Long-Term Clinical Outcomes of Myopic Patients Having Thin Residual Corneal Thickness after Excimer Laser Surface Ablation.
To investigate and compare the long-term safety, efficacy, and accuracy of PRK (photorefractive keratectomy) and LASEK (laser epithelial keratomileusis) in myopic corneas having residual corneal thickness less than 400 micron meters (µm). The medical reports of the patients who had undergone excimer laser surface ablation between 2007-2011 and had a residual corneal thickness less than 400 µm were retrospectively reviewed. Forty-two eyes of 42 patients with a mean age of 28.79±7.76 years were enrolled into the study. Twenty-two PRK and 20 LASEK procedures were performed. The mean follow-up time was 45.00±11.80 months. At the end of follow-up, no ectasia was detected. Nineteen percent of eyes had trace haze. No eyes lost any lines in corrected distance visual acuity. Eighty-one percent of the patients had an uncorrected distance visual acuity better than 20/40. The regression rate was 16.7%. Sixty-two percent of eyes were within ±1.00 D. The safety and efficacy indexes were 1.19±0.42 and 1.00±0.40, respectively. There was not any difference between LASEK and PRK regarding achieved spherical equivalent refraction, haze ratio, visual acuity, safety, efficacy, and regression. Both PRK and LASEK are safe and effective in myopic corneas having thin residual thickness.


Evidence of endothelial dysfunction in the development of Alzheimer's disease: Is Alzheimer's a vascular disorder?
The etiology of Alzheimer's disease (AD) remains unclear. The emerging view is that cerebrovascular dysfunction is a feature not only of cerebrovascular diseases, such as stroke, but also of neurodegenerative conditions, such as AD. In AD, there is impaired structure and function of cerebral blood vessels and cells in the neurovascular unit. These effects are mediated by vascular oxidative stress. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier and reduces the brain's repair capacity. Such injury can exacerbate the cognitive dysfunction exerted by incident ischemia and coexisting neurodegeneration. This article summarises data regarding cardiovascular risk factors, vascular abnormalities and brain endothelial damage in AD. In view of accumulating evidence of vascular pathology in AD, we also review the literature (MEDLINE, EMBASE) for clinical evidence of impaired endothelial function in AD. A total of 15 articles investigating endothelial dysfunction in AD were identified. 10 of these articles showed impaired endothelial function in AD patients. The current literature suggests endothelial dysfunction may be involved in the pathogenesis of AD. This aspect of AD pathology is particularly interesting in view of its potential for therapeutic intervention. Future research on endothelial function in AD should concentrate on population-based analysis and combine multiple methods to evaluate endothelial function.


Genetic characterization and molecular identification of the bloodmeal sources of the potential bluetongue vector Culicoides obsoletus in the Canary Islands, Spain.
Culicoides (Diptera: Ceratopogonidae) biting midges are vectors for a diversity of pathogens including bluetongue virus (BTV) that generate important economic losses. BTV has expanded its range in recent decades, probably due to the expansion of its main vector and the presence of other autochthonous competent vectors. Although the Canary Islands are still free of bluetongue disease (BTD), Spain and Europe have had to face up to a spread of bluetongue with disastrous consequences. Therefore, it is essential to identify the distribution of biting midges and understand their feeding patterns in areas susceptible to BTD. To that end, we captured biting midges on two farms in the Canary Islands (i) to identify the midge species in question and characterize their COI barcoding region and (ii) to ascertain the source of their bloodmeals using molecular tools. Biting midges were captured using CDC traps baited with a 4-W blacklight (UV) bulb on Gran Canaria and on Tenerife. Biting midges were quantified and identified according to their wing patterns. A 688 bp segment of the mitochondrial COI gene of 20 biting midges (11 from Gran Canaria and 9 from Tenerife) were PCR amplified using the primers LCO1490 and HCO2198. Moreover, after selected all available females showing any rest of blood in their abdomen, a nested-PCR approach was used to amplify a fragment of the COI gene from vertebrate DNA contained in bloodmeals. The origin of bloodmeals was identified by comparison with the nucleotide-nucleotide basic alignment search tool (BLAST). The morphological identification of 491 female biting midges revealed the presence of a single morphospecies belonging to the Obsoletus group. When sequencing the barcoding region of the 20 females used to check genetic variability, we identified two haplotypes differing in a single base. Comparison analysis using the nucleotide-nucleotide basic alignment search tool (BLAST) showed that both haplotypes belong to Culicoides obsoletus, a potential BTV vector. As well, using molecular tools we identified the feeding sources of 136 biting midges and were able to confirm that C. obsoletus females feed on goats and sheep on both islands. These results confirm that the feeding pattern of C. obsoletus is a potentially important factor in BTV transmission to susceptible hosts in case of introduction into the archipelago. Consequently, in the Canary Islands it is essential to maintain vigilance of Culicoides-transmitted viruses such as BTV and the novel Schmallenberg virus.


Long-term nitrate removal through methane-dependent denitrification microorganisms in sequencing batch reactors fed with only nitrate and methane.
Denitrifying anaerobic methane oxidation (damo) bioprocesses can remove nitrate using methane as the electron donor, which gains great concern due to the current stringent discharge standard of nitrogen in wastewater treatment plants. To obtain an engineering acceptable nitrogen removal rate (NRR) and demonstrate the long-term stable ability of damo system under conditions of nitrate and methane, two sequencing batch reactors (SBRs) fed with only nitrate and methane were operated for more than 600 days at 30 °C. The NRR of 21.91 ± 0.73 mg NO3--N L-1 day-1 was obtained which is, to the best of our knowledge, the highest rate observed in the literatures under such conditions. The temperature was found to significantly affect the system performance. Furthermore, the microbial community was analyzed by using real-time PCR technique. The results showed that the microbial consortium contained damo archaea and bacteria. These two microbes cooperated to maintain the long-term stability. And the number of damo archaea was higher than that of damo bacteria with the ratio of 1.77. By using methane as the electron donor, damo archaea reduced nitrate to nitrite coupled to methane oxidation and damo bacteria reduce the generated nitrite to nitrogen gas. The first step of nitrate to nitrite taken by damo archaea might be the limiting step of this cooperation system. SBR could be a suitable reactor configuration to enrich slow-growing microbes like damo culture. These results demonstrated the potential application of damo processes for nitrogen removal of wastewater containing low C/N ratios.


Adaptation and Validation of the Motivated Strategies for Learning Questionnaire for Spanish Adolescents.
This work adapts and validates the scale of the motivated strategies for learning questionnaire (MSLQ), which is used to measure motivation. For this, an instrumental design was carried out with the purpose of analyzing the psychometric properties of the instrument. The sample consisted of 307 participants enrolled in compulsory secondary education. Reliability with fit indices were good in model B (proposed) with composite reliability, global reliability index, and Cronbach's alpha. The original model (A) presented small problems that had to be adjusted when carrying out the translation. We concluded that adaptation and subsequent validation of the MSLQ instrument into a Spanish context was positive. In this sense, adequate adjustment rates have been achieved. However, in its contextual adequacy, the need arises to modify the presentation of the items alluding to intrinsic motivation due to the difficulty of measuring such a construct. Among the implications reached in this study is the possibility of having a validated instrument for the Spanish adolescent context to measure motivation on educational aspects. Furthermore, this tool can serve as the basis for the design of other instruments that measure this construct in other age ranges.


Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection.
We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population. Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10(-3) between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (< or =F1, F1+/-1, > or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis. Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients.


Assessing patient-centered care in patients with chronic health conditions attending chiropractic practice: protocol for a mixed-methods study.
The management of chronic health conditions increasingly requires an organized, coordinated, and patient-centered approach to care. The Chronic Care Model (CCM) has been adopted in primary care to improve care delivery for those with chronic health conditions. Chiropractors manage chronic health conditions; however, little is known if such care is patient-centered. The primary aim of this study is to determine to what extent chiropractic patients with chronic health conditions perceive their care is patient-centred. We will assess concordance with the CCM using the Patient Assessment of Chronic Illness Care (PACIC) survey in study patients. We will also explore perception of how patient-centered the care provided by chiropractors is for those with chronic health conditions according to patients and chiropractors. We will use a sequential mixed methods design with quantitative priority. In the quantitative component patients will complete a written questionnaire providing sociodemographic, health status, and health care interaction information, all of which will serve as the independent variables. Patients will also complete a modified version of the PACIC; the average overall score will be the dependent variable. In the qualitative component semi-structured interviews and focus groups with patients and chiropractors will be conducted. A pilot study will be conducted to determine if the modified PACIC will perform adequately in measuring concordance with the CCM for chiropractic care. Pilot testing will also allow for assessment of the interview and focus groups guides. Variables found to be significantly associated will be included in a multivariate linear regression analysis to identify significant predictors of the dependent variable. Qualitative data will be analyzed using an inductive thematic analysis to provide meaning to the quantitative results. There is a paucity of research describing the extent to which chiropractic care for patients with chronic health conditions is concordant with the CCM. This study will examine this relationship and the perceptions and experiences of patients and chiropractors regarding how patient-centered chiropractic care is for these patients.


