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Biomedical subjects

S Anderson

Publications and source records attributed to S Anderson.

At least 379 records · Page 21Linked to original sources
PubMed1991

Proper and improper folding of proteins in the cellular environment.

Protein folding in the cellular environment involves an interplay between the intrinsic biophysical properties of a protein, in both its folded and unfolded states, and various accessory proteins that aid the process. Factors such as peptidyl prolyl isomerase, protein disulfide isomerase, thioredoxin, and SecB may interact with the unfolded forms of specific classes of proteins, while members of the hsp70/DnaK and hsp60/GroEL molecular chaperone families may play a more general role in folding. Secretion, proteolysis, and aggregation are other in vivo processes that depend greatly on the folding behavior of a given protein. Intrinsic folding rates, or even translation rates, of nascent proteins may be optimized by natural selection to ensure smooth coordination with all the cellular components required for a successful folding reaction.

Bacterial Proteins↗
PubMed1991

Renal hemodynamic effects of calcium antagonists in rats with reduced renal mass.

The intrarenal hemodynamic effects of antihypertensive agents vary considerably, and these microcirculatory effects may contribute to long-term structural sequelae in the setting of chronic renal disease. To investigate the consequences of blood pressure reduction with calcium antagonists, 5/6 nephrectomized Munich-Wistar rats underwent baseline determinations of mean arterial pressure, whole kidney function, and single nephron glomerular filtration rate, after which intravenous infusions of verapamil or diltiazem were given in doses that acutely normalized blood pressure; control rats received saline vehicle. During the baseline period, all rats exhibited comparably elevated values for mean arterial pressure and single nephron glomerular filtration rate. During the experimental infusion, control rats exhibited continued single nephron hyperfiltration (84 +/- 8 nl/min) as a result of elevations in both glomerular capillary plasma flow rate (330 +/- 36 nl/min) and glomerular capillary hydraulic pressure (68 +/- 3 mm Hg), whereas the glomerular capillary ultrafiltration coefficient was low [0.050 +/- 0.009 nl/(sec.mm Hg)]. Both verapamil (148 +/- 6 to 103 +/- 3 mm Hg, p less than 0.05) and diltiazem (154 +/- 6 to 102 +/- 2 mm Hg, p less than 0.05) normalized arterial pressure, which did not change in control rats (150 +/- 7 to 142 +/- 8 mm Hg). Single nephron hyperfiltration and hyperperfusion were comparable among groups during the experimental period; compared with baseline values, diltiazem (97 +/- 8 to 71 +/- 7 nl/min, p less than 0.05) but not verapamil (90 +/- 7 to 83 +/- 6 nl/min, p = NS) modestly lowered the single nephron glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Anemia ameliorates progressive renal injury in experimental DOCA-salt hypertension.

To explore the role of systemic hematocrit in the vascular adaptations which characterize desoxycorticosterone-salt hypertension, studies were performed in three groups of rats with uninephrectomy, desoxycorticosterone administration, and 1% saline in the drinking water. One group received recombinant human erythropoietin to increase hematocrit, and another group was subjected to phlebotomy and fed a low-iron diet to induce anemia. Control rats exhibited systemic and glomerular capillary hypertension, proteinuria, and substantial glomerular sclerosis at 8 wk. Erythropoietin modestly increased hematocrit and blood pressure and substantially aggravated glomerular capillary pressure, proteinuria, and glomerular sclerosis. In contrast, reduction of hematocrit with a low-iron diet significantly attenuated systemic and glomerular hypertension, proteinuria, and sclerosis. It was concluded that the pace of progression of glomerular injury can be limited by chronic reduction in hematocrit, which effectively ameliorates both systemic and glomerular hypertension in this model of salt-sensitive hypertensive renal disease.

Anemia↗
PubMed1991

Nitric oxide: a potential mediator of amino acid-induced renal hyperemia and hyperfiltration.

