Differential effects of phototherapy, adalimumab and betamethasone-calcipotriol on effector and regulatory T cells in psoriasis.

BACKGROUND: Psoriasis is a chronic T-cell-mediated skin disease with marked social and economic burdens. Current treatments are unsatisfactory, with unpredictable remission times and incompletely understood modes of action. Recent advances in our understanding of the pathogenesis of psoriasis have identified the imbalance between CD4+ T effector cells, particularly the T helper (Th)17 subset, and regulatory T cells (Tregs) as key to the development of psoriatic lesions, and therefore a novel therapeutic target. OBJECTIVES: To quantify in patients the effects of three commonly used psoriasis treatment modalities on the Th1, Th2, Th17 and Treg subsets, and to test whether any change correlates with clinical response. METHODS: Flow cytometry was used to enumerate Th1, Th2, Th17 and Treg subsets in blood and skin of patients with psoriasis before and after receiving any of the following treatments: narrowband ultraviolet B (NB-UVB), adalimumab and topical betamethasone-calcipotriol combination (Dovobet® ) RESULTS: All patients responded clinically to the treatments. NB-UVB significantly increased the numbers of circulating and skin Tregs, while, by contrast, adalimumab reduced Th17 cells in these compartments, and Dovobet had dual effects by both increasing Tregs and reducing Th17 cells. CONCLUSIONS: The differential effects reported here for the above-mentioned treatment modalities could be exploited to optimize or design therapeutic strategies to overcome the inflammatory drivers more effectively and restore the Th17-Treg balance in psoriasis.

Determination of natural and depleted uranium in urine at the ppt level: an interlaboratory analytical exercise.

An analytical exercise was initiated in order to determine those procedures with the capability to measure total uranium and uranium (238U/235U) isotopic ratios in urine samples containing >0.02 microg U kg-1 urine. A host laboratory prepared six identical sets of twelve synthetic urine samples containing total uranium in the range of 25 to 770 ng U kg-1 urine and with 238U/235U isotopic ratios ranging from 138 (100% NU) to 215 (51% DU). Sets of samples were shipped to five testing laboratories (four based in Canada and one based in Europe). Each laboratory utilized one of the following analytical techniques: sector field inductively coupled plasma mass spectrometry (ICP-SF-MS), quadrupole inductively coupled plasma mass spectrometry (ICP-Q-MS), thermal ionization mass spectrometry (TIMS), and instrumental/delayed neutron activation analysis (I/DNAA), in their analyses.

An examination of uranium levels in Canadian forces personnel who served in the Gulf War and Kosovo.

A uranium bioassay program was conducted involving 103 active and retired Canadian Forces personnel. The total uranium concentrations in each of two 24-h urine collections were analyzed separately at independent commercial laboratories by inductively coupled plasma mass spectrometry (ICP-MS) and by instrumental neutron activation analysis (INAA). The mean and median concentrations were determined to be 4.5 ng L(-1) and 2.8 ng L(-1), respectively, from ICP-MS and 17 ng L(-1) and 15 ng L(-1), respectively, from INAA. The total uranium concentrations were sufficiently low so that isotopic (238U:235U ratio) assays could not be performed directly from urine samples. Isotopic assays were performed on hair samples from 19 of the veterans participating in the testing. The isotopic hair assays were scattered around the natural 238U:235U ratio of 137.8, ranging from 122 +/- 21 to 145 +/- 16 (1sigma). Due to concern expressed in the media over possible depleted uranium exposure and long-term retention in bone, a single bone sample (vertebrate bone marrow) from a deceased member of the Canadian Forces was also analyzed for total uranium content and isotopic ratio by ICP-MS. The sample was shown to have 16.0 +/- 0.3 microg kg(-1) uranium by dry weight and a 238U:238U isotopic ratio of 138 +/- 4, consistent with natural uranium.

Hyperthermia and chemotherapy: preclinical considerations.

Malignant cells appear to be selectively sensitive to thermal injury. The precise mechanism of cell death after thermal exposure has not been established, but the phenomenon has been demonstrated by both in vitro and in vivo techniques. Synergy of hyperthermia and chemotherapy has been demonstrated for several agents, but in vitro results are not uniformly confirmed in vivo. In some agents (methyl-CCNU) no synergy was found in vivo. In others (adriamycin) synergy was only demonstrated at drug doses with intolerable toxicity. Studies of the effects of hyperthermia on drug pharmacokinetics are desirable for future clinical trial design.

In vitro uptake of calcium by dermis of patients with pseudoxanthoma elasticum.

The calcification of dermal elastic fibers is a characteristic feature of affected skin from patients with pseudoxanthoma elasticum (PXE). Punch biopsies of normal skin and of affected and unaffected skin from patients with PXE were obtained to study dermal calcification in vitro. Before incubation, the calcium, magnesium, and phosphorus content of normal and PXE unaffected dermis were similar and that of PXE affected dermis was significantly higher. Dermal samples were incubated for 2 and 4 days at 37 degrees C. in a calcium phosphate buffer and the Ca and P content were measured. After 4 days of incubation, both PXE affected and unaffected dermis took up significantly more Ca and PO4 than normal dermis. Thus in vitro uptake study could clearly distinguish between normal and PXE dermis. PXE is a disease of variable expression and mild or subclinical forms are difficult to diagnose. Dermal biopsies from clinicallu normal relatives of patients with PXE were obtained and the in vitro uptake of Ca and PO4 was measured. The results show that several of these individuals had elevated uptakes of Ca and PO4 similar to the unaffected dermis of the PXE patient. The results suggest that this test may be used as a diagnostic aid in the detection of individuals with mild forms of PXE and may be a genetic marker for PXE.