Effects of Bilateral Hearing Aid Use on Balance in Experienced Adult Hearing Aid Users.

PURPOSE: The purpose of this study was to evaluate the balance of experienced adult hearing aid users with and without their hearing aids via computerized posturography. METHOD: Computerized posturography was accomplished by employing the Sensory Organization Test (SOT) on the NeuroCom Balance Master (Natus Medical Incorporated). The SOT assessed each participant's balance and the strategy used to maintain balance in 6 progressively challenging conditions. Twenty-two adults using bilateral at-the-ear hearing aids participated in the study. All participants completed all SOT protocols with and without their hearing aids. RESULTS: No statistically significant differences in participants' balance were identified regardless of the presence or absence of their hearing aids during the SOT. CONCLUSIONS: These results failed to support previous research, which indicated that amplification of auditory input could benefit balance in individuals with hearing and balance disorders. Further research utilizing randomized controlled trials is needed to resolve the disparity between the current results and those of previous studies.

Meta-analysis of cytokine gene polymorphisms and outcome of heart transplantation.

We performed a systematic review and meta-analysis with the aim of assessing the association between cytokine gene polymorphisms and graft rejection in heart transplantation. We identified relevant studies from Medline and Embase using PubMed and Ovid search engines, respectively. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Four to 5 studies were included in pooling of 3 gene polymorphisms. The prevalences of the minor alleles for TNF α -308, TGF ß 1-c10, and TGF ß 1-c25 were 0.166 (95% CI: 0.129, 0.203), 0.413 (95% CI: 0.363, 0.462), and 0.082 (95% CI: 0.054, 0.111) in the control groups, respectively. Carrying the A allele for the TNF α -308 had 18% (95% CI of OR: 0.46, 3.01) increased risk, but this was not significant for developing graft rejection than the G allele. Conversely, carrying the minor alleles for both TGF ß 1-c10 and c25 had nonsignificantly lower odds of graft rejection than major alleles, with the pooled ORs of 0.87 (95% CI: 0.65, 1.18) and 0.70 (95% CI: 0.40, 1.23), respectively. There was no evidence of publication bias for all poolings. An updated meta-analysis is required when more studies are published to increase the power of detection for the association between these polymorphisms and allograft rejection.

Early expression profile of inflammatory markers and kidney allograft status.

Cellular rejection after renal transplantation, in general, occurs as a result of an interaction between immunologic processes that maintain graft tolerance versus allograft rejection. A potential mechanism that triggers such processes might be through the activation of the innate immune response initiated during organ procurement and ischemia/reperfusion injury, contributing to delayed graft function or graft dysfunction. Our goal was to test the impact of molecular markers that have key roles in innate immunity such as cytokines, Toll-like receptors (TLRs), and allograft inflammatory factor-1 (AIF- 1) at early times after transplantation. Blood samples from a total of 90 patients who received kidney transplants were included in this study. Three samples from each patient at different time intervals (pretransplantation, day 3, and day 6 after transplantation) were tested using a quantitative reverse transcriptase polymerase chain reaction. The mRNA transcripts were tested in association with glomerular filtration rates (GFR) as a measure of allograft function. Surgical samples obtained from transplant nephrectomy were used in a tissue array for immunohistochemistry testing. In peripheral blood mononuclear cells, the mean ± standard error of mean (SEM) for interleukin 18 (IL-18), and IL-10 mRNA expression were increased and interferon-γ was decreased in association with high GFR post-transplantation as compared with the pretransplantation expression levels. The mean ± SEM for expression level of AIF-1 was increased 1.5-fold and for TLR-2 and TLR-4 were increased 1.2 to 1.4-fold in samples obtained on day 6 post-transplantation in association with low GFR (P < .05). In neutrophils, the mean ± SEM levels of TLR-2 mRNA was increased 2-fold on day 6 in association with high GFR (P < .005), but was reduced 2.8-fold in association with low GFR (P < .002). In conclusion, the mRNA profiles of biomarkers presented here appeared to be informative for prediction of allograft status and outcome.

