Catabolism of very low density lipoprotein B apoprotein in man.

The turnover and the catabolic fate of the B apoprotein of very low density lipoprotein (VLDL-B) was studied in 15 normal and hyperlipidemic subjects using reinjected autologous VLDL labeled with radioiodine. The specific radioactivity-time curve of the B apoprotein in total VLDL (S(f)20-400) was multiexponential but conformed to a two-pool model during the first 48 h of catabolism. The flux was highest in several hypertriglyceridemic subjects. The mass of pool A exceeded the intravascular content of VLDL-B by 30% on average, indicating extravascular metabolism of VLDL. The two-pool model might reflect the input of several populations of particles or heterogeneity of catabolic processes or pools. The flux of B apoprotein was also measured in several subclasses of VLDL, in smaller intermediate density lipoproteins, and in low density lipoproteins (LDL). In three subjects the flux was similar in S(f) 60-400 and in S(f) 12-60 lipoproteins, suggesting that VLDL was catabolized at least to a particle in the density range S(f) 12-60. Subsequent catabolism appeared to proceed by two pathways: in normotriglyceridemic subjects, B apoprotein flux in the S(f) 20-400 and in S(f) 12-20 lipoproteins was similar, whereas in hypertriglyceridemic subjects flux through S(f) 12-20 accounted for only part of the VLDL-B flux. The flux of low density lipoprotein B apoprotein (LDL-B), which is believed to be derived from VLDL catabolism, was calculated from the area between the specific activity time curves of VLDL-B and LDL-B. In subjects with normal plasma triglyceride concentration, LDL-B flux was from 91% to 113% of that of VLDL-B; but in three hypertriglyceridemic subjects showing high rates of VLDL-B transport, LDL-B flux was only one-third that of VLDL-B. This suggests that when VLDL-B flux is high, VLDL is substantially catabolized by a route other than through LDL and possibly leaves the circulation as a particle in the S(f) 20-60 density range.

Suppression by diets rich in fish oil of very low density lipoprotein production in man.

The highly polyunsaturated fatty acids in fish oils lower the plasma triglyceride concentration. We have studied the effect of a diet rich in fish oil on the rate of production of the triglyceride-transporting very low density lipoprotein (VLDL). Seven subjects, five normal and two with hypertriglyceridemia received up to 30% of daily energy needs from a fish oil preparation that was rich in eicosapentaenoic acid and docosahexaenoic acid, omega-3 fatty acids with five and six double bonds, respectively. Compared with a diet similarly enriched with safflower oil (in which the predominant fatty acid is the omega-6 linoleic acid, with two double bonds), the fish oil diet lowered VLDL lipids and B apoprotein concentrations profoundly. High density lipoprotein lipids and A1 apoprotein were also lowered, but the effect on low density lipoprotein (LDL) concentration was inconsistent. The daily production or flux of VLDL apoprotein B, calculated from reinjected autologous 125I-labeled lipoprotein, was substantially less in six subjects studied after 3 wk of fish oil, compared with after safflower oil. This effect on flux was more consistent than that on the irreversible fractional removal rate, which was increased in the four normolipidemic but inconsistent in the hypertriglyceridemic subjects. This suggests that fish oil reduced primarily the production of VLDL. The daily production of VLDL triglyceride, calculated from the kinetics of the triglyceride specific radioactivity-time curves after [3H]glycerol was injected, also showed very substantial reductions in five subjects studied. The marked suppression in VLDL apoprotein B and VLDL triglyceride formation was found not to be due to diminished plasma total free fatty acid or plasma eicosapentaenoic flux, calculated during constant infusions of [14C]eicosapentaenoic acid and [3H]oleic acid in four subjects. In two subjects there was presumptive evidence for substantial independent influx of LDL during the fish oil diet, based on the precursor-product relationship between the intermediate density lipoprotein and LDL apoprotein B specific radioactivity-time curves.

Increased synthesis of carbamoyl-phosphate synthase II (EC 6.3.5.5) in hepatoma 3924A.

