Histopathological and epidemiological profile of cases of primary cutaneous melanoma diagnosed in Criciuma-SC between 2005 and 2007.
Melanoma is a skin tumor with the highest mortality, despite representing only 5% of the total. The incidence has increasing all over the world especially among fair-skinned individuals and the Criciuma, with a predominance of Italian ethnic,most susceptible to this type of tumor. To know the epidemiological profile and histopathology of primary cutaneous melanoma in Criciuma,and compares them with literature. We conducted a retrospective study, sectional and the pathological reports of melanoma primary in Criciuma, between January 2005 and December 2007. Were analyzed the population affected by sex and age, topography, histologic type, the Clark level and Breslow thickness. There were 72 reports. The age ranged from 15 to 85 years, with an average of 51 years. The most frequent localization in men was the trunk (60%) in women predominated in the lower limbs(30.5%). The most frequent histological type was the extensive superficial (50%). The Clark's level, the most frequent was level III(32.3%) followed by Level I (29.2%). Most melanomas Breslow had in situ(29.6%). The profile of patients with cutaneous melanoma in Criciúma-SC has characteristics similar to those described in the literature and world with regard to gender, age, topography and histology. The topography of the lesion, the study shows the importance of a clinical stricter mainly the trunk in men and women in the lower limbs. In this study there is a high incidence of melanoma per 100,000 in habitants, higher than the national average and state. On the other hand, melanomas showed a predominance of Breslow considered more favorable prognosis.


Are optical distortions used as a cue for material properties of thick transparent objects?
Fleming, Jäkel, and Maloney (2011) asked subjects to match perceived material properties of thick, clear transparent objects in photo-realistic scenes by adjusting the refractive index. They found approximate correspondence between standard and test objects but also large systematic deviations. Nevertheless, they concluded that estimated refraction is used as an indicator for material properties of light-transmitting objects and emphasized the role of object-induced background distortions in this process. This, however, seems not plausible, because the necessary information for inferring the refractive index from distortions-for example, the object's exact shape and thickness, its background distance, and the undistorted background-was not available in their situation. A more plausible alternative explanation is that the subjects did not match estimated refractive indices, but instead performed simple similarity matches based directly on image attributes related to background distortions or specular reflections. We tested this hypothesis in a similar matching experiment in which it was possible to predict the refractive index for a similarity match based on background distortions and for a similarity match based on specular reflections. Our subjects always chose a value between these two predictions. The specular reflection tends to be the dominant factor as soon as it becomes clearly noticeable. Our findings are compatible with the assumption that the subjects tried to find a compromise between two image-based similarity criteria. They do not seem to be consistent with the assumption that the matches are made on the basis of internal estimates of refractive indices.


Reduced vessel density in deep capillary plexus correlates with retinal layer thickness in choroideremia.
To assess retinal layer thickness in choroideremia (CHM) and to reveal its correlation with optical coherence tomography (OCT) angiography (OCTA) findings. The study was designed as an observational, cross-sectional clinical series of patients with CHM, which included 14 CHM eyes and 14 age-matched controls. Multimodal imaging included OCT and OCTA. The vessel density (VD) of superficial capillary (SCP), deep capillary (DCP) and choriocapillaris (CC) plexuses was analysed by OCTA. The apparently preserved retinal islet and atrophic regions were investigated separately. Main outcome measures were as follows: best-corrected visual acuity (BCVA), total retinal layers, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), ellipsoid zone-retinal pigment epithelium (EZ-RPE) layer, choroidal thickness and VDs of SCP, DCP and of CC. Mean BCVA was 0.0±0.0 LogMAR in both groups. GCL, ONL, EZ-RPE and choroid were significantly thinned in CHM, particularly in the atrophic region. OPL was unaffected in the apparently preserved islet, whereas INL and IPL were similarly thinned in the atrophic and apparently preserved retina. DCP appeared severely affected in both regions, while CC was only altered in the atrophic retina. Significant correlations were found between OCT and OCTA parameters. Our study showed severe alterations in both outer and inner retinal layers of patients with CHM. The extended retinal involvement might be the consequence of neuronal and vascular trophic factor reduction produced by the primarily altered RPE and/or secondary Müller glial cell reaction.


Body size mediated coexistence in swans.
Differences in body sizes may create a trade-off between foraging efficiency (foraging gains/costs) and access to resources. Such a trade-off provides a potential mechanism for ecologically similar species to coexist on one resource. We explored this hypothesis for tundra (Cygnus columbianus) and trumpeter swans (Cygnus buccinator), a federally protected species, feeding solely on sago pondweed (Stuckenia pectinata) tubers during fall staging and wintering in northern Utah. Foraging efficiency was higher for tundra swans because this species experienced lower foraging and metabolic costs relative to foraging gains; however, trumpeter swans (a) had longer necks and therefore had access to exclusive resources buried deep in wetland sediments and (b) were more aggressive and could therefore displace tundra swans from lucrative foraging locations. We conclude that body size differentiation is an important feature of coexistence among ecologically similar species feeding on one resource. In situations where resources are limiting and competition for resources is strong, conservation managers will need to consider the trade-off between foraging efficiency and access to resources to ensure ecologically similar species can coexist on a shared resource.


Side-to-side anterior tibial translation on monopodal weightbearing radiographs as a sign of knee decompensation in ACL-deficient knees.
To evaluate the influence of time from injury and meniscus tears on the side-to-side difference in anterior tibial translation (SSD-ATT) as measured on lateral monopodal weightbearing radiographs in both primary and secondary ACL deficiencies. Data from 69 patients (43 males/26 females, median age 27-percentile 25-75: 20-37), were retrospectively extracted from their medical records. All had a primary or secondary ACL deficiency as confirmed by MRI and clinical examination, with a bilateral weightbearing radiograph of the knees at 15°-20° flexion available. Meniscal status was assessed on MRI images by a radiologist and an independent orthopaedic surgeon. ATT and posterior tibial slope (PTS) were measured on the lateral monopodal weightbearing radiographs for both the affected and the contralateral healthy side. A paired t-test was used to compare affected/healthy knees. Independent t-tests were used to compare primary/secondary ACL deficiencies, time from injury (TFI) (≤ 4 years/ > 4 years) and meniscal versus no meniscal tear. ATT of the affected side was significantly greater than the contralateral side (6.2 ± 4.4 mm vs 3.5 ± 2.8 mm; p < 0.01). There was moderate correlation between ATT and PTS in both the affected and healthy knees (r = 0.43, p < 0.01 and r = 0.41, p < 0.01). SSD-ATT was greater in secondary ACL deficiencies (4.7 ± 3.8 vs 1.9 ± 3.2 mm; p < 0.01), patients with a TFI greater than 4 years (4.2 ± 3.8 vs 2.0 ± 3.0 mm; p < 0.01) and with at least one meniscal tear (3.9 ± 3.8 vs 0.7 ± 2.2 mm; p < 0.01). Linear regression showed that, in primary ACL deficiencies, SSD-ATT was expected to increase (+ 2.7 mm) only if both a meniscal tear and a TFI > 4 years were present. In secondary ACL deficiencies, SSD-ATT was mainly influenced by the presence of meniscal tears regardless of the TFI. SSD-ATT was significantly greater in secondary ACL deficiencies, patients with a TFI greater than 4 years and with at least one meniscal tear. These results confirm that SSD-ATT is a time- and meniscal-dependent parameter, supporting the concept of gradual sagittal decompensation in ACL-deficient knees, and point out the importance of the menisci as secondary restraints of the anterior knee laxity. Monopodal weightbearing radiographs may offer an easy and objective method for the follow-up of ACL-injured patients to identify early signs of soft tissue decompensation under loading conditions. Level III.


Interaction of RNA viruses of the natural virome with the African malaria vector, Anopheles coluzzii.
Mosquitoes are colonized by a little-studied natural virome. Like the bacterial microbiome, the virome also probably influences the biology and immunity of mosquito vector populations, but tractable experimental models are lacking. We recently discovered two novel viruses in the virome of wild Anopheles and in colonies of the malaria vector Anopheles coluzzii: Anopheles C virus and Anopheles cypovirus. Here, we describe biological interactions between these two viruses and An. coluzzii mosquitoes. Viral abundance varies reproducibly during mosquito development. DNA forms of these viruses were not detected, and thus viral persistence is likely based on vertical transmission of RNA genomes. At least Anopheles C virus is vertically transmitted by an intraembryonic route. Relative abundance of the two viruses is inversely correlated in individual mosquitoes. One possible mechanism for this could be interactions with host immunity, and functional genomic analysis indicated differential influence of at least the Toll and JAK/STAT immune signaling pathways upon the viruses. The nonrandom distributions and interactions with host immunity suggest that these and other members of the natural virome may constitute a source of unrecognized heterogeneity in mosquito vector populations.


The allocation of early blastomeres to the ectoderm and endoderm is variable in the sea urchin embryo.
During sea urchin development, a tier-to-tier progression of cell signaling events is thought to segregate the early blastomeres to five different cell lineages by the 60-cell stage (E. H. Davidson, 1989, Development 105, 421-445). For example, the sixth equatorial cleavage produces two tiers of sister cells called 'veg1' and 'veg2,' which were projected by early studies to be allocated to the ectoderm and endoderm, respectively. Recent in vitro studies have proposed that the segregation of veg1 and veg2 cells to distinct fates involves signaling between the veg1 and veg2 tiers (O. Khaner and F. Wilt, 1991, Development 112, 881-890). However, fate-mapping studies on 60-cell stage embryos have not been performed with modern lineage tracers, and cell interactions between veg1 and veg2 cells have not been shown in vivo. Therefore, as an initial step towards examining how archenteron precursors are specified, a clonal analysis of veg1 and veg2 cells was performed using the lipophilic dye, DiI(C16), in the sea urchin species, Lytechinus variegatus. Both veg1 and veg2 descendants form archenteron tissues, revealing that the ectoderm and endoderm are not segregated at the sixth cleavage. Also, this division does not demarcate cell type boundaries within the endoderm, because both veg1 and veg2 descendants make an overlapping range of endodermal cell types. The allocation of veg1 cells to ectoderm and endoderm during cleavage is variable, as revealed by both the failure of veg1 descendants labeled at the eighth equatorial division to segregate predictably to either tissue and the large differences in the numbers of veg1 descendants that contribute to the ectoderm. Furthermore, DiI-labeled mesomeres of 32-cell stage embryos also contribute to the endoderm at a low frequency. These results show that the prospective archenteron is produced by a larger population of cleavage-stage blastomeres than believed previously. The segregation of veg1 cells to the ectoderm and endoderm occurs relatively late during development and is unpredictable, indicating that later cell position is more important than the early cleavage pattern in determining ectodermal and archenteron cell fates.


