The editor's report--1988.
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Pathology, Clinical↗
Biomedical subjects
K Fisher
Publications and source records attributed to K Fisher.
Low-affinity transport of pyroglutamyl-histidine in renal brush-border membrane vesicles.
These studies were performed to determine if a low-affinity carrier is present in the luminal membrane of proximal tubular cells for the transport of the dipeptide, pyroglutamyl-histidine (pGlu-His). We have previously described the existence of a specific, high-affinity, low-capacity [transport constant (Kt) = 9.3 X 10(-8) M, Vmax = 6.1 X 10(-12) mol.mg-1.min-1] carrier for pGlu-His in renal brush-border membrane vesicles. In the present study, we sought to demonstrate that multiple carriers exist for the transport of a single dipeptide by determining whether a low-affinity carrier also exists for the uptake of pGlu-His. Transport of pGlu-His into brush-border membrane vesicles was saturable over the concentration range of 10(-5)-10(-3) M, yielding a Kt of 6.3 X 10(-5) M and a Vmax of 2.2 X 10(-10) mol.mg-1.min-1. Uptake was inhibited by the dipeptides glycyl-proline, glycyl-sarcosine, and carnosine but not by the tripeptide pyroglutamyl-histidyl-prolinamide. We conclude that 1) pGlu-His is transported across the luminal membrane of the proximal tubule by multiple carriers and 2) the lower affinity carrier, unlike the higher affinity carrier, is nonspecific with respect to other dipeptides.
Biological Transport↗
Monolayer coupling in phosphatidylserine bilayers: distinct phase transitions induced by magnesium interacting with one or both monolayers.
We have investigated the thermotropic behavior of phospatidylserine bilayers interacting with Mg2+ either on one side or both sides, using differential scanning calorimetry. Large unilamellar vesicles (LUV) of phosphatidylserine exposed to Mg2+ on the external side only displayed an upward shift of the gel-liquid transition temperature (Tm) of about 6-8 degrees C relative to the Tm of LUV in Na+. Mg2+ was shown not to enter the vesicle interior, by means of fluorescence measurements on encapsulated 8-hydroxyquinoline-5-sulfonate. Multilamellar vesicles prepared in the presence of Mg2+, or vesicles prepared by Mg2+-induced fusion of small unilamellar vesicles, had Tm values that were shifted upward by about 16-17 C degrees. When the latter preparation was treated with EDTA to produce vesicles with Mg2+ inside and Na+ outside, the Tm was found to be shifted again by only 6-8 degrees C. These observations indicate that the monolayer interacting with Na+ fluidizes the monolayer interacting with Mg2+, and that the latter tends to solidify the former. The two monolayers thus appear to be coupled, possibly by hydrocarbon chain interdigitation.
Animals↗
Regulation of reconstituted renal Na+/H+ exchanger by calcium-dependent protein kinases.
Studies were performed to determine the effect of protein phosphorylation mediated by calcium-calmodulin-dependent multifunctional protein kinase II and calcium-phospholipid-dependent protein kinase on Na+/H+ exchange activity. Proteins from the apical membrane of the proximal tubule of the rabbit kidney were solubilized in octyl glucoside and incubated in phosphorylating solutions containing the protein kinase. 22Na+ uptake was determined subsequently after reconstitution of the proteins into proteoliposomes. Calcium-calmodulin-dependent multifunction protein kinase II inhibited the amiloride-sensitive component of proton gradient-stimulated Na+ uptake in a dose-dependent manner. The inhibitory effect of this kinase had an absolute requirement for calmodulin, Ca2+, and ATP. Calcium-phospholipid-dependent protein kinase stimulated the amiloride-sensitive component of proton gradient-stimulated Na+ uptake in a dose-dependent manner. The stimulating effect of this kinase had an absolute requirement for ATP, Ca2+, and an active phorbol ester. These experiments indicate that Na+/H+ exchange activity of proteoliposomes reconstituted with proteins from renal brush-border membranes are inhibited by protein phosphorylation mediated by calcium-calmodulin-dependent multifunctional protein kinase II and stimulated by that mediated by calcium-calmodulin-dependent protein kinase.
Adenosine Triphosphate↗
Comparison of propofol and thiopental for the induction of anesthesia.
