Evidence for a regulatory role of CTP : choline phosphate cytidylyltransferase in the synthesis of phosphatidylcholine in fetal lung following premature birth.

The sequence of reactions which function to incorporate choline into phosphatidylcholine was investigated in lung from fetuses following premature delivery. The rate of [methyl-14C]choline incorporation by rat lung slices into phosphatidylcholine increases following premature delivery at both 20 and 21 days gestation. The increase in choline incorporation is primarily due to an increased specific activity of phosphorylcholine resulting from a decreased pool size of phosphorylcholine. The decrease in the concentration of phosphorylcholine following premature delivery is apparently caused by an increased activity of cytidylyltransferase which leads to an increase in the conversion of phosphorylcholine to phosphatidylcholine. The total activity of choline kinase, cytidylyltransferase, cholinephosphotransferase and phosphatidate phosphohydrolase did not change significantly. However, the cytidylyltransferase activity in the microsome fraction increased following premature delivery at 20 and 21 days gestation. The amount of cytidylyltransferase in the H form in the cytosol fraction increased following premature delivery at 21 days gestation but not at 20 days gestation. The results are interpreted to indicate that the active form of cytidylyltransferase in lung cells is the membrane-bound enzyme and this form increases following birth resulting in an increased synthesis of phosphatidylcholine.

An economic evaluation of donepezil in the treatment of Alzheimer's disease.

Using data from a longitudinal survey of caregivers of Alzheimer's disease patients, we calculated the average per-patient direct medical costs over a 6-month period for a matched sample of patients (N = 376). A group of patients receiving donepezil for 6 months was compared with a group not receiving this form of drug therapy. The groups were matched by disease severity, age, sex, and comorbidity. The average age in the two groups was 74 years, with 50% female and 90% white. Patients in both groups had a mean of 1.6 comorbid conditions. No patients in either group were institutionalized at the beginning of the 6-month period, and all patients were taking at least one prescription drug, including donepezil. Mean 6-month direct medical expenses for a patient receiving donepezil were $3443, including the cost of the drug, whereas the per-patient mean expenses for the comparison group were $3476. Although the patients receiving donepezil had greater expenditures for prescription drugs, these costs were offset by a slower rate of institutionalization. At the end of the 6-month period, 5% of donepezil patients were institutionalized, compared with 10% of the nondonepezil patients. The cost of receiving donepezil treatment for 6 months did not result in a significantly higher per-patient mean direct cost.

Detection of equine and bovine T- and B-lymphocytes in formalin-fixed paraffin-embedded tissues.

Formalin-fixed paraffin-embedded sections of equine and bovine lymph nodes, spleen, thymus, and Peyer's patches were incubated with monoclonal antibodies to B-lymphocyte markers BLA.36, B29, and mb-1 and T-lymphocyte markers CD3 and CD5. The monoclonal antibody BLA.36 reacted with 80-90% of lymphocytes in the germinal centers and mantle zones of follicles in lymph nodes, spleen, and Peyer's patches. In addition, 90% of lymphocytes in the marginal zone of the spleen, and variable numbers of lymphocytes within lymph node medullary cords were immunopositive for BLA.36. Antibodies to B29 and mb-1 produced similar staining patterns as BLA.36 with fewer positive cells in the germinal centers and medullary cords. BLA.36, B29, and mb-1 reacted with 30-50% of lymphocytes in the medulla of the thymus and with 5-10% of lymphocytes in the cortex. CD3 and CD5 reacted with 90% of lymphocytes in the paracortex and parafollicular zones of lymph nodes, spleen, and Peyer's patches; 40-50% of lymphocytes in the medullary cords of lymph nodes, and scattered positive cells within follicles. Anti-CD3 antibody reacted with 95% of lymphocytes in the splenic red pulp, but antibodies directed against CD5 reacted only faintly with approximately 5-10% of lymphocytes in the red pulp. CD3 and CD5 reacted with 50-60% of cells in the medulla of the thymus and with 40-80% of lymphocytes in the thymic cortex. The biochemical characterization of the antibodies by Western blotting against lysates of equine and bovine peripheral blood mononuclear cells confirmed that antibodies to BLA.36, mb-1, B29, CD3, and CD5 detected molecules of the same approximate molecular mass as found on lymphoid cells of human beings and rats.

Optimization of knee ligament position for lateral extraarticular reconstruction.