[Multicentric study of deaths by homicide in Latin American countries].
This article is a descriptive epidemiological study of deaths by homicide in Latin American countries (Argentina, Brazil, Colombia and Mexico) from 1990 to 2007. Deaths due to external causes and homicides, as codified in the 9th and 10th revisions of the International Classification of Diseases/ICD, were analyzed considering sex, age and manner of assault. The numbers, ratios and adjusted rates for deaths by homicide are presented. A linear regression model was used to ascertain the trend of homicide rates by age group. During the period, 4,086,216 deaths from external causes and 1,432,971 homicides were registered in these countries. Deaths from external causes rose 54.5% in Argentina but fell in the other countries (37% in Mexico, 31.8% in Colombia, and 8.1% in Brazil). The ratio for deaths by homicide for both sexes was 9.1 in Colombia, 4.4 in Brazil and 1.6 in Mexico, using the Argentinian rates as a benchmark. There were differences in the evolution of homicide rates by age and sex in the countries: the rate rose in Brazil and fell in Colombia for all age groups. The need to prioritize young males in public policies related to health care and prevention is stressed, as well as the need for the region to adopt inclusive policies and broaden and consolidate democracy and the rights of inhabitants.


Spin label and 2H-NMR studies on the interaction of melanotropic peptides with lipid bilayers.
The interaction of the cationic tridecapeptide alpha-melanocyte stimulating hormone (alpha-MSH) and the biologically more active analog [Nle4, DPhe7]-alpha-MSH with lipid membranes was investigated by means of ESR of spin probes incorporated in the bilayer, and NMR of deuterated lipids. All spin labels used here, stearic acid and phospholipid derivatives labeled at the 5th and 12th position of the hydrocarbon chain, and the cholestane label, incorporated into anionic vesicles of DMPG (1,2-dimyristoyl-sn-glycero-3-phosphoglycerol) in the liquid-crystalline phase, indicated that both peptides decrease the motional freedom of the acyl chains. No peptide effect was detected with neutral lipid bilayers. Changes in the alpha-deuteron quadrupolar splittings and spin lattice relaxation time of DMPG deuterated at the glycerol headgroup paralleled the results obtained with ESR, showing that the peptides cause a better packing both at the headgroup and at the acyl chain bilayer regions. The stronger effect caused by the more potent analog in the membrane structure, when compared to the native hormone, is discussed in terms of its larger lipid association constant and/or its deeper penetration into the bilayer.


Dentifrices, mouthwashes, and remineralization/caries arrestment strategies.
While our knowledge of the dental caries process and its prevention has greatly advanced over the past fifty years, it is fair to state that the management of this disease at the level of the individual patient remains largely empirical. Recommendations for fluoride use by patients at different levels of caries risk are mainly based on the adage that more is better. There is a general understanding that the fluoride compound, concentration, frequency of use, duration of exposure, and method of delivery can influence fluoride efficacy. Two important factors are (1) the initial interaction of relatively high concentrations of fluoride with the tooth surface and plaque during application and (2) the retention of fluoride in oral fluids after application. Fluoride dentifrices remain the most widely used method of delivering topical fluoride. The efficacy of this approach in preventing dental caries is beyond dispute. However, the vast majority of currently marketed dentifrice products have not been clinically tested and have met only the minimal requirements of the FDA monograph using mainly laboratory testing and animal caries testing. Daily use of fluoride dental rinses as an adjunct to fluoride dentifrice has been shown to be clinically effective as has biweekly use of higher concentration fluoride rinses. The use of remineralizing agents (other than fluoride), directed at reversing or arresting non-cavitated lesions, remains a promising yet largely unproven strategy. High fluoride concentration compounds, e.g., AgF, Ag(NH3)2F, to arrest more advanced carious lesions with and without prior removal of carious tissue are being used in several countries as part of the Atraumatic Restorative Treatment (ART) approach. Most of the recent innovations in oral care products have been directed toward making cosmetic marketing claims. There continues to be a need for innovation and collaboration with other scientific disciplines to fully understand and prevent dental caries.


A long-term effect of distal radius fracture on the sensorimotor control of the wrist joint in older adults.
Sensorimotor control can be disturbed because of pain and trauma. There is scarce comprehension about which component of the sensorimotor system would benefit the most from treatment in distal radius fracture (DRF). The purpose of this study was to determine whether the sensorimotor control of subjects with a history of DRF impaired compared with healthy subjects. If so, which component of the sensorimotor system is most affected. Nine healthy participants and 11 participants with a DRF history executed posture and reproduction tasks in interaction with a robotic wrist manipulator. A posture task with force perturbations assess sensorimotor control. Position and force reproduction tasks assessed sensory feedback. Electromyography recorded the muscle activity to study the motor part of the sensorimotor system. Cross-sectional case-control. The results showed that the motor responses to the perturbations during the posture task did not differ significantly, whereas the position reproduction did significantly differ between the 2 groups. Moreover, participants with a DRF history did not adapt to the changed dynamics of the environment during the posture task, whereas the controls did. The results of this study imply that processing of sensory position feedback is impaired in people with a DRF history while sensorimotor control during a posture task is unaffected. A possible explanation for these results is that different neural networks are involved during reproduction and posture tasks. A history of DRF is related to disturbed processing of sensory feedback of the sensorimotor system, especially the Joint Position Sense, which leads to an impairment in detecting a changed environment and adapting to it. Impaired Joint Position Sense and thereby the inability to adapt adequately to a changing environment should be taken into account during the rehabilitation of patients with DRF.


Hidden Hearing Loss? No Effect of Common Recreational Noise Exposure on Cochlear Nerve Response Amplitude in Humans.
This study tested hypothesized relationships between noise exposure and auditory deficits. Both retrospective assessment of potential associations between noise exposure history and performance on an audiologic test battery and prospective assessment of potential changes in performance after new recreational noise exposure were completed. Methods: 32 participants (13M, 19F) with normal hearing (25-dB HL or better, 0.25-8 kHz) were asked to participate in 3 pre- and post-exposure sessions including: otoscopy, tympanometry, distortion product otoacoustic emissions (DPOAEs) (f2 frequencies 1-8 kHz), pure-tone audiometry (0.25-8 kHz), Words-in-Noise (WIN) test, and electrocochleography (eCochG) measurements at 70, 80, and 90-dB nHL (click and 2-4 kHz tone-bursts). The first session was used to collect baseline data, the second session was collected the day after a loud recreational event, and the third session was collected 1-week later. Of the 32 participants, 26 completed all 3 sessions. Results: The retrospective analysis did not reveal statistically significant relationships between noise exposure history and any auditory deficits. The day after new exposure, there was a statistically significant correlation between noise "dose" and WIN performance overall, and within the 4-dB signal-to-babble ratio. In contrast, there were no statistically significant correlations between noise dose and changes in threshold, DPOAE amplitude, or AP amplitude the day after new noise exposure. Additional analyses revealed a statistically significant relationship between TTS and DPOAE amplitude at 6 kHz, with temporarily decreased DPOAE amplitude observed with increasing TTS. Conclusions: There was no evidence of auditory deficits as a function of previous noise exposure history, and no permanent changes in audiometric, electrophysiologic, or functional measures after new recreational noise exposure. There were very few participants with TTS the day after exposure - a test time selected to be consistent with previous animal studies. The largest observed TTS was approximately 20-dB. The observed pattern of small TTS suggests little risk of synaptopathy from common recreational noise exposure, and that we should not expect to observe changes in evoked potentials for this reason. No such changes were observed in this study. These data do not support suggestions that common, recreational noise exposure is likely to result in "hidden hearing loss".


Incorporation of reporter-labeled nucleotides by DNA polymerases.
The incorporation of fluorescently labeled nucleotides into DNA by DNA polymerases has been used extensively for tagging genes and for labeling DNA. However, we lack studies comparing polymerase efficiencies for incorporating different fluorescently labeled nucleotides. We analyzed the incorporation of fluorescent deoxynucleoside triphosphates by 10 different DNA polymerases, representing a cross-section of DNA polymerases from families A, B, and reverse transcriptase. The substitution of one or more different reporter-labeled nucleotides for the cognate nucleotides was initially investigated by using an in vitro polymerase extension filter-binding assay with natural DNA as a template. Further analysis on longer DNA fragments containing one or more nucleotide analogs was performed using a newly developed extension cut assay. The results indicate that incorporation of fluorescent nucleotides is dependent on the DNA polymerase, fluorophore, linker between the nucleotide and the fluorophore, and position for attachment of the linker and the cognate nucleotide. Of the polymerases tested, Taq and Vent exo DNA polymerases were most efficient at incorporating a variety of fluorescently labeled nucleotides. This study suggests that it should be feasible to copy DNA with reactions mixtures that contain all four fluorescently labeled nucleotides allowing for high-density labeling of DNA.


The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study.
Although biomarker studies of late-onset Alzheimer's disease suggest pathology to be present decades before diagnosis, little is known about cognitive performance at this stage. A sample of 210 adults (aged 40-59) of whom 103 have a parent diagnosed with dementia (family history subgroup) underwent computerized cognitive testing. Apolipoprotein E (apoE) status was determined, and 193 subjects had magnetic resonance imaging. Distance from dementia onset was estimated in relation to age of parental diagnosis, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Scores were calculated. Lower hippocampal volumes (P = .04) were associated with poorer spatial location recall and higher Dementia Risk Scores with poorer visual recognition (P = .0005), and lower brain and hippocampal volume (P < .0001, P = .04, respectively). Family history subgroup participants closer to dementia onset had lower scores on visual working memory (P = .05), whereas those with an APOE ε4 allele performed better on form perception (P = .005). Middle-aged adults at risk of dementia show evidence of poorer cognitive performance, principally in visuospatial functions.