Long-term effects of superoxide and DNA repair on lizard telomeres.
Telomeres are the non-coding protein-nucleotide "caps" at chromosome ends that contribute to chromosomal stability by protecting the coding parts of the linear DNA from shortening at cell division, and from erosion by reactive molecules. Recently, there has been some controversy between molecular and cell biologists, on the one hand, and evolutionary ecologists on the other, regarding whether reactive molecules erode telomeres during oxidative stress. Many studies of biochemistry and medicine have verified these relationships in cell culture, but other researchers have failed to find such effects in free-living vertebrates. Here, we use a novel approach to measure free radicals (superoxide), mitochondrial "content" (a combined measure of mitochondrial number and size in cells), telomere length and DNA damage at two primary time points during the mating season of an annual lizard species (Ctenophorus pictus). Superoxide levels early in the mating season vary widely and elevated levels predict shorter telomeres both at that time as well as several months later. These effects are likely driven by mitochondrial content, which significantly impacts late season superoxide (cells with more mitochondria have more superoxide), but superoxide effects on telomeres are counteracted by DNA repair as revealed by 8-hydroxy-2'-deoxyguanosine assays. We conclude that reactive oxygen species and DNA repair are fundamental for both short- and long-term regulation of lizard telomere length with pronounced effects of early season cellular stress detectable on telomere length near lizard death.


A plant 35S CaMV promoter induces long-term expression of luciferase in Atlantic salmon.
The long-term persistence and activity of a naked plasmid DNA (pGL3-35S) containing a luc gene (reporter gene) controlled by a plant 35S CaMV promoter was studied in Atlantic salmon (Salmo salar L.) after injection. Atlantic salmon (mean weight 70 grams) were injected intramuscularly with 100 μg of plasmid DNA. Blood, different tissues and organs were sampled at different time points up to day 535 after injection. Southern blot analysis suggested the presence of extra-chromosomally open circular, linear and supercoiled topoforms of pGL3-35S at day 150 after injection. At day 536 open circular and supercoiled topoforms were detected. Luciferase activity was detected at the injection site up to 536 days post-injection of pGL3-35S, where it peaked at day 150 and decreased to approximately 17% of its maximum activity by day 536. Our study demonstrated that a plasmid containing the 35S promoter was able to induce expression of a reporter gene/protein in fish in vivo and that the plasmid DNA persisted for a prolonged time after intramuscular injection.


Molecular signatures of obstructive sleep apnea in adults: a review and perspective.
The consequences of obstructive sleep apnea (OSA) are largely mediated by chronic intermittent hypoxia and sleep fragmentation. The primary molecular domains affected are sympathetic activity, oxidative stress and inflammation. Other affected domains include adipokines, adhesion molecules and molecules that respond to endoplasmic reticulum stress. Changes in molecular domains affected by OSA, assessed in blood and/or urine, can provide a molecular signature for OSA that could potentially be used diagnostically and to predict who is likely to develop different OSA-related comorbidities. High-throughput discovery strategies such as microarrays, assessing changes in gene expression in circulating blood cells, have the potential to find new candidates and pathways thereby expanding the molecular signatures for OSA. More research is needed to fully understand the pathophysiological significance of these molecular signatures and their relationship with OSA comorbidities. Many OSA subjects are obese, and obesity is an independent risk factor for many comorbidities associated with OSA. Moreover, obesity affects the same molecular pathways as OSA. Thus, a challenge to establishing a molecular signature for OSA is to separate the effects of OSA from obesity. We propose that the optimal strategy is to evaluate the temporal changes in relevant molecular pathways during sleep and, in particular, the alterations from before to after sleep when assessed in blood and/or urine. Such changes will be at least partly a consequence of chronic intermittent hypoxia and sleep fragmentation that occurs during sleep.


Mixing ratio dependent complex coacervation versus bicontinuous gelation of pectin with in situ formed zein nanoparticles.
We report on the competitive phenomenon of complex coacervation versus bicontinuous gelation between pectin (P, a polyanionic carbohydrate, [P] = 0.01-2% (w/v)) and zein nanoparticles (Z, a hydrophobic protein and a weak polyampholyte, [Z] = 0.1 and 0.5% (w/v), in an ethanolic solution of effective concentration 4 and 27% (v/v)), which was studied below (pH ≈ 4), and above (pH ≈ 7.4) the pI (≈ 6.2) of zein at room temperature, 25 °C. The uniqueness of this study arises from the interaction protocol used, where the pectin used was in the extended polyelectrolyte (persistence length ≈ 10 nm) conformation while zein was used as a charged globular nanoparticle (size ≈ 80-120 nm) that was formed in situ. Their mixing ratio, r = [P] : [Z] (w/w), was varied from 0.02 to 4.0 (for [Z] = 0.5% (w/v)), and from 0.1 to 7.5 (for [Z] = 0.1% (w/v)) in the ionic strength range 10-4 to 10-2 M NaCl. Zeta potential data revealed that at pH ≈ 4, the complementary binding condition, r = 1 : 1 (equivalent to 1 : 5 molecule/nanoparticle) demarcated the coacervate from the gel region. The measured rigidity (G0, low frequency storage modulus) of these materials revealed the following: for r < 1, (low pectin content samples, coacervate region) the material had lower values of Gcoac0, whereas for r > 1, an excess of pectin facilitated gelation with Ggel0 ≫ Gcoac0. Above pI, surface patch binding caused associative interactions and complex coacervation though both biopolymers had similar net charge. The network density was used as a descriptor to distinguish between the coacervate and gel samples. Their microstructures were probed by small angle neutron scattering (SANS), and viscoelastic properties by rheology. Simple modeling shows that formation of the interpolymer complex was favored in higher protein containing samples. Mixing ratio dependent selective coacervation (a kinetic process) and bicontinuous gelation (a thermodynamic process) are rarely seen to coexist in biopolymer interactions.


Sources of PCR-induced distortions in high-throughput sequencing data sets.
PCR permits the exponential and sequence-specific amplification of DNA, even from minute starting quantities. PCR is a fundamental step in preparing DNA samples for high-throughput sequencing. However, there are errors associated with PCR-mediated amplification. Here we examine the effects of four important sources of error-bias, stochasticity, template switches and polymerase errors-on sequence representation in low-input next-generation sequencing libraries. We designed a pool of diverse PCR amplicons with a defined structure, and then used Illumina sequencing to search for signatures of each process. We further developed quantitative models for each process, and compared predictions of these models to our experimental data. We find that PCR stochasticity is the major force skewing sequence representation after amplification of a pool of unique DNA amplicons. Polymerase errors become very common in later cycles of PCR but have little impact on the overall sequence distribution as they are confined to small copy numbers. PCR template switches are rare and confined to low copy numbers. Our results provide a theoretical basis for removing distortions from high-throughput sequencing data. In addition, our findings on PCR stochasticity will have particular relevance to quantification of results from single cell sequencing, in which sequences are represented by only one or a few molecules.


Plasma calprotectin and its association with cardiovascular disease manifestations, obesity and the metabolic syndrome in type 2 diabetes mellitus patients.
Plasma calprotectin is a potential biomarker of cardiovascular disease (CVD), insulin resistance (IR), and obesity. We examined the relationship between plasma calprotectin concentrations, CVD manifestations and the metabolic syndrome (MetS) in patients with type 2 diabetes mellitus (T2DM) in order to evaluate plasma calprotectin as a risk assessor of CVD in diabetic patients without known CVD. An automated immunoassay for determination of plasma calprotectin was developed based on a fecal Calprotectin ELIA, and a reference range was established from 120 healthy adults. Plasma calprotectin concentrations were measured in 305 T2DM patients without known CVD. They were screened for carotid arterial disease, peripheral arterial disease (PAD), and myocardial ischemia (MI) by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy. The reference population had a median plasma calprotectin concentration of 2437 ng/mL (2.5-97.5% reference range: 1040-4262 ng/mL). The T2DM patients had significantly higher concentrations (3754 ng/mL, p < 0.0001), and within this group plasma calprotectin was significantly higher in patients with MetS (p < 0.0001) and also in patients with autonomic neuropathy, PAD, and MI compared with patients without (p < 0.001, p = 0.021 and p = 0.043, respectively). Plasma calprotectin was by linear regression analysis found independently associated with BMI, C-reactive protein, and HDL cholesterol. However, plasma calprotectin did not predict autonomic neuropathy, PAD, MI or CVD when these variables entered the multivariable regression analysis as separate outcome variables. T2DM patients had higher concentrations of plasma calprotectin, which were associated with obesity, MetS status, autonomic neuropathy, PAD, and MI. However, plasma calprotectin was not an independent predictor of CVD, MI, autonomic neuropathy or PAD. NCT00298844.


