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The RAS signaling pathway is constitutively activated in psoriatic keratinocytes. We expressed activated H-RAS(V12G) in suprabasal keratinocytes of adult mice and observed rapid development of a psoriasis-like skin phenotype characterized by basal keratinocyte hyperproliferation, acanthosis, hyperkeratosis, intraepidermal neutrophil microabscesses, and increased T helper type 1 (Th1)/Th17 and T cell type 1 (Tc1)/Tc17 skin infiltration. The majority of skin-infiltrating CD8(+) T cells coexpressed IFN-γ and IL-17A. When RAS was expressed on a Rag1-/- background, microabscess formation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation were suppressed. Depletion of CD8(+), but not CD4(+), T cells reduced cutaneous and systemic inflammation, the RAS-induced increase in cutaneous Th17 and IL-17(+) γδ T cells, and epidermal hyperproliferation to levels similar to a Rag1-/- background. Reconstitution of Rag1-/- inducible RAS mice with purified CD8(+) T cells restored microabscess formation and epidermal hyperproliferation. Neutralization of IFN-γ, but not of IL-17A, in CD8(+) T-cell-reconstituted Rag1-/- mice expressing RAS blocked CD8-mediated skin inflammation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation. These results show that CD8(+) T cells can orchestrate skin inflammation with psoriasis-like pathology in response to constitutive RAS activation in keratinocytes, and this is primarily mediated through IFN-γ.

The average free choline level was determined to be 14 mumol/L in peritoneal dialysates and 22 mumol/L in the plasma of 30 patients on continuous ambulatory peritoneal dialysis (CAPD). Daily choline loss via dialysate averaged 129 mumol with 32 mumol choline lost per dwell. Daily choline loss via the dialysate was positively correlated with plasma choline concentrations. Choline levels in dialysate during CAPD exceed plasma levels of choline 9 mumol/L in healthy individuals.

The average free choline level was determined to be 14 M in peritoneal dialysates and 22 M in plasma of thirty patients on continuous ambulatory peritoneal dialysis (CAPD). Daily choline loss via dialysate averaged 129 moles with 32 moles choline lost per dwell. Daily choline loss via the dialysate was positively correlated with plasma choline concentrations. Choline levels in dialysate during CAPD exceed plasma levels of choline (9 M) in healthy individuals.

Urinary tract infections (UTI) due to gram-negative bacteria are a serious complication in patients with polycystic kidney disease (PKD). Endotoxin, a component of the cell wall of gram-negative bacteria, has been reported to be pro-cystogenic in experimental animals. Because endotoxin levels in urines (endotoxiuria) from PKD patients have not been reported, the Limulus amebocyte lysate (LAL) assay, which detects picogram quantities of endotoxin, was used to probe for this cyst-promoting chemical. Fifteen PKD patients (seven females, eight males), asymptomatic for UTI, were tested and compared with 10 female and 10 male controls. All urines were assessed for (1) evidence of aerobic bacteria by routine quantitative cultures, (2) bacteria and pyuria by microscopic examination of gram-stained urine, and (3) bacterial endotoxin by the LAL assay. LAL tests were positive in 73% (11/15) of PKD patients, but only 25% (5/20) of controls (P = 0.0058). There was no significant difference in test positivity between PKD females (71%) and males (75%). There was no correlation of age, degree of renal dysfunction, or urine osmolality with endotoxiuria. Routine quantitative cultures were negative for gram-negative bacteria in PKD patients and all controls (except one female), as were microscopic findings for intact bacteria and pyuria. Thus endotoxiuria, in the absence of classical signs, symptoms, and microbiological findings of UTI, raises the possibility that endotoxin is available intrarenally to promote cystogenesis even before a potential susceptibility of PKD patients to classical UTI is manifested. Sources of urinary endotoxin observed in PKD patients, such as cryptic intrarenal sites or leakage from the gastrointestinal (GI) tract, remain to be defined.