The association between cytokine gene polymorphisms and graft rejection in liver transplantation: a systematic review and meta-analysis.

We investigated the contribution of polymorphisms in cytokine genes (TNFa-308, IL10-1082 and -592, TGFb1-c10 and c25, and IFNg+874) on the risk of graft rejection in liver transplantation. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. In total, 12 studies were eligible and included in the study. Data extraction and assessments for risk of bias were independently performed by two reviewers. Data for allele frequencies, allelic, and genotypic effects were pooled. Heterogeneity and publication bias were assessed. Pooled minor allele frequencies for TNFa-308, IL10-1082, TGFb1-c10, TGFb1-c25, IFNg+874, and IL10-592 were 0.140 (95% CI: 0.083, 0.198), 0.432 (95% CI: 0.392, 0.472), 0.387 (95% CI: 0.307, 0.467), 0.090 (95% CI: 0.056, 0.123), 0.460 (95% CI: 0.392, 0.528), and 0.224 (95% CI: 0.178, 0.269), respectively. OnlyTNFa-308 and IL10-1082 polymorphisms were significantly associated with graft rejection. Patients who carried minor homozygous genotypes for these two polymorphisms were at 3.5 and 1.69 times higher risk of graft rejections than patients who carried major homozygous genotypes. The estimated lambdas were 0.41 and 0.47, suggesting an additive mode of effect was most likely. However, we could not detect the associations of TGFb1at c10 and c25, INFg+874, and IL10-592 polymorphisms and graft rejection. In summary, our systematic review has demonstrated that TNFa-308 and IL10-1082 are potential risk factors of poor outcomes in liver transplantation. Future updated meta-analysis studies to confirm the power of these genotypes in association with allograft rejection are needed.

Differential association of cytochrome P450 3A4 genotypes with onsets of breast tumors in African American versus Caucasian patients.

INTRODUCTION: Malignant breast tumors are often hormone-dependent, and to this end, both estrogen and progesterone receptors are good prognostic markers for evaluation of the outcomes after therapy. In addition, HER-2/neu, whose expression is increasingly being associated with poor prognosis of breast cancer, has predictive potential after immunotherapy. Cytochrome P450 3A4 is highly involved in the metabolism of steroids. Thus, we investigated the impact of CYP 3A4 gene variants in association with clinical outcomes in African American (AFAM) versus Caucasian (CAU) patients with breast cancer diagnosis. METHODS: Patients who had undergone biopsy procedures for diagnosis or for partial or radical mastectomy were recruited. The CYP 3A4 genotypes (A or G) were detected using polymerase chain reaction amplification and primers designed for a single nucleotide polymorphism. The messenger RNA (mRNA) transcripts were screened by reverse transcription-polymerase chain reaction. Clinical data including tumor staging, pathology grades, and family history were evaluated. RESULTS: Frequency of the CYP 3A4-G (mutated variant) was significantly increased in AFAM patients as compared with controls (P < 0.001). No statistically significant difference was observed between the genotypes comparing the benign versus ductal carcinomas in situ (DCIS) or infiltrating ductal carcinomas (IDCAs). In AFAM patients, GG alleles were increased in IDCA with stage III tumors, and in CAU patients, the AA alleles were increased with stage III tumors. The mRNA expression was reduced in patients with IDCA versus DCIS or benign tumors (benign vs IDCA, P < 0.0009; DCIS vs IDCA, P < 0.005), as well in HER-2/neu-positive tumors versus samples negative for receptors (P < 0.0024). CONCLUSIONS: Genotype association was affected by race. Expression levels of total CYP 3A4 mRNA were inversely correlated with clinical diagnosis. This may suggest mRNA testing as an additional tool that accelerates improvement in the diagnosis of the onsets of breast cancer.

Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1.

