Mammary carcinogen-protein binding potentials: novel and biologically relevant structure-activity relationship model descriptors.

Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen-non-carcinogen model had a concordance between experimental and predicted results of 71%, and the mammary carcinogen-non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and oestrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin; the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.

Phenotypic screening of mutations in Pmr1, the yeast secretory pathway Ca2+/Mn2+-ATPase, reveals residues critical for ion selectivity and transport.

Thirty-five mutations were generated in the yeast secretory pathway/Golgi ion pump, Pmr1, targeting oxygen-containing side chains within the predicted transmembrane segments M4, M5, M6, M7, and M8, likely to be involved in coordination of Ca(2+) and Mn(2+) ions. Mutants were expressed in low copy number in a yeast strain devoid of endogenous Ca(2+) pumps and screened for loss of Ca(2+) and Mn(2+) transport on the basis of hypersensitivity to 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and Mn(2+) toxicity, respectively. Three classes of mutants were found: mutants indistinguishable from wild type (Class 1), mutants indistinguishable from the pmr1 null strain (Class 2), and mutants with differential sensitivity to BAPTA and Mn(2+) toxicity (Class 3). We show that Class 1 mutants retain normal/near normal properties, including (45)Ca transport, Golgi localization, and polypeptide conformation. In contrast, Class 2 mutants lacked any detectable (45)Ca transport; of these, a subset also showed defects in trafficking and protein folding, indicative of structural problems. Two residues identified as Class 2 mutants in this screen, Asn(774) and Asp(778) in M6, also play critical roles in related ion pumps and are therefore likely to be common architectural components of the cation-binding site. Class 3 mutants appear to have altered selectivity for Ca(2+) and Mn(2+) ions, as exemplified by mutant Q783A in M6. These results demonstrate the utility of phenotypic screening in the identification of residues critical for ion transport and selectivity in cation pumps.

Intraarticular epithelioid sarcoma.

A case of an intraarticular epithelioid sarcoma is presented. The patient was a 35 year old man who presented with a 10 months history of a chronic monoarthritis. The MRI showed a diffuse lesion involving the synovial membrane of the knee. There was a marked increased signal on T2 weighted images. Most epithelioid sarcomas involve the subcutaneous tissues of the hands or feet. This presentation is unusual and this entity should be considered in the differential diagnosis of an intraarticular proliferative process.

The treatment of osteoarthritis of the knee with pulsed electrical stimulation.

OBJECTIVE: The safety and effectiveness of pulsed electrical stimulation was evaluated for the treatment of osteoarthritis (OA) of the knee. METHODS: A multicenter, double blind, randomized, placebo controlled trial that enrolled 78 patients with OA of the knee incorporated 3 primary efficacy variables of patients' pain, patients' function, and physician global evaluation of patients' condition, and 6 secondary variables that included duration of morning stiffness, range of motion, knee tenderness, joint swelling, joint circumference, and walking time. Measurements were recorded at baseline and during the 4 week treatment period. RESULTS: Patients treated with the active devices showed significantly greater improvement than the placebo group for all primary efficacy variables in comparisons of mean change from baseline to the end of treatment (p < 0.05). Improvement of > or = 50% from baseline was demonstrated in at least one primary efficacy variable in 50% of the active device group, in 2 variables in 32%, and in all 3 variables in 24%. In the placebo group improvement of > or = 50% occurred in 36% for one, 6% for 2, and 6% for 3 variables. Mean morning stiffness decreased 20 min in the active device group and increased 2 min in the placebo group (p < 0.05). No statistically significant differences were observed for tenderness, swelling, or walking time. CONCLUSION: The improvements in clinical measures for pain and function found in this study suggest that pulsed electrical stimulation is effective for treating OA of the knee. Studies for longterm effects are warranted.

Intravenous pulsed steroids in rheumatoid arthritis: a comparative dose study.

This prospective, double blind study was undertaken to test the efficacy of intravenous "minipulse" (100 mg) methylprednisolone (MP) therapy versus standard pulse (1000 mg) MP therapy in rheumatoid arthritis (RA). Thirty-six patients with RA synovitis flares were randomized to receive either 100 or 1000 mg MP IV QD x 3 doses. These 2 universally comparable groups exhibited no statistically significant differences in their striking prompt and sustained clinical improvement. These data suggest that minipulse MP is as efficacious as conventional pulse MP in the treatment of RA flares.

Prevalence of hepatitis B markers in patients and staff in a hospital for the mentally handicapped.

Patients and staff at a hospital for the mentally handicapped were screened for markers of infection with hepatitis B virus. Of 436 patients, 14 (3.2%) were carriers of hepatitis B surface antigen (HBsAg), of whom four were carriers of hepatitis B e antigen (HBeAg) and were considered to be 'infectious'. One-quarter of the patients had markers of hepatitis B infection. Males were four times more likely to have markers than females; and 13 of the 14 carriers of HBsAg were male. Patients with Down's Syndrome (DS) were six times more likely to be HBsAg positive, but were not more likely to have markers of infection than other patients. Phenytoin therapy did not predispose to carriage of HBsAg. Of 439 staff members, 26 (5.9%) had markers of hepatitis B infection. It was not considered that staff were at increased risk of infection with hepatitis B virus at the hospital, and that post-exposure prophylaxis for hepatitis B should continue. It is suggested that patients with DS who are not immune to hepatitis B should be offered immunization.

Transient hyperphosphatasaemia of infancy following rotavirus infection.

A child with transient hyperphosphatasaemia of infancy is reported. The syndrome followed rotavirus infection. Reports of transient hyperphosphatasaemia of infancy are reviewed.

Asplenia syndrome in one of mono-zygotic twins.

One of mono-zygotic twins who had the asplenia syndrome with severe cardiac malformations is described, the other twin being normal. This is the first documented case of situs ambiguus in mono-zygotic twins. The relationship of situs ambiguus to situs inversus, which has previously been described in a number of mono-zygotic twin pairs (some concordant and some discordant) is unclear.