Report of the Nursing Education Unit, State Education Department and New York State Board of Nursing.
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Education, Nursing↗
Biomedical subjects
J Griffin
Publications and source records attributed to J Griffin.
Clinical pharmacology of low-dose cytosine arabinoside.
Low doses of cytosine arabinoside (ara-C) have recently been administered by intravenous (IV) infusion and intermittent subcutaneous (SC) injection to patients with pre-leukemia and acute leukemia. Our studies have demonstrated that the continuous IV infusion of low-dose (20 mg/m2/d) ara-C produces hematologic improvement in patients with preleukemic syndromes. The present work has monitored plasma ara-C levels in five of these patients. The results demonstrate mean steady-state plasma levels ranging from 1.8 to 6.9 X 10(-8) mol/L. The range for total drug exposure (area under the curve) for the 14-day course was 6.5 to 15.9 X 10(-6) mol/L X hour. These findings have been compared to the pharmacokinetics of ara-C (10 mg/m2) given by bolus SC injection. This dose schedule resulted in peak ara-C levels 15 minutes after injection that were tenfold to 30-fold higher than the mean plasma level achieved during continuous IV infusion in the same patient. Furthermore, there was no detectable plasma ara-C at six hours after bolus injection. The differences in ara-C pharmacology for the continuous IV infusion and bolus SC injection dose schedules may contribute to the variability in response and toxicity achieved with these regimens.
Acute Disease↗
Cloning and identification of the H-2Dp gene.
We have cloned six different class I genes from a B10.P sperm library. After cotransfection with the herpes simplex tk gene, one L-cell line was found to react with six H-2Dp-specific monoclonal antibodies. The cell line L12a did not react with Kp-specific monoclonal antibodies. This identification was confirmed by mapping a 2.5 kb Bam H1 restriction fragment present in the lambda 12a DNA clone to the D-TL region of H-2p. Only a single 8.8 kb Bam H1 fragment can be assigned to Kp by restriction fragment length polymorphism, while many others map to the D-TL interval. A restriction map of lambda 12a is presented.
Animals↗
Torsade de pointes complicating acute myocardial infarction.
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Electrocardiography↗
Effect of ara-A on differentiation and proliferation of HL-60 cells.
The HL-60 human leukemic promyelocytic cell line can be induced to mature into terminally differentiated cells using certain chemotherapeutic agents. We have recently demonstrated that two inhibitors of DNA synthesis, cytosine arabinoside (ara-C) and aphidicolin, can induce HL-60 differentiation with the appearance of monocytic markers. These pyrimidine antimetabolites may have affected DNA methylation patterns and resulted in altered gene expression, or the differentiated phenotype may have occurred by inhibition of DNA replication. Consequently, we have extended these studies by using the purine analog, adenine arabinoside (ara-A), which also acts as an inhibitor of DNA synthesis. The results demonstrate that ara-A also induces HL-60 non-specific esterase activity and enhances expression of myeloid cell surface antigens, MY-4 and MO-1. The induction of a differentiated phenotype by ara-A occurs after partial inhibition of DNA synthesis, a finding similar to that observed with ara-C and aphidicolin. These observations indicate that purine, as well as pyrimidine analog inhibitors of DNA polymerization can induce differentiation of HL-60 cells along a monocytic lineage. These findings may be relevant to recent clinical trials that have employed low doses of ara-C in an attempt to induce differentiation of malignant hematopoietic cells.
Antibodies, Monoclonal↗
Influence of hyperglycemia on insulin's in vivo effects in type II diabetes.
