Nilotinib Improves Bioenergetic Profiling in Brain Astroglia in the 3xTg Mouse Model of Alzheimer's Disease.

Current treatments targeting amyloid beta in Alzheimer's disease (AD) have minimal efficacy, which results in a huge unmet medical need worldwide. Accumulating data suggest that brain mitochondrial dysfunction play a critical role in AD pathogenesis. Targeting cellular mechanisms associated with mitochondrial dysfunction in AD create a novel approach for drug development. This study investigated the effects of nilotinib, as a selective tyrosine kinase inhibitor, in astroglia derived from 3xTg-AD mice versus their C57BL/6-controls. Parameters included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX), citrate synthase (CS) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB), key regulators of mitochondrial dynamics (mitofusin (Mfn1), dynamin-related protein 1 (Drp1)), and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulin-dependent protein kinase II (CaMKII), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)). Nilotinib increased OCR, ATP, COX, Mfn1, and OXPHOS levels in 3xTg astroglia. No significant differences were detected in levels of Drp1 protein and CS activity. Nilotinib enhanced mitochondrial numbers, potentially through a CaMKII-PGC1α-Nrf2 pathway in 3xTg astroglia. Additionally, nilotinib-induced OCR increases were reduced in the presence of the NF-κB inhibitor, Bay11-7082. The data suggest that NF-κB signaling is intimately involved in nilotinib-induced changes in bioenergetics in 3xTg brain astroglia. Nilotinib increased translocation of the NF-κB p50 subunit into the nucleus of 3xTg astroglia that correlates with an increased expression and activation of NF-κB. The current findings support a role for nilotinib in improving mitochondrial function and suggest that astroglia may be a key therapeutic target in treating AD.

Oiling of the continental shelf and coastal marshes over eight years after the 2010 Deepwater Horizon oil spill.

We measured the temporal and spatial trajectory of oiling from the April, 2010, Deepwater Horizon oil spill in water from Louisiana's continental shelf, the estuarine waters of Barataria Bay, and in coastal marsh sediments. The concentrations of 28 target alkanes and 43 target polycyclic aromatic hydrocarbons were determined in water samples collected on 10 offshore cruises, in 19 water samples collected monthly one km offshore at 13 inshore stations in 2010 and 2013, and in 16-60 surficial marsh sediment samples collected on each of 26 trips. The concentration of total aromatics in offshore waters peaked in late summer, 2010, at 100 times above the May, 2010 values, which were already slightly contaminated. There were no differences in surface or bottom water samples. The concentration of total aromatics declined at a rate of 73% y-1 to 1/1000th of the May 2010 values by summer 2016. The concentrations inside the estuary were proportional to those one km offshore, but were 10-30% lower. The oil concentrations in sediments were initially different at 1 and 10 m distance into the marsh, but became equal after 2 years. Thus, the distinction between oiled and unoiled sites became blurred, if not non-existent then, and oiling had spread over an area wider than was visible initially. The concentrations of oil in sediments were 100-1000 times above the May 2010 values, and dropped to 10 times higher after 8 years, thereafter, demonstrating a long-term contamination by oil or oil residues that will remain for decades. The chemical signature of the oil residues offshore compared to in the marsh reflects the more aerobic offshore conditions and water-soluble tendencies of the dissolved components, whereas the anaerobic marsh sediments will retain the heavier molecular components for a long time, and have a consequential effect on the ecosystems.

Exercise training as a novel primary treatment for localised prostate cancer: a multi-site randomised controlled phase II study.