BACKGROUND: Evidence suggests that injury-induced activation of the recipient's innate immune response determines the outcome of allograft transplantation. The mechanism responsible for the induction of such innate immune response is not clear yet. We hypothesized that in cardiac transplantation settings, the initial myocardial ischemia and postischemia graft reperfusion may release allograft inflammatory factor (AIF) 1, causing Toll-like receptor (TLR)-mediated activation of macrophages and dendritic cells, leading to the production of cytokines and the activation of adaptive alloimmunity. Therefore, our goal was to validate the presence of these biomarkers in the peripheral blood and biopsy specimens of patients presenting allograft rejection. METHODS: We studied 90 peripheral blood and 30 endomyocardial biopsy specimens from patients who had undergone cardiac transplantation. Specimens were tested by quantitative reverse-transcription polymerase chain reaction to determine TLR-2 and -4 and AIF-1 expression levels, correlating with clinical rejection grades. The group differences for mRNA transcript levels between the rejection grades were determined by 1-way analysis of variance. The level of significance was set at P < .05 for comparison between the groups. RESULTS: The mean ± SEM level of TLR-2 mRNA expression was increased 1.7-fold in monocytes (P < .05) and 4.2-fold in biopsy samples from groups with grade 3A compared with grade 1A or grade 0 rejection (P < .0001). AIF-1 expression was increased 2.4-fold in monocytes (P < .05) and 4.2-fold in biopsy samples comparing grade 3A versus 1A rejections. The TLR-4 mRNA expression was also increased in the group with 3A rejections; however, the difference was only significant in biopsy specimens (P < .0001). CONCLUSIONS: Our data demonstrated that expression profiles of AIF-1 and TLR-2 correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting their potential as diagnostic biomarkers for early detection of allograft rejection.

Combined analysis of allograft inflammatory factor-1, interleukin-18, and Toll-like receptor expression and association with allograft rejection and coronary vasculopathy.

In cardiac transplantation settings, the initial myocardial ischemia and reperfusion may cause myocyte tissue injury and the release of allograft inflammatory factor-1 (AIF-1). This in part may trigger the innate immune response through the modulation of Toll-like receptor-2 (TLR-2) and AIF-1 expression and function, causing the release of proinflammatory cytokines. The goal was to demonstrate these markers in the peripheral blood and biopsy specimen from recipients with cardiac allograft rejection and coronary vasculopathy (CV). Peripheral blood and endomyocardial specimens were tested by reverse transcriptase-polymerase chain reaction and immunohistochemistry stains for identification of TLR-2, -4, interleukin-18, and AIF-1 markers and analyzed against clinical rejection grades for rejection. The differences for mRNA transcript levels were determined by one-way analysis of variance. The mRNA expression levels were significantly varied for TLR-2 in monocytes with different rejection grades (P < 0.0001). The mean +/- SEM level of mRNA expression for 3A grade rejection was 64.21 +/- 3.8; grade 1A, 38.4 +/- 3.5; and for Grade 0 was 38.46 +/- 2.8. The TLR-4 mRNA expression was increased but the specificity was not statistically significant. The TLR-2 immunoreactivity was strongly detected in infiltrating mononuclear cells and cardiac myocytes in Grade 3A rejection. AIF-1 expression was increased significantly in the group with 3A rejection and Grade III CV as compared with Grade 0 or 1A. Interleukin-18 receptors were strongly detected in Grade 3A rejection and CV. The expression profiles of AIF-1, TLR-2, and interleukin-18 were correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection.

Varying ratios of wavelengths in dual wavelength LED photomodulation alters gene expression profiles in human skin fibroblasts.

