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1.  Quantitative 45Ca autoradiography of human bone 
Bone from 7 terminally ill men who received 45Ca ½ to 23 days before death was studied by quantitative autoradiography. Short-term exchangeable calcium was located on bone surfaces, and had an apparent mass of 3.4 Gm. The time of maximal surface 45Ca activity was 2.5 days. Diffuse activity of low intensity from long-term exchange accounted for 16.9 ± 3.3 per cent (mean ± S.E.) of total uptake; in the 2 patients having plasma 45Ca measurements; the rate of diffuse uptake ranged from 10 to 25 per cent of the normal accretion rate. However, focal activity of intermediate intensity accounted for 49.8 to 68.4 per cent of uptake and was believed to be due to both long-term exchange and secondary mineralization. An unexpected finding was that 7.5 ± 1.6 per cent of activity was associated with bone resorption surfaces. Because of the terminal illness, bone formation was suppressed, and only 5.9 ± 2.4 per cent of activity was associated with hot spots.
PMCID: PMC3078128  PMID: 5286527
2.  Neuropsychiatric status after liver transplantation 
A neuropsychiatric study of individuals who underwent successful liver transplantation an average of 3 years previously was conducted to assess quality of life in terms of cognitive capacity and psychiatric status, as well as social and behavioral functioning. Compared with a control group of patients with Crohn’s disease, liver transplant patients did not differ on measures of intelligence, language, attention, concentration, spatial organization, memory, or learning. Performance on these diverse aspects of cognitive functioning was in the normal ranges for both groups when compared with normative or standardized test values. The control and liver transplant patients were not different from each other on measures of psychiatric status or social functioning; however, both groups exhibited some disruption of functioning in these two areas when contrasted with normative values. We conclude that relatively young individuals (mean age in this study, 27.8 years) do not exhibit debilitating long-term neuropsychiatric disability after liver transplantation, although some disturbance in social and psychiatric adjustment was observed.
PMCID: PMC2972588  PMID: 6371166
3.  31P-NMR SPECTROSCOPY OF RAT LIVER DURING SIMPLE STORAGE OR CONTINUOUS HYPOTHERMIC PERFUSION1 
SUMMARY
The ATP content and intracellular pH (pHi)3 of isolated rat liver before, during, and after cold preservation in either UW-lactobionate (UW, n=10) or Euro-Collins (EC, n=8) solutions were monitored using phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy. The 31P-NMR spectra were obtained on a 4.7-Tesla system operating at 81 MHz. Fructose metabolism, liver enzyme release, O2 consumption, and rat survival after liver transplantation were also evaluated. During simple cold storage (SCS), the ATP level declined to undetectable levels with both preservation solutions while the pHi declined to approximately 7.0. In contrast, during continuous hypothermic perfusion (CHP), hepatic ATP levels remained measurable during the 24-hour EC preservation and actually increased significantly (p>0.01) during UW preservation. After reperfusion at 37°C with Krebs-lactate, the SCS livers treated with EC differed significantly from the UW livers in terms of their ATP and pHi as well as their response to a fructose challenge. In contrast, livers undergoing CHP demonstrated similar behaviors with both solutions. These results demonstrate an increase in the hepatic ATP content during CHP which occurs with UW but is not seen with EC. On the other hand, only livers that were simply stored with UW achieved significant survival after transplant, while CHP livers were affected by vascular damage as demonstrated by fatal thrombosis after transplant. These data suggest that ATP content is not the only determinant of good liver function although a system of hypothermic perfusion might further improve liver preservation efficacy should injury to vascular endothelium be avoided.
PMCID: PMC2964138  PMID: 1402332
31Phosphorus-Nuclear Magnetic Resonance Spectroscopy; Liver Preservation and Transplantation; UW; ATP; Intracellular pH; Fructose
4.  Effect of an antiandrogenic H2 receptor antagonist on hepatic regeneration in rats 
Because biochemical “feminization” of the liver In males is observed with hepatic regeneration and because the hepatic regenerative response in females is greater than that in males, the possibility that antiandrogens might potentiate liver regeneration was investigated. Before 70% hepatectomy, adult male Wistar rats were treated with cimetidine, an antiandrogenic H2 antagonist, at doses up to 10 times greater than those used clinically. Control animals received either the saline vehicle or ranitidine, an H2 antagonist without antiandrogenic properties. Treatment with cimetidine reduced the hepatic cytosolic androgen receptor content compared with ranitidine treatment. Hepatectomy caused a further reduction in androgen receptor activity in all groups. Hepatic cytosolic estrogen receptor activity was comparable in all groups throughout the study. Moreover, the rate of liver growth and the levels of ornithine decarboxylase and thymidine kinase activity induced as part of the regenerative response were similar in all groups. Thus, cimetidine, despite its ability to bind to androgen receptors, and ranitidine, an H2 receptor antagonist without antiandrogen action, do not modulate the hepatic regenerative response to a 70% partial hepatectomy.
