Biomedical subjects
L H Smith
Publications and source records attributed to L H Smith.
[Multifactorial genesis of urolithiasis in patients with enteral hyperoxaluria].
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Chemical softness and acute metal toxicity in mice and Drosophila.
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Beta-adrenergic blocking agents. 22. 1-Phenoxy-3-[[(substituted-amido) alkyl]amino]-2-propanols.
The synthesis of a series of 1-phenoxy-3-[[(substituted-amido)alkyl]amino]-2-propanols is described. Many of the compounds are more potent than propanolol as beta blockers, while having cardioselectivity comparable to that of practolol, when given intravenously to anesthetized cats. The structure-activity relationships shown by this series of compounds provide further evidence that the addition of substituents to the alkylamino moeity of a beta blocker can confer cardioselectivity and that amidic substituents are remarkably effective.
beta-adrenergic blocking agents. 24. Heterocyclic substituted 1-(aryloxy)-3-[[(amido)alkyl]amino]propan-2-ols.
The synthesis of a series of 1-(aryloxy)-3-[[(amido)alkyl]amino] propan-2-ols where either the aryl moiety is heterocyclic or the amidic group is substituted by a heterocyclic moiety is described. Several of the compounds were more potent than propranolol when given intravenously to anesthetized rats. In contrast to previous findings with beta-blockers based on heterocyclic moieties and with either an isopropylamino or tert-butylamino substituent on the side chain, several compounds proved to be cardioselective when further examined in anesthetized cats. The detailed structure-activity relationships shown by this series of compounds are discussed.
Rheumatoid arthritis: from Rubens to restriction maps.
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Triamterene urolithiasis: solubility, pk, effect on crystal formation, and matrix binding of triamterene and its metabolites.
The commonly used diuretic Tri and its metabolites have been identified recently as major components of some kidney stones. We have carried out basic physical chemical studies to determine the mechanism of Tri incorporation into kidney stones. The solubility and pK of Tri and its major metabolites, Tri-OH and the Tri-So4, have been determined at 37 C in 0.15 M NaCl. The effect of Tri and its metabolites on crystal formation has been measured in the calcium oxalate monohydrate, hydroxyapatite, and uric acid crystal systems. Tri and its metabolites do not promote crystal nucleation, growth, or aggregation in any of these crystal systems and are not incorporated as these crystals form. We can demonstrate binding of Tri and its metabolites to the protein matrix isolated from kidney stones. These data suggest that Tri and its metabolites to the protein matrix isolated from kidney stones. These data suggest that Tri and its metabolites do not promote the formation of kidney stones but rather become incorporated into existing stones or stone nidi by binding to the protein matrix found in all kidney stones.
Percutaneous renal stone removal.
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Intussusception: analysis of 98 cases.
A retrospective study of the clinical features and surgical management of 98 cases of paediatric intussusception treated in New Zealand during the past 16 years is presented. The classic triad of vomiting, rectal bleeding and abdominal pain occurred in only 20 percent of patients. Barium enema examination was used in 67 patients but successful reduction was achieved in only 13. Laparotomy was performed in 85 patients with 1 operative death. Gangrenous bowel was found in 17 patients and 24 required bowel resection with no associated mortality. This high rate of bowel resection appears to be related to the long duration of symptoms before the diagnosis was established. It is concluded that earlier diagnosis is the single factor most likely to reduce morbidity.
Interaction between benzo[a]pyrene and mouse skin in organ culture.
An in vitro method for studying the interaction between tritiated benzo[a]pyrene ([3H]BP) and intact mouse skin was investigated. [3H]BP was applied to the epidermal surface of the skin floating on medium, and radioactivity in the medium was measured periodically. After 48-h incubation, about 45% of the radioactivity was in the medium; of this amount, about 80% accumulated during the first 24 h. Incubation temperature, metabolic inhibitors, and the amount of BP applied caused pronounced effects on accumulation; slight to moderate effects were noted for the type and volume of medium and vehicle used. Results of the temperature and inhibitor experiments indicated that accumulation of radioactivity depended on cell viability. About 80% of the radioactivity in the medium was water soluble, showing that biotransformation of BP by skin cells occurred. We are using the skin organ culture method to help understand the interaction of mammalian skin with hydrocarbon mixtures. A study of these interactions may lead to metabolic, cytotoxic, and macromolecular-binding profiles that characterize a carcinogenic mixture of hydrocarbons.
