factor in acute serum sickness nephritis

Monocytes have been demonstrated to play an important role in acute serum sickness (AcSS) nephritis. Because accumulation of monocytes within the glomeruli could be the result of local lymphokine production, we studied migration inhibition factor (MIF) activity in supernatants from glomerular cultures, analyzed its temporal relationship with monocyte and lymphocyte accumulation, and tested the effect of anti-T lymphocyte monoclonal antibody on local MIF production. AcSS was induced in 12 rabbits, and one additional rabbit had antigen elimination without proteinuria. Single nephrectomy was performed at the time of antigen elimination in all animals; the remaining kidney was removed four days (4 rabbits) or 14 days afterwards (5 rabbits). In glomerular cross sections (gcs), lymphocytes were identified using monoclonal antibody M108, and monocytes by nonspecific esterase stain (ES). MIF activity was determined in supernatants of cultures of isolated glomeruli by the agarose microdroplet method. Peak of MIF activity (84.3 +/- 2.6%, SEM) was observed the first day of proteinuria in association with peak of lymphocyte infiltration (1.15 +/- 0.1 lymphocytes/gcs) and monocyte infiltration (2.4 +/- 0.3 mean ES score/gcs). MIF activity diminished by day 4 (66.0 +/- 6.3%) and reached control levels by day 14 (12.8 +/- 3.2%). There was a significant correlation between lymphocyte infiltration and MIF activity (r = 0.776, P less than 0.0001) as well as between MIF activity and monocyte accumulation (r = 0.858, P less than 0.0001). In five additional rabbits with AcSS, glomeruli were isolated, treated successively with M108 and normal rabbit serum, and supernatants harvested from 24-hour cultures were tested for MIF activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid turn-over of plasma membrane sphingomyelin and cholesterol in baby hamster kidney cells after exposure to sphingomyelinase

Plasma membrane sphingomyelin in baby hamster kidney (BHK-21) cells was hydrolyzed with sphingomyelinase ( Staphylococcus aureus) and the effects on membrane cholesterol translocation and the properties of membrane bound adenylate cyclase and Na +/K +-ATPase were determined. Exposure of confluent BHK-21 cells to 0.1 U/ml of sphingomyelinase led to the degradation (at 37°C) of about 60% of cell sphingomyelin. No simultaneous hydrolysis of phosphatidylcholine occurred. The hydrolysis of sphingomyelin subsequently led to the translocation (within 40 min) of about 50–60% of cell [ 3H]cholesterol from a cholesterol oxidase susceptible pool to an oxidase resistant compartment. The translocation of [ 3H]cholesterol from the cell surface to intracellular membranes was accompanied by a paralleled increase in [ 3H]cholesterol ester formation. When cells were first exposed to sphingomyelinase (to degrade sphingomyelin) and then incubated without the enzyme in serum-free media, the mass of cell sphingomyelin decreased initially (by 60%), but then began to increase and reached control levels within 3–4 h. The rapid re-synthesis of sphingomyelin was accompanied by an equally rapid normalization of cell [ 3H]cholesterol distribution. The re-formation of cell sphingomyelin also led to a decreased content of cellular [ 3H]cholesterol esters, indicating that unesterified [ 3H]cholesterol was pulled out of the cholesterol ester cycle and transported to the cell surface. Exposure of BHK-21 cells to sphingomyelinase further led to a dramatically decreased activity of ouabain-sensitive Na +/K +-ATPase, whereas forskolin-stimulated adenylate cyclase activity was not affected. The activity of Na +/K +-ATPase returned to normal in parallel with the normalization of cell sphingomyelin mass and cholesterol distribution. We conclude that sphingomyelin has profound effects on the steady-state distribution of cell cholesterol, and that manipulations of cell sphingomyelin levels directly and reversibly affects the apparent distribution of cholesterol. Changes in the lipid composition of the plasma membrane also appears to selectively affect important metabolic reactions in that compartment.

