Biomedical subjects

T J Hall

Publications and source records attributed to T J Hall.

At least 37 records · Page 2Linked to original sources

PubMed1995

Taxol inhibits osteoclastic bone resorption.

We have examined the effect of the anti-tumor compound taxol, on osteoclastic bone resorption. In the bone slice assay, taxol (0.1-0.001 microM) dose-dependently inhibited bone resorption with an IC50 of 0.08 microM. Osteoclast survival on bone slices was unaffected by 0.01-1 microM taxol, but 10 microM was cytotoxic. Taxol (1 microM) also inhibited osteoclast spreading (45%) on fibronectin-coated slides. The antiproliferative effects of taxol are due to its unique ability to stabilize microtubules. Primary osteoclasts are nonproliferating end cells, so taxol probably inhibits bone resorption by interfering with other microtubule-dependent functions such as cell polarization, motility or vesicle exocytosis. Since these inhibitory effects on osteoclasts in vitro are seen with therapeutically relevant concentrations, taxol therapy may have beneficial side-effects e.g. inhibition of hypercalcemia and bone metastases.

Animals↗

PubMed1995

Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, inhibits osteoclastic bone resorption in vitro.

Phosphatidylinositol 3-kinase (Pl3-k) is involved in cellular signaling via the phosphoinositol pathway leading to mitogenesis in response to growth factors in proliferating cells, as well as cytoskeletal changes and secretory responses in terminally differentiated cells. The fungal metabolite, wortmannin, is a potent and selective inhibitor of Pl3-k at nanomolar concentrations. We show that wortmannin dose-dependently (0.001-1 microM) inhibits bone resorption by isolated rat osteoclasts in the bone slice pit assay with an IC50 of approximately 5 nM. Wortmannin was not cytotoxic since osteoclast morphology and survival on bone slices was unaffected by concentrations up to 1 microM. Since primary osteoclasts are terminally differentiated cells and osteoclast cytoplasmic spreading and morphology was unaffected by wortmannin, we suggest that Pl3-k signaling is involved in vesicle exocytosis and ruffled border membrane formation that are required for osteoclastic bone resorption to take place.

Androstadienes↗

PubMed1995

Effects of endothelin-1 on renal microvasculature measured using quantitative ultrasound.

Renal vascular resistance is an important feature of kidney function and disease. To maintain adequate blood flow, renal vascular resistance varies in response to changes in systemic pressure. Vascular resistance is largely determined by arteriolar diameter, which is regulated by local and systemic factors. We used quantitative ultrasound techniques to follow renal vascular changes in anesthetized dogs during local intraarterial infusion of a potent vasoconstrictor, endothelin-1 (ET-1). Average arteriolar diameters were estimated by analyzing echo-signal spectra (5-15 MHz) obtained from renal cortex in vivo before, during, and after ET-1 infusion. At calculated arterial concentrations of 0.01 nM, 0.1 nM, and 1.0 nM, ET-1 reduced the average arteriolar diameter of 38 +/- 2 microns by 2%, 63%, and 91%, respectively, without producing a significant change in systemic blood pressure. Changes in scatterer size were consistent with the observed changes in renal hemodynamics detected using Doppler techniques. In addition, acoustic attenuation was found to increase with ET-1 concentration. These data suggest that quantitative ultrasound methods are sensitive to changes in renal arteriolar diameter, and may be a new noninvasive method for continuously monitoring changes in vascular resistance.

Animals↗

PubMed1995

Laparoscopic plication of perforated ulcer: results of a selective approach.