The effect of cannabis use on memory function: an update.
Investigating the effects of cannabis use on memory function appears challenging. While early observational investigations aimed to elucidate the longer-term effects of cannabis use on memory function in humans, findings remained equivocal and pointed to a pattern of interacting factors impacting on the relationship between cannabis use and memory function, rather than a simple direct effect of cannabis. Only recently, a clearer picture of the chronic and acute effects of cannabis use on memory function has emerged once studies have controlled for potential confounding factors and started to investigate the acute effects of delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the main ingredients in the extract of the cannabis plant in pharmacological challenge experiments. Relatively consistent findings have been reported regarding the acute impairments induced by a single dose of Δ9-THC on verbal and working memory. It is unclear whether they may persist beyond the intoxication state. In the long-term, these impairments seem particularly likely to manifest and may also persist following abstinence if regular and heavy use of cannabis strains high in Δ9-THC is started at an early age. Although still at an early stage, studies that employed advanced neuroimaging techniques have started to model the neural underpinnings of the effects of cannabis use and implicate a network of functional and morphological alterations that may moderate the effects of cannabis on memory function. Future experimental and epidemiological studies that take into consideration individual differences, particularly previous cannabis history and demographic characteristics, but also the precise mixture of the ingredients of the consumed cannabis are necessary to clarify the magnitude and the mechanisms by which cannabis-induced memory impairments occur and to elucidate underlying neurobiological mechanisms.


Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat.
Neurons within the lateral hypothalamus (LH) are thought to be able to evoke behavioural responses that are coordinated with an adequate level of autonomic activity. Recently, the acute pharmacological inhibition of LH has been shown to depress wakefulness and promote NREM sleep, while suppressing REM sleep. These effects have been suggested to be the consequence of the inhibition of specific neuronal populations within the LH, i.e. the orexin and the MCH neurons, respectively. However, the interpretation of these results is limited by the lack of quantitative analysis of the electroencephalographic (EEG) activity that is critical for the assessment of NREM sleep quality and the presence of aborted NREM-to-REM sleep transitions. Furthermore, the lack of evaluation of the autonomic and thermoregulatory effects of the treatment does not exclude the possibility that the wake-sleep changes are merely the consequence of the autonomic, in particular thermoregulatory, changes that may follow the inhibition of LH neurons. In the present study, the EEG and autonomic/thermoregulatory effects of a prolonged LH inhibition provoked by the repeated local delivery of the GABAA agonist muscimol were studied in rats kept at thermoneutral (24°C) and at a low (10°C) ambient temperature (Ta), a condition which is known to depress sleep occurrence. Here we show that: 1) at both Tas, LH inhibition promoted a peculiar and sustained bout of NREM sleep characterized by an enhancement of slow-wave activity with no NREM-to-REM sleep transitions; 2) LH inhibition caused a marked transitory decrease in brain temperature at Ta 10°C, but not at Ta 24°C, suggesting that sleep changes induced by LH inhibition at thermoneutrality are not caused by a thermoregulatory impairment. These changes are far different from those observed after the short-term selective inhibition of either orexin or MCH neurons, suggesting that other LH neurons are involved in sleep-wake modulation.


Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 188.8.131.52) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development.
The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 220.127.116.11) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.


Ion-abrasion scanning electron microscopy reveals surface-connected tubular conduits in HIV-infected macrophages.
HIV-1-containing internal compartments are readily detected in images of thin sections from infected cells using conventional transmission electron microscopy, but the origin, connectivity, and 3D distribution of these compartments has remained controversial. Here, we report the 3D distribution of viruses in HIV-1-infected primary human macrophages using cryo-electron tomography and ion-abrasion scanning electron microscopy (IA-SEM), a recently developed approach for nanoscale 3D imaging of whole cells. Using IA-SEM, we show the presence of an extensive network of HIV-1-containing tubular compartments in infected macrophages, with diameters of approximately 150-200 nm, and lengths of up to approximately 5 microm that extend to the cell surface from vesicular compartments that contain assembling HIV-1 virions. These types of surface-connected tubular compartments are not observed in T cells infected with the 29/31 KE Gag-matrix mutant where the virus is targeted to multi-vesicular bodies and released into the extracellular medium. IA-SEM imaging also allows visualization of large sheet-like structures that extend outward from the surfaces of macrophages, which may bend and fold back to allow continual creation of viral compartments and virion-lined channels. This potential mechanism for efficient virus trafficking between the cell surface and interior may represent a subversion of pre-existing vesicular machinery for antigen capture, processing, sequestration, and presentation.


Inhibition of plant-pathogenic fungi by the barley cystatin Hv-CPI (gene Icy) is not associated with its cysteine-proteinase inhibitory properties.
The recombinant barley cystatin Hv-CPI inhibited the growth of three phytopathogenic fungi (Botrytis cinerea, Colletotrichum graminicola, and Plectosphaerella cucumerina) and the saprotrophic fungus Trichoderma viride. Several mutants of barley cystatin were generated by polymerase chain reaction approaches and both their antifungal and their cysteine-proteinase inhibitory properties investigated. Point mutants R38-->G, Q63-->L, and Q63-->P diminished their capacity for inhibiting papain and cathepsin B, retaining their antifungal properties. However, mutant C68-->G was more active for papain and cathepsin B than the wild type. These results indicate that in addition to the consensus cystatin-reactive site, Q63-V64-V65-A66-G67, the A37-R38-F39-A40-V41 region, common to all cereal cystatins, and the C68 residue are important for barley cystatin activity. On the other hand, the K92-->P mutant is inactive as a fungicide, but still retains measurable inhibitory activity for papain and cathepsin B. Against B. cinerea, the antifungal effect of Hv-CPI and of its derived mutants does not always correlate with their activities as proteinase inhibitors, because the Q63-->P mutant is inactive as a cystatin, while still inhibiting fungal growth, and the K92-->P mutant shows the reciprocal effects. These data indicate that inhibition of plant-pathogenic fungi by barley cystatin is not associated with its cysteine-proteinase inhibitory activity. Moreover, these results are corroborated by the absence of inhibition of intra- and extramycelia-proteinase activities by barley cystatin and by other well-known inhibitors of cysteine-proteinase activity in the fungal zymograms of B. cinerea.


The Vacuolar Manganese Transporter MTP8 Determines Tolerance to Iron Deficiency-Induced Chlorosis in Arabidopsis.
Iron (Fe) deficiency is a widespread nutritional disorder on calcareous soils. To identify genes involved in the Fe deficiency response, Arabidopsis (Arabidopsis thaliana) transfer DNA insertion lines were screened on a high-pH medium with low Fe availability. This approach identified METAL TOLERANCE PROTEIN8 (MTP8), a member of the Cation Diffusion Facilitator family, as a critical determinant for the tolerance to Fe deficiency-induced chlorosis, also on soil substrate. Subcellular localization to the tonoplast, complementation of a manganese (Mn)-sensitive Saccharomyces cerevisiae yeast strain, and Mn sensitivity of mtp8 knockout mutants characterized the protein as a vacuolar Mn transporter suitable to prevent plant cells from Mn toxicity. MTP8 expression was strongly induced on low-Fe as well as high-Mn medium, which were both strictly dependent on the transcription factor FIT, indicating that high-Mn stress induces Fe deficiency. mtp8 mutants were only hypersensitive to Fe deficiency when Mn was present in the medium, which further suggested an Mn-specific role of MTP8 during Fe limitation. Under those conditions, mtp8 mutants not only translocated more Mn to the shoot than did wild-type plants but suffered in particular from critically low Fe concentrations and, hence, Fe chlorosis, although the transcriptional Fe deficiency response was up-regulated more strongly in mtp8. The diminished uptake of Fe from Mn-containing low-Fe medium by mtp8 mutants was caused by an impaired ability to boost the ferric chelate reductase activity, which is an essential process in Fe acquisition. These findings provide a mechanistic explanation for the long-known interference of Mn in Fe nutrition and define the molecular processes by which plants alleviate this antagonism.


Exploring cultural drivers for wildlife trade via an ethnoprimatological approach: a case study of slender and slow lorises (Loris and Nycticebus) in South and Southeast Asia.
Illegal and unsustainable trade in wildlife is a major conservation challenge. For Asian primates, economic and cultural traditions, and increased forest access mean that trade may have become detrimental for certain species. Slow and slender lorises (Nycticebus and Loris) are primates particularly prevalent in trade, determined until now by focused counts of lorises in regional markets. Here, we use international trade statistics and a participant-observer approach to assess culturally specific drivers for trade in lorises in South and Southeast Asia, to provide a broader context to help mitigate this practice. Analysis of international records for the last 30 years revealed that live animal trade was more prevalent than trade in body parts (slow lorises, 86.4%; slender lorises, 91.4%), with Laos, Cambodia, and Thailand the largest exporters. We then examine drivers of international and domestic trade based on long-term data from 1994-2009 in Sri Lanka, Cambodia, and Indonesia. We show that slender lorises are important in Sri Lankan folklore, but their use as pets and for traditional medicine is rare. Trade in Bengal slow and pygmy lorises in Cambodia for use in traditional medicines, a practice with deeply historical roots, is widespread. Despite its own set of myths about the magical and curative properties of lorises, trade in Javan, Bornean, and greater slow lorises in Indonesia is largely for pets. Conservation practices in Asia are often generalized and linked with the region's major religions and economies. We show here that, in the case of wildlife trade, culturally specific patterns are evident among different ethnic groups, even within a country. Revealing such patterns is the foundation for developing conservation management plans for each species. We suggest some participatory methods for each country that may aid in this process.


