PubMed Health⌕ Search

Biomedical subjects

S Howell

Publications and source records attributed to S Howell.

At least 109 records · Page 6Linked to original sources
PubMed1987

Use of nude mouse xenografts as preclinical drug screens: in vivo activity of established chemotherapeutic agents against melanoma and ovarian carcinoma xenografts.

To evaluate the utility of nude mouse xenografts as preclinical drug screens, the activity of ten established chemotherapeutic agents was evaluated against seven melanoma and three ovarian carcinoma xenografts. Xenografts were established using primary explants from patients who had not received chemotherapy and serially passaged as sc tumors in nude mice. In vivo drug activities for dactinomycin, carmustine, vinblastine, melphalan, amsacrine, cisplatin, bleomycin, mitomycin, doxorubicin, and etoposide were evaluated by 4 weekly ip injections of 10% less than LD10 doses. Plots of relative tumor growth versus time were nearly log-linear. Analysis of in vivo activity was performed using percent control growth (treated/control tumor volume) and by calculation of a novel growth delay index obtained by fitting growth curves to a quadratic regression model. Both modes of data analysis identified alkylating agents (melphalan, carmustine, and mitomycin) as the most active drugs against human melanomas. Melphalan, mitomycin, and cisplatin showed the greatest activity against ovarian xenografts. However, complete tumor regressions were noted only with melphalan, mitomycin, and cisplatin against a single ovarian tumor xenograft. Correlation analysis suggested xenograft tumor growth rate was an important determinant of drug response. These results suggest that preclinical, new-drug screening with melanoma xenografts would identify drugs such as alkylating agents as active, and may not provide an advantage over murine leukemia screens. However, screening with ovarian xenografts may more closely reflect clinical drug activity. Criteria for detecting active drugs in such systems are discussed.

Animals↗
PubMed1986

The preoperative and postoperative investigation of TSH and prolactin release in the management of patients with hyperprolactinaemia due to prolactinomas and nonfunctional pituitary tumours: relationship to adenoma size at surgery.

We report here our results of the pre- and post-operative assessment of prolactin and TSH status in 41 hyperprolactinaemic patients who underwent pituitary surgery over a 5 year period. Preoperatively in patients with prolactinomas (n = 33) the TSH response to domperidone decreased with increasing adenoma size. When the data are expressed on a group mean basis the exaggerated TSH response to domperidone in preoperative prolactinoma patients was reduced significantly in patients rendered normoprolactinaemic by surgery but persisted in those who remained hyperprolactinaemic. Similarly the reduced preoperative PRL responses to domperidone and TRH were significantly increased by successful surgery. In contrast patients with stalk-compression hyperprolactinaemia (n = 6) due to larger lesions which were not prolactinomas all showed reduced or absent TSH responses to domperidone. The PRL responses to domperidone and TRH were reduced or absent both in patients with prolactinomas and in those with stalk-compression hyperprolactinaemia. All patients with stalk-compression hyperprolactinaemia showed a delayed pattern of TSH response to TRH with 60 min values being greater than 20 min ones. In contrast a normal pattern of TSH response to TRH was observed in all patients with hyperprolactinaemia due to prolactinomas. Postoperatively TSH and PRL responses were largely unchanged in patients with stalk-compression hyperprolactinaemia regardless of whether normoprolactinaemia was restored by surgery. In conclusion a reduced or absent PRL response to TRH or domperidone is not diagnostic of the presence of a prolactinoma since it occurs in hyperprolactinaemic patients with prolactinomas or stalk-compression. In contrast, the TSH response to acute dopamine antagonism is exaggerated in most patients with small prolactinomas but not in those with stalk-compression hyperprolactinaemia and we have found this to be helpful diagnostically since the presence of an exaggerated TSH response to dopamine antagonism is evidence against the presence of stalk-compression hyperprolactinaemia. The observation of a delayed TSH response to TRH in a hyperprolactinaemic patient should alert the clinician to the possibility of stalk-compression hyperprolactinaemia due to a large lesion which may not be a prolactinoma.

Adenoma↗
PubMed1986

Effects of aminophylline and salbutamol on diaphragmatic force during compensated metabolic acidosis.