We reviewed our experience with laparoscopy for perforated ulcer from April 1, 1992, to March 31, 1993. All patients admitted to the gastrointestinal surgery service with a diagnosis of perforated viscus had evaluation for possible laparoscopic Graham plication (LGP). Of eight patients considered, five had successful diagnostic laparoscopy. Two patients with anterior duodenal ulcers had LGP. Operative times were 85 and 106 minutes; postoperative stays were 5 and 8 days. Three procedures were converted to formal laparotomy when laparoscopy revealed gastric or prepyloric ulcers. Three patients had immediate laparotomy because of known disease process. Two additional patients were treated with open plication by other surgeons; their operative times were 98 and 110 minutes and postoperative stays, 6 and 4 days. Hospital charges averaged $6,573 for the two laparoscopic plications, $7,511 for the four plications not done laparoscopically, and $20,995 for the two cases converted to open plication. A selective approach allowed two Graham patch closures to be done laparoscopically without complications, at a cost comparable to that of open surgery.

Adult↗

PubMed1995

Contrast-detail analysis of image degradation due to lossy compression.

A contrast-detail (CD) experiment was performed to study the effect of lossy compression on computed radiographic (CR) images. Digital CR images of a phantom were compressed by quantizing the full-frame discrete cosine transform and Huffman encoding the result. Since low-contrast detectability is directly linked to an important radiological task, namely, the detection of noncalcified pulmonary nodules in adult chest radiographs, the goal of the study was to quantify any loss in low-contrast detectability due to compression. Compression ratios varied significantly among compressed images, despite the use of fixed compression parameters; detectability could be specified by a single parameter of a CD curve; there was no significant reduction in detectability for an average compression ratio of 11:1; and, there was a statistically significant degradation in detectability for an average compression ratio of 125:1.

Humans↗

PubMed1995

Ultrasound contrast-detail analysis: a comparison of low-contrast detectability among scanhead designs.

Contrast-detail (CD) analysis was used to compare the low-contrast detection capabilities of expert observers using different array-type scanhead technologies. Five expert observers viewed five different contrast targets to obtain CD curves for each scanhead. Differences in CD curves are interpreted in terms of the image contrast, resolution, and noise. It was found that differences in low-contrast detectability were due to differences in beam properties. Clinical images obtained during patient examinations are used to show how some clinically relevant tasks are distributed in their contrast and size.

Biometry↗

PubMed1995

Measurements of ultrasonic backscatter coefficients in human liver and kidney in vivo.

Ultrasonic backscatter coefficients, in the range of 2.0-4.0 MHz, were measured in normal human livers and kidneys in vivo. In liver, data were acquired and analyzed from 15 normal volunteers and 19 patients with hepatitis. No significant difference between normal and chronic hepatitis was found. The power-law fit to the backscatter coefficient in normal liver as a function of frequency was eta(f) = 4.5 x 10(-5) f1.6 cm-1 Str-1. This is comparable to that measured by other investigators in in vitro preparations of human and animal liver and to that measured by two other teams of investigators in in vivo human liver. In kidney, data were acquired from 11 normal volunteers. The power-law fit to the backscatter coefficient in normal kidney was eta (f) = 2.3 x 10(-5) f2.1 cm-1 Str-1. This is in the range of that measured by other investigators in in vitro preparations of human and animal kidney. In order to assess the system dependence of in vivo abdominal organ backscatter coefficients, measurements were performed using two different ultrasonic data-acquisition systems. The two systems exhibited close agreement.

Chronic Disease↗

PubMed1995

Familial juvenile polyposis: patterns of recurrence and implications for surgical management.