Multiframe temporal estimation of cardiac nonrigid motion.
A robust, flexible system for tracking the point to point nonrigid motion of the left ventricular (LV) endocardial wall in image sequences has been developed. This system is unique in its ability to model motion trajectories across multiple frames. The foundation of this system is an adaptive transversal filter based on the recursive least-squares algorithm. This filter facilitates the integration of models for periodicity and proximal smoothness as appropriate using a contour-based description of the object's boundaries. A set of correspondences between contours and an associated set of correspondence quality measures comprise the input to the system. Frame-to-frame relationships from two different frames of reference are derived and analyzed using synthetic and actual images. Two multiframe temporal models, both based on a sum of sinusoids, are derived. Illustrative examples of the system's output are presented for quantitative analysis. Validation of the system is performed by comparing computed trajectory estimates with the trajectories of physical markers implanted in the LV wall. Sample case studies of marker trajectory comparisons are presented. Ensemble statistics from comparisons with 15 marker trajectories are acquired and analyzed. A multiframe temporal model without spatial periodicity constraints was determined to provide excellent performance with the least computational cost. A multiframe spatiotemporal model provided the best performance based on statistical standard deviation, although at significant computational expense.


Caudate nucleus dopamine d(2) receptors in vascular dementia.
Caudate nucleus dopamine (DA) D(2) receptors were studied in patients with vascular dementia (VaD) and in a control group using [(3)H]raclopride as a radioligand. There was no significant difference in the number of DA D(2) receptors in the VaD group as compared with controls. The binding affinity was significantly lower in the VaD group. When the VaD group was subdivided into subjects with or without neuroleptic treatment, there were no differences in the numbers of receptors as compared with controls, and the significant differences in binding affinity remained for both VaD subgroups. The present results are discussed with reference to the previous finding of a reduced density of caudate nucleus DA uptake sites in the same VaD group and to results from studies on DA D(2) receptors in Alzheimer's disease and Parkinson's disease.


MR imaging of the cranial meninges with emphasis on contrast enhancement and meningeal carcinomatosis.
MR imaging was used to investigate normal and abnormal meningeal enhancement, with an emphasis on meningeal carcinomatosis. Three groups of patients were studied on a 1.5-T system. In group 1, the normal meninges were examined in 20 patients and were found to show fine linear enhancement in short segments, especially in a parasagittal distribution. In group 2, all gadolinium-enhanced head scans were reviewed retrospectively. Abnormal meningeal enhancement was detected in 52 patients. In some of these, the enhancement was associated with pathologic conditions of the meninges, including leptomeningeal tumor and meningeal infections and other inflammatory conditions; in others the enhancement was adjacent to subdural hematomas, subacute infarcts, and skull lesions, such as metastases or postoperative defects. In group 3, 30 cases of meningeal carcinomatosis were studied prospectively. Enhancement was seen in approximately two-thirds of cases and usually was quite diffuse and applied to the inner table of the skull. Frank nodules were seen less often. Contrast-enhanced CT was equal to MR in the detection of nodules but was nearly always unable to show diffuse meningeal enhancement against the inner table of the skull. Contrast-enhanced MR was more sensitive than contrast-enhanced CT in the examination of normal and abnormal meninges. Abnormal findings, such as meningeal carcinomatosis, were demonstrated more often by MR than by CT.


Changes in practice and organisation surrounding blood transfusion in NHS trusts in England 1995-2005.
Between 1996 and 2005 in the UK, the Serious Hazards of Transfusion (SHOT) scheme has reported 105 deaths and 296 patients developing major morbidity due to transfusion. Accurate patient identification and monitoring of patients during blood transfusion are vital in ensuring patient safety, and national guidelines have been in place since 1999. There have been numerous initiatives in the UK in recent years promoting safe and appropriate use of blood and this paper reports the results of the 2005 National Comparative Audit of transfusion practice, and compares this audit with previous audits and survey results. The 2005 audit consisted of two parts looking at organisational factors and bedside practice. To enable comparison with previous audits and surveys the 2005 data have been limited to English NHS sites (217 sites for organisational, 211 sites for bedside practice). Hospital transfusion committees were well established by 2003 though hospital transfusion teams have lagged behind. 86% of hospitals reported having established teams by 2005 although only 52% reported having all essential elements of the team in place. Only 38% reported having trained at least half of their nurses in blood transfusion. Bedside practice has improved, although in 2005, 6% of patients receiving a blood transfusion had no identification wristband in place, and in 9% of those who did, the details were incomplete. Observation of vital signs during transfusions has also improved, although in 2005, 13% of patients receiving a transfusion had had no observations recorded. This paper document the progress that has been made in the UK in establishing an effective infrastructure for the support of safe transfusion practice, and the measurable improvements in bedside transfusion practice. There remain, however, many areas of poor practice, and the improvements have not been seen across all hospitals. It is still too early to say whether progress made is being translated into a reduction in serious transfusion errors at the bedside. Further progress needs to be made.


Uncertainty analysis in a large-scale water quality integrated catchment modelling study.
Receiving water quality simulation in highly urbanised areas requires the integration of several processes occurring at different space-time scales. These integrated catchment models deliver results with a significant uncertainty level associated. Still, uncertainty analysis is seldom applied in practice and the relative contribution of the individual model elements is poorly understood. Often the available methods are applied to relatively small systems or individual sub-systems, due to limitations in organisational and computational resources. Consequently this work presents an uncertainty propagation and decomposition scheme of an integrated water quality modelling study for the evaluation of dissolved oxygen dynamics in a large-scale urbanised river catchment in the Netherlands. Forward propagation of the measured and elicited uncertainty input-parametric distributions was proposed and contrasted with monitoring data series. Prior ranges for river water quality-quantity parameters lead to high uncertainty in dissolved oxygen predictions, thus the need for formal calibration to adapt to the local dynamics is highlighted. After inferring the river process parameters with system measurements of flow and dissolved oxygen, combined sewer overflow pollution loads became the dominant uncertainty source along with rainfall variability. As a result, insights gained in this paper can help in planning and directing further monitoring and modelling efforts in the system. When comparing these modelling results to existing national guidelines it is shown that the commonly used concentration-duration-frequency tables should not be the only metric used to select mitigation alternatives and may need to be adapted in order to cope with uncertainties.


Variations in the care of HIV-infected adults in the United States: results from the HIV Cost and Services Utilization Study.
Studies of selected populations suggest that not all persons infected with human immunodeficiency virus (HIV) receive adequate care. To examine variations in the care received by a national sample representative of the adult US population infected with HIV. Cohort study that consisted of 3 interviews from January 1996 to January 1998 conducted by the HIV Cost and Services Utilization Consortium. Multistage probability sample of 2864 respondents (68% of those targeted for sampling), who represent the 231400 persons at least 18 years old, with known HIV infection receiving medical care in the 48 contiguous United States in early 1996 in facilities other than emergency departments, the military, or prisons. The first follow-up consisted of 2466 respondents and the second had 2267 (65% of all surviving sampled subjects). Service utilization (<2 ambulatory visits, at least 1 emergency department visit that did not lead to hospitalization, at least 1 hospitalization) and medication utilization (receipt of antiretroviral therapy and prophylaxis against Pneumocystis carinii pneumonia). Inadequate HIV care was commonly reported at the time of interviews conducted from early 1996 to early 1997 but declined to varying degrees by late 1997. Twenty-three percent of patients initially and 15% of patients subsequently had emergency department visits that did not lead to hospitalization, 30% initially and 26% subsequently of those who had CD4 cell counts below 0.20 x 10(9)/L did not receive P carinii pneumonia prophylaxis, and 41% initially and 15% subsequently of those who had CD4 cell counts below 0.50 x 10(9)/L did not receive antiretroviral therapy (protease inhibitor or nonnucleoside reverse transcriptase inhibitor). Inferior patterns of care were seen for many of these measures in blacks and Latinos compared with whites, the uninsured and Medicaid-insured compared with the privately insured, women compared with men, and other risk and/or exposure groups compared with men who had sex with men even after CD4 cell count adjustment. With multivariate adjustment, many differences remained statistically significant. Even by early 1998, fewer blacks, women, and uninsured and Medicaid-insured persons had started taking antiretroviral medication (CD4 cell count adjusted P values <.001 to <.005). Access to care improved from 1996 to 1998 but remained suboptimal. Blacks, Latinos, women, the uninsured, and Medicaid-insured all had less desirable patterns of care. Strategies to ensure optimal care for patients with HIV requires identifying the causes of deficiency and addressing these important shortcomings in care.


