Biomedical subjects

L R Nelson

Publications and source records attributed to L R Nelson.

At least 19 recordsLinked to original sources

PubMed1995

Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix).

OBJECTIVE: To determine if daily subcutaneous doses of ganirelix will suppress and maintain E2 < or = 30 pg/mL (conversion factor to SI unit, 3.671), the serum profiles of LH and FSH during and after cessation of treatment, the time-course of the resumption of normal ovarian function after ganirelix cessation, and to identify side effects of daily treatment. DESIGN: Open-label nonrandomized clinical study. SETTING: Normal human volunteers in an academic research center. PATIENTS: Women 21 to 45 years of age, with documented ovulatory menstrual cycles. INTERVENTIONS: Ganirelix was administered subcutaneously daily for 8 days. Blood samples were obtained during dosing as well as before and after cessation of dosing. MAIN OUTCOME MEASURES: Changes in serum E2, LH, FSH, P, and ganirelix. RESULTS: Ganirelix treatment rapidly decreased serum levels of gonadotropins and E2 after both 1 and 2 mg administration. Twenty-four hours after the first dose of ganirelix, E2 decreased from a mean +/- SEM of 50 +/- 8 and 67 +/- 11 pg/mL at baseline to 25 +/- 4 and 20 +/- 3 in the 1 mg and 2 mg groups, respectively. Estradiol remained suppressed (mean levels < 26 pg/mL) on all subsequent 7 days of ganirelix dosing in both groups. After the final dose of ganirelix, there was a rapid return of ovarian function in all volunteers. All women had P levels indicative of ovulation in the subsequent cycle, and the mean number of days from the final ganirelix dose to the next menses was 25.8 +/- 2.1 and 27.3 +/- 1.6 in the 1 and 2 mg groups, respectively. CONCLUSIONS: Daily ganirelix administration is effective in suppressing the pituitary-gonadal axis and has a side effect profile that should be well tolerated.

Adult↗

PubMed1995

Anaesthetic agents decrease the activity of nitric oxide synthase from human polymorphonuclear leucocytes.

Nitric oxide (NO) inhibitors reduce the threshold for anaesthesia. We have investigated the action of anaesthetic agents on human nitric oxide synthase (NOS) activity. Thiopentone reduced mean NOS activity to 36.6 (SD 8.9) % of control at 100 mumol litre-1 (P < 0.001) and 50.9 (20.3) % at 1 mmol litre-1 (P < 0.05). Ketamine showed similar effects, with activity reduced to 67.0 (17.6) % (P < 0.05) and 57.7 (8.5) % (P < 0.001) at 100 mumol litre-1 and 1 mmol litre-1, respectively. Etomidate 100 mumol litre-1 did not significantly alter activity (88.2 (8.1) %) but 1 mmol litre-1 did (60.6 (10.4) %, P < 0.005). Halothane also caused a significant decrease in NOS activity at all concentrations. This effect was specific as other enzymes were unaffected. We conclude that anaesthetic agents have a profound effect on NOS activity and as inhibition of NO release augments anaesthesia, we suggest that this may play a role in the mechanism of anaesthesia in humans.

Anesthetics↗

PubMed1994

Corneal endothelium five years after transplantation.

We asked the recipients of 500 consecutive corneal transplants to return for examination and endothelial photography at two months and at one, three, and five years postoperatively. Thirty-six regrafts and 70 fellow eyes of bilateral cases were excluded, leaving 394 eyes for analysis. We also recorded episodes of graft rejection and failure. In 129 grafts in patients who returned at each postoperative interval and had no rejection episodes, the mean endothelial cell density continued to decrease 7.8% per year from three years to five years after keratoplasty, compared with approximately 0.5% per year in unoperated-on normal corneas. The mean cell loss compared with the preoperative examination was 58.9% five years after keratoplasty. The percentage of hexagonal cells did not return to preoperative levels by five years after keratoplasty, suggesting that the endothelium continued to be unstable. The mean corneal thickness increased significantly with time. The Kaplan-Meier rates of rejection episodes and failure were 19% and 17%, respectively, five years after keratoplasty. Eyes with posterior chamber lens implants lost more endothelial cells by five years after keratoplasty than did eyes with open-looped anterior chamber lens implants. Low endothelial cell densities were statistically significantly associated with increased corneal thickness and with an increased risk of subsequent failure. The central endothelial cells of successful corneal transplants five years after keratoplasty form an unstable monolayer with continued accelerated loss of cells and abnormal cellular morphologic features. This process results in fewer endothelial cells remaining on the central graft with an associated increase in stromal swelling and graft failure.