PMCID: PMC2963569  PMID: 3397626
5.  Acute renal response to large doses of intravenous prednisolone in kidney homograft recipients and in normal subjects 
The immediate renal response to large intravenous doses of prednisolone was studied in 18 kidney homograft recipients and in 6 normal subjects. Clearance rates of inulin (CIN), creatinine (CCR), p-aminohippurate (CPAH), and electrolytes were measured over 3 one-hour periods following intravenous infusion of prednisolone (1 Gm.) and compared with corresponding clearance rates after a placebo infusion. CIN, CCR, and CPAH rates and (CCRCIN) ratios exhibited a substantial decrease during all collection periods following the infusion of prednisolone, both in the normal subjects and in the patients. Fractional excretion of potassium (CKCIN) increased in a progressive fashion reaching peak values after 3 hours. Biphasic variations were observed in the fractional excretion of sodium (CNACIN); an increase during the first hour was followed by a decrease during the third hour. The changes in the fractional excretions of ultrafiltrable calcium (CCaCIN), ultrafiltrable magnesium (CMgCIN), and phosphorus (CPCIN) were minimal. Normal subjects exhibited significant decreases in CCaCIN and CMgCIN following the infusion of prednisolone; there was no significant change in the patients. CPCIN increased significantly both in the normal subjects and in the patients. These results indicate that acute suppression of kidney function is a general renal response to large doses of glucocorticoids. The marked decrease in the creatinine clearance ratio (CCRCIN) observed after the administration of prednisolone is consistent with a depressed tubular secretion of creatinine and emphasizes the inadequacy of CCR as an indication of glomerular filtration rate (GFR) under conditions in which large doses of glucocorticoids are employed.
PMCID: PMC2963570  PMID: 4936366
6.  Does hyperprolactinemia affect hepatic regeneration independent of sex steroids? 
Prolactin, administered exogenously, has been shown to be trophic to the liver, causing increases in the liver weight–to–body weight ratio, in ornithine decarboxylase activity, and in thymidine kinase activity. To investigate the effect of endogenous hyperprolactinemia on hepatic regeneration, pituitary isografts were placed beneath the renal capsule in rats 2 weeks before the rats underwent a two-thirds partial hepatectomy. Prolactin levels 2 weeks after the transplant were greater in the animals with the pituitary isografts compared with levels in controls. The increase in the liver weight–to–body weight ratio after hepatectomy was similar in the rats with pituitary transplant and the controls. However, chronic hyperprolactinemia was associated with increased basal levels of ornithine decarboxylase activity and thymidine kinase activity. Both ornithine decarboxylase activity and thymidine kinase activity increased after partial hepatectomy, and the magnitude of the changes was similar for both groups of animals. The levels of estrogen receptor activity before the partial hepatectomy and the reduction in receptor activity that follows partial hepatectomy were similar in the two groups of animals. Moreover, the levels of androgen receptor activity within the liver before partial hepatectomy and the increase in receptor activity after hepatectomy were similar in the two groups of animals. Thus, chronic sustained hyperprolactinemia has no beneficial effect on the hepatic regenerative response, despite induction of both basal ornithine decarboxylase and thymidine kinase activities.
PMCID: PMC2962417  PMID: 3183497
7.  Albumin macroaggregates and measurements of regional blood flow: Validity and application of particle sizing by Coulter counter 
A method is described for rapid determination of the distribution of particle sizes of albumin macroaggregates by using an electronic counter (Coulter counter). The applicability of this method of analysis to batch quality control has been demonstrated by examining batches before and after changes were made in the mode of synthesis. Seven injections of macroaggregates were made, in 3 experiments, into the arterial inflow of the isolated rabbit heart (perfused with Ringer’s solution), and the coronary venous effluent was analyzed for the distribution of particle sizes; 98.1 per cent of the emerging particles had volumes less than 120 µ3, and 97 per cent had maximal diameters less than 10 µ. An increase, up to twentyfold, in the numbers of particles of these sizes was found in the effluent when compared to the particle distribution in the injectate. This suggested that aggregate fragmentation had occurred within the heart.