Interplay between syntax and semantics during sentence comprehension: ERP effects of combining syntactic and semantic violations.
This study investigated the effects of combined semantic and syntactic violations in relation to the effects of single semantic and single syntactic violations on language-related event-related brain potential (ERP) effects (N400 and P600/SPS). Syntactic violations consisted of a mismatch in grammatical gender or number features of the definite article and the noun in sentence-internal or sentence-final noun phrases (NPs). Semantic violations consisted of semantically implausible adjective-noun combinations in the same NPs. Combined syntactic and semantic violations were a summation of these two respective violation types. ERPs were recorded while subjects read the sentences with the different types of violations and the correct control sentences. ERP effects were computed relative to ERPs elicited by the sentence-internal or sentence-final nouns. The size of the N400 effect to the semantic violation was increased by an additional syntactic violation (the syntactic boost). In contrast, the size of the P600/SPS to the syntactic violation was not affected by an additional semantic violation. This suggests that in the absence of syntactic ambiguity, the assignment of syntactic structure is independent of semantic context. However, semantic integration is influenced by syntactic processing. In the sentence-final position, additional global processing consequences were obtained as a result of earlier violations in the sentence. The resulting increase in the N400 amplitude to sentence-final words was independent of the nature of the violation. A speeded anomaly detection task revealed that it takes substantially longer to detect semantic than syntactic anomalies. These results are discussed in relation to the latency and processing characteristics of the N400 and P600/SPS effects. Overall, the results reveal an asymmetry in the interplay between syntax and semantics during on-line sentence comprehension.


Emerging biosignature of brain function and intervention in pediatric bipolar disorder.
Pediatric bipolar disorder (PBD) is a complex illness with a chronic course, requiring multiple medications over the longitudinal course of illness, with limited recovery and high relapse rate. Beyond the placebo controlled trials of monotherapy, there is an increased need to understand how each medication influences regions of affective and cognitive circuitry function by normalization or deployment of alternative circuitry regions. Functional studies are beginning to unravel the improved function in the fronto-limbic and fronto-temporal affective circuitry, and based on the paradigm administered, also in the interfacing cognitive fronto-striato-temporo-parietal regions. Treatment studies illustrated a pattern of improvement in functional activity consistently among the affective ventrolateral and medial prefrontal regions, and variably in the cognitive dorsolateral prefrontal cortex. While there is decreased activity in amygdala with treatment for mania or depression among patients with PBD, there appears to be residual increased amygdala activity regardless of response, relative to healthy controls, suggesting a trait-like abnormality. Parallel biochemical abnormalities in magnetic resonance spectroscopic studies and fronto-limbic activity in magnetic resonance imaging studies of brain function at baseline provide maiden data on predicting outcome. This preliminary cohort of studies that probed the hypothesized circuitries underlying specific symptom constructs, coupled with futuristic paradigms and analytic methods, serve as a guidepost to generate the next generation of studies and build on the emerging biosignature towards specific treatment targets for personalized medicine in PBD.


Gene expression patterns in visual cortex during the critical period: synaptic stabilization and reversal by visual deprivation.
The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.


Cellular adaptation facilitates sparse and reliable coding in sensory pathways.
Most neurons in peripheral sensory pathways initially respond vigorously when a preferred stimulus is presented, but adapt as stimulation continues. It is unclear how this phenomenon affects stimulus coding in the later stages of sensory processing. Here, we show that a temporally sparse and reliable stimulus representation develops naturally in sequential stages of a sensory network with adapting neurons. As a modeling framework we employ a mean-field approach together with an adaptive population density treatment, accompanied by numerical simulations of spiking neural networks. We find that cellular adaptation plays a critical role in the dynamic reduction of the trial-by-trial variability of cortical spike responses by transiently suppressing self-generated fast fluctuations in the cortical balanced network. This provides an explanation for a widespread cortical phenomenon by a simple mechanism. We further show that in the insect olfactory system cellular adaptation is sufficient to explain the emergence of the temporally sparse and reliable stimulus representation in the mushroom body. Our results reveal a generic, biophysically plausible mechanism that can explain the emergence of a temporally sparse and reliable stimulus representation within a sequential processing architecture.


Longitudinal scoliosis behavior in Chiari malformation with and without syringomyelia.
The objective of this study was to understand the natural history of scoliosis in patients with Chiari malformation type I (CM-I) with and without syringomyelia. A retrospective review of data was conducted. Patients with CM-I were identified from a cohort of 14,118 individuals age 18 years or younger who had undergone MRI over an 11-year period at the University of Michigan. Patients eligible for study inclusion had a coronal curve ≥ 10° on radiography, associated CM-I with or without syringomyelia, and at least 1 year of clinical follow-up prior to any surgery. Curve magnitude at initial diagnosis, prior to posterior fossa decompression (PFD; if applicable), and at the last follow-up (prior to any surgical correction of scoliosis) was recorded, and clinical and radiographic characteristics were noted. The change in curve magnitude by 10° was defined as curve progression (increase by 10°) or regression (decrease by 10°). Forty-three patients met the study inclusion criteria and were analyzed. About one-third (35%) of the patients presented with symptoms attributed to their CM-I. The mean degree of scoliosis at presentation was 32.6° ± 17.7°. Twenty-one patients (49%) had an associated syrinx. The mean tonsil position below the level of the foramen magnum was 9.8 ± 5.8 mm. Patients with a syrinx were more likely to have a curve > 20° (86% vs 41%, p = 0.002). Curve magnitude remained stable (≤ ±10°) in 77% of patients (33/43), progressed in 16% (7/43), and regressed in 7% (3/43). Mean age was higher (14.8 ± 0.59 years) among patients with regressed curves (p = 0.026). All regressed curves initially measured ≤ 20° (mean 14° ± 5.3°), and none of the patients with regressed curves had a syrinx. The change in curve magnitude was statistically similar in patients with (7.32° ± 17.7°) and without (5.32° ± 15.8°) a syrinx (p = 0.67). After a mean follow-up of 3.13 ± 2.04 years prior to surgery, 27 patients (63%) ultimately underwent posterior fossa or scoliosis correction surgery. For those who eventually underwent PFD only, the rate of change in curve magnitude prior to surgery was 0.054° ± 0.79°. The rate of change in curve magnitude was statistically similar before (0.054° ± 0.79°) and after (0.042° ± 0.33°) surgery (p = 0.45) for patients who underwent PFD surgery only. The natural history of scoliosis in the presence of CM-I is variable, though most curves remained stable. All curves that regressed were ≤ 20° at initial diagnosis, and most patients in such cases were older at scoliosis diagnosis. Patients who underwent no surgery or PFD only had similar profiles for the change in curve magnitude, which remained relatively stable overall, as compared to patients who underwent PFD and subsequent fusion, who demonstrated curve progression. Among the patients with a syrinx, no curves regressed, most remained stable, and some progressed. Understanding this variability is a first step toward building a prediction model for outcomes for these patients.


Evaluation of methyl fluoride and dimethyl ether as inhibitors of aerobic methane oxidation.
Methyl fluoride (MF) and dimethyl ether (DME) were effective inhibitors of aerobic methanotrophy in a variety of soils. MF and DME blocked consumption of CH(4) as well as the oxidation of CH(4) to CO(2), but neither MF nor DME affected the oxidation of [C]methanol or [C]formate to CO(2). Cooxidation of ethane and propane by methane-oxidizing soils was also inhibited by MF. Nitrification (ammonia oxidation) in soils was inhibited by both MF and DME. Production of N(2)O via nitrification was inhibited by MF; however, MF did not affect N(2)O production associated with denitrification. Methanogenesis was partially inhibited by MF but not by DME. Methane oxidation was approximately 100-fold more sensitive to MF than was methanogenesis, indicating that an optimum concentration could be employed to selectively block methanotrophy. MF inhibited methane oxidation by cell suspensions of Methylococcus capsulatus; however, DME was a much less effective inhibitor.


How Can Pricing and Reimbursement Policies Improve Affordable Access to Medicines? Lessons Learned from European Countries.
This article discusses pharmaceutical pricing and reimbursement policies in European countries with regard to their ability to ensure affordable access to medicines. A frequently applied pricing policy is external price referencing. While it provides some benchmark for policy-makers and has been shown to be able to generate savings, it may also contribute to delay in product launch in countries where medicine prices are low. Value-based pricing has been proposed as a policy that promotes access while rewarding useful innovation; however, implementing it has proven quite challenging. For high-priced medicines, managed-entry agreements are increasingly used. These agreements allow policy-makers to manage uncertainty and obtain lower prices. They can also facilitate earlier market access in case of limited evidence about added therapeutic value of the medicine. However, these agreements raise transparency concerns due to the confidentiality clause. Tendering as used in the hospital and offpatent outpatient sectors has been proven to reduce medicine prices but it requires a robust framework and appropriate design with clear strategic goals in order to prevent shortages. These pricing and reimbursement policies are supplemented by the widespread use of Health Technology Assessment to inform decision-making, and by strategies to improve the uptake of generics, and also biosimilars. While European countries have been implementing a set of policy options, there is a lack of thorough impact assessments of several pricing and reimbursement policies on affordable access. Increased cooperation between authorities, experience sharing and improving transparency on price information, including the disclosure of confidential discounts, are opportunities to address current challenges.


