HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.
The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.


An overview of sarcopenia: facts and numbers on prevalence and clinical impact.
Human muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1-2%. Muscle strength declines by 1.5% between ages 50 and 60 and by 3% thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5-13% of elderly people aged 60-70 years are affected by sarcopenia. The numbers increase to 11-50% for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail-sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.


L'eggo My Ego: Reducing the Gender Gap in Math by Unlinking the Self from Performance.
Stereotype threat can vary in source, with targets being threatened at the individual and/or group level. This study examines specifically the role of self-reputational threat in women's underperformance in mathematics. A pilot study shows that women report concerns about experiencing self-reputational threat that are distinct from group threat in the domain of mathematics. In the main study, we manipulated whether performance was linked to the self by asking both men and women to complete a math test using either their real name or a fictitious name. Women who used a fictitious name, and thus had their self unlinked from the math test, showed significantly higher math performance and reported less self-threat and distraction, relative to those who used their real names. Men were unaffected by the manipulation. These findings suggest that women's impaired math performance is often due to the threat of confirming a negative stereotype as being true of the self. The implications for understanding the different types of threats faced by stereotyped groups, particularly among women in math settings, are discussed.


Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry.
Computational studies of organic systems are frequently limited to static pictures that closely align with textbook style presentations of reaction mechanisms and isomerization processes. Of course, in reality chemical systems are dynamic entities where a multitude of molecular conformations exists on incredibly complex potential energy surfaces (PES). Here, we borrow a computational technique originally conceived to be used in the context of biological simulations, together with empirical force fields, and apply it to organic chemical problems. Replica-exchange molecular dynamics (REMD) permits thorough exploration of the PES. We combined REMD with density functional tight binding (DFTB), thereby establishing the level of accuracy necessary to analyze small molecular systems. Through the study of four prototypical problems: isomer identification, reaction mechanisms, temperature-dependent rotational processes, and catalysis, we reveal new insights and chemistry that likely would be missed using static electronic structure computations. The REMD-DFTB methodology at the heart of this study is powered by i-PI, which efficiently handles the interface between the DFTB and REMD codes.


Efficient peptide-MHC-I binding prediction for alleles with few known binders.
In silico methods for the prediction of antigenic peptides binding to MHC class I molecules play an increasingly important role in the identification of T-cell epitopes. Statistical and machine learning methods in particular are widely used to score candidate binders based on their similarity with known binders and non-binders. The genes coding for the MHC molecules, however, are highly polymorphic, and statistical methods have difficulties building models for alleles with few known binders. In this context, recent work has demonstrated the utility of leveraging information across alleles to improve the performance of the prediction. We design a support vector machine algorithm that is able to learn peptide-MHC-I binding models for many alleles simultaneously, by sharing binding information across alleles. The sharing of information is controlled by a user-defined measure of similarity between alleles. We show that this similarity can be defined in terms of supertypes, or more directly by comparing key residues known to play a role in the peptide-MHC binding. We illustrate the potential of this approach on various benchmark experiments where it outperforms other state-of-the-art methods. The method is implemented on a web server: http://cbio.ensmp.fr/kiss. All data and codes are freely and publicly available from the authors.


Diversity and rearrangement of the human T cell rearranging gamma genes: nine germ-line variable genes belonging to two subgroups.
We describe nine T cell gamma variable (V) gene segments isolated from human DNA. These genes, which fall into two subgroups, are mapped in two DNA regions covering 54 kb and probably represent the majority of human V gamma genes. One subgroup (V gamma I) contains eight genes, consisting of four active genes and four pseudogenes. The single V gamma II gene is potentially active. Sequence analysis of the V gamma I genes shows variation clustered in hypervariable regions, but somatic variability is restricted to N-region diversity. Studies on rearrangement in T cell lines and in thymic DNA show that major rearrangements can be observed that are attributable to the five active V gamma genes. In addition, human cells with the phenotype of helper T cells can undergo productive V gamma-J gamma joining.


Super-resolution optical microscopy of lipid plasma membrane dynamics.
Plasma membrane dynamics are an important ruler of cellular activity, particularly through the interaction and diffusion dynamics of membrane-embedded proteins and lipids. FCS (fluorescence correlation spectroscopy) on an optical (confocal) microscope is a popular tool for investigating such dynamics. Unfortunately, its full applicability is constrained by the limited spatial resolution of a conventional optical microscope. The present chapter depicts the combination of optical super-resolution STED (stimulated emission depletion) microscopy with FCS, and why it is an important tool for investigating molecular membrane dynamics in living cells. Compared with conventional FCS, the STED-FCS approach demonstrates an improved possibility to distinguish free from anomalous molecular diffusion, and thus to give new insights into lipid-protein interactions and the traditional lipid 'raft' theory.


Ring-fusion as a perylenediimide dimer design concept for high-performance non-fullerene organic photovoltaic acceptors.
A series of perylenediimide (PDI) dimers are evaluated as acceptors for organic photovoltaic (OPV) cells. The materials are characterized using a wide variety of physical and computational techniques. These dimers are first linked at the bay position of each PDI molecule via an aromatic spacer; subsequent photocyclization affords ring-fused dimers. Thus, photocyclization of the thiophene-linked dimer 2,5-bis-[N,N'-bis-perylenediimide-1-yl]-thiophene (T1) affords the twisted acceptor [2,3-b:2',3'-d]-bis-[N,N'-bis-perylenediimide-1,12-yl]-thiophene (T2), while photocyclization of the thienothiophene-linked dimer, 2,5-bis-[N,N'-bis-perylenediimide-1-yl]-thienothiophene (TT1) affords the planar acceptor [2,3-b:2',3'-d]-bis-[N,N'-bis-perylenediimide-1,12-yl]-thienothiophene (TT2). Furthermore, a dimer linked by a phenylene group, 1,4-bis-[N,N'-bis-perylenediimide-1-yl]-benzene (Ph1), can be selectively photocyclized to form either the twisted dimer, [1,2:3,4]-bis-[N,N'-bis-perylenediimide-1,12-yl]-benzene (Ph1a) or the planar dimer [1,2:4,5]-bis-[N,N'-bis-perylenediimide-1,12-yl]-benzene (Ph2b). Ring-fusion results in increased electronic coupling between the PDI units, and increased space-charge limited thin film electron mobility. While charge transport is efficient in bulk-heterojunction blends of each dimer with the polymeric donor PBDTT-FTTE, in the case of the twisted dimers ring fusion leads to a significant decrease in geminate recombination, hence increased OPV photocurrent density and power conversion efficiency. This effect is not observed in planar dimers where ring fusion leads to increased crystallinity and excimer formation, decreased photocurrent density, and decreased power conversion efficiency. These results argue that ring fusion is an effective approach to increasing OPV bulk-heterojunction charge carrier generation efficiency in PDI dimers as long as they remain relatively amorphous, thereby suppressing excimer formation and coulombically trapped charge transfer states.


1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.


Magnitude of blood pressure reduction and clinical outcomes in acute intracerebral hemorrhage: intensive blood pressure reduction in acute cerebral hemorrhage trial study.
Evidence supports early intensive blood pressure (BP) lowering in acute intracerebral hemorrhage, but uncertainty persists over whether potential benefits and harms vary according to the magnitude of BP reduction. We aimed to determine whether larger systolic BP (SBP) reductions were associated with better outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). INTERACT2 was an international, open, blinded end point, randomized controlled trial of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated SBP (150-220 mm Hg) assigned to intensive (target SBP <140 mm Hg) or guideline-recommended (SBP <180 mm Hg) treatment. Associations of BP reduction (baseline minus average of achieved SBP) during 3 time periods post randomization (15-60 minutes, 1-24 hours, and 2-7 days) on poor outcome (death or major disability) at 90 days were analyzed in multivariable logistic regression models with odds ratios and 95% confidence intervals. Larger SBP reductions within the first hour after randomization were associated with lower risks of poor outcome: compared with minimal reduction (<10 mm Hg), odds ratios were 0.80 (95% confidence interval, 0.63-1.02) for moderate (10-20 mm Hg) and 0.65 (0.52-0.82) for large (≥20 mm Hg) reductions (P trend <0.01). Similar associations were also observed for SBP reductions during 1 to 24 hours (P<0.01) and 2 to 7 days (P 0.02). No heterogeneity in associations for patients above or below baseline SBP 180 mm Hg was reported (P>0.30). Optimal recovery from intracerebral hemorrhage was observed in hypertensive patients who achieved the greatest SBP reductions (≥20 mm Hg) in the first hour and maintained for 7 days. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.


Developing a Reporting Guideline for Social and Psychological Intervention Trials.
Social and psychological interventions are often complex. Understanding randomized controlled trials (RCTs) of these complex interventions requires a detailed description of the interventions tested and the methods used to evaluate them; however, RCT reports often omit, or inadequately report, this information. Incomplete and inaccurate reporting hinders the optimal use of research, wastes resources, and fails to meet ethical obligations to research participants and consumers. In this article, we explain how reporting guidelines have improved the quality of reports in medicine and describe the ongoing development of a new reporting guideline for RCTs: Consolidated Standards of Reporting Trials-SPI (an extension for social and psychological interventions). We invite readers to participate in the project by visiting our website, in order to help us reach the best-informed consensus on these guidelines (http://tinyurl.com/CONSORT-study).


Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs.
Cocaine and a number of 3beta-phenyltropane cocaine analogs were investigated for their potential to block various pharmacological effects of nicotine in animals. They blocked the antinociceptive effect of nicotine in the tail-flick test after systemic administration in a dose-dependent manner. Similarly, cocaine was also able to block nicotine-induced motor impairment in mice. Furthermore, cocaine blocked nicotine-induced seizures at a lower potency than for antinociception, but failed to block nicotine's effect on body temperature and drug discrimination. The antagonistic potencies of the 3beta-phenyltropane cocaine analogs were not correlated with their affinity for monoamines transporters. Additionally, bupropion, nomifensin, GBR 12909, and nisoxetine, but not methylphenidate and fluoxetine, blocked nicotine-induced antinociception; however, their antagonistic potencies were unrelated to their affinities for the transporters. Taken together, these results suggest that the mechanism of cocaine's antagonistic activity is not related to its binding and uptake of inhibition on monoamine neurotransporters. The failure of lidocaine and procaine to antagonize nicotine's effects in the tail-flick assay rules out local anesthetic effects. In addition, cocaine blocked differentially the response of nicotine in the oocyte receptor expression system for the alpha4beta2 and alpha3beta2 subtypes in a dose-dependent manner. Our results suggest that cocaine is a noncompetitive nicotinic antagonist with some selectivity for neuronal nicotinic receptor subtypes. Our studies also demonstrate that 3beta-phenyltropane analogs constitute a new class of nicotinic antagonists. Elucidation of the mechanism of action of this new class of antagonists may provide an explanation for the effectiveness of agents such as bupropion for the treatment of smoking cessation.


Long-term changes of bacterial and viral compositions in the intestine of a recovered Clostridium difficile patient after fecal microbiota transplantation.
Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infections (RCDIs). However, long-term effects on the patients' gut microbiota and the role of viruses remain to be elucidated. Here, we characterized bacterial and viral microbiota in the feces of a cured RCDI patient at various time points until 4.5 yr post-FMT compared with the stool donor. Feces were subjected to DNA sequencing to characterize bacteria and double-stranded DNA (dsDNA) viruses including phages. The patient's microbial communities varied over time and showed little overall similarity to the donor until 7 mo post-FMT, indicating ongoing gut microbiota adaption in this time period. After 4.5 yr, the patient's bacteria attained donor-like compositions at phylum, class, and order levels with similar bacterial diversity. Differences in the bacterial communities between donor and patient after 4.5 yr were seen at lower taxonomic levels. C. difficile remained undetectable throughout the entire timespan. This demonstrated sustainable donor feces engraftment and verified long-term therapeutic success of FMT on the molecular level. Full engraftment apparently required longer than previously acknowledged, suggesting the implementation of year-long patient follow-up periods into clinical practice. The identified dsDNA viruses were mainly Caudovirales phages. Unexpectedly, sequences related to giant algae-infecting Chlorella viruses were also detected. Our findings indicate that intestinal viruses may be implicated in the establishment of gut microbiota. Therefore, virome analyses should be included in gut microbiota studies to determine the roles of phages and other viruses-such as Chlorella viruses-in human health and disease, particularly during RCDI.


Provider Responses to Positive Developmental Screening: Disparities in Referral Practices?
Guidelines recommend universal screening for developmental concerns in young children in pediatric primary care, with referral to early intervention (EI) as early as possible for children with a positive screen. However, participation in EI differs by child race, ethnicity, language, and sex. This study evaluated disparities in rates of referral to EI and estimated the factors associated with referral before and immediately after a positive developmental screen. Children seen in a large primary care network that has implemented universal developmental screening were included if they screened positive on the Survey of Well-being of Young Children (SWYC) Milestones during a 16- to 30-month well-child visit (n = 7358). Demographics, screening results, and referrals were extracted from the electronic health record. Among children who screened positive, 17.5% were already in EI, and 39.9% were referred to EI during the visit with positive screen; 42.5% were not referred. In adjusted regression, the following factors were associated with being in EI before the positive screen: lower SWYC score and being male, older, and White. The following factors were associated with new referral to EI during a visit with positive SWYC: having lower SWYC score or lower income and being male, older, and Black race. The finding that White children were more likely referred before developmental screening and non-White children more likely referred at the time of positive screen suggests that screening decreases disparities by increasing referral for children with developmental delays from traditionally underserved backgrounds.


Patients with low back pain differ from those who also have leg pain or signs of nerve root involvement - a cross-sectional study.
Leg pain associated with low back pain (LBP) is recognized as a risk factor for a poor prognosis, and is included as a component in most LBP classification systems. The location of leg pain relative to the knee and the presence of a positive straight leg raise test have been suggested to have clinical implications. To understand differences between such leg pain subgroups, and whether differences include potentially modifiable characteristics, the purpose of this paper was to describe characteristics of patients classified into the Quebec Task Force (QTF) subgroups of: 1) LBP only, 2) LBP and pain above the knee, 3) LBP and pain below the knee, and 4) LBP and signs of nerve root involvement. Analysis of routine clinical data from an outpatient department. Based on patient reported data and clinical findings, patients were allocated to the QTF subgroups and described according to the domains of pain, activity limitation, work participation, psychology, general health and clinical examination findings. A total of 2,673 patients aged 18-95 years (median 47) who were referred for assessment of LBP were included. Increasing severity was consistently observed across the subgroups from LBP only to LBP with signs of nerve root involvement although subgroup differences were small. LBP patients with leg pain differed from those with LBP only on a wide variety of parameters, and patients with signs of nerve root involvement had a more severe profile on almost all measures compared with other patients with back-related leg pain. LBP patients with pain referral to the legs were more severely affected than those with local LBP, and patients with signs of nerve root involvement were the ones most severily affected. These findings underpin the concurrent validity of the Quebec Task Force Classification. However, the small size of many between-subgroup differences amid the large variability in this sample of cross-sectional data also underlines that the heterogeneity of patients with LBP is more complex than that which can be explained by leg pain patterns alone. The implications of the observed differences also require investigation in longitudinal studies.


Wavelength dispersion of nonlinear dielectric function of Cu nanoparticle materials.
The wavelength dispersions of third-order nonlinear optical response for Cu nanoparticle materials have been experimentally evaluated from transient spectra measured with the pump-probe method. The evaluated dispersions were analyzed on hot electron contribution using the Maxwell-Garnett approximation with the Drude model for intraband transition and first principles calculation for interband transition. The wavelength dispersion didn't directly reflect the dispersion of a local electric field factor. The interband transition term in hot electron contribution strongly dominated the dispersion around the surface Plasmon resonance by Fermi smearing. Intrinsic interband contribution to the nonlinearity was suggested from the analysis. Particle-size and host-medium dependence of the nonlinearity were also simulated.


Human Merkel cell regeneration in skin derived from cultured keratinocyte grafts.
Human Merkel cell regeneration in epidermis derived from cultured keratinocyte autografts was studied from 6 days to 6 years after transplantation. Cultured keratinocyte sheets derived from skin of the sole, axilla, groin, or scalp were transplanted to full-thickness wounds in 20 pediatric patients treated for massive burns or giant congenital nevi. Normal age- and site-matched skin as well as meshed split-thickness autografts from the same patients served as controls. Merkel cells were identified by immunohistochemistry using antibodies to cytokeratins #8 and #18. Cultured keratinocytes in vitro expressed no neuroendocrine markers, but nonspecific, simple-epithelial cytokeratin expression was observed in about 20% of cells. After transplantation, Merkel cells were identified only in cultured grafts derived from sole skin and appeared in the epidermis as early as 21 days postgrafting. Dermal Merkel cells were rarely observed, but their appearance invariably succeeded that of intraepidermal Merkel cells. Regenerated Merkel cells were never innervated, and their emergence was unrelated either spatially or temporally to epidermal reinnervation. In skin bridges of meshed split-thickness grafts, Merkel cells survived after degeneration of associated neurites, but no Merkel cells appeared within re-epithelialized interstices. Among the neuroendocrine markers tested, Merkel cells in cultured grafts, meshed skin grafts or normal pediatric skin expressed only neuron-specific enolase. They failed to stain for calcitonin, chromogranin A, Leu-7, synaptophysin, bombesin, or vasoactive intestinal polypeptide by immunohistochemistry. These findings suggest that: (a) Merkel cells derive from keratinocyte precursors which undergo neuroendocrine differentiation in the epidermis; (b) that keratinocyte stem cells are capable of undergoing Merkel cell differentiation postnatally; (c) that postnatal Merkel cell differentiation may be body-site dependent; and (d) that Merkel cell development and maintenance is independent of neural induction.