Renal surgery can "precipitate" stone disease in mild asymptomatic primary hyperparathyroidism.
We report on a patient in whom 3 large renal calculi formed within 12 weeks after pyeloplasty. Subsequently, a parathyroid adenoma was found. This report illustrates the need to evaluate thoroughly a patient with borderline elevation of serum calcium before renal surgery. Current research indicates that primary hyperparathyroidism is more prevalent than thought previously. A majority of patients with primary hyperparathyroidism have mild asymptomatic disease detected solely by routine serum chemistry screening tests.
A quantitative radioimmunoassay for DNA-binding antibodies.
An RIA is described for the measurement of serum immunoglobulins capable of binding to double-stranded or single-stranded DNA. DNA attached to Sephadex G-50 by UV irradiation was used as a solid-phase immunoabsorbent for DNA-binding proteins from serum. GAH IgG (125l-labeled) and GAH IgM (131l-labeled) were used to detect the human immunoglobulins bound onto the washed DNA-Sephadex. The quantities of immunoglobulins bound were determined by comparison with a standard curve constructed by dilution of a plasma from a SLE patient containing known amount of bound, DNA-specific IgM and IgG. Another RIA was employed for measuring levels of IgG and IgM. In combination with measurements of the total serum IgM and IgG, the RIA allowed for the determination of the fraction of the total serum IgM or IgG that was specific for double- or single-stranded DNA. For pool of normal human sera the quantities were as follows: 0.04% of the total IgM and 0.001% of the total IgG bound double-stranded DNA; 0.22% of the total IgM and 0.05% of the total IgG bound single-stranded DNA. This capability is important because information regarding the quantitative measurement of antibodies to DNA and their class determination may be of significance in monitoring the status of subjects with SLE.
Binding of benzo [a]pyrene to epidermal DNA and RNA as detected by synchronous luminescence spectrometry at 77 K.
The fluorescence associated with benzo[a]pyrene [BP] moieties covalently attached to the nucleic acid (DNA plus RNA) isolated from the epidermis of BP-treated mice was examined at 77 K in frozen aqueous solutions by use of a photon-counting fluorimeter operating in the synchronous scanning mode. The excitation and emission wavelengths were scanned simultaneously with the monochromators set 28 nm apart. This setting coincides with the difference in wavelength between the excitation and emission maxima for the fluorescence of bound BP. Currently the level of detection is in the order of 1 BP residue per 200,000 bases in 40 microgram of nucleic acid. This amount of nucleic acid can be isolated from the skin of a single mouse. The method described here is generally useful for detecting the binding to DNA of nonradioactive carcinogenic polynuclear aromatic which might occur following the topical application to animal skin in vivo of complex hydrocarbon mixtures such as synthetic fuels and crude oils.
Beta-adrenergic blocking agents. 19. 1-Phenyl-2-[[(substituted-amido)alkyl]amino]ethanols.
The synthesis of a series of derivatives of 1-phenyl-2-[[(substituted amido)alkyl]amino]ethanols is described. The compounds were investigated for beta-adrenoceptor blocking properties, and many showed a surprising degree of potency and beta 1-cardioselectivity when tested in vivo in anesthetized cats. The structure-activity relationships shown by this series of compounds are discussed and related to known beta-adrenergic blocking agents.
Renal brush border membrane adaptation to phosphorus deprivation: effects of fasting versus low-phosphorus diet.