New disulfido molybdenum-manganese complexes exhibit facile addition of small molecules to the sulfur atoms.
The reaction of Mn(2)(CO)(7)(mu-S2) (1) with [CpMo(CO)(3)](2) (Cp = C(5)H(5)) and [Cp*Mo(CO)(3)](2) (Cp* = C(5)(CH(3))(5)) yielded the new mixed-metal disulfide complexes CpMoMn(CO)(5)(mu-S2) (2) and Cp*MoMn(CO)(5)(mu-S2) (3) by a metal-metal exchange reaction. Compounds 2 and 3 both contain a bridging disulfido ligand lying perpendicular to the Mo-Mn bond. The bond distances are Mo-Mn = 2.8421(10) and 2.8914(5) A and S-S = 2.042(2) and 1.9973(10) A for 2 and 3, respectively. A tetranuclear metal side product CpMoMn(3)(CO)(13)(mu3-S)(mu4-S) (4) was also isolated from the reaction of 1 with [CpMo(CO)(3)](2). Compounds 2 and 3 react with CO to yield the dithiocarbonato complexes CpMoMn(CO)(5)[mu-SC(=O)S] (5) and Cp*MoMn(CO)(5)[mu-SC(=O)S] (6) by insertion of CO into the S-S bond. Similarly, tert-butylisocyanide was inserted into the S-S bond of 2 and 3 to yield the complexes CpMoMn(CO)(5)[mu-S(C=NBu(t))S] (7) and Cp*MoMn(CO)(5)[mu-S(C=NBu(t))S] (8), respectively. Ethylene and dimethylacetylene dicarboxylate also inserted into the S-S bond of 2 and 3 at room temperature to yield the ethanedithiolato ligand bridged complexes CpMoMn(CO)(5)(mu-SCH(2)CH(2)S) (9), Cp*MoMn(CO)(5)(mu-SCH(2)CH(2)S) (10), CpMoMn(CO)(5)[mu-SC(CO(2)Me)=C(CO(2)Me)S] (11), and Cp*MoMn(CO)(5)[mu-SC(CO(2)Me)=C(CO(2)Me)S] (12). Allene was found to insert into the S-S bond of 2 by using one of its two double bonds to yield the complex CpMoMn(CO)(5)[mu-SCH(2)C(=CH(2))S] (13). The molecular structures of the new complexes 2-7 and 9-13 were established by single-crystal X-ray diffraction analyses.


Cell-cell adhesion in plant grafting is facilitated by β-1,4-glucanases.
Plant grafting is conducted for fruit and vegetable propagation, whereby a piece of living tissue is attached to another through cell-cell adhesion. However, graft compatibility limits combinations to closely related species, and the mechanism is poorly understood. We found that Nicotiana is capable of graft adhesion with a diverse range of angiosperms. Comparative transcriptomic analyses on graft combinations indicated that a subclade of β-1,4-glucanases secreted into the extracellular region facilitates cell wall reconstruction near the graft interface. Grafting was promoted by overexpression of the β-1,4-glucanase. Using Nicotiana stem as an interscion, we produced tomato fruits on rootstocks from other plant families. These findings demonstrate that the process of cell-cell adhesion is a potential target to enhance plant grafting techniques.


Endoscopic changes in the upper airway after mandibular distraction osteogenesis.
Children with micrognathia secondary to craniofacial disorders can experience significant airway and feeding difficulties. Mandibular distraction osteogenesis (MDO) is one treatment of severe micrognathia. We examined endoscopic images for upper airway (UA) soft tissue changes after MDO. We hypothesized that MDO produces consistent changes in UA soft tissue, which correlate with symptom resolution. This retrospective chart review included 16 patients undergoing MDO from 2002 to 2007. Demographic data, symptom information, and preoperative and early and late postoperative endoscopic images were collected. Blinded randomized images of UA soft tissues were quantitatively analyzed using ImageJ. To compare nonstandardized images, ratios of UA dimensions were made. Preoperative and early and late postoperative ratios were statistically analyzed with Student's t-test. Sixteen patients with a mean age of 237 days were included. Mean distance distracted was 12 mm. There were significant changes in relative dimensions of the supraglottic space in the early postoperative period, which were not maintained in the late postoperative period. Nevertheless, all experienced complete relief of airway obstruction. Our study showed a significant increase in supraglottic space dimensions after MDO that was not maintained over time. This is likely because of the limitation of images and measurement methods. Despite this, significant clinical improvement was seen in all patients, with resolution of airway obstruction. This suggests supraglottic changes as well as tongue base alterations are related to clinical improvement. Further investigation of alterations in UA after MDO is needed to continue characterizing these changes.


Glucose sensor with a Sagnac interference optical system.
The angle of optical rotation was measured by detecting the phase difference between clockwise and counterclockwise circular polarized light that propagated in a sensing loop. This polarimeter, or glucose sensor, consisted of a Sagnac interference optical system with a polarization-maintaining optical fiber, so it was not affected by the control limitations of the polarization rotation angle or the optical power fluctuation that occurs with scattered light, reflection, or polarization rotation in an optical system. The angle of rotation was measured from the phase difference of the glucose sensor when the concentration of glucose was changed. We confirmed that the resolution of optical rotation was 5×10(-4) deg, and the resolution of the glucose concentration was 1 mg/dl accordingly. The measured specific rotation of glucose was mostly equal to a physical property value. One applications of this glucose sensor is in measuring the blood sugar levels of diabetic patients.


Chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS): a critical review.
Multiple sclerosis (MS) is a chronic disease of the central nervous system with not yet completely understood pathogenesis. The so called "chronic cerebrospinal venous insufficiency (CCSVI) theory" has recently emerged, supporting the concept of a cerebrospinal venous drainage impairment as the cause of MS. Since the first publication on this topic with a claimed 100% specificity and sensitivity of the condition for MS diagnosis, CCSVI theory has generated a scientific and mass media debate with a great hope for the miracle of a new possible endovascular treatment of MS ("liberation procedure"). We critically summarize the available evidence on CCSVI discussing inconsistent and incomplete replication of the original results by different groups, methodological limitations and potential therapeutic implications. We conclude that the available data are insufficient to establish conclusively a clear relationship between MS and CCSVI and do not support the role of CCSVI as the primary cause of MS. Until credible scientific evidence replicates the original results, any proposed invasive treatments of CCSVI should be discouraged.


Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.
Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.


A departmental initiative for clinical and translational research.
To encourage departmental research activities, the Department of Medicine of the Medical College of Georgia (MCG) introduced an internally funded Translational Research Program (TRP) in 2014. Patterned after the Vanderbilt Institute for Clinical and Translational Research, the program offers research studios for project guidance, research mentoring and the availability of limited financial support through research vouchers. Additional academic services include abstract reviewing, conducting research conferences, organizing departmental research programs for students, and offering courses in biostatistics. During the first 15 months of its existence, the TRP working group addressed 132 distinct activities. Research mentoring, publications, and the conduct of research studios or voucher approvals encompassed 49% of working group activities. Other academic services constituted the remaining 51%. Twenty-four per cent of TRP committee activities involved research mentoring of 32 investigators (25% faculty and 75% trainees). Mentored projects generated 17 abstracts, 2 manuscripts and $87,000 in funds. The TRP conducted 13 research studios; trainees presented 54%. The TRP reviewed 36 abstracts for local and state organizations. Monthly research conferences and statistical courses were conducted and well attended. Our experience thus far indicates that a departmental TRP may serve to facilitate the growth of patient-oriented research with minimal financial support. It requires active engagement of volunteer faculty and departmental leadership willing to balance research with the other demands of the academic mission.


Towards the evaluation of defects in MoS2 using cryogenic photoluminescence spectroscopy.
Characterization of the type and density of defects in two-dimensional (2D) transition metal dichalcogenides (TMDs) is important as the nature of these defects strongly influences the electronic and optical properties of the material, especially its photoluminescence (PL). Defect characterization is not as straightforward as it is for graphene films, where the D and D' Raman scattering modes easily indicate the density and type of defects in the graphene layer. Thus, in addition to the Raman scattering analysis, other spectroscopic techniques are necessary to perform detailed characterization of atomically thin TMD layers. We demonstrate that PL spectroscopy performed at liquid helium temperatures reveals the key fingerprints of defects in TMDs and hence provides valuable information about their origin and concentration. In our study, we address defects in chemical vapor deposition (CVD)-grown MoS2 monolayers. A significant difference is observed between the as-grown monolayers compared with the CVD-grown monolayers transferred onto a Si/SiO2 substrate, which contain extra defects due to the transfer process. We demonstrate that the temperature-dependent Raman and PL micro-spectroscopy techniques enable disentangling the contributions and locations of various defect types in TMD systems.


Simulating within-vector generation of the malaria parasite diversity.
Plasmodium falciparum, the most virulent human malaria parasite, undergoes asexual reproduction within the human host, but reproduces sexually within its vector host, the Anopheles mosquito. Consequently, the mosquito stage of the parasite life cycle provides an opportunity to create genetically novel parasites in multiply-infected mosquitoes, potentially increasing parasite population diversity. Despite the important implications for disease transmission and malaria control, a quantitative mapping of how parasite diversity entering a mosquito relates to diversity of the parasite exiting, has not been undertaken. To examine the role that vector biology plays in modulating parasite diversity, we develop a two-part model framework that estimates the diversity as a consequence of different bottlenecks and expansion events occurring during the vector-stage of the parasite life cycle. For the underlying framework, we develop the first stochastic model of within-vector P. falciparum parasite dynamics and go on to simulate the dynamics of two parasite subpopulations, emulating multiply infected mosquitoes. We show that incorporating stochasticity is essential to capture the extensive variation in parasite dynamics, particularly in the presence of multiple parasites. In particular, unlike deterministic models, which always predict the most fit parasites to produce the most sporozoites, we find that occasionally only parasites with lower fitness survive to the sporozoite stage. This has important implications for onward transmission. The second part of our framework includes a model of sequence diversity generation resulting from recombination and reassortment between parasites within a mosquito. Our two-part model framework shows that bottlenecks entering the oocyst stage decrease parasite diversity from what is present in the initial gametocyte population in a mosquito's blood meal. However, diversity increases with the possibility for recombination and proliferation in the formation of sporozoites. Furthermore, when we begin with two parasite subpopulations in the initial gametocyte population, the probability of transmitting more than two unique parasites from mosquito to human is over 50% for a wide range of initial gametocyte densities.