Different profiles of desensitization dynamics in guinea‐pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine

1. In the present study we investigated desensitization phenomena of guinea-pig jejunal longitudinal smooth muscle responses after stimulation with 100 microM histamine or methacholine, using a superfusion method. 2. Histamine H1-receptor-mediated contractions appear to be rapidly reduced after application of 100 microM histamine. Muscarinic responses were not affected following desensitization with 100 microM histamine, indicating a homologous desensitization. 3. Initial contractions to 0.3 microM histamine were reduced by 90%, recovered quickly, but did not reach control levels within 1 h. Desensitization of histamine responses could be separated into two phases; a rapid, but transient, desensitization and a more sustained desensitization. As a consequence of this sustained effect the pD2 for histamine shifted from 6.7 +/- 0.1 (control) to 6.1 +/- 0.1 (desensitized). 4. Desensitization with 100 microM methacholine caused a heterologous desensitization, reflected by the development of a refractory period, in which neither histamine nor methacholine was able to elicit a contraction. After a few minutes responses to both agents recovered to control levels. 5. During the refractory period after methacholine desensitization, muscle strips were still responsive to 40 mM KCl but did not contract in response to 10 mM caffeine, suggesting that the heterologous desensitization is caused by a modification of an intracellular Ca2(+)-store, which is used by both histamine and methacholine. 6. The recovery of the responses after methacholine desensitization was not dependent on extracellular Ca2+, suggesting that the recovery is not dependent on refilling of the intracellular Ca2+ store with extracellular Ca2+. 7. The protein kinase C activator, phorbol-12,13-dibutyrate, concentration-dependently inhibited histamine- and methacholine-induced contractions. Protein kinase C seems therefore not to be implicated in the observed homologous H,-receptor desensitization. 8. These data suggest that different forms of desensitization can be distinguished in this model, each with a different time course and dependent on the applied stimulus.

Effects of kainic acid-induced seizures and ischemia on c- fos-like proteins in rat brain

We have analyzed the brain pattern and time-course of c- fos-like proteins expression in kainic acid-induced seizures in the rat. C- fos-like immunoreactivity increased initially in the hippocampus, notably in the dentate gyrus, at the time of the first limbic motor seizure (90 min after kainate). C- fos-like labelling progressively involved different structures of the limbic system when the rats manifested a permanent epileptic state (3–6 h). The labelling was still conspicuous 12 h after kainate treatment and progressively declined to reach control levels 48 h after kainate. This time-course is similar to that produced by kainic acid on 2-deoxyglucose consumption and correlates with the electrographic changes previously described, supporting the idea that c- fos-like immunostaining may provide a useful marker of neuronal activity, with a cellular resolution. Since anoxic-ischemic treatment produces a very slight and transient increase in c- fos-like immunostaining restricted to the fascia dentata, c- fos-like expression is seizure-related and not due to a local hypoxia or ischemia.

ATP is required for receptor-mediated endocytosis in intact cells.

We have demonstrated a requirement for cellular ATP in the receptor-mediated endocytosis of transferrin. This has been accomplished using a novel assay for endocytosis based on acquisition of resistance to the membrane impermeable reducing agent, glutathione (GSH). Diferric-transferrin was conjugated to biotin via a cleavable disulfide bond and iodinated. Internalization of 125I-biotin-S-S-transferrin (125I-BSST) was quantitated by adsorption to avidin-Sepharose after treatment of cells with GSH. Receptor-mediated endocytosis of 125I-BSST was severely inhibited in ATP-depleted cells. Similar results were obtained when ATP was depleted by incubation of cells either under a N2-atmosphere or in the presence of NaN3 and NaF. The latter treatment, alone, also resulted in a loss of surface transferrin receptors which could not be correlated to reductions in cellular ATP. In contrast to the acquisition of GSH resistance, the apparent internalization of 125I-BSST as assessed by inaccessibility to antitransferrin antibodies reached control levels in ATP-depleted cells. Our biochemical and morphological data suggested that, although ATP is required for receptor-mediated endocytosis, in ATP-depleted cells ligands can become efficiently sequestered into deeply invaginated pits that are inaccessible to large probes such as antibodies, but remain accessible to small molecules such as GSH.