Immunological effects of ayahuasca in humans.
Ayahuasca is a botanical hallucinogen traditionally used by indigenous groups of the northwest Amazon. In the last decade, the use of ayahuasca has spread from Brazil, Colombia, Ecuador, and Peru to the U.S., Europe, Asia, and Africa. Despite acute and long-term evidence of good tolerability and safety for ayahuasca administered in the laboratory or ritually consumed in religious contexts, little is known about the immunological impact of ayahuasca on humans. Since ayahuasca is used by an increasing number of consumers, and considering its therapeutic potential, more information is needed regarding ayahuasca potential risks. This article presents a brief overview of the available data regarding the immunological impact of ayahuasca in humans.


Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin.
The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced β-catenin binding resulting in increased cytosolic and nuclear β-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/β-catenin signaling.


Wooden, metallic, hair, bone, and plant foreign bodies in horses: 37 cases (1990-2005).
To characterize features of diagnosis, treatment, and outcome in horses with foreign bodies, exclusive of enteric, inhaled, and foot-penetrating foreign bodies. Retrospective case series. 37 horses with foreign bodies. The incidence of equine foreign bodies from 1990 through 2005 was determined by review of data from veterinary schools participating in the Veterinary Medical Database (VMDB). Medical records of horses with foreign bodies at Purdue University were reviewed, and the following information was retrieved: clinical history; signalment; results of physical, radiographic, and ultrasonographic examinations; results of microbial culture of the draining tract or foreign body material; surgical findings; antimicrobial and anti-inflammatory treatments; and complications of the surgical procedure. Long-term follow-up information was obtained from owners or referring veterinarians. The incidence of foreign bodies in horses with records in the VMDB was 1730/10,000 horse admissions. A preoperative diagnosis of foreign bodies was confirmed via ultrasonography in most horses examined (15/17 horses) and with plain film radiography in a quarter of horses examined (7/24 horses). Wood foreign bodies were the most common (59%; 22/37), followed by metal (24%; 9/37), hair (8%; 3/37), nonsequestrum bone (5%; 2/37), and plant material (3%; 1/37). Postoperative complications associated with the foreign body were more likely to develop with wood foreign bodies (3/22) than with other types of foreign bodies (1/15). Wood was the most common penetrating foreign body in the horses in our study and was the type associated with the highest incidence of complications. Ultrasonography was more effective in locating foreign bodies than was radiography (plain and contrast) and should be performed in all horses with suspected foreign bodies.


Impact of cigarette smoking on cancer risk in the European prospective investigation into cancer and nutrition study.
Our aim was to assess the impact of cigarette smoking on the risk of the tumors classified by the International Agency for Research on Cancer as causally associated with smoking, referred to as tobacco-related cancers (TRC). The study population included 441,211 participants (133,018 men and 308,193 women) from the European Prospective Investigation Into Cancer and Nutrition. We investigated 14,563 participants who developed a TRC during an average follow-up of 11 years. The impact of smoking cigarettes on cancer risk was assessed by the population attributable fraction (AF(p)), calculated using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country. The proportion of all TRC attributable to cigarette smoking was 34.9% (95% CI, 32.5 to 37.4) using the smoking prevalence among cases and 36.2% (95% CI, 33.7 to 38.6) using the smoking prevalence from the population. The AF(p) were above 80% for cancers of the lung and larynx, between 20% and 50% for most respiratory and digestive cancers and tumors from the lower urinary tract, and below 20% for the remaining TRC. Using data on cancer incidence for 2008 and our AF(p) estimates, about 270,000 new cancer diagnoses per year can be considered attributable to cigarette smoking in the eight European countries with available data for both men and women (Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Sweden, Denmark).


Endoscopic endonasal approach for nonvestibular schwannomas.
Nonvestibular schwannomas of the skull base often represent a challenge owing to their anatomic location. With improved techniques in endoscopic endonasal skull base surgery, resection of various ventral skull base tumors, including schwannomas, has become possible. To assess the outcomes of using endoscopic endonasal approach (EEA) for nonvestibular schwannomas of the skull base. Seventeen patients operated on for skull base schwannomas by EEA at the University of Pittsburgh Medical Center from 2003 to 2009 were reviewed. Three patients underwent combined approaches with retromastoid craniectomy (n = 2) and orbitopterional craniotomy (n = 1). Three patients underwent multistage EEA. The rest received a single EEA operation. Data on degree of resection were found for 15 patients. Gross total resection (n = 9) and near-total (>90%) resection (n = 3) were achieved in 12 patients (80%). There were no tumor recurrences or postoperative cerebrospinal fluid leaks. In 3 of 7 patients with preoperative sensory deficits of trigeminal nerve distribution, there were partial improvements. Patients with preoperative reduced vision (n = 1) and cranial nerve VI or III palsies (n = 3) also showed improvement. Five patients had new postoperative trigeminal nerve deficits: 2 had sensory deficits only, 1 had motor deficit only, and 2 had both motor and sensory deficits. Three of these patients had partial improvement, but 3 developed corneal neurotrophic keratopathy. An EEA provides adequate access for nonvestibular schwannomas invading the skull base, allowing a high degree of resection with a low rate of complications.


Efficiency of treatments for controlling Trichoderma spp during spawning in cultivation of lignicolous mushrooms.
Trichoderma spp is the cause of the green mold disease in mushroom cultivation production. Many disinfection treatments are commonly applied to lignocellulose substrates to prevent contamination. Mushroom growers are usually worried about the contaminations that may occur after these treatments during handling or spawning. The aim of this paper is to estimate the growth of the green mold Trichoderma sp on lignocellulose substrates after different disinfection treatments to know which of them is more effective to avoid contamination during spawning phase. Three different treatments were assayed: sterilization (121 °C), immersion in hot water (60 and 80 °C), and immersion in alkalinized water. Wheat straw, wheat seeds and Eucalyptus or Populus sawdust were used separately as substrates. After the disinfection treatments, bagged substrates were sprayed with 3 mL of suspension of conidia of Trichoderma sp (10(5) conidia/mL) and then separately spawned with Pleurotus ostreatus or Gymnopilus pampeanus. The growth of Trichoderma sp was evaluated based on a qualitative scale. Trichoderma sp could not grow on non-sterilized substrates. Immersions in hot water treatments and immersion in alkalinized water were also unfavorable treatments for its growth. Co- cultivation with mushrooms favored Trichoderma sp growth. Mushroom cultivation disinfection treatments of lignocellulose substrates influence on the growth of Trichoderma sp when contaminations occur during spawning phase. The immersion in hot water at 60 °C for 30 min or in alkalinized water for 36 h, are treatments which better reduced the contaminations with Trichoderma sp during spawning phase for the cultivation of lignicolous species.


Cancer prevalence, incidence and mortality in people who experience incarceration in Ontario, Canada: A population-based retrospective cohort study.
Evidence suggests that many risk factors for cancer are overrepresented in people who experience incarceration, and data on cancer epidemiology are limited for this population. We aimed to describe cancer prevalence, incidence and mortality in adults admitted to provincial custody in Ontario, Canada in 2000. We linked data on 48,166 adults admitted to provincial custody in Ontario in 2000 with Ontario Cancer Registry data to 2012. We calculated cancer prevalence in the 10 years prior to admission to custody in 2000, incidence between 2000 and 2012 and mortality between 2000 and 2011. Standardized for age, we calculated incidence and mortality ratios by sex compared to the general population of Ontario. The 10-year cancer prevalence was 0.4% in men and 0.6% in women at admission to provincial custody in 2000. Between 2000 and 2012, 2.6% of men and 2.8% of women were diagnosed with new cancer. The standardized incidence ratio for cancer was 1.0 (95% CI 0.9-1.0) for men and 0.9 (95% CI 0.7-1.0) for women compared to the general population, and was significantly increased for cervical, head and neck, liver and lung cancers. The standardized mortality ratio was 1.6 (95% CI 1.4-1.7) in men and 1.4 (95% CI 1.0-1.9) in women, and was significantly increased for head and neck, liver, and lung cancers. There is an excess burden of cancer in people who experience incarceration. Cancer prevention should include people who experience incarceration, and the period of incarceration may offer an opportunity for intervention.


Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro.
Vitamin A and D analogues play an important role in epidermal homeostasis and are used in the treatment of various skin diseases. The failure of retinoid and vitamin D treatments is sometimes difficult to explain. We analyzed the effect of all-trans retinoic acid (all-trans RA), 13-cis retinoic acid (13-cis RA), ergocalciferol and cholecalciferol in keratinocyte cultures established from adult donors, on the cell proliferation by means of [(3)H]thymidine incorporation and apoptosis after fluorescein diacetate/trypan blue staining. All tested agents exerted a dose-dependent inhibition of keratinocyte proliferation in the concentration range of 1.25-5 microM. Based on IC(50) values, the antiproliferative efficiency was as follows: cholecalciferol > ergocalciferol = all-trans RA > 13-cis RA. The observed effect of cholecalciferol and ergocalciferol, but not retinoids, involved the induction of apoptotic cell death. Combining vitamins A and D did not further increase the proliferation block and even displayed an antagonistic effect. The susceptibility of keratinocytes to the antiproliferative action of vitamins A and D was markedly different in cell cultures derived from different donors, indicating a possible predictive value of the in vitro testing for the efficiency of the clinical response to these agents.


