Us versus them: social identity shapes neural responses to intergroup competition and harm.
Intergroup competition makes social identity salient, which in turn affects how people respond to competitors' hardships. The failures of an in-group member are painful, whereas those of a rival out-group member may give pleasure-a feeling that may motivate harming rivals. The present study examined whether valuation-related neural responses to rival groups' failures correlate with likelihood of harming individuals associated with those rivals. Avid fans of the Red Sox and Yankees teams viewed baseball plays while undergoing functional magnetic resonance imaging. Subjectively negative outcomes (failure of the favored team or success of the rival team) activated anterior cingulate cortex and insula, whereas positive outcomes (success of the favored team or failure of the rival team, even against a third team) activated ventral striatum. The ventral striatum effect, associated with subjective pleasure, also correlated with self-reported likelihood of aggressing against a fan of the rival team (controlling for general aggression). Outcomes of social group competition can directly affect primary reward-processing neural systems, which has implications for intergroup harm.


Role of resident macrophages, peripheral neutrophils, and translymphatic absorption in bacterial clearance from the peritoneal cavity.
Microbial pathogens within the peritoneal cavity are thought to encounter three categories of host defense mechanisms: (i) removal mechanisms, which occur via diaphragmatic lymphatic absorption; (ii) killing mechanisms, in which host phagocytes act as effector cells; and (iii) sequestration mechanisms due to fibrin trapping and the formation of adhesions between visceral surfaces. We sought to define and quantitate the relative role of the first two components in an experimental rat model of Escherichia coli peritonitis in which fibrinous adhesions do not form. Intraperitoneal challenge with greater than or equal to 2 X 10(8) CFU of viable E. coli led to an initial decline in bacterial numbers followed by ongoing proliferation and greater than 50% mortality. With inocula of less than or equal to 5 X 10(7) CFU, elimination of bacteria occurred after moderate initial proliferation, and no mortality ensued. Nonviable, radiolabeled E. coli organisms were utilized to examine bacterial clearance via translymphatic absorption and phagocytosis. Both processes were extremely rapid, serving to eliminate free bacteria rapidly within the peritoneal cavity. Although macrophages and polymorphonuclear leukocytes within the peritoneal cavity demonstrated similar phagocytic capacities, the predominance of macrophages at the time of the initial bacterial insult led to the conclusion that these cells, in addition to translymphatic absorption, represent the first line of host defenses, acting to eliminate bacteria in the incipient stages of infection.


Use of Recommended Non-surgical Knee Osteoarthritis Management in Patients prior to Total Knee Arthroplasty: A Cross-sectional Study.
Our aim was to assess prior use of core recommended non-surgical treatment among patients with knee osteoarthritis (OA) scheduled for total knee arthroplasty (TKA), and to assess potential patient-level correlates of underuse, if found. This was a cross-sectional study of patients undergoing TKA for primary knee OA at 2 provincial central intake hip and knee clinics in Alberta, Canada. Standardized questionnaires assessed sociodemographic characteristics, social support, coexisting medical conditions, OA symptoms and coping, and previous non-surgical management. Multivariable logistic regression was used to assess the patient-level variables independently associated with receipt of recommended non-surgical knee OA treatment, defined as prior use of pharmacotherapy for pain, rehabilitation strategies (exercise or physiotherapy), and weight loss if overweight or obese (body mass index ≥ 25 kg/m2). There were 1273 patients included: mean age 66.9 years (SD 8.7), 39.9% male, and 44.1% had less than post-secondary education. Recommended non-surgical knee OA treatment had been used by 59.7% of patients. In multivariable modeling, the odds of having received recommended non-surgical knee OA treatment were significantly and independently lower among individuals who were older (OR 0.97, 95% CI 0.95-0.99), male (OR 0.33, 0.25-0.45), and who lacked post-secondary education (OR 0.70, 0.53-0.93). In a large cross-sectional analysis of knee OA patients scheduled for TKA, 40% of individuals reported having not received core recommended non-surgical treatments. Older individuals, men, and those with less education had lower odds of having used recommended non-surgical OA treatments.