Reversible effects of sphingomyelin degradation on cholesterol distribution and metabolism in fibroblasts and transformed neuroblastoma cells

Plasma-membrane sphingomyelin appears to be one of the major determinants of the preferential allocation of cell cholesterol into the plasma-membrane compartment, since removal of sphingomyelin leads to a dramatic redistribution of cholesterol within the cell [Slotte & Bierman (1988) Biochem. J. 250, 653-658]. In the present study we examined the long-term effects of sphingomyelin degradation on cholesterol redistribution in cells and determined the reversibility of the process. In a human lung fibroblast-cell line, removal of 80% of the sphingomyelin led to a rapid and transient up-regulation (3-fold) of acyl-CoA:cholesterol acyltransferase (ACAT) activity, and also, within 30 h, to the translocation of about 50% of the cell non-esterified cholesterol from a cholesterol oxidase-susceptible compartment (i.e. the cell surface) to oxidase-resistant compartments. At 49 h after the initial sphingomyelin degradation, the cell sphingomyelin level was back to 45% of the control level, and the direction of cell cholesterol flow was toward the cell surface, although the original distribution was not achieved. In a transformed neuroblastoma cell line (SH-SY5Y), the depletion of sphingomyelin led to a similarly rapid and transient up-regulation of ACAT activity, and to the translocation of about 25% of cell-surface cholesterol into internal membranes (within 3 h). The flow of cholesterol back to the cholesterol oxidase-susceptible pool was rapid, and a pretreatment cholesterol distribution was reached within 20-49 h. Also, the resynthesis of sphingomyelin was faster in SH-SY5Y neuroblastoma cells and reached control levels within 24 h. The findings of the present study show that the cellular redistribution of cholesterol, as induced by sphingomyelin degradation, is reversible and suggest that the normalization of cellular cholesterol distribution is linked to the re-synthesis of sphingomyelin.

Effects of oil spills on macro-invertebrates of saltmarshes and mangrove forests in Botany Bay, New South Wales, Australia

In Botany Bay, Australia, saltmarshes and mangrove forests are not uncommonly threatened by oil spills. Studies were done to examine the short and long-term effects of spills on molluscs and crustaceans in these habitats. Mortality of some species followed simulated spills but densities reached control levels within a few weeks. Sampling of areas previously affected by spills also provided little, if any, evidence of long-term effects. There were few residual effects of the oil; therefore recolonisation would normally be relatively rapid, depending only on the size of the patch affected and the rate of recruitment from the plankton.

The effect of chronic paracetamol administration to rats on the glycosaminoglycan content of patellar cartilage

Male Wistar rats were treated with paracetamol (200 mg/kg twice a day) for 2, 3, 4 and 9 weeks. During the first four weeks of paracetamol administration the serum sulfate concentration was significantly decreased. However, during the fourth until the ninth week, the serum sulfate concentration was only diminished to a small and insignificant extent. The paracetamol administration did not lead to serious liver or renal toxicity, as determined by alanine aminotransferase and creatinine levels in the serum of the rats. The paracetamol-induced serum sulfate depletion, observed during the first four weeks of the experiment, led to a significantly lower glycosaminoglycan content of the patellar cartilage of the rats after three and four weeks paracetamol treatment. When after the fourth week the serum sulfate concentration rose to nearly normal levels also the glycosaminoglycan content in the rat patellar cartilage reached control levels. These data indicate that the serum sulfate depletion might be the causative factor for the observed reduction in glycosaminoglycan content of rat patellar cartilage.

The significance of high molecular weight kininogen for contact activation of rat blood coagulation,in vitro.

The involvement of the high molecular weight rat kininogen in the activation of the rat contact system by kaolin-cephalin, kaolin, sulfatides and ellagic acid has been investigated, using a rat plasma congenitally devoid of this kininogen. Coagulation times induced by these activators were shorter in normal as well as in deficient rat plasma than in normal human plasma. Coagulation times were prolonged in deficient rat plasma, when the incubation times was three min or less. By kaolin or cephalin-kaolin, this prolongation disappeared when the incubation time reached ten min. The activation of plasma prekallikrein developed slowly in deficient plasma with all the triggers but reached control level after ten min of incubation. By kaolin-cephalin, the activation of Hageman factor was weak and slow in deficient plasma during the ten min of incubation. In rat, high molecular weight kininogen plays thus a role in the activation of the contact system by these triggers. But this role seems to be less important than in human plasma.