BACKGROUND AND OBJECTIVE: LED photomodulation has been shown to profoundly influence cellular behavior. A variety of parameters with LED photomodulation can alter cellular response in vitro. The effects of one visible and one infrared wavelength were evaluated to determine the optimal ratio to produce a net increase in dermal collagen by altering the ratio of total energy output of each wavelength. The ratio between the two wavelengths (590 and 870 nm) was shifted in 25% increments. STUDY DESIGN/MATERIALS AND METHODS: Human skin fibroblasts in culture were exposed to a 590/870 nm LED array with total combined energy density fixed at 4.0 mW/cm.. The ratio of 590/870 nm tested parameters were: 100/0%, 75/25%, 50/50%, 25/75%, and 0/100%. These ratios were delivered using pulsed duty cycle of exposure (250 milliseconds "on" time/100 milliseconds "off" time/100 pulses) for a total energy fluence of 0.1 J/cm.. Gene expression was examined using commercially available extra cellular matrix and adhesion molecule RT PCR Arrays (SA Biosciences, Frederick, MD) at 24 hours post-exposure. RESULTS: Different expression profiles were noticed for each of the ratios studied. Overall, there was an average (in an 80 gene array) of 6% expression difference in up or downregulation between the arrays. The greatest increase in collagen I and decrease in collagenase (MMP-1) was observed with 75/25% ratio of 590/870 nm. The addition of increasing proportions of IR wavelengths causes alteration in gene expression profile. The ratios of the wavelengths caused variation in magnitude of expression. CONCLUSIONS: Cell metabolism and gene expression can be altered by simultaneous exposure to multiple wavelengths of low energy light. Varying the ratios of specific wavelength intensity in both visible and near infrared light therapy can strongly influence resulting fibroblast gene expression patterns.

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data.

BACKGROUND: Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation. METHODS: Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age. RESULTS: One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for >/=3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6). CONCLUSION: Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

Molecular analysis of inflammatory markers in trauma patients at risk of postinjury complications.

BACKGROUND: Genetic differences associated with individual's immune responses appear to be a major contributing factor to the development of trauma- induced sepsis. Thus, effective treatment of sepsis requires the identification of the patients who are at increased risk for sepsis. METHODS: Sixty-eight patients, of which the majority had an injury severity score >15, and 118 controls from the same geographic region were genotyped. Cytokine and Toll-like receptor (TLR) genotypes and expressions were tested using polymerase chain reaction (PCR). RESULTS: Fifty percent of African American and 42% of Caucasian patients developed posttrauma sepsis. Frequency distribution of the polymorphism for some cytokine genes such as Interleukin (IL)-10 low/high and interferon (IFN)-gamma low producer were statistically different between the septic and aseptic patients, for others, such as tumor necrosis factor (TNF)-alpha, IL-6, and IL-18, there was no statistical difference. The TLR-2 genotypes (A/G) were considered a sepsis risk marker as compared with A/A (62.5% versus 37.5%, p < 0.03; relative risk = 2.5) in African American patients. Cytokine mRNA levels correlated with genotype definition, particularly, for IL-10, IL-6, IL-18, and TNF-alpha. A time course study demonstrated a significant difference in cytokines expression profile in septic and aseptic patients before the development of sepsis. CONCLUSION: Monitoring cytokine expression levels before the disease might predict the outcome of sepsis. A large cohort study is needed to assess the diagnostic potential of the genotypes.

Role of biomarkers in incisional hernias.

Incisional hernias represent one of the most common complications of laparotomies. Previous investigations have suggested that a disorder in collagen fiber structure and production level may be an important pathologic cause of abdominal wall hernias. We hypothesized that a cross-examination of multiple extracellular matrix biomarkers might identify underlying defects contributing to the development of hernias. We examined two patient populations: patients with incisional hernias (presenting for hernia repair) and patients with no hernia after previous laparotomy (undergoing a second laparotomy). Patients with previous wound infections, open abdomens, or on steroids were excluded. Fascia samples were obtained from all patients at the time of their second operation and they were studied. Western blots and reverse transcriptase-polymerase chain reaction were used to determine the ratio of type I, III, and IV collagens, as well as matrix metalloproteinase 1 (MMP1) and MMP2 in both groups. Values of P < 0.05 were considered statistically significant. At the protein level, collagen I/III ratio was slightly decreased in patients with incisional hernias compared with those with no hernia, whereas it was significantly decreased at the mRNA transcript level (0.49 vs 1.03, P < 0.01, respectively). The MMP-1 mRNA transcripts were not different in incisional hernia (IH) versus nonincisional hernia, but the MMP-2 level was significantly increased in patients with IH. Reduced collagen I/III and MMP-1/MMP-2 ratios in IH might be consequence of the biological activities between key elements participating in the development of IH after laparotomies. The potential role of MMP-2-specific inhibitors in preventing IH is of significance for future studies.