Carbamoyl-phosphate synthase II (glutamine-hydrolyzing) (EC 6.3.5.5) (synthase II) is the first and rate-limiting enzyme in the de novo UTP biosynthetic pathway. Leucine pulse-labeling in the rat demonstrated that in the rapidly proliferating hepatoma 3924A the ratio of radioactivity of synthase II to that of total cytosolic protein was 168.2 +/- 11.0 (SE) X 10(-3). This synthetic rate for the tumor enzyme was 9.7-fold higher than that for the liver synthase II, 17.4 +/- 4.0 X 10(-3). Since the degradation rate for hepatoma 3924A enzyme (t1/2 = 65.5 h) was similar to the rate for liver synthase II (t1/2 = 69.3 h), the increase in tumor synthase II activity and amount was due primarily to an elevation in enzyme synthesis in the presence of an unaltered catabolic rate. The results indicate that the reprogramming of gene expression in the hepatoma entails an increased production rate of the rate-limiting enzyme of UTP synthesis. This increase in the activity, concentration, and synthesis of tumor synthase II should provide a heightened capacity for the de novo pyrimidine biosynthetic pathway, thus conferring a selective advantage to the cancer cells.

Increased carbamoyl-phosphate synthetase II concentration in rat hepatomas: immunological evidence.

Carbamoyl-phosphate synthetase II (glutamine hydrolyzing, EC 6.3.5.5) (synthetase II), the rate-limiting enzyme of de novo uridine monophosphate biosynthesis, was purified 230-fold to apparent homogeneity from rapidly growing rat hepatoma 3924A. The antiserum (produced in rabbits against purified hepatoma 3924A enzyme) yielded a single precipitin line with crude and partially purified synthetase II of normal liver and three hepatomas. In hepatomas of slow (20), intermediate (7787), and rapid (3924A) growth rates, synthetase II activity was elevated 1.5-, 2.3-, and 7.9-fold, and the amount of antiserum required to inactivate the activity was 1.6-, 2.3-, and 8.2-fold higher than that in normal liver. Thus the increase in synthetase II activity in the tumors was due to an elevation in the amount of the synthetase II enzyme protein.

Purine enzymology of human colon carcinomas.

The purpose of this study was to elucidate the purine enzymic programs of human primary colorectal carcinomas. Marked alteration in the enzymology of the human colon neoplasm clearly distinguished it from that of the normal colon mucosa. In the human colon mucosa, the activities of ribonucleotide reductase, inosine phosphate dehydrogenase, formylglycinamidine ribonucleotide synthetase, guanosine phosphate synthetase, and amidophosphoribosyltransferase were 0.042, 5.2, 5.6, 8.2 and 36.0 nmol/h/mg protein, respectively, and in the colon carcinomas the activities increased to 755, 575, 295, 280, and 294% of the normal values. The activities of the salvage enzymes, adenine and hypoxanthine-guanine phosphoribosyltransferases, were 310, 249, and 602 nmol/h/mg protein, respectively, whereas in the tumors, only the activity of adenine phosphoribosyltransferase was increased (2-fold). The markedly higher absolute enzymic capacity for salvage in the tumors accounts, in part at least, for the lack of chemotherapeutic success of inhibitors of enzymes of de novo synthesis that have been used in the clinical treatment of colorectal carcinomas. Combinations of inhibitors of de novo biosynthesis and blockers of the salvage enzymes or of salvage transport (e.g., dipyridamole) should improve the chemotherapy of colon neoplasms. Since in the colon carcinoma the activities of glutamine-utilizing enzymes (guanosine phosphate and formylglycinamidine ribonucleotide synthetase and amidophosphoribosyltransferase) were markedly increased, and the glutamine concentration was decreased (50%), treatment with an antiglutamine agent (e.g., acivicin) should be of relevance. Since the activity of ribonucleotide reductase, the rate-limiting enzyme of nucleic acid biosynthesis, was markedly increased in the colon neoplasms, combination chemotherapy might include drugs against this enzyme.

