Showing papers by "Oregon Health & Science University published in 1987"

Antidepressant and circadian phase-shifting effects of light

Abstract: Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light.

Mu and delta receptors belong to a family of receptors that are coupled to potassium channels.

Abstract: The effects of agonists at mu and delta opioid receptors were compared by measuring membrane currents under voltage clamp from neurons of the rat nucleus locus coeruleus and guinea pig submucous plexus. In each tissue, the appropriate selective agonist (Tyr-D-Ala-Gly-MePhe-Gly-ol for mu receptors in locus coeruleus or Tyr-D-Pen-Gly-Phe-D-Pen for delta receptors in submucous plexus) increased the conductance of an inwardly rectifying potassium conductance and strongly hyperpolarized the membrane. The properties of the potassium conductance affected by the two opioids could not be distinguished. Experiments with intracellular application of guanosine 5'-[gamma-thio]triphosphate indicated that a guanine nucleotide-binding regulatory protein was involved in the coupling between opioid receptor and potassium channel, but there was no evidence for activation of either cAMP-dependent protein kinase or protein kinase C. It is noted that a number of vertebrate neurotransmitter receptors are coupled to potassium channels. The potassium conductance associated with these channels has properties similar to the conductance activated by mu and delta opioids; this family includes the following receptors: acetylcholine M2, norepinephrine alpha 2, dopamine D2, 5-hydroxytryptamine 5-HT1, adenosine A1, gamma-aminobutyric acid GABAB, and somatostatin. It is suggested that this conductance is a conserved neuronal effector coupled to one of the receptor types that mediates the effects of each of several major transmitters. The mu and delta opioid receptors appear to be unusual in that both utilize this same effector mechanism.

Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function.

Abstract: Dose-related cyclosporine-induced renal dysfunction is the most frequent adverse effect noted with this exciting immunosuppressive drug. To investigate pathogenetic factors involved, we studied renal tubular function and afferent arteriolar morphology during severe experimental cyclosporine-induced reduction in glomerular filtration rate. Pair-fed male rats were given cyclosporine 50 mg/kg or olive oil vehicle alone by gavage for periods of 3-14 days. Glomerular filtration rate declined progressively, reaching a nadir of 0.18 +/- .05 ml/min/100 g vs. .86 +/- .03 ml/min/100 g in controls at 14 days (P less than 0.001). Despite the severe reduction in glomerular filtration rate there was no difference in fractional sodium excretion, fractional lithium excretion, enzymuria, or in vitro renal cortical slice uptake of tetraethylammonium in cyclosporine and vehicle-treated animals. Light microscopy showed vacuolar changes without evidence of tubular necrosis at 7 and 14 days in cyclosporine-treated rats. Progressive decline in the diameter of the afferent arteriole was noted by scanning electron microscopy. By day 14 the lumenal diameter of afferent arterioles from cyclosporine-treated animals was 8.9 +/- 0.4 micron vs. 13.5 +/- 0.4 micron in controls (P less than 0.05). We conclude that afferent arteriolar vasoconstriction rather than direct tubular injury is a major pathogenetic factor in experimental cyclosporine nephrotoxicity.

Cellular mechanisms of opioid tolerance: studies in single brain neurons.

Abstract: Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at mu-opioid receptors were studied on neurons from rats that had been chronically treated with morphine; these were compared with actions on neurons from control rats. Tolerance to the opioid-induced increase in potassium conductance was observed, and this was more pronounced for normorphine than for [Met5]enkephalin and [D-Ala2, Mephe4, Gly5-ol]enkephalin: experiments with the irreversible receptor blocker beta-chlornaltrexamine indicated that normorphine had lower intrinsic efficacy than [Met5]enkephalin and [D-Ala2 MePhe4, Gly5-ol]enkephalin. This adaptation was not due to any change of the properties of the potassium conductance activated by mu-receptors because both full and partial agonists at alpha 2-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of mu-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the mu-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with mu-receptors and/or their coupling to potassium channels, 2) the intrinsic efficacy of an opioid determines the degree of tolerance observed, and 3) tolerance and physical dependence can be dissociated at the cellular level.

Diagnostic reasoning strategies of nurses and nursing students.