Palliative care and advance care planning for pancreas and other cancers.
The principles of palliative care are fundamental to support and treat the physical, mental, and psychosocial health of patients living with pancreatic cancer. In addition to its proven advantages to help manage disease-related symptoms, improve accurate illness understanding, and enhance the quality of life and survival outcomes for patients with advanced disease, the inclusion of palliative care principles (whether by a specialist or by the primary oncology team) with standard oncologic care strengthens timely and quality advance care planning (ACP). The primary objective of this review article is to underscore the significant value of palliative care integration and ACP in oncology, including but not limited to care at the end of life, with a particular focus on its relevance to patients with advanced pancreatic cancer.


Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes.
The present study has investigated the direct opioid delta receptor-mediated antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II, as well as that of the less delta-selective [D-Ser2,Leu5,Thr6]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala2,Leu5,Cys6] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala2] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala2]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related antinociception which was partially antagonized by either beta-funaltrexamine (beta-FNA) or by ICI 174,864 (N,N-dialyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET antinociception in beta-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the antinociception produced by DSLET in control or in beta-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the antinociception produced by i.c.v. DSLET in either control or in beta-FNA-pretreated mice.(ABSTRACT TRUNCATED AT 250 WORDS)


Epidemiology of HIV among injecting and non-injecting drug users: current trends and implications for interventions.
Injecting drug use is a major driver of HIV infections in Eastern Europe, the Commonwealth of Independent States, North Africa, the Middle East, and many parts of Asia and North America. We provide a global overview of the epidemiology of HIV infection among drug users and present current drug use trends that may constitute important epidemic drivers. We describe trends in ethnic disparities among injecting drug using (IDU) populations in the United States, and comment upon how these trends may now be changing. We present examples where HIV infection among non-IDUs who use cocaine, crack, and methamphetamine by other routes of administration is similar to that among IDUs, and discuss potential mechanisms of HIV spread in this overlooked population. Finally, we comment upon the potential implications of these observations for HIV interventions among IDU and non-IDU populations, taking into account different strategies that are needed in settings where HIV and/or injecting drug use has been established, or threatens to emerge.


A consumer-choice health plan for the 1990s. Universal health insurance in a system designed to promote quality and economy (2).
We describe the characteristics necessary for a plan for universal health insurance to find broad acceptance. Such a plan must represent incremental, not radical, change; must respect the preferences of voters, patients, and providers; must avoid major disruption in satisfactory existing arrangements; must avoid creating major windfall gains or losses; must avoid large-scale income redistribution; and must not be inflationary. Our proposal would create a framework that would encourage the efficient organization of care. Successful organizations would probably be those that attracted the loyalty and commitment of physicians, integrated insurance and the provision of care, and aligned the interests of doctors and patients toward high-quality, cost-effective care. The proposal's chief potential disadvantage would be its effect on the employment opportunities of low-wage workers, but this effect could be minimized. In addition, we discuss a proposal to mandate coverage by employers of full-time employees, legislation enacted recently in Massachusetts, high-risk pools, and the system followed in Canada, comparing each of these alternatives with our proposal.


Acute cigarette smoke or extract exposure rapidly activates TRPA1-mediated calcium influx in primary human airway smooth muscle cells.
Tobacco smoking is the largest risk factor for developing chronic obstructive pulmonary disease (COPD), and is associated with hyperresponsiveness of airway smooth muscle (ASM). Chronic exposure to cigarette smoke (CS) leads to airway inflammation and remodelling. However, the direct effect of gaseous CS or CS extract (CSE) on human airway smooth muscle cell (hASMC) function remains poorly understood. This study investigated the acute effect of CS/CSE on calcium homeostasis, a key regulator of ASM physiology and pathophysiology. Primary hASMC were isolated from non-smoking donor lungs, and subjected to Ca2+ imaging studies. We found that both CS, and CSE, rapidly elevated cytosolic Ca2+ in hASMC through stimulation of plasmalemmal Ca2+ influx, but excluded store-operated and L-type Ca2+ channels as mediators of this effect. Using a specific pharmacological inhibitor, or shRNA-driven knockdown, we established that both CS and CSE stimulated Ca2+ influx in hASMC through the neurogenic pain receptor channel, transient receptor potential ankyrin 1 (TRPA1). CS/CSE-dependent, TRPA1-mediated Ca2+ influx led to myosin light-chain phosphorylation, a key process regulating ASM contractility. We conclude that TRPA1 is likely an important link between CS/CSE exposure and airway hyperresponsiveness, and speculate that acute CS/CSE-induced Ca2+ influx could lead to exacerbated ASM contraction and potentially initiate further chronic pathological effects of tobacco smoke.


