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Adult↗
Biomedical subjects
M J Fox
Publications and source records attributed to M J Fox.
III. Instantaneous inhibition by compound 48/80 of tissue factor-initiated extrinsic coagulation is mediated by the downregulation of factor VII activation.
Our previous study has demonstrated a unique biological function of compound 48/80 (48/80) in the downregulation of monocytic tissue factor (TF)-initiated hypercoagulation in response to bacterial endotoxin (lipopolysaccharide, LPS) [A. J. Chu et al. (1999) Biochim. Biophys. Acta 1472, 386-395]. The inhibition was not due to the blockade of LPS cell signaling as evidenced by the unaffected LPS-induced TF synthesis. In the present study, we investigate the direct inhibitory action of 48/80 on the extrinsic coagulation cascade. TF-initiated coagulation was assayed by a single-stage clotting assay. Chromogenic assays dissected the extrinsic pathway to measure the activities of FVII, FX, and prothrombin by monitoring the hydrolyses of nitroaniline-conjugated substrates, identifying the inhibitory site(s). We report that 48/80 in vitro instantaneously inhibited rabbit brain thromboplastin (rbTF)-initiated coagulation in a dose-dependent manner. 48/80 preferentially inhibited FVII activation without any detectable effect on FVIIa, FXa, and thrombin activities. Neither FX activation nor prothrombin activation was affected. The significant inhibition on FVII activation was found to be noncompetitive with a fourfold reduction in the apparent Vmax of FVIIa formation from 7.1 to 1.7 nM/min, while the apparent Km (approximately 365 nM) remained unaffected. Western blotting analysis further confirmed that FVIIa formation derived from FVII was significantly diminished by 48/80, which was accompanied by blocked FVII binding to rbTF. In conclusion, 48/80 readily blocked FVII binding to rbTF, leading to diminished FVII activation and FVIIa formation. As a result, TF-initiated extrinsic coagulation was downregulated.
Animals↗
Extracellular Ca(2+) suppresses endotoxin-inducible tissue factor activation in monocytic THP-1 cells.
BACKGROUND: Monocytic tissue factor (TF), an initiator of extrinsic blood coagulation, is often activated under various inflammatory conditions including endotoxemia. This activation could be a contributing factor to the manifestation of disseminated intravascular coagulation following septic shock. HYPOTHESIS: We herein determine if extracellular Ca(2+) ([Ca(2+)](ex)) regulates bacterial endotoxin (LPS)-inducible monocytic TF activation. METHODS: We have employed a model monocytic cell line (THP-1) to explore the mode of action of [Ca(2+)](ex) on the modulation of LPS-induced TF activation. TF activity was measured by a single stage clotting assay, while TF expression as well as LPS recognition and its receptor expression were studied in immunofluorescent approaches. RESULTS: LPS-induced TF activation was inversely correlated to [Ca(2+)](ex). Upon exposure of THP-1 cells to LPS (1.5 microg ml(-1)) for 6 h in the Hanks' medium without CaCl(2), TF was activated by nearly 10-fold. TF activation appreciably decreased with the increasing [Ca(2+)](ex). No more than 3.5-fold TF activation was detected at 5 mM [Ca(2+)](ex). Consistent with the significantly lower degree of TF activation, LPS-induced TF expression at 5 mM [Ca(2+)](ex) was 60 per cent less than that without [Ca(2+)](ex). FACScan analysis showed that LPS recognition was significantly blocked at 5 mM [Ca(2+)](ex) which however had no effect on the expression of CD14 and CD11b, the proposed major LPS receptors. Moreover, LPS binding in vitro was significantly inhibited by 5 mM CaCl(2). CONCLUSION: Our results demonstrate that [Ca(2+)](ex) blocked LPS recognition without affecting its receptor expression on THP-1 monocytes. This insensitivity to LPS thereby resulted in the depressed inducible monocytic TF expression and activation.