Alternative management strategies for localised prostate cancer are required to reduce morbidity and overtreatment. The aim of this study was to evaluate the feasibility, safety and acceptability of exercise training (ET) with behavioural support as a primary therapy for low/intermediate risk localised prostate cancer. Men with low/intermediate-risk prostate cancer were randomised to 12 months of ET or usual care with physical activity advice (UCwA) in a multi-site open label RCT. Feasibility included acceptability, recruitment, retention, adherence, adverse events and disease progression. Secondary outcomes included quality of life and cardiovascular health indices. Of the 50 men randomised to ET (n = 25) or UCwA (n = 25), 92% (n = 46) completed 12 month assessments. Three men progressed to invasive therapy (two in UCwA). In the ET group, men completed mean: 140 mins per week for 12 months (95% CI 129,152 mins) (94% of target dose) at 75% Hrmax. Men in the ET group demonstrated improved body mass (mean reduction: 2.0 kg; 95% CI -2.9,-1.1), reduced systolic (mean: 13 mmHg; 95%CI 7,19) and diastolic blood pressure (mean:8 mmHg; 95% CI 5,12) and improved quality of life (EQ.5D mean:13 points; 95% CI 7,18). There were no serious adverse events. ET in men with low/intermediate risk prostate cancer is feasible and acceptable with a low progression rate to radical treatment. Early signals on clinically relevant markers were found which warrant further investigation.

Impact of rapid identification of Staphylococcus aureus bloodstream infection without antimicrobial stewardship intervention on antibiotic optimization and clinical outcomes.

Few studies have evaluated the clinical impact of polymerase chain reaction (PCR) for Staphylococcus aureus bloodstream infections in resource-limited settings that lack direct antimicrobial stewardship intervention. This retrospective cohort study compared patients with standard microbiological identification (n=343) to those with additional identification by (PCR) (n=130). Time to initiation of optimal therapy was similar between groups but substantially shorter in the PCR group for those infected with methicillin susceptible S. aureus (median 40.0h vs. 28.3h, P=0.001). After controlling for confounding factors including infectious diseases consultation, the PCR group had a shorter time to initiation of optimal therapy by 9.7h (95% CI 4.3-15.0h). Clinical outcomes were similar in the non-PCR and PCR groups. While time to initiation of optimal therapy was shorter in the PCR group, greater reductions may be realized through additional education, direct antimicrobial stewardship intervention, or additional clinician notification.

"And DPSIR begat DAPSI(W)R(M)!" - A unifying framework for marine environmental management.

The marine environment is a complex system formed by interactions between ecological structure and functioning, physico-chemical processes and socio-economic systems. An increase in competing marine uses and users requires a holistic approach to marine management which considers the environmental, economic and societal impacts of all activities. If managed sustainably, the marine environment will deliver a range of ecosystem services which lead to benefits for society. In order to understand the complexity of the system, the DPSIR (Driver-Pressure-State-Impact-Response) approach has long been a valuable problem-structuring framework used to assess the causes, consequences and responses to change in a holistic way. Despite DPSIR being used for a long time, there is still confusion over the definition of its terms and so to be appropriate for current marine management, we contend that this confusion needs to be addressed. Our viewpoint advocates that DPSIR should be extended to DAPSI(W)R(M) (pronounced dap-see-worm) in which Drivers of basic human needs require Activities which lead to Pressures. The Pressures are the mechanisms of State change on the natural system which then leads to Impacts (on human Welfare). Those then require Responses (as Measures). Furthermore, because of the complexity of any managed sea area in terms of multiple Activities, there is the need for a linked-DAPSI(W)R(M) framework, and then the connectivity between marine ecosystems and ecosystems in the catchment and further at sea, requires an interlinked, nested-DAPSI(W)R(M) framework to reflect the continuum between adjacent ecosystems. Finally, the unifying framework for integrated marine management is completed by encompassing ecosystem structure and functioning, ecosystem services and societal benefits. Hence, DAPSI(W)R(M) links the socio-ecological system of the effects of changes to the natural system on the human uses and benefits of the marine system. However, to deliver these sustainably in the light of human activities requires a Risk Assessment and Risk Management framework; the ISO-compliant Bow-Tie method is used here as an example. Finally, to secure ecosystem health and economic benefits such as Blue Growth, successful, adaptive and sustainable marine management Responses (as Measures) are delivered using the 10-tenets, a set of facets covering all management disciplines and approaches.

Effect of probiotic on innate inflammatory response and viral shedding in experimental rhinovirus infection - a randomised controlled trial.