A kinematic study of five adult cadaver knees was performed to determine the behavior of the separation distances connecting all combinations of a network of points on the lateral side of the knee. Measurements were obtained between each pair of points at the level of the capsule for seven different angles of flexion ranging from 0 to 125 degrees. The data obtained allow further analysis of tendinous reconstructions attached to each pair of points as regards stretching and laxity throughout a normally occurring range of motion. The Rowe-Zarins combined intra- and extraarticular reconstruction, the Sling-and-Reef procedure, and other extraarticular methods were analyzed in light of these data. Attachment of a reconstruction at the proximal anterolateral tibia, in front of Gerdy's tubercle paired with femoral attachment high and proximal to the origin of the lateral collateral ligament on the femur, was observed to demonstrate favorable behavior for several reasons. First, such a check reign represents an obvious, major restraint to anterior translation as it is positioned well posteriorly on the femur and anteriorly on the tibia. Second, the attachment points were seen to demonstrate maximum separation between 15 and 45 degrees of flexion, thereby not being forced into any undesirable stretching if the knee were to move normally throughout the other portions of the motion cycle. Consequently, obligate stretch with full flexion or full extension would appear unlikely. Separation distances between attachment points were highly dependent upon changes in the femoral fixation point and much less variable as a result of tibial attachment position. Placing the knee through a flexion-extension range of motion with the tibia held unnaturally in external rotation, which is frequently done in the operating room, violates the normal kinematic pattern of knee motion. As a result, unsuitable attachment points may erroneously appear well behaved. This observation may offer one important explanation for long-term stretching of a ligament reconstruction which appeared satisfactorily tight and strong at the time of surgery. The data obtained allow proper positioning of anterolateral reconstructions so that this mode of stretching will not be encountered as a result of normal knee motion.

Immunosuppression and intracellular calcium signaling in splenocytes from chicks infected with chicken anemia virus, CL-1 isolate.

Hematocrits, histopathology, concanavalin A-induced lymphocyte proliferation, intracellular calcium signaling, and lymphocyte subpopulations were analyzed over a 6-week period in individual chicks inoculated with the CL-1 isolate of chicken anemia virus. Lymphoid depletion/atrophy was present in the thymus and bone marrow by 11 days post-infection (PI). Anemia was present at 14 days PI. The mean lymphocyte proliferation stimulation index (SI) of the inoculated group was significantly lower than that of the control group at 11 days PI. This response was reversed at 18 days PI, when the SI of the inoculated group was significantly higher than that of the controls; values subsequently returned to baseline. The increase in intracellular calcium levels in CAV-infected chicks and controls paralleled the proliferative response. Percentages of CD3-, CD4-, CD8-, and natural-killer-positive-staining cells decreased significantly at 18 and 25 days PI. The most dramatic decrease occurred in the CD8-positive-staining cell population at 18 and 25 days PI.

The week-old hip fracture: indication for prophylactic use of a vena cava filter? Report of two cases.

Occasional patients will present a week or more after sustaining a hip fracture. Though these patients are at high risk for asymptomatic deep venous thrombosis and pulmonary embolism, anticoagulation may be contraindicated prior to surgery. Two recent cases involving such a situation are reported. In the first, the patient sustained a fatal intraoperative pulmonary embolism. In the second, a transvenous Greenfield vena caval filter was placed prior to surgery. An extremely high suspicion of asymptomatic deep venous thrombosis is necessary when evaluating a patient whose hip fracture has been untreated for a week or more. If studies demonstrate a deep venous thrombosis preoperatively, placement of an inferior vena caval filter may be indicated.

The relationship between donepezil and behavioral disturbances in patients with Alzheimer's disease.

The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer's disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezilfor 6 months (n=84) were compared with patients not on donepezil (n=248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (P< or =0.011). Specifically, donepezil patients were described as significantly (P< or =0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (P< or =0.005). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD.

A technique for simultaneous fracture repair and augmentation of the atrophic edentulous mandible.

A technique that uses autogenous rib grafts for repair of fractures of an atrophic, edentulous mandible and augmentation of the ridge has been presented. Nine cases have been treated in this manner. We advocate this treatment to promote healing of the fractures and to provide necessary mandibular bone for future vestibuloplasty and, ultimately, restoration of function with denture construction.

Impact of donepezil on caregiving burden for patients with Alzheimer's disease.

Comprehensive Alzheimer's disease (AD) treatment should address caregiver well-being. We predicted that caregiver burden would be lower among caregivers of AD patients who received donepezil relative to caregivers of patients not treated with donepezil. A self-administered, nationwide survey of AD caregivers was used to match caregivers of patients treated with donepezil (n = 274) to caregivers of patients not treated with donepezil (n = 274). The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Respondents were three-quarters female, with an average age of 60 years. Results demonstrated that donepezil caregivers reported significantly lower scores on difficulty of caregiving. This difference remained when statistical controls for multiple patient and caregiver variables were imposed. However, selection factors must be recognized as a possible explanation for differences. The groups reported no difference on the time-demand subscale. In conclusion, better management of AD symptoms through donepezil treatment may reduce the burden of caregiving, providing physicians with a pharmacologic approach to improving quality of life for AD patients and their families.

Heterophil function and resistance to staphylococcal challenge in broiler chickens naturally infected with avian leukosis virus subgroup J.