In vivo transfer of cholesteryl esters from high density lipoproteins to very low density lipoproteins in man.

The fate of cholesteryl esters in high density lipoprotein (HDL) was studied to determine whether the transfer of esterified cholesterol from HDL to other plasma lipoproteins occurred to a significant extent in man. HDL cholesteryl ester, labelled in vitro with [3H] cholesterol, was injected into human subjects. Labelling of cholesteryl esters in very low density (VLDL) occurred rapidly and by 3 h, the esterified cholesterol in VLDL reached peak specific radioactivity. The removal rate of cholesteryl esters from HDL appeared to be exponential and of the order of 0.2/h; calculation of the apparent flux was about 150 mg/h which approximates reported values for total cholesterol esterification in human plasma in vivo. The rapid rate of labelling of VLDL from HDL suggests that the transfer of HDL cholesteryl esters to VLDL may represent a significant pathway for the disposal of HDL cholesterol.

Altered adrenergic receptor density in myocardial hibernation in humans: A possible mechanism of depressed myocardial function.

BACKGROUND: Alterations in adrenergic receptor densities can potentially contribute to myocardial dysfunction. Their relevance to myocardial hibernation in humans is unknown. METHODS AND RESULTS: Accordingly, 22 transmural myocardial biopsies were obtained in 11 patients with ischemic ventricular dysfunction during bypass surgery, guided by transesophageal echocardiography. Patients underwent dobutamine echocardiography (DE) and rest scintigraphic studies before revascularization and DE at 3 to 4 months. alpha- and ss-receptor density (ARD and BRD) and extent of fibrosis were quantified from the myocardial biopsies. Of the 22 segments, 16 had abnormal rest function and 6 were normal. Severely hypokinetic or akinetic segments showed a 2.4-fold increase in ARD with a concomitant 50% decrease in BRD compared with normal segments. An increase in ARD, a decrease in BRD to a lesser extent, and thus an increase in ARD/BRD ratio were seen in dysfunctional segments with contractile reserve compared with normal segments and were most pronounced in those without contractile reserve (P:<0.001). Similar findings were observed if recovery of function or scintigraphic uptake was analyzed as a marker for viability. No significant relation between either ARD or BRD and percent myocardial fibrosis was noted (r=0.37 and -0.39, respectively). CONCLUSIONS: Thus, graded and reciprocal changes in alpha- and ss-adrenergic receptor densities occur in viable, hibernating myocardium and may account in part for the observed depression in resting myocardial function and preserved contractile reserve in this entity.

Deceleration time in ischemic cardiomyopathy: relation to echocardiographic and scintigraphic indices of myocardial viability and functional recovery after revascularization.

BACKGROUND: In patients with heart failure secondary to left ventricular (LV) systolic dysfunction, a short deceleration time (DT) successfully predicts clinical outcome. The impact of myocardial viability and revascularization on the mitral inflow velocities, however, is unknown. METHODS AND RESULTS: Forty patients with ischemic cardiomyopathy underwent (201)Tl scintigraphy (SPECT) and 2D, Doppler, and dobutamine echocardiography (DE, to 40 microg. kg(-1). min(-1)) 2 days before CABG. Echocardiography was repeated 3 months after revascularization to determine recovery of function. Significant correlations were present between DT and LV contractile reserve by DE (r=0.72), scar perfusion defect by SPECT (r=-0.69), and the change in ejection fraction (DeltaEF) after surgery (r=0.77) (all P:<0.01). DT >150 ms effectively identified (sensitivity 79%, specificity 81%) patients with DeltaEF >/=5%. The population was divided into 2 groups according to DT: group 1 (DT >150 ms, n=21) and group 2 (DT

Relation of the contractile reserve of hibernating myocardium to myocardial structure in humans.