Ingestion of probiotics appears to have modest effects on the incidence of viral respiratory infection. The mechanism of these effects is not clear; however, there is evidence from animal models that the probiotic may have an effect on innate immune responses to pathogens. The purpose of this randomised, placebo-controlled study was to determine the effect of administration of Bifidobacterium animalis subspecies lactis Bl-04 on innate and adaptive host responses to experimental rhinovirus challenge. The effect on the response of chemokine (C-X-C motif) ligand 8 (CXCL8) to rhinovirus infection was defined as the primary endpoint for the study. 152 seronegative volunteers who had been supplemented for 28 days, 73 with probiotic and 79 with placebo, were challenged with RV-A39. Supplement or placebo administration was then continued for five days during collection of specimens for assessment of host response, infection, and symptoms. 58 probiotic and 57 placebo-supplemented volunteers met protocol-defined criteria for analysis. Probiotic resulted in higher nasal lavage CXCL8 on day 0 prior to virus challenge (90 vs 58 pg/ml, respectively, P=0.04, ANCOVA). The CXCL8 response to rhinovirus infection in nasal lavage was significantly reduced in the probiotic treated group (P=0.03, ANCOVA). Probiotic was also associated with a reduction in nasal lavage virus titre and the proportion of subjects shedding virus in nasal secretions (76% in the probiotic group, 91% in the placebo group, P=0.04, Fisher Exact test). The administration of probiotic did not influence lower respiratory inflammation (assessed by exhaled nitric oxide), subjective symptom scores, or infection rate. This study demonstrates that ingestion of Bl-04 may have an effect on the baseline state of innate immunity in the nose and on the subsequent response of the human host to rhinovirus infection. Clinicaltrials.gov registry number: NCT01669603.

Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics.

Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP ( p = 0.0005), mitochondrial complex I and III activities ( p = 0.0001 and p = 0.0003, respectively), NAD+ levels ( p = 0.0057) and increased lactate production ( p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function.

Beyond the treatment effect: Evaluating the effects of patient preferences in randomised trials.

The treatments under comparison in a randomised trial should ideally have equal value and acceptability - a position of equipoise - to study participants. However, it is unlikely that true equipoise exists in practice, because at least some participants may have preferences for one treatment or the other, for a variety of reasons. These preferences may be related to study outcomes, and hence affect the estimation of the treatment effect. Furthermore, the effects of preferences can sometimes be substantial, and may even be larger than the direct effect of treatment. Preference effects are of interest in their own right, but they cannot be assessed in the standard parallel group design for a randomised trial. In this paper, we describe a model to represent the impact of preferences on trial outcomes, in addition to the usual treatment effect. In particular, we describe how outcomes might differ between participants who would choose one treatment or the other, if they were free to do so. Additionally, we investigate the difference in outcomes depending on whether or not a participant receives his or her preferred treatment, which we characterise through a so-called preference effect. We then discuss several study designs that have been proposed to measure and exploit data on preferences, and which constitute alternatives to the conventional parallel group design. Based on the model framework, we determine which of the various preference effects can or cannot be estimated with each design. We also illustrate these ideas with some examples of preference designs from the literature.

Incremental effects of 28 days of beta-alanine supplementation on high-intensity cycling performance and blood lactate in masters female cyclists.

Within the aging population, there exists a subset of individuals termed masters athletes (MA). As masters-level competition increases in popularity, MA must find methods to enhance individual athletic performance. Longitudinal beta-alanine (BA) supplementation is suggested to enhance physical capability during exercise; however, these effects have not been evaluated in MA. To examine the longitudinal effects of BA on time to exhaustion (TTE), total work completed (TWC), and lactate clearance in female MA cyclists. Twenty-two female MA (age = 53.3 ± 1.0) participated in this double-blind design. Subjects were randomly assigned to BA (n = 11; 800 mg BA + 8 g dextrose) or placebo (PLA; n = 11; 8 g dextrose) groups and supplemented 4 doses/day over 28 days. Every 7 days, subjects completed a cycling TTE at 120% VO2max, and TWC was calculated. Blood lactate was measured at baseline, immediate post, and 20-min post each TTE. No significant differences existed between groups for any variable at baseline (p > 0.05). After 28 days supplementation, BA had greater TTE (23 vs 1% change) and TWC (21 vs 2% change) than PLA (p < 0.05). Following the 20-min TTE recovery, lactate was 24% lower in BA compared to PLA (4.35 vs. 5.76 mmol/L, respectively). No differences existed for variables during intermittent weeks. 28 days of BA supplementation increased cycling performance via an enhanced time to exhaustion and total work completed with associated lactate clearance during passive rest in female MA.

