Altered functional responsiveness of thymocyte subsets from CD3delta- deficient mice to TCR-CD3 engagement

CD3delta-deficient (delta degrees) mice are defective in alphabeta T cell development. Here we explore the capacity of TCR-CD3 signaling complexes expressed on delta degrees thymocytes to mediate the following functional outcomes in response to antibody cross-linking: (i) the transition from the CD4-CD8- to CD4+CD8+ stage, (ii) the transition from the CD4+CD8+ to CD4+CD8- or CD4-CD8+ stages and (iii) the induction of apoptosis. We provide evidence that CD3deltaepsilon complexes are dispensable for mediating the anti-CD3-mediated CD4-CD8- to CD4+CD8+ transition. On the other hand, CD3delta is critical at the CD4+CD8+ stage. We demonstrate that CD4+CD8+ thymocytes from delta degrees mice, unlike delta degrees CD4-CD8- thymocytes and wild-type CD4+CD8+ thymocytes, require prolonged or consecutive stimuli to elicit functional responses. Depending on the nature of the secondary stimulus, delta degrees thymocytes can be induced to undergo apoptosis or preferential maturation to the CD4-CD8+ stage. Taken together these results indicate that the signaling capacity of the TCR-CD3 complex is noticeably altered in the absence of CD3delta. The essential role of CD3delta at the CD4+CD8+ stage of development correlates with the onset of TCRalpha rearrangement, consistent with a critical structural and/or functional relationship between CD3delta and TCRalpha.      

Mounting and calibration of stairs on piezoelectric force platforms

To calculate the centre of pressure using piezoelectric force plates mounted on pads, no net tensile stresses may be imposed on the surface of the plate. This condition is violated when stairs are attached to the plates, unless the plates are preloaded. Typical shear forces encountered when climbing stairs were used to determine required preloads of approximately 16.4 N/cm step height. Vertical and horizontal loads were applied at known locations on the steps, and points of application were calculated. Deviations were within ± 3 mm. The effect of point of application inaccuracy on calculated joint moments is considerable. A 2 cm medial shift in the point of application resulted in calculated peak knee abduction/adduction moment errors of 35%.     

Species differences in response to trichloroethylene. I. Pharmacokinetics in rats and mice

The elimination of radioactivity in two strains of rats and mice following a single po dose of trichloro[14C]ethylene at dose levels from 10 to 2000 mg/kg has shown a marked dose dependence in rats but not in mice. The metabolism of trichloroethylene in the mouse was linear over the range of doses used, whereas in the rat it became constant and independent of dose at 1000 mg/kg and above. At the 10-mg/kg dosage, both species metabolized trichloroethylene almost completely, 60% of the dose being excreted in urine with only 1 to 4% being eliminated unchanged in expired air in the first 24 hr. At 2000 mg/kg, 78% of the dose was eliminated unchanged in the rat, but only 14% in the mouse. Consequently at high dosages, the mouse was exposed to significantly higher concentrations of trichloroethylene metabolites than the rat. Blood level kinetics of trichloroethylene and its metabolites confirmed a faster rate of metabolism in the mouse than in the rat. Peak concentrations of the metabolites were reached within 2 hr of dosing in the mouse compared to 10 to 12 hr in the rat. The concentrations of both trichloroethanol (4X) and trichloroacetic acid (7X) were significantly higher in the mouse than in the rat. Whereas trichloroethanol was rapidly eliminated from blood, the higher concentrations of trichloroacetic acid were maintained for over 30 hr. The high blood quantities of trichloroethylene-derived trichloroacetic acid are known to induce hepatic peroxisome proliferation in mice but are insufficient to induce this response in rats. These data suggest that trichloroacetic acid blood amounts, peroxisome proliferation, and the link between peroxisomes and liver cancer are the basis of species difference in response to trichloroethylene.     

Chemotherapy of advanced prostatic cancer Evaluation of response parameters

A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide, 5 fluorouracil, and standard therapy. Parameters of response were studied in 110 patients who could be evaluated. Thirty-six patients (33 per cent) were considered to have an objective response, that is, becoming stable (29 patients) or in partial regression (7 patients). Negative response parameters (predictors of a poor response to chemotherapy or standard therapy leading to progress) included (1) bone marrow evidence of prostatic cancer, (2) abnormal liver scan, (3) prior radiation therapy (indirectly through increased toxicity to chemotherapy), and (4) luck of bilateral orchiectomy prior to randomization. Positive indicators (predictors of good responses) included (1) reduction of primary tumor mass, especially after administration of 5 fluorouracil or cyclophosphamide, and (2) hemoglobin values. There were more objective responders to cyclophosphamide than standard therapy whether the hemoglobin was initially normal or low. Indeterminate parameters of response included weight gain, presence of bony or soft tissue metastases, relief of pain, performance status, excretory urography, and biochemical determinations of liver and renal function.     

Acute community-acquired pneumonias

Of 81 adult patients with community-acquired pneumonia, bacterial infections were found in 37%, mycoplasma and viral infections in 21%, and tuberculosis in 6%; no pathogen could be identified in 46% of cases. More than one agent was identified in 12% of patients. Streptococcus pneumoniae, the most common pathogen, was found in 63%, Haemophilus influenzae in 26,7%, Staphylococcus aureus in 6,7%, and other Gram-negative organisms in 10% of patients with proven bacterial pneumonia. Most clinical and radiographic features were of little value in differentiating between different aetiological agents, but Gram-stained sputum gave a valuable early guide to therapy in 60% of cases of proven bacterial pneumonia. Blood culture was positive in 13,6% of cases. All the organisms conformed to their usual sensitivity patterns. Since Strept. pneumoniae is the predominant pathogen, penicillin should be the drug of choice in the immediate 'blind' treatment of community-acquired pneumonia.     

Thyroid disease in pregnancy.

It is frequently difficult to establish a diagnosis of hyperthyroidism in association with pregnancy. Signs and symptoms suggestive of hyperthyroidism may occur in normal pregnancy. Moreover, tests to rule out hyperthyroidism under these conditions are not readily available. Mild hyperthyroidism is not a hazard to an otherwise normal pregnancy and does not require therapy on the basis of this presumption. Hyperthyroidism of a clinically significant degree is safely treatable by medical means without hazard to the fetus. Hyperthyroidism is an uncommon cause for the failure of pregnancy to proceed to term. Treatment with thyroid based on a presumption of this diagnosis is justified, but such patients should be studied carefully after delivery to establish the true state of thyroid function for the future. Other conditions of thyroid dysfunction, including thyroiditis, thyroid carcinoma, nontoxic goiter, and ovarian struma rarely interfere with an otherwise normal pregnancy.