Abstract: This study described and compared the cognitive strategies of diagnostic reasoning used by junior nursing students (n = 15), senior nursing students (n = 13), and practicing nurses (n = 15). Verbal responses to three videotaped vignettes provided the data. Findings suggested that diagnostic reasoning processes of both nurses and nursing students can be described by a general model developed from studies of physicians. Subjects activated diagnostic hypotheses early in the encounter and used systematic information gathering to rule in and rule out hypotheses. With increased levels of knowledge and experience, there was a trend toward more systematic data acquisition and greater accuracy in diagnosis. The number of hypotheses activated, the earliness with which they were activated, and their diagnostic accuracy were task-specific components of the process, but selection of data-acquisition strategies appeared to be more generalizable across cases.

Is angelman syndrome an alternate result of del(15)(qllql3)

Abstract: Two unrelated females, age 15 and 5 years respectively, were studied cytogenetically because of severe mental retardation, seizures and ataxia-like incoordination. A similar deletion of the proximal long arm of chromosome 15 was found in both patients. Re-evaluation showed no voracious appetite or obesity; normal size of hands and feet, minimal to no hypotonia by history or examination and facial features not typical of the Prader-Willi syndrome. However, the facial appearance of the girls was similar to each other with mild hypertelorism. The similarity of these girls and dissimilarity to Prader-Willi syndrome suggest a different syndrome, perhaps the result of deletion of a different segment of 15q. The findings of ataxic-like movements, frequent, unprovoked and prolonged bouts of laughter and facial appearance are more compatible with the diagnosis of Angelman syndrome.

Rat corticotropin-releasing hormone gene: sequence and tissue-specific expression.

Abstract: The rat corticotropin releasing hormone (CRH) gene has been isolated and characterized by DNA sequence analysis. The gene exhibits a structural organization similar to that of the human CRH gene. The nucleotide sequence encoding the entire rat CRH precursor is located on the second exon, while exon I encodes the 5′-untranslated region of them RNA. Analysis of the nucleotide sequence homology between the human and rat CRH genes reveals several highly conserved regions including the CRH peptide-encoding sequence and the 5′-flanking sequence. RNA blot analysis demonstrates that CRH mRNA can be observed in numerous regions of the rat brain as well as the spinal cord, adrenal gland, pituitary, and testis.

Two mammalian genes transcribed from opposite strands of the same DNA locus.

Abstract: This report describes the characterization of a genomic locus in the rat that encodes overlapping genes occupying both strands of the same piece of DNA One gene (strand) encodes gonadotropin-releasing hormone (GnRH) A second gene, SH, is transcribed from the other DNA strand to produce RNA of undefined function The RNAs transcribed from each DNA strand are spliced and polyadenylated, and share significant exon domains GnRH is expressed in the central nervous system while SH transcripts are present in the heart Thus, the genome of a mammalian organism encodes two distinct genes by using both strands of the same DNA

On-off phenomenon: Relation to levodopa pharmacokinetics and pharmacodynamics

Abstract: Motor function in the moderately to severely affected parkinsonian patient is critically dependent upon delivery of levodopa to the striatum. This, in turn, is influenced by the fluctuating plasma concentrations of levodopa produced by the drug's short half-life and erratic absorption, and by modifiable transport at the blood-brain barrier. Duration of response to a single dose of levodopa is proportional to peak plasma drug levels, and paradoxical responses may occur when plasma concentrations are in the vicinity of minimum effective concentrations. Thus the strategy of administering frequent, small doses of levodopa may contribute additional unpredictability to a fluctuating clinical response imposed by pharmacokinetic factors.

Crossover second toe deformity.

Abstract: The crossover second toe deformity occurs when the lateral collateral ligament and joint capsule of the second metatarsophalangeal joint deteriorate. The second toe initially deviates in a medial direction but with time deviates dorsally and crosses up and over the great toe. A total of 17 patients (22 toes) were evaluated and 11 patients (15 toes) underwent surgical correction. A 90 degree satisfactory rate was noted at 42 months follow-up.