BACKGROUND: Familial juvenile polyposis predisposes to the development of carcinoma of the colon. Optimum surgical management and recommended surveillance of affected individuals are still being defined. STUDY DESIGN: A retrospective review of experience with a kindred identified in 1988 was carried out. RESULTS: Of 34 living members, 15 have been investigated, and histologically typical juvenile polyps were found in 11. In each instance, polyps were most numerous in the right colon, with few polyps in the descending colon and none in the rectum. Eight patients have had subtotal colectomies with ileorectal anastomoses; the remaining patients were managed by polypectomy (with one recurrence after ten years). In addition to juvenile polyps, polyps with adenomatous or villous elements were identified in three patients. One of these patients had invasive adenocarcinoma in a large mixed polyp of the cecum. Two patients with polyps had coexisting carcinoma of the stomach. All patients have been followed up with periodic upper and lower gastrointestinal endoscopy. Polyps have recurred in the rectal remnants of three patients at a mean of 36 months after subtotal colectomy. Two patients have undergone conversion to total proctocolectomy with ileoanal anastomosis and J pouch; one patient was found to have juvenile polyps in the pouch 40 months after surgery. CONCLUSIONS: Despite the preponderance of right-sided polyps at initial diagnosis, the rapid recurrence of polyps after subtotal colectomy argues in favor of performing proctocolectomy with preservation of anal sphincter function (restorative proctocolectomy) at the time of initial surgery. Patients with a small number of polyps may choose instead to undergo periodic colonoscopy with colonoscopic polypectomy. An algorithm for surveillance and follow-up is proposed.

Adenocarcinoma↗

PubMed1995

Molecular oncology and the surgeon.

The last 20 years have witnessed a flood of new developments and discoveries in the fields of molecular biology and oncology. Dozens of human genes associated with cancer predisposition syndromes and the malignant and metastatic process have been identified and characterized. These findings have led to a greater understanding of this complex disease and inaugurated a new era of investigations seeking more effective diagnostic protocols and therapies. This review summarizes a few of the many salient discoveries and discusses the clinical implications for the surgeon.

Carcinogens↗

PubMed1994

Role of hsp70 in cytokine production.

Interleukin-1 and tumor necrosis factor-alpha are potent, multifunctional cytokine mediators of inflammation and immune responses that are produced primarily by activated monocytes and macrophages. Three published papers by different groups have shown that heat shock and chemical stress with heavy metal salts or sulfhydryl reagents, all of which induce the expression of heat shock protein 70 (hsp70), concomitantly inhibit the production of these cytokines in human monocytes and mouse macrophages activated by lipopolysaccharide. These papers are reviewed and discussed in some detail. Other studies suggest that various anti-inflammatory drugs, including acetylsalicyclic acid, auranofin and dexamethasone, can also facilitate HSP expression in macrophages. However, while these studies are interesting, it is clear that not a great deal of work has been done and/or published in this area. Since many pharmaceutical companies are developing cytokine synthesis inhibitors as potential anti-inflammatory drugs, one aim of this article is to emphasize that understanding the molecular mechanism(s) that lead to increased HSP expression and decreased cytokine biosynthesis may assist in achieving this goal.

Animals↗

PubMed1994

A reappraisal of the effect of extracellular calcium on osteoclastic bone resorption.

During bone resorption osteoclasts are exposed to high levels of extracellular calcium solubilized from bone mineral and it has been suggested that this may act as a physiological negative feedback to control the resorptive process. We have confirmed that calcium (1.5-20 mM) dose-dependently inhibits osteoclastic bone resorption when added at the start (t = 0 hr) of the 24 hr bone slice assay. When 20 mM calcium was added at t = 0, 1, 3 or 6 hr after osteoclast attachment to bone slices, resorption was inhibited by 100%, 100%, -10% and 6% respectively. In contrast, human calcitonin (1 ng/ml) inhibited bone resorption by 100%, 100%, 91% and 52% when added at t = 0, 1, 3 and 6 hr respectively. Osteoclasts were not seen on bone slices after 24 hr incubation when 20 mM calcium was added at t = 0 or 1 hr, but when calcium was added at t = 3 or 6 hr osteoclast numbers were similar to controls, indicating that 20 mM calcium is not toxic to osteoclasts. Human calcitonin did not significantly affect osteoclast numbers regardless of time of addition to the bone slice assay. The absence of osteoclasts on bone slices exposed to 20 mM calcium at early time points indicates that high levels of extracellular calcium prevent osteoclast adhesion to bone slices, and later addition of high Ca(e) to the assay does not inhibit ongoing osteoclastic bone resorption.

Animals↗

PubMed1994

Evidence that c-src is involved in the process of osteoclastic bone resorption.