Genetics and Epigenetics of Myelodysplastic Syndromes and Response to Drug Therapy: New Insights.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied. The most common molecular abnormalities were TET2, ASXL1 as well as molecules involved in spliceosome machinery (U2AF1, SRSF2 and SF3B1). Patients with defects in TET2 molecule show better response to treatment with azacitidine. IDH and DNMT3A mutations are associated with a good response to decitabine therapy. In addition, patients with del5q subtype harboring TP53 mutation do not show a good response to lenalidomide therapy. In general, the results of this study show that molecular abnormalities can be associated with the occurrence of a specific morphological phenotype in patients. Therefore, considering the morphology of patients, different gene profiling methods can be selected to choice the most appropriate therapeutic measure in these patients in addition to faster and more cost-effective diagnosis of molecular abnormalities.


Food safety: revising the statute.
There is increasing recognition that federal food safety laws and policies need to be revised. Congressional debate on proposed amendments to the Food, Drug, and Cosmetic Act has generated several different perspectives on how the food safety laws should be changed. Before a consensus can be reached, scientists, regulators, the food industry, and consumers will have to review such complex and controversial issues as the level of acceptable risk, the value of risk-benefit analysis, the proper role of independent scientific review, and the reliability of quantitative risk assessment.


The protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodeling.
Skeletal muscle differentiation requires the coordinated activity of transcription factors, histone modifying enzymes, and ATP-dependent chromatin remodeling enzymes. The type II protein arginine methyltransferase Prmt5 symmetrically dimethylates histones H3 and H4 and numerous nonchromatin proteins, and prior work has implicated Prmt5 in transcriptional repression. Here we demonstrate that MyoD-induced muscle differentiation requires Prmt5. One of the first genes activated during differentiation encodes the myogenic regulator myogenin. Prmt5 and dimethylated H3R8 (histone 3 arginine 8) are localized at the myogenin promoter in differentiating cells. Modification of H3R8 required Prmt5, and reduction of Prmt5 resulted in the abrogation of promoter binding by the Brg1 ATPase-associated with the SWI/SNF chromatin remodeling enzymes and all subsequent events associated with gene activation, including increases in chromatin accessibility and stable binding by MyoD. Prmt5 and dimethylated H3R8 were also associated with the myogenin promoter in activated satellite cells isolated from muscle tissue, further demonstrating the physiological relevance of these observations. The data indicate that Prmt5 facilitates myogenesis because it is required for Brg1-dependent chromatin remodeling and gene activation at a locus essential for differentiation. We therefore conclude that a histone modifying enzyme is necessary to permit an ATP-dependent chromatin remodeling enzyme to function.


Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.
Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.


Dietary Additive Probiotics Modulation of the Intestinal Microbiota.
The importance of the intestinal microbiota of animals is widely acknowledged because of its vital role in the health of animals. There are complex communities of microbiota, which colonize the gastrointestinal tract. Intestinal microbiota are conductive to animal health and the development of the host immune system. Probiotics are commonly used dietary additives where they provide the host with many beneficial functions, such as modulating intestinal homeostasis and promoting gut health. These beneficial effects of probiotics may accrue from the inhibiting the growth of pathogenic bacteria and promoting the growth of beneficial flora in the gastrointestinal tract. Probiotics colonization and its impact on gut microbiota members are highly species specific. Different probiotics have been shown to have dramatically different capacities of modulation physiological function. This review summarizes existing studies of the influence of dietary additive probiotics on the gut microbiota in different animals, such as humans, mice, pigs and chickens, to clarify the contribution of different kinds of probiotics to the intestinal microbiota. Moreover, the probable mechanism for the benefits of dietary supplementation with probiotics will be discussed.