The Arabidopsis thaliana MYB60 promoter provides a tool for the spatio-temporal control of gene expression in stomatal guard cells.
Plants have evolved different strategies to resist drought, of which the best understood is the abscisic acid (ABA)-induced closure of stomatal pores to reduce water loss by transpiration. The availability of useful promoters that allow for precise spatial and temporal control of gene expression in stomata is essential both for investigating stomatal regulation in model systems and for biotechnological applications in field crops. Previous work indicated that the regulatory region of the transcription factor AtMYB60 specifically drives gene expression in guard cells of Arabidopsis, although its activity is rapidly down-regulated by ABA. Here, the activity of the full-length and minimal AtMYB60 promoters is reported in rice (Oryza sativa), tobacco (Nicotiana tabacum), and tomato (Solanum lycopersicum), using a reporter gene approach. In rice, the activity of both promoters was completely abolished, whereas it was spatially restricted to guard cells in tobacco and tomato. To overcome the negative effect of ABA on the AtMYB60 promoter, a chimeric inducible system was developed, which combined the cellular specificity of the AtMYB60 minimal promoter with the positive responsiveness to dehydration and ABA of the rd29A promoter. Remarkably, the synthetic module specifically up-regulated gene expression in guard cells of Arabidopsis, tobacco, and tomato in response to dehydration or ABA. The comparative analysis of different native and synthetic regulatory modules derived from the AtMYB60 promoter offers new insights into the functional conservation of the cis-mechanisms that mediate gene expression in guard cells in distantly related dicotyledonous species and provides novel tools for modulating stomatal activity in plants.


Exploring the potential of using cattle for malaria vector surveillance and control: a pilot study in western Kenya.
Malaria vector mosquitoes with exophilic and zoophilic tendencies, or with a high acceptance of alternative blood meal sources when preferred human blood-hosts are unavailable, may help maintain low but constant malaria transmission in areas where indoor vector control has been scaled up. This residual transmission might be addressed by targeting vectors outside the house. Here we investigated the potential of insecticide-treated cattle, as routinely used for control of tsetse and ticks in East Africa, for mosquito control. The malaria vector population in the study area was investigated weekly for 8 months using two different trapping tools: light traps indoors and cattle-baited traps (CBTs) outdoors. The effect of the application of the insecticide deltamethrin and the acaricide amitraz on cattle on host-seeking Anopheles arabiensis was tested experimentally in field-cages and the impact of deltamethrin-treated cattle explored under field conditions on mosquito densities on household level. CBTs collected on average 2.8 (95% CI: 1.8-4.2) primary [Anopheles gambiae (s.s.), An. arabiensis and An. funestus (s.s.)] and 6.3 (95% CI: 3.6-11.3) secondary malaria vectors [An. ivulorum and An. coustani (s.l.)] per trap night and revealed a distinct, complementary seasonality. At the same time on average only 1.4 (95% CI: 0.8-2.3) primary and 1.1 (95% CI: 0.6-2.0) secondary malaria vectors were collected per trap night with light traps indoors. Amitraz had no effect on survival of host-seeking An. arabiensis under experimental conditions but deltamethrin increased mosquito mortality (OR 19, 95% CI: 7-50), but only for 1 week. In the field, vector mortality in association with deltamethrin treatment was detected only with CBTs and only immediately after the treatment (OR 0.25, 95% CI: 0.13-0.52). Entomological sampling with CBTs highlights that targeting cattle for mosquito control has potential since it would not only target naturally zoophilic malaria vectors but also opportunistic feeders that lack access to human hosts as is expected in residual malaria transmission settings. However, the deltamethrin formulation tested here although used widely to treat cattle for tsetse and tick control, is not suitable for the control of malaria vectors since it causes only moderate initial mortality and has little residual activity.


Updating comparative effectiveness reviews: current efforts in AHRQ's Effective Health Care Program.
To review the current knowledge and efforts on updating systematic reviews (SRs) as applied to comparative effectiveness reviews (CERs). This article outlines considerations for updating CERs by including a definition of the updating process, describing issues around assessing whether to update, and providing general guidelines for the update process. Key points to consider include (1) identifying when to update CERs, (2) how to update CERs, and (3) how to present, report, and interpret updated results in CERs. Currently, there is little information about what proportion of SRs needs updating. Similarly, there is no consensus on when to initiate updating and how best to carry it out. CERs need to be regularly updated as new evidence is produced. Lack of attention to updating may lead to outdated and sometimes misleading conclusions that compromise health care and policy decisions. The article outlines several specific goals for future research, one of them being the development of efficient guideline for updating CERs applicable across evidence-based practice centers.


Income-targeted marketing as a supply-side barrier to low-income solar adoption.
Low- and moderate-income (LMI) households remain less likely to adopt rooftop solar photovoltaics (PV) than higher-income households. A transient period of inequitable adoption is common among emerging technologies but stakeholders are calling for an accelerated transition to equitable rooftop PV adoption. To date, researchers have focused on demand-side drivers of PV adoption inequity, but supply-side factors could also play a role. Here, we use quote data to explore whether PV installers implement income-targeted marketing and the extent to which such strategies drive adoption inequity. We find that installers submit fewer quotes to households in low-income areas and those households that receive fewer quotes are less likely to adopt. The data suggest that income-targeted marketing explains about one-quarter of the difference in PV adoption rates between LMI and higher-income households. Policymakers could explore a broader suite of interventions to address demand- and supply-side drivers of PV adoption inequity.


Emergence and establishment of Usutu virus infection in wild and captive avian species in and around Zurich, Switzerland--genomic and pathologic comparison to other central European outbreaks.
In late summer 2006 considerable mortality in wild and captive Passeriformes and Strigiformes was observed in Zurich, Switzerland. All animals were found in a range of 2 km(2). Observed clinical signs involved depression, ruffled plumage, incoordination, seizures and peracute death. Nutritional status was generally moderate to poor in wild birds, and variable in captive animals. Necropsy showed marked splenomegaly, a mild hepatomegaly, and pulmonary hyperemia in most animals. Histopathologic lesions were very discrete and consisted mainly of neuronal necrosis, leucocytolysis in and around the brain blood vessels, and miliary liver necrosis. The diagnosis Usutu virus (USUV) infection was established by USUV-specific immunohistochemistry and reverse transcription-polymerase chain reaction. Partial nucleotide sequence comparisons revealed>99% identity between the viruses that emerged in Zurich in 2006, in Vienna in 2001, and in Budapest in 2005. Since 2008 a significantly lower mortality was observed in wild Passeriformes, but USUV infection was confirmed for the first time beyond Zurich city limits. Indoor housing and regular treatment against ectoparasites are likely to have prevented acute USUV disease in captive Strigiformes. USUV is a mosquito-borne flavivirus causing fatalities in various avian species. After the initial European outbreaks in Austria in 2001 it appears that the virus has extended its range in Central Europe and has established a transmission cycle between local bird and mosquito species. Further episodes of increased avian mortality in the forthcoming years, with impact on wild and captive bird populations, predominantly Passeriformes and Strigiformes, can be anticipated. Furthermore, the possibility of broader dispersal of USUV in Europe during the next mosquito seasons must be considered and an increased mortality in Passeriformes and Strigiformes must be expected until protective "flock immunity" is established. Collections of valuable and endangered Passeriformes and Strigiformes, especially young of the year, should therefore be housed indoors or treated against ectoparasites at acceptable intervals between July and September each year.


Optical phase erasure and its application to format conversion through cascaded second-order processes in periodically poled lithium niobate.
We describe a new optical phase erasure characteristic of periodically poled lithium niobate (PPLN) by using cascaded second-harmonic generation and difference-frequency generation with the signal set at the quasi-phase-matching wavelength. A simple analytical expression is derived clearly explaining the operation principle. It is interesting that the optical phase erasure feature enables an all-optical format conversion from carrier-suppressed return to zero (CSRZ) to return to zero (RZ). We experimentally and theoretically demonstrate a PPLN-based 40 Gbits/s all-optical CSRZ-to-RZ format conversion. Moreover, tunable and multicasting CSRZ-to-RZ format conversions are also verified in the experiment.


Efficient transformation of Bacillus thuringiensis requires nonmethylated plasmid DNA.
The transformation efficiency of Bacillus thuringiensis depends upon the source of plasmid DNA. DNA isolated from B. thuringiensis, Bacillus megaterium, or a Dam- Dcm- Escherichia coli strain efficiently transformed several B. thuringiensis strains, B. thuringiensis strains were grouped according to which B. thuringiensis backgrounds were suitable sources of DNA for transformation of other B. thuringiensis strains, suggesting that B. thuringiensis strains differ in DNA modification and restriction. Efficient transformation allowed the demonstration of developmental regulation of cloned crystal protein genes in B. thuringiensis.


Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin.
Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of angiostatin action remains unknown, identification of F(1)-F(O) ATP synthase as the major angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the angiostatin response. Previous studies noting the presence of F(1) ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F(1) ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by angiostatin as well as by antibodies directed against the alpha- and beta-subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics.


Importance of cycle timing for the function of the molecular chaperone Hsp90.
Hsp90 couples ATP hydrolysis to large conformational changes essential for activation of client proteins. The structural transitions involve dimerization of the N-terminal domains and formation of 'closed states' involving the N-terminal and middle domains. Here, we used Hsp90 mutants that modulate ATPase activity and biological function as probes to address the importance of conformational cycling for Hsp90 activity. We found no correlation between the speed of ATP turnover and the in vivo activity of Hsp90: some mutants with almost normal ATPase activity were lethal, and some mutants with lower or undetectable ATPase activity were viable. Our analysis showed that it is crucial for Hsp90 to attain and spend time in certain conformational states: a certain dwell time in open states is required for optimal processing of client proteins, whereas a prolonged population of closed states has negative effects. Thus, the timing of conformational transitions is crucial for Hsp90 function and not cycle speed.


Silencing steroid receptor coactivator-1 in the nucleus of the solitary tract reduces estrogenic effects on feeding and apolipoprotein A-IV expression.
We previously found that 17β-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.


Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.
Generation of new HIV-1 virions requires the constant supply of proteins, nucleotides, and energy; however, it is not known which cellular pathways are perturbed and what molecular mechanisms are employed. We hypothesized that HIV-1 may regulate pathways that control synthesis of biomolecules in the cell. In this study, we provide evidence that HIV-1 hyperactivates mammalian target of rapamycin complex 1 (mTORC1), the central regulator of biosynthesis. Mechanistically, we identify the viral regulatory gene tat (transactivator) as being responsible for increasing mTORC1 activity in a PI3K-dependent manner. Furthermore, we show that hyperactivation of mTORC1 leads to activation of the enzyme, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase, and repression of initiation factor 4E-binding protein 1 activity. These are regulators of nucleotide biogenesis and protein translation, respectively. Moreover, we are able to replicate these results in HIV-1 latent cell line models. Finally, we show that inhibition of mTORC1 or PI3K inhibits viral replication and viral reactivation as a result of a decrease in biosynthesis. Overall, our study identifies a new avenue in HIV-1 biology that can lead to development of novel therapeutic targets.-Kumar, B., Arora, S., Ahmed, S., Banerjea, A. C. Hyperactivation of mammalian target of rapamycin complex 1 by HIV-1 is necessary for virion production and latent viral reactivation.


Risk and Outcomes: Are Adolescents Charged with Sex Offenses Different from Other Adolescent Offenders?
Juveniles who have committed sexual offenses are subject to specialized treatment and policies based on their assumed unique dangerousness, despite contradictory evidence. Limited information is available regarding risk factors and their relationships to outcomes in this population. The comparative frequency and predictive utility of empirically supported risk factors for general delinquency were examined using data from the Pathways to Desistance study. Adolescent males who committed sexual offenses (n = 127) were compared to adolescent males who committed non-sexual offenses (n = 1021). At the start of the study, the sample ranged in age from 14 to 18 (M = 16.00, SD = 1.12) and self-identified as primarily African American (44 %), Latino (29 %), or White (25 %). Outcomes were measured over 7 years and included general and sexual recidivism, involvement in school and work, and positive relationships with peers and adults. The results indicated a few small differences in the presence of risk factors and their relationship to outcomes, with many similarities. Juveniles who have committed sexual offenses had equivalent general recidivism but higher sexual recidivism, though this rate was low (7.87 %, or 10 of the 127 adolescents who had committed sexual offenses). New clinical and policy approaches may be needed given the similarities between groups.


Further evidence of Chelonid herpesvirus 5 (ChHV5) latency: high levels of ChHV5 DNA detected in clinically healthy marine turtles.
The Chelonid herpesvirus 5 (ChHV5) has been consistently associated with fibropapillomatosis (FP), a transmissible neoplastic disease of marine turtles. Whether ChHV5 plays a causal role remains debated, partly because while FP tumours have been clearly documented to contain high concentrations of ChHV5 DNA, recent PCR-based studies have demonstrated that large proportions of asymptomatic marine turtles are also carriers of ChHV5. We used a real-time PCR assay to quantify the levels of ChHV5 Glycoprotein B (gB) DNA in both tumour and non-tumour skin tissues, from clinically affected and healthy turtles drawn from distant ocean basins across four species. In agreement with previous studies, higher ratios of viral to host DNA were consistently observed in tumour versus non-tumour tissues in turtles with FP. Unexpectedly however, the levels of ChHV5 gB DNA in clinically healthy turtles were significantly higher than in non-tumour tissues from FP positive turtles. Thus, a large proportion of clinically healthy sea turtle populations worldwide across species carry ChHV5 gB DNA presumably through persistent latent infections. ChHV5 appears to be ubiquitous regardless of the animals' clinical conditions. Hence, these results support the theory that ChHV5 is a near ubiquitous virus with latency characteristics requiring co-factors, possibly environmental or immune related, to induce FP.


THE FIBRINOLYTIC ACTIVITY OF HEMOLYTIC STREPTOCOCCI.
Broth cultures of hemolytic streptococci derived from patients are capable of rapidly liquefying normal human fibrin clot. The active fibrinolytic principle is also contained in sterile, cell-free filtrates of broth cultures. The degree of activity of filtrates parallels the activity of whole broth cultures sufficiently closely to indicate that large amounts of the fibrinolytic substance are freely excreted into the surrounding medium and pass readily through Berkefeld V, Seitz, and Chamberland filters. The occurrence of fibrinolysis is most strikingly observed when plasma or fibrinogen is mixed with active cultural material before clot formation is effected. Under the standard experimental conditions described, complete dissolution of human plasma clot (whole oxalated plasma + CaCl(2)) occurs in about 10 minutes; complete dissolution of human fibrinogen clot (chemically isolated fibrinogen + thrombin) takes place in about 2 minutes. Titration of filtrate activity is recorded in Table IV. Twenty-eight strains of Streptococcus hemolyticus, isolated from patients suffering from various manifestations of streptococcus infection, have been tested for the capacity to liquefy fibrin clot. Broth cultures of all of the strains induced fibrinolysis. Of 18 strains of Streptococcus hemolyticus of animal origin, only three were capable of causing dissolution of clot. Completely negative results were obtained with 38 strains of other bacterial species. The list is presented on pages 492 and 493. The plasma of many patients recovered from acute hemolytic streptococcus infections, when clotted in the presence of active cultures, is highly resistant to fibrinolysis. Furthermore, serum, derived from patients whose plasma clot is resistant, often confers on normal plasma clot an antifibrinolytic property. One example of the resistance possessed by the blood of convalescent patients is presented in this report. A second paper, now in preparation, will give in detail a large number of observations on the relation of infection to the development of resistance to the fibrinolytic activity of hemolytic streptococci. In contrast to the susceptibility of normal human fibrin clot to liquefaction by active culture, normal rabbit fibrin clot is totally resistant to dissolution when tested under comparable conditions. The insusceptibility of rabbit fibrin clot is manifest provided the coagulum is composed of rabbit constituents. When human thrombin is used to clot rabbit plasma or fibrinogen in the presence of active cultures, fibrinolysis is not prohibited. The rôle of thrombin in determining the resistance or susceptibility of rabbit fibrin to dissolution offers a suggestive approach to problems relating to the underiving mechanism.


A neural basis for real-world visual search in human occipitotemporal cortex.
Mammals are highly skilled in rapidly detecting objects in cluttered natural environments, a skill necessary for survival. What are the neural mechanisms mediating detection of objects in natural scenes? Here, we use human brain imaging to address the role of top-down preparatory processes in the detection of familiar object categories in real-world environments. Brain activity was measured while participants were preparing to detect highly variable depictions of people or cars in natural scenes that were new to the participants. The preparation to detect objects of the target category, in the absence of visual input, evoked activity patterns in visual cortex that resembled the response to actual exemplars of the target category. Importantly, the selectivity of multivoxel preparatory activity patterns in object-selective cortex (OSC) predicted target detection performance. By contrast, preparatory activity in early visual cortex (V1) was negatively related to search performance. Additional behavioral results suggested that the dissociation between OSC and V1 reflected the use of different search strategies, linking OSC preparatory activity to relatively abstract search preparation and V1 to more specific imagery-like preparation. Finally, whole-brain searchlight analyses revealed that, in addition to OSC, response patterns in medial prefrontal cortex distinguished the target categories based on the search cues alone, suggesting that this region may constitute a top-down source of preparatory activity observed in visual cortex. These results indicate that in naturalistic situations, when the precise visual characteristics of target objects are not known in advance, preparatory activity at higher levels of the visual hierarchy selectively mediates visual search.