Distinct bacterial assemblages reside at different depths in Arctic multiyear sea ice.
Bacterial communities in Arctic sea ice play an important role in the regulation of nutrient and energy dynamics in the Arctic Ocean. Sea ice has vertical gradients in temperature, brine salinity and volume, and light and UV levels. Multiyear ice (MYI) has at least two distinct ice layers: old fresh ice with limited permeability, and new saline ice, and may also include a surface melt pond layer. Here, we determine whether bacterial communities (1) differ with ice depth due to strong physical and chemical gradients, (2) are relatively homogenous within a layer, but differ between layers, or (3) do not vary with ice depth. Cores of MYI off northern Ellesmere Island, NU, Canada, were subsectioned in 30-cm intervals, and the bacterial assemblage structure was characterized using 16S rRNA gene pyrotag sequencing. Assemblages clustered into three distinct groups: top (0-30 cm); middle (30-150 cm); and bottom (150-236 cm). These layers correspond to the occurrence of refrozen melt pond ice, at least 2-year-old ice, and newly grown first-year ice at the bottom of the ice sheet, respectively. Thus, MYI houses multiple distinct bacterial assemblages, and in situ conditions appear to play a less important role in structuring microbial assemblages than the age or conditions of the ice at the time of formation.


Through the eye of a Gobi khulan - Application of camera collars for ecological research of far-ranging species in remote and highly variable ecosystems.
The Mongolian Gobi-Eastern Steppe Ecosystem is one of the largest remaining natural drylands and home to a unique assemblage of migratory ungulates. Connectivity and integrity of this ecosystem are at risk if increasing human activities are not carefully planned and regulated. The Gobi part supports the largest remaining population of the Asiatic wild ass (Equus hemionus; locally called "khulan"). Individual khulan roam over areas of thousands of square kilometers and the scale of their movements is among the largest described for terrestrial mammals, making them particularly difficult to monitor. Although GPS satellite telemetry makes it possible to track animals in near-real time and remote sensing provides environmental data at the landscape scale, remotely collected data also harbors the risk of missing important abiotic or biotic environmental variables or life history events. We tested the potential of animal born camera systems ("camera collars") to improve our understanding of the drivers and limitations of khulan movements. Deployment of a camera collar on an adult khulan mare resulted in 7,881 images over a one-year period. Over half of the images showed other khulan and 1,630 images showed enough of the collared khulan to classify the behaviour of the animals seen into several main categories. These khulan images provided us with: i) new insights into important life history events and grouping dynamics, ii) allowed us to calculate time budgets for many more animals than the collared khulan alone, and iii) provided us with a training dataset for calibrating data from accelerometer and tilt sensors in the collar. The images also allowed to document khulan behaviour near infrastructure and to obtain a day-time encounter rate between a specific khulan with semi-nomadic herders and their livestock. Lastly, the images allowed us to ground truth the availability of water by: i) confirming waterpoints predicted from other analyses, ii) detecting new waterpoints, and iii) compare precipitation records for rain and snow from landscape scale climate products with those documented by the camera collar. We discuss the added value of deploying camera collars on a subset of animals in remote, highly variable ecosystems for research and conservation.


Rural Assertive Community Treatment and Telepsychiatry.
Assertive community treatment (ACT) is an evidence-based treatment for patients with severe and persistent mental illness. ACT has been shown to reduce inpatient hospitalization and is increasingly being used as a mainstay of evidence-based psychiatric practice for these clinical populations. The increasing implementation of evidence-based practices has led to the expansion of ACT in rural areas. Variability in the adaptation of ACT in rural areas has included accommodation by teams to multiple barriers. One way to increase psychiatric professional efficiency in rural areas is with telepsychiatry and possibly with rural ACT, but with unknown effects on fidelity and outcomes. Telepsychiatry has been considered a means of expanding the reach of and access to ACT. Concerns about the use of telepsychiatry by ACT teams include the psychiatrist's ability to develop a relationship with patients and staff and difficulties observing the patient's entire living environment via telemedicine. The Piedmont Community Services Board (CSB) Program for Assertive Community Treatment (PACT) serves patients in southwestern Virginia in collaboration with the Virginia Tech Carilion School of Medicine. The Piedmont CSB PACT uses telemedicine to expand the treating psychiatrist's reach and contact with PACT patients, increasing the efficiency of the psychiatrist's PACT time. Telemedicine is used for crisis intervention and augmentation of regular ongoing visits. The goals of this project were to measure patient, staff, and psychiatrist comfort and satisfaction with the use of telepsychiatry in ACT in addition to monitoring routine outcome measures.


Long-term cognitive outcome of bilateral subthalamic deep brain stimulation in Parkinson's disease.
The effect of subthalamic deep brain stimulation (STN DBS) on cognition in Parkinson's disease (PD) remains controversial, and it is unclear which factors are related to cognitive decline and dementia after STN DBS, especially over the long term. To this end, we analyzed the cognitive outcome of 103 non-demented patients with PD who were followed-up for at least 12 months after bilateral STN DBS surgery. Preoperatively, the patients were evaluated with the Unified Parkinson's Disease Rating Scale and neuropsychological tests. The rate of global cognitive decline and the incidence of dementia during follow-up for up to 7 years (mean 42.4 ± 24.5 months) were calculated, and preoperative clinical and neuropsychological factors associated with postoperative global cognitive decline or dementia were analyzed. The prevalence of mild cognitive impairment (MCI) and its relation to later cognitive decline or dementia were also evaluated. The annual decline in the mini-mental state examination score was 0.4 ± 1.7 with impaired attention and executive function and a higher levodopa equivalent dose at baseline being the predictors of a faster global cognitive decline after STN DBS. Dementia developed in 13 patients with an incidence rate of 35.7 per 1,000 person-years. Impaired executive function at baseline predicted dementia. At baseline, 63.1 % of the patients had PD-MCI, and these patients were more likely to develop dementia than those without PD-MCI. This study showed that dysfunctions in the frontostriatal circuitry at baseline were associated with a risk of subsequent global cognitive decline and dementia in patients with PD who underwent STN DBS. In addition, preoperative PD-MCI was a risk factor for dementia after STN DBS.


ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.


Comparative responses of the carotid and vertebral arterial systems of rhesus monkeys to betahistine.
A newly developed photoelectric method was used in 5 rhesus monkeys to measure the mean transit time of blood through the carotid and vertebral arteries, together with measurement of the blood flow through the tissues of the fronto-parietal area supplied by the carotid artery and of the cerebellar tonsil supplied by the vertebral artery. Following intravenous administration of betahistine mesylate, a histamine analog, the mean transit times of blood through the 2 arteries were equally shortened by 10%, despite a 20% decrease in the mean arterial blood pressure (P less than 0.05). The cerebral tissue and cerebellar tissue blood flow was increased by betahistine, from 70.4 to 81.4 ml/100g/min and from 73.2 to 84.0 ml/100g/min, respectively. Since histamine has been reported to produce a decrease in cardiac output, the increase in cerebral blood flow confirmed that betahistine is a selective cerebral vasodilating agent. However, by comparing the hemodynamic data for the two cerebral arterial systems, it can be concluded that the responses of the carotid and vertebral arterial systems to the vasodilating action of betahistine were essentially the same in extent.


Nonhomogeneous left ventricular regional shortening during acute right ventricular pressure overload.
Acute right ventricular pressure overload shifts the interventricular septum leftward and decreases systolic shortening of the left ventricular (LV) septal-lateral diameter. These changes should alter regional shortening in the LV minor axis. To test this hypothesis, LV minor axis circumferential segment lengths of the septum and anterior, lateral, and posterior walls were measured during pulmonary artery or venae caval constriction in seven open-chest dogs with intact pericardia. Starting at an end-diastolic pressure of 10 mm Hg, venae caval constriction decreased LV end-systolic pressure by 19 +/- 6% and stroke volume by 40 +/- 15% and produced uniform decreases in systolic shortening and end-diastolic length around the minor axis. However, during pulmonary artery constriction resulting in similar decreases in end-systolic pressure (22 +/- 7%) and stroke volume (39 +/- 11%), decreases in systolic shortening were significantly larger in the anterior (-34 +/- 10%) and posterior (-33 +/- 21%) walls than in the septum (-10 +/- 9%) or lateral wall (-8 +/- 13%). The mechanisms of these large anterior and posterior shortening decreases differed: anterior end-diastolic length decreased more than posterior and lateral end-diastolic lengths, while posterior end-systolic length decreased less than anterior and lateral end-systolic lengths. Similar changes were seen at starting end-diastolic pressures of 5 and 15 mm Hg. Propranolol did not alter this nonuniform response, while pericardiectomy attenuated the regional variations. Thus, changes in LV geometry during acute right ventricular pressure overload are associated with nonuniform regional changes in systolic shortening in the LV minor axis that are enhanced by the pericardium.


Outcome for client-owned domestic rabbits undergoing limb amputation: 34 cases (2000-2009).
To describe morbidity, function, outcome, and owner satisfaction associated with limb amputation in domestic rabbits. Retrospective case series. 34 client-owned domestic rabbits. Medical records of domestic rabbits undergoing limb amputation for any cause between 2000 and 2009 were reviewed. The Kaplan-Meier method was used to estimate survival rate and median survival time, and variables were analyzed for relationship to risk of morbidity resulting in euthanasia and to outcome (survival vs nonsurvival [death or euthanasia]). Owners were interviewed to determine satisfaction with outcome of the procedure. 28 rabbits underwent pelvic limb amputation, and 6 underwent thoracic limb amputation. At the last follow-up, 18 rabbits were dead, 9 were alive, and 7 were lost to follow-up. Median overall survival time was 720 days (range, 4 to 3,250 days). Acute and delayed or chronic complications were observed in 22 of 34 and 19 of 32 rabbits, respectively, most commonly difficulty ambulating, hygiene issues, and pododermatitis (cutaneous ulcers at the hock). Six rabbits were euthanized because of complications at a median of 104 days (range, 4 to 399 days) after surgery. Risk of morbidity resulting in euthanasia increased with heavier body weight and concurrent disease affecting ambulation at the time of amputation. Weight, age, and pododermatitis at the time of amputation were significantly negatively associated with survival time. Thirty-one (91%) owners were satisfied with the outcome. Although limb amputation was tolerated by most rabbits and most owners were satisfied, complications resulted in death in 6 of 34 (18%) rabbits, and 19 of 32 (59%) developed chronic complications. Amputation in heavy rabbits or those with concurrent pododermatitis, musculoskeletal disease, or neurologic disease should be considered carefully. Because of the small sample size and retrospective nature of this study, results should be interpreted as exploratory and hypothesis generating.


