Biomedical subjects
Publications and source records attributed to H Baker.
Four patients with erythropoietic protoporphyria (EPP) are reported, in whom oral iron produced clear-cut clinical and biochemical deterioration. This suggests that there are two biochemically and genetically distinct sub-groups of EPP patients distinguished by their dramatically different response to oral iron.
Serotoninergic fibers have been reported in both the abducens and facial nuclei of the cat. Furthermore, serotoninergic dorsal raphe and oculomotor internuclear neurons occupy similar locations in the periaqueductal gray overlying the oculomotor and trochlear motor nuclei. To resolve the issue of whether these two populations of neurons overlap, serotoninergic fibers were assayed in the abducens and facial nucleus; then the morphologies and distributions of identified serotoninergic neurons and oculomotor internuclear neurons were determined. Both the abducens and facial nuclei contained varicosities labelled with antibody to serotonin, but a much higher density of immunoreactive fibers was present in the latter, especially in its medial aspect. Distinct synaptic profiles labelled with antibodies to serotonin were observed in both nuclei. In both cases, terminal profiles contained numerous small, predominantly spheroidal, synaptic vesicles as well as a few, large, dense-core vesicles. These profiles made synaptic contacts onto dendritic and, in the facial nucleus, somatic profiles that occasionally displayed asymmetric, postsynaptic, membrane densifications. Following injection of horseradish peroxidase into either the abducens or facial nuclei, double-label immunohistochemical techniques demonstrated that the serotoninergic and oculomotor internuclear neurons form two distinct cell populations. The immunoreactive serotoninergic cells were distributed within the dorsal raphe nucleus, predominantly caudal to the retrogradely labelled oculomotor internuclear neurons. The latter were located in the oculomotor nucleus along its dorsal border and in the adjacent supraoculomotor area. Intracellular injection of horseradish peroxidase revealed that oculomotor internuclear neurons have multipolar somata with up to ten long, tapering dendrites that bifurcate approximately five times. Their dendritic fields were generally contained within the nucleus and adjacent supraoculomotor area. In contrast, putative serotoninergic neurons were often spindle-shaped and exhibited far fewer primary dendrites. Many of these long, narrow, sparsely branched dendrites crossed the midline and extended to the surface of the cerebral aqueduct. In the vicinity of the aqueduct they branched repeatedly to form a dendritic thicket. The axons of the intracellularly stained serotoninergic neurons emerged either from the somata or the end of a process with dendritic morphology, and in some cases they produced axon collaterals within the periaqueductal gray. Thus the oculomotor internuclear and serotoninergic populations differ in both distribution and morphology.(ABSTRACT TRUNCATED AT 400 WORDS)
Adoptive immunotherapy of human cancer was investigated in our institution as part of a National Cancer Institute extramural group study. This treatment, for patients with metastatic malignant melanoma, hypernephroma, and colon carcinoma, consisted of three phases: (a) 5 days of i.v. high-dose (10(5) units/kg every 8 h) interleukin 2, (b) 6 1/2 days of rest plus leukapheresis; and (c) 4 days of high-dose interleukin 2 plus three infusions of autologous lymphokine-activated killer cells. Toxicities included fever, chills, tachycardia, hypotension, vomiting, diarrhea, and fluid retention. Ascorbic acid is known to be important to cell-mediated immunity, and it has been reported to be depleted during physiologically stressful events. Therefore, we determined plasma ascorbic acid levels in patients (n = 11) before adoptive immunotherapy and before and after Phases 1, 2, and 3 of treatment. Patients entering the trial were not malnourished. Mean plasma ascorbic acid levels were normal (0.64 +/- 0.25 mg/dl) before therapy. Mean levels dropped by 80% after the first phase of treatment with high-dose interleukin 2 alone (0.13 +/- 0.08 mg/dl). Mean plasma ascorbic acid levels remained severely depleted (0.08 to 0.13 mg/dl) throughout the remainder of the treatment, becoming undetectable (less than 0.05 mg/dl) in eight of 11 patients during this time. Values obtained from 24-h urine collections on two of two patients indicated that ascorbate was not excreted in the urine. Plasma ascorbic acid normalized in three of three patients tested 1 mo after the completion of treatment. Unlike the results for ascorbic acid, blood pantothenate and plasma vitamin E remained within normal limits in all 11 patients throughout the phases of therapy. Responders (n = 3) differed from nonresponders (n = 8) in that plasma ascorbate levels in the former recovered to at least 0.1 mg/dl (frank clinical scurvy) during Phases 2 and 3, whereas levels in the latter fell below this level.