Alimentary phosphorus deprivation due to a low-phosphorus diet (LPD) elicits a profound antiphosphaturia and an increase in sodium-dependent inorganic phosphate (Pi) uptake by renal cortical brush border membrane (BBM) vesicles. But, in alimentary phosphorus deprivation due to total fasting, high urinary excretion of Pi persists. In the present study, we determined whether low tubular reabsorption of Pi in fasting is due to a diminished capacity of the specific Pi transport system with the renal cortical luminal BBM or whether it is due to a reduced transepithelial reabsorption of Pi because of metabolic conditions occurring in proximal tubule cells during fasting. Sodium-dependent Pi transport in compared with fasted rats or rats fed a normal phosphorus diet. Sodium-dependent uptake of D-glucose was significantly lower in LPD rats, compared with fast animals or animals fed a normal diet. Thus, in contrast to LPD, fasting does nt elicit an increase in Pi transport and a decrease in D-glucose transport across the isolated renal BBM. The same differences in BBM transport of Pi were present also in thyroparathyroidectomized rats. Further experiments demonstrated that the adaptation of renal function and the renal BBM transport to LPD are overridden by a subsequent period of total fasting. Results of the present study show that fasting both prevents and reverses the renal response of rats to alimentary phosphorus deprivation. The differences in Pi excretion between fasted rats, LPD rats, and LPD rats subsequently fasted are attributed, at least in part, to specific adaptive changes in sodium-dependent Pi transport across the luminal BBM, rather than to alterations in other cellular (metabolic) components of transepithelial Pi reabsorption in the proximal tubule.
Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide.
The cause of hyperphosphatemia in patients with tumoral calcinosis never been explained. We studied two related patients who had tumoral calcinosis and hyperphosphatemia and two normal controls to determine their renal tubular response to parathyroid hormone (PTH) and acetazolamide (ACZ). During baseline periods, the patients had abnormally low fractional excretion of phosphorus (FEP) despite their hyperphosphatemia. Values for patients were 0.114 and 0.128; for controls, values were 0.193 and 0.165. PTH caused an increase in FEP and urinary cAMP in both patients and controls. ACZ also increased FEP in both groups, and the effects of PTH and ACZ were additive, suggesting that patients with tumoral calcinosis have normal sensitivities to PTH and normal responses to ACZ. Levels of vitamin D metabolites in the patients were normal. We conclude that patients with tumoral calcinosis have a reduced ability to excrete phosphorus. This defect does not seem to be due to impaired PTH secretion, an abnormal phosphaturic response to this hormone, or a disturbance of vitamin D metabolism.
Orthophosphate therapy decreases urinary calcium excretion and serum 1,25-dihydroxyvitamin D concentrations in idiopathic hypercalciuria.
Orthophosphate treatment of patients with idiopathic hypercalciuria reduces the urinary excretion of calcium. To examine the role of altered vitamin D metabolism in reducing the renal excretion of calcium, we studied 11 patients with idiopathic hypercalciuria before and after 2 weeks of treatment with oral neutral orthophosphate (2 g phosphorus/day). Variables measured were urine calcium and phosphorus and seseserum calcium, phosphorus, immunoreactive parathyroid hormone, and 1,25-dihydroxyvitamin D [1,25-(OH)2D]. Oral phosphate treatment significantly decreased urine calcium excretion [mean change (delta), -123 mg/24 h], increased urine phosphorus (mean delta, serum levels of 1,25-(OH)2D (mean delta, -22 pg/ml). Pretreatment levels of 1,25-(OH)2D were high when compared with levels in age-matched controls, whether assessed as the arithmetic mean (57 vs. 33 pg/ml; P < 0.025), the logarithmically normalized (42 vs. 27 pg/ml). Phosphate treatment decreased serum levels of 1,25-(OH)2D to a mean of 35 pg/ml (logarithmically normalized mean, 22 pg/ml; median, 21 pg/ml), values not significantly different from those of normal controls. Serum calcium and phosphorus concentrations were not changed by treatment. Serum immunoreactive parathyroid hormone values increased minimally within the normal range (mean delta, +2 microleq/ml; P <0.025). We conclude that the effect of oral phosphate therapy in decreasing urinary calcium excretion may involve the reduced synthesis of 1,25-(OH)2D, independent of altered parathyroid function.