Single-molecule trapping dynamics of sugar-uptake channels in marine bacteria.
Stochastic fluctuations of ion current through one chitoporin (ChiP) channel within a bilayer lipid membrane in sugar solution are analyzed. These reflect single-molecule dynamics, which indicate that ChiP has multiple binding sites for sugar and exploits interactions between bound molecules to direct sugar passage. Since ChiP is used by marine bacteria, this is likely an adaptive strategy to enhance sugar translocation from rough water.


In vitro assessment of the Lenz effect on heart valve prostheses at 1.5 T.
Increasing numbers of patients with cardiac valve prostheses are being referred for magnetic resonance imaging (MRI) despite concerns about the potential for functional valve impedance due to Lenz forces. This study aims to determine, in vitro, the occurrence of Lenz forces on 9 heart valve prostheses at 1.5 T and assess the risk of impedance of valve function. A specially designed hydro-pneumatic system was used to record pressure changes across the valve indicative of any MR induced alteration in leaflet performance. Nine cardiac valve prostheses were exposed to the B0 field at 1.5 T. Each valve was advanced through the B0 field and continuous signals from high frequency pressure transducers were recorded and pressure drops across the valve were assessed using time correction superimposition. The delta p across the valve was assessed as a marker of any MRI induced alteration in leaflet performance. All prostheses produced sinusoidal waveforms. Profiles were asymmetrical and there was no consistency in complex shape and valve type/sub-group. Irregularities in pressure profiles of 4 prostheses were detected indicating resistance of the occluder to the B0 field. This study provides empirical evidence of the Lenz Effect on cardiac valve prostheses exposed to the MR B0 field causing functional valve impedance and increasing the risk of valvular regurgitation and reduced cardiac output. Thus, it is essential to consider the potential for the Lenz Effect when scanning cardiac valve implant patients in order to safeguard their wellbeing.


Coupling in silico and in vitro analysis of peptide-MHC binding: a bioinformatic approach enabling prediction of superbinding peptides and anchorless epitopes.
The ability to define and manipulate the interaction of peptides with MHC molecules has immense immunological utility, with applications in epitope identification, vaccine design, and immunomodulation. However, the methods currently available for prediction of peptide-MHC binding are far from ideal. We recently described the application of a bioinformatic prediction method based on quantitative structure-affinity relationship methods to peptide-MHC binding. In this study we demonstrate the predictivity and utility of this approach. We determined the binding affinities of a set of 90 nonamer peptides for the MHC class I allele HLA-A*0201 using an in-house, FACS-based, MHC stabilization assay, and from these data we derived an additive quantitative structure-affinity relationship model for peptide interaction with the HLA-A*0201 molecule. Using this model we then designed a series of high affinity HLA-A2-binding peptides. Experimental analysis revealed that all these peptides showed high binding affinities to the HLA-A*0201 molecule, significantly higher than the highest previously recorded. In addition, by the use of systematic substitution at principal anchor positions 2 and 9, we showed that high binding peptides are tolerant to a wide range of nonpreferred amino acids. Our results support a model in which the affinity of peptide binding to MHC is determined by the interactions of amino acids at multiple positions with the MHC molecule and may be enhanced by enthalpic cooperativity between these component interactions.


Estimating the prevalence of atrial fibrillation from a three-class mixture model for repeated diagnoses.
Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and irregular heartbeat, with or without perceivable symptoms. In clinical practice, the electrocardiogram (ECG) is often used for diagnosis of AF. Since the AF often arrives as recurrent episodes of varying frequency and duration and only the episodes that occur at the time of ECG can be detected, the AF is often underdiagnosed when a limited number of repeated ECGs are used. In studies evaluating the efficacy of AF ablation surgery, each patient undergoes multiple ECGs and the AF status at the time of ECG is recorded. The objective of this paper is to estimate the marginal proportions of patients with or without AF in a population, which are important measures of the efficacy of the treatment. The underdiagnosis problem is addressed by a three-class mixture regression model in which a patient's probability of having no AF, paroxysmal AF, and permanent AF is modeled by auxiliary baseline covariates in a nested logistic regression. A binomial regression model is specified conditional on a subject being in the paroxysmal AF group. The model parameters are estimated by the Expectation-Maximization (EM) algorithm. These parameters are themselves nuisance parameters for the purpose of this research, but the estimators of the marginal proportions of interest can be expressed as functions of the data and these nuisance parameters and their variances can be estimated by the sandwich method. We examine the performance of the proposed methodology in simulations and two real data applications.


The first reported case of non-compacted cardiomyopathy in a preterm infant with Ebstein's anomaly.
Non-compaction of the ventricular myocardium is a congenital dysfunction of ventricular morphogenesis caused by the arrest of normal embryogenesis of the ventricles. It is considered as a rare disease and can involve both ventricles but commonly the left ventricle. It is classified into isolated non-compaction of the ventricles and non-compaction associated with other congenital heart defects. Its association with Ebstein's anomaly is very rare. We are reporting a rare case of severe heart failure and complex cardiac anomaly including biventricular non-compaction cardiomyopathy, Ebstein's anomalies and large patent ductus arteriosus with severe persistent pulmonary hypertension in a 31-weeks-old preterm infant. The infant recovered smoothly and continued to be asymptomatic and off medications throughout his 2 years follow-up period. Up to our knowledge, this is the youngest and first patient yet reported to have this disease at this age with good recovery.


The role of patient-physician trust in moderating medication nonadherence due to cost pressures.
Prescription drug costs constitute a burden for many chronically ill adults and are strongly related to patients' likelihood of using less medication than prescribed. We examined the extent to which patients' trust in their physicians may moderate the impact of economic constraints and other risk factors for cost-related adherence problems. A total of 912 patients with diabetes recruited from 5 Veterans Affairs health systems completed a detailed cross-sectional survey. Patients reported their level of physician trust using a standard scale and were stratified into high-trust (n = 557) and low-trust (n = 355) groups. We fit multivariate logistic regression models with terms characterizing the interactions between physician trust and (1) patients' out-of-pocket medication costs and (2) patients' income, as well as other possible risk factors for cost-related underuse. Patients with higher out-of-pocket costs were more likely to forgo medications because of cost pressures when physician trust levels were low. Having a low income was only associated with cost-related adherence problems in the context of low physician trust. Patients who reported medication underuse for reasons other than cost were 4 times as likely as other patients to also report cost-related underuse, and those with significant depressive symptoms had more than twice the risk of cost-related underuse compared with those without depression (both P<.05). These findings suggest that a trusting physician relationship may moderate the impact of cost pressures on patients' medication adherence. More generally, addressing noncost barriers to adherence may reduce rates of cost-related medication underuse.


EEG differences between eyes-closed and eyes-open resting conditions.
Recent work has attempted to clarify the energetics of physiological responding and behaviour by refining and separating the operational definitions of "arousal" and "activation", which have different effects on physiological responding and behaviour. At the EEG level, we relate the former to widespread activity, and the latter to task-specific topographically-focussed activity reflecting regional processing. This study aimed to investigate this further in terms of differences in EEG activity between eyes-closed and eyes-open resting conditions. EEG activity was recorded from 28 university students during both eyes-closed and eyes-open resting conditions, Fourier transformed to provide estimates for absolute power in the delta, theta, alpha and beta bands, and analysed in 9 regions across the scalp. Skin conductance level was also measured as an indicator of arousal level. Across the eyes-closed conditions, skin conductance levels were negatively correlated with mean alpha levels. Skin conductance levels increased significantly from eyes-closed to eyes-open conditions. Reductions were found in across-scalp mean absolute delta, theta, alpha and beta from the eyes-closed to eyes-open condition. Topographic changes were also evident in all bands except for alpha, with reduced lateral frontal delta and posterior theta, and decreased posterior/increased frontal beta in the eyes-open condition. In particular, the topographic beta effects indicate that the across-scalp reduction arose from focal reductions rather than global changes. The obtained results confirm the use of mean alpha level as a measure of resting-state arousal under eyes-closed and eyes-open conditions. The focal nature of EEG effects in the other bands suggests that these reflect cortical processing of visual input, producing differences in activation between eyes-closed and eyes-open resting conditions, rather than just the simple increase in arousal level shown in alpha. This study demonstrates that the eyes-closed and eyes-open conditions provide EEG measures differing in topography as well as power levels. These differences should be recognised when evaluating EEG research, and considered when choosing eyes-open or eyes-closed baseline conditions for different paradigms.


Assessment of erythrocyte damage and in-line pressure changes associated with simulated transfusion of canine blood through microaggregate filters.
To determine whether passage of whole blood through a microaggregate filter by use of a syringe pump would damage canine erythrocytes. Blood samples obtained from 8 healthy client-owned dogs. Whole blood was passed through a standard microaggregate filter by use of a syringe pump at 3 standard administration rates (12.5, 25, and 50 mL/h). Prefilter and postfilter blood samples were collected at the beginning and end of a simulated transfusion. Variables measured at each time point included erythrocyte osmotic fragility, mean corpuscular fragility, RBC count, hemoglobin concentration, RBC distribution width, and RBC morphology. In-line pressure when blood passed through the microaggregate filter was measured continuously throughout the simulated transfusion. After the simulated transfusion was completed, filters were visually analyzed by use of scanning electron microscopy. Regardless of administration rate, there was no significant difference in mean corpuscular fragility, RBC count, hemoglobin concentration, or RBC distribution width between prefilter and postfilter samples. Additionally, there were no differences in in-line pressure during the simulated transfusion among administration rates. Echinocytes were the erythrocyte morphological abnormality most commonly observed at the end of the transfusion at administration rates of 12.5 and 25 mL/h. Results suggested that regardless of the administration rate, the microaggregate filter did not alter fragility of canine RBCs, but may have altered the morphology. It appeared that the microaggregate filter would not contribute to substantial RBC damage for transfusions performed with a syringe pump.