Distal residues in the oxygen binding site of haemoglobin studied by protein engineering

Abstract: The geometries of the Fe–O2 and Fe–CO bonds in myoglobin and haemoglobin differ significantly from those in free porphyrin model compounds1–6. It has been suggested that steric hindrance by Val-Ell and His-E7 and a hydrogen bond between His-E7 and oxygen2,4,7 affect the geometry and electronic state of the Fe-ligand bond, and that these interactions may be important in controlling oxygen affinity8. We have produced mutant haemoglobins in E. coli9–11 having Val(67β)E11 replaced by Ala, Met, Leu or Ile and His(58β)E7 by Gin, Val or Gly. We have studied the effect of these mutations on the equilibrium and kinetics of ligand binding. The conformation of the new side chains and their effect on the protein structure have been examined by X-ray crystallography, and the vibrational properties of the Fe–CO bond observed by resonance Raman spectroscopy12. We found that the steric hindrance of ligand binding by the E11 residue and the polarity of the E7 residue in the β subunit are critical for fine-tuning ligand affinity.

Clinical effects of diaper types on the skin of normal infants and infants with atopic dermatitis

Abstract: Cloth diapers, cellulose core diapers (conventional disposable diapers), and cellulose core diapers containing absorbent gelling material were examined for their effects on diaper rash and skin microbiology of normal infants and infants with atopic dermatitis in a 26-week double-blind clinical trial. Infants with atopic dermatitis wearing the diapers containing absorbent gelling material had significantly lower diaper rash grades than infants with atopic dermatitis wearing cloth diapers at five of eight grading visits. Infants with atopic dermatitis wearing conventional cellulose core diapers had statistically less rash at one of eight visits. There was no statistically significant difference between diaper types at three of the eight visits. At no time did the cloth group have less diaper rash than the conventional cellulose or absorbent gelling material disposable diaper group. A statistical correlation between the severity of general atopic dermatitis outside the diaper area and the diaper rash condition under the diaper occurred only in the atopic dermatitis group wearing cloth diapers. Isolation of microorganisms from the intact, uninvolved skin surface both inside and outside the diaper showed no biologically significant changes in the presence or numbers of selected skin organisms. Repeated isolation, at multiple grading visits of Staphylococcus aureus from uncompromised skin inside the diaper area was infrequent but correlated with the diagnosis of atopic dermatitis when observed.

Computed tomography in the diagnosis of blunt intestinal and mesenteric injuries.

Abstract: Twenty-four patients with signs on computed tomography (CT) of mesenteric or intestinal injury were treated over a 5-year period (1980-1984). All patients were the victims of blunt abdominal trauma. Nine patients with CT evidence of mesenteric or bowel hematomas were observed without adverse outcome. Fifteen were operatively explored, with 14 having injuries similar to the findings on the preoperative CT scans. In the group that had surgery, either thickened bowel or free intraperitoneal fluid (blood or less dense fluid) or both were present in all but one patient. Extraluminal air (three cases) or Gastrografin (Squibb) (one case) were absolute indications for surgery, as were bowel wall or mesenteric hematomas accompanied by substantial amounts of intraperitoneal fluid. The patient's history, physical examination, and initial laboratory values are important in proper selection of patients for CT evaluation. We feel that CT appears to offer certain definite advantages over peritoneal lavage in evaluation of bowel and mesenteric injuries and can reliably help to distinguish the injuries that require surgical repair from those that can be safely monitored and observed.

Control of growth and differentiation in vitro of human keratinocytes cultured in serum-free medium.

Abstract: • Normal human proliferative keratinocytes can be serially cultured in serum-free medium. The medium and culture conditions that have been developed support the growth of these cells in the absence of a feeder layer and in the absence of contaminating fibroblasts. Using this system, the nutritional and hormonal factors that affect the growth and differentiation of these cells have been studied in the absence of undefined supplements. The data suggest that the control of proliferation and differentiation in keratinocytes may take place by unique mechanisms. The defined serum-free conditions that have been developed provide an excellent system for the study of nutritional disorders that affect human epidermal cells. In addition, the culture system can be used to propagate large numbers of cells for use in autografts for cases of severe burns. (Arch Dermatol1987;123:1541a-1544a)

Time-course and steroid specificity of aromatase induction in rat hypothalamus-preoptic area.