Results of a remediation program for students at risk for failure on the NCLEX exam.

Forty-seven nursing students identified as at risk for failure on the NCLEX licensure exam took a commercially available exit exam before and after participation in a remedial test-taking course. Results indicated that participation in the course contributed to a significant increase (p < .001) in exit exam scores.

Frequency distribution of cytochrome P450 3A4 gene polymorphism in ethnic populations and in transplant recipients.

CYP 3A4 plays a vital role in the metabolism of many drugs including immunosuppressants. An association between a transition of A --> G at position -290 of the 5'-regulatory region of the CYP 3A4 gene and an effect on the level of transcription has been reported. The CYP 3A4-G variant frequency varies substantially in different populations. In addition it has been demonstrated in association with several disease conditions, including clinical grades of prostate cancer, breast cancer, secondary leukemia, hypercholesterolemia and diabetes. We sought to determine the frequency distributions, in African American (AFAM) and Caucasian (CAU) populations as well as patients with multiple complex diseases, such as those that had undergone cardiac or renal transplantation. Sequence-specific primers and PCR were used to determine genotype variation in 206 AFAM and 108 CAU individuals. CYP 3A4-G genotype was present with a higher frequency in AFAM individuals as compared with CAU (83% vs. 3%, p < 0.0001, RR = 3.9). The homozygous AA allele was predominantly present in CAU (97%) but only 17% in AFAM (p < 0.0001, RR = 2.5). In contrast, the homozygous GG allele was only detected in AFAM group (14.6%). The frequency distribution of homozygous GG and AA alleles were inversely present in male vs. female patients with CTx or RTx. Pre-transplantation clinical conditions demonstrated that hypertension (HTN), hyperlipidemia and to a lesser extent diabetes (DM) were present in CTx and RTx patients with homozygous GG alleles. In addition, 75% of AFAM patients with homozygous GG genotype experienced multiple rejection episodes with severity grades of 3A after cardiac transplantation, and 31.5% of homozygous GG patients with RTx suffered from rejections (p < 0.05; RR = 2.4). In conclusion, CYP 3A4 genotype demonstrated a remarkable interindividual variation between AFAM and CAU populations, and furthermore CTx patients with homozygous GG genotype were at higher risk of developing rejection as compared with RTx patients. This indicates an underlying heterogeneity with regard to the disease characteristics as well as the therapy regimen.

Theoretical z -pinch scaling relations for thermonuclear-fusion experiments.