BACKGROUND: Although dobutamine echocardiography (DE) is widely used to assess myocardial viability in humans, little is known about the relation between contractile reserve and myocardial structure. METHODS AND RESULTS: We evaluated 20 patients with coronary disease (64+/-13 years old, ejection fraction 28+/-7.5%) with DE (up to 40 micrograms . kg(-1). min(-1)), rest-redistribution (201)Tl single photon emission CT, and quantitative angiography before bypass surgery. During surgery, patients underwent transmural myocardial biopsies (n=37) guided by transesophageal echocardiography to determine the extent of interstitial fibrosis and intracellular and interstitial proteins by histopathology and immunohistochemistry. Among the 37 segments biopsied, 16 recovered function as assessed 2 to 3 months later. Segments with postoperative functional recovery had more wall thickening at low-dose DE (28% versus 3%, P<0.001), higher thallium uptake (69% versus 48%, P=0.03), and less interstitial fibrosis (2% versus 28%, P<0.001). Quantitative angiographic parameters did not predict recovery of function. Segments with DE viability (contractile reserve and/or ischemia) had less fibrosis (2.7% versus 28%, P<0.001), less vimentin and fibronectin (both P<0.01), more glycogen (P=0.016), and higher thallium uptake (64% versus 35.5%, P<0.05) than those without viability. Viable segments by both DE and thallium had less fibrosis (1%) than those viable by 1 of the 2 techniques (9%) or not viable by both (28%, P=0.005). Thickening at low-dose DE correlated well with the extent of interstitial fibrosis (r=-0.83, P<0.01). CONCLUSIONS: Contractile reserve during DE correlates inversely with the extent of interstitial fibrosis and the amount of fibronectin and vimentin and directly with rest-redistribution thallium uptake.

Severe Takayasu's arteritis of the pulmonary arteries: report of a case with successful surgical treatment.

Although involvement of the aorta and its large branches is more common, Takayasu's arteritis involving the pulmonary arteries is well recognized. This report describes an adolescent girl with an uncommonly severe form of Takayasu's arteritis involving the pulmonary arteries. A successful surgical treatment is presented.

Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans.

OBJECTIVES: We sought to evaluate the relation of segmental tissue Doppler (TD) velocities to both the regional amount of interstitial fibrosis and the myocyte beta-adrenergic receptor density in humans. BACKGROUND: The systolic myocardial velocity (Sm) and early diastolic myocardial velocity (Em) acquired by TD are promising new indexes of left ventricular function. However, their structural and functional correlates in humans are still unknown. METHODS: Ten patients with coronary artery disease underwent echocardiographic examination including TD imaging, along with transmural endomyocardial biopsy at the time of coronary bypass surgery (two biopsies per patient for a total of 20 specimens). The specimens were analyzed for percent interstitial fibrosis and beta-adrenergic receptor density. RESULTS: Normal segments (n = 8) had a higher beta-adrenoceptor density (2,280 +/- 738 vs. 1,373 +/- 460, p = 0.03) and a lower amount of interstitial fibrosis (13 +/- 3.3% vs. 28 +/- 11.5%, p = 0.002) than dysfunctional segments (n = 12). Myocardial systolic velocity and Em were also significantly higher (9.5 +/- 2.7 vs. 5.9 +/- 1.8 cm/s, p = 0.025 and 11.3 +/- 2.8 vs. 6.4 +/- 2.1 cm/s, p = 0.002, respectively) in normal segments. A significant relationship was present between Em and the beta-adrenergic receptor density (r = 0.78, p < 0.001) and percent interstitial fibrosis (r = -0.7, p = 0.0026), which together accounted for 81% of the variance observed in Em. Likewise, a significant relationship was present between Sm and the beta-adrenergic receptor density (r = 0.68, p < 0.001) and the percent interstitial fibrosis (r = -0.66, p = 0.004) and together accounted for 62% of the variance observed in Sm. CONCLUSIONS: Systolic myocardial velocity and Em are strongly dependent on both the number of myocytes and the myocardial beta-adrenergic receptor density.