Proline-rich regions in transcriptional complexes: heading in many directions.
Although many protein complexes are now known, the precise details of how each component operates are rarely understood. Through a combination of bioinformatics and analysis of gene-trapped mouse clones, Enkhmandakh et al. were able to deduce the modular function for a part of Ssdp1, a crucial component of the Ldb1 transcriptional complex, which plays a central role in mammalian head development. A proline-rich module from Ssdp1 is likely responsible for transactivation, and this region is curiously mobile, occurring in different proteins in different species. The results underscore the importance of protein modularity in complex organization, as well as the role of irregular or disordered parts of proteins in crucial biological processes.


SEIFEM 2017: from real life to an agreement on the use of granulocyte transfusions and colony-stimulating factors for prophylaxis and treatment of infectious complications in patients with hematologic malignant disorders.
The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 108 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.


Impact of Chronic Obstructive Pulmonary Disease on Incidence, Microbiology and Outcome of Ventilator-Associated Lower Respiratory Tract Infections.
To determine the impact of chronic obstructive pulmonary disease (COPD) on incidence, microbiology, and outcomes of ventilator-associated lower respiratory tract infections (VA-LRTI). Planned ancillary analysis of TAVeM study, including 2960 consecutive adult patients who received invasive mechanical ventilation (MV) > 48 h. COPD patients (n = 494) were compared to non-COPD patients (n = 2466). The diagnosis of ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP) was based on clinical, radiological and quantitative microbiological criteria. No significant difference was found in VAP (12% versus 13%, p = 0.931), or VAT incidence (13% versus 10%, p = 0.093) between COPD and non-COPD patients. Among patients with VA-LRTI, Escherichia coli and Stenotrophomonas maltophilia were significantly more frequent in COPD patients as compared with non-COPD patients. However, COPD had no significant impact on multidrug-resistant bacteria incidence. Appropriate antibiotic treatment was not significantly associated with progression from VAT to VAP among COPD patients who developed VAT, unlike non-COPD patients. Among COPD patients, patients who developed VAT or VAP had significantly longer MV duration (17 days (9-30) or 15 (8-27) versus 7 (4-12), p < 0.001) and intensive care unit (ICU) length of stay (24 (17-39) or 21 (14-40) versus 12 (8-19), p < 0.001) than patients without VA-LRTI. ICU mortality was also higher in COPD patients who developed VAP (44%), but not VAT(38%), as compared to no VA-LRTI (26%, p = 0.006). These worse outcomes associated with VA-LRTI were similar among non-COPD patients. COPD had no significant impact on incidence or outcomes of patients who developed VAP or VAT.


The EuBIVAS: Within- and Between-Subject Biological Variation Data for Electrolytes, Lipids, Urea, Uric Acid, Total Protein, Total Bilirubin, Direct Bilirubin, and Glucose.
The European Federation of Clinical Chemistry and Laboratory Medicine European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined data describing biological variation (BV) of clinically important measurands. Here, EuBIVAS-based BV estimates of serum electrolytes, lipids, urea, uric acid, total protein, total bilirubin, direct bilirubin, and glucose, as well as their associated analytical performance specifications (APSs), are presented. Samples were drawn from 91 healthy individuals (38 male, 53 female; age range, 21-69 years) for 10 consecutive weeks at 6 European laboratories. Samples were stored at -80 °C before duplicate analysis of all samples on an ADVIA 2400 (Siemens Healthineers). Outlier and homogeneity analyses were performed, followed by CV-ANOVA on trend-corrected data, when relevant, to determine BV estimates with CIs. The within-subject BV (CVI) estimates of all measurands, except for urea and LDL cholesterol, were lower than estimates available in an online BV database, with differences being most pronounced for HDL cholesterol, glucose, and direct bilirubin. Significant differences in CVI for men and women/women <50 years of age were evident for uric acid, triglycerides, and urea. The CVA obtained for sodium and magnesium exceeded the EuBIVAS-based APS for imprecision. The EuBIVAS, which is fully compliant with the recently published Biological Variation Data Critical Appraisal Checklist, has produced well-characterized, high-quality BV estimates utilizing a stringent experimental protocol. These new reference data deliver revised and more exacting APS and reference change values for commonly used clinically important measurands, thus having direct relevance to diagnostics manufacturers, service providers, clinical users, and ultimately patients.


Virtual implant planning in the edentulous maxilla: criteria for decision making of prosthesis design.
To evaluate prosthetic parameters in the edentulous anterior maxilla for decision making between fixed and removable implant prosthesis using virtual planning software. CT- or DVT-scans of 43 patients (mean age 62 ± 8 years) with an edentulous maxilla were analyzed with the NobelGuide software. Implants (≥3.5 mm diameter, ≥10 mm length) were virtually placed in the optimal three-dimensional prosthetic position of all maxillary front teeth. Anatomical and prosthetic landmarks, including the cervical crown point (C-Point), the acrylic flange border (F-Point), and the implant-platform buccal-end (I-Point) were defined in each middle section to determine four measuring parameters: (1) acrylic flange height (FLHeight), (2) mucosal coverage (MucCov), (3) crown-Implant distance (CID) and (4) buccal prosthesis profile (ProsthProfile). Based on these parameters, all patients were assigned to one of three classes: (A) MucCov ≤ 0 mm and ProsthProfile≥45(0) allowing for fixed prosthesis, (B) MucCov = 0-5 mm and/or ProsthProfile = 30(0) -45(0) probably allowing for fixed prosthesis, and (C) MucCov ≥ 5 mm and/or ProsthProfile ≤ 30(0) where removable prosthesis is favorable. Statistical analyses included descriptive methods and non-parametric tests. Mean values were for FLHeight 10.0 mm, MucCov 5.6 mm, CID 7.4 mm, and ProsthProfile 39.1(0) . Seventy percent of patients fulfilled class C criteria (removable), 21% class B (probably fixed), and 2% class A (fixed), while in 7% (three patients) bone volume was insufficient for implant planning. The proposed classification and virtual planning procedure simplify the decision-making process regarding type of prosthesis and increase predictability of esthetic treatment outcomes. It was demonstrated that in the majority of cases, the space between the prosthetic crown and implant platform had to be filled with prosthetic materials.


Aberrationless phase difference amplification in holographic interferometry.
Two improved techniques of aberrationless phase difference amplification are presented. Both make use of double-exposure holographic interferometry. In contrast to the ordinary technique, not only the state of the tested object is changed between exposures but also the direction of the hologram fringes. This approach allows one to separate desired higher diffraction orders of the double-exposed hologram, to eliminate setup aberrations, and, consequently, to achieve an amplification of the phase difference given by the tested object alone.


Postural stability in stroke patients: vectorial expression of asymmetry, sway activity and relative sequence of reactive forces.
Bilateral force measurements on the supporting limbs in postural sway while standing still were made to evaluate post-cerebral-vascular accident (CVA) patients during rehabilitation. Normal subjects of the same age group were tested as controls. From the force tracings obtained, three oscillation frequencies were identified, with orders of magnitudes of 7, 1 and 0.1 Hz, respectively, of which the middle frequency, i.e. that corresponding to 1 Hz, was selected for subsequent processing and analysis. These included the determination of relative sequence of the force vectors on both feet and evaluation of timings and amplitudes of the waveforms. Weight-bearing imbalance was defined in the vertical direction to express the difference between the average forces supported by each of the legs. In the horizontal plane, two parameters were defined: sway total activity (SA), to represent the vector summation of the absolute values of the horizontal force components acting on both legs; and asymmetry (ASYM) to express the difference in activities between the two legs. The results presented disclose the reactive force patterns acting on each of the legs of post-CVA hemiplegic individuals, in comparison with normal individuals. Although these forces were shown to act synchronously on both legs, they appeared to be asymmetrical in nature, with a typical vectorial pattern for every individual, which generally differed from that of normal subjects. Sway activity was found to be significantly higher in hemiplegics compared with the normal controls.


Unmasking sarcoidosis following surgery for Cushing disease.
We present a patient with Cushing disease apparently suppressing sarcoidosis, which was unmasked following surgical resection of a pituitary adrenocorticotropin (ACTH)-producing microadenoma. Case report and a short review of the literature published in this area. A 46-year-old Caucasian woman presented with symptoms of hypercortisolism such as progressive weight gain, Cushingoid appearance, proximal myopathy, easy bruising, and amenorrhea. Blood testing including inferior petrosal sinus sampling uncovered an ACTH-producing microadenoma in the right aspect of the anterior pituitary gland for which the patient underwent transphenoidal resection. Maintenance corticosteroid therapy was implemented, and the signs and symptoms of Cushing disease began to resolve. Three months after surgery, multiple erythematous painful nodules developed on the patient's arms. Erythema nodosum (EN) was diagnosed clinically and a suspicion of underlying sarcoidosis was substantiated by lung imaging and elevated plasma interleukin (IL)-2 receptor. One month later, the lesions spontaneously resolved without therapy other than maintenance glucocorticoid replacement. Physicians should be aware that patients undergoing successful treatment of Cushing syndrome may have a flare-up or emergence of a corticosteroid-responsive disease.