We have developed wire-array z -pinch scaling relations for plasma-physics and inertial-confinement-fusion (ICF) experiments. The relations can be applied to the design of z -pinch accelerators for high-fusion-yield (approximately 0.4 GJ/shot) and inertial-fusion-energy (approximately 3 GJ/shot) research. We find that (delta(a)/delta(RT)) proportional (m/l)1/4 (Rgamma)(-1/2), where delta(a) is the imploding-sheath thickness of a wire-ablation-dominated pinch, delta(RT) is the sheath thickness of a Rayleigh-Taylor-dominated pinch, m is the total wire-array mass, l is the axial length of the array, R is the initial array radius, and gamma is a dimensionless functional of the shape of the current pulse that drives the pinch implosion. When the product Rgamma is held constant the sheath thickness is, at sufficiently large values of m/l, determined primarily by wire ablation. For an ablation-dominated pinch, we estimate that the peak radiated x-ray power P(r) proportional (I/tau(i))(3/2)Rlphigamma, where I is the peak pinch current, tau(i) is the pinch implosion time, and phi is a dimensionless functional of the current-pulse shape. This scaling relation is consistent with experiment when 13 MA < or = I < or = 20 MA, 93 ns < or = tau(i) < or = 169 ns, 10 mm < or = R < or = 20 mm, 10 mm < or = l < or = 20 mm, and 2.0 mg/cm < or = m/l < or = 7.3 mg/cm. Assuming an ablation-dominated pinch and that Rlphigamma is held constant, we find that the x-ray-power efficiency eta(x) congruent to P(r)/P(a) of a coupled pinch-accelerator system is proportional to (tau(i)P(r)(7/9 ))(-1), where P(a) is the peak accelerator power. The pinch current and accelerator power required to achieve a given value of P(r) are proportional to tau(i), and the requisite accelerator energy E(a) is proportional to tau2(i). These results suggest that the performance of an ablation-dominated pinch, and the efficiency of a coupled pinch-accelerator system, can be improved substantially by decreasing the implosion time tau(i). For an accelerator coupled to a double-pinch-driven hohlraum that drives the implosion of an ICF fuel capsule, we find that the accelerator power and energy required to achieve high-yield fusion scale as tau(i)0.36 and tau(i)1.36, respectively. Thus the accelerator requirements decrease as the implosion time is decreased. However, the x-ray-power and thermonuclear-yield efficiencies of such a coupled system increase with tau(i). We also find that increasing the anode-cathode gap of the pinch from 2 to 4 mm increases the requisite values of P(a) and E(a) by as much as a factor of 2.

Nanosecond electrical explosion of thin aluminum wires in a vacuum: experimental and computational investigations.

Experimental and computational investigations of nanosecond electrical explosion of a thin Al wire in vacuum are presented. We have demonstrated that increasing the current rate leads to increased energy deposited before voltage collapse. The experimental evidence for synchronization of the wire expansion and light emission with voltage collapse is presented. Hydrocarbons are indicated in optical spectra and their influence on breakdown physics is discussed. The radial velocity of low-density plasma reaches a value of approximately 100 km/s. The possibility of an over-critical phase transition due to high pressure is discussed. A one-dimensional magnetohydrodynamic (MHD) simulation shows good agreement with experimental data. The MHD simulation demonstrates separation of the exploding wire into a high-density cold core and a low-density hot corona as well as fast rejection of the current from the wire core to the corona during voltage collapse. Important features of the dynamics for the wire core and corona follow from the MHD simulation and are discussed.

Corona-free electrical explosion of polyimide-coated tungsten wire in vacuum.

We present experimental evidence of corona-free electrical explosion of dielectric-coated W wire in vacuum. A fast current rise of approximately 150 A/ns and a coating of 2 microm polyimide are both needed to achieve the corona-free regime of explosion. Breakdown is absent in corona-free explosion; the wire remains resistive, and this allows anomalously high energy deposition (approximately 20 times atomization enthalpy). MHD simulations reproduce the main differences between corona and corona-free explosions. A corona-free explosion of a wire can be useful for the generation of a hot plasma column by direct energy deposition.

Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone.