Ultrasound diagnosis of pulmonary sling with proximal stenosis of left pulmonary artery and patent arterial duct.
Authors discuss methods of echocardiographic diagnosis of the pulmonary sling with stenosis and hypoplasia of the left pulmonary artery and patent arterial duct with massive left-to-right shunt, based on a case of the newborn with resistant to treatment heart failure, with initial diagnosis of patent ductus arteriosus, referred to surgical treatment. The optimal echocardiographic views permitting establish diagnosis of the pulmonary sling were suggested. The special attention was paid to high parasternal and suprasternal views visualizing vessels of the upper mediastinum as well as characteristic differences between the normal and pathologic picture. The typical features of the echocardiogram suggesting pulmonary sling, like the lack of the left pulmonary artery in its expected position, and the abnormal branching pattern of the right pulmonary artery were indicated. The greatest diagnostic difficulties in visualization of the abnormal route of the left pulmonary artery were related to the presence of air-containing tissues, like lungs and central airways between the ultrasound probe and area of interest. The other was the masking influence of the large patent arterial duct, that may mimic the left pulmonary artery arising from the pulmonary trunk. The other entities requiring differentiation with sling, like aplasia of the left lung, the direct or indirect aortic origin of the left pulmonary artery, were discussed. The role of other visualization technics, like computed 3D tomography, and magnetic nuclear resonance, as well as direct visualization of central airways with bronchoscopy in establishing precise diagnosis were stressed.


A neural circuit model of decision uncertainty and change-of-mind.
Decision-making is often accompanied by a degree of confidence on whether a choice is correct. Decision uncertainty, or lack in confidence, may lead to change-of-mind. Studies have identified the behavioural characteristics associated with decision confidence or change-of-mind, and their neural correlates. Although several theoretical accounts have been proposed, there is no neural model that can compute decision uncertainty and explain its effects on change-of-mind. We propose a neuronal circuit model that computes decision uncertainty while accounting for a variety of behavioural and neural data of decision confidence and change-of-mind, including testable model predictions. Our theoretical analysis suggests that change-of-mind occurs due to the presence of a transient uncertainty-induced choice-neutral stable steady state and noisy fluctuation within the neuronal network. Our distributed network model indicates that the neural basis of change-of-mind is more distinctively identified in motor-based neurons. Overall, our model provides a framework that unifies decision confidence and change-of-mind.


Ion permeation by a folded multiblock amphiphilic oligomer achieved by hierarchical construction of self-assembled nanopores.
A multiblock amphiphilic molecule 1, with a tetrameric alternating sequence of hydrophilic and hydrophobic units, adopts a folded structure in a liposomal membrane like a multipass transmembrane protein, and is able to transport alkali metal cations through the membrane. Hill's analysis and conductance measurements, analyzed by the Hille equation, revealed that the tetrameric assembly of 1 forms a 0.53 nm channel allowing for permeation of cations. Since neither 3, bearing flexible hydrophobic units and forming no stacked structures in the membrane, nor 2, a monomeric version of 1, is able to transport cations, the folded conformation of 1 in the membrane is likely essential for realizing its function. Thus, function and hierarchically formed higher-order structures of 1, is strongly correlated with each other like proteins and other biological macromolecules.


How well do ICD-9 physician claim diagnostic codes identify confirmed pertussis cases in Alberta, Canada? A Canadian Immunization Research Network (CIRN) Study.
Rates of Bordetella pertussis have been increasing in Alberta, Canada despite vaccination programs. Waning immunity from existing acellular component vaccines may be contributing to this. Vaccine effectiveness can be estimated using a variety of data sources including diagnostic codes from physician billing claims, public health records, reportable disease and laboratory databases. We sought to determine if diagnostic codes from billing claims (administrative data) are adequately sensitive and specific to identify pertussis cases among patients who had undergone disease-specific laboratory testing. Data were extracted for 2004-2014 from a public health communicable disease database that contained data on patients under investigation for B. pertussis (both those who had laboratory tests and those who were epidemiologically linked to laboratory-confirmed cases) in Alberta, Canada. These were deterministically linked using a unique lifetime person identifier to the provincial billing claims database, which contains International Classification of Disease version 9 (ICD-9) diagnostic codes for physician visits. We examined visits within 90 days of laboratory testing. ICD-9 codes 033 (whooping cough), 033.0 (Bordetella pertussis), 033.1 (B. parapertussis), 033.8 (whooping cough, other specified organism), and 033.9 (whooping cough, other unspecified organism) in any of the three diagnostic fields for a claim were classified as being pertussis-specific codes. We calculated sensitivity, specificity, positive (PPV) and negative (NPV) predictive values. We identified 22,883 unique patients under investigation for B. pertussis. Of these, 22,095 underwent laboratory testing. Among those who had a laboratory test, 2360 tested positive for pertussis. The sensitivity of a pertussis-specific ICD-9 code for identifying a laboratory-confirmed case was 38.6%, specificity was 76.9%, PPV was 16.0%, and NPV was 91.6%. ICD-9 codes from physician billing claims data have low sensitivity and moderate specificity to identify laboratory-confirmed pertussis among persons tested for pertussis.


Linking models of polymerization and dynamics to predict branched polymer structure and flow.
We present a predictive scheme connecting the topological structure of highly branched entangled polymers, with industrial-level complexity, to the emergent viscoelasticity of the polymer melt. The scheme is able to calculate the linear and nonlinear viscoelasticity of a stochastically branched "high-pressure free radical" polymer melt as a function of the chemical kinetics of its formation. The method combines numerical simulation of polymerization with the tube/entanglement physics of polymer dynamics extended to fully nonlinear response. We compare calculations for a series of low-density polyethylenes with experiments on structural and viscoelastic properties. The method provides a window onto the molecular processes responsible for the optimized rheology of these melts, connecting fundamental science to process in complex flow, and opens up the in silico design of new materials.


Connectivity of somatosensory cortical area 1 forms an anatomical substrate for the emergence of multifinger receptive fields and complex feature selectivity in the squirrel monkey (Saimiri sciureus).
Converging evidence shows that interaction of digit-specific input, which is required to form global tactile percepts, begins as early as area 3b in the primary somatosensory cortex with the involvement of intrinsic lateral connections. How tactile processing is further elaborated in area 1, the next stage of the somatosensory cortical hierarchy, is less understood. This question was investigated by studying the tangential distribution of intrinsic and interareal connections of finger representations of area 1. Retrogradely labeled cell densities and anterogradely labeled fibers and terminal patches were plotted and quantified with respect to the hand representation by combining tract tracing with electrophysiological mapping and intrinsic signal optical imaging in somatosensory areas. Intrinsic connections of distal finger pad representations of area 1 spanned the representation of multiple digits indicating strong cross-digit connectivity. Area 1 distal finger pad regions also established high-density connections with homotopic regions of areas 3b and 2. Although similar to area 3b, connections of area 1 distributed more widely and covered a larger somatotopic representation including more proximal parts of the finger representations. The lateral connectivity pattern of area 1 is a suitable anatomical substrate of the emergence of multifinger receptive fields, complex feature selectivity, and invariant stimulus properties of the neurons.


A Retrospective Analysis of Dental Implants Replacing Failed Implants in Grafted Maxillary Sinus: A Case Series.
To evaluate the survival rate of dental implants replacing failed implants in grafted maxillary sinuses using the lateral approach vs nongrafted posterior maxillae. A retrospective analysis was conducted to study the survival of secondary dental implants inserted in the posterior maxilla in previously failed implant sites between the years 2000 and 2010. The study group consisted of patients who had also undergone maxillary sinus augmentation, and the control group consisted of patients in whom implants in the posterior maxilla had failed. Clinical and demographic data were analyzed using a structured form. Seventy-five patients with a total of 75 replaced implants were included in the study. The study group comprised 40 patients and the control group, 35 patients. None of the replaced implants in the study group failed, resulting in an overall survival of 100%; three replaced implants in the control group failed (92% survival). The main reason for the primary implant removal was lack of osseointegration (35 [87.5%] of 40 study group implants and 23 [65.7%] of 35 control group implants [P = .027]). The difference between the groups with regard to the timing of primary implant failure was statistically significant. The study group had more early failures of the primary implant than did the control group (77% vs 62%; P = .038). Dental implants replaced in the posterior maxilla had a high survival rate. A higher rate of survival was found in augmented maxillary sinus sites. Within the limits of the present study, it can be concluded that previous implant failures in the grafted maxillary sinus should not discourage practitioners from a second attempt.