We investigated the effects of aminophylline and salbutamol on tetanic force generated by the diaphragm during compensated metabolic acidosis in dogs. Anesthetized, mechanically ventilated animals were prepared with an open thorax. A cast was placed around the abdomen to maintain length and geometry of the diaphragm during contractions. A thin-walled latex balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi). Pdi served as the index of diaphragmatic force of contraction. We measured Pdi during supramaximal phrenic stimulation at low and high frequencies and also during spontaneous inspiratory efforts for a constant diaphragmatic EMG activity. Compensated metabolic acidosis significantly reduced Pdi at all stimulation frequencies (p less than 0.05). The mean percent decrease at low frequencies was greater than at high (p less than 0.05). Pdi was decreased during spontaneous contractions as well (p less than 0.05). Administration of aminophylline significantly improved Pdi at all frequencies of phrenic stimulation (p less than 0.05) and during spontaneous inspiratory efforts (p less than 0.05). Infusion of salbutamol did not have a significant effect on Pdi at any frequency of stimulation but did produce a small potentiating effect during spontaneous contractions (p less than 0.05). We also recorded and analyzed the Pdi response to a single supramaximal impulse to the phrenic nerve, referred to as a twitch, to gain insight into possible cellular mechanisms underlying alterations in tetanic force of contraction. Compensated metabolic acidosis led to a significant reduction in peak twitch tension (PTT) (p less than 0.05) and half relaxation time (1/2RT) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1985

Management of selected patients with hyperprolactinaemia by partial hypophysectomy.

Results are reported in 35 patients with prolactinomas who underwent pituitary surgery within the past five years. After surgery prolactin concentrations became normal in 26 patients and symptoms were alleviated, and nine normal pregnancies were achieved in seven women, including all those who had complained of infertility. Normal prolactin concentrations were restored in 16 of 17 patients with tumours 5-19 mm in diameter but in only six of 11 with tumours less than or equal to 4 mm and four of seven with tumours greater than or equal to 20 mm. Normal prolactin concentrations were restored in all those with preoperative concentrations below 1000 mU/l but in none of those with concentrations above 10 000 mU/l. Although not all of the patients were followed up for five years, hyperprolactinaemia did not recur in any patient whose prolactin concentration had returned to normal six weeks after surgery. This included 16 patients with macroprolactinomas (greater than 10 mm in diameter), who were followed up for from two to five years. These data contrast strikingly with those reported by others at similar stages of follow up and show clearly that partial hypophysectomy offers an acceptable alternative treatment for selected patients with prolactinomas.

Adenoma↗
PubMed1985

Effects of neostigmine and salbutamol on diaphragmatic fatigue.

We studied the effects of neostigmine and salbutamol on the force generated by the fatigued diaphragm in anesthetized dogs. Mechanically ventilated animals were prepared with an open thorax. A thin-walled latex balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi) and a rigid cast was fixed around the abdomen to limit changes in diaphragmatic length and geometry during contractions. Pdi was the index of force generated by the diaphragm. We measured Pdi during supramaximal phrenic stimulation at different frequencies and during spontaneous inspiratory efforts. The diaphragm was fatigued by repeated phrenic stimulation. Fatigue significantly reduced Pdi at all frequencies of stimulation and during spontaneous contractions (P less than 0.05). The reduction in Pdi was associated with a decrease in peak twitch tension (PTT) to 50% of control (P less than 0.05). Infusion of neostigmine restored PTT to values equivalent with or greater than control (P less than 0.05) and improved Pdi at low stimulation frequencies (P less than 0.05) and during spontaneous inspiratory efforts (P less than 0.05). Infusion of salbutamol had no effect on PTT, but did significantly shortened twitch half relaxation time (P less than 0.05). Salbutamol also had no effect on Pdi during stimulated and spontaneous contractions. We conclude that neostigmine improves force generated by the fatigued diaphragm by increasing twitch amplitude while salbutamol did not have a positive inotropic effect.

Albuterol↗
PubMed1985

Arterial CO2 partial pressure affects diaphragmatic function.