Ketene as a Reaction Intermediate in the Carbonylation of Dimethyl Ether to Methyl Acetate over Mordenite.
Unprecedented insight into the carbonylation of dimethyl ether over Mordenite is provided through the identification of ketene (CH2CO) as a reaction intermediate. The formation of ketene is predicted by detailed DFT calculations and verified experimentally by the observation of doubly deuterated acetic acid (CH2DCOOD), when D2O is introduced in the feed during the carbonylation reaction.


Urinary pH as a determinant of prostaglandin E2 excretion by the conscious rat.
The urinary excretion of prostaglandin E2 (PGE2) was measured in conscious rats under conditions which produced either acid or alkaline urine, but a similar change in fluid and solute excretion. Oral isotonic saline increased both urine flow and sodium excretion but did not alter urinary PGE2 output (which remained constant at 80 pmol/3 h per rat) or urine pH (6.2). When the urine was made alkaline (pH 7.8) by oral sodium bicarbonate or carbonate, urinary PGE2 was approximately 3-fold greater (P less than 0.001) than the control (pH 6.2). The urine flow and sodium output were also increased. When the urine was made acidic (pH 5.7) by oral ammonium chloride, urinary PGE2 excretion was reduced (P less than 0.01) to approximately half the control output. The urine flow and sodium output increased. Within a group of 12 rats receiving oral isotonic saline a positive linear correlation coefficient (P less than 0.002) was established between urine pH and PGE2 excretion. The results indicate that urine pH may be a determinant of PGE2 excretion in unrestrained, conscious rats. It seems likely that this effect of pH is mediated by a change in the passive reabsorption of PGE2 in the distal nephron, although alternative explanations such as altered tubular secretion or synthesis cannot be categorically excluded.


Screening for Colorectal Cancer and Evolving Issues for Physicians and Patients: A Review.
Colorectal cancer (CRC) is the second-leading cause of cancer death in the United States. Screening can reduce CRC mortality and incidence, and numerous screening options, although available, complicate informed decision making. This review provides evidence-based tools for primary care physicians to identify patients with higher-than-average-risk and engage patients in informed decision making about CRC screening options. Recently, the US Preventive Services Task Force recommended any of 8 CRC screening approaches for average-risk individuals, beginning at age 50 years. Only 2 methods have been shown in randomized clinical trials to reduce mortality: fecal occult blood testing and flexible sigmoidoscopy. Of the 8 programs, screenings using the fecal immunochemical test annually and colonoscopy every 10 years are now the most commonly used tests in the United States and among the most effective in reducing CRC mortality as determined by decision models. With the exception of primary screening using colonoscopy, all of the other screening approaches have multiple steps. Adherence to each phase of a multistep program is critical to achieving maximal effectiveness of the screening program. It is likely that each of the recommended programs can reduce CRC mortality, but other key outcomes may differ such as lifetime burden of colonoscopy, complications, patient acceptance, and cost. Decisions about the timing of screening cessation should be individualized. CRC screening is effective if patients adhere to the steps in each screening program. There is no evidence that one program is superior to another. Informed decision-making tools are provided to assist patients and clinicians with the goal of improving adherence to effective screening.


Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.
Using the photopigment melanopsin, intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light to drive circadian clock resetting and pupillary constriction. We now report that ipRGCs are more abundant and diverse than previously appreciated, project more widely within the brain, and can support spatial visual perception. A Cre-based melanopsin reporter mouse line revealed at least five subtypes of ipRGCs with distinct morphological and physiological characteristics. Collectively, these cells project beyond the known brain targets of ipRGCs to heavily innervate the superior colliculus and dorsal lateral geniculate nucleus, retinotopically organized nuclei mediating object localization and discrimination. Mice lacking classical rod-cone photoreception, and thus entirely dependent on melanopsin for light detection, were able to discriminate grating stimuli from equiluminant gray and had measurable visual acuity. Thus, nonclassical retinal photoreception occurs within diverse cell types and influences circuits and functions encompassing luminance as well as spatial information.


investigating acid production by Streptococcus mutans with a surface-displayed pH-sensitive green fluorescent protein.
Acidogenicity and aciduricity are the main virulence factors of the cavity-causing bacterium Streptococcus mutans. Monitoring at the individual cell level the temporal and spatial distribution of acid produced by this important oral pathogen is central for our understanding of these key virulence factors especially when S. mutans resides in multi-species microbial communities. In this study, we explored the application of pH-sensitive green fluorescent proteins (pHluorins) to investigate these important features. Ecliptic pHluorin was functionally displayed on the cell surface of S. mutans as a fusion protein with SpaP. The resulting strain (O87) was used to monitor temporal and spatial pH changes in the microenvironment of S. mutans cells under both planktonic and biofilm conditions. Using strain O87, we revealed a rapid pH drop in the microenviroment of S. mutans microcolonies prior to the decrease in the macro-environment pH following sucrose fermentation. Meanwhile, a non-uniform pH distribution was observed within S. mutans biofilms, reflecting differences in microbial metabolic activity. Furthermore, strain O87 was successfully used to monitor the S. mutans acid production profiles within dual- and multispecies oral biofilms. Based on these findings, the ecliptic pHluorin allows us to investigate in vivo and in situ acid production and distribution by the cariogenic species S. mutans.


Decompressive craniectomy or medical management for refractory intracranial hypertension: an AAST-MIT propensity score analysis.
Moderate/severe traumatic brain injury (TBI) management involves minimizing cerebral edema to maintain brain oxygen delivery. While medical therapy (MT) consisting of diuresis, hyperosmolar therapy, ventriculostomy, and barbiturate coma is the standard of care, decompressive craniectomy (DC) for refractory intracranial hypertension (ICH) has gained renewed interest. Since TBI treatment guidelines consider DC a second-tier intervention after MT failure, we sought to determine if early DC (<48 hours) was associated with improved survival in patients with refractory ICH. Eleven Level 1 trauma centers provided clinical data and head computed tomographic scans for patients with a Glasgow Coma Scale (GCS) score of 13 or less and radiographic evidence of TBI excluding deaths within 48 hours. Computed tomographic scans were graded according to the Marshall classification. A propensity score to receive DC (regardless of whether DC was performed) was calculated for each patient based on patient characteristics, physiology, injury severity, GCS, severity of intracranial injury, and treatment center. Patients who actually received a DC were matched to patients with similar propensity scores who received MT for analysis. Outcomes were compared between early (<48 hours of injury) primary or secondary DC and matched controls and then between early primary DC only and matched controls. There were 2,602 patients who met the inclusion criteria ,of whom 264 (10.1%) received DC (either primary or secondary to another cranial procedure) and 109 (5%) had a DC that was primary. Variables associated with performing a DC included sex, race, intracranial pressure monitor placement, in-house trauma attending, traumatic subarachnoid hemorrhage, midline shift, and basal cistern compression. There was no survival benefit with early primary DC compared with the controls (relative risk, 1.07; 95% confidence interval, 0.67-1.73; p = 0.77), and resource use was higher. Early DC does not seem to significantly improve mortality in patients with refractory ICH compared with MT. Neurosurgeons should pause before entertaining this resource-demanding form of therapy. Therapeutic care/management, level III.


Intergenerational transmission of ethnic identity and life satisfaction of Roma minority adolescents and their parents.
This study investigates intergeneration transmission of ethnic identity as a resource for life satisfaction of Roma adolescents and their parents. Historically, Roma represent the largest ethnic minority in Europe. They have been exposed to severe discrimination, social exclusion, and poverty. Therefore, identifying resources for their life satisfaction is theoretically and practically important. The present study included 1093 participants, of which there were 171 Roma adolescents (age: M = 14.96 years, SD = 1.85), 155 mothers (age: M = 36.16 years, SD = 5.77) and 123 fathers (age: M = 39.68 years, SD = 6.06). Further, a comparison group of 248 mainstream adolescents with their mothers (n = 221) and fathers (n = 175) was also included in the study. Adolescents and their parents provided data on ethnic identity (MEIM; Phinney, 1992) and life satisfaction (SWLS; Diener, Emmons, Larsen, & Griffin, 1985). Results indicated that Roma youth were lower on endorsement of ethnic identity and average on life satisfaction compared to their mainstream peers. A structural equation model showed that ethnic identity was a positive predictor of life satisfaction for both adolescents and their Roma parents. Furthermore, parents' ethnic identity was a predictor of adolescent life satisfaction. We concluded that for Roma youth and their parents, ethnic identity represents a salient source for life satisfaction and an intergenerational continuity of identity and life satisfaction exists.