PMCID: PMC2943139  PMID: 5414411
8.  Autoradiographic method for quantitation of deposition and distribution of radiocalcium in bone 
A method is described for quantitating autoradiographs of bone-seeking isotopes in microscopic sections of bone. Autoradiographs of bone sections containing 45Ca and internal calibration standards are automatically scanned with a microdensitometer. The digitized optical density output is stored on magnetic tape and is converted by computer to equivalent activity of 45Ca per gram of bone. The computer determines the total 45Ca uptake in the bone section and, on the basis of optical density and anatomic position, quantitatively divides the uptake into 4 components, each representing a separate physiologic process (bone formation, secondary mineralization, diffuse long-term exchange, and surface short-term exchange). The method is also applicable for quantitative analysis of microradiographs of bone sections for mineral content and density.
PMCID: PMC2942796  PMID: 5416906
10.  Aspirin Therapy for Inhibition of Platelet Reactivity in the Presence of Erythrocytes in Patients with Vascular Disease 
Inhibition of erythrocyte (RBC) promotion of platelet reactivity could improve the antiplatelet effect of aspirin (ASA). We tested different ASA regimens for optimal inhibition of platelets and the effects of RBC in patients with a history of vascular diseases. Collagen-induced platelet activation (14C-5HT, TXA2 release) and platelet recruitment (proaggregatory activity of cell-free releasates from activated platelets) were measured in PRP, platelet-RBC (Hct 40%) and whole blood (WB) in 206 patients initially on 200–300 mg ASA/day. Their regimen was modified to bi-weekly 500 mg (loading dose, L) plus daily or twice-daily low-dose ASA (50 or 100 mg). TXA2 was inhibited with all regimens. Percentage of patients with suboptimal inhibition of platelet recruitment in WB was: 200–300 ASA/day (41%), L-50/day (87%), L-100/day (58%), L-50/twice-daily (39%) and L-100/twice-daily (20%; p<0.05 vs. other regimens). 14C-5HT release was inhibited to the greatest extent with L-100/twice-daily in PRP+RBC or WB (p<0.05 vs. other regimens) due to greater inhibition of the RBC prothrombotic effect. Compared to other ASA regimens, L-100 twice-daily (equivalent to 221 mg ASA/day in the 14 day cycle), reduced by >50% the proportion of patients with suboptimal inhibition of platelet recruitment in WB and inhibited 14C-5HT release to the greatest extent.
doi:10.1016/j.lab.2005.12.005
PMCID: PMC1600016  PMID: 16697769
aspirin; blood cells; platelets; erythrocytes; cardiovascular diseases; cerebrovascular disorders; thrombosis; ADP: adenosine 5′-diphosphate; ASA: acetylsalicylic acid; BID: twice-daily; 14C-5HT: 14C-serotonin; COX-1: cyclooxygenase-1; L: loading dose; OD: daily; PRP: platelet-rich plasma; RBC: erythrocyte; TXA2: thromboxane A2; WB: whole blood
11.  The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma 
Thioredoxin-1 (Trx-1) is a small redox protein that is over-expressed in many human tumors, where it is associated with aggressive tumor growth and decreased patient survival. Trx-1 is secreted by tumor cells and is present at increased levels in the plasma of cancer patients. PX-12 is an irreversible inhibitor of Trx-1 currently in clinical development as an antitumor agent. We have used SELDI-TOF mass spectroscopy to measure plasma Trx-1 from patients treated with PX-12 during a Phase I study. Mean plasma Trx-1 levels at pretreatment were significantly elevated in the cancer patients at 182.0 ng/ml compared to 27.1 ng/ml in plasma from healthy volunteers. PX-12 treatment significantly lowered plasma Trx-1 in cancer patients, with the greatest decrease seen in patients having the highest Trx-1 pretreatment levels. High plasma vascular endothelial growth factor (VEGF) levels have been correlated to decreased patient survival. PX-12 treatment also lowered plasma VEGF levels in cancer patients with high pretreatment levels. SELDI-TOF mass spectrometry identified 7 additional plasma proteins whose levels decreased following PX-12 administration, one of which was identified as a truncated form of transthyretin. The results of this study suggest that the lowering of elevated levels of plasma Trx-1 in cancer patients may provide a surrogate for the inhibition of tumor Trx-1 by PX-12. Furthermore, PX-12 decreases plasma VEGF levels which may contribute to the antitumor activity of PX-12.
doi:10.1016/j.lab.2005.09.001
PMCID: PMC1432091  PMID: 16459166
PX-12; thioredoxin-1; VEGF

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