Antigens, CD↗
I. Suppression by compound 48/80 of bacterial endotoxin-inducible monocytic tissue factor activity: direct blockade of factor VII binding to THP-1 monocytes.
Hypercoagulation with upregulated monocytic tissue factor (TF) activity often occurs under a variety of inflammatory conditions including endotoxemia. The antagonism to bacterial endotoxin (LPS) signaling often results in the depression in TF upregulation. We herein report that compound 48/80 (48/80) significantly depressed LPS-induced TF activity in human and cebus monkey peripheral blood monocytes. Employing a model monocyte-like cell line (THP-1), we explored the regulatory mechanism to identify the inhibitory site(s) of 48/80. We determine whether the inhibition results from the blockade of LPS signaling. 48/80 dose-dependently inhibited LPS-induced TF activity. Chase of LPS-challenged cells with 48/80 also significantly offset TF upregulation. In immunofluorescent approaches, FACScan analysis revealed that 48/80 had no effect on either LPS recognition or the expression of its receptors (CD14 and CD11b). Moreover, LPS-induced TF expression as well as synthesis remained unaffected in the presence of 48/80. Consistent with the independence of LPS action, 48/80 was also able to inhibit TF activity induced by A23187, ionomycin, or Quin-2 AM. Interestingly, 48/80 significantly decreased the FVII binding to either resting or LPS-challenged cells. In conclusion, our results elucidate that the inhibitory action of 48/80 was independent of LPS signaling including recognition, receptor expression, and the induced TF expression/ synthesis. However, 48/80 was able to directly block FVII binding to monocytic TF, thereby resulting in such antagonism to LPS-induced TF-initiated extrinsic coagulation.
Animals↗
Effect of refrigeration on shear bond strength of three dentin bonding systems.
PURPOSE: To determine whether use of dentin bonding agents directly from refrigerated storage would have adverse effects on their shear bond strength to dentin. MATERIALS AND METHODS: Resin-based composite cylinders were bonded to dentin on the ground occlusal surfaces of 60 extracted human molars using three different dentin bonding systems at 3.0 degrees C and 23.5 degrees C. The cylinders were then debonded using an Instron testing machine in compression mode at 0.5 mm/sec. The results were interpreted with t-test and Student-Newman-Keuls post hoc analysis. RESULTS: Scotchbond Multi-Purpose demonstrated significantly lower shear bond strengths at 23.5 degrees C (P < 0.05) than all other groups at both 3.0 degrees C and 23.5 degrees C. All-Bond 2 and Prime & Bond had higher shear bond strengths at refrigerated temperature, but the differences were insignificant in magnitude.
Bisphenol A-Glycidyl Methacrylate↗
Advancing wave-like epitheliopathy. Clinical features and treatment.
PURPOSE: The purpose of the study is to describe an entity referred to as advancing wave-like epitheliopathy and successful treatment of this keratopathy with 1% silver nitrate solution. METHODS: Eleven eyes of 7 patients were identified with advancing wave-like epitheliopathy. A thorough history and physical examination was performed on each patient, and attempts were made to identify the cause for the epitheliopathy. Six eyes with associated visual loss due to the epitheliopathy involving the visual axis were treated with 1% silver nitrate solution to the superior conjunctival limbus. RESULTS: Possible causes for the epitheliopathy included use of antiglaucomatous medications or contact lens care solutions (6 of 11 eyes), soft contact lens wear (4 of 11 eyes), a history of ocular surgery (3 of 11 eyes), or the presence of an underlying dermatologic or inflammatory disorder (3 of 11 eyes). All patients treated with 1% silver nitrate solution (6 of 6 eyes) experienced resolution of their symptoms with either complete or partial resolution of the epitheliopathy. CONCLUSIONS: Advancing wave-like epitheliopathy is a keratopathy characterized by centripetally advancing waves of coarse, irregular epithelium arising from the superior limbus. The cause appears to be multifactorial. Symptoms include ocular redness, irritation, and a decrease in visual acuity if the visual axis is involved. Application of 1% silver nitrate solution to the superior limbus is well tolerated and effective in treating this condition.