The purpose of this study was to examine in an in vivo preparation acute variations of PCO2 on diaphragmatic contractility. Plaster casts were snugly fit around the abdomen of six open-chested dogs, moving the abdominal contents rostrally. Diaphragmatic contractions against this very fixed load in response to phrenic nerve stimulation (supramaximal voltage at 1, 20, 50, and 80 Hz) or during spontaneous inspiratory efforts were virtually isometric (quasi-isometric). Transdiaphragmatic pressure (Pdi) measured by an abdominal balloon was used as an index of diaphragmatic contractility. Arterial PCO2 (PaCO2) was reduced by hyperventilation and raised by increasing PICO2. Pdi values in response to stimulation at 1, 20, 50, and 80 Hz in ranges I (PaCO2 = 0-19 Torr) and II (PaCO2 = 20-34 Torr) did not differ statistically from the control Pdi values (range III; PaCO2 = 35-45 Torr). In range IV (PaCO2 = 46-70 Torr) Pdi values for stimulations of 20, 50, and 80 Hz were significantly lower than control. In range V (PaCO2 = 71-90 Torr), VI (PaCO2 = 91-101 Torr), and VII (PaCO2 greater than or equal to 102 Torr) Pdi values were significantly less than those in range IV at all frequencies of stimulation. In the four dogs measured during spontaneous inspiratory efforts the integrated diaphragmatic electromyogram (Edi) was correlated with the Pdi. As PaCO2 rose (range III to VII), the Pdi values observed at 25, 50, 75, 100% of the maximum Edi (of range III) were significantly lower than the Pdi value of range III.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkalosis, Respiratory↗
PubMed1985

Effects of uncompensated and compensated metabolic acidosis on canine diaphragm.

We investigated the effects of metabolic acidosis and compensated metabolic acidosis on force of contraction of the diaphragm in anesthetized dogs. Mechanically ventilated animals were prepared with an open thorax. A balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi), and a plaster cast was placed around the abdomen to maintain length and geometry of the diaphragm. The force of contraction was evaluated by measuring Pdi during supramaximal phrenic stimulation at different frequencies and also during spontaneous inspiratory efforts. In 13 dogs with an arterial pH (pHa) of 7.38 and arterial PCO2 (PaCO2) of 36.5 Torr, metabolic acidosis was produced by infusion of HCl until pHa equaled 6.98 and PaCO2 equaled 36.4 Torr. Pdi at all frequencies greater than 10 Hz was significantly reduced (P less than 0.05). The dogs were then hyperventilated until pHa was 7.34 and PaCO2 was 12.8 Torr. Pdi was significantly reduced again at all frequencies (P less than 0.05) except 5 Hz. The percent reduction in Pdi by compensated acidosis was significantly greater at low-frequency stimulation than at high (P less than 0.05). Similar qualitative results were observed during spontaneous inspiratory efforts where Pdi was compared at constant magnitudes of diaphragmatic electromyograms. Twitch characteristics revealed that metabolic acidosis led to a significant shortening of twitch relaxation time (P less than 0.05), and compensated metabolic acidosis added to this effect a significant decrease in twitch amplitude (P less than 0.05).

Acidosis↗
PubMed1985

Effects of aminophylline, isoproterenol, and neostigmine on hypercapnic depression of diaphragmatic contractility.

We investigated the effects of aminophylline, isoproterenol, and neostigmine on decreased diaphragmatic contractility induced by hypercapnia. With the thorax open, the animal receiving mechanical ventilation, and a plaster cast around the abdomen, constant length and geometry of the diaphragm were maintained. Contractility was assessed by analysis of transdiaphragmatic pressure (Pdi) generated during supramaximal phrenic stimulation at different frequencies. Bilateral phrenectomy was performed to prevent spontaneous diaphragm movement. Hypercapnia (PaCO2, 85 mmHg) reduced Pdi by 10% at low and high frequencies of stimulation. Subsequently, aminophylline (20 mg/kg) restored Pdi to the control value at every frequency of stimulation (p less than 0.05), whereas neostigmine (0.25 and 1.0 mg) restored Pdi at low frequencies only (p less than 0.05). Isoproterenol did not improve Pdi at any frequency. Analysis of twitch characteristics revealed that hypercapnia reduced peak twitch amplitude by 17%, this being the underlying cause of the decrease in Pdi. Low and high doses of all 3 drugs significantly reversed this effect by improving peak twitch tension to values equal with or greater than control values (p less than 0.05). In addition, aminophylline (40 mg/kg) and neostigmine (0.25 and 1.0 mg) significantly increased time to peak tension of the twitch (p less than 0.05) and isoproterenol (5 and 20 micrograms/min) significantly decreased twitch half relaxation time (p less than 0.05). We conclude that aminophylline and neostigmine improve diaphragmatic contractility during hypercapnia by virtue of their potentiating effect on twitch amplitude, whereas isoproterenol does not increase contractility because the process underlying the decrease in twitch duration masks the effect of an improved twitch amplitude.

Aminophylline↗
PubMed1985

Clonal origin of mouse liver cell tumors.