The present study was designed to quantitate the interaction between the decrease in target tissue insulin action seen in subjects with Type II diabetes and the mass action effect of glucose exerted via the prevailing hyperglycemic state. To this end, euglycemic glucose clamp studies were performed in 26 control subjects using insulin infusion rates of 15, 40, 120, 240, and 1,200 mU/M2 per min and in 10 Type II diabetic subjects using insulin infusion rates of 120 and 1,200 mU/M2 per min. The results of these euglycemic studies indicated that insulin-stimulated peripheral glucose disposal was decreased in the Type II diabetics due to a combined receptor (rightward shift in the dose-response curve) and postreceptor defect in insulin action (decreased maximal response), whereas the decrease in insulin-mediated suppression of hepatic glucose output (HGO) was consistent with a defect in insulin binding (rightward shift in dose-response curve). Hyperglycemic glucose clamp studies were also performed in the Type II diabetics at their respective fasting serum glucose levels (mean [+/- SE] 280 +/- 17 mg/dl) employing insulin infusion rates of 15, 40, 120, and 1,200 mU/M2 per min. In the presence of their basal level of hyperglycemia, the noninsulin-dependent diabetes mellitus (NIDDM) subjects exhibited rates of overall glucose disposal that were similar to those observed in control subjects studied at euglycemia at similar steady state insulin concentrations. This suggests that in Type II diabetics, the mass action effect of glucose partially compensates for the marked decrease in insulin-stimulated glucose uptake observed under euglycemic conditions. However, even in the presence of hyperglycemia, insulin levels below 100 microU/ml had little effect and maximally effective insulin levels increased peripheral glucose disposal only 2.8-fold (142 +/- 7-413 +/- 47 mg/M2 per min) above basal in the Type II diabetics, compared with a sixfold increase (75 +/- 4-419 +/- 34 mg/M2 per min) in the control subjects studied at euglycemia. Thus, the severe insulin resistance that is a characteristic feature of NIDDM remains apparent. Basal HGO was elevated in the NIDDM subjects (157 +/- 6 vs. 76 +/- 4 mg/M2 per min for controls) and a high degree of correlation was found between the basal rate of HGO and the fasting glucose level (r = 0.80, P less than 0.01). The presence of hyperglycemia augmented insulin-mediated suppression of HGO, but did not restore it to normal. We concluded that: (a) in the presence of basal hyperglycemia, physiologic insulin levels exerts a diminished effect to suppress HGO and stimulate peripheral glucose disposal in NIDDM; (b) basal HGO is elevated in untreated Type II diabetics, and this may serve to maintain the level of hyperglycemia required to compensate for the decrease in peripheral insulin action; and (c) fasting hyperglycemia exerts a suppressive effect on HGO but does not completely compensate for the decrease in hepatic insulin action in Type II diabetics.
Adult↗
The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects.
Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemic action remain controversial. We have quantitated glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time. The mean fasting serum glucose level fell from an initial value of 264 +/- 17 mg/dl to 178 +/- 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemia (fasting serum glucose greater than 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P less than 0.001) and fell from 141 +/- 12 mg/m2/min before therapy to 107 +/- 11 mg/m2/min after 3 mo of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Involvement of spermidine in proliferation and differentiation of human promyelocytic leukemia cells.
The polyamines putrescine, spermidine, and spermine have been implicated in the regulation of cell proliferation and differentiation. Previous studies, however, have demonstrated that the polyamines are essential for proliferation, but not differentiation, of HL-60 human promyelocytic leukemia cells. We have extended these findings by demonstrating a highly significant relationship between intracellular spermidine levels and HL-60 proliferation. However, in contrast to previous studies, we have also demonstrated that induction of HL-60 differentiation with dimethyl sulfoxide, hexamethylene bisacetamide, butyric acid, or retinoic acid is inhibited by alpha-difluoromethyl ornithine (DFMO) depletion of intracellular putrescine and spermidine. Further, the addition of exogenous spermidine abrogates DFMO inhibition of HL-60 differentiation, thus confirming the involvement of this polyamine in the expression of a differentiated phenotype. The discrepancy between our results and those of previous studies probably stems from the nearly complete, rather than partial, depletion of intracellular spermidine achieved in the present work. The results of the present study thus demonstrate the involvement of spermidine in both proliferation and induction of HL-60 differentiation with certain agents.
Acetamides↗
Polyamine requirements for induction of HL-60 promyelocyte differentiation by leukocyte-conditioned medium and phorbol ester.
The polyamines putrescine, spermidine, and spermine have been implicated in the regulation of both proliferation and differentiation. Spermidine is required for DNA replication, and the intracellular depletion of this polyamine can be used to distinguish cellular events related to proliferation. We have demonstrated previously that depletion of intracellular spermidine results in cytostasis of human HL-60 promyelocytes. The inhibition of HL-60 proliferation is associated with inhibition of differentiation induced by dimethyl sulfoxide, hexamethylene bisacetamide, butyric acid, and retinoic acid. The present studies extend these findings by monitoring the effects of spermidine depletion and inhibition of DNA replication on induction of HL-60 differentiation by leukocyte-conditioned medium and phorbol ester. The results demonstrate that both inducers enhance intracellular polyamine levels. However, depletion of intracellular spermidine inhibits induction of HL-60 differentiation by leukocyte-conditioned medium, but not by phorbol ester. Further, the addition of exogenous spermidine abrogates the inhibition of proliferation, and leukocyte-conditioned medium induced HL-60 differentiation, confirming the requirement of this polyamine for the expression of a differentiated phenotype. The present results and our previous findings suggest that spermidine is required for induction of HL-60 differentiation by a variety of agents, including leukocyte-conditioned medium, but that phorbol ester induces HL-60 differentiation in the absence of polyamine biosynthesis and DNA replication.