Changes in growth characteristics and macromolecular synthesis on recovery from severe hypoxia

Chinese hamster ovary cells subjected to severe hypoxia stop growing. When oxygen was reintroduced growth resumed, but at a slower rate. The longer the hypoxic stress, the slower the recovery growth rate. Six hours of hypoxia caused very little decrease in growth rate while a 24 h period almost halved the rate. Short hypoxic periods resulted in almost no growth lag, while longer periods caused significant lag. Clonogenic survival was 60% after 12 h of hypoxia and rose slowly during recovery, reaching control levels after 60 h. Following 24 h of hypoxia, survival remained around 60% throughout recovery. The cell cycle distribution after hypoxia was similar to that of aerobic cultures. After 4-6 h of recovery, a subpopulation of cells entered S phase, and reached G2 by 12 h. During this time few G2-M cells divided. With longer recovery, cells much larger than aerobic cells emerged, containing greater than 4C DNA content and enhanced amounts of RNA. When these cells were isolated, they exhibited slightly slower growth kinetics, greatly lengthened lag time and decreased survival when compared to aerobic cells or the smaller cells. Most of the extra DNA and RNA was lost within one cell cycle.

Septohippocampal system and the prelimbic sector of frontal cortex: A neuropsychological battery analysis in the rat

Rats with lesions in the posterodorsal septal area (aimed at transecting the precommissural fornix) and rats with lesions in the prelimbic sector of the medial frontal cortex were tested postoperatively on a neuropsychological test battery comprised of the following tasks: time-spent-eating in two adaptation boxes, time-to-emerge and ambulation in an open field, general activity, contingently-reinforced (continuous) and schedule-specific (delayed non-matching-to-sample) T-maze alternation, visual and olfactory discrimination in a T-maze, temporal alternation (response patterning) and tactile Go/No-Go discrimination in a runway, approach-avoidance conflict in the runway, step-through inhibitory avoidance, one-way active avoidance, two-way active avoidance, and conditioned taste aversion. It was found that: (1) rats with septal (SEP) lesions spent more time eating than control (CON) rats and rats with lesions in prelimbic cortex (PRE). PRE rats did not differ from CON rats; (2) PRE rats emerged into an open field faster, and spent less time in home cage than CON and SEP rats. SEP rats stayed in home cage less than CON rats. PRE and SEP rats crossed more squares in the open field than CON rats; (3) SEP and PRE rats were more active than CON rats; (4) SEP rats performed the contingently-reinforced and schedule-specific T-maze alternation tasks worse than PRE rats, and PRE rats performed these tasks worse than CON rats. PRE, but not SEP, rats showed improvement with continued practice at brief intertrial and interrun intervals. However, the performance of PRE rats deteriorated at longer intervals and did not reach CON levels even with continued practice; (5) CON, SEP and PRE rats performed a visual discrimination task in the T-maze equally well. However, SEP rats performed an olfactory discrimination task in the same maze better than CON and PRE rats; (6) SEP, as opposed to CON and PRE, rats were not able to pattern their responses in a straight runway; (7) SEP and CON, but not PRE, rats were able to master a tactile Go/No-Go discrimination task in the runway; (8) SEP and PRE rats took a higher number of shocks than CON rats in an approach-avoidance conflict test, but there were no group differences in total running latency; (9) CON, SEP and PRE rats did not differ in the performance of the step-through inhibitory-avoidance task; (10) CON and SEP rats had a higher number of avoidance responses than PRE rats in the one-way active-avoidance task; (11) SEP rats performed the first session of the two-way active-avoidance task better than CON and PRE rats; (12) PRE rats drank less water than CON and SEP rats, and SEP rats drank less saline than CON and PRE rats; (13) CON, but not SEP and PRE, rats were able to learn a conditioned taste aversion task; (14) intraperitoneal injections of physostigmine did not ameliorate the low performance of SEP rats in the schedule-specific T-maze alternation task 4 months after the first postoperative test. The results can be considered consistent with the hypothesis that the septohippocampal system and the prelimbic sector of the medial frontal cortex are important for working/representational memory mechanisms. However, our study indicates that there seems to be a hierarchy such that the septohippocampal system plays a larger role than the prelimbic cortex. Additionally, our data suggest that the prelimbic cortex is involved in the shifting of cognitive strategies.