The role of nitric oxide in the modulation of systemic and renal hemodynamics was examined by using N omega-monomethyl-L-arginine (L-NMMA, 110 micrograms/kg/min), a competitive inhibitor of the conversion of L-arginine to nitric oxide. L-NMMA or saline vehicle (9.6 microL/min) was infused intravenously into anesthetized euvolemic Munich-Wistar rats. After 30 min, L-NMMA resulted in a uniform increase in mean arterial blood pressure (111 +/- 1 to 128 +/- 2 mmHg; P less than 0.05) and a modest reduction in renal plasma flow rate (4.4 +/- 0.2 to 4.2 +/- 0.1 mL/min; P less than 0.05), without change in glomerular filtration rate (1.16 +/- 0.03 to 1.15 +/- 0.03 mL/min); vehicle had no effect on these renal parameters. These rats were then subdivided to receive an intravenous infusion (37 microL/min) of either 10% glycine, 11.4% mixed amino acids, or equiosmolar dextrose. L-NMMA pretreatment markedly attenuated glycine-induced hyperfiltration (10 +/- 6 versus 33 +/- 5%, L-NMMA versus vehicle; P less than 0.05) and obliterated the renal hyperemic response (-7 +/- 6 versus 16 +/- 4%, L-NMMA versus vehicle; P less than 0.05). L-NMMA also caused modest blunting of the mixed amino acid-induced hyperfiltration (18 +/- 4 versus 30 +/- 4%, L-NMMA versus vehicle; P = 0.056) but failed to curtail the renal hyperemia (16 +/- 6 versus 20 +/- 4%). Dextrose had no effect on glomerular filtration rate or renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Pathophysiologic effects of biliary shockwave lithotripsy in a canine model.

At least 10 extracorporeal shockwave lithotripters are under investigation in the United States for treatment of biliary stone disease. Few reports, however, have documented the potential side effects of this new treatment method. In this study, we performed a series of acute and chronic studies in dogs exposed to varying numbers of shockwaves directed at the gallbladder wall via a transthoracic or transabdominal targeting approach. When shockwaves were directed transthoracically, pulmonary hemorrhagic contusions were found which were sometimes large in size. When a transabdominal approach was used, however, only focal areas of hemorrhage were found in the gallbladder wall and adjacent liver with no alterations in postlithotripsy pancreatic or liver enzymes, and normal cholecystokinin-octapeptide stimulated oral cholecystograms were obtained 6 days after treatment. Biliary shockwaves appear to cause few side effects under normal conditions but should be used with caution in patients with potential bleeding disorders. Until further studies are performed, lung tissue should be avoided in the shockwave beam path during treatment.

Abdomen↗
PubMed1991

Hand and wrist strengthening exercises during rehabilitation of a patient with hereditary distal myopathy.

The effects of isometric and resistive strengthening exercises on myopathic distal muscles were examined by implementing a program of hand and wrist exercises during the rehabilitation of a patient with adult-onset hereditary distal myopathy. A 78-year-old man with this diagnosis for 18 years entered the hospital after a lumbar laminectomy and complete bedrest for seven weeks. After a three-week course of twice-daily Velcro board, therapeutic putty, and table-side isometric exercises, his hand and wrist manual muscle testing score, hand grasp and pinch strength, and nine-hole peg test times had all improved. In addition, the patient had moved from minimum-moderate assist in dressing and hygiene, and maximum assist in homemaking, to stand-by assist in both areas. The outcome demonstrates the feasibility and functional value of isometric and resistive strengthening exercises in muscles severely affected by a myopathic process.

Activities of Daily Living↗
PubMed1990

Does the Kunitz domain from the Alzheimer's amyloid beta protein precursor inhibit a kallikrein responsible for post-translational processing of nerve growth factor precursor?

Alternative splicing of the Alzheimer's amyloid beta protein precursor (ABPP) message leads to the production of several variants of this precursor polypeptide. Two of these variants contain a domain that is highly homologous to members of the Kunitz class of protease inhibitors. In order to initiate a study of the physiological role of this domain, we have produced active ABPP Kunitz inhibitor by constructing and expressing a synthetic gene in E. coli. Nerve growth factor (NGF) deficiency has been suggested as a possible cause of the neural degeneration characteristic of Alzheimer's disease, and trypsin and gamma-NGF are the two enzymes that have been shown to be capable of processing beta-NGF precursor to active, mature beta-NGF in vitro, therefore, the specificity of purified recombinant ABPP Kunitz inhibitor was analyzed with respect to these two proteases. Binding of isolated ABPP Kunitz domain both to trypsin (Ki,app less than 10 nM and to gamma-NGF (Ki,app = 300 nM) was observed. This difference in binding to the two proteases correlates with the approximately 20-fold higher rate observed for in vitro processing of the beta-NGF precursor by trypsin compared to processing by gamma-NGF, indicating that perhaps the inhibitor mimics the interaction of the beta-NGF precursor with proteases. The kallikrein actually responsible for beta-NGF precursor processing in vivo is unknown, but these results suggest that it is capable of being significantly inhibited by exposure to the ABPP Kunitz domain.

Alzheimer Disease↗
PubMed1990

Denaturant-dependent folding of bovine pancreatic trypsin inhibitor mutants with two intact disulfide bonds.

