The design and synthesis of purine inhibitors of CDK2. III.

Cyclin-dependent kinases (CDKs) belong to a class of enzymes that control the ability of a cell to enter into and proceed through the cell division cycle. Using purine as a scaffold, we have synthesized a number of nanomolar inhibitors of CDK-2/cyclin E. In this report, the synthesis of a series of piperidine-substituted purine analogs will be presented, as well as some of their in vitro and in vivo biological effects.

Tuberculosis contact tracing: are the British Thoracic Society guidelines still appropriate?

The value of contact tracing in South Glamorgan for the period May 1987 to December 1989 was assessed. Tuberculosis was diagnosed in six (3.5%) of 170 close contacts. All were young and were detected in the initial screening. Tuberculosis was not found among 441 casual contacts. The value of follow up of contacts after the initial screening and of screening casual contacts in districts with a low prevalence of tuberculosis is questioned.

Audit of a tuberculosis contact tracing clinic.

OBJECTIVE: To determine the efficiency of tuberculosis contact tracing in South Glamorgan 1987-9. DESIGN: Review of records of contact tracing clinic and of data from the Mycobacterium Reference Unit. The clinic's practice was compared with 1983 British Thoracic Society's recommendations. SETTING: Health authority tuberculosis control programme. MAIN OUTCOME MEASURES: Proportion of contacts screened, follow up attendance rates, number of secondary cases detected, and quality of record keeping. RESULTS: 101 index patients and 611 contacts were identified. 596 (97.5%) contacts were screened, of whom 139 should not have been. Of 356 contacts requiring a Heaf test, 237 were tested, seven refused the test, and 112 had chest radiography without a Heaf test. 95 contacts were unnecessarily tested. 87 contacts had chest radiography unnecessarily and seven should have had radiography but did not. 34 contacts were given follow up appointments inappropriately and seven were overlooked for follow up. Tuberculosis was diagnosed in five asymptomatic contacts, all at initial screening and all close contacts of index patients with pulmonary disease. CONCLUSION: Inadequacy of data, non-adherence to contact tracing guidelines, and failure to define the term highly infectious index case resulted in many contacts being unnecessarily screened or followed up. IMPLICATIONS: The efficiency of tracing contacts would be improved by specifying smear results and ethnic origin of the index case on the notification form, clearly classifying contacts as close or causal, and clearly defining the term highly infectious.

Synthesis of arachidonate cyclo-oxygenase products by rheumatoid and nonrheumatoid synovial lining in nonproliferative organ culture.

Specimens of human rheumatoid and nonrheumatoid synovial lining were maintained in nonproliferative organ culture for 20 hours. The culture fluids were then assayed for prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)) by specific radioimmunoassay. The presence of each of these substances was confirmed by gas chromatography and mass spectrometry. Rheumatoid tissue produced significantly more of each cyclo-oxygenase product than nonrheumatoid tissue.

The effect of zinc on alkaline phosphatase activity in rheumatoid synovial tissue.

To examine the reported beneficial effect of zinc in rheumatoid arthritis, rheumatoid synovial tissue has been maintained in vitro in non-proliferative culture with or without zinc sulphate in the culture medium. Alkaline phosphatase activity was measured by microdensitometry of the cytochemical reaction in cryostat sections; the activity in blood vessels was measured separately from that in the supporting tissue below the synovial surface. Zinc enhanced this activity optimally at concentrations of between 10(-5) and 10(-4) mol/l.

Effect of glucocorticoids on the hexose monophosphate pathway in human rheumatoid synovial lining cells in vitro and in vivo.

Human rheumatoid synovial lining cells have up to four times the capacity to oxidize glucose 6-phosphate, the first step of the hexose monophosphate pathway, as do the nonrheumatoid cells. The reducing equivalents produced by this system have many significant metabolic effects. Exposure of these cells by 10(-5) M prednisolone in vitro, or to 6 mg/day in vivo, causes some depression of this activity in the rheumatoid synovial lining cells; less than this dose of steroid, or the administration of nonsteroidal drugs in vivo, has little or no effect. The depression of activity produced by 6 mg/day does not bring this activity down to the value found in nonrheumatoid synoviocytes.