Actin in the human erythrocyte forms short protofilaments which are only long enough to accommodate tropomyosin monomers (Shen, B.W., Josephs, R. and Steck, T.L. (1986) J. Cell Biol. 102, 997-1006). This interaction between actin and tropomyosin monomers is predicted to be weak, since tropomyosin polymerization parallels its affinity for F-actin. We examine the binding of human erythrocyte tropomyosin to actin in the presence and absence of spectrin and its ability to polymerize. The binding of human erythrocyte tropomyosin to F-actin is not affected appreciably by the present of spectrin. Saturating F-actin with erythrocyte tropomyosin, however, weakens the binding of spectrin dimers to actin. Although tropomyosin from human erythrocyte and rabbit cardiac muscle have similar affinity for F-actin, the polymerizability of erythrocyte tropomyosin as determined by viscosity measurements is much reduced relative to muscle tropomyosin. This unusual property of erythrocyte tropomyosin is likely due to differences in its primary structure from other known tropomyosin at the amino and carboxyl terminal regions which are responsible for its head-to-tail polymerization and cooperative binding to F-actin. Analysis of the distribution of tyrosine by 2-dimensional tryptic mapping of 125I-labelled erythrocyte tropomyosin shows that tyrosine at positions 162, 214, 221, 261 and 267 in rabbit cardiac tropomyosin are conserved in human erythrocyte tropomyosin but Tyr-60 is absent. This observation suggests that erythrocyte tropomyosin has a carboxyl terminal region similar to its muscle counterparts but its amino terminal region resembles that of platelet tropomyosin which also lacks Tyr-60.
Methotrexate is frequently used in the treatment of severe psoriasis, and its hepatotoxicity has long been recognized by dermatologists. Pulmonary complications resulting from use of the drug are uncommon but should be considered in any patient on methotrexate who develops pulmonary symptoms in the absence of infection. We describe two patients, one who developed an acute pneumonitis and one with progressive pulmonary fibrosis following long-term, low-dose methotrexate for psoriasis. Early recognition of these complications by lung function testing and withdrawal of the drug, when necessary, may arrest or reverse methotrexate-induced lung disease.
Folate, thiamin, nicotinate, biotin, riboflavin, pantothenate, vitamins A, B6, B12, C, E, and beta-carotene were determined in: (a) eight patients before and after one plasma exchange; (b) in one patient after five consecutive treatments; (c) in three patients before and 2-8 weeks after plasmapheresis. Vitamin B12, beta-carotene, vitamin B6, and vitamins A, C, E were depressed after acute or chronic plasmapheresis. Concentrations of folate, thiamin, nicotinate, biotin, riboflavin, and pantothenate were essentially unchanged after one plasma exchange.
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There have been some reports that folic acid inhibits phenytoin-induced gingival hyperplasia. The purpose of this double-blind study was to quantify clinically the effects of both systemic and topical administration of folic acid on phenytoin-induced gingival overgrowth in man. For a period of 6 months, one group of phenytoin patients received 2 daily topical applications of a folate solution. An additional group received 2 daily doses of systemic folate while a control group received placebo medication. Results indicate that throughout the 180-day period of the study, the topical folate significantly inhibited gingival hyperplasia to a greater extent than either systemic folate or placebo groups.