Antibodies, Monoclonal↗
Ultrasonic evaluation of simple and ectopic ureteroceles.
Ureteroceles appear as transonic intravesical lesions on ultrasonic demonstration of the bladder, producing a 'cyst within a cyst' appearance. Four patients, three with simple ureteroceles and one with an ectopic ureterocele were investigated by intravenous urography (IVU), ultrasound (US) and cystoscopy. Two patients had bilateral simple ureteroceles with non-dilated ureters and two had unilateral ureteroceles, one simple, and one ectopic with a hydroureter. Previously ultrasonography of the fluid-filled bladder has demonstrated only large ureteroceles. The present study was successful in demonstrating both large and small ureteroceles.
Adult↗
Tidal volume and airway pressure on high frequency jet ventilation.
The principle of jet injector indicates that large tidal volumes may be delivered on high frequency jet ventilation (HFJV) without increasing airway pressure. Fifteen dogs were ventilated on HFJV in 2 separate experiments. In the first one, tidal volume was maintained constant at 10 ml/kg, while PEEP, respiratory rate, and cannula size were changed in 16 different experimental conditions. In the second experiment, driving pressure was progressively increased from 5 to 45 psig, and PEEP, respiratory rate, and injector size were changed in 32 experimental conditions. Mean airway pressure, tidal volume, driving pressure, thoracic aortic mean pressure, and abdominal aortic mean pressure were the variables measured. Tidal volume linearly increased with driving pressure, while airway pressure only increased when tidal volume exceeded 25 ml/kg. Blood pressure was inversely related to mean airway pressure. Tidal volume was twice as high with the 1.62 mm injector, as compared to the 1.06 mm injector, although resistances are 6 times higher with the smaller injector. The difference is related to the higher entrainment, which is observed when jet flow velocity increases, as is the case when the injector cannula is smaller. The experiments confirmed that HFJV follows the physical principles of jet mixing and entrainment.
Animals↗
High frequency jet ventilation in experimental airway disruption.
Anecdotal observations suggest that high frequency jet ventilation (HFJV) is beneficial in major airway disruption. Quantitative evaluation is, however, unavailable. In 12 healthy mongrel dogs, a tracheal window of increasing size, from 0.5 x 1 cm to 1.5 x 2 cm, was opened. Dogs were supported on volume-cycled ventilation (VCV) and on HFJV, using injector cannulas of 1.06 and 1.62 mm internal diameter. The tracheal window was then closed and an upper lobectomy performed, followed by total pneumonectomy. Arterial blood gases were obtained after 10 min in each experimental condition. VCV could maintain life-supporting blood gases only with the tracheal window of 0.5 x 1 cm. HFJV, delivered with a 1.06-mm injector cannula, was adequate with a tracheal window of 1 x 1 cm, or after a lobectomy. In all experimental conditions, HFJV delivered with a 1.62-mm injector effectively maintained alveolar ventilation and arterial oxygenation. Gas transport on HFJV is based, in part, on the principles of jet mixing and entrainment; increasingly large tidal volumes can be delivered under conditions of low and constant pressure. Air leaks through pathological openings remain constant even when tidal volume is increased, so that alveolar ventilation can be adequately maintained.
Airway Obstruction↗
Mechanisms of insulin resistance in aging.