L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences.
The kynurenine pathway (KP) is the major route for tryptophan (TRP) metabolism in most mammalian tissues. The KP metabolizes TRP into a number of neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). Elevated metabolite concentrations in the central nervous system are associated with the pathophysiology of several inflammation-related neuropsychiatric diseases. During an inflammatory response, the initial KP metabolic step is primarily regulated by indoleamine 2,3-dioxygenase 1 (IDO1), which produces KYN from TRP. Following this initial step, the KP has 2 distinct branches; one branch is regulated by kynurenine 3-monooxygenase (KMO) and is primarily responsible for the 3-HK and QUIN production, and the other branch is regulated by kynurenine aminotransferase (KAT), which produces KYNA, an N-methyl-d-aspartate receptor and alpha-7-nicotinic acetylcholine receptor antagonist. Unbalanced KP metabolism has been demonstrated in distinct neuropsychiatric diseases; thus, understanding the mechanisms that regulate KP enzyme expression and activity is important. These enzymes are expressed by specific cell types, and the induction of enzyme expression by inflammatory stimuli also shows cell type specificity. This review provides an overview and discusses the current understanding of the influence of KP enzyme expression and activity in different cell types on the pathophysiological mechanisms of specific neuropsychiatric diseases. Moreover, the potential use of KP enzyme inhibition as a therapeutic strategy for treating neurological diseases is briefly discussed. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.


Complementary medicine and safety: a systematic investigation of design and reporting of systematic reviews.
The objective of this study was to examine the methods used in systematic reviews of safety across a range of complementary therapies to assess the variation in approach and the potential for developing guidance on conduct and reporting. Systematic reviews focusing on safety were retrieved from NHS Evidence and searches of major databases. A pre-prepared template was used for data extraction. Information extracted included details of search strategies, sources, participants, interventions, reported adverse event/effect(s) and causality assessment. Data extraction was carried out by one researcher and a check for accuracy by a second researcher. Methods were assessed against criteria based on guidance provided by the Cochrane Adverse Effects Methods Group. A total of 2563 citations were screened and 88 systematic reviews were selected for inclusion. The majority focused on the safety of herbs and nutritional supplements. Approximately half the reviews covered all aspects of safety; other reviews addressed specific adverse effects or interactions. Types of data included in the reviews did not always reflect the focus of the review. Search strategies, sources used, quality assessment and assessment of causality also varied. Detailed examination and comparison of the methods has highlighted several areas in which there is potential for development of guidelines and consensus on standards. These include search strategies, sources of information, data extraction and assessment of causality. The value of systematic reviews in relation to large outcome studies requires further consideration.


3-Hydroxy-2'-methoxy-6-methylflavone: a potent anxiolytic with a unique selectivity profile at GABA(A) receptor subtypes.
Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA(A) receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA(A) receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2'-methoxy-6-methylflavone (3-OH-2'MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1-3γ2L but not α3/5β1-3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC(50) values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2'MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4-11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2'MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2'MeO6MF for α4β2/3δ receptors (EC(50) values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA(A) receptors. 3-OH-2'MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2'MeO6MF (1-100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2'MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA(A) receptor subtypes.


Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease.
What are the factors influencing the success rate for couples undergoing preimplantation genetic testing (PGT) for polycystic kidney disease (PKD)? In our study cohort, the live birth delivery rate is significantly associated with female age while the male infertility accompanying autosomal dominant PKD (ADPKD) does not substantially affect the clinical outcome. While women with ADPKD have no specific fertility problems, male ADPKD patients may present with reproductive system abnormalities and infertility. This retrospective cohort study involves 91 PGT cycles for PKD for 43 couples (33 couples for PKD1, 2 couples for PKD2 and 8 couples for autosomal recessive PKD (ARPKD)) from January 2005 until December 2016 with follow-up of transfers until end of 2017. Sixteen single-cell clinical tests for PKD based on multiplex PCR of short tandem repeat markers, with or without a specific mutation were developed and applied for diagnosis of 584 Day 3 cleavage stage embryos. In 18 couples, the male partner was affected with ADPKD (=Group A) and 12 of them had a documented infertility status. Group A underwent 52 cycles to oocyte retrieval. For 18 other couples, the female partner was affected with ADPKD (=Group B) and four male partners from this group had a documented history of infertility. This group underwent 31 cycles to OR. Genetic analysis resulted in 545 embryos (93.3%) with a diagnosis, of which 215 (36.8%) were genetically transferable. Transfer of 74 embryos in 53 fresh cycles and of 34 cryopreserved embryos in 33 frozen-warmed embryo transfer cycles resulted in a live birth delivery rate of 38.4% per transfer with 31 singleton live births, two twin live births and one ongoing pregnancy. The observed cumulative delivery rate was 57.8% per couple after five treatment cycles. Thirty cryopreserved embryos still remain available for transfer. The clinical pregnancy rate per transfer (fresh + frozen; 45.9% in group A versus 60.0% in group B, P < 0.05) and the live birth delivery rate per transfer (fresh + frozen; 27.0% in group A versus 42.9% in group B, P < 0.05) was significantly lower for couples with the male partner affected with ADPKD compared with couples with the female partner affected with ADPKD. However, a multivariate logistic regression analysis showed that only female age was associated with live birth delivery rate (odds ratio = 0.87; 95% CI: 0.77-0.99; P = 0.032). This study is based on retrospective data from a single centre with Day 3 one-cell and two-cell biopsy. Further analysis of a larger cohort of PKD patients undergoing PGT is required to determine the impact of male infertility associated with ADPKD on the cumulative results. Knowledge about factors affecting the clinical outcome after PGT can be a valuable tool for physicians to counsel PKD patients about their reproductive options. Males affected with ADPKD who suffer from infertility should be advised to seek treatment in time to improve their chances of conceiving a child. No funding was obtained. There are no competing interests to declare. Not applicable.


Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent.
The objective of this study was to investigate the pharmacologic characteristics of omidenepag isopropyl (OMDI), a compound developed as a novel intraocular pressure (IOP)-lowering agent, with better IOP control and fewer side effects than other prostanoid receptor agonists such as prostaglandin F receptor (FP) agonists. Binding activities of OMDI and its hydrolyzed form, omidenepag (OMD), to human recombinant prostanoid receptors (DP1-2, EP1-4, FP, and IP) were evaluated. Based on these binding assays, the agonistic activities of OMDI and OMD were further evaluated using cultured cells expressing selected prostanoid receptors. The pharmacokinetics of OMDI after topical administration was assessed in rabbits by measurement of the concentrations of both OMDI and OMD in aqueous humor. The ocular hypotensive effect of OMDI was evaluated in ocular normotensive rabbits, dogs, and both ocular normotensive and hypertensive monkeys. OMD was determined to be a selective EP2 receptor agonist. OMDI weakly bound to EP1; however, the agonistic activity of OMDI to this receptor was not demonstrated in the functional assay. After topical administration of OMDI, OMD was detected in aqueous humor whereas OMDI was not detectable. OMDI significantly lowered IOP in both ocular normotensive and hypertensive animals. The significant ocular hypotensive effects of OMDI were demonstrated by both single and repeated dosing, and its effective duration suggests sufficient efficacy by once-daily dosing. These studies demonstrated that OMDI is hydrolyzed in the eye to OMD, an EP2 receptor agonist, with a significant ocular hypotensive effect in both ocular normotensive and hypertensive animal models.


Assessment of ultrasound morbidity indicators of schistosomiasis in the context of large-scale programs illustrated with experiences from Malian children.
We assessed morbidity indicators for both Schistosoma haematobium and Schistosoma mansoni infections and evaluated the appropriateness of the World Health Organization (WHO) guidelines for ultrasound in schistosomiasis in the context of large-scale control interventions. Abdominal and urinary tract ultrasonography was performed on 2,247 and 2,822 school children, respectively, from 29 randomly selected schools in Mali before the implementation of mass anthelminthic drug administration. Using two-level logistic regression models, we examined associations of potential factors with the risk of having a positive ultrasound global score (morbidity indicative of S. haematobium infection), abnormal image pattern scores, dilatation of the portal vein, and/or enlarged liver (morbidity indicative of S. mansoni infection). The WHO protocol was found useful for detection of S. haematobium pathology but overestimated the risk of portal vein dilatation and left liver lobe enlargement associated with S. mansoni infection. We conclude that ultrasonography should be included in large-scale control interventions, where logistics allow, but cautiously.


Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components.
We investigated the composition of the endogenous ligand-bound type I interleukin-1 (IL-1) receptor (IL-1RI) signaling complex using immunoprecipitation and tandem mass spectrometry. Three proteins with approximate molecular masses of 60 (p60), 36 (p36), and 90 kDa (p90) became phosphorylated after treatment with IL-1. Phosphorylation in vitro of p60 has been reported previously, but its identity was unknown. We showed using tandem mass spectrometry that p60 is identical to interleukin-1 receptor-associated kinase (IRAK)-4. MS also enabled detection of IL-1, IL-1RI, IL-1 receptor accessory protein (IL-1RAcP), and myeloid differentiation primary response protein 88 (MyD88) in the complex. The p60 protein (IRAK-4) was the earliest component of the complex to be phosphorylated. Phosphorylated IRAK-4 from the receptor complex migrated more slowly in SDS-PAGE than its unphosphorylated form as did recombinant IRAK-4 autophosphorylated in vitro. Phosphorylation was restricted to serine and threonine residues. IRAK-4, p36, IL-1RAcP, and MyD88 bound to the liganded receptor within 15 s of activation by IL-1 and remained associated upon prolonged activation, suggesting that the signaling complex is very stable. The p90 phosphoprotein was only transiently associated with the receptor. This behavior and its size were consistent with it being IRAK-1. Our work revealed that liganding of IL-1RI causes its strong and stable association with IL-1RAcP, MyD88, and the previously unidentified protein p60 (IRAK-4). The only component of the IL-1RI signaling complex that dissociated is IRAK-1. Our study is therefore the first detailed description of the endogenous IL-1RI complex.