Idebenone is an antioxidant lower molecular weight analogue of coenzyme Q10. Previously, idebenone was shown to be a very effective antioxidant in its ability to protect against cell damage from oxidative stress in a variety of biochemical, cell biological, and in vivo methods, including its ability to suppress sunburn cell (SBC) formation in living skin. However, no clinical studies have been previously conducted to establish the efficacy of idebenone in a topical skincare formulation for the treatment of photodamaged skin. In this nonvehicle control study, 0.5% and 1.0% idebenone commercial formulations were evaluated in a clinical trial for topical safety and efficacy in photodamaged skin. Forty-one female subjects, aged 30-65, with moderate photodamaged skin were randomized to use a blind labelled (either 0.5% or 1.0% idebenone in otherwise identical lotion bases) skincare preparation twice daily for six weeks. Blinded expert grader assessments for skin roughness/dryness, fine lines/wrinkles, and global improvement in photodamage were performed at baseline, three weeks and six weeks. Electrical conductance readings for skin surface hydration and 35 mm digital photography were made at baseline after six weeks. Punch biopsies were taken from randomly selected subjects, baseline and after six weeks, and stained for certain antibodies (interleukin IL-6, interleukin IL-1b, matrixmetalloproteinase MMP-1, collagen I) using immunofluorescence microscopy. After six weeks' use of the 1.0% idebenone formula, a 26% reduction in skin roughness/dryness was observed, a 37% increase in skin hydration, a 29% reduction in fine lines/wrinkles, and a 33% improvement in overall global assessment of photodamaged skin. For the 0.5% idebenone formulation, a 23% reduction in skin roughness/dryness was observed, a 37% increase in skin hydration, a 27% reduction in fine lines/wrinkles, and a 30% improvement in overall global assessment of photodamaged skin. The immunofluorescence staining revealed a decrease in IL-1b, IL-6, and MMP-1 and an increase in collagen I for both concentrations.

Idebenone: a new antioxidant - Part I. Relative assessment of oxidative stress protection capacity compared to commonly known antioxidants.

Topical applications of skin care products containing antioxidants have become increasingly popular. Numerous studies have elucidated the biological effects of these substances. General antiaging effects, anti-inflammatory properties, photoprotective properties, and prevention of ultraviolet (UV) immunosuppression have been documented. However, a standardized method to characterize and compare the properties and oxidative stress protection capacity of antioxidants was lacking. A multistep in vitro process utilizing a variety of biochemical and cell biological methods combined with in vivo studies was designed to compare the oxidative stress protective capacity of commonly used antioxidants. Data were presented for L-ascorbic acid, dl-alpha-tocopherol, kinetin, dl-alpha lipoic acid, ubiquinone, and idebenone. Methods included using UV-induced radical trapping/scavenging capacity measured by photochemiluminescence, pro-oxidative systems (LDL-CuSO(4), microsome-NADPH/ADP/Fe(3+)) with measurement of primary and secondary oxidation products, UVB irradiation of human keratinocytes, and in vivo evaluation, using the human sunburn cell (SBC) assay. Correlation and trends between in vitro and in vivo results were established, and the standardized test protocol was used to quantify oxidative stress protection capacity of antioxidants. Summarizing and totaling the data equally weighted for each oxidative stress study, the overall oxidative protection capacity scores of 95, 80, 68, 55, 52, and 41 were obtained for idebenone, dl-alpha tocopherol, kinetin, ubiquinone, L-ascorbic acid, and dl-alpha lipoic acid, respectively. The higher the score, the more effective the overall oxidative stress protection capacity of the antioxidant became. This multistep protocol may serve as a standard in investigating and comparing new putative antioxidants for topical use as well as a valuable tool to assess the anti-inflammatory properties, photoprotective properties, and prevention of UV immunosuppression of topical antioxidants.

Use of cDNA microarrays to analyze responses to pneumococcal virulence factors.