We compared the safety, efficacy, and side effects of induction of anesthesia with propofol (2.5 mg/kg), a new intravenous agent, and thiopental (4.0 mg/kg) in 62 patients in American Society of Anesthesiologists class I or II. There was no significant difference between induction times for the propofol (40.0 +/- 2.0 sec) and thiopental (44.0 +/- 4.0 sec) groups. Propofol administration produced a significant fall (P less than .05) in systolic blood pressure (SBP), from 134.1 +/- 2.6 mm Hg before injection to 128.3 +/- 2.4, 118.2 +/- 2.7, and 114.4 +/- 2.8 mm Hg one, two, and three minutes after injection, respectively. Diastolic blood pressure (DBP) fell significantly (P less than .05) during the three postinjection periods. Heart rate (HR) rose significantly (P less than .05), from 78.6 +/- 3.1 beats per minute before injection to 89.4 +/- 3.4 beats per minute one minute after injection. In patients given thiopental, SBP fell significantly (P less than .05), from 131.7 +/- 2.7 mm Hg before induction to 126.4 +/- 3.4 and 126.9 +/- 4.0 mm Hg two and three minutes after injection, respectively. The DBP did not change significantly in the thiopental group, but the HR rose significantly (P less than .05), from 73.3 +/- 2.8 beats per minute before injection to 83.9 +/- 3.0, 90.1 +/- 2.3, and 84.2 +/- 2.4 beats per minute one, two, and three minutes after injection, respectively. In 94% of patients given propofol, there were apneic periods of more than 60 seconds, compared to 50% in the thiopental group (P less than .05). There was a significant difference (P less than .05) between groups for the incidence of pain on injection; 31% of the patients receiving propofol had pain, compared to 3% of those receiving thiopental.
Adolescent↗
Ecological evaluation of a rehabilitative environment for spinal cord injured people: behavioural mapping and feedback.
A behavioural mapping procedure was used to describe the behavioural profile, pattern of interaction and location of patients and staff in a rehabilitation unit for traumatically spinal cord injured people. Naturalistic observations were randomly obtained by trained observers during two observational periods, using 10 behavioural categories drafted from the observational literature. Feedback of the results was given to staff between the observational periods. Results suggested that patients spent a considerable proportion of their time in solitary and disengaged behaviours. Analysis of the behavioural profile of patients revealed little difference between the therapeutic day and the evening. Patients were also observed to spend large amounts of time in the ward area during the day. These results are at variance with the concept of active rehabilitation, and also raise questions concerning institutionalization. The efficacy of feedback in initiating institutional change is also examined. Comparison is made with previous research and strategies for change are suggested.
Environment↗
Carrier-mediated transport of pyroglutamyl-histidine in renal brush border membrane vesicles.
These studies were performed to determine if a transmembrane carrier for pyroglutamyl-histidine (pGlu-His) is present in the luminal membrane of renal proximal tubular cells. Previous studies have suggested the intact transepithelial transport of pGlu-His, a dipeptide formed by the hydrolysis of luteinizing hormone-releasing hormone by enzymes associated with the brush border in the proximal nephron. With the use of a renal brush border membrane vesicle preparation, pGlu-His showed H+-stimulated, Na-independent, saturable transport into an osmotically active space. High-pressure liquid chromatographic analysis of both the intravesicular and extravesicular fluids indicated intact uptake of the dipeptide. The transport constant (Kt) and Vmax for pGlu-His transport were 9.3 X 10(-8) M and 6.1 X 10(-12) mol.mg-1.min-1, respectively. Transport of pGlu-His was not inhibited by the dipeptides glycyl-proline, glycyl-sarcosine, and N-beta-alanyl-L-histidine, which have been previously shown to be transported into renal brush border vesicles via a single, low-affinity, high-capacity, Na-independent, and H+-stimulated peptide carrier. In addition, the gamma-glutamyl-containing peptides gamma-glutamyl-histidine and N(N-L-gamma-glutamyl-L-cysteinyl)glycine and the tripeptide pyroglutamyl-histidyl-prolinamide were without an inhibitory effect. In contrast, transport of pGlu-His was inhibited by the dipeptide pyroglutamyl-alanine. This study demonstrates the existence of a high-affinity, low-capacity H+ cotransport system for pGlu-His in the proximal tubular luminal plasmalemma, which appears to be specific for pyroglutamyl-containing dipeptides. The data indicate that multiple dipeptide carriers are present in the proximal nephron.