HtrA serine proteases as potential therapeutic targets in cancer.
The human HtrA family of serine proteases consists of four members: HtrA1, HtrA2, HtrA3 and HtrA4. Although prokaryotic HtrA proteins are well characterized in their dual roles as chaperones and proteases that degrade misfolded proteins in the periplasm, some members of mammalian HtrA proteins are described as potential modulators of programmed cell death and chemotherapy-induced cytotoxicity. Goal of this review article is to describe the molecular alterations associated with these HtrA serine proteases and how these alterations may be associated with tumor behavior and response to chemotherapy. We will also discuss evidence that chemotherapeutic drugs regulate the expression and activation of HtrA serine proteases and that these proteases contributes to programmed cell death. Finally, we will discuss the potential role of epigenetic therapy in targeting the expression and activation of HtrA serine proteases and the mechanisms by which these proteases enhance cytotoxic effect of conventional chemotherapy.


[Dual-source computed tomography in inpatients with atypical chest pain].
To evaluate the potential usefulness of dual-source CT (DSCT) in the diagnostic work-up of inpatients with atypical chest pain of unknown etiology. Forty-one consecutive inpatients (25 male, 16 female; mean age 55.6+/-17.39 years) with atypical chest pain underwent DSCT to determine the cause of pain. Images were acquired with retrospective ECG gating after the administration of 120ml of iodinated contrast medium at 4ml/s using the bolus tracking technique. Two readers analyzed the images in consensus. DSCT was diagnostic in all patients. We detected pulmonary embolisms in five patients and aortic disease in two (one aortic ulcer and one sacular aneurysm). Anomalies of the coronary arteries were depicted in 15 patients, two of whom presented luminal stenosis >50%. Extracardiovascular findings at DSCT included pneumonia in eleven patients, sarcoidosis in one, and non-small cell lung carcinoma in one. Pleural effusion was detected in four patients and pericardial effusion in another four. No pathological findings were observed in 22% of subjects. Evolution was favorable in all patients. No patients were readmitted for persistent pain or new onset of acute chest pain during the follow-up period. DSCT can rule out most life-threatening clinical conditions that cause chest pain and is useful in determining the cause of chest pain in inpatients.


The effect of preoperative weight loss and body mass index on postoperative outcome in patients with esophagogastric carcinoma.
Studies have shown that weight loss is associated with adverse outcomes in all treatment modalities for esophagogastric carcinoma. Because of the increased prevalence of obesity and the effectiveness of perioperative nutrition, a number of patients are now obese or have normal body mass index (BMI) at the time of treatment. We investigated the relationship between weight loss, BMI, and outcome of surgery for patients with esophagogastric carcinoma. Data were collected over a 38-month period for all patients diagnosed with operable esophagogastric cancer at two UK centers. All patients underwent resection by a single Consultant Upper Gastrointestinal Surgeon and the use of perioperative jejunal feeding was universal. Ninety-three patients (57 male) underwent esophagogastric resection; 48 had no preoperative weight loss (34 with a BMI > 25 and 14 with a BMI < 25). Forty-five patients had preoperative weight loss (20 with BMI > 25 and 25 with BMI < 25). There was no significant difference in complication rates, median hospital stay, or mortality between the four groups. A significantly higher number of patients displaying preoperative weight loss were found to have stage III disease, but difference in survival of up to 3 years did not reach statistical significance on multivariate analysis. Preoperative weight loss and low BMI did not significantly influence the complication rate, perioperative mortality rate, length of hospital stay, or short-term prognosis. We conclude that preoperative weight loss can not be reliably used as an independent predictor of poor outcome in patients undergoing surgery for esophagogastric carcinoma. However, patients with preoperative weight loss and low BMI are more likely to have advanced disease.


Bilateral choroidal melanomas. Case report and incidence.
A 55-year-old woman had bilateral choroidal melanoma. To our knowledge, this is the second reported case in the United States. To calculate the incidence of bilateral cases, we determined the incidence of unilateral choroidal and ciliary body melanomas among the white population in Iowa. We also studied the incidence of these melanomas by different age and sex groups. One of 2,500 whites will develop a choroidal melanoma during his or her lifetime. Based on these values and those of life expectancy in patients harboring a choroidal melanoma, we calculated the risks of developing a second primary melanoma in the other eye. In a population of 50 million whites, 1 person will develop a bilateral choroidal melanoma during his or her lifetime. In other words, a bilateral case is expected to occur once every 18 years in the United States.


Potato protease inhibitor II suppresses postprandial appetite in healthy women: a randomized double-blind placebo-controlled trial.
The effect of potato protease inhibitor II (PI2) on postprandial appetite was examined in a randomized double-blind placebo-controlled cross-over trial involving 44 healthy women. In separate test sessions, participants consumed a capsule containing placebo or potato extract standardized to 15 or 30 mg PI2 after overnight fasting. One hour later, a standard 390 kcal breakfast was served. At regular time points during the three-hour period after breakfast, appetite was measured by visual analog scales, and blood samples were collected for assay of cholecystokinin, insulin, and glucose. Compared with the placebo, consumption of 15 mg or 30 mg PI2 one hour prior to a standard breakfast meal resulted in significantly lower postprandial hunger, desire to eat, and prospective consumption, as well as significantly higher postprandial fullness. Consumption of 15 mg PI2 also resulted in significantly higher postprandial plasma levels of cholecystokinin compared with the placebo. No significant main effect of treatment was found on insulin and glucose. No adverse events were reported. Results from the study revealed that consumption of potato PI2 at the examined doses was well tolerated, suppressed subjective appetite in a dose-dependent manner, and increased plasma concentrations of cholecystokinin. Future studies are needed to evaluate the long-term effect of PI2 on body weight.


Amplitude normalization reduces cervical vestibular evoked myogenic potential (cVEMP) amplitude asymmetries in normal subjects: proof of concept.
The cervical vestibular evoked myogenic potential (cVEMP) is an acoustically synchronized, signal averaged, brief inhibitory response of a contracted muscle usually resulting from an acoustic stimulus. The cVEMP is recorded from the tonically contracted sternocleidomastoid muscle (SCM). The presence and amplitude of the cVEMP is related to both the integrity of the sacculo-collic pathway and magnitude of electromyographic (EMG) activity at the time of recording. Measurement variables include the absolute latency of the primary positive going component (referred to as P13) and interaural (i.e., left versus right) latency differences. Also measured is the peak-to-peak interaural amplitude asymmetry (IAA; percent difference in amplitude, left versus right). It is known that the amplitude of the cVEMP is positively correlated with the magnitude of tonic EMG from which the evoked potential is extracted. Thus, if EMG amplitude is uncontrolled, one cannot determine whether cVEMP asymmetries are occurring due to unilateral end organ disease or asymmetric tonic EMG activity. Two methods have been suggested to control for tonic EMG activity. These include (1) patient self-monitoring of EMG activity with biofeedback and (2) mathematical correction (i.e., amplitude normalization) of the left and right cVEMP waveforms. Currently, it is unknown how effective amplitude normalization techniques are at reducing cVEMP amplitude asymmetry in the presence of varying levels of EMG. The purpose of this investigation was to determine whether the use of amplitude correction techniques would reduce significantly the P13-N23 IAA data in otologically and neurologically intact adults when the level of EMG was varied between right and left sides. A prospective, repeated measures design was used for three different investigations in which cVEMPs were recorded and then processed using amplitude correction. Subjects were 20 otologically and neurologically health young adults between 21 and 29 yr of age. cVEMPs were recorded at four different EMG target levels ranging from 100 to 400 μV. The absolute peak-to-peak amplitude of P13-N23, absolute latency of P13, and the left/right amplitude asymmetry of P13-N23 were measured both with and without the use of EMG amplitude correction techniques. IAAs were calculated using 10 different conditions of varying EMG asymmetry with and without amplitude correction. Data were analyzed using repeated measures analysis of variance (ANOVA) to detect tonic EMG level-dependent differences separately for P13 latency, P13-N23 peak-to-peak amplitude, and mean root mean square (RMS) amplitude cVEMP responses. The amplitude of cVEMP responses from the left and right side were used to calculate IAA for subsequent analyses. Linear regression analyses compared level of tonic EMG with cVEMP amplitude. A one-way multivariate analysis of variance (MANOVA) was used to determine if IAAs were significantly reduced following amplitude correction. Any differences found were investigated using unplanned linear contrasts. The uncorrected cVEMP amplitude and RMS EMG all increased significantly with increases in the EMG target levels. With amplitude correction, cVEMP amplitude did not change significantly with changes in RMS EMG or EMG target levels. These findings suggest that the use of amplitude correction techniques represent an effective method of neutralizing the factor of variability in tonic EMG level on the cVEMP that would be otherwise uncontrolled. Indeed when correction is employed in cases of extreme tonic EMG asymmetry, the upper limit of percent IAA is roughly half of that when EMG correction techniques are not used. Our findings are also in agreement with those of Bogle et al (2013) showing that the input/output growth function for P13/N23 amplitude is not linear but, in fact, saturates at supra-maximal stimulation levels. Accordingly, and contrary to what has been published previously, achieving maximum muscle activation may produce a paradoxically inferior signal-to-noise ratio and in some cases result in an artificially small (or undetectable) corrected cVEMP amplitude. cVEMP amplitude either asymptotes (if maximum EMG amplitude saturation occurs at the same stimulus intensity as yields the maximum cVEMP amplitude), or the cVEMP can become smaller if EMG amplitude can increase further beyond the stimulus intensity that yields that largest P1-N1 amplitude. In the latter case the noise increases further to reach maximum and creates a disadvantageous signal (cVEMP) to noise (tonic EMG) ratio.