BACKGROUND & OBJECTIVES: The complex interactions that occur between host and pathogen during bacteraemia caused by Streptococcus pneumoniae are not well understood. Upon entering the blood stream the pneumococcus intiates responses through contact with naïve monocytes and macrophages resulting in an inflammatory response. To elucidate the role of microbial virulence factors in the host response to the pneumococcus, cDNA microarray analysis was used to identify genes in THP-1 cells, a human monocytic cell line, that are responsive to pneumococcal virulence factors. METHODS: S. pneumoniae D39, a serotype 2 pneumococcus, and PLN an isogenic mutant of D39 that does not express pneumolysin were used. Gene expression profiles elicited by both wild-type and mutant were compared with that of THP-1 cells not exposed to pneumococci. Results obtained from microarray analysis were confirmed and further characterized using reverse transcriptase (RT)-PCR, real-time RT-PCR, and ELISA. RESULTS: Genes in THP-1 cells that were responsive to the pneumococcus independent of the presence of the specific virulence factor, pneumolysin, were identified. THP-1 cell genes that were differentially expressed independent of pneumolysin included the ones involved in cell-to-cell signaling and antipathogen responses. Those that were responsive to pneumolysin included genes encoding adhesion molecules, chemokines, cytokine receptors, and cell cycle and apoptosis proteins. INTERPRETATION & CONCLUSION: The global transcriptional response of naïve monocytes to contact with the pneumococcus was characterized and the utility of cDNA microarray analysis in elucidating the role of specific factors in host-pathogen interactions were demonstrated.

X-ray emission from z pinches at 10 7 A: current scaling, gap closure, and shot-to-shot fluctuations.

We have measured the x-ray power and energy radiated by a tungsten-wire-array z pinch as a function of the peak pinch current and the width of the anode-cathode gap at the base of the pinch. The measurements were performed at 13- and 19-MA currents and 1-, 2-, 3-, and 4-mm gaps. The wire material, number of wires, wire-array diameter, wire-array length, wire-array-electrode design, normalized-pinch-current time history, implosion time, and diagnostic package were held constant for the experiments. To keep the implosion time constant, the mass of the array was increased as I2 (i.e., the diameter of each wire was increased as I), where I is the peak pinch current. At 19 MA, the mass of the 300-wire 20-mm-diam 10-mm-length array was 5.9 mg. For the configuration studied, we find that to eliminate the effects of gap closure on the radiated energy, the width of the gap must be increased approximately as I. For shots unaffected by gap closure, we find that the peak radiated x-ray power P(r) proportional to I1.24+/-0.18, the total radiated x-ray energy E(r) proportional to I1.73+/-0.18, the x-ray-power rise time tau(r) proportional to I0.39+/-0.34, and the x-ray-power pulse width tau(w) proportional to demonstrate that the internal energy and radiative opacity of the pinch are not responsible for the observed subquadratic power scaling. Heuristic wire-ablation arguments suggest that quadratic power scaling will be achieved if the implosion time tau(i) is scaled as I(-1/3). The measured 1sigma shot-to-shot fluctuations in P(r), E(r), tau(r), tau(w), and tau(i) are approximately 12%, 9%, 26%, 9%, and 2%, respectively, assuming that the fluctuations are independent of I. These variations are for one-half of the pinch. If the half observed radiates in a manner that is statistically independent of the other half, the variations are a factor of 2(1/2) less for the entire pinch. We calculate the effect that shot-to-shot fluctuations of a single pinch would have on the shot-success probability of the double-pinch inertial-confinement-fusion driver proposed by Hammer et al. [Phys. Plasmas 6, 2129 (1999)]. We find that on a given shot, the probability that two independent pinches would radiate the same peak power to within a factor of 1+/-alpha (where 0< or =alpha<<1) is equal to erf(alpha/2sigma), where sigma is the 1sigma fractional variation of the peak power radiated by a single pinch. Assuming alpha must be < or =7% to achieve adequate odd-Legendre-mode radiation symmetry for thermonuclear-fusion experiments, sigma must be <3% for the shot-success probability to be > or =90%. The observed (12/2(1/2))%=8.5% fluctuation in P(r) would provide adequate symmetry on 44% of the shots. We propose that three-dimensional radiative-magnetohydrodynamic simulations be performed to quantify the sensitivity of the x-ray emission to various initial conditions, and to determine whether an imploding z pinch is a spatiotemporal chaotic system.