Adolescent↗

PubMed1994

Human corneal endothelial tolerance to glycerol, dimethylsulfoxide, 1,2-propanediol, and 2,3-butanediol.

We exposed human corneas to various concentrations of four cryoprotectants by one of two methods: a gradual increase to the final concentration (ramp method) and a series of steps to the final concentration (step method). Endothelial damage was manifest as a decrease in the number of endothelial cells per unit area. The highest concentrations that did not cause a loss of endothelial cells by the ramp and step methods, respectively, were 4.3 and 2.0 M glycerol, 2.0 and 4.3 M dimethylsulfoxide, 2.0 and 3.0 M 1,2-propanediol, and 2.0 and 2.5 M 2,3-butanediol. The ramp method achieved higher final concentrations with the more slowly permeating glycerol, but required low toxicity. The step method achieved higher final concentrations with the more toxic cryoprotectants by limiting the exposure time, but required more rapid permeation. None of the four cryoprotectants was tolerated at concentrations sufficient for vitrification at practical cooling and warming rates.

Adolescent↗

PubMed1994

Human corneal studies with a vitrification solution containing dimethyl sulfoxide, formamide, and 1,2-propanediol.

We tested the tolerance of human corneas to a vitrification solution, modified VS41A, containing 3.1 M dimethyl sulfoxide, 3.1 M formamide, and 2.2 M 1,2-propanediol in a carrier solution consisting of the corneal storage medium CPTES with 2.5% w/v chondroitin sulfate. Seven human corneas were exposed for 10 min each to graded concentrations of the solution at 0 degree C, remaining in the full-strength solution for 10 min. The corneas had significantly more endothelial cell damage (P < 0.05) than seven mated control corneas, but it was minimal (4.3% cell loss). Attempts at vitrification and rewarming of three corneas exposed to the solution by this protocol, however, resulted in ice formation in the peripheral corneal stroma and severe endothelial damage. Presumably, equilibration with the cryoprotectant in the thicker periphery of the human cornea had not occurred. Ice did not form on the center of one cornea, and substantial numbers of central endothelial cells survived after vitrification in this case. Immersion of the human corneas for 25 min in each of the four graded solutions at 0 degree C was required for sufficient penetration of the cryoprotectant to allow total corneal vitrification and rewarming without ice formation. This prolonged exposure to modified VS41A caused unacceptable damage to the corneal endothelium, however. Successful vitrification of human corneas with this solution will require a safe method for obtaining corneal equilibration with the cryoprotectant.

Cornea↗

PubMed1994

Continued endothelial cell loss ten years after lens implantation.

PURPOSE: To investigate the effects of cataract extraction and lens implantation on the central corneal endothelium 10 years after surgery. METHODS: The authors conducted a prospective study of 253 consecutive eyes that underwent cataract extraction with or without lens implantation by one surgeon from 1976 to 1982. Three types of lens implant were used during this period. The protocol included ophthalmic examinations and specular microscopy on all eyes preoperatively, and 2 months and 1, 3, 5, and 10 years postoperatively. RESULTS: The 10-year analysis was conducted on 67 (26%) of the 253 total eyes. The remaining patients died (86 eyes [34%]), were unable to return 10 years later (93 eyes [37%]), or had secondary implants (5 eyes [2%]) or penetrating keratoplasty (2 eyes [1%]). There were no statistically significant differences among the median 10-year endothelial cell losses of 36% in 17 control cataract extractions without lens implantation (15 extracapsular and 2 intracapsular), 40% in 15 medallion iris suture implants, 32% in 28 transiridectomy clip implants, and 32% in 7 posterior chamber implants. The median exponential rate of chronic cell loss from 1 to 10 years after surgery was 2.5% per year, which did not differ significantly among the three implant groups or between the implants (2.4% per year) and controls (2.7% per year). The chronic cell loss rate was significantly higher (7.2% per year) in six eyes with cornea guttata, which was the only preoperative endothelial morphologic feature that was significantly associated with the chronic cell loss rate. CONCLUSIONS: Ten years after cataract extraction, eyes continued to lose endothelial cells from the central cornea at a rate of 2.5% per year, 2.5 to 8.0 times the rate in healthy unoperated eyes. The rate was not affected significantly by the presence of the three types of lens implants that the authors used. Postoperative eyes with cornea guttata continued to lose cells at more than twice this rate. Preoperative specular microscopy did not provide additional information helpful in predicting postoperative endothelial status or outcome.

