Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.

BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase.

We have identified a novel fungal metabolite that is an inhibitor of human farnesyl-protein transferase (FPTase) by randomly screening natural product extracts using a high-throughput biochemical assay. Clavaric acid [24, 25-dihydroxy-2-(3-hydroxy-3-methylglutaryl)lanostan-3-one] was isolated from Clavariadelphus truncatus; it specifically inhibits human FPTase (IC50 = 1.3 microM) and does not inhibit geranylgeranyl-protein transferase-I (GGPTase-I) or squalene synthase activity. It is competitive with respect to Ras and is a reversible inhibitor of FPTase. An alkaline hydrolysis product of clavaric acid, clavarinone [2,24,25-trihydroxylanostan-3-one], lacking the 3-hydroxy-3-methylglutaric acid side chain is less active as a FPTase inhibitor. Similarly, a methyl ester derivative of clavaric acid is also inactive. In Rat1 ras-transformed cells clavaric acid and lovastatin inhibited Ras processing without being overtly cytotoxic. Excess mevalonate reversed the effects of lovastatin but not of clavaric acid suggesting that the block on Ras processing by clavaric acid was due to inhibition of FPTase and not due to inhibition of HMG-CoA reductase. Despite these results, the possibility existed that clavaric acid inhibited Ras processing by directly inhibiting HMG-CoA reductase. To directly examine the effects of clavaric acid and clavarinone on HMG-CoA reductase, cholesterol synthesis was measured in HepG2 cells. No inhibition of HMG-CoA reductase was observed indicating that the inhibition of Ras processing by this class of compounds is due to inhibition of FPTase. To date, clavaric acid is the second reported nitrogen-free compound that competes with Ras to inhibit FPTase activity. A series of related compounds derived from computer-based similarity searches and subsequent rational chemical synthetic design provided compounds that exhibited a range of activity (0.04 --> 100 microM) against FPTase. Modest changes in the structures of these inhibitors dramatically change the inhibitory activity of these inhibitors.

Alveolar hydatid disease. Review of the surgical experience in 42 cases of active disease among Alaskan Eskimos.

OBJECTIVE: The authors reviewed the pathophysiology and clinical management of endemic alveolar hydatid disease in Alaskan Eskimos, incorporating recent developments in diagnosis and treatment. SUMMARY BACKGROUND DATA: Alveolar hydatid disease is a highly lethal zoonotic infection caused by the larval stage of Echinococcus multilocularis. This cestode is restricted geographically to northern climates, where foxes and small rodents represent the natural hosts. Domestic dogs also may serve as definitive hosts, and thus, transmit the parasite to humans. Human infection is characterized by the development of a cancer-like hepatic mass, which may extend to adjacent structures or metastasize to distant sites. If the infection goes untreated, mortality reaches 80%. METHODS: The medical records of all patients with alveolar hydatid disease diagnosed or treated at the Alaska Native Medical Center between 1951 and 1993 were reviewed. Forty-two cases of active disease are presented. RESULTS: Nine patients underwent resection of hepatic lesions with intent to cure, and each had a favorable result. Average post-diagnosis survival of those patients was 22 years; six still are living and free of disease. Partial resections or drainage procedures were performed in ten patients. Chemotherapy was used to augment the surgical treatment of eight patients, and four received chemotherapy alone, resulting in improved outcomes compared with historic controls. Late complications included hepatic abscess, biliary obstruction, and portal venous hypertension. CONCLUSIONS: Whereas alveolar hydatid disease rarely is encountered in other areas of North America, the biologic potential for spread of the disease may be increasing because of illegal importation of infected foxes to the Eastern seaboard. Therefore, the surgical community should maintain an awareness of the diagnosis and management of this potentially devastating parasitic infection.

Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice.

The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its transforming activity. Cell-active inhibitors of the enzyme that catalyzes this reaction, protein farnesyltransferase, have been shown to selectively block ras-dependent transformation of cells in culture. Here we describe the protein farnesyltransferase inhibitor 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionylmethioninesulfone methyl ester (L-739,749), which suppressed the anchorage-independent growth of Rat1 cells transformed with viral H-ras and the human pancreatic adenocarcinoma cell line PSN-1, which harbors altered K-ras, myc, and p53 genes. This compound also suppressed the growth of tumors arising from ras-transformed Rat1 cells in nude mice by 66%. Under the same conditions, doxorubicin inhibited tumor growth by 33%. Control tumors formed by v-raf- or v-mos-transformed Rat1 cells were unaffected by L-739,749. Furthermore, mice treated with L-739,749 exhibited no evidence of systemic toxicity. This is a demonstration of antitumor activity in vivo using a synthetic small molecule inhibitor of protein farnesyltransferase.