The equilibrium and kinetic behavior of the guanidine hydrochloride (Gdn-HCl) induced unfolding/refolding of four bovine pancreatic trypsin inhibitor (BPTI) mutants was examined by using ultraviolet difference spectroscopy. In three of the mutants, we replaced the buried 30-51 disulfide bond with alanine at position 51 and valine (Val30/Ala51), alanine (Ala30/Ala51), or threonine (Thr30/Ala51) at position 30. For the fourth mutant, the solvent-exposed 14-38 disulfide was substituted by a pair of alanines (Ala14/Ala38). All mutants retained the 5-55 disulfide. Experiments were performed under oxidizing conditions; thus, both the unfolded and folded forms retained two native disulfide bonds. Equilibrium experiments demonstrated that all four mutants were destabilized relative to wild-type BPTI. However, the stability of the 30-51 mutants increased with the hydrophobicity of the residue substituted at position 30. Kinetic experiments showed that all four mutants contained two minor slow refolding phases with characteristics of proline isomerization. The specific behavior of the phases depended on the location of the disulfide bonds. The major unfolding/refolding phase for each of the 30-51 mutants was more than an order of magnitude slower than for Ala14/Ala38 or for BPTI in which the 14-38 disulfide bond was specifically reduced and blocked with iodoacetamide [Jullien, M., & Baldwin, R. L. (1981) J. Mol. Biol. 145, 265-280]. Since this effect is independent of the stability of the protein, it is consistent with a model in which the proper docking of the interior residues of the protein is the rate-limiting step in the folding of these mutants.

Amino Acid Sequence↗
PubMed1990

The effect of the one-chain to two-chain conversion in tissue plasminogen activator: characterization of mutations at position 275.

Tissue plasminogen activator (t-PA) is homologous to other serine proteases and contains an apparent activation cleavage site at arginine 275. It has been demonstrated that this arginine-275 can be replaced with either glutamic acid (Tate, K. M., Higgins, D. L., Holmes, W. E., Winkler, M. E., Heyneker, H. L., and Vehar, G. A. Biochemistry 26, 338-343, 1987) or glycine (Peterson, L. C., Johannessen, M., Foster, D., Kumar, A., and Mulvihill, E. Biochim. Biophys. Acta 952, 245-254, 1988; Boose, J. A., Kuismanen, E., Gerard, R., Sambrook, J. and Gething, M.-J. Biochemistry 28, 635-643, 1989) so that the product of the plasminogen activation reaction, plasmin, can no longer hydrolyze the one-chain form of t-PA to the two-chain form. These "one-chain" t-PA variants had diminished activity, compared to wild-type t-PA, in the absence of a cofactor, but in the presence of the fibrin(ogen) cofactor the two variants had activity similar to wild-type t-PA. In order to compare the effects of all possible substitutions, t-PA variants with each of the other nineteen amino acids besides arginine at position 275 were produced by site-directed mutagenesis. All were recovered from cell culture supernatants completely in the one-chain form, except for R275 (wild-type) and R275K, which were partially converted to the two-chain form. These latter two species could be completely converted to the two-chain form by plasmin. In addition, these two forms showed significantly more plasminogen activating activity in the absence of a fibrin(ogen) cofactor, compared to the other 18 variants. In the presence of a cofactor, all of the t-PA mutants had plasminogen activating activity equivalent to wild-type t-PA, except for R275C. The R275C t-PA had comparatively less clot lysis and fibrin binding activity as well. Presumably the new cysteine in this variant was involved in a mixed disulfide or caused misfolding of the molecule resulting in decreased activity. The difference in the plasminogen activating activity of one- and two-chain forms of t-PA was investigated by determining the apparent Michaelis constants and the apparent turnover numbers for R275E t-PA, which remains in the one-chain form throughout the assay, and two-chain R275 t-PA. The kinetic constants were measured in both the presence and the absence of plasmin-digested fibrinogen.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1990

1H NMR observation of tissue myoglobin: an indicator of cellular oxygenation in vivo.

Cellular oxygen status is a critical parameter. To measure the oxygen tension in vivo, however, demands extant techniques to surmount two experimental difficulties: invasive experimental protocols and imprecise tissue localization. NMR techniques have the potential to overcome these obstacles. Indeed we show in this study that cellular myoglobin is NMR visible and its proximal histidyl NH signal in the deoxy state can be used to monitor changes in cellular oxygenation. Coupled with recent advances in NMR signal localization, this 1H NMR strategy promises to lead directly to cellular oxygen measurement in specific tissue regions in vivo.