Avian leukosis virus subgroup J has a high tropism for myeloid lineage cells and frequently induces neoplastic transformation of myelocytes. The impact of congenital avian leukosis virus subgroup J infection on the function of circulating heterophils and susceptibility to staphylococcal infection was investigated. Six-week-old broiler chickens negative for exogenous avian leukosis viruses or congenitally infected with avian leukosis virus subgroup J were inoculated intravenously with 10(6) colony-forming units of Staphylococcus aureus, and pre- and postinoculation heterophil function was assessed. All chickens developed a leukocytosis with heterophilia after inoculation, but total leukocyte and heterophil counts were significantly higher in leukosis-negative chickens than in virus-infected chickens. Tenosynovitis was more severe in leukosis-negative chickens, and 2/10 (20%) of the virus-infected chickens had no histologic evidence of tenosynovitis. Osteomyelitis in the tibiotarsus or tarsometatarsus developed in 5/10 (50%) of the chickens in each group. S. aureus was recovered from the hock joint of 6/10 (60%) of the chickens in each group. Heterophils from all chickens exhibited similar phagocytic ability pre- and postinoculation. Heterophils from virus-infected chickens exhibited less bactericidal ability preinoculation than did heterophils from leukosis-negative chickens. However, postinoculation bactericidal ability was similar in both groups. Avian leukosis virus subgroup J provirus was present in heterophils isolated from congenitally infected chickens. Heterophils isolated from broiler chickens congenitally infected with avian leukosis virus subgroup J exhibit no significant functional deficits, and infected and uninfected chickens exhibit similar susceptibility to staphylococcal infection.

The effect of enrofloxacin on cell proliferation and proteoglycans in horse tendon cells.

Fluoroquinolone antibiotics have been used widely in humans and domestic animals, including horses, because of their broad-spectrum bactericidal activity, and relative safety. The use of fluoroquinolones, however, is not without risk. Tendonitis and spontaneous tendon rupture have been reported in people during or following therapy with fluoroquinolones. We have studied the effects of enrofloxacin, a fluoroquinolone antibiotic used commonly in domestic animals, on tendon cell cultures established from equine superficial digital flexor tendons. Effects on cell proliferation and morphology were studied using cell counting and scanning electron microscopy. Monosaccharide content and composition was determined by gas chromatography-mass spectrometry analysis. Western and Northern blot analyses were utilized to evaluate the synthesis and expression of two proteoglycans, biglycan and decorin. Our data demonstrate that enrofloxacin inhibits cell proliferation, induces morphological changes, decreases total monosacharide content and alters small proteoglycan synthesis at the glycosylation level in equine tendon cell cultures. These effects are more pronounced in juvenile tendon cells than in adult equine tendon cells. We hypothesize that morphological changes and inhibition of cell proliferation are a result of impaired production of biglycan and decorin, proteoglycans involved in fibrillogenesis of collagen, the most important structural component of the tendon of enrofloxacin-treated tendon cells. Our findings suggest that fluoroquinolones should be used with caution in horses, especially in foals.

Negative thyroid hormone control of human growth hormone gene expression is mediated by 3'-untranslated/3'-flanking DNA.

The intact human growth hormone (hGH) gene is negatively regulated by triiodothyronine (T3) treatment in transfected rat pituitary tumor cells. We now demonstrate that this responsiveness is mediated by a negative thyroid hormone response element (nTRE) localized to the proximal 3'-untranslated/3'-flanking region (3'-UT/FR). This region binds thyroid hormone receptors specifically and with high affinity. nTRE function was promoter-dependent, since it suppressed the activity of a positive TRE in the human chorionic somatomammotropin promoter, partially repressed activity of the herpes simplex virus TK promoter, but did not function with the human actin or Rous sarcoma virus promoters. T3 treatment did not alter transcript termination sites nor selectively affect the stability of transcripts containing the hGH 3'-UT/FR when transcription was blocked by actinomycin D treatment. The function of the nTRE depended on its location in the 3'-UT/FR; it was inactive when positioned down-stream of the simian virus 40 (SV40) 3'-UT/FR, and it acted as a positive TRE when placed upstream of the hGH promoter. These results demonstrate a novel localization of a TRE with unique properties which suggests expanded mechanisms by which thyroid hormone receptors can affect gene expression.

Prospective trial evaluating early initiation of feeding in patients with newly placed one-step button gastrostomy devices.

The purpose of this study was to prospectively assess the feasibility and safety of early feeding in patients with newly placed one-step button (OSB) gastrostomy devices. Twenty-five patients who underwent percutaneous endoscopic button gastrostomy placement were prospectively enrolled. The patients underwent radiographic assessment (Gastrografin gastrograms) 3 hr after gastrostomy placement. Contrast extravasation was not documented in any patient. Aside from one patient who aspirated the contrast solution after the radiologic study, all others (96%) were successfully fed on the day the gastrostomy buttons were placed. In this prospective study of patients with newly placed OSB gastrostomy devices, early initiation of feeding was feasible and safe. In a fashion similar to their tube-style counterparts, button gastrostomy devices provide adequate apposition between the stomach and abdominal wall immediately after their initial placement.

Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor.

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.