Performing arts medicine.

Arts medicine has come of age, resulting from 3 important developments over the past decade: improved methods of diagnosis and treatment, an awareness that artists suffer from special problems related to their occupation and lifestyle, and the establishment of health programs emphasizing an interdisciplinary approach to these patients. We focus on the patterns of illness afflicting performing artists, specifically dancers, singers, actors, and instrumental musicians, and explain some of the things a health care team can do in treating these patients. The conditions governing these patients' lives--early exposure to high expectations of excellence, incessant demands for perfection, long periods of intense practicing, fierce competition, high levels of anxiety associated with performance, and uncertain careers--need to be understood. Levels of disease and disability are remarkably high, but artists often ignore symptoms. We discuss the musculoskeletal, neurologic, vocal, psychological, and other syndromes found among performers and some of the difficulties in treating them. The prevention of injury, conservative management, collaboration with teachers, and a psychotherapeutic approach are desirable. Arts medicine programs for professional consultation exist in several major cities of the United States and abroad. Although research is needed regarding the effectiveness of health care services for performing artists, the scientific literature devoted to this field is growing.

Biomechanical abnormalities in musicians with occupational cramp/focal dystonia.

Occupational factors and peripheral injuries are frequently implicated in the development of hand cramps and the syndrome of persistent manual incoordination among musicians and others most commonly given a diagnosis of focal limb dystonia. In an attempt to gain insight into the character and influence of risk factors in the evolution of this disorder, the authors conducted detailed evaluations of 33 individuals who responded to a questionnaire sent to university- and conservatory-level music schools in Germany in September 1989. Response was invited from any musician with complaints of impaired hand control. Of the 33 individuals accepted for evaluation, 18 were musicians who met clinical criteria for the diagnosis of occupational cramp/focal dystonia (OC/FD). Nineteen of the original 33 subjects underwent a quantitative biochemical assessment, comparing active and passive ranges of motion at all joints below the shoulder with those for cohorts of unimpaired musicians, matched for gender and musical instrument. Of the 19 tested biomechanically, 14 had OC/FD and the remaining five had either persistent pain or nonspecific movement idiosyncracies interfering with playing. Compared with the matched groups of normals, no consistent biomechanical abnormality was found in the non-OC/FD group; in the OC/FD group two thirds had marked limitation of passive and/or active abduction range between the central digits of both hands. Based on detailed training and performance histories in these subjects, the authors conclude that a specific biomechanical condition in the hand can interfere with certain high-speed digital movements required in musical instrument performance. Unintended muscle synergies, postures, and movement patterns can develop as attempts are made to increase the speed and fluency of such movements. As rehearsal is intensified, degraded movements are stabilized ("programmed"). In this situation, OC/FD appears to represent an aberrant outcome of normal motor learning whose physiologic correlates mimic neuropathologically based dystonia. The implications for prevention are discussed.

Coping with test stress: microcomputer software for treatment of test anxiety.

Test anxiety, described as "the most virulent impediment to effective role functioning in an educational setting" (Myers, R. A. 1986, Research on educational and vocational counseling; Handbook of Psychotherapy and Behavior Change, pp. 728), is readily treatable through use of relaxation and desensitization strategies. To reduce clinician involvement, and thus potentially reduce costs to clients, a microcomputer program, Coping with Test Stress, was developed and tested. Initial case findings suggest that the Coping with Test Stress program may be useful in treating test anxiety among college graduate students.

Cloning and sequencing of a [NiFe] hydrogenase operon from Desulfovibrio vulgaris Miyazaki F.