Administration, Topical↗
The management of impalement injury.
Four cases of impalement injury are described. The principles of management are discussed, these being minimal manipulation of the object before and during transport, preoperative planning, a multidisciplinary approach, and wound care.
Abdominal Injuries↗
Ureteral lithotripsy with the electromechanical impactor.
Electrohydraulic lithotripsy (EHL) of ureteral calculi has proved to be an effective and relatively inexpensive method of intracorporeal lithotripsy. However, the potential for significant ureteral injury is an everpresent concern with conventional EHL. The electromechanical impactor (EMI), an innovative modification of a standard EHL probe, has been shown in initial investigations to be capable of fragmenting urinary calculi with a greater margin of safety. Herein, we describe our preliminary experience with this new device in 23 patients with ureteral calculi. In nine patients selected to undergo EMI treatment, the device could not be employed because of either inability to access the stone with the large endoscope required (six cases) or device malfunction (three cases). Among the patients in whom the EMI was used, five required an additional modality of intracorporeal lithotripsy to complete stone fragmentation. In the remaining nine patients, stone fragmentation was achieved with the EMI as the sole modality of lithotripsy, for an overall success rate of 39% (9/23). There were no complications directly related to use of the EMI as noted endoscopically or on postoperative imaging. The EMI appears to be a safe device for intracorporeal lithotripsy. Its application to a large population of patients with ureteral stones may be limited by the probe size (5F), which precludes its use with the smaller rigid and flexible ureteroscopes.
Adolescent↗
Effects of various concomitant medications on gastric alcohol dehydrogenase and the first-pass metabolism of ethanol.
Inhibition of gastric alcohol dehydrogenase (ADH) has been shown to enhance alcohol absorption in man under certain circumstances. To determine whether various medications might affect alcohol absorption, we screened 18 compounds for an effect on ADH. Salicylic acid, acetaminophen, propranolol, ethacrynic acid, and three H2-receptor antagonists all inhibited rat gastric ADH in vitro, indicating that several commonly used medications have the potential to enhance alcohol absorption. Of these, cimetidine, ranitidine, and nizatidine were studied further to define their effect on alcohol absorption in man and to assess the clinical relevance of the effect. Both ranitidine and nizatidine enhanced the absorption of small doses of alcohol (0.15 g/kg) in the morning by 63% and 64% and increased Cmax by 48% and 54% respectively (p less than 0.001), effects similar to those reported by others for cimetidine. The effect of ranitidine given before dinner was greatly attenuated with increases in Cmax of 8% (NS) and AUC of 21% (p = 0.02). Cimetidine 800 mg hs did not affect the absorption of 0.15 g/kg alcohol given in the evening, and cimetidine 400 mg bid decreased absorption by 14% (p = 0.11). Cimetidine 300 mg qid had no effect on larger doses of alcohol given at dinner. We conclude that many commonly used medications affect gastric ADH, but that the increase in the actual amount of alcohol absorbed is quite small, and demonstrable only under special conditions.
Acetaminophen↗
The clinical spectrum of Staphylococcus aureus pulmonary infection.
Staphylococcus aureus causes serious pulmonary infections in adults. Prior descriptions of this entity have depended on diagnosis of expectorated sputum cultures that are often contaminated. To better characterize this infection, we retrospectively reviewed the medical records of 31 adults with S aureus pulmonary infection diagnosed by culture specimens uncontaminated by the upper respiratory flora. Our results support the concept that S aureus pulmonary infections usually occur in older adults (sixth decade or older) with concomitant illnesses that are typically nosocomial. However, in contrast to previous reports, the chest roentgenograms in these patients typically showed multilobar infiltrates (60 percent), predominantly in the lower lobes (64 percent), and often bilateral (48 percent). Pleural involvement (48 percent) was more common than previously reported, and abscess formation (16 percent) occurred infrequently. Sputum cultures were found to be sensitive but nonspecific diagnostic tools. Despite antibiotic therapy, reinfection occurred in 10 percent of patients and the mortality rate was 32 percent.