Baboons undergoing orthotopic concordant cardiac xenotransplantation surviving more than 300 days: effect of immunosuppressive regimen.
We reviewed long-term survival among hosts in 3 consecutive series of a rhesus monkey-baboon orthotopic cardiac xenotransplantation model with reference to host immune response, including the effectiveness in preventing rejection and limiting toxicity concerning infection, to evaluate specific immunosuppressive regimens for long-term outcomes. Six juvenile baboons surviving more than 300 days after transplantation were reviewed. Regimen A consisted of splenectomy, FK506, methotrexate, and antilymphocyte globulin. Regimen B consisted of pretransplantation and chronic maintenance with cyclosporine A (INN: ciclosporin), methotrexate, and antithymocyte globulin. Regimen C was the same as regimen B plus pretransplantation total lymphoid irradiation and intraoperative donor bone marrow cell infusion. Rejections were detected by means of echocardiography. Long-term survivors in 3 groups were followed for a range of 332 to 515 days (mean, 436 days). Rejection frequency in regimens A, B, and C was 0.35, 0.58, and 0.18 per month, and rescue therapy days were 23 (4.8%), 123 (9.5%), and 20 (2.4%), respectively (P <.0001). Infection frequency was 0.58, 0.56, and 0.19 per month, and therapy days were 192 (38.2%), 164 (12.6%), and 7 (0.9%), respectively (P <.0001). Concerning the host immune response, interleukin 2-activated T cells of all groups during rejection-free periods showed lower numbers compared with those of control animals (P <.0005), and regimen C was the lowest among 3 groups (P <.01). The production of xenoantibody was sufficiently attenuated in all groups. Regimen C leads to long-term survival with fewer rejection and infection episodes by means of suppression of the interleukin 2 pathway and xenoantibody production.


Report: Maximizing recycling participation to reduce waste to landfill: a study of small to medium-sized enterprises in Hobart, Tasmania, Australia.
Small to medium-sized enterprises (SMEs) in Hobart, Tasmania, Australia face many barriers to recycling participation. This study first investigated the volumes and types of waste produced by SMEs. Significant barriers were then identified and key motivators to recycle examined. Using the Australia New Zealand Standard of Industrial Classification, stratified sampling of SMEs (n = 436) was undertaken. Inadequate storage space, paucity of readily available information on recycling services and the lack of staff allocated to sort and recycle were identified as major barriers. Cardboard, paper and plastic waste were produced in large volumes with only a small percentage being recycled and these were identified as target areas for local government. Recommendations include the appointment of a dedicated recycling officer to maximize recycling participation for the reduction of waste to landfill and to undertake further research on minimizing recycling costs.


A new R package and web application for detecting bilateral asymmetry in parasitic infections.
When parasites invade paired structures of their host non-randomly, the resulting asymmetry may have both pathological and ecological significance. To facilitate the detection and visualisation of asymmetric infections we have developed a free software tool, Analysis of Symmetry of Parasitic Infections (ASPI). This tool has been implemented as an R package (https://cran.r-project.org/package=aspi) and a web application (https://wayland.shinyapps.io/aspi). ASPI can detect both consistent bias towards one side, and inconsistent bias in which the left side is favoured in some hosts and the right in others. Application of ASPI is demonstrated using previously unpublished data on the distribution of metacercariae of species of Diplostomum von Nordmann, 1832 in the eyes of ruffe Gymnocephalus cernua (Linnaeus). Invasion of the lenses appeared to be random, with the proportion of metacercariae in the left and right lenses showing the pattern expected by chance. However, analysis of counts of metacercariae from the humors, choroid and retina revealed asymmetry between eyes in 38% of host fish.


