Further studies on thyroxin-binding globulin-dependence in equilibrium dialysis assays of free thyroxin.
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Dialysis↗
Biomedical subjects
J C Nelson
Publications and source records attributed to J C Nelson.
A piece of my mind. A snorkel, a 5-iron, and a pen.
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Drug Industry↗
Examination of paralysis in Drosophila temperature-sensitive paralytic mutations affecting sodium channels; a proposed mechanism of paralysis.
We have used the identified cells of the Drosophila Giant Fiber System (GFS) to study the defects induced by the temperature-sensitive paralytic mutations no action potential (nap) and paralytic (para). These mutations paralyze at elevated temperatures, reported as due to a block of action potential propagation. We found, however, that the cells of the GFS still were able to respond to stimuli at 7-10 degrees C above the temperature causing mutant paralysis. Stimulus threshold and conduction time both decrease with increasing temperature in the mutants in a manner indistinguishable from wild-type. Since action potentials can propagate efficiently in the mutants at elevated temperatures, we looked for other neural defects that might be involved in producing paralysis. We did find reduced neuronal function at sites such as electrical synapses and axonal branch points where current may be limiting. These sites had weakened following frequency, occasional failures, and increased conduction times. We believe the non-temperature-dependent defects in nap and para uncover the normally temperature-sensitive traits latent within all neurons. Increasing temperature increases the rates of channel activation and inactivation. At higher temperatures, Na+ inactivation and K+ activation encroach upon the Na(+)-activation time, reducing inward sodium current. In addition to this normal temperature-dependent effect, the mutations decrease the number of sodium channels in neurons in a non-temperature-dependent manner. These two reductions in sodium current combine to prevent spiking threshold from being reached at current limited sites. The temperature at which a sufficient number of these sites block should be the temperature of paralysis.
Action Potentials↗
Early protooncogene expression during hemin-induced differentiation of human erythroleukemic cells.
In situ hybridization was used to study the effects of hemin on the expression of the oncogenes c-myc, c-fos, and myb, and on the mRNA level of erythroid porphobilinogen deaminase (PBG-D) and alpha-globin in HEL cells during differentiation. The technique was effective in detecting changes in mRNA levels in small numbers of HEL cells. Hemin stimulation of HEL cells results in an early increase in myb and c-myc expression and a decrease in c-fos mRNA, while increased PBG-D and alpha-globin expression is not seen until 8 h after hemin treatment. Blast-like cells display expression of c-myc, alpha-globin and PBG-D, while the more differentiated cells give a positive response to both c-fos and myb. During HEL cell differentiation, the mechanism of hemin stimulation appears to be through the up regulation of myb and c-myc mRNA and down regulation of c-fos. The subsequent expression of PBG-D and alpha-globin may indicate that early increases in protooncogene expression are first required for the normal progression of erythropoiesis to occur.
Cell Differentiation↗
Does melancholia predict response in major depression?
We examined the value of the melancholic distinction for predicting response to 1 week of hospitalization without antidepressant drugs and to a 4-week fixed plasma level desipramine (DMI) trial in patients with unipolar non-psychotic major depression. Both DSM-III and III-R criteria were tested. Response to hospitalization (HDRS less than or equal to 12) was much less common in DSM-III melancholic than in non-melancholic patients (1 of 19 vs. 18 of 37, chi 2 = 8.69, df = 1, P less than 0.001) and severity did not account for this association. DSM-III-R melancholia criteria were also associated with poor hospital response but slightly less predictive. Melancholic patients, however, diagnosed with either set of criteria, were not more likely to respond to drug treatment on any of the measures examined.
Adult↗
Predictors of hospital outcome without antidepressants in major depression.
Fifty-two consecutive inpatients with nonpsychotic unipolar major depression were assessed for response to 1 week of hospitalization without antidepressants. Each was rated at admission and at 1 week using the Hamilton Rating Scale for Depression (HRSD). Fifteen of 52 responded (HRSD score less than or equal to 12), 10 of whom improved by greater than or equal to 50% change in the HRSD score. Five variables were correlated with lack of hospital response: DSM-III melancholia, panic disorder, the DSM-III-R item "absence of personality disorder," admission severity, and age. Multiple regression showed an independent association between hospital outcome and the first three variables. Response to 1 week of hospitalization was found in 70% (14 of 20) of the patients who had none of the three identified predictors: melancholia, panic, and absence of personality disorder. In patients with one or more of these predictors, only 3% (1 of 32) responded.
Adult↗
Psychotogenic drug use and neuroleptic response.
When fixed doses of haloperidol or perphenazine were used in two separate studies, we found that psychotic males with a prior history of psychotogenic drug use had a poorer early neuroleptic response even in the early stages of their psychotic disorder than psychotic males who had not previously used significant amounts of psychotogenic drugs. Relative neuroleptic refractoriness may be characteristic of some dual diagnosis patients at the beginning of their illness. Antecedent psychotogenic drug use may contribute to the development of psychosis and to relative neuroleptic refractoriness by means of effects upon dopaminergic mechanisms.
Adolescent↗
Desipramine and its 2-hydroxy metabolite in patients taking or not taking methadone.