Abstract: We studied the time-course and steroid specificity for aromatase induction in the hypothalamus-preoptic area (HPOA) of the adult male rat. Aromatase activity (AA) was measured in tissue homogenates by using a radiometric assay that quantifies the stereospecific production of 3H2O from [1 beta-3H] androstenedione. We found that by 48 h after administration of testosterone, HPOA AA was significantly (p less than 0.01) greater than control values in castrated rats. In contrast, AA was significantly (p less than 0.01) reduced 12 h after castration, and reached its lowest levels by 4 days after castration. Several other steroids, administered in 3-cm Silastic capsules for 7 days, were tested for their capacity to induce hypothalamic AA. In addition to testosterone, only 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol were effective. Neither the stereoisomers of these compounds nor several other steroids, including estradiol, progesterone, and corticosterone, were active. This profile of activity indicates that the induction of HPOA AA is androgen-specific and, together with the demonstrated time-course of induction, lends further support to the hypothesis that androgens regulate AA through a receptor mechanism and the synthesis of new protein.

Experimental intrahepatic portacaval anastomosis: use of expandable Gianturco stents.

Abstract: Original Gianturco expandable stents and their modifications were used to create an experimental intrahepatic portacaval anastomosis (EIPCA) in 30 young domestic swine without portal hypertension. The study focused on the design of a suitable stent, the technique of its application, and the evaluation of short-term patency of the EIPCA. A stent with a 2.5-cm-long body and wire skirts on both ends was most suitable for EIPCA creation. Well-positioned stents shunted most of the portal blood in the inferior vena cava circulation and remained patent for 4-6 weeks. Ingrowth of liver parenchyma and abundant proliferation of the intima and connective tissue inside the stent lumen in these rapidly growing animals gradually decreased EIPCA patency, and thrombus formation with diminished blood flow closed them completely.

Marked decline in trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels.

Abstract: To define the association of age-related changes in bone mineral content to gonadal function in normal men, we measured radial (largely cortical) and vertebral (largely trabecular) bone mineral content (BMC), testosterone (total and free), estrone and estradiol-17B levels in 62 healthy subjects, ages 30 to 92. Radial BMC fell 2 to 3.4% per decade but vertebral trabecular BMC declined more rapidly at 12% per decade. Of the sex steroids measured the only statistically significant change occurred in free testosterone levels which decreased with age (r = -.57, P less than .0001). Free testosterone levels correlated significantly with trabecular vertebral BMC (r = .458, P less than .0002) but not with bone mineral measures at the predominantly cortical radial sites. However, by multiple regression analysis free testosterone did not add to the effect of age on vertebral BMC. There were no associations of total testosterone, estrone, or estradiol levels to bone mineral content at any of the three sites measured in these healthy men. Age-related declines in male gonadal function do not appear to be of primary importance in male age-related bone loss.

Gianturco expandable wire stents in the treatment of superior vena cava syndrome recurring after maximum-tolerance radiation.

Abstract: Two patients with superior vena cava syndrome (SVCS) recurring after maximum-tolerance radiation were treated by placing a Gianturco expandable wire stent (GEWS) into the obstructed superior vena cava. The SVCS symptoms rapidly disappeared and good short-term (6 months) palliation was achieved. GEWS placement is a promising therapeutic alternative for palliation of SVCS symptoms when other therapeutic modes cannot be used or are not effective.

Molecular genetics of the VDAC ion channel: structural model and sequence analysis.

Abstract: The voltage-dependent anion-selective channel of the outer mitochondrial membrane provides a unique system in which to study the molecular basis of voltage gating of ion flow. We have cloned and sequenced acDNA coding for this protein in yeast. From the derived amino acid sequence, we have generated a preliminary model for the secondary structure of the protein which suggests that the protein forms a “β-barrel” type structure. Comparison of the VDAC amino acid sequence with that of the bacterial porins has indicated that the two classes of molecules appear to be unrelated.

Peripheral pharmacokinetics of levodopa in untreated, stable, and fluctuating parkinsonian patients.