A complication following ACL reconstruction using bioabsorbable cross-pins.
This is a case of a proximal pin migration after ACL reconstruction in medial soft tissue with pain, inflammatory reaction and functional reduction. 33-year-old male presented at our clinic with a complete ACL rupture. Reconstruction with autogenous gracilis and semitendinosus hamstring tendons was performed and graft fixed in the femoral canal with two PLLA bioabsorbable pins (RIGIDFIX® Cross Pin System). Two months postoperatively the patient presented swelling and pain on the medial side of the knee, full range of motion and negative results at the Lachman and Pivot shift tests. MRI examination showed the superior femoral tunnel crossing both the lateral and medial cortex lodging the pin in the knee's medial soft tissue corresponding to the swelling area reported by the patient. The tendon graft was properly positioned. After surgical removal of the pin through a small skin incision, the pain and swelling promptly subsided allowing the patient return to normal activities in few weeks without any pain. In our opinion the painful swelling of the knee was due to a displacement of the pin that had been accidentally lodged in the soft tissues instead of the bone causing a foreign-body reaction resulting in granuloma formation with local inflammation. This dislodgement could have been due to an inappropriately long femoral tunnel.


Risks of hormonally active pharmaceuticals to amphibians: a growing concern regarding progestagens.
Most amphibians breed in water, including the terrestrial species, and may therefore be exposed to water-borne pharmaceuticals during critical phases of the reproductive cycle, i.e. sex differentiation and gamete maturation. The objectives of this paper were to (i) review available literature regarding adverse effects of hormonally active pharmaceuticals on amphibians, with special reference to environmentally relevant exposure levels and (ii) expand the knowledge on toxicity of progestagens in amphibians by determining effects of norethindrone (NET) and progesterone (P) exposure to 0, 1, 10 or 100 ng l(-1) (nominal) on oogenesis in the test species Xenopus tropicalis. Very little information was found on toxicity of environmentally relevant concentrations of pharmaceuticals on amphibians. Research has shown that environmental concentrations (1.8 ng l(-1)) of the pharmaceutical oestrogen ethinylestradiol (EE2) cause developmental reproductive toxicity involving impaired spermatogenesis in frogs. Recently, it was found that the progestagen levonorgestrel (LNG) inhibited oogenesis in frogs by interrupting the formation of vitellogenic oocytes at an environmentally relevant concentration (1.3 ng l(-1)). Results from the present study revealed that 1 ng NET l(-1) and 10 ng P l(-1) caused reduced proportions of vitellogenic oocytes and increased proportions of previtellogenic oocytes compared with the controls, thereby indicating inhibited vitellogenesis. Hence, the available literature shows that the oestrogen EE2 and the progestagens LNG, NET and P impair reproductive functions in amphibians at environmentally relevant exposure concentrations. The progestagens are of particular concern given their prevalence, the range of compounds and that several of them (LNG, NET and P) share the same target (oogenesis) at environmental exposure concentrations, indicating a risk for adverse effects on fertility in exposed wild amphibians.


Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer's Disease and Vascular Dementia: A Cross-Sectional Study.
Objectives: Cystatin C (Cys C) and high-density lipoprotein (HDL) play critical roles in neurodegenerative diseases, such as dementia, Alzheimer's disease (AD) and vascular dementia (VaD). However, whether they can be used as reliable biomarkers to distinguish patients with dementia from healthy subjects and to determine disease severity remain largely unknown. Methods: We conducted a cross-sectional study to determine plasma Cys C and HDL levels of 88 patients with dementia (43 AD patients, 45 VaD patients) and 45 healthy age-matched controls. The severity of dementia was determined based on the Schwab and England Activities of Daily Living (ADL) Scale, the Mini-mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Lawton Instrumental ADL (IADL) Scale, and the Hachinski Ischemia Scale (Hachinski). Receiver operating characteristic (ROC) curves were calculated to determine the diagnostic accuracy of Cys C and HDL levels in distinguishing patients with dementia from healthy subjects. Results: We found that plasma Cys C levels were higher, but HDL levels were lower in AD and VaD patients respectively, compared to healthy control subjects. Yet, Cys C levels were highest among patients with VaD. Interestingly, plasma Cys C levels were significantly correlated with IADL Scale scores. In addition, the ROC curves for Cys C (area under the curve, AUC 0.816 for AD, AUC 0.841 for VaD) and HDL (AUC 0.800 for AD, AUC 0.731 for VaD) exhibited potential diagnostic value in distinguishing AD/VaD patients from healthy subjects. While the ROC curve for the combination of Cys C and HDL (AUC 0.873 for AD, AUC 0.897 for VaD) showed higher diagnostic accuracy in distinguishing AD/VaD patients from healthy subjects than the separate curves for each parameter. Conclusions: Our findings suggest that the inflammatory mediators Cys C and HDL may play important roles in the pathogenesis of dementia, and plasma Cys C and HDL levels may be useful screening tools for differentiating AD/VaD patients from healthy subjects. Plasma Cys C levels were higher in patients with AD/VaD than in healthy subjects.Plasma HDL levels were lower in patients with AD/VaD than in healthy subjects.Plasma Cys C levels were significantly correlated with dementia.The ROC curve for the combination of Cys C and HDL showed potential diagnostic value in distinguishing AD/VaD from healthy subjects.


An Information-Based Approach for Mediation Analysis on High-Dimensional Metagenomic Data.
The human microbiome plays a critical role in the development of gut-related illnesses such as inflammatory bowel disease and clinical pouchitis. A mediation model can be used to describe the interaction between host gene expression, the gut microbiome, and clinical/health situation (e.g., diseased or not, inflammation level) and may provide insights into underlying disease mechanisms. Current mediation regression methodology cannot adequately model high-dimensional exposures and mediators or mixed data types. Additionally, regression based mediation models require some assumptions for the model parameters, and the relationships are usually assumed to be linear and additive. With the microbiome being the mediators, these assumptions are violated. We propose two novel nonparametric procedures utilizing information theory to detect significant mediation effects with high-dimensional exposures and mediators and varying data types while avoiding standard regression assumptions. Compared with available methods through comprehensive simulation studies, the proposed method shows higher power and lower error. The innovative method is applied to clinical pouchitis data as well and interesting results are obtained.


Relationship between duration of brain death and hemodynamic (in)stability on progressive dysfunction and increased immunologic activation of donor kidneys.
Consistent difference in graft survival after renal transplantation has been shown when cadaveric transplants are compared to the living related donor situation, in favor of the latter. Recently, evidence has been put forward that brain death has significant effects on the donor organ quality. In this study, we aimed to assess the relation between brain death-induced hemodynamic instability in combination with the duration of brain death on the function and immunogenicity status of potential donor kidneys. In Wistar rats, short-term (1 hour) or long-term (6 hours) brain death in the presence or absence of hemodynamic stability was applied. Sham-operated rats served as controls (1 hour and 6 hours). Organ function was studied by monitoring serum creatinine, lactate dehydrogenase (LDH), lactate, and total protein content. Expression of cell adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)] and the influx of leukocytes in the kidney assessed the immunologic status of the kidney. Progressive organ dysfunction was most pronounced in hemodynamically unstable brain-dead donors reflected by increased serum creatinine levels. Regardless of hemodynamic status, a progressive inflammatory activation by cell adhesion molecule expression and an influx of leukocytes could be observed in kidneys of brain-dead rats compared with nonbrain-dead controls. Brain death causes progressive kidney dysfunction. Also, inflammatory responses reflecting tissue injury are caused by brain death. When hemodynamic instability in the brain-dead donor is not corrected, kidney dysfunction is enhanced and immune activation occurs faster and is more profound. The observed changes may predispose the graft for additional ischemia/reperfusion injury during the transplant process and hence accelerate rejection of the graft after transplantation.


An assessment of measures to predict the outcome of driving evaluations in patients with cerebral damage.
The evaluation of the ability of patients to return to driving after cerebral damage stands out as one of the most important tasks confronted by rehabilitation professionals. The present study was designed to critically assess evaluations that were developed at one facility to determine fitness to drive: an offroad, predriver evaluation of skills regarded as important in driving and an on-road, behind-the-wheel evaluation of abilities needed to drive in actual traffic situations. The evaluation results of 3-patients with cerebral damage due to traumatic head injury or cerebrovascular accident were studied retrospectively. Only 4 out of 21 items on the predriver evaluation significantly predicted the outcome of the predriver evaluation and none of the predriver evaluation items predicted the outcome of the behind-the-wheel evaluation. Only 6 of the 26 tasks on the behind-the-wheel evaluation significantly predicted the outcome of the behind-the-wheel evaluation. None of the items on the predriver evaluation or the behind-the-wheel evaluation explained a significant portion of variance related to outcome. The lack of internal and predictive validity of driver evaluations is discussed in light of these findings, and recommendations are given for improving the predictive power of driving evaluations.