Hemodynamic compromise (tricuspid stenosis and insufficiency) caused by an unruptured aneurysm of the sinus of Valsalva.

A patient is described with an unruptured aneurysm of the noncoronary sinus of Valsalva that occupied the right ventricular inflow tract and caused dynamic tricuspid stenosis and insufficiency. Results of two-dimensional echocardiography delineated the anatomy of the aneurysm and pulsed Doppler examination provided evidence that the aneurysm was unruptured. The unruptured aneurysm was resected successfully.

BARCODE-ALL: accelerated and cost-effective genetic risk stratification in acute leukemia using spectrally addressable liquid bead microarrays.

An increasing number of risk-stratifying genetic lesions in acute leukemia are being discovered and characterized. To translate this important and increasing volume of information from the research laboratory into effective clinical care, however, new, fast and comprehensive assays are needed. Toward this end, we have developed a two-stage multiplexing assay of broad applicability, which combines multiplex polymerase chain reaction with multiplex detection on spectrally addressable liquid bead microarrays. Using pediatric lymphoblastic leukemia as a model system, we demonstrate that all seven of the fusion transcripts resulting from risk-stratifying chromosomal translocations can be assayed in a single well of a 96-well multiplate with 100% specificity and sensitivity, within 6 h of specimen collection. The assay is automatic and high throughput and represents a significant improvement over previously available assays targeting the same genetic changes. We conclude that user-defined assays that multiplex both target selection and detection may have broad applicability in the management of hematological malignancies.

Laparoscopic resection of splenic artery aneurysms.

BACKGROUND: Laparoscopic techniques used to manage asymptomatic splenic artery aneurysms have been reported infrequently. METHODS: A laparoscopic splenic artery aneurysm resection was attempted for six consecutive patients. RESULTS: One patient underwent conversion to laparotomy because of a tear in the splenic vein. Among the five successful laparoscopic splenic artery aneurysm resections, the mean estimated blood loss was 37 +/- 12.6 ml, the mean operative time was 187.6 +/- 79.2 min, and the mean postoperative length of hospital stay was 1.8 +/- 1.3 days. The mean time to a clear liquid diet was 5.3 +/- 0.5 h, and the mean time to a regular diet was 1 +/- 0 day. The mean duration of narcotic analgesic use was 5.4 +/- 1.5 days, and the mean time to resumption of regular activities was 12.7 +/- 1.6 days. CONCLUSIONS: These cases illustrate the benefit of a laparoscopic approach with brief hospitalizations, early resumption of diet and regular activity, and minimal use of postoperative narcotic analgesics.

A young male with bone pain.

A 38-year-old male presented with a 6-month history of pain in the right thigh associated with weight loss. His full blood count was normal, as were his biochemistry, immunology, autoimmune screen and prostate-specific antigen. Inflammatory markers were elevated. All preliminary radiological investigations were normal. Bone scan and magnetic resonance imaging were highly suggestive of a leukaemic process. Bone marrow biopsy and peripheral blood film confirmed the diagnosis of an acute biphenotypic leukaemia. This case report highlights the fact that bone pain associated with a normal peripheral blood count may be the presentation of an acute haematological disorder in both adults and children.

Fat-soluble-vitamin status during the first year of life in infants with cystic fibrosis identified by screening of newborns.

We investigated the fat-soluble-vitamin status during the first year of life in 36 infants with cystic fibrosis (CF) consecutively identified by screening of newborns. At initial evaluation (at age 51.0 +/- 26.7 d) 36% of patients were hypoalbuminemic, 21% had low serum retinol, 35% had low serum 25-hydroxyvitamin D. 38% had low serum alpha-tocopherol and low ratios of serum vitamin E to total lipids, and none had elevated protein in vitamin K absence (PIVKA). Hypoalbuminemia was more common in breast-fed than in formula-fed infants. Seventy-two-hour fecal fat excretion correlated inversely with serum alpha-tocopherol. Treatment with oral pancreatic enzyme supplements, a multiple vitamin, and additional vitamin E was associated with normalization of serum albumin, retinol, and 25-hydroxyvitamin D and negative PIVKA at age 6 and 12 mo. Approximately 10% of patients remained vitamin E deficient. Biochemical evidence of fat-soluble-vitamin deficiencies is common before age 3 mo in patients with CF and, except for vitamin E, these deficiencies corrected with standard therapy.