Nonintegral stoichiometry in CFTR gating revealed by a pore-lining mutation.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) protein superfamily. Unlike most other ABC proteins that function as active transporters, CFTR is an ATP-gated chloride channel. The opening of CFTR's gate is associated with ATP-induced dimerization of its two nucleotide-binding domains (NBD1 and NBD2), whereas gate closure is facilitated by ATP hydrolysis-triggered partial separation of the NBDs. This generally held theme of CFTR gating-a strict coupling between the ATP hydrolysis cycle and the gating cycle-is put to the test by our recent finding of a short-lived, post-hydrolytic state that can bind ATP and reenter the ATP-induced original open state. We accidentally found a mutant CFTR channel that exhibits two distinct open conductance states, the smaller O1 state and the larger O2 state. In the presence of ATP, the transition between the two states follows a preferred O1→O2 order, a telltale sign of a violation of microscopic reversibility, hence demanding an external energy input likely from ATP hydrolysis, as such preferred gating transition was abolished in a hydrolysis-deficient mutant. Interestingly, we also observed a considerable amount of opening events that contain more than one O1→O2 transition, indicating that more than one ATP molecule may be hydrolyzed within an opening burst. We thus conclude a nonintegral stoichiometry between the gating cycle and ATP consumption. Our results lead to a six-state gating model conforming to the classical allosteric mechanism: both NBDs and transmembrane domains hold a certain degree of autonomy, whereas the conformational change in one domain will facilitate the conformational change in the other domain.


Afebrile seizure subsequent to initial febrile seizure.
Febrile seizure (FS) is the most common paediatric neurological problem. The purpose of this study was to determine the frequency of afebrile seizures subsequent to FS in children with initial FS and to evaluate its risk factors. A prospective study was conducted on all children (age 6 months to 6 years) referred with initial FS to the Shahid Sadoughi Hospital, Yazd, Iran, between August 2004 and March 2006, who were followed up for at least 15 months for the occurrence of subsequent afebrile seizures. 161 boys and 120 girls (mean age 2.12 ± 1.33 years) were followed up for 34.1 ± 7.8 months. 87 (31%) patients had complex FS and 19 (6.7%) patients had subsequent afebrile seizure, with a mean occurrence time of 10.6 ± 6.4 months. Univariate analysis using chi-square test showed that initial FS within one hour of developing fever (p = 0.0001), neurodevelopmental delay (p = 0.0001), family history of epilepsy (p = 0.0001), recurrent FS (p = 0.003) and focal FS (p = 0.04) were risk factors for subsequent afebrile seizure. On multivariate analysis, neurodevelopmental delay (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.3-3.4), initial FS within one hour of developing fever (OR 1.7, 95% CI 1.2-2.1) and family history of epilepsy (OR 1.5, 95% CI 1.1-1.9) were significant factors. Special attention should be paid to children with FS during history-taking and developmental assessments to identify high-risk patients and those who might need prophylactic anticonvulsants.


Liquid tunable diffractive/refractive hybrid lens.
We present a liquid tunable diffractive/refractive hybrid lens fabricated through what we believe to be a novel process that combines single-point diamond turning with soft lithography techniques. The hybrid lens achieves focal length tunability by changing its shape and, at the same time, utilizes the unique dispersion property of diffractive surfaces to enhance its spectral performance within a wide tuning range.


Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy.
In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir > or = F2) is variable. Constitutional and liver disease-related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)-RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy-six of 286 (26.6%) had stage > or =F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage <F2 and TE > or = 7.1 kPa (false positive). No patient with discordant results had cirrhosis. By Dale model, aspartate aminotransferase (AST) was found to be the unique variable significantly related (P = 0.046) with discordance between biopsy and TE. Discordance rate was 43.4% (82 patients) with AST < 1.5 x UNL vs 25.8% (25 patients) with AST > or = 1.5 x UNL (P = 0.004). False negative rate was 43.4 (82 patients) with AST < 1.5 x UNL vs 17.1% (13 patients) with AST > or = 1.5 x UNL (P < 0.001). Areas under the receiver operating characteristic (AUROC) for F > or = 2, according to AST < 1.5 x UNL vs > or = 1.5 x UNL were 0.738 (95% CI: 0.683-0.812) and 0.854(95% CI: 0.754-0.907). Transient elastography is not adequate on its own to rule out or to rule in significant fibrosis, as it is influenced by major variations in biochemical activity of liver disease. Liver stiffness, at low levels of AST, can underestimate fibrosis.