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Desipramine↗
Value of the DST for predicting response of patients with major depression to hospitalization and desipramine.
The authors examined the value of the dexamethasone suppression test (DST) for predicting response of patients with unipolar, nonpsychotic major depression to 1 week of hospitalization without antidepressant drugs and to a 4-week trial of desipramine at a fixed plasma level. The rates of response to hospitalization without drug treatment (defined as a score of 12 or less on the Hamilton Rating Scale for Depression) were not significantly different for the patients with a positive DST and those with a negative DST. This finding differs from those of prior studies of the DST and response to placebo. The responses of the DST-positive and DST-negative patients to desipramine also did not differ, a finding that replicates those in some prior reports.
Adult↗
Evidence for altered desipramine disposition in methadone-maintained patients treated for cocaine abuse.
Plasma concentrations of desipramine (DMI) and its 2-hydroxy metabolite (OHDMI) were compared among 72 patients being treated with desipramine for either depression (n = 39) or cocaine abuse (n = 33). Eleven cocaine abusers who were concurrently maintained on methadone had a significantly lower ratio of DMI dose to plasma concentration (0.9) than the depressives (2.2) or nonmethadone cocaine abusers (2.0). Their OHDMI/DMI ratios were significantly lower (0.19) than for either the other 22 cocaine abusers (0.39) or the depressed (0.50) patients. This difference was not due to DMI dosage. Although the underlying mechanism cannot be determined from these plasma studies, possible reduced hydroxylation of DMI in methadone patients suggests the need for DMI plasma monitoring.
Adult↗
Differentiating various abnormalities of thyroxin binding to serum proteins by radioelectrophoresis of thyroxin and immunoassay of binding proteins.
Using the simple method of protein analysis described here, we could identify thyroxin (T4)-binding-protein abnormalities in euthyroid patients with hyperthyroxinemia or hypothyroxinemia. Serum incubated with [125I]thyroxin was analyzed by agarose gel electrophoresis, with bromphenol blue staining of protein. The relative distribution of radioactive T4 was determined for each binding protein--thyroxin-binding globulin (TBG), transthyretin, albumin, and T4-binding immunoglobulin (when present)--and the mass of T4 bound to each was determined. We also used sensitive immunoassays to quantify TBG, transthyretin, and albumin concentrations, then calculated the mass of T4 (as determined by electrophoresis) bound per unit mass of the respective binding protein. When the concentration of binding proteins was altered (e.g., TBG excess or TBG deficiency), the T4 binding/mass ratio for each protein remained within the expected range; but when the functional affinity of a binding protein was altered--as in dysalbuminemic hyperthyroxinemia and in low-T4 nonthyroidal illness--this ratio was abnormal. This procedure can be used to help identify TBG excess, TBG deficiency, dysalbuminemic hyperthyroxinemia, prealbumin-associated hyperthyroxinemia, variant TBG with reduced affinity for T4, euthyroid sickness, and T4-binding autoantibodies.
Autoantibodies↗
The relationship between blood perphenazine levels, early resolution of psychotic symptoms, and side effects.
Serum perphenazine concentrations and early resolution of psychosis were examined to determine if blood level monitoring could be used to maximize drug efficacy while limiting extrapyramidal side effects (EPS). Sixty-six acutely psychotic inpatients were given perphenazine 0.5 mg/kg/day for 10 days, and their response was rated blind to blood level. Although 36 of 66 patients showed resolution of psychosis, neither perphenazine nor N-dealkylated perphenazine levels were related to global response or to Brief Psychiatric Rating Scale (BPRS) totals. Improvement in two individual BPRS items (hallucinations and conceptual disorganization) was related to serum perphenazine levels and suggestive of a lower therapeutic threshold of 0.8 ng/mL. Perphenazine level was not correlated with EPS; but benztropine, given only if required for serious EPS, was more likely to be used when perphenazine levels were elevated. The data suggest that higher perphenazine levels were no more effective than moderate levels but that higher levels may be associated with increased EPS; the data also suggest that individual symptoms rather than global response were associated with a lower therapeutic perphenazine threshold.
Adult↗
A scale for rating tricyclic response in major depression: the TRIM.
We describe the construction and validation of the TRIM, an empirically derived scale designed to rate tricyclic antidepressant response in major depression. Symptoms selected were those that improved in direct association with therapeutic desipramine plasma levels, were frequently present, were substantially correlated with the scale total, could be reliably rated, and for which interview ratings were concordant with observed behavior. Eight symptoms met these criteria and were included. The sensitivity of the TRIM was tested and compared with the Hamilton Rating Scale for Depression (HAM-D) and the Montgomery Asberg Depression Scale (MADS) in a new 4-week prospective desipramine study of nonpsychotic unipolar inpatients with major depression. TRIM 4-week totals were significantly associated with total desipramine plus hydroxydesipramine plasma concentrations, r = -0.32, p less than 0.05, but HAM-D and MADS scores were not. Using multiple regression to control for pretreatment severity, TRIM scores were significantly associated with desipramine plus hydroxydesipramine levels, while HAM-D and MADS scores were not. The data appear to validate the sensitivity of the TRIM and illustrate that scales designed for drug response may detect drug effects that global scales do not.