Aged↗

PubMed1994

Long-term observation of morphologic and functional features of cat corneal endothelium after wounding.

PURPOSE: (1) To test the hypothesis that corneas with enlarged endothelial cells (and thus less intercellular space) have decreased endothelial permeability to small polar solutes. (2) To measure corneal endothelial ouabain binding (Na+/K+ ATPase "pump site" density) and Descemet's membrane production after endothelial wounding. METHODS: Bilateral specular microscopy and anterior segment fluorophotometry were performed at 2-month intervals for 1 year in ten cats after mechanically damaging the corneal endothelium in one eye of each. The measurements were repeated at 2 years in four cats and at 3 years in two cats. Eighteen months after wounding, endothelial ouabain binding was measured in both eyes of six cats. Transmission electron micrographs of Descemet's membrane were analyzed in both eyes of six cats at 18 months, two cats at 2 years, and two cats at 3 years after wounding. RESULTS: From 6 to 12 months after wounding, the endothelial permeability to carboxyfluorescein was significantly decreased (P < 0.05), and the mean endothelial cell size was significantly increased (P < 0.001) in the damaged eyes. The enlarged endothelial cells persisted in the few cats observed 2 and 3 years after wounding. There was no significant difference in endothelial ouabain binding between the damaged and control corneas in six cats tested 18 months after wounding. On subsequent histologic examination, a layer of abnormal Descemet's membrane was present in all ten wounded eyes, with additional normal Descemet's membrane posterior to it, between the abnormal layer and the endothelial cells. CONCLUSIONS: The results are consistent with the hypothesis that corneal endothelial permeability to small polar solutes varies directly with the amount of intercellular space available for diffusion across the monolayer. The results also confirm clinical reports of decreased endothelial permeability in corneas with enlarged endothelial cells. In histopathologic specimens, a layer of abnormal Descemet's membrane can be a historical marker for a period of endothelial damage and corneal decompensation.

Animals↗

PubMed1990

Brain anti-cytoxic edema agents.

The work described in this chapter has indicated that improved outcome from an experimental head injury model can be achieved by drugs which are non-diuretic derivatives of loop diuretics, namely indanyl and fluorenyl compounds which are derivatives of ethacrynic acid. These drugs were originally identified by us on the basis of their efficacy in inhibiting [K+]-stimulated, HCO3(-)-dependent swelling of brain cerebrocortical slices. Swelling of glial cells (astrocytes) has long been known to be associated with such slice swelling and astrocyte swelling is a major locus of cytotoxic or cellular brain edema. Qualitative and quantitative electron microscope studies have shown that L644,711, a particularly effective member of the fluorenyl class of drugs, inhibits astrocytic swelling associated with an experimental animal head injury model. We have suggested that astrocytic swelling in pathological states may be partly due to activation of Cl-/HCO3- and Na+/H+ exchange systems driven by increased astrocytic intracellular hydration of CO2, and recent work has indeed shown that the ability of the indanyl and fluorenyl drugs to inhibit brain slice swelling and protect against head injury correlates closely with their ability to inhibit Cl-/HCO3- exchange. All these data suggest that astrocytic swelling, which seems to precede neuronal degeneration and breakdown of the blood-brain barrier, is deleterious and that prevention of such swelling can lead to effective therapy. We have used primary astrocytic cultures to explore reasons why astrocytic swelling could be harmful. Exposing such astrocytes to hypotonic medium causes rapid swelling with a slower return to normal volume in the continued presence of hypotonic medium, a process known as regulatory volume decrease or RVD. Such RVD is associated with marked release of several amino acids, including L-glutamate. L644,711 and other Cl-/HCO3- transport inhibitors such as SITS and furosemide, but not the selective Na+ + K+ + 2Cl- co-transport inhibitor bumetanide, inhibit such swelling-induced release of L-glutamate. Thus, L644,711 and other drugs may be effective in promoting recovery from head injury and other pathological states in which astrocytic swelling occurs either by initially preventing the swelling or inhibiting the release of excitotoxic excitatory amino acids if swelling does occur, perhaps depending at what time the drug is given.