Animals↗
The effects of rocking on the state and respiration of normal and excessive cryers.
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Arousal↗
Effect of dietary cholesterol on plasma cholesterol concentration in subjects following reduced fat, high fibre diet.
One hundred and sixty eight subjects participated in a randomised crossover study to determine whether halving or doubling the present dietary cholesterol intake from eggs had any influence on blood cholesterol concentration in people following current dietary recommendations. During the first eight weeks all participants were advised to follow a reduced fat diet (26% total energy for hyperlipidaemic patients, 35% total energy for normolipidaemic volunteers) with an increased ratio of polyunsaturated to saturated fatty acids. This background diet was continued throughout the 16 week experimental period, during which participants ate either two or seven eggs a week. A small but significant increase in total cholesterol was seen after four weeks in the group eating seven eggs a week compared with that in the group eating two eggs a week, but this was no longer apparent after eight weeks. Previous studies suggesting that dietary cholesterol has a greater effect on the serum cholesterol concentration either have been carried out against a background of a higher fat intake or have contrasted extreme cholesterol intakes. A further reduction in dietary cholesterol seems to be unnecessary in those people who have already reduced their intake of saturated fat and increased the ratio of polyunsaturated to saturated fatty acids and fibre rich carbohydrate.
Cholesterol↗
A Northern California Oncology Group randomized trial of leucovorin plus 5-fluorouracil versus sequential methotrexate, 5-fluorouracil, and leucovorin in patients with advanced colorectal cancer who failed treatment with 5-fluorouracil or 5-fluorodeoxyuridine alone.
The current study was initiated to confirm preliminary reports that 20% or more of patients with colorectal cancer who fail treatment with 5-fluorouracil (FUra) will respond to treatment with either leucovorin plus FUra or with sequential methotrexate, FUra, leucovorin. One hundred two patients with advanced, measureable colorectal cancer who failed treatment with FUra and/or 5-fluorodeoxyuridine (FUdR) were randomized to treatment with either high-dose leucovorin plus FUra (Arm B) or sequential methotrexate, FUra, leucovorin (Arm C). In this interim report, 92 patients were evaluable for toxicity and 89 patients were evaluable for response. Grade 3 or 4 nonhematologic toxicity which was primarily gastrointestinal was experienced by 25% of patients on both treatment arms during at least 1 treatment cycle. Hematologic toxicity was minimal. Among 43 evaluable patients on Arm B, there were 2 complete responses (5%) and 1 minor response (3%). Among 46 evaluable patients on Arm C, there was 1 complete response (2%), 1 partial response (2%), and 6 minor responses (14%). The median time to treatment failure was 2.2 months on Arm B and 3.5 months on Arm C. The median survival was 8.3 months on Arm B and 8.7 months on Arm C. Colorectal cancers that are resistant to FUra are cross-resistant to both experimental combinations.
Antineoplastic Combined Chemotherapy Protocols↗
Prednimustine in refractory non-Hodgkin's lymphoma: a phase II study of the Northern California Oncology Group.
Fifty-six patients with advanced non-Hodgkin's lymphoma (NHL) were entered into a phase II study of prednimustine, an ester of chlorambucil and prednisolone. All patients were refractory to extensive prior combination chemotherapy. Therapy with prednimustine, 100 mg/m2/day orally, was given for three consecutive days every 2 weeks. The overall response rate in 43 evaluable patients was 30% (13/43), with 9% (4/43) achieving complete response (CR) and 21% (9/43) achieving partial response (PR). In the favorable histology subgroup (23 patients), the response rate was 39% (9/23), with 4% (1/23) achieving CR and 35% (8/23) achieving PR. In the unfavorable histology subgroup (20 patients), responses were seen in 20% (4/20) with 15% (3/20) achieving CR, all in heavily pretreated diffuse histiocytic lymphoma. Toxicity of this regimen was mild, with leukopenia below 3,000/mm3 in 22% and thrombocytopenia below 90,000/mm3 in 16% of patients. A positive correlation was observed between response and hematologic toxicity, indicating the potential for a dose-escalation schedule in future trials. These data confirm activity of prednimustine in NHL refractory to standard treatment. In view of its relatively mild toxicity, we conclude that prednimustine is an appropriate agent to test in combination chemotherapy regimens in this group of lymphomas.
Adult↗
Noninvasive ergonovine maleate provocative testing for coronary artery spasm: the need for routine thallium-201 imaging.