Circadian variation of the QT interval in patients with sudden cardiac death after myocardial infarction.

To evaluate the potential prognostic value of the circadian variation of QT intervals in predicting sudden cardiac death (SCD) in patients after myocardial infarction (MI), 15 pairs of post-MI patients (15 died suddenly within 1 year after MI [SCD victims] and 15 remained event-free [MI survivors]) were studied (mean age 60 +/- 8 years; 24 men and 6 women). The pairs were matched for age, gender, infarct site, presence of Q wave, left ventricular ejection fraction, thrombolytic and beta-blocker therapy. Fourteen normal subjects served as controls (mean age 55 +/- 9 years; 12 men). A 24-hour Holter electrocardiographic (ECG) recording was obtained from each subject. All recordings were analyzed using a Holter ECG analyser. QT, RR, and heart rate-corrected QT intervals (QTc) were automatically calculated by the analyzer, and hourly and 24-hour mean values of each measurement were derived from each recording. There was a pronounced circadian variation in the QT interval in parallel with the trend in the RR interval in normal subjects and in MI survivors. Circadian variation in both indexes was blunted in SCD victims. The QT interval was significantly longer at night than during the day in normal subjects (388 +/- 28 vs 355 +/- 21 ms, p = 0.001) and in MI survivors (358 +/- 25 vs 346 +/- 15 ms, p = 0.008), but not in SCD victims (357 +/- 32 vs 350 +/- 31 ms, p = 0.6). The 24-hour mean value of the QT interval in SCD victims did not differ significantly from that in normal subjects or MI survivors. The QT interval at night was significantly shorter in SCD victims than in normal subjects (357 +/- 32 vs 388 +/- 28 ms, p = 0.02), but daytime values were similar. The QT interval in SCD victims did not differ significantly from that of MI survivors at any time. The QTc interval exhibited a small circadian variation in normal subjects. This variation was abolished in SCD victims and MI survivors. The 24-hour mean value of QTc was significantly longer in SCD victims than in normal subjects (424 +/- 25 vs 402 +/- 21 ms, p = 0.02), and in MI survivors (424 +/- 25 vs 404 +/- 32 ms, p < 0.05). The QTc interval of SCD victims differed from that of normal subjects during both the day (421 +/- 25 vs 400 +/- 17 ms, p = 0.02) and night (424 +/- 26 vs 403 +/- 23 ms, p = 0.03). Thus, blunted circadian variation in QT intervals, abolished circadian variation in QTc intervals, and prolonged QTc intervals may suggest an increased risk of SCD in patients after MI.

Amphotericin B: a biological response modifier in targeting against the salvage pathways.

Dipyridamole, a nucleoside transport inhibitor which blocks the rescue effect of exogenous nucleosides, is a compound of interest for use in combination with antimetabolites of de novo purine and pyrimidine biosynthesis. This study has provided evidence that the dipyridamole inhibitory effect on nucleoside incorporation varied markedly during the course of cell growth in culture. Human colon cancer HT-29 cells in lag and log phases were highly sensitive to the blocking action of dipyridamole on thymidine incorporation with IC50 values of 0.06 and 0.07 microM respectively. In contrast, stationary phase cells were comparatively insensitive to dipyridamole with an IC50 of 46 microM. Amphotericin B restored the sensitivity of stationary phase cells to dipyridamole, lowering the IC50 value for thymidine incorporation to 0.03 microM. A similar pattern was observed for cytidine incorporation. Amphotericin B also enhanced the growth inhibitory action of dipyridamole in stationary phase cells. The combination of amphotericin B and dipyridamole should be potentially useful in cancer chemotherapy.