Abstract: We compared the pharmacokinetics of oral and IV infusions of levodopa in untreated, stable, and fluctuating patients pretreated with carbidopa. After oral dosing, mean peak plasma levodopa levels, time to peak level concentration after oral levodopa, and area under the curve were similar in all groups. Absorption was proportional to dose. Plasma elimination half-lives, clearance rates, and volumes of distribution after levodopa infusions were similar in all groups. 3-O-Methyldopa levels were similar in stable and fluctuating subjects. We conclude that the peripheral pharmacokinetics of levodopa do not differ between untreated, stable, and fluctuating patients, and that altered peripheral kinetics of the drug are unlikely to explain the development of the fluctuating state.

Genetic evidence for androgen-dependent and independent control of aromatase activity in the rat brain.

Abstract: To investigate the role of androgen receptors in the regulation of brain aromatase activity (AA) in adult rats, the levels of AA in discrete brain areas of androgen-insensitive testicular feminized (Tfm) rats were compared with those in their normal male littermates (NL). AA was measured in homogenates of brain tissue by using a radiometric assay that quantifies the production of 3H2O from [lβ-3H]androstenedione as an index of estrogen formation. Initially, we assessed the capability of block-dissected tissues to aromatize androgens. We found that the AA in the amygdala and hypothalamus-preoptic area of Tfm rats was significantly lower (p < 0.001) than the AA in NL despite the fact that circulating androgen concentrations in the Tfm were significantly higher. Kinetics studies demonstrated that the apparent Michaelis constant was equivalent for both groups (0.02-0.03 μM)- Administration of testosterone propionate to castrated males produced 3 to 4-fold elevations of AA in NL, but did not affect brain AA in...

An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: report of two cases

Abstract: We describe 2 patients with marked elevations of anticardiolipin antibodies who developed multiple-organ disease characterized by a noninflammatory vasculopathy. Their cases were remarkable for the fulminant nature of their thrombotic diathesis, which was heralded by a prominent livedo reticularis of the extremities. Both patients had a serologic profile and salivary gland biopsy findings that were consistent with a diagnosis of primary Sjogren's syndrome.

Aggressive angiographic diagnosis in acute lower gastrointestinal hemorrhage.

Abstract: To assess the value of recently developed aggressive pharmacologic angiographic techniques for the diagnosis of acute lower gastrointestinal hemorrhage, we reviewed our experience with 63 consecutive patients referred for angiography. Hemorrhage was severe as indicated by a mean blood transfusion requirement of 9.4 units. Extravasation of contrast (46%), or an obvious vascular abnormality suggestive of a bleeding site (32%), was identified in 78% of patients. Extravasation was seen more frequently in patients with greater than or equal to 3 units of transfusion (66%) than in those with less than 3 units of transfusion (17%, P less than 0.001). After the introduction of pharmacologic techniques using heparin, tolazoline, streptokinase, and indwelling arterial catheters, the percentage of studies with extravasation of contrast increased from 32 to 65% (P less than 0.01). Application of aggressive angiographic techniques increases the diagnostic yield of angiography in acute severe lower gastrointestinal hemorrhage while exposing the patient to modest increased procedure-related risks which can be accepted in selected patients.

A hypervariable repeated sequence on human chromosome 1p36

Abstract: When used to probe Southern blots of TaqI-digested DNAs from unrelated individuals, p1–79, a 900 bp subclone of a random human cosmid, revealed at least 50 fragments, many of which were polymorphic. Each of 27 unrelated individuals tested with p1–79 displayed a distinct band pattern. Similar variation was seen with several other enzymes, including HaeIII, MspI, PstI and PvuII, whereas other enzymes yielded primarily large fragments of greater than 40 kb. In situ hybridization of p1–79 showed that the loci of hybridization are clustered on human chromosome band 1p36; localization of all TaqI fragments to chromosome 1 was confirmed with a human-rodent somatic cell hybrid panel. DNA sequencing of p1–79 revealed several copies of a 39 bp repeat whose variation in copy number might be the basis of the observed length polymorphisms. Studies of 3-generation Utah families suggest that the numerous restriction fragments homologous to p1–79 are inherited as haplotypes, implying that recombination within this cluster of loci is rare and allowing the cluster to serve as a useful marker for human gene mapping.