Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax,bcl-xS) gene expression

Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2, IL-4, IL-7 and IL-15, which can all signal through the γ chain of the IL-2R (IL-2Rγ), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes (bcl-2 and bcl-x_L), but causes little change in expression of bax and bcl-x_S, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common γ chain cytokines can be dissociated. Thus, when proliferation is blocked, the common γ chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common γ chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common γ-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).     

Quantitative coronary arteriography: design and validation

The authors assessed the performance of an automatic and rapid coronary quantification method by evaluating its accuracy in a stenosis phantom. Measurements were obtained with a lucite phantom with 2-, 3-, and 4-mm vessel diameters and concentric stenoses of 33%, 50%, 67%, and 75%. Direct digital angiographic images as well as 10 X 10 spot films and 35-mm cine angiography films were acquired with and without structural noise and mask subtraction. The films were digitized with magnification factors of one and two. An interactive analysis program was used to automatically determine the vessel edges with a Gaussian fit to the cross-sectional density profiles perpendicular to the center line of the vessel. Relative changes of the densitometric cross-sectional area along the vessel were used to assess the percentage of stenosis. Densitometric measurements were comparable in both digital and cine angiograms (r = .99 and r = .98, respectively); however, diameter measurements showed a higher variability and were dependent on the amount of magnification applied to the images.     

Inappropriate antidiuretic hormone secretion in Wernicke's encephalopathy

A case of the syndrome of inappropriate secretion of antidiuretic hormone in association with Wernicke''s encephalopathy is described, where both responded to intravenous vitamin B complex. Thiamine may be life-saving in hyponatraemia with neurological signs due to Wernicke''s encephalopathy.     

Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma

Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor.(Pathology Oncology Research Vol 12, No 3, 184–187)     

Ciclazindol: An oral agent with weight reducing properties and hypoglycaemic activity

In a single blind crossover study, ciclazindol, 10-(m-chlorophenyl)-2, 3, 4, 10-tetrahydropyrimide (1, 2 alpha) indol-10-ol hydrochloride (Fig. 1), has been found to have hypoglycaemic action, and to produce reduction in appetite and weight. The mode of action appears to be different from either biguanides or sulphonylureas. Side-effects were few and mild. Metformin 500 mg b.d. had comparable hypoglycaemic effect but did not suppress appetite. Ciclazindol may be useful as a mild oral hypoglycaemic agent for obese patients, and would be suitable for once daily administration.     

Sunglasses: are they necessary in Christchurch?

Concern over potential eye injury from sunlight prompted this study to see if the levels of sunlight in Christchurch posed a particular risk to our population's eyes, whether the populace was aware of any risk and whether effective sunglasses were freely available to the public. While there has been a 4% to 9% increase in UV radiation since 1969 due to global ozone depletion, no firm evidence was found that focal ozone depletion was a particular problem in New Zealand. Christchurch residents were poorly informed about the ocular hazards of sunlight. A questionnaire completed by 200 adults disclosed 32% were unaware of the particular danger of UV light and only 3% knew that snow blindness, eclipse burns and cataracts could all be caused by sunlight. Fifty-four sunglasses were analysed for labelling and for transmission characteristics of their lenses. The standard of labelling of the sunglasses was poor with only 53% making reference to UV transmission characteristics and only three pairs stating that they adhered to the New Zealand Sunglass Standard. Attention is drawn to the need to improve public awareness of the potential for eye injury from sunlight and to improve the standard of labelling of sunglasses.     

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics

A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).