Distribution and recovery trajectory of Macondo (Mississippi Canyon 252) oil in Louisiana coastal wetlands.

We measured the concentration of petroleum hydrocarbons in 405 wetland sediment samples immediately before the April 2010 Deepwater Horizon disaster led to their broad-scale oiling, and on nine trips afterwards. The average concentrations of alkanes and PAHs were 604 and 186 times the pre-spill baseline values, respectively. Oil was distributed with some attenuation up to 100m inland from the shoreline for alkanes, but increased for aromatics, and was not well-circumscribed by the rapid shoreline assessments (a.k.a. SCAT) of relative oiling. The concentrations of target alkanes and PAHs in June 2013 were about 1% and 5%, respectively, of the February 2011 concentrations, but remained at 3.7 and 33 times higher, respectively, than in May 2010. A recovery to baseline conditions suggests that the concentration of alkanes may be near baseline values by the end of 2015, but that it may take decades for the PAH concentrations to be that low.

Sediment-preserved diatom assemblages can distinguish a petroleum activity signal separately from the nutrient signal of the Mississippi River in coastal Louisiana.

We analyzed the preserved diatom assemblages in dated sediment cores collected from five locations in the Louisiana Bight to test if there was a signature of petroleum extraction activities (hopanes and barium) distinct from the well-documented effects of nutrient loading. The results of a multi-dimensional scaling analysis indicate that the diatom assemblage changes documented throughout the 40 year record could be explained by three variables: barium and hopanes concentrations, and Mississippi River nitrogen loading. The results of a canonical correspondence analysis demonstrated that these signals could be distinguished through correlations with specific diatom species. The abundance of Actinoptychus senarius, for example, was negatively correlated with barium and the Pseudo-nitzschia delicatissima complex was positively correlated with nitrogen loading. These results provide a "proof-of-concept" demonstration that diatom assemblages preserved in the sediments can be used to study the effects of petroleum extraction activities, and that these 'petroleum signals' may be distinguished from other significant influences such as nutrient loading.

Optimal allocation of participants for the estimation of selection, preference and treatment effects in the two-stage randomised trial design.

Outcomes in clinical trials may be affected by the choice of treatment that participants might make, if they were indeed allowed to choose (a so-called selection effect), and by whether they actually receive their preferred treatment (a preference effect). Selection and preference effects can be important, but they cannot be estimated in the conventional trial design. An alternative approach is the two-stage randomised trial, in which participants are first randomly divided into two subgroups. In one subgroup, participants are randomly assigned to treatments, while in the other, participants are allowed to choose their own treatment. This approach yields estimates of the direct treatment effect, and of the preference and selection effects. The latter two provide insight that goes considerably beyond what is possible in the standard randomised trial. In this paper, we determine the optimal proportion of participants who should be allocated to the choice subgroup. The precision of the estimated selection, preference and treatment effects are functions of: the total sample size; the proportion of participants allocated to choose their treatment; the variances of the outcome; the proportions of participants who select each treatment in the choice group; and the selection, preference and treatment effects themselves. We develop general expressions for the optimum proportion of participants in the choice group, depending on which effects are of primary interest. We illustrate the results with trial data comparing alternative clinical management strategies for women with abnormal results on cervical screening.

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats.