We have studied 17 elderly and 27 non-elderly, nonobese subjects (mean age 69+/-1 and 37+/-2 yr, respectively) to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a 75-g oral glucose tolerance test, suggesting an insulin resistant state. Peripheral insulin sensitivity was assessed in both groups using the euglycemic glucose clamp technique during an insulin infusion rate of 40 mU/m(2) per min. Similar steady-state serum insulin levels led to a peripheral glucose disposal rate of 151+/-17 mg/m(2) per min in the elderly compared with a value of 247+/-12 mg/m(2) per min in the nonelderly, thus documenting the presence of insulin resistance in the elderly subjects. Insulin binding to isolated adipocytes and monocytes was similar in the elderly and nonelderly groups (2.34+/-0.33 vs. 2.62+/-0.24% and 5.04+/-1.10 vs. 5.12+/-1.07%), respectively. Thus, insulin resistance in the presence of normal insulin binding suggests the presence of a postreceptor defect in insulin action. This was confirmed by performing additional euglycemic clamp studies using infusion rates of 15 and 1,200 mU/m(2) per min to assess the contours of the dose-response relationship. These studies revealed a 39 and 25% decrease in the glucose disposal rate in the elderly subjects, respectively. The results confirm the presence of a postreceptor defect as well as a rightward shift in the dose-response curve. Insulin's ability to suppress hepatic glucose output was less in the elderly subjects during the 15 mU/m(2) per min insulin infusion (77+/-5 vs. 89+/-4% suppression), but hepatic glucose output was fully and equally suppressed in both groups during the 40 and 1,200 mU/m(2) per min infusion. Finally, a significant inverse relationship was observed between the degree of glucose intolerance in the individual elderly subjects, as reflected by the 2-h serum glucose level during the oral glucose tolerance test, and the degree of peripheral insulin resistance as assessed by the glucose disposal rate during the 40 mU/m(2) per min insulin infusion (r = 0.59, P < 0.01).We conclude that carbohydrate intolerance develops as part of the aging process. This carbohydrate intolerance appears to be the consequence of peripheral insulin resistance caused by a postreceptor defect in target tissue insulin action, which causes both a decrease in the maximal rate of peripheral glucose disposal and a rightward shift in the insulin action dose-response curve. In elderly subjects, the severity of the abnormality in carbohydrate tolerance is directly correlated to the degree of peripheral insulin resistance.
Adipose Tissue↗
Hepatic amoebic abscess communicating with the biliary tree.
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Biliary Fistula↗
Generation time of leukaemic blast progenitor cells.
Previous studies have indicated that the generation time of human leukaemic cells is longer than that of normal haematopoietic cells. We have employed a modification of the thymidine (TdR)-suicide technique to measure directly the generation time of leukaemic progenitor cells capable of colony formation. The results obtained with two human leukaemic cell lines (KG-1 and HL-60) and with blast progenitor cells from two patients with acute myelogenous leukaemia indicate generation times ranging from 9 X 0-22 X 0 hr and S-phase durations ranging from 5 X 5-8 X 0 hr. Using the same technique, the generation time of normal bone marrow CFU-c was determined to be 9-11 hr. These findings suggest that the proliferation rate of human leukaemic blast progenitor cells is similar to that of normal haematopoietic stem cells.
Adolescent↗
An enzyme-linked immunosorbent assay (ELISA) for the detection of monoclonal antibodies to cell surface antigens on viable cells.
A rapid and inexpensive ELISA method is described which is suitable for the large scale screening of monoclonal antibodies to cell surface antigens. The use of acrylic plates and viable cells eliminates background and false positive reactions, and avoids modification of surface antigens caused by fixation. This facilitates easy and rapid detection of positives by visual inspection of the plates. The specificity and sensitivity of the methods is comparable to indirect immunofluorescence or radioimmunoassay. The advantages of this ELISA system when compared to these methods and to previously described ELISA systems utilizing fixed cells are discussed.
Animals↗
Antiarrhythmic efficacy of amiodarone in recurrent ventricular tachycardia evaluated by multiple electrophysiological and ambulatory ECG recordings.
Thirty-three patients with recurrent drug-refractory ventricular tachycardia were treated with oral amiodarone during an average period of 6.1 months. In-hospital monitoring for two weeks or more, electrophysiological tests and ambulatory ECG were used to evaluate the results. Twenty patients are still using the drug with complete control of the arrhythmia. Eleven have failed the drug, ten due to recurrence of documented ventricular tachycardia. Only three patients failed after the first month of therapy. Two patients died, one suddenly. The drug was discontinued in a further two patients due to side-effects. Other side-effects were tolerable or manageable by dose adjustments alone. Five patients showed evidence of inadequate arrhythmia control between days 15 and 32 of therapy but subsequently responded to the drug for 4-9 months, giving further support to the concept that in some patients at least 30 days of therapy is necessary for the full effect of the drug to appear. In 16 of the 20 patients tested by arrhythmia induction study while on the drug, ventricular tachycardia could still be induced. Seven (44%) of these eventually failed the drug. Arrhythmia recurred in one of those four in whom tachycardia could not be induced. Amiodarone is a valuable drug in the management of recurrent ventricular tachycardia, refractory to other antiarrhythmic drugs.
Adult↗