Animals↗

PubMed1989

Tolerance of human corneal endothelium to glycerol.

As an initial step in the development of a method for corneal cryopreservation by vitrification, we attempted to establish the maximum concentration of glycerol to which human corneal endothelium could be exposed at 4 degrees C for 15 min without damage. Damage was defined as an increase in mean endothelial cell size or the inability to maintain corneal thickness for 1 week after exposure to glycerol. Using a system for long-term corneal perfusion, we perfused 24 paired human corneas with glycerol at 4 degrees C. The concentration of glycerol increased at a rate of 20% (w/v) (2.2 M) per hour until the desired maximum concentration was reached for that cornea, stabilized for 15 min, and then decreased at the same rate. The corneas were then perfused at 37 degrees C with Dulbecco's medium at a rate of 5 microliters/min under 18 mm Hg intracameral pressure for 7 days with daily measurements of corneal thickness. Endothelial morphology was examined by specular microscopy and by scanning electron microscopy. After 7 days of perfusion at 37 degrees C, there was a statistically significant direct relationship between the maximum concentration of glycerol to which the experimental eyes had been exposed and the increase in mean endothelial cell size. The mean endothelial cell size increased in corneas exposed to glycerol concentrations of 40, 50, and 60% (w/v), but did not differ significantly from baseline measurements in the corneas exposed to 30% glycerol or less. Thus, there was no detectable damage to human corneas exposed to 30% (w/v) (3.3 M) glycerol in this system. Tolerance of higher concentrations may be achieved by changes in the rates of addition and removal of glycerol or in the composition of the perfusate.

Adult↗

PubMed1989

The morphology and function of healing cat corneal endothelium.

We mechanically damaged the entire corneal endothelium of one eye of each of ten cats and then examined both eyes by fluorophotometry and specular microscopy for 5 months. Six weeks after damage, when the corneas had cleared sufficiently to make accurate measurements, the mean endothelial permeability to carboxyfluorescein was increased 11% (P = 0.02) and the mean central corneal thickness was increased 11% (P = 0.05) in the damaged eyes. The mean endothelial pump rate was decreased 29% (P = 0.05), indicating that the increase in permeability was insufficient to explain the increase in thickness. The permeability returned to normal by 3 months and the pump rate by 5 months. Six weeks after damage, the mean endothelial cell size was increased 89% (P less than 0.01), the mean coefficient of variation of cell size was increased 200% (P less than 0.01), and the mean percentage of hexagonal cells was decreased 34% (P less than 0.01). By 5 months, the mean cell size had changed very little, and none of the three morphologic measurements had returned to normal. As in rabbits, the endothelial barrier in cats recovers before the pump after wounding. Unlike in rabbits, functional recovery in cats requires at least several months. Such prolonged functional recovery after endothelial trauma might also be expected in humans who, like cats and unlike rabbits, have little capacity for endothelial mitosis during healing.

Animals↗

PubMed1989

A system for long-term corneal perfusion.

Seventy-two human corneas were maintained in a perfusion system at 37 degrees C and 18 mm Hg intracameral pressure for 1 to 3 weeks. Corneal thickness, which was initially greater than normal because the enucleated eyes were kept at 4 degrees C before excision of the corneas, decreased slowly during the period of incubation. Endothelial removal or perfusion with ouabain (10(-4) M) induced irreversible stromal swelling. Cooling to 4 degrees C for 8 hr during perfusion caused stromal swelling that disappeared after rewarming to 37 degrees C; less stromal swelling occurred with cooling after 3 weeks of perfusion than after 3 days. No enlargement of central endothelial cells was noted in most corneas by serial specular microscopy. Electron microscopy demonstrated reversal of postmortem changes and maintenance of normal intracellular ultrastructure for 3 weeks. This system for long-term corneal perfusion will allow controlled studies of the effects of new methods of corneal preservation and other perturbations upon the corneal endothelium in situ.