A hydrogenase operon was cloned from chromosomal DNA isolated from Desulfovibrio vulgaris Miyazaki F with the use of probes derived from the genes encoding [NiFe] hydrogenase from Desulfovibrio vulgaris Hildenborough. The nucleic acid sequence of the cloned DNA indicates this hydrogenase to be a two-subunit enzyme: the gene for the small subunit (267 residues; molecular mass = 28763 Da) precedes that for the large subunit (566 residues; molecular mass = 62495 Da), as in other [NiFe] and [NiFeSe] hydrogenase operons. The amino acid sequences of the small and large subunits of the Miyazaki hydrogenase share 80% homology with those of the [NiFe] hydrogenase from Desulfovibrio gigas. Fourteen cysteine residues, ten in the small and four in the large subunit, which are thought to co-ordinate the iron-sulphur clusters and the active-site nickel in [NiFe] hydrogenases, are found to be conserved in the Miyazaki hydrogenase. The subunit molecular masses and amino acid composition derived from the gene sequence are very similar to the data reported for the periplasmic, membrane-bound hydrogenase isolated by Yagi and coworkers, suggesting that this hydrogenase belongs to the general class of [NiFe] hydrogenases, despite its low nickel content and apparently anomalous spectral properties.

Organization of the genes encoding [Fe] hydrogenase in Desulfovibrio vulgaris subsp. oxamicus Monticello.

The genes encoding the periplasmic [Fe] hydrogenase from Desulfovibrio vulgaris subsp. oxamicus Monticello were cloned by exploiting their homology with the hydAB genes from D. vulgaris subsp. vulgaris Hildenborough, in which this enzyme is present as a heterologous dimer of alpha and beta subunits. Nucleotide sequencing showed that the enzyme is encoded by an operon in which the gene for the 46-kilodalton (kDa) alpha subunit precedes that of the 13.5-kDa beta subunit, exactly as in the Hildenborough strain. The pairs of hydA and hydB genes are highly homologous; both alpha subunits (420 amino acid residues) share 79% sequence identity, while the unprocessed beta subunits (124 and 123 amino acid residues, respectively) share 71% sequence identity. In contrast, there appears to be no sequence homology outside these coding regions, with the exception of a possible promoter element, which was found approximately 90 base pairs upstream from the translational start of the hydA gene. The recently discovered hydC gene, which may code for a 65.8-kDa fusion protein (gamma) of the alpha and beta subunits and is present immediately downstream from the hydAB genes in the Hildenborough strain, was found to be absent from the Monticello strain. The implication of this result for the possible function of the hydC gene product in Desulfovibrio species is discussed.

Injury patterns for occupants of small trucks.

A limited number of studies have been completed on the factors contributing to accident-related injuries sustained by occupants of pickup trucks. The increasing number and changing pattern of use of light trucks necessitates the need to critically review this vehicle type with respect to contributing accident factors and associated injuries. This paper investigates the injury mechanisms of occupants of pickup trucks and the surfaces that the occupants contact in roadway accidents. Selection of cases from the Canadian vehicle database was based on the location of the vehicles' most severe impact deformation. The overall occupant injury severity was examined with respect to impact location, impact speed, and magnitude of occupant compartment intrusion. The results of the investigation illustrate the benefits of seat belt restraint use. In addition, identification of frequent injury contact surfaces establishes a reference for improved vehicle design initiatives and standards.

Ultrastructural changes in acetylcholinesterase activity in the deafferented spinal trigeminal nucleus.

Acetylcholinesterase (AChE) activity was investigated in synaptic areas of the cat spinal trigeminal nucleus (pars interpolaris and pars caudalis) ipsilateral and contralateral to complete retrogasserian rhizotomy. Vibratome sections of tissue taken from animals of 1, 3, 6, 14, and 21 days survival were examined by electron microscopy following a histochemical reaction for AChE activity employing a method based on the Karnovsky-Roots technique for demonstrating reaction product. As degeneration progressed with survival time, enzymatic activity was initially reduced in synaptic clefts of injured afferent terminals and subsequently was enhanced throughout the extracellular space, including within synaptic clefts of possibly reinnervated sites. These changes in enzymatic activity with primary deafferentation are discussed in relation to the process of reinnervation, the development of neuronal hyperactivity, and possible noncholinergic functions of AChE.

Hyperbaric hydrogen therapy: a possible treatment for cancer.

Hairless albino mice with squamous cell carcinoma were exposed to a mixture of 2.5 percent oxygen and 97.5 percent hydrogen at a total pressure of 8 atmospheres for periods up to 2 weeks in order to see if a free radical decay catalyzer, such as hydrogen, would cause a regression of the skin tumors. Marked aggression of the tumors was found, leading to the possibility that hyperbaric hydrogen therapy might also prove to be of significance in the treatment of other types of cancer.