Estrogen deficiency results in accelerated bone turnover with a net increase in bone resorption. Subcutaneous administration of leptin attenuates bone loss in ovariectomized (ovx) rats by reducing bone resorption. However, in addition to its direct beneficial effects, leptin has been reported to have indirect (central nervous system-mediated) antiosteogenic effects on bone, which may limit the efficacy of elevated serum leptin to prevent estrogen deficiency-associated bone loss. The present study evaluated the long-term effects of increased hypothalamic leptin transgene expression, using recombinant adeno-associated virus-leptin (rAAV-Lep) gene therapy, on bone mass, architecture, and cellular endpoints in sexually mature ovx Sprague-Dawley rats. Ovx rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained for 10 weeks. Additional controls consisted of ovary-intact rats and ovx rats pair-fed to rAAV-Lep rats. Lumbar vertebrae were analyzed by micro-computed tomography and tibiae by histomorphometry. Cancellous bone volume was lower and osteoclast perimeter, osteoblast perimeter, and bone marrow adipocyte density were greater in ovx rats compared to ovary-intact controls. In contrast, differences among ovx groups were not detected for any endpoint evaluated. In conclusion, whereas estrogen deficiency resulted in marked cancellous osteopenia, increased bone turnover and marrow adiposity, increasing hypothalamic leptin transgene expression in ovx rats had neither detrimental nor beneficial effects on bone mass, architecture, or cellular endpoints. These findings demonstrate that the antiresorptive effects of subcutaneous leptin administration in ovx rats are mediated through leptin targets in the periphery.

Developmental and functional studies of the SLC12 gene family members from Drosophila melanogaster.

The electroneutral cation-chloride cotransporter gene family, SLC12, contains nine members in vertebrates. These include seven sodium and/or potassium-coupled chloride transporters and two membrane proteins of unknown function. Although SLC12 family members have been identified in a number of lower species, the functional properties of these proteins are unknown. There are five SLC12 homologues in Drosophila melanogaster, including at least one member on each of the four main branches of the vertebrate phylogenetic tree. We have employed in situ hybridization to study the expression patterns of the Drosophila SLC12 proteins during embryonic development. Our studies indicate that all five members of this family are expressed during early embryogenesis (stages 1-6), but that spatial and temporal expression patterns become more refined as development proceeds. Expression during late embryogenesis was seen predominantly in the ventral nerve cord, salivary gland, gut, and anal pad. In parallel studies, we have carried out transport assays on each of the five Drosophila homologues, expressed as recombinant proteins in the cultured insect cell line High Five. Under our experimental conditions, we found that only one of these proteins, CG4357, transported the potassium congener (86)Rb. Additional experiments established that rubidium transport via CG4357 was saturable (K(m) = 0.29 +/- 0.05 mM), sodium-dependent (half-saturation constant = 53 +/- 11 mM), chloride-dependent (half-saturation constant = 48 +/- 5 mM), and potently inhibited by bumetanide (inhibitor constant = 1.17 +/- 0.08 muM), a specific inhibitor of Na(+)-K(+)-2Cl(-) cotransporters. Taken together, our results provide strong evidence that CG4357 is an insect ortholog of the vertebrate Na(+)-K(+)-2Cl(-) cotransporters.

Childhood exposure to adversity and risk of substance-use disorder in two American Indian populations: the meditational role of early substance-use initiation.

OBJECTIVE: We examined the relationship of childhood exposure to adversity and risk of substance-use disorder in two culturally distinct American Indian reservation communities, exploring both the role of early initiation of substance use in mediating this relationship and variation in risk across types of adversity exposure. METHOD: The American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project provided data from 2,927 American Indians on the occurrence and age at onset of adversities, substance use, and substance-use-disorder symptoms. RESULTS: The risk of substance-use disorder associated with early adversity was explained partially by early initiation of substance use. Three types of adversity (major childhood events, traumas, and witnessed violence) were associated with early onset of substance use and increased risk of substance-use disorder. Gender and tribe were also related to variation in both early substance use and substance-use disorder. CONCLUSIONS: Early exposure to adverse events was associated with early substance use and the subsequent development of substance-use disorders among American Indians. public health initiatives targeting substance use and substance-use disorders in American Indian communities should include efforts to help children in these communities cope with adversities they encounter.

Potato agriculture, late blight science, and the molecularization of plant pathology.