The clonal origin of tumors was studied in a large series of liver cell tumors in mice. Tumors were induced with phenobarbitone alone or following N-nitroso-diethylamine administration in female mice heterozygous for the sparse-fur strain. In this strain, a histochemical technique can be used in heterozygotes to differentiate clearly between liver cells expressing the histochemically positive normal or the histochemically negative abnormal form of the X-linked enzyme ornithine carbamoyl transferase. Three hundred twenty-seven liver tumors in heterozygous female Spf mice were studied: 157 (48%) were uniformly negative, and 160 (49%) were positive (some with partial enzyme loss). One hundred fifty-four liver tumors in normal mice were studied; all were positive, with a frequency of partial enzyme loss similar to that seen in the heterozygotes. Ten (3%) of the tumors in the heterozygotes contained some separate groups of positive and negative cells, but no tumor was made up exclusively of such groups. Even the smallest recognizable tumors were made up of single-phenotype cells, which suggested that a polyclonal origin followed at a later stage by clonal selection was unlikely. It is concluded that at least 97% of the tumors were of single-cell origin, and that convincing evidence of a polyclonal origin was completely lacking. It is also concluded that the histochemical demonstration of an X-linked enzyme in tumors induced in female animals heterozygous for an abnormal form of that enzyme provides an extremely useful technique for the study of the origins of neoplasia.

Animals↗
PubMed1984

High-performance liquid chromatographic measurement of exogenous thiosulfate in urine and plasma.

A simple technique using reverse-phase ion-pair liquid chromatography for measurement of exogenous thiosulfate is described. Accurate measurement of thiosulfate in plasma and urine was permitted by precolumn derivatization with monobromobimane, a substance that readily yields fluorescent compounds upon reaction with a variety of biologically important nucleophiles including glutathione, cysteine, and sulfite. Using an injection volume of 50 microliters, as little as 0.16 nmol of thiosulfate was reliably measured. The interassay precision of the method was reflected by a coefficient of variation of 7.7% while the coefficient of variation for interassay analysis was 2.6%. Recovery of thiosulfate from plasma was 96.9 +/- 3.2% and greater than 98% from urine. The simplicity, sensitivity, and precision of the method make it ideal for the study of thiosulfate and other important nucleophiles in body fluids.

Chromatography, High Pressure Liquid↗
PubMed1984

Isoproterenol and aminophylline improve contractility of fatigued canine diaphragm.

We investigated the effects of aminophylline and isoproterenol on diaphragmatic fatigue produced by phrenic stimulation in dogs. With a cast around the abdomen, the diaphragm contracted quasi-isometrically while the thorax was open and the animal was ventilated. We assessed contractility by measuring transdiaphragmatic pressure during supramaximal stimulation of the phrenic nerves at different frequencies and also during spontaneous inspiratory efforts. At doses of 20, 40, and 80 mg/kg, aminophylline significantly improved contractility (p less than 0.01) in a dose-dependent manner during low, but not during high frequency stimulation. The maximal improvement (24%) was observed with 80 mg/kg. With intravenously administered doses of 5 and 10 micrograms/min of isoproterenol, contractility was also significantly enhanced (p less than 0.05) during low frequency stimulation. Maximal improvement (12%) occurred with 5 micrograms/min. Similar results were obtained when spontaneous inspiratory efforts were recorded and transdiaphragmatic pressure was compared at a given diaphragmatic electrical activity before and after administration of each drug. Maximal improvement was 23% with aminophylline and 11% with isoproterenol. Analysis of twitch characteristics revealed that peak tension was increased significantly (p less than 0.025) by both drugs. In addition, isoproterenol caused a marked decrease in the time course of relaxation. We conclude that aminophylline and isoproterenol improve contractility of the fatigued diaphragm by increasing the amplitude of the underlying small twitch. Furthermore, the smaller effect of isoproterenol may be the result of reduced relaxation time of the twitch.

Aminophylline↗
PubMed1983

Studies of X-chromosome inactivation with an improved histochemical technique for ornithine carbamoyltransferase.

