Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

Emerging evidence indicates that Huntington's disease (HD) may be described as multi-organ pathology. In this context, we and others have contributed to demonstrate that the disease is characterized by an impairment of the homeostasis of gastro-intestinal (GI) tract. Sphingolipids represent a class of molecules involved in the regulation and maintenance of different tissues and organs including GI system. In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally in R6/2 HD mice. Our findings indicate, for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the potential to counteract the peripheral disturbances which may usually complicate the management of the disease and affect patient's quality of life.

Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a serious adverse drug reaction caused by transient antibodies against platelet factor 4 (PF4)/heparin complexes, resulting in platelet activation and potentially fatal arterial and/or venous thrombosis. Most cases of HIT respond to cessation of heparin and administration of an alternative non-heparin anticoagulant, but there are cases of persisting HIT, defined as thrombocytopenia due to platelet activation/consumption for greater than seven days despite standard therapy. These patients remain at high risk for thrombotic events, which may result in limb-loss and mortality. Intravenous immunoglobulin (IVIg) has been proposed as an adjunct therapy for these refractory cases based on its ability to saturate FcγRIIa receptors on platelets, thus preventing HIT antibody binding and platelet activation. We describe 2 cases of persisting HIT (strongly positive antigen and functional assays, and persisting thrombocytopenia >7 days) with rapid clinical response to IVIg. We performed in-vitro experiments to support IVIg response. Healthy donor platelets (1 × 10e6) were treated with PF4 (3.75 µg/mL) for 20 min followed by 1-hour incubation with patients' sera. Platelet activation with and without addition of IVIg (levels equivalent to those reached in a patient after treatment with 2 gm/Kg) was evaluated in the PF4-dependent P-selectin expression assay (PEA). A significantly decreased platelet activation was demonstrated after the addition of IVIg to both patient samples, which correlated well with the rapid clinical response that each patient experienced. Thus, our study supports the use of IVIg as an adjunct therapy for persisting HIT.

Electrical measurement of moisturizing effect on skin hydration and barrier function in psoriasis patients.

Transepidermal water loss (TEWL) in psoriatic skin lesions seems to be related to the severity of the psoriasis, and the electrical capacitance and conductance of the skin are indicators of the hydration level of the stratum corneum. We compared the characteristics of these electrical measurements, in assessing the persistent effect of a moisturizing cream on skin hydration and barrier function in psoriasis patients. Seventeen Korean psoriasis patients were recruited. Their right leg was treated with the moisturizer twice daily for 6 weeks, while their left leg was used as the control site. For each patient, one psoriatic plaque on each leg was selected as the involved psoriatic lesion. Uninvolved psoriatic skin was regarded as the apparently healthy looking skin 4-5 cm away from the periphery of the psoriatic lesion. The TEWL, electrical capacitance and conductance were measured, in order to evaluate the barrier function and hydration level of the stratum corneum. The clinical and biophysical data for each patient were recorded at the start of the study and after 2, 4 and 6 weeks. The degree of skin dryness at the applied area improved progressively. The electrical capacitance at the treated psoriatic lesion increased significantly after 2 weeks, and this improvement was maintained during the entire study period. However, no noticeable change was observed in the electrical conductance. The TEWL showed an inverse pattern to that of the skin capacitance, decreasing during the study period. The skin capacitance and TEWL exhibited good correlation with the visual assessment of skin dryness, but the skin conductance did not. Our data suggest that electrical capacitance and TEWL may be useful in the evaluation of the effect of a moisturizer on the hydration status and barrier function of psoriatic skin.

The characterization of molecular organization of multilamellar emulsions containing pseudoceramide and type III synthetic ceramide.

To investigate the molecular organization and phase behavior of physiologic lipid mixtures that contain either newly synthesized pseudoceramide or type III synthetic ceramide, various analytical techniques were used. The phase transition temperatures detected in differential scanning calorimetry analysis were 51.19 and 50.52 for the pseudoceramide-containing physiologic lipid mixture and synthetic type III ceramide-containing lipid mixture, respectively. From the small angle XRD patterns, the multilamellar emulsion-pseudoceramide showed 11.5 nm and 7.61 nm lamellar phases, while the multilamellar emulsion-synthetic ceramide showed only a 7.61 nm lamellar phase. The nonceramide containing lipid mixture did not show any distinct repeat pattern. Lateral packing distances of multilamellar emulsion-pseudoceramide and multilamellar emulsion-synthetic ceramide were measured as 0.4119 and 0.4110 nm at 30, respectively, which indicated the presence of hexagonal lattice. On the contrary, non-multilamellar emulsion did not show any definite repeat pattern. Transmission electron microscopy observation showed nearly comparable lamellar structures in all of the tested emulsions compared to the structure of human stratum corneum intercellular lipid. Decrease of water contents resulted in phase transition into liquid phase for all the tested emulsions, whereas phase transition into orthorhombic phase was observed only in multilamellar emulsion-pseudoceramide. From these results, we concluded that the molecular organization of multilamellar emulsion-pseudoceramide was characterized as the lateral hexagonal phase and both the long and short periodicity lamellar phases, which showed structural similarity with the native human stratum corneum intercellular lipid.

Risk factors for an early increase in dose of vasoactive agents for intracavernous pharmacotherapy.

AIMS: This study was to identify factors that influence the early increase in the dose of intracavernous vasoactive agents to maintain erection for satisfactory intercourse and to elucidate when the dose increase would begin. METHODS: Seventy-nine patients using intracavernous pharmacotherapy with tri-mix (PGE(1), papaverine, and phentolamine) over a 3- to 4-year period were enrolled. At 3-month intervals, patients were questioned about changes in dose to maintain erection for satisfactory intercourse and frequency of injection, and underwent examination of the penis. The patients were divided into 2 groups: group A, dose increase of > or = 20% after initiating home therapy, and group B, no change or an increase in dose < 20%. RESULTS: A significant increase (p < 0.01) in dose was started 2-3 years after initiating pharmacotherapy. The initial doses of group A at 2-3 and 3-4 years were significantly higher than those of group B (p < 0.01). There were no significant differences in the age of the patients, duration of erectile dysfunction, incidence of accompanying vascular risk factors, frequency of injection, or incidence of fibrous plaques between group A and group B, both at 2-3 and 3-4 years. CONCLUSION: The initial dose of intracavernous vasoactive agents (tri-mix) may be a unique risk factor for the early increase in dose to maintain erection for satisfactory intercourse.