Effects of underfeeding and refeeding on GH and thyroid hormone secretion in young, middle-aged, and old rats

The effects of a 50% reduction in normal food intake for a period of 10 weeks were measured on secretion of growth hormone (GH), thyroxine (T 4), and triiodothyronine (T 3) in 5 1 2 −6 1 2 - month-old, and 17 1 2 −18 1 2- month-old male rats. In full-fed controls, GH, T 3, and T 4 were lower in the old and middle-aged than in the young rats. By the 10th week of underfeeding, GH, T 3, and T 4 were reduced in all age groups, but the decrease in T 3 and T 4 in the middle-aged and old rats was greater than in the young rats. Pulses of GH ceased in all the underfed groups. Upon refeeding for 5 days, pulses of GH and levels of GH returned to full-fed control values in the young and middle-aged but not in the old rats. T 3 values in the young and middle-aged rats returned to full-fed control levels, but remained below control levels in the old rats. T[in4 values reached control levels in all age groups upon refeeding. The differences in the response to underfeeding and refeeding by the middle-aged and old rats as compared to the young rats may be due to their initially lower secretion of GH and thyroid hormones and to the age-related decrease in neuroendocrine function.

Phosphatidylinositol 4,5-bisphosphate hydrolysis in human sperm stimulated with follicular fluid or progesterone is dependent upon Ca2+ influx

Hydrolysis of the phospholipid phosphatidylinositol 4,5-bisphosphate is thought to be intimately involved in agonist-induced changes in intracellular Ca2+ levels. Recently we have shown that human preovulatory follicular fluid, which induces exocytosis in human sperm, can stimulate a rapid, transient increase in sperm cytosolic [Ca2+] [Thomas & Meizel (1988) Gamete Res. 20, 397-411]. We report here that both a Sephadex G-75 column fraction, derived from follicular fluid, and progesterone (a component of both the G-75 fraction and whole follicular fluid) stimulate rapid hydrolysis of PtdIns(4,5)P2 and PtdIns4P in human sperm. We also report that progesterone stimulates a rapid influx of Ca2+ in human sperm. Human spermatozoa were labelled for 24 h with myo-[3H]inositol and then treated with either the G-75 fraction or progesterone. A 30-65% loss of label was detected in PtdIns(4,5)P2 and PtdIns4P within 15 s of stimulus addition; no changes were observed in PtdIns during 2 min of treatment. The loss of label from both lipids was accompanied by an increase in water-soluble inositol phosphates. Production of both InsP3 and InsP2 was seen within 10 s; however, InsP3 was rapidly removed and had reached control levels by 1 min. Similarly, formation of InsP2 reached a peak by 30 s and then began a decline accompanied by a corresponding increase in InsP. No increases in InsP4 were seen in sperm treated in this fashion. Stimulated hydrolysis of the phosphoinositides and release of inositol phosphates were both blocked by the Ca2+ antagonist La3+. Likewise, the progesterone-induced increase in intracellular Ca2+ was inhibited by La3+, and phosphoinositide hydrolysis stimulated by this hormone was dependent upon the presence of extracellular Ca2+.

Radiation-induced changes in the ultrastructure and mechanical function of the rat heart.

A time sequence study was performed to study the early effects of radiation on the ultrastructure of the rat heart. Wistar rats were exposed to 20 Gy electron irradiation to a field including the heart and a third of the lung. The hearts were excised at varying time intervals (1 h-180 days), and the ultrastructure of perfusion-fixed subepicardium and subendocardium studied. Changes were observed in both myocytes and interstitium at all time intervals. The most pronounced change observed in the myocyte was that of intercalated disc damage which reached a peak at 30 days post-irradiation. Mitochondrial damage, characterized by swelling and fenestration in areas of myofibrillar contracture, was focal and relatively scarce. Swelling of the capillary endothelial cells and collapse of the capillaries were marked up to 60 days. Of significance was the observation that the damage to both myocytes and interstitium receded after 60 days and the hearts exhibited an almost normal ultrastructure from 100 to 180 days post-irradiation. Mechanical function of these hearts followed a similar pattern: maximal depression was observed 60 days after irradiation. Thereafter the work performance of these hearts improved significantly, almost reaching control levels after 180 days.