Patients with alcoholic hepatitis with plasma B12 levels above 800 pg/ml have overt clinical manifestations of liver disease including severe hepatocellular damage. High plasma B12 levels significantly correlate (P less than 0.0001) with standard liver function tests, e.g. bilirubin, cholylglycine, alkaline phosphatase, AST and prothrombin time as an index of the severity of hepatic damage. Decrease in plasma B12 to normal titres implies a decrease in the severity of alcoholic liver disease, whereas increased plasma B12 levels relate to increased severity and mortality.
These studies document species differences in the distribution of the peptide substance P and the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) within a central nervous system region of a number of mammalian species including the mouse, rat, guinea pig, rabbit, cat, and two species of hamster (Chinese and Syrian). Substance P-containing neuronal perikarya were observed in the main olfactory bulb (MOB) of both species of the hamster, but not in the MOB of the other species examined. In the accessory olfactory bulb (AOB), however, neuronal staining was observed in all species except the mouse. The number of stained somata and their intensity varied such that label was most prominent in the rat followed in decreasing order by the rabbit, guinea pig, cat, and hamster. The mouse displayed no perikaryal staining. Stained somata in AOB were found in the internal granule cell layer with dendritic processes ramifying through the internal plexiform layer to arborize within the mitral cell layer. The distribution of substance P-stained neurons in the MOB also differed between the two hamster strains. In the Syrian hamster, neurons were primarily juxtaglomerular. In the Chinese hamster, labeled perikarya were found in both the juxtaglomerular region and within the superficial aspect of the external plexiform layer (EPL). The mean longest diameter of the majority of substance P-labeled neurons in both species was greater than 10 micron, suggesting that they were tufted cells. Those in the EPL of the Chinese hamster were the largest (17 micron). Species differences also were observed in the distribution of substance P-positive axons and terminals within the MOB. Label was distributed primarily in the internal granule cell layer of the Syrian hamster and the internal plexiform layer of the Chinese hamster. Tyrosine hydroxylase staining was similar among species with the exception of the Syrian hamster. In the latter species, an additional large population of neurons was found within the external plexiform layer. In all other species, TH-stained neurons were found scattered throughout the MOB and occasionally the AOB but were not numerous in the EPL. Although most TH neurons were larger than 10 microns, in all species a population of smaller TH cells was observed primarily in the glomerular layer, suggesting that most neurons labeled with TH are tufted cells but that some may be periglomerular cells.(ABSTRACT TRUNCATED AT 400 WORDS)
The sensory neurons of the olfactory epithelium, as a consequence of their odor detection function, contact both the external environment and the central nervous system. The possibility that substances applied to the epithelium might reach the central nervous system was investigated by the intranasal application of peroxidase-conjugated wheat germ agglutinin (WGA-HRP). WGA-HRP was transported through olfactory receptor axons to the glomerulus of the olfactory bulb. Reaction product was localized electron microscopically to tubulovesicular profiles and dense bodies in sensory axons. Evidence of transneuronal transport was indicated by reaction product localized in dense bodies in dendrites postsynaptic to receptor cell axons. Periglomerular, tufted and mitral cells in the olfactory bulb also were transneuronally labeled. Anterograde transneuronal labeling occurred in the olfactory tubercle, piriform cortex and surrounding the lateral olfactory tract. Retrograde transneuronal label was found in neurons of the basal forebrain with the largest number of perikarya in the lateral nucleus of the horizontal limb of the diagonal band, a major source of cholinergic afferents to the olfactory bulb. These data suggest that substances, specifically those which bind to receptors, are transported from the olfactory receptor neurons in the nasal epithelium to the brain. Thus, the olfactory system may provide a route of entry for exogenous substances to the basal forebrain.
Both tyrosine hydroxylase (TH), the first enzyme in the catecholamine synthetic pathway, and substance P were localized previously to juxtaglomerular neurons in the hamster main olfactory bulb. These neurons had similar features and distribution suggesting that the enzyme, a marker for dopaminergic neurons, and the peptide transmitter, respectively, might coexist in the same cells. To determine if the two antigens occurred in the same neurons specific antibodies and a two color double label technique were utilized. Co-localization of the transmitters was not observed in any region of the olfactory bulb. In addition, interspecies differences were observed in the distribution of both TH and substance P labeled neurons which support the lack of co-localization in the double label studies. The data suggest that olfactory bulb neurons of similar morphology and distribution may synthesize different transmitters.