Studies of X-linked enzymes provide an approach to the study of tumour and normal cellular development. We have assessed the technique for the histochemical demonstration of one such enzyme, ornithine carbamoyltransferase (EC 2.1.3.3). Various stages in the Mizutani technique for ornithine carbamoyltransferase were re-examined, and the resulting improved technique applied to normal mice and to mice of the sparse fur strain (Spf) known to have an abnormal form of ornithine carbamoyltransferase inherited as an X-linked characteristic. Positive enzyme activity was present in all hepatocytes from normal mice, the strongest reaction being present in the periportal area with a gradual reduction of activity towards the centrilobular region. No activity was demonstrable in hepatocytes from hemizygous male Spf mice. In heterozygous female Spf mice, there was a clear-cut separation of ornithine carbamoyl-transferase-positive and -negative cells. These were present in very variable proportions in different liver lobes and different animals. Preliminary studies were also carried out using a high pH reaction mixture to detect the abnormal enzyme. These studies demonstrate conclusively the X-linkage of ornithine carbamoyltransferase in mice, showing the mosaic pattern of distribution predicted by the Lyon hypothesis. They show that the Spf strain of mice can be used for studies of both development and tumorigenesis in the liver, and that histochemical study of an animal strain with an X-linked enzyme abnormality provides a powerful investigative tool.

Animals↗
PubMed1983

Inhibition of decidual prolactin release by a decidual peptide.

Conditioned media from cultures of human decidual explants and aqueous extracts of human decidual tissue contain a factor that causes a reversible dose-dependent inhibition of decidual PRL release in vitro. Decidual explants incubated for 30 min in medium containing 50, 100, and 250 micrograms/ml of a dialyzed and lyophilized preparation of decidual conditioned medium (DCM) released 32.4 +/- 2.7%, 70.9 +/- 4.5%, and 100.0%, respectively, less PRL than control explants. DCM, however, had no measurable effect on the synthesis of decidual PRL or the synthesis and release of trichloroacetic acid-precipitable 35S-labeled proteins. The effect was of short duration and completely reversible. The inhibition of decidual PRL release was not due to PRL, since 500 micrograms/ml human pituitary PRL (a PRL concentration 40 times that in the minimal effective dose of DCM) added to the incubation medium of decidual explants had no effect on the synthesis or release of decidual PRL or trichloroacetic acid-precipitable 35S-labeled decidual proteins. The inhibitory activity eluted from Sephadex G-200 with an apparent molecular weight of 38,000-45,000 daltons, was heat labile, was destroyed by treatment with trypsin, and was unaffected by extraction with acetone-ethanol. These results strongly suggest that the release of decidual PRL is under local control, regulated in part by a factor(s) other than PRL that is released by the decidua.

Animals↗
PubMed1982

Low-frequency fatigue in isolated skeletal muscles and the effects of methylxanthines.

1. A form of skeletal muscle fatigue was examined with isolated animal and human muscle preparations. The possibility that methylxanthines could overcome this was investigated. 2. Prolonged contractile activity resulted in a long-lasting impairment of force generation at low frequencies of stimulation at times when the force at higher frequencies had substantially recovered. This was seen with both fast-twitch and slow-twitch animal muscles and with samples of isolated human muscle. 3. The decrease in low-frequency force was due to a decrease in twitch amplitude, suggesting damage to the processes involved in excitation--contraction coupling. 4. Caffeine and theophylline at concentrations of 1 mmol/l rapidly and completely reversed the effects of this form of fatigue in both animal and human muscle preparations. 5. Agents that potentiate muscle force production could be an effective means of counteracting the effects of an important form of skeletal muscle fatigue, but a clinically useful compound would need to be more potent than the methylxanthines currently in use.

Animals↗
PubMed1982

The effect of aminophylline on inspiratory muscle contractility.

The effects of aminophylline on diaphragmatic muscle contractility were studied in 8 dogs. The relationships of the electromyographic signal from the diaphragm and the pressures developed by this muscle were compared before and after the administration of aminophylline in doses of 6, 20, 40, 80, and 120 mg/kg. Measurements were made during occluded inspiratory efforts at functional residual capacity. In a second group of 4 dogs the relationships were compared while the rib cage expansion was limited by a plaster cast. Finally, in a third group of 4 dogs after the diaphragm had been paralyzed by phrenicotomy, the relationship of pleural pressure to the electromyographic signal of the intercostal muscles was assessed before and after administration of aminophylline. In all cases, aminophylline progressively shifted the electromyographic pressure relationship up and to the left. This effect became significant (p less than 0.01) at a dose of 20 mg/kg, reached a peak at 80 mg/kg, and then declined at a dose of 120 mg/kg. The amount producing blood concentrations closest to the human therapeutic blood concentration was 20 mg/kg. The peak increase in pressure compared with the control values were 58% in the first group, 27% in the second group, and 52% in the third group (p less than 0.01). We conclude that aminophylline increases respiratory muscle contractility in a dose-related manner. This may have important therapeutic and pathophysiologic implications.

Aminophylline↗