Animals↗

PubMed1988

Ultrastructural features of a brain injury model in cat. I. Vascular and neuroglial changes and the prevention of astroglial swelling by a fluorenyl (aryloxy) alkanoic acid derivative (L-644,711).

We present qualitative and quantitative ultrastructural observations on the changes induced in neuroglia and blood vessels of gray matter of cat brain by an experimental acceleration-deceleration injury which, when used alone, causes negligible morbidity and mortality, but, when combined with systemic hypoxia, leads to coma and delayed death in approximately 50% of experimental subjects. An increase in the proportion of neuropil occupied by astrocytic cytoplasm is detectable qualitatively in layer Vb of pericruciate cortex 20 min after injury without hypoxia, and is maximal (22%, as measured morphometrically, vs 11.4% in controls) 40 min afterward. Near-normal values (14.1%) are obtained 100 min following the insult. If trauma is succeeded 40 min later by a 60-min period of hypoxia, there is prolongation of astrocytic edema and other neuroglial accompaniments of the traumatic lesion, such as aggregation of nuclear nucleoprotein granules and, in astrocytes, fusion of rosette ribosomes and enlargement of mitochondria. A decrease in luminal area occurs in capillaries 40 min after trauma applied alone. Hypoxia without trauma leads to a significant increase in capillary luminal area, which, however, is abolished when trauma precedes the hypoxic interlude. Intravenous injection of a non-diuretic, fluorenyl derivative (L-644,711) of (aryloxy)alkanoic acid loop diuretics, completely prevents the astrocytic swelling ordinarily present 40 min after acceleration-deceleration injury. Also, L-644,711 improves mortality and morbidity scores in cats subjected to trauma with hypoxia. We suggest that astroglial swelling may be a critical step in the evolving pathology of this head injury model and its prevention, as by L-644,711 administration, may have relevance to the treatment of cerebral edema in human head injury and other clinical disorders accompanied by astrocytic swelling.

Animals↗

PubMed1987

Cortical blood flow regulation during hypoxemia in experimental head injury.

The mechanism of increased susceptibility of the traumatized brain to hypoxemia (HYP) was investigated by measuring the local cortical blood flow (LCBF) by hydrogen clearance. Following pentobarbital anesthesia and head injury (HI) using a repetitive acceleration/deceleration injury, five surviving cats were ventilated to maintain arterial PCO2 (28.3 +/- 1.8 Torr, mean +/- SEM). Three control (C) animals received no head injury. LCBF (ml/min/100 g) measurements at two cortical locations were made between 30 and 60 min postinjury, at 10 min and 40 min of HYP (PaO2 = 29.5 +/- 2.6 Torr), and at 30-min intervals for 4.5 hr after HYP. Before HYP, LCBF was not different in cortical areas in C (84 +/- 12 ml/min/100 g) and HI (81 +/- 17 ml/min/100 g) animals. In C animals LCBF increased to 141 +/- 10 after 10 min of HYP and remained elevated at 40 min (P less than 0.05). Ten minutes post-HYP, LCBF fell to 56 +/- 8 ml/min/100 g. Hypoxemia did not increase LCBF significantly in HI animals (87 +/- 17 ml/min/100 g). Post-HYP, LCBF in HI animals remained unchanged. In 78% of HI LCBF measurements, clearances following a brief H2 inhalation were faster than clearances following tissue equilibration with H2. This may be due to nonhomogeneous tissue perfusion in HI animals. In conclusion, after head injury there may be an attenuated microvascular blood flow response to hypoxemia and flow inhomogeneities which will accentuate tissue hypoxia.

Animals↗

PubMed1987

Improved recovery from a traumatic-hypoxic brain injury in cats by intracisternal injection of an anion transport inhibitor.