Animals↗
PubMed1990

Consideration of individual bioequivalence.

Current procedures for assessing the bioequivalence of two formulations are based on the concept of average bioequivalence. That is, they assess whether the average responses between individuals on the two formulations are similar. Average bioequivalence, however, is not sufficient to guarantee that an individual patient could be expected to respond similarly to the two formulations. To have reasonable assurance that an individual patient could be switched from a therapeutically successful formulation to a different formulation (e.g., a generic substitute) requires a different notion of bioequivalence. We propose a simple, valid statistical procedure for assessing individual bioequivalence. The decision rule, TIER (Test of Individual Equivalence Ratios), requires the specification of the minimum proportion of subjects in the applicable population for which the two formulations being tested must be bioequivalent (a regulatory decision). The TIER rule is summarized in terms of the minimum number of subjects with bioavailability ratios falling within the specified equivalence interval necessary to be able to claim bioequivalence for given sample size and Type I (alpha) error. We recommend that the corresponding lower bounds (one-sided confidence intervals) for the proportion of bioequivalent subjects be calculated. TIER is partly motivated by the U.S. FDA's 75/75 Rule (at least 75% of the individual subject bioavailability ratios must be within 75-125%). TIER retains the sensible idea of considering the individual ratios but, unlike the 75/75 rule, is a statistically valid procedure.

Humans↗
PubMed1990

Renal effects of converting enzyme inhibitors in hypertension and diabetes.

Recent studies in animal models suggest that glomerular capillary hyperperfusion and hypertension, rather than ischemia, cause renal injury. Interventions that control glomerular capillary hypertension may protect against progressive injury, even in the presence of continued systemic hypertension. In the absence of systemic hypertension, diabetes mellitus is a prominent clinical example of glomerular hypertension. Animal studies have shown that glomerular hemodynamic abnormalities, especially elevations in glomerular pressure, play an important role in the pathogenesis of diabetic glomerulopathy. A number of clinical observations suggest that angiotensin converting enzyme (ACE) inhibitors may delay the progression of diabetic nephropathy by their effects on renal hemodynamics. In experimental animals, comparisons between calcium channel blockers and ACE inhibitors have shown the latter to be more effective in protecting the kidneys. Preliminary clinical studies indicate that ACE inhibitors may have advantages in preserving renal function in hypertensive and diabetic patients with renal failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Intravenous fluid load and recovery. A double-blind comparison in gynaecological patients who had day-case laparoscopy.

The effect of intra-operative fluid and dextrose administration upon recovery was tested in a randomised, double-blind trial. Three groups of 25 patients, each undergoing laparoscopic examination as day cases, were studied. The two groups who received fluid (20 ml/kg compound sodium lactate solution) showed significant improvement (p less than 0.05) in the variables that reflected hydration. The fluid group who also received dextrose (1 g/kg) exhibited further significant improvement. Intra-operative fluid and dextrose administration appears to confer some benefit upon recovery in patients who have minor surgery.

Adolescent↗
PubMed1990

Renal hemodynamic and natriuretic effects of manganese and interactions with atrial natriuretic peptide.

Manganese (Mn2+) is a cofactor for guanylate cyclase (GC), which is involved in the generation of guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger for atrial natriuretic peptide (ANP) action. Mn2+ is also, however, a nonselective calcium-channel blocker. We examined the effects of infusion of MnCl2 into normal rats and its interaction in vivo and in vitro with GC and ANP. MnCl2 significantly increased glomerular filtration rate (GFR) and effective renal plasma flow rate (RPF). These effects were caused by selective afferent arteriolar vasodilatation, which allowed the glomerular capillary plasma flow rate and hydraulic pressure to rise, thus elevating single-nephron GFR. Urinary Na+ excretion (UNaV) also increased with MnCl2. The natriuresis was, unlike ANP, not mediated by GC activation and cGMP production, as MnCl2 had no effect on either urinary cGMP excretion or cGMP accumulation in intact inner medullary collecting duct cell (IMCD) suspensions, nor did it affect Na(+)-dependent oxygen consumption in these cells. When superimposed on an infusion of ANP, MnCl2 resulted in significant increases in UNaV, GFR, and RPF. These effects were associated with small but significant increments in urinary cGMP excretion. However, MnCl2 did not affect in vitro cGMP production in intact IMCDs or glomeruli in response to ANP stimulation. It is uncertain therefore whether the in vivo augmentation of the natriuretic effect of ANP by MnCl2 is related to GC activation and cGMP production.

Animals↗