Adult↗
Calpain I activation is not correlated with aggregation in human platelets.
Calpain-catalysed hydrolysis of platelet substrates such as cytoskeletal and calmodulin-binding proteins, and of protein kinase C, is assumed to contribute to platelet aggregation. We have measured calpain I activation by immunoblotting, and [Ca2+]i (cytoplasmic Ca2+ concn.) by fura-2 fluorescence, in parallel with measurement of aggregation, in stirred human platelets treated at different [Ca2+]ext (extend Ca2+ concns.) with A23187, leupeptin, phorbol ester and thrombin. Hydrolysis of actin-binding protein, and [3H]5-hydroxytryptamine release, were also measured in some cases. A rise in [Ca2+]i, platelet aggregation and calpain activation often occurred together. With some combinations of agonists and [Ca2+]ext, however, this correlation was clearly not maintained. It was shown: (a) that activation of calpain and its hydrolysis of platelet substrates were not strictly necessary conditions for platelet secretion and aggregation; (b) conversely, that calpain activation could occur without aggregation.
Annexins↗
Antihypertensive effectiveness of very low doses of hydrochlorothiazide: results of the PHICOG Trial.
A large, multicenter, randomized, placebo-controlled, double-blind trial was carried out to determine the effects of the lowest dose of commercially available hydrochlorothiazide. Thus, Dyazide (which contains 25 mg of hydrochlorothiazide and 50 mg of triamterene in an approximately 50% bioavailable form), one capsule, was given daily to patients with either mild or moderate hypertension (supine diastolic blood pressure of 95 to 115 mmHg) for eight weeks. At the end of this eight-week period, supine diastolic blood pressure (SDBP) fell by 11.3 +/- 6.7 mmHg (mean +/- SD) in the Dyazide-treated compared to 4.6 +/- 6.9 mmHg in the placebo-treated group (P less than 0.001). In two thirds of the patients receiving active treatment the fall in SDBP was more than 10 mmHg, and in over half SDBP was completely normalized (ie, SDBP less than 90 mmHg). Supine systolic blood pressure fell by 14.7 +/- 12.3 mmHg in the Dyazide-treated group compared to 5.3 +/- 11.6 mmHg in the placebo-treated group (P less than 0.001). Approximately 80% of the antihypertensive effect occurred within two weeks and after four weeks there was no further significant reduction. Mildly (SDBP = 95 to 104 mmHg) and moderately (SDBP = 105 to 115 mmHg) hypertensive patients responded similarly to treatment. All studied subpopulations responded to treatment with a reduction of SDBP of at least an average of 10 mmHg; the best responders were blacks, women, the elderly (greater than 65 years old), and patients weighing less than 170 lbs. Side effects were mild and infrequent. In conclusion, by examining the effects of Dyazide (one capsule/day), this investigation demonstrated the effectiveness of low-dose hydrochlorothiazide in antihypertensive therapy and quantified it both in the general population and in clinically relevant subpopulations.
Adolescent↗
Relationship between leukotriene C4 and an uteroglobin-like protein in nasal and tracheobronchial mucosa of children. Implication in acute respiratory illnesses.