Transgenic mice lacking a functional c-src gene have osteopetrosis, a bone disorder characterized by defective osteoclast function. We have investigated the effects of selective protein tyrosine kinase inhibitors that are known to inhibit c-src, on osteoclast activity in the bone slice assay. Geldanamycin, herbimycin A and monorden (0.001-10 microM) all dose-dependently inhibited bone resorption with IC50 values of 8, 70 and 86 nM, respectively. At concentrations of 0.001-1 microM, the compounds were not cytotoxic as judged by osteoclast morphology and survival on bone slices. In order to determine whether c-src plays a role in signal transduction associated with osteoclast activation prior to bone resorption commencing, or in the resorptive process itself, we performed kinetic experiments using human calcitonin as a positive control. Calcitonin inhibited all bone resorption subsequent to its addition at t = 0, 3 or 6 hr (100%, approximately 90% and approximately 50% inhibition, respectively), after the start of the 24 hr bone slice assay. Similar results were obtained with herbimycin A and geldanamycin (1 microM) added at t = 0, 3 or 6 hr, and with monorden (1 microM) added at t = 0 and 6 hr. These results indicate that c-src plays a crucial and continuous role in the process of osteoclastic bone resorption, most likely related to the translocation and/or fusion of exocytic vesicles to the ruffled border membrane.

Animals↗

PubMed1994

Cytotoxicity of vacuolar H(+)-ATPase inhibitors to UMR-106 rat osteoblasts: an effect on iron uptake into cells?

Treatment of rat osteoblastic UMR-106 cells with bafilomycin A1 rhamnoside or concanamycin A, which are potent and specific inhibitors of the vacuolar H(+)-ATPase (V-ATPase), caused a rapid rounding up of the cells (within 6 hr), inhibition of cell growth (IC50 = 3.3 nM and 0.5 nM, respectively, at 24 hr) and cell death at 54 hr. Since proliferating cells have an absolute requirement for iron and the V-ATPase plays a crucial role in iron uptake into cells via the transferrin cycle, the effect of the iron chelator, desferal, was tested on UMR-106 cells. A time-dependent cell rounding, suppression of cell growth followed by cell death very similar to that observed with the V-ATPase inhibitors was seen. Therefore, the in vitro and in vivo toxicity of V-ATPase inhibitors may be due, at least in part, to their preventing iron uptake into cells.

Animals↗

PubMed1994

Promethazine inhibits osteoclastic bone resorption in vitro.

Several studies have shown that promethazine can reduce age-related osteopenia in mice. Furthermore, prolonged treatment with promethazine (50 mg/day) increases bone mineral content in the lumbar spine in post-menopausal women with osteopenia. However, the mechanism of action of promethazine has not been elucidated. The present study shows that promethazine HCl (0.01-10 microM) dose-dependently inhibits bone resorption by isolated rat osteoclasts in the bone slice assay with an IC50 of approximately 1 microM. Since these concentrations are likely to be achieved in vivo, it is suggested that the beneficial effect of promethazine on osteopenia is at least partly due to a direct inhibitory effect on osteoclast activity.

Aging↗

PubMed1994

Hydrochlorothiazide inhibits osteoclastic bone resorption in vitro.

Long-term thiazide diuretic use is associated with higher bone mineral density and reduced hip fracture rates, which are attributed to increased serum calcium levels and decreased parathyroid activity that lead to decreased bone resorption. The present study shows that 1-100 microM hydrochlorothiazide (HCTZ) dose dependently inhibits bone resorption by isolated rat osteoclasts in the bone slice assay with an IC50 of approximately 20 microM. At these concentrations, HCTZ did not affect osteoclast survival on bone slices and had no effect on the proliferation of UMR-106 rat osteoblasts, indicating that the compound is not cytotoxic. However, such concentrations of HCTZ are unlikely to be achieved in man where therapeutic doses are usually 12.5-100 mg/day. That the in vitro effect of HCTZ on bone resorption may be due to inhibition of osteoclast carbonic anhydrase is discussed.