Antidepressive Agents, Tricyclic↗
Expression of rat liver heme oxygenase gene during development.
We studied the genetic expression during fetal development of heme oxygenase, the rate-limiting enzyme in the oxidation of heme to bilirubin. The transcription of the heme oxygenase gene in livers of fetal and neonatal rats (9 days before birth to 28 days after birth) was examined. Hybridization analyses of total RNA from livers of these animals using cDNA for rat heme oxygenase as the probe revealed a single mRNA species of approximately 18 S in every sample examined. The mRNA level was above the adult level throughout the course of study and reached a maximum 24 h after birth. The high level of heme oxygenase mRNA in fetuses was unaffected when Sn-protoporphyrin, a potent inhibitor of heme oxygenase, was administered to their mothers. On the other hand, the mRNA levels in the mothers treated with this heme analog were substantially increased, possibly by the same mechanism as for the induction by heme. Sn-protoporphyrin potentiates induction of heme oxygenase mRNA in cobalt chloride-pretreated rats, and also acts as a potent inhibitor of heme oxygenase enzyme activities. Our results also indicate that high heme oxygenase levels during fetal maturation are due to an increase in transcription of the gene. Thus, Sn-protoporphyrin which crosses the placenta controls fetal hyperbilirubinemia by direct enzyme inhibition.
Age Factors↗
Clinical implications of the pharmacokinetics of tricyclic antidepressants.
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Antidepressive Agents, Tricyclic↗
Elderly patients admitted to the psychiatric unit of a general hospital.
Elderly psychiatric patients who are cared for in general hospital psychiatric settings have not been clearly characterized in the literature in terms of demographics, primary diagnoses, hospital course, and outcome. The authors reviewed charts of 168 patients over the age of 60 years admitted to a general hospital inpatient psychiatry unit over a 5-year period in order to develop a demographic and clinical profile of this patient population. Results indicated that the large majority of patients had affective syndromes; dementia was the second most common diagnosis. Length of stay correlated with severity of depressive illness, while a diagnosis of dementia was associated with a shorter hospitalization. Outcome measures showed favorable response to treatment in three-fourths of this population of elderly psychiatric patients. These data suggest that the general hospital acute inpatient setting is well suited to care for the combined medical and mental illnesses of elderly psychiatric patients.
Activities of Daily Living↗
Age at onset in late-life delusional depression.
Mean age at onset was not significantly different in 39 delusional and 70 nondelusional unipolar depressed patients over 60 years of age. The finding was unchanged when sex, concurrent dementia, and medical illness were examined.
Age Factors↗
A new inherited abnormality of thyroxine-binding globulin (TBG-San Diego) with decreased affinity for thyroxine and triiodothyronine.
Evaluation of a family in which males were clinically euthyroid despite having low serum total T4 (TT4) and free T4 index (FT4I) values revealed the presence of a new inherited T4-binding globulin (TBG) variant (TBG-San Diego). Two brothers had low TT4 (39 and 49 nmol/L; normal range, 64-154 nmol/L) and FT4I (4.0 and 4.4; normal range, 6.0-10.5) values, while their grandfather, despite treatment with T4, had a low TT4 (53 nmol/L) and normal FT4I (7.2) in the presence of suppressed TSH (less than 0.1 mU/L). When measured by RIA, the mean TBG concentration (TBG-RIA) of the three affected males was low normal [160 +/- 56 (+/- SD) nmol/L; normal range, 151-253]. Their TBG-binding capacity measured by a T4 binding assay at saturation (TBG-CAP) was similar, giving a mean TBG-RIA/TBG-CAP ratio not significantly different from 1.0. In these males, the TBG affinity for T4 (Ka = 0.48 +/- 0.04 x 10(10) mol-1) was less than that in subjects with the common type TBG (TBG-C; Ka = 1.10 +/- 0.14 x 10(10) mol-1; P less than 0.0001) and similar to that in Aboriginal males from Australia with the variant TBG-A (0.52 +/- 0.10 x 10(10) mol-1). TBG affinity for T3 in the affected males (Ka = 0.68 +/- 0.05 x 10(9) mol-1) was less than that in subjects with TBG-C (1.39 +/- 0.12 x 10(9) mol-1; P less than 0.00001), but greater than that in males with TBG-A (0.44 +/- 0.03 x 10(9) mol-1; P less than 0.0005). The rate of TBG denaturation at 56 C was increased in the affected males (t1/2 = 28.4 and 26.9 min) compared to that in subjects with TBG-C (t1/2 = 54.1 +/- 7.1 min), but was lower than that in males with TBG-A (t1/2 = 20.8 +/- 1.9). A value intermediate between those in affected males and normal subjects was found in serum from an obligatory heterozygote. Microheterogeneity on isoelectric focusing was normal. The exact nature of this structural TBG variant is not yet known. The presence of a TBG mutant should be considered in healthy, clinically euthyroid patients with low serum TT4 and free T4 index values, especially when such low values are found in several members of the same family.
Adult↗