Secretions from the nose and nasopharynx (NPS) are more readily accessible than tracheobronchial secretions (TBS) for clinical investigations, but it is unclear whether changes in mediator release in the nasopharynx reflect similar changes in the tracheobronchial tree. In order to clarify this question, NPS and TBS were taken from 20 children with tracheotomy and tested for the presence of leukotriene C4 (LTC4) and uteroglobin-like protein (UTG-LP). LTC4 and UTG-LP were measured both when the children were healthy and when they had clinical evidence of an acute respiratory tract illness. The mean concentration of LTC4 in NPS and TBS increased during illness although the mean concentration in NPS was significantly higher than in TBS during respiratory illness. In healthy children UTG-LP was detected only in TBS. During acute respiratory illness the concentration of UTG-LP in TBS decreased but remained significantly higher than in NPS. Data presented in this study indicate that changes in the LTC4 concentration in NPS appear to reflect changes in LTC4 concentration in TBS although the levels of LTC4 in NPS were significantly higher than in TBS. An inverse correlation between the concentrations of LTC4 and UTG-LP in NPS and TBS was demonstrated.
Acute Disease↗
99Tcm-HMPAO single photon emission tomography in the diagnosis of cerebral barotrauma.
Cerebral barotrauma, or the neurological manifestation of the "bends", is a relatively common disease of divers and aviators. To date, however, no-one has succeeded in demonstrating a cerebral or spinal cord lesion in vivo following a decompression incident, despite the presence of definitive clinical signs and symptoms of central nervous system involvement. This paper describes the use of 99Tcm-labelled hexamethylpropyleneamine oxime (99Tcm-HMPAO) with single photon emission tomography in a study of three individuals involved in driving accidents. All three suffered cerebral barotrauma during decompression and all exhibited clinical signs and symptoms of dysbarism to a varying degree. Imaging was performed at time intervals ranging from 2 h to several days following the incidents. The results showed well defined cerebral ischaemic lesions in all three subjects. We conclude that 99Tcm-HMPAO imaging provides a significant advance in locating and demonstrating cerebral lesions following barotrauma and will contribute greatly to our understanding of the pathophysiological processes involved.
Adolescent↗
Incidence and management of diarrhea during longterm auranofin therapy.
The incidence, severity, and management of diarrhea during longterm administration of auranofin (AF)--up to 33 months--were evaluated prospectively in 137 patients with active rheumatoid arthritis. At least 1 episode of diarrhea was reported in 101 patients (74%), but the rate of occurrence/patient-months of therapy was 24% (569 events/2,370 patient-months of treatment). The monthly prevalence declined from a range of 30-40% during the initial 6 months to about 10% for patients treated for 18-24 months. Most diarrhea was intermittent and mild; only 11 patients (8%) discontinued treatment because of diarrheal symptoms. No intervention was required in 46 of the 101 patients affected. In 44 others, loose stools were successfully managed with antidiarrheal medications, a reduction in dosage, or both. Although diarrhea is a common event during AF administration, particularly early in therapy, for most patients it usually does not significantly interfere with treatment.
Adult↗
Ulcerative keratitis associated with contact lens wear.
A review of 573 cases of ulcerative keratitis cultured at the Bascom Palmer Eye Institute from January 1977 through September 1982 showed that 118 cases (21%) were associated with contact lens wear; of these, 64 were culture-positive. Of these culture-positive cases, 50 (78%) were caused by gram-negative bacteria, nine (14%) by gram-positive organisms, and two (3%) by fungal organisms. Of the 264 culture-positive ulcers not associated with contact lens wear, 119 (45%) were caused by gram-negative bacteria, 74 (28%) by gram-positive organisms, and 63 (24%) by fungal organisms. These statistically significant differences suggested that the organisms associated with ulcerative keratitis within our geographic region are modified by contact lens use. Pseudomonas was the organism most frequently isolated from ulcers associated with contact lenses and was responsible for nearly two thirds of the culture-positive cases.
Contact Lenses↗
Ischemic optic neuropathy secondary to intestinal hemorrhage.
A 70-year-old man presented with bilateral ischemic optic neuropathy. Workup revealed anemia that proved to be secondary to blood loss from an occult small bowel sarcoma. Ischemic optic neuropathy is an uncommon complication of gastrointestinal hemorrhage. It is important to recognize the association of visual loss and severe blood loss when they occur concurrently, so that proper treatment may be promptly instituted.
Aged↗