Metabolism and pharmacokinetics of 1-(2''-trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP117) in the rat

A modified endoscopic technique for anterior cruciate ligament (ACL) reconstruction using an autologous patellar tendon graft is described using the early results for 120 patients. A special technique using an oscillating hollow saw allows for the rapid and standardized harvest of cylindrical bone plugs, ensuring safe and adequate femoral press-fit fixation. The complications encountered included one fracture of a bone back on plugging in as well as two cases with revision procedures for interference screw fixation due to insufficient femoral anchorage. Within the framework of a prospective study, all 120 patients underwent a control arthroscopy after the first postoperative year showing viable and mechanically stable grafts in 64 (53.3%) of the patients. In 44 patients (36.7%), viable though somewhat lax grafts were found, whereas the remaining 12 patients (10%) only showed insufficient tissue residues. All of these cases were the result of a ventral misplacement of the femoral insertion site representing the primary complication of transtibial technique. The results of the control arthroscopies showed a highly significant correlation with the clinical results for the IKDC score obtained in a follow-up after an average 29 (18 to 36) months. The results for stability according to the IKDC rating scale showed a normal or near-normal knee function in 76.7%. With regard to the subjective results in the IKDC rating scale, 83.3% of the patients (n = 100) assessed their knee function as normal or almost normal. The location and positioning of the femoral and tibial tunnel were evaluated in an exact radiographic evaluation showing an "ideal position" of the graft in only 94 cases (78.3%). Statistically, a significant correlation of stability with the femoral fixation site could be shown.     

Calcineurin-immunosuppressor complexes

Crystal structures of the Ser/Thr phosphatase calcineurin (protein phosphatase 2B) have recently been solved by X-ray crystallography, both in the free-protein state, and complexed with the immunophilin/immunosuppressant FKBP12/FK506. Core elements of the calcineurin phosphatase have been found to be similar to the corresponding elements of Ser/Thr phosphatase 1 and purple acid phosphatase. The structures provide a basis for understanding calcineurin inhibition by a ternary complex of immunophilin and immunosuppressant proteins.     

Pathology of diseases in wild desert tortoises from California

Twenty-four ill or dead desert tortoises (Gopherus agassizii) were received between March 1992 and July 1995 for necropsies from the Mojave and Colorado deserts of California (USA). Diseases observed in these animals included cutaneous dyskeratosis (n = 7); shell necrosis (n = 2); respiratory diseases (n = 7); urolithiasis (n = 3); and trauma (n = 5). In tortoises with cutaneous dyskeratosis the horn layer of shell was disrupted by multiple crevices and fissures and, in the most severe lesions, dermal bone showed osteoclastic resorption, remodeling, and osteopenia. In tortoises with shell necrosis, multiple foci of necrotic cell debris and heterophilic inflammation within the epidermal horn layer were subtended by necrotic dermal bone colonized by bacteria and fungi. Of the seven tortoises with respiratory disease, five were diagnosed with mycoplasmosis. The diagnosis of mycoplasmosis was based on the presence of chronic proliferative rhinitis and positive serologic tests and/or isolation of Mycoplasma sp. Chronic fungal pneumonia was diagnosed in one tortoise with respiratory disease. In the three tortoises with urolithiasis, two were discovered dead, and the live tortoise had renal and articular gout. Traumatic injuries consisted of one tortoise entombed within its burrow, one tortoise burned in a brush fire, two tortoises struck by moving vehicles, and one tortoise attacked by a predator. While the primary cause of illness could be attributed to one or two major disease processes, lesions were often found in multiple organ systems, and a variety of etiologies were responsible for morbidity and mortality.     

Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif

Phorbol ester treatment of MCF-7 cells led to the tyrosine phosphorylation and activation of PKC delta. However, through Western blot analysis and in vitro immunecomplex kinase assays, we detected a differential localization of tyrosine-phosphorylated PKC delta and catalytically active PKC delta. Catalytically active PKC delta was concentrated in Triton X-100 solubilized-membrane fractions while tyrosine-phosphorylated PKC delta was localized to the cytosol fraction. Phorbol ester treatment of MCF-7 cells stimulated both the time-dependent in vivo association of Src with PKC delta, evidenced in Src immunoprecipitates by the co-immunoprecipitation of PKC delta, and activation of Src, evidenced in Src immunoprecipitates as an increase in reactivity with a Src antibody (clone 28) reactive only with active Src (dephosphorylated on residue 530) and in Src and PKC delta immunoprecipitates by an increase in Src kinase activity. While our data are consistent with reports in the literature showing the activator/stimulus-dependent tyrosine phosphorylation of PKC delta, our data show that the tyrosine phosphorylation of PKC delta is not essential for kinase activity. These results are the first to demonstrate an in vivo association between PKC delta and active Src in the absence of over-expression of either PKC delta or Src, and support the association of Src and PKC delta towards a physiological function.     

Religiosity and remission of depression in medically ill older patients

PURPOSE: The purpose of this study was to compare the fractional contributions of the three pathways of lactate transport (band 3 system, nonionic diffusion, and monocarboxylate pathway) into red blood cells (RBC) from trained and untrained humans. METHODS: Blood samples were obtained from 19 male subjects: 5 untrained, 5 aerobically-trained, 5 competitive collegiate cross-country runners, and 4 competitive collegiate sprinters. The influx of lactate into the RBC was measured by a radioactive tracer technique using [14C]lactate. Discrimination of each pathway of lactate transport was achieved by using PCMBS (1 mM) to block the monocarboxylate pathway and DIDS (0.2 mM) to block the band 3 system. Nonionic diffusion was calculated as the difference between total lactate influx and the sum of band 3 and monocarboxylate lactate influx. RESULTS: Total lactate influx into the RBC from the more aerobic individuals (trained subjects and cross-country runners) was significantly faster at 1.6 mM lactate concentration ([La]) as compared with the influx into RBC of the untrained subjects. Total influx of lactate was significantly higher (P < 0.05) in the RBC from the sprinters as compared with that in the RBC from the untrained subjects at 41 mM [La]. There were no significant differences among the four groups with regard to the total influx of lactate at 4.1, 8.1, and 20 mM [La]. In general, the percentage of total lactate influx accounted for by each of the three parallel pathways at 1.6, 8.1, and 41.0 mM [La] was not different among the four groups of subjects. CONCLUSIONS: Overall, the groups were more similar than different with regard to RBC lactate influx.     

Crossing the midline: a study of four-year-old children

Selenomethionine, an amino acid occurring in proteins in place of methionine, reacts efficiently with oxidants, e.g., peroxynitrite, a biological oxidant generated in inflammatory states, to produce the oxidation product, methionine selenoxide. The present work describes the rapid and efficient reduction of the selenoxide to selenomethionine by glutathione in a stoichiometric reaction utilizing two equivalents of thiol. This nonenzymatic reaction establishes a defense line against peroxynitrite or other oxidants by selenomethionine residues in proteins, maintained by the ubiquitous thiol, glutathione.     

Use of saline-filled tissue expanders to protect the small bowel from radiation

Over the past 7 years, 58 saline-filled tissues expanders (TEs) have been temporarily placed in 57 patients. The indications for TE placement were: small bowel exclusion from external-beam radiation therapy (N = 25), interstitial RT (N = 16), or both (N = 13) when there was insufficient omentum to provide adequate exclusion. Of the 57 patients, 24 had primary tumors (4 colon, 4 endometrial, and 11 rectal cancer; 3 sarcomas, 1 schwannoma; and 1 vaginal cancer). The remaining 33 patients (58%) had recurrent cancers (3 anal, 8 colon, and 16 rectal cancers; and 6 sarcomas), of whom 26 (79%) had received prior RT. Of the 58 TEs, 15 were placed superior to the iliac vessels and 43 were placed in the pelvis. Complications included post-withdrawal enterocutaneous fistulae in four patients, TE deflation in three patients, and TE extrusion in one patient. Improvements in TE design and removal techniques have reduced the incidence of these complications. When no native tissue is available for small bowel exclusion, the saline-filled TE is a safe, effective substitute.