Pharmacokinetics of p-Aminohippuric Acid and Inulin in Rabbits with Aristolochic Acid Nephropathy.
The characteristics of aristolochic acid nephropathy (AAN) are interstitial fibrosis and atrophy of the proximal tubules, but with no change in glomeruli. To investigate the effects of AA on renal functions and the pharmacokinetics (PKs) of p-aminohippuric acid (PAH) and inulin, New Zealand white rabbits were used in this study. The plasma concentrations of PAH and inulin were determined by validated HPLC methods. After a single intravenous administration of 0.5 mg/kg aristolochic acid sodium (AANa), rabbits exhibited mild to moderate nephrotoxicity on the 7th day. Significant tubulointerstitial damage to kidney specimens was found, but there were no remarkable glomerular changes. Clearance rates of PAH and inulin both significantly decreased in AANa-treated rabbits. In addition, there was a significant correlation among the degree of tubulointerstitial changes and PK parameters of PAH after AANa administration, but no correlation was noted with the PKs of inulin. With mild to moderate AAN in rabbits, the renal plasma flow significantly decreased by 55%, and the glomerular filtration rate also significantly decreased by 85%. In conclusion, major renal lesions were found on proximal tubules after AANa administration. The PKs of PAH and inulin significantly changed, and kidney functions, including the RPF and GFR, were reduced.


Single dose oral etoricoxib for acute postoperative pain in adults.
Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain. The drug is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). A number of studies in acute postoperative pain have now been published. To assess the analgesic efficacy and adverse effects of a single oral dose of etoricoxib for moderate to severe postoperative pain. We searched Cochrane CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Database, and reference lists of articles. Date of the most recent search: December 2008. Randomised, double-blind, placebo-controlled clinical trials of single dose, oral etoricoxib for acute postoperative pain in adults. Two review authors independently assessed trials for inclusion in the review and quality, and extracted data. The area under the pain relief versus time curve was used to derive the proportion of participants prescribed etoricoxib or placebo with at least 50% pain relief over six hours, using validated equations. Relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Information on use of rescue medication was used to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. Information on adverse effects was also collected. Five studies (880 participants) were included in the review. All five studies reported on 120 mg, with 655 participants in a comparison with placebo. At least 50% pain relief was reported by 64% with etoricoxib 120 mg and 10% with placebo (NNT 1.9 (1.7 to 2.1)). For dental studies only the NNT was 1.6 (1.5 to 1.8). Two studies also reported on higher doses of 180 and 240 mg, with 249 participants. At least 50% pain relief was reported by 79% with etoricoxib 120 mg and 12% with placebo (NNT 1.5 (1.3 to 1.7)).Significantly fewer participants used rescue medication when taking etoricoxib 120 mg than those taking placebo (NNT to prevent remedication 2.4 (2.1 to 2.9)), and the median time to use of rescue medication was 20 hours. Adverse events were reported at a similar rate to placebo, with no serious events. Single dose oral etoricoxib produces high levels of good quality pain relief after surgery. The 120 mg dose is as effective as, or better than, other commonly used analgesics.


In-vivo Antioxidant Effects of Ethyl Acetate Fraction of Mentha spicata L. on 4-Nitroquinoline-1-Oxide Injected Mice.
Antioxidant effects of ethyl acetate fraction of Mentha spicata (L.) were evaluated against 4-nitroquinoline-1-oxide injected mice. For this study, experiment setup consisted of 36 albino mice of either sex divided into 6 groups: Control (25% DMSO in water), ethyl acetate fraction (EAF) alone group (80, 160 mg/Kg body weight-bwt), 4-NQO (7.5 mg/Kg bwt-IP) alone and 4-NQO + EAF. EAF and vehicles were administered orally for five consecutive days. 4-NQO (7.5 mg/Kg bwt) was injected intraperitoneally on the 6(th) day. After 24 h, the animals were killed; liver sample was extracted and used for bio-assay. 4-NQO alone treated group decreased (27-60%) the antioxidant activities and promoted lipid peroxidation (LPO-60%) over their respective control values. Pretreatment with EAF, at the maximum dose (160 mg/Kg bwt) brought down the LPO up to 87% enhanced by 4-NQO. Among the enzymatic antioxidants, glutathione S-transferase (GST) was the most affected enzyme with 4-NQO and the least was catalase (CAT). Pretreatment with EAF (160 mg/Kg bwt), the restoration of antioxidants like glutathione peroxidase, superoxide dismutase, and CAT were found equal or less than 1.2 fold higher than that of the respective control values whereas, GST was observed to be the most restored antioxidant. Be reduced glutathione (GSH) and the least vitamin C over their control values. EAF restored the GSH and Vitamin E levels were found to be 1.2 fold higher than the respective control values.


Attracting neurology's next generation: A qualitative study of specialty choice and perceptions.
To better understand the reasons medical students select or avoid a career in neurology by using a qualitative methodology to explore these factors, with the long-term objective of attracting more graduates to the field. In 2017, 27 medical students and 15 residents participated in 5 focus groups, and 33 fourth-year medical students participated in semistructured individual interviews. Participants were asked predefined open-ended questions about specialty choice, experiences in their basic neuroscience course and neurology clerkship, and perceptions about the field. Interviews were audio recorded and transcribed. We used a flexible coding methodology to generate themes across groups and interviews. Four main analytical themes emerged: (1) early and broad clinical exposure allows students to "try on" neurology and experience the variety of career options; (2) preclerkship experiences and a strong neuroscience curriculum lay the foundation for interest in the field; (3) personal interactions with neurology providers may attract or deter students from considering the specialty; and (4) persistent stereotypes about neurologists, neurology patients, and treatment options harm student perceptions of neurology. Efforts to draw more students to neurology may benefit from focusing on clinical correlations during preclerkship neuroscience courses and offering earlier and more diverse clinical experiences, including hands-on responsibilities whenever possible. Finally, optimizing student interactions with faculty and residents and reinforcing the many positive aspects of neurology are likely to favorably affect student perceptions.


Taking to the skies.
The role of Helicopter EMS must be to improve patient care and/or to ensure the most rapid transport of critically ill or injured patients. It has been suggested by Rhee et al, that the aeromedical service can be justified when the speed of the helicopter transport, the skills of the medical crew, and/or the ability of the helicopter to overcome environmental obstacles is likely to contribute to improved patient outcome. If one adds the essentials of well-trained, professional personnel and equipment, the "helicopter" becomes an important part of the overall medical care system and an essential component in improving patient outcome. While reviewing the role of the HEMS, it cannot be sufficiently emphasized that such a service in no way replaces an established ground ambulance system. A proficient, well-trained and well-equipped ground EMS program remains the backbone of an efficient pre-hospital and interhospital system. HEMS cannot be viewed as an isolated component of any EMS system. Instead, it must serve to complement the existing resources of the community. These is sufficient literature to suggest that the use of air medical services in transporting patients to tertiary care facilities or trauma centers has led to an improvement in overall survival rates. At the same time, an apparent paradox in mortality rate has occurred at the receiving hospital. While more patients are saved by speedy transport to a hospital, the mortality rate in that hospital may actually increase. Some patients who may have died from their injuries at the scene, or in transit, now die upon admission.(ABSTRACT TRUNCATED AT 250 WORDS)


Alterations in the glycolipid composition and cellular properties of ovarian carcinoma-derived RMG-1 cells on transfection of the alpha1,2-fucosyltransferase gene.
Transfection of the mouse Fut1 and Fut2, and human FUT1 genes into human ovarian carcinoma-derived RMG-1 cells resulted in 20-30-fold increases in cellular alpha1,2-fucosyltransferase activity, and in alteration of the glycolipid composition, including not only fucosylated products, but also precursor glycolipids. Although globo-series glycolipids were not significantly affected by the transfection, the major glycolipids belonging to the lacto-series type 1 chain family in RMG-1 cells and the transfectants were the Lc4Cer, Lewis a (Le)a and Leb, and H-1 glycolipids, respectively, suggesting that fucosylation of Lc4Cer to the H-1 glycolipid prevents the further modification of Lc4Cer to Lea and Leb in the transfectants. Also, the lacto-series type 2 chains in RMG-1 cells were LeX, NeuAc-nLc4Cer and NeuAc-LeX, and those in the transfectants were LeX and LeY, indicating that the sialylation of nLc4Cer and LeX is restricted by increased fucosylation of LeX. As a result, the amount of sialic acid released by sialidase from the transfectants decreased to 70% of that from RMG-1 cells, and several membrane-mediated phenomena, such as the cell-to-cell interaction between cancer cells and mesothelial cells, and the cell viability in the presence of an anticancer drug, 5-fluorouracil, for the transfectants was found to be increased in comparison to that for RMG-1 cells. These findings indicate that cell surface carbohydrates are involved in the biological properties, including cell-to-cell adhesion and drug resistance, of cancer cells.


Is There a Causal Relation between Maternal Acetaminophen Administration and ADHD?
Recent epidemiological studies reported an association between maternal intake of acetaminophen (APAP) and attention deficit hyperactivity disorder (ADHD) in their children. However, none of these studies demonstrated causality. Our objective was to determine whether exposure to APAP during pregnancy result in hyperkinetic dysfunctions in offspring, using a murine model. Pregnant CD1 mice (N = 8/group) were allocated to receive by gavage either APAP (150 mg/kg/day, equivalent to the FDA-approved maximum human clinical dose), or 0.5% carboxymethylcellulose (control group), starting on embryonic day 7 until delivery. Maternal serum APAP and alanine transaminase (ALT) concentrations were determined by ELISA and kinetic colorimetric assays, respectively. Open field locomotor activity (LMA) in the 30-day old mouse offspring was quantified using Photobeam Activity System. Mouse offspring were then sacrificed, whole brains processed for magnetic resonance imaging (MRI; 11.7 Tesla magnet) and for neuronal quantification using Nissl stain. The association between APAP exposure and LMA in mouse offspring was analyzed using a mixed effects Poisson regression model that accounted for mouse offspring weight, gender, random selection, and testing time and day. We corrected for multiple comparisons and considered P<0.008 as statistically significant. Maternal serum APAP concentration peaked 30 minutes after gavage, reaching the expected mean of 117 μg/ml. Serum ALT concentrations were not different between groups. There were no significant differences in vertical (rearing), horizontal, or total locomotor activity between the two rodent offspring groups at the P level fixed to adjust for multiple testing. In addition, no differences were found in volumes of 29 brain areas of interest on MRI or in neuronal quantifications between the two groups. This study refutes that hypothesis that prenatal exposure to APAP causes hyperkinetic dysfunction in mouse offspring. Due to lack of accurate assessment of ADHD in murine models, our results should be taken with caution when compared to the reported clinical data.


Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease.
To describe a novel missense mutation, Asp678Asn (D678N), in the amyloid precursor protein (APP) gene in a Japanese pedigree of probable familial Alzheimer's disease (FAD). The proband was a women of 72. Symptoms of dementia that fulfilled the criteria for probable Alzheimer's disease appeared at about 60 years of age, and slowly worsened over more than 10 years without evident cerebrovascular complications, either clinically or neuroradiologically. Polymerase chain reaction single strand conformational polymorphism (PCR-SSCP) analysis followed by sequence analysis was used to examine genomic DNA of the proband for mutations in the APP gene exons 16 and 17. Analysis of the APP exon 16 in the proband showed a GAC to AAC nucleotide substitution in codon 678 of the APP gene, causing an amino acid substitution of Asp to Asn (D678N). Heterozygosity of the APP D678N mutation was found in the proband and in the demented elder sister. The production and accumulation of mutated Abeta (Asn7-Abeta) or the misfunction of D678N mutant APP may have pathogenic properties for the development of Alzheimer's disease in this pedigree.


Revisiting regulation of potassium homeostasis in Escherichia coli: the connection to phosphate limitation.
Two-component signal transduction constitutes the predominant strategy used by bacteria to adapt to fluctuating environments. The KdpD/KdpE system is one of the most widespread, and is crucial for K+ homeostasis. In Escherichia coli, the histidine kinase KdpD senses K+ availability, whereas the response regulator KdpE activates synthesis of the high-affinity K+ uptake system KdpFABC. Here we show that, in the absence of KdpD, kdpFABC expression can be activated via phosphorylation of KdpE by the histidine kinase PhoR. PhoR and its cognate response regulator PhoB comprise a phosphate-responsive two-component system, which senses phosphate limitation indirectly through the phosphate transporter PstCAB and its accessory protein PhoU. In vivo two-hybrid interaction studies based on the bacterial adenylate cyclase reveal pairwise interactions between KdpD, PhoR, and PhoU. Finally, we demonstrate that cross-regulation between the kdpFABC and pstSCAB operons occurs in both directions under simultaneous K+ and phosphate limitation, both in vitro and in vivo. This study for the first time demonstrates direct coupling between intracellular K+ and phosphate homeostasis and provides a mechanism for fine-tuning of the balance between positively and negatively charged ions in the bacterial cell.


World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer.
It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat precancerous cervical lesions and for treatment of histologically confirmed CIN 2-3. Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel. There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization. Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries.


The higher-order structure of chromatin: evidence for a helical ribbon arrangement.
Both intact and nuclease-isolated chromatin fibers have been examined at different degrees of salt-induced compaction, using a variety of preparation techniques. The results suggest that the initial folding step in nucleosome packing involves the formation of a zig-zag ribbon as has been proposed by others (Thoma F., T. Koller, and A. Klug, 1979, J. Cell Biol., 83:403-427; Worcel A., S. Strogartz, and D. Riley, 1981, Proc. Natl. Acad. Sci. USA, 78:1461-1465), and that subsequent compaction occurs by coiling of the ribbon to form a double helical structure. This type of folding generates a fiber in which the nucleosome-nucleosome contacts established in the zig-zag ribbon are maintained and in which the histone H1 molecules occupy equivalent sites. The diameter of the fiber is not dependent upon the nucleosome repeat length. Direct mass values for individual isolated fibers obtained from electron scattering measurements showed that the mass per length was dependent on ionic strength, and ranged from 6.0 X 10(4) daltons/nm at 10 mM NaCl to 27 X 10(4) daltons/nm at 150 mM salt. These values are equivalent to 2.5 nucleosomes/11 nm at 10 mM NaCl and to 11.6 nucleosomes/11 nm at 150 mM salt and are consistent with the range of packing ratios for the proposed helical ribbon.


Hypocholesterolemic and Prebiotic Effects of a Whole-Grain Oat-Based Granola Breakfast Cereal in a Cardio-Metabolic "At Risk" Population.
Meta-analyses of randomized controlled trials (RTC) have confirmed the hypocholesterolaemic effect of oats and oat based fibers. However, the mechanisms by which oats or oat fractions lower cholesterol is not totally clear. Recognizing the important role of the gut microbiome in metabolism and metabolic disease risk, we examined the impact of whole grain oat Granola (WGO) on the human gut microbiota and cardio-metabolic risk factors using a randomized crossover dietary intervention in at risk individuals (ClinicalTrials.gov Identifier: NCT01925365). We randomized 32 individuals at risk of developing cardio-metabolic disease by virtue of mild hypercholesterolaemia or glucose intolerance, into two groups consuming either 45 g of WGO or non-whole grain (NWG) breakfast cereals daily for two 6-week intervention periods separated by a 4-week wash out period in a randomized, controlled, crossover, double-blinded design. Confirming the cholesterol lowering effect of WGO, we observed a significant time by treatment interaction, for total cholesterol (TC) (P = 0.0001) and LDL-cholesterol (LDL-C) (P = 0.02) compared to NWG. A significant time by treatment interaction was also observed for the relative abundance of fecal bifidobacteria (P = 0.0001), lactobacilli (P = 0.001) and total bacterial count (P = 0.008), which were all elevated after consumption of WGO. Daily consumption of WGO resulted in a prebiotic effect on the human gut microbiota composition and significant reductions in TC and LDL-C concentrations. Prebiotic modulation of the human gut microbiota may thus constitute a previously unrecognized mechanism contributing to the hypocholesterolaemic effects of whole grain oat Granola.


Suicides by opium and its derivatives, in England and Wales, 1850-1950.
In the mid-nineteenth century opium and its derivatives, such as laudanum and morphine, were the most common poisons in suicides in England and Wales. With legislative restrictions on these 'dangerous drugs' such a use declined. This study attempts to show this trend and indicates the large variety of these opium-related suicides.


A framework for offline evaluation and optimization of real-time algorithms for use in neurofeedback, demonstrated on an instantaneous proxy for correlations.
Interest in real-time fMRI neurofeedback has grown exponentially over the past few years, both for use as a basic science research tool, and as part of the search for novel clinical interventions for neurological and psychiatric illnesses. In order to expand the range of questions which can be addressed with this tool however, new neurofeedback methods must be developed, going beyond feedback of activations in a single region. These new methods, several of which have already been proposed, are by their nature complex, involving many possible parameters. Here we suggest a framework for evaluating and optimizing algorithms for use in a real-time setting, before beginning the neurofeedback experiment, by offline simulations of algorithm output using a previously collected dataset. We demonstrate the application of this framework on the instantaneous proxy for correlations which we developed for training connectivity between different network nodes, identify the optimal parameters for use with this algorithm, and compare it to more traditional correlation methods. We also examine the effects of advanced imaging techniques, such as multi-echo acquisition, and the integration of these into the real-time processing stream.


Studies of operant and reflexive key pecks in the pigeon.
The duration of pigeons' key pecks was studied in three experiments. Experiment I revealed that key pecks early in exposure to continuous reinforcement were of short duration, as were key pecks observed on an omission procedure in which pecks prevented food delivery. Key pecks later in exposure to continuous reinforcement, and those that occurred on positive automaintenance procedures, were of long duration. In Experiment II, pigeons were exposed to fixed-interval and fixed-ratio reinforcement schedules, and durations were recorded separately for each quarter of each interval or ratio. On fixed interval, durations were shorter in the first quarter of each interval than in subsequent quarters; on fixed ratio, durations were longer in the first quarter of the ratio than in subsequent quarters. These data parallel observations of concurrent operant responding and salivation in dogs. In Experiment III, pigeons were exposed to a discrete trial, differential-reinforcement-of-low-rate 6-sec schedule. Durations of responses in the first 2 sec of the trial were substantially shorter than those of responses that occurred later. The data from all three experiments support the view that the pigeon's "key peck" actually consists of two subclasses of peck, one reflexive and one operant.


An Optical/Photoacoustic Dual-Modality Probe: Ratiometric in/ex Vivo Imaging for Stimulated H2S Upregulation in Mice.
Tracking signaling H2S in live mice demands responsive imaging with fine tissue imaging depth and low interferences from tissue scattering/autofluorescence and probe concentration. With complementary advantages of fluorescence and photoacoustic (PA) imaging, optical/PA dual-modality imaging was suggested for in/ex vivo H2S imaging. Therefore, a meso-benzoyloxyltricarboheptamethine cyanine, HS-CyBz, was prepared as the first ratiometric optical/PA dual-modality probe for H2S, profiting from a keto-enol transition sensing mechanism. Tail intravenous injection of this probe leads to probe accumulation in the liver of mice, and the endogenous H2S upregulation triggered by S-adenosyl-l-methionine has been verified by ratiometric optical/PA imaging, suggesting the promising potential of this ratiometric dual-modality imaging.


Metabolism of Scoparone in Experimental Animals and Humans.
Scoparone, a major constituent of the Chinese herbal medicine Yin Chen Hao, expresses beneficial effects in experimental models of various diseases. The intrinsic doses and effects of scoparone are dependent on its metabolism, both in humans and animals. We evaluated in detail the metabolism of scoparone in human, mouse, rat, pig, dog, and rabbit liver microsomes in vitro and in humans in vivo. Oxidation of scoparone to isoscopoletin via 6-O-demethylation was the major metabolic pathway in liver microsomes from humans, mouse, rat, pig and dog, whereas 7-O-demethylation to scopoletin was the main reaction in rabbit. The scoparone oxidation rates in liver microsomes were 0.8 - 1.2 µmol/(min*g protein) in mouse, pig, and rabbit, 0.2 - 0.4 µmol/(min*g protein) in man and dog, and less than 0.1 µmol/(min*g) in rat. In liver microsomes of all species, isoscopoletin was oxidized to 3-[4-methoxy-ρ-(3, 6)-benzoquinone]-2-propenoate and esculetin, which was formed also in the oxidation of scopoletin. Human CYP2A13 exhibited the highest rate of isoscopoletin and scopoletin oxidation, followed by CYP1A1 and CYP1A2. Glucuronidation of isoscopoletin and scopoletin was catalyzed by the human UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, and UGT2B17. Dog was most similar to man in scoparone metabolism. Isoscopoletin glucuronide and sulfate conjugates were the major scoparone in vivo metabolites in humans, and they were completely excreted within 24 h in urine. Scoparone and its metabolites did not activate key nuclear receptors regulating CYP and UGT enzymes. These results outline comprehensively the metabolic pathways of scoparone in man and key preclinical animal species.