By the mid-1980s nucleic-acid based methods were penetrating the farthest reaches of biological science, triggering rivalries among practitioners, altering relationships among subfields, and transforming the research front. This article delivers a "bottom up" analysis of that transformation at work in one important area of biological science, plant pathology, by tracing the "molecularization" of efforts to understand and control one notorious plant disease -- the late blight of potatoes. It mobilizes the research literature of late blight science as a tool through which to trace the changing typography of the research front from 1983 to 2003. During these years molecularization intensified the traditional fragmentation of the late blight research community, even as it dramatically integrated study of the causal organism into broader areas of biology. In these decades the pathogen responsible for late blight, the oomycete "Phytophthora infestans," was discovered to be undergoing massive, frightening, and still largely unexplained genetic diversification -- a circumstance that lends the episode examined here an urgency that reinforces its historiographical significance as a case-study in the molecularization of the biological sciences.

Nail swelling as a pre-formulation screen for the selection and optimisation of ungual penetration enhancers.

INTRODUCTION: Targeting drug treatment to fungal infections that reside within or below the nail plate is problematic due to the highly restrictive barrier of the human nail. To optimise topical formulations for ungual drug delivery, inclusion of an effective penetration enhancer (PE) is imperative. At present, in vitro nail permeation studies can take weeks or months in order to obtain any meaningful data because the lack of a simple in vitro model to identify and develop nail PEs makes the selection and optimisation of novel PEs an empirical and inefficient process. The aim of this study was to compare three methods for pre-formulation screening of putative ungual PEs and then to select the most suitable technique for screening candidates that may enhance the permeation of therapeutic agents through the human nail. METHODS: Three screening techniques were evaluated; nail swelling (weight increase of human nail clippings), horse hoof swelling (weight increase of horse hoof clippings) and nail penetration of a radiolabelled permeability probe. Four test PEs were evaluated using each screening method and nail swelling was identified as a simple, rapid, economic, relevant and reliable technique. This screen was then used to evaluate 20 potential PEs. Thioglycolic acid (TA), hydrogen peroxide (H(2)O(2)) and urea H(2)O(2) produced the greatest nail weight increases; 71.0+/-4.6%, 69.2+/-6.6%, and 69.0+/-9.9 respectively. To confirm the relationship between human nail swelling and altered ungual barrier function, a permeation study was performed in human nails using caffeine as a model penetrant. RESULTS AND DISCUSSION: Human nails pre-treated with TA in vitro had a 3.8-fold increase in caffeine flux compared to the control (TA-free solution). This study illustrated the potential to use human nail clipping swelling as a surrogate marker of PE activity for topical ungual drug delivery.

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. METHODS: Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. RESULTS: For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. CONCLUSIONS: Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.

Relations among questionnaire and laboratory measures of rhinovirus infection.

Due to high incidence and quality-of-life impact, upper respiratory infection substantially impacts on population health. To test or compare treatment effectiveness, a well-designed and validated illness-specific quality-of-life instrument is needed. Data reported in the current study were obtained from a trial testing echinacea for induced rhinovirus infection. Laboratory-assessed biomarkers included interleukin (IL)-8, nasal neutrophil count (polymorphonuclear neutrophils (PMN)), mucus weight, viral titre and seroconversion. The questionnaires used included the general health short form (SF)-8 (24-h recall version), the eight-item Jackson cold scale, and the 44-item Wisconsin Upper Respiratory Symptom Survey (WURSS). In total, 399 participants were inoculated with rhinovirus and monitored over 2,088 person-days. Statistically significant associations were found among nearly all variables. Between-questionnaire correlations were: WURSS-Jackson = 0.81; WURSS-SF-8 = 0.62; and Jackson-SF-8 = 0.60. Correlations with laboratory values were as follows: WURSS-mucus weight = 0.53; Jackson-mucus weight = 0.55; WURSS-viral titre = 0.37; Jackson-viral titre = 0.46; WURSS-IL-8 = 0.31; Jackson-IL-8 = 0.36; WURSS-PMN = 0.31; and Jackson-PMN = 0.28. Neither WURSS nor Jackson yielded satisfactory cut-off scores for diagnosis of infection. Symptomatic and biological outcomes of upper respiratory infection are highly variable, with only modest associations. While Wisconsin Upper Respiratory Symptom Survey and Jackson questionnaires both correlate with biomarkers, neither is a good predictor of induced infection. The inclusion of functional and quality-of-life items in the Wisconsin Upper Respiratory Symptom Survey does not significantly decrease the strength of association with laboratory-assessed biomarkers.