Cats, injured by a mechanical plus hypoxic model of traumatic brain injury, were treated by intracisternal injection of a modified loop diuretic (L-644,711). This drug inhibits the chloride/bicarbonate anion exchange transport system. The treatment resulted in a significant decrease in mortality from 61 to 21%, and an improvement in both neurological status and EEG activity of the surviving animals. The dose of drug given intracisternally was at least 175 times less than the dosage we previously found was needed to achieve a comparable effect when the drug was given intravenously. The present results suggest that certain types of head injury can be treated by drugs which affect cellular anion transport processes in the brain.

Animals↗

PubMed1986

Morphine analgesia is potentiated in adult rats prenatally exposed to ethanol.

Exposure to inescapable, intermittent footshock elicits an opioid-mediated stress-induced analgesia in rats. We have previously shown that this response is markedly potentiated in adult rats, prenatally exposed to ethanol. To further investigate our hypothesis that endogenous opioid pain-inhibitory systems are modified by prenatal ethanol exposure, we have measured the analgesic response to morphine, in vitro brain opiate receptor binding characteristics, and occupation of brain opiate receptors following systemic administration of morphine. Compared to controls, rats prenatally exposed to ethanol had significantly enhanced morphine analgesia. This enhancement, however, does not appear attributable to changes in number or affinity of mu or delta opiate receptors, or to altered occupation of receptors by morphine.

Animals↗

PubMed1986

Pituitary-adrenal responses to morphine and footshock stress are enhanced following prenatal alcohol exposure.

The effect of prenatal ethanol exposure on pituitary-adrenal function in adult offspring was assessed by measuring corticosterone (CS) levels in plasma following exposure to two forms of footshock stress, intermittent and continuous, and after administration of 20 mg/kg of morphine. The footshock experiments were conducted at two time points in the circadian pituitary-adrenal cycle. Prenatally ethanol-exposed (E) rats had higher levels of CS than pair-fed and normal controls following intermittent footshock when tested at the crest of the CS circadian rhythm. However, this difference was not present when intermittent footshock was presented at the trough of the circadian cycle. At either time of day, there were no differences among the prenatal treatment groups in the basal condition or following continuous footshock. In addition, E rats had significantly higher levels of plasma CS than controls following morphine. Plasma adrenocorticotropin (ACTH) levels were measured after intermittent footshock at the crest of the circadian rhythm and were significantly higher in E rats than in controls. These results extend our previous reports of enhanced activation of the hypothalamo-pituitary-adrenal axis in response to other stressors as well as to ethanol in adult rats exposed to ethanol in utero. They also confirm that E rats are differentially hyperresponsive only to intermittent footshock stress, not to continuous footshock, as we had found to be the case when the analgesia induced by these two stressors was the dependent measure.

Adrenocorticotropic Hormone↗

PubMed1985

Banding of rubro-olivary terminations in the principal inferior olivary nucleus of the chimpanzee.

An electrolytic lesion centered just dorsal to, and grazing the superior surface of, the rostral red nucleus (RNr) was produced stereotactically in a single chimpanzee. Perikarya of the ipsilateral RNr exhibited retrograde cell changes, demonstrating interruption of its efferent fibers. The degenerated rubro-olivary tract was followed in silver impregnated material to the ipsilateral compact part of the pedunculopontine nucleus, pontine reticular formation and inferior olivary complex. Within the inferior olivary complex, terminations were banded and restricted to the principal subnucleus.

Animals↗

PubMed1985

Opioid but not nonopioid stress-induced analgesia is enhanced following prenatal exposure to ethanol.

Two neurochemically distinct forms of stress-induced analgesia were examined in adult rats following prenatal ethanol exposure. Rats were exposed to ethanol during the last 2 weeks of gestation through a liquid diet presented to the dams. Analgesia testing was conducted when the offspring were 150-210 days of age. Two forms of footshock stress were administered; one that resulted in a naloxone-sensitive (opioid-mediated) analgesia and one that resulted in a naloxone-insensitive (nonopioid) form of analgesia. Rats prenatally exposed to ethanol demonstrated significantly enhanced opioid-mediated analgesia, but unaltered nonopioid analgesia compared to controls. These results confirm previous findings that prenatal exposure to ethanol leads to long-term alterations in responding to some, but not all forms of stress. The possibility that prenatal exposure to ethanol leads to perturbations in the endogenous opioid systems is discussed.

Analgesia↗