Technoeconomic and life-cycle analysis of single-step catalytic conversion of wet ethanol into fungible fuel blendstocks.
Technoeconomic and life-cycle analyses are presented for catalytic conversion of ethanol to fungible hydrocarbon fuel blendstocks, informed by advances in catalyst and process development. Whereas prior work toward this end focused on 3-step processes featuring dehydration, oligomerization, and hydrogenation, the consolidated alcohol dehydration and oligomerization (CADO) approach described here results in 1-step conversion of wet ethanol vapor (40 wt% in water) to hydrocarbons and water over a metal-modified zeolite catalyst. A development project increased liquid hydrocarbon yields from 36% of theoretical to >80%, reduced catalyst cost by an order of magnitude, scaled up the process by 300-fold, and reduced projected costs of ethanol conversion 12-fold. Current CADO products conform most closely to gasoline blendstocks, but can be blended with jet fuel at low levels today, and could potentially be blended at higher levels in the future. Operating plus annualized capital costs for conversion of wet ethanol to fungible blendstocks are estimated at $2.00/GJ for CADO today and $1.44/GJ in the future, similar to the unit energy cost of producing anhydrous ethanol from wet ethanol ($1.46/GJ). Including the cost of ethanol from either corn or future cellulosic biomass but not production incentives, projected minimum selling prices for fungible blendstocks produced via CADO are competitive with conventional jet fuel when oil is $100 per barrel but not at $60 per barrel. However, with existing production incentives, the projected minimum blendstock selling price is competitive with oil at $60 per barrel. Life-cycle greenhouse gas emission reductions for CADO-derived hydrocarbon blendstocks closely follow those for the ethanol feedstock.


3D fusion of functional cardiac magnetic resonance imaging and computed tomography coronary angiography: accuracy and added clinical value.
To evaluate the accuracy and added diagnostic value of 3-dimensional (3D) image fusion of computed tomography coronary angiography (CTCA) and functional cardiac magnetic resonance (CMR) for assessing hemodynamically relevant coronary artery disease (CAD). Twenty-seven patients with significant coronary stenoses on prospectively electrocardiography-gated dual-source CTCA, confirmed by catheter angiography and perfusion defects on CMR at 1.5 T were included. Surface representations and volume-rendered images from 3D-fused CTCA/CMR data were generated using a software prototype. Fusion accuracy was evaluated by calculating surface distances of blood pools and Dice similarity coefficients. Two independent, blinded readers assigned myocardial defects to culprit coronary arteries with side-by side analysis of CTCA and CMR and using fused CTCA/CMR. Added value of fused CTCA/CMR was defined as change in assignment of culprit coronary artery to myocardial defect compared with side-by-side analysis. 3D fusion of CTCA/CMR was feasible and accurate (surface distance of blood pools: 4.1 ± 1.3 mm, range: 2.4-7.1 mm; Dice similarity coefficients: 0.78 ± 0.08, range: 0.51-0.86) in all patients. Side-by-side analysis of CTCA and CMR allowed no assignment of a single culprit artery to a myocardial defect in 6 of 27 (22%) patients. Fused CTCA/CMR allowed further confinement of culprit coronary arteries in 3 of these 6 patients (11%). Myocardial defects were reassigned in 2 of 27 (7%) patients using fused CTCA/CMR, whereas the results remained unchanged in 22 of 27 (81%) patients. Interobserver agreement for assignment of culprit arteries to myocardial defects increased with fused CTCA/CMR (k = 0.66-0.89). 3D fusion of low-dose CTCA and functional CMR is feasible and accurate, and adds, at a low radiation dose, diagnostic value for the assessment of hemodynamically relevant CAD as compared with side-by-side analysis alone. This technique can be clinically useful for the following: planning of surgical or interventional procedures in patients having a high prevalence of CAD and for improved topographic assignment of coronary stenoses to corresponding myocardial perfusion defects.


Long term results (15-30 years) of surgical repair of aortic coarctation.
The late outcome in 226 patients who survived surgical repair of aortic coarctation was assessed 15-30 years after operation. Twenty six patients died during the follow up mainly from causes related to surgical repair or to associated cardiovascular anomalies. The survival rates of patients operated on between the ages of four and 20 years are 97%, 97%, 92% at 10, 20, and 30 years after operation. For patients operated on after the age of 20 the corresponding rates are 93%, 85%, and 68%. This difference is statistically significant from the fifteenth year of follow up onwards. The survival of patients operated on before the age of 20 is not significantly different from that of a comparable general Italian population. Recoarctation occurred in only 8% of patients who had end to end anastomosis, whereas it occurred in 35% of those who had other types of operation. Two thirds of the patients were hypertensive at the last visit. The actuarial curve shows that blood pressure was normal in most patients 5-10 years after operation, but 30 years after coarctation repair only 32% of patients are expected to be normotensive. Thus early repair of aortic coarctation appears to improve long term survival. Intervention in older patients and when blood pressure is high seem to be the most important predictors of late hypertension.


CD2 regulates responsiveness of activated T cells to interleukin 12.
Interleukin (IL) 12 is a 70-kD heterodimeric cytokine produced by antigen-presenting cells (APCs) such as macrophages in response to infectious pathogens and interferon (IFN) gamma. The varied immunomodulatory effects of IL-12 include the stimulation of proliferation and IFN-gamma production by T cells, and it also has a central role in the development of the T helper cell type 1 immune phenotype. We undertook the production of antibodies capable of modulating the response of T cells to IL-12, and in the process we discovered two antibodies that inhibited the ability of IL-12 to stimulate T cell proliferation. In this report, we demonstrate that these anti-bodies recognize CD2, and we show how antibodies directed toward either the adhesion domain of CD2 or its ligand, CD58, specifically inhibit IL-12 induced proliferation and IFN-gamma production by phytohemagglutinin-activated T cells, leaving the response to IL-12 unaffected. A three-to fourfold reduction in proliferation and IFN-gamma production was observed at IL-12 concentrations as high as 1 nM, with complete inhibition occurring at < or = 1 pM. This novel effect is not directly mediated at the level of the IL-12 receptor, as shown by the inability of these antibodies to block IL-12 binding to activated T cells. Furthermore, by using activating pairs of CD2 antibodies, we show that CD2 stimulation strongly synergizes with IL-12, even at 0.1 pM, in inducing both T cell proliferation and IFN-gamma production. Cytolytic T lymphocyte-associated antigen 4-immunoglobulin-mediated inhibition of the B7/CD28 interaction did not affect the T cell response to either IL-12 or IL-2, but the removal of APCs selectively diminished the proliferative response to IL-12. Based on this data, we hypothesize that CD2 has a central role in an IL-12/IFN-gamma positive feedback loop between T cell and APC, providing the key functional link via a CD2/CD58 interaction that controls T cell responsiveness to IL-12. This model provides a basis for future investigations aimed at defining the signaling mechanisms that mediate this cytokine-specific regulatory effect of CD2, and it offers insight into how a cytokine receptor and distinct adhesion molecule can interact to modulate responsiveness to that cytokine. In addition, it underscores the possibility that the clinical potential of an immunomodulatory drug like IL-12 may be governed by the presence or absence of specific costimulation.


Detection of Helicobacter pylori in gastric biopsy and resection specimens.
To compare the sensitivity of detecting Helicobacter pylori in gastric biopsy and resection specimens using tinctorial and silver impregnation stains, immunohistochemistry and the polymerase chain reaction (PCR). Formalin fixed, paraffin wax embedded tissue from 33 gastric biopsy specimens (26 showing chronic gastritis and seven showing low grade mucosa associated lymphoid tissue (MALT) lymphoma) together with blocks of uninvolved mucosa from gastrectomy specimens for MALT lymphoma (five cases) were studied. Consecutive sections were stained using haematoxylin and eosin, Giemsa, the Warthin-Starry silver stain, and a polyclonal antibody directed against H pylori using an immunoperoxidase technique following heat induced antigen retrieval. PCR analysis of DNA extracted from a further section was carried out using primers which amplified a 411 base pair fragment of the urease A gene. H pylori was detected in 14 (37%) sections stained with haematoxylin and eosin, 21 (55%) with Giemsa, 23 (61%) with Warthin-Starry, and 25 (66%) stained with the antibody. Seventeen (45%) cases were positive on PCR. Immunohistochemistry was positive in all cases in which H pylori was detected by other methods. Immunohistochemistry using an immunoperoxidase technique following heat induced antigen retrieval for detecting H pylori in gastric biopsy and resection specimens is highly sensitive and easy to use.


A durable monolithic polymer foam for efficient solar steam generation.
Efficient and cost-effective solar steam generation requires self-floating evaporators which can convert light into heat, prevent unnecessary heat loss and greatly accelerate evaporation without solar concentrators. Currently, the most efficient evaporators (efficiency of ∼80% under 1 sun) are invariably built from inorganic materials, which are difficult to mold into monolithic sheets. Here, we present a new polymer which can be easily solution processed into a self-floating monolithic foam. The single-component foam can be used as an evaporator with an efficiency at 1 sun comparable to that of the best graphene-based evaporators. Even at 0.5 sun, the efficiency can reach 80%. Moreover, the foam is mechanically strong, thermally stable to 300 °C and chemically resistant to organic solvents.