Effect of testosterone on serum immunoactive inhibin concentrations in intact and hypophysectomized male rats

Intact and hypophysectomized rats were treated with graded doses of testosterone via subcutaneous Silastic implants over a 13-week period. Serum inhibin concentrations fell 50% (P less than 0.001) after 2 weeks of hypophysectomy, remaining suppressed at this level for 13 weeks. The administration of testosterone to hypophysectomized rats (serum testosterone values 2-12 ng/ml; control values 5.5 ng/ml) was without effect on serum inhibin values. In contrast, administration of testosterone to intact animals for 7 weeks resulted in an initial fall (P less than 0.05) in inhibin levels to 50-70% of controls then increasing to reach control levels at higher doses. Serum FSH concentrations were similarly biphasic with increasing dose of testosterone and values for these two hormones were significantly correlated (r = 0.44, P less than 0.01). Segments of seminiferous tubules in culture from rats after various times of hypophysectomy showed a partly suppressed secretion of inhibin. The administration of testosterone did not modify inhibin production although inhibin production was sensitive to FSH. It is concluded that (1) serum inhibin concentrations are partly suppressed after hypophysectomy and testosterone has no effect on serum inhibin values; and (2) the suppression of serum inhibin in intact rats treated with increasing doses of testosterone is attributable to the concomitant fall in serum FSH concentrations.

The effects of gamma interferon on the natural killer and tumor cells of children with neuroblastoma. A preliminary report

Human neuroblastoma cells lack HLA-A,-B,-C molecules which can be induced in vitro by gamma interferon (gamma IFN). To test the hypothesis that the same induction would occur in vivo leading to tumor regression, a Phase I study was initiated. Seven patients with neuroblastoma were entered on a Phase I study of recombinant gamma IFN in children. Three received 0.05 mg/m2 intravenously (IV) three times a week, three received 0.1 mg/m2 for 4 weeks, and one patient withdrew from study before receiving adequate treatment for evaluation. No significant clinical response was seen. The side effects were fever and chills, and no serious toxicity occurred. Natural killer (NK) and lymphocyte activated killer (LAK) precursor activity of peripheral blood mononuclear cells was determined before and during treatment, and expression of HLA-A,B,C molecules was looked for on the tumor cells in the bone marrow of five patients. The NK activity initially low, reached control levels in six patients, but the increase was transient. The LAK precursor activity remained normal. Expression of HLA-A,B,C, initially absent, was induced on the neuroblastoma cells in four of six patients.

Eftects of Gonadectomy and Steroids on Pituitary Gonadotropin Secretion in a Frog, Rana Pipiens1

Secretory dynamics of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured at various times following gonadectomy in adult male grass frogs, Rana pipiens. Plasma levels and in vitro initial secretory rates of both LH and FSH increased significantly within 1 wk and remained elevated for 3-4 wk of castration. Pituitary FSH and LH content were unchanged. However, dissociation between the two gonadotropins (Gth) occurred thereafter: Secretion of FSH remained elevated for 70 days, but those of LH declined to control levels after 30 days. In vitro secretion of Gth from gonadectomized (gonadx) frogs declined progressively over time reaching control levels after 24 h incubation. The results indicate that elevated pituitary secretion contributes to the observed circulating LH and FSH levels in gonadx frogs, and that FSH and LH may be controlled independently. Replacement therapy with 17 beta-estradiol (E2) suppressed post-gonadectomy increases in plasma Gth and in vitro responses to GnRH, whereas 5 alpha-dihydrotestosterone (DHT) had little effect in vivo and augmented GnRH responses in long-term castrates. In vitro, E2 also inhibited, while 48 h of DHT treatment had no effect on GnRH responsiveness of pituitaries from gonadx frogs. The actions of these steroids were opposite to those typically observed in mammals (and birds), and support the hypothesis that E2 may contribute to seasonal testicular regression in ranid frogs.