Recent studies suggest that neurons containing adrenocorticotropin and catecholamines are localized to similar areas of the brain. In this immunocytochemical study, the distributions of neurons and terminals containing adrenocorticotropin and tyrosine hydroxylase, the first enzyme in the catecholamine biosynthetic pathway, were compared using the peroxidase-antiperoxidase technique. Neurons containing adrenocorticotropin and tyrosine hydroxylase formed overlapping hyperbolic lamina in the mediobasal hypothalamus. Although adrenocorticotropin and tyrosine hydroxylase containing neurons often formed small clusters, no double labeled cells were observed. Overlap also occurred between adrenocorticotropin and tyrosine hydroxylase terminal fields in several diencephalic nuclei including the periventricular hypothalamic gray and paraventricular thalamus. In contrast, other regions displayed striking compartmentalization of terminal fields; for example, in both the paraventricular hypothalamus and central nucleus of the amygdala, adrenocorticotropin was located in ventral and tyrosine hydroxylase in more dorsal aspects of the nuclei. Adjacent sections also showed a close correspondence between adrenocorticotropin terminals and tyrosine hydroxylase cell bodies in paraventricular, periventricular, dorsomedial and ventral hypothalamic nuclei. These data provide anatomical substrates for potential functional interactions between catecholamine and adrenocorticotropin systems in forebrain.
Metabolically active B12 analogs and inactive B12 analogs were measured in plasma, red blood cells (RBC), and pooled pernicious anemia serum. B12 values by Lactobacillus leichmannii, Escherichia coli, Euglena gracilis, and radioisotope dilution method (RIDA) as assays for total B12 (active analogs + inactive analogs) were compared to Ochromonas malhamensis values as index of only metabolically active B12. B12 values above those with O malhamensis distinguished inactive analogs from active B12. Inactive analogs contribute 85, 97, 135, and 163% above active B12 activity in normal plasma when E gracilis, L leichmannii, RIDA, and E coli, respectively, were used for B12 analysis. RIDA B12 determinations for active B12 in plasma showed that 44% of the B12 measured was still due to inactive analogs when compared to O malhamensis B12 activity. Inactive B12 analogs contributed 21, 151, and 224% above O malhamensis active B12 in RBC when E gracilis, L leichmannii, and E coli, respectively, were used.
Vitamin E was administered orally (400 IU twice a day) to adult male humans for 28 days as either dl-alpha-tocopheryl acetate (all-rac-alpha-tocopheryl acetate) or d-alpha-tocopheryl acetate (RRR-alpha-tocopheryl acetate). Plasma alpha-tocopherol rose rapidly and fell at the same rate following cessation of supplementation with both forms of vitamin E. No significant differences in plasma alpha- or gamma-tocopherol levels were found between the two forms of vitamin E following their administration. The results confirm the currently accepted biopotencies of 1.0 IU/mg and 1.36 IU/mg, respectively for the two forms of vitamin E. Supplementation with either form of alpha-tocopheryl acetate resulted in depressing plasma gamma-tocopherol to less than 1/3 of initial levels; also the gamma/alpha ratio was depressed to less than 1/7 of the initial value. The study suggests that the gamma/alpha vitamin E ratio might also serve as a sensitive index of alpha-tocopherol ingestion.
Severe psoriasis is commonly associated with depression and may be its cause. The hazards of treating such patients with lithium are well known (Lazarus & Gilgor, 1979), but other drugs may also destabilize psoriasis. We report a patient in whom the anti-depressant trazodone hydrochloride (Molipaxin, Roussel), a serotonin antagonist, provoked generalized pustular psoriasis (GPP).
We have made a detailed study of pulmonary function in patients receiving long-term, low-dose methotrexate for psoriasis. We were unable to detect any changes indicative of early pulmonary damage.