We administered ergonovine and used both electrocardiographic monitoring and thallium-201 [201Tl] imaging to detect reversible ischemia in 100 patients. Patients already established as having coronary artery spasm and those with nonbypassed, proximal, high-grade coronary artery stenosis were excluded. No complication occurred in any patient. The use of thallium imaging in addition to electrocardiographic monitoring resulted in a higher degree of sensitivity than did ECG monitoring alone. Fourteen patients demonstrated evidence of coronary artery spasm as documented by 201Tl imaging but of the 14, significant ECG changes occurred in only 50%, and classic ST segment elevation in 21%. Thus, in carefully selected patients the noninvasive provocation of coronary spasm can be accomplished safely, but ECG monitoring must be combined with thallium-201 imaging to achieve an acceptable degree of sensitivity.
Adult↗
The treatment of established micrometastases with syngeneic macrophages.
We demonstrated that macrophages injected systemically can profoundly inhibit the incidence of experimentally induced metasis. In our system mice bearing established micro-metastases were treated with one, two, or three i.v. injections of activated macrophages. Specificially activated (immune) macrophages were most efficient in reducing the number of metastases, but non-specifically activated macrophages were also effective in reducing the metastatic incidence. Macrophage play a major role in host defense against neoplasia (9,22) and have been shown to influence the outcome of spontaneous metastasis (9). Rat sarcomas whose macrophage content was found to be high were also shown to be non-metastatic. Conversly, rat sarcomas with low macrophage content were found to be metastatic (9). Our current data demonstrate that the systemic injection of syngeneic activated (exogenous) macrophages can bring about a significant reduction of lethal cancer metastases. Apparently, treatment with activated macrophages can increase the rate of tumor cell destruction as compared to the rate of tumor cell proliferation which ultimately leads to inhibition of clinical metastasis.
Animals↗
Thallium-201: quantitation of right ventricular hypertrophy in chronically hypoxic rats.
Sprague Dawley rats were divided into two groups. Ten were kept in room air and 10 in hypobaric hypoxia (air at 380 mm Hg). After two weeks all were injected intravenously with 50 muCi of 201Tl and sacrificed. The right and left ventricles were separated, weighed, and measured for radioactivity in a gamma well counter. Left and right ventricular mass ratios (MR) correlated with 201Tl radioactivity ratios (TAR) in both control and hypoxic rats: r = 0.962 where MR = 0.863 TAR + 0.27. Myocardial 201Tl uptake reflects and quantitates normal and abnormal ventricular mass, the abnormal mass in this model consisting of right ventricular hypertrophy associated with hypoxic pulmonary hypertension.
Animals↗
Outside contract services may be a bargain for many.
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Contract Services↗
Resolution and reconstitution of Rhodospirillum rubrum pyridine dinucleotide transhydrogenase. Proteolytic and thermal inactivation of the membrane component.
Pyridine dinucleotide transhydrogenase of the Rhodospirillum rubrum chromatophore membrane was readily resolved by a washing procedure into two inactive components, a soluble transhydrogenase factor protein and an insoluble membrane-bound factor. Transhydrogenation was reconstituted on reassociation of these components. The capacity of the membrane factor to reconstitute enzymatic activity was lost after proteolysis of soluble transhydrogenase factor-depleted membranes with trypsin. NADP+ or NADPH, but neither NAD+ nor NADH, stimulated by several fold the rate of trypsin-dependent inactivation of the membrane factor. Substantial protection of the membrane factor from proteolytic inactivation was observed in the presence of Mg2+ ions, an inhibitor of transhydrogenation, or when the soluble transhydrogenase factor was bound to the membrane. Coincident with the loss of enzymatic reconstitutive capacity of the membrane factor was a loss in the ability of the membranes to bind the soluble transhydrogenase factor in a stable complex. The membrane component was inactivated by preincubating soluble transhydrogenase factor-depleted membranes at temperatures above 45 degrees. NADP+, NADPH, or Mg2+ ions, but neither NAD+ nor NADH, protected against inactivation. These studies indicate that (a) the binding of NADP+ or NADPH to the membrane factor promotes a conformational alteration in the protein such that its themostability and susceptibility to proteolysis are increased, and (b) the inhibitory Mg2+ ion-binding site resides in the membrane component.
Bacterial Chromatophores↗