Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases.

Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occur in other types of dementia such dementia with Lewy bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n-3 long-chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the ß-amyloidogenic pathway, including ß-amyloid precursor protein, presenilin 1, ß-secretase, and PrP, are redistributed between lipid rafts and nonraft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy body diseases. In addition, redistribution of proteins linked to the ß-amyloidogenic pathway in DLB can facilitate generation of ß-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly ß-amyloid deposition, in DLB.

Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy.

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P= 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P= 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival.

Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AßPP interaction in early stages of Alzheimer's disease.

In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3-32.0 °C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that ß-secretase/AßPP (amyloid-ß protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AßPP.

Incorporating breast cancer care data into clinical assessment.

Participation in the ONS Foundation-supported Breast Cancer Care Quality Measures Set pilot study was an opportunity for staff at a National Cancer Institute-designated comprehensive cancer center to improve their process for introducing a change in practice. The institution's treatment area revised a documentation tool, and the medical practice area embarked on an education project based on evidence-based practice from the Oncology Nursing Society's Putting Evidence Into Practice initiative. After implementation, an increase in the number of patients being assessed for the quality measures of fatigue and sleep-wake disturbances was noted. In addition, the number of patients being educated on neutropenia using evidence-based information increased.

Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer's disease and facilitates APP/BACE1 interactions.

The presence of lipid alterations in lipid rafts from the frontal cortex in late stages of Alzheimer's disease (AD) has been recently demonstrated. Here, we have isolated and analyzed the lipid composition of lipid rafts from different brain areas from control and AD subjects at initial neuropathologic stages. We have observed that frontal cortex lipid rafts are profoundly altered in AD brains from the earliest stages of AD, namely AD I/II. These changes in the lipid matrix of lipid rafts affected both lipid classes and fatty acids and were also detected in the entorhinal cortex, but not in the cerebellum from the same subjects. Paralleling these changes, lipid rafts from AD frontal and entorhinal cortices displayed higher anisotropy for environment-sensitive probes, indicating that lipid changes in AD lipid rafts increased membrane order and viscosity in these domains. The pathophysiological consequences of these alterations in the development and progression of AD were strengthened by the significant, and specific, accumulation of ß-secretase within the lipid rafts of AD subjects even at the earliest stages. Our results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing of amyloid precursor protein.

Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson's disease and incidental Parkinson's disease.

Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders.

In vitro and in vivo laser treatments of tattoos: high efficiency and low fluences.

OBJECTIVE: To analyze the absorption of tattoo inks related to their in vivo and in vitro behavior under laser irradiation to improve laser-assisted tattoo removal. DESIGN: The absorption of 21 tattoo inks in a wavelength range from 300 to 800 nm was characterized by reflection spectroscopy from samples consisting of inks mixed in gelatin. Tattoo inks were removed in vitro using pulsed laser radiation with different variables, and morphologic analysis of the irradiated areas was performed. SETTING: An interdisciplinary laser laboratory with a common industrial project with the Spanish company Milesman S.A. PARTICIPANT: One person was voluntarily tattooed with 2 of the studied inks. MAIN OUTCOME MEASURES: (1) First approach to the optimum dose for pigment removal in in vitro models. (2) Correlation between the in vitro and in vivo situations at the optimum dose. RESULTS: Reflection spectroscopy facilitated selection of the most adequate laser wavelengths for tattoo removal. Red, orange, and rose inks were successfully lightened at 532 nm with 0.6 J/cm2; brown at 1064 nm with 0.3 J/cm2; yellow and green at 448 nm with 2.6 J/cm2; and blue at 600 nm with 0.9 J/cm2. Similar colors in in vitro and in vivo tattoos responded with the same efficiency to the laser variables. CONCLUSIONS: High efficiency is reached in the removal of in vivo tattoos by using an irradiation wavelength at which the percentage of reflection from the pigment is minimal. Under this condition, laser pulses can be used with a low fluence, minimizing adverse effects and clinical time.

Zinc finger proteins act as transcriptional repressors of alkaloid biosynthesis genes in Catharanthus roseus.

In Catharanthus roseus cell suspensions, the expression of several terpenoid indole alkaloid biosynthetic genes, including two genes encoding strictosidine synthase (STR) and tryptophan decarboxylase (TDC), is coordinately induced by fungal elicitors such as yeast extract. To identify molecular mechanisms regulating the expression of these genes, a yeast one-hybrid screening was performed with an elicitor-responsive part of the TDC promoter. This screening identified three members of the Cys(2)/His(2)-type (transcription factor IIIA-type) zinc finger protein family from C. roseus, ZCT1, ZCT2, and ZCT3. These proteins bind in a sequence-specific manner to the TDC and STR promoters in vitro and repress the activity of these promoters in trans-activation assays. In addition, the ZCT proteins can repress the activating activity of APETALA2/ethylene response-factor domain transcription factors, the ORCAs, on the STR promoter. The expression of the ZCT genes is rapidly induced by yeast extract and methyljasmonate. These results suggest that the ZCT proteins act as repressors in the regulation of elicitor-induced secondary metabolism in C. roseus.