Enzymic programs of rat bone marrow and the impact of acivicin and tiazofurin.

The in vivo actions of two antimetabolites, acivicin (NSC-163501) and tiazofurin (NSC-286193), were examined on the enzymic programs of rat bone marrow. From the bone marrow of the femurs, 100,000 g supernatant fractions were prepared; enzymic activities were measured by isotopic assays, and cellularity was determined. In the normal bone marrow, the specific activities of pyrimidine de novo synthetic enzymes, CDP reductase, dTMP synthase, CTP synthase, carbamoyl-phosphate synthase II (synthase II), orotidine 5'-phosphate decarboxylase and aspartate carbamoyltransferase, were 1, 2.7, 5, 10, 63 and 601 nmol/hr/mg protein, respectively, whereas those of the salvage enzymes, deoxycytidine, thymidine, cytidine and uridine kinases were 3, 43, 149, and 367 nmol/hr/mg protein, respectively. In purine biosynthesis, the activities of the de novo synthetic enzymes, IMP dehydrogenase, formylglycinamidine ribonucleotide (FGAM) synthase, GMP synthase, amidophosphoribosyl-transferase (AT) and adenylosuccinate synthase were 16, 8, 107, 78 and 124 nmol/hr/mg protein, respectively, and those of the salvage enzymes, adenine, hypoxanthine and guanine phosphoribosyl-transferases, were 340, 407, and 1018 nmol/hr/mg protein, respectively. The sequence of events was elucidated after a single i.p. injection of acivicin (5 mg/kg) or tiazofurin (200 mg/kg). Within 2 hr after acivicin injection, CTP, GMP and FGAM synthases lost 85-90%, while AT and synthase II lost 50 and 80%, respectively, of their activities. The activities rose to near normal range by 72-96 hr. The bone marrow cellularity decreased, reaching a nadir at 24 and 48 hr, and returning to normal range by 72 and 92 hr; thymidine kinase activity followed a similar pattern. Tiazofurin injection depressed IMP dehydrogenase activity to 20% by 2 hr with a rebound to normal range by 48 and 72 hr. The cellularity decreased more slowly, reaching its lowest point at 24 hr and returning to normal range at 72 hr. For acivicin the marked depletion of the activities of the glutamine-utilizing enzymes and for tiazofurin that of IMP dehydrogenase might account, in part at least, for the bone marrow toxicity of these antimetabolites. Because of the presence in the bone marrow of high activities of purine and pyrimidine salvage enzymes, it should be possible to design methods utilizing nucleosides and nucleobases to protect the bone marrow from the action of antimetabolites.

The relationship between conductance and functional residual capacity during drug-induced bronchoconstriction.

UNLABELLED: We wondered if the inverse changes in airway conductance (Gaw) and functional residual capacity (FRC) during histamine (H) and acetylcholine (ACH) challenge are interrelated or occur at random. In 14 normal and 14 asthmatic subjects, we determined FRC and Gaw changes corresponding to changes in specific airway conductance (SGaw) around -40 percent produced by an aerosol of H or ACH inhaled quantitatively and with measured lung deposition. We also assessed the elastic recoil following H inhalation (5A). We found that in 11 normal and nine asthmatic subjects, after H or nine normal and 11 asthmatic subjects after ACH, Gaw and 1/FRC were linearly and directly related (p less than 0.05). The steepness of this slope was directly related to the resting Gaw values. A similar relation was uncovered in the literature for asthmatic patients at rest or during recovery from natural asthma. As the elastic recoil was normal and did not change after H, it could not explain delta FRC at delta SGaw of -40 percent. IN CONCLUSION: (1) during H or ACH challenge, Gaw-FRC relationship in normal or asthmatic subjects tends to be hyperbolic and dependent on resting Gaw; (2) such a relationship is seemingly present in other bronchoconstrictor responses with a different pathogenesis; and (3) during bronchoconstriction, as Gaw vs FRC is no longer linear, SGaw becomes volume dependent.