Animals↗

PubMed1994

The integration of laparoscopy into a surgical residency and implications for the training environment.

Although laparoscopic cholecystectomy is now an accepted part of resident training, the impact of operative laparoscopy (OL) upon the residency environment has not been examined in detail. We reviewed the first 3 years' experience with OL and the process by which it was introduced into our residency program. Data were obtained from our prospective computerized surgical laparoscopic registry as well as from a survey conducted midway in this experience. At that time, a questionnaire was sent to current residents in the program and residents who graduated after the inception of the OL program were interviewed by telephone. OL cases increased each year and comprised a progressively greater percentage of total cases. Residents performed over 97% of cases, with attending surgeons as first assistants. Initially, only senior-level residents participated as surgeons; however, after the first year we noted a significant tendency for cases to filter down the ranks. Junior-level residents have already participated in more laparoscopic than open cholecystectomies and expressed considerable concern about training in open procedures. Graduated residents without exception were able to obtain privileges to perform OL without additional training. They did not feel that resident education was compromised by the advent of laparoscopy. Both current and graduated residents considered didactic sessions including animal laboratories and simulators an important part of training.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effects of the cytokine synthesis inhibitor CGP 47969A on nitric oxide production by lipopolysaccharide-stimulated J774A.1 macrophages.

CGP 47969A is a novel inhibitor of the biosynthesis of interleukin-1 and other cytokines, being developed as an anti-arthritic. The effect of the compound on lipopolysaccharide (LPS; 1 microgram/ml) stimulated nitric oxide (NO) production by the mouse macrophage cell line, J774A.1, was examined in the present study. CGP 47969A inhibited NO production in a concentration-dependent fashion (0.1-10 microM; IC50 = 2 microM) in a 24 h assay. Dexamethasone (Dex), which inhibits cytokine and inducible nitric oxide synthase (iNOS) gene transcription, and N-methyl arginine (NMA), a substrate analogue inhibitor of NOS activity, also inhibited NO production in this assay system with IC50 values of approximately 5 nM and 100 microM, respectively. When iNOS expression was induced by LPS for 24 h, CGP 47969A and Dex did not inhibit NO production, whereas NMA retained activity (IC50 = 40 microM). In time course experiments, CGP 47969A (10 microM) or Dex (1 microM) were added to J774A.1 cultures at t = 0, 1, 3 or 6 h after LPS. Dex inhibited NO production by 86%, 57%, 35% and 15% at these time points, while CGP 47969A inhibited by 90%, 91%, 89% and 76%. Taken together, the results indicate that CGP 47969A inhibits NO production by an effect similar to the inhibitory effect on cytokine production rather than by inhibition of iNOS enzyme activity per se or iNOS gene expression. The ability of CGP 47969A to inhibit cytokine and NO production may explain its efficacy in animal models of arthritis.

Animals↗

PubMed1994

A pharmacological assessment of the mammalian osteoclast vacuolar H(+)-ATPase.

It is well established that osteoclasts use a vacuolar-type H(+)-ATPase (V-ATPase) for proton pumping during bone resorption and that specific V-ATPase inhibitors such as bafilomycin A1 abolish osteoclastic bone resorption in the bone slice assay. It has been reported that the V-ATPase in avian osteoclasts can be distinguished from the V-ATPase expressed in most other cells, by virtue of its inhibition by vanadate and nitrate ions. In order to determine whether the V-ATPase in mammalian osteoclasts can be similarly distinguished, we have investigated the effects of vanadate and nitrate on bone resorption by rat osteoclasts in the bone slice assay, in comparison with known V-ATPase inhibitors, bafilomycin A1 and WY 47766, that also inhibit the chicken osteoclast V-ATPase. The results indicate that, unlike the avian osteoclast V-ATPase, the mammalian osteoclast V-ATPase is pharmacologically similar to the V-ATPase in other cells.

Animals↗