Accelerated increase in plant species richness on mountain summits is linked to warming.
Globally accelerating trends in societal development and human environmental impacts since the mid-twentieth century 1-7 are known as the Great Acceleration and have been discussed as a key indicator of the onset of the Anthropocene epoch 6 . While reports on ecological responses (for example, changes in species range or local extinctions) to the Great Acceleration are multiplying 8, 9 , it is unknown whether such biotic responses are undergoing a similar acceleration over time. This knowledge gap stems from the limited availability of time series data on biodiversity changes across large temporal and geographical extents. Here we use a dataset of repeated plant surveys from 302 mountain summits across Europe, spanning 145 years of observation, to assess the temporal trajectory of mountain biodiversity changes as a globally coherent imprint of the Anthropocene. We find a continent-wide acceleration in the rate of increase in plant species richness, with five times as much species enrichment between 2007 and 2016 as fifty years ago, between 1957 and 1966. This acceleration is strikingly synchronized with accelerated global warming and is not linked to alternative global change drivers. The accelerating increases in species richness on mountain summits across this broad spatial extent demonstrate that acceleration in climate-induced biotic change is occurring even in remote places on Earth, with potentially far-ranging consequences not only for biodiversity, but also for ecosystem functioning and services.


The effects of APOE on brain activity do not simply reflect the risk of Alzheimer's disease.
Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk.


Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype.
How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with ≥30% phenylalanine reduction at ≥1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term ≥30% reduction in mean phenylalanine concentration and/or ≥4 g/day and/or ≥50% increase of natural protein intake. Genotype was collected if available. 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with ≥1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.


Histologic correlation of image-guided core biopsy with excisional biopsy of nonpalpable breast lesions.
To examine the histologic correlation between image-guided large-core needle biopsy (LCNB) and excisional biopsy of nonpalpable breast lesions. Histologic findings of LCNB and excision specimens were reviewed for patients who underwent image-guided LCNB of nonpalpable breast lesions from April 1, 1993, to March 31, 1996. Histologic diagnosis of the excision specimen was used as a criterion standard. Follow-up ranged from 1 to 4 years. A dedicated breast imaging clinic on the campus of an urban community hospital. Five hundred fifty-two patients with nonpalpable mammographically detected abnormalities. Histologic diagnoses of LCNB and excision specimens (part of a prospectively designed, ongoing quality audit process). Histologic findings were benign in 389 LCNB specimens (70.5%) and abnormal in 163 (29.5%). The benign LCNB specimens remained benign on clinical and radiologic follow-up, with 1 missed malignant diagnosis. One hundred seventy-three patients underwent excision following LCNB, resulting in 10 benign and 163 abnormal specimens. Diagnoses of 102 LCNB specimens showing invasive cancer were confirmed on excision. Of 54 patients in whom LCNB specimens showed ductal carcinoma in situ (DCIS), 10 showed DCIS plus invasive cancer on excision. Of 6 patients in whom LCNB specimens showed atypical duct hyperplasia (ADH), 1 was benign, 1 showed ADH and invasive cancer, 3 showed ADH and DCIS, and 1 remained ADH exclusively on excision. The histologic diagnosis for 10 benign LCNBs remained benign after excision. Correlation coefficient was 0.93 (P < .001). Benign disease and invasive cancer of the breast can be diagnosed with a high level of confidence using image-guided LCNB. The histologic diagnosis for patients whose LCNB specimens show ADH or DCIS may change after excision.


The multiple burdens of zoonotic disease and an Ecohealth approach to their assessment.
Zoonoses occur at the interface of human and animal disease and partly because their impact and management fall across two sectors they are often neglected. The Global Burden of Disease captures the impact of zoonoses on human health in terms of disability-adjusted life years (DALYs). Based on this, we estimate that in low income countries, zoonoses and diseases which recently emerged from animals make up 26 % of the DALYs lost to infectious disease and 10 % of the total DALYs lost. In contrast, in high income countries, zoonoses and diseases recently which emerged from animals represent less than 1 % of DALYs lost to infectious disease and only 0.02 % of the total disease burden. We present a framework that captures the costs of zoonoses and emerging disease to human, animal and ecosystem health in terms of cost of treatment, cost of prevention, health burden and intangible and opportunity costs. We also discuss how ecohealth concepts of transdisciplinarity, participation and equity can help in assessing the importance of zoonoses in developing countries and illustrate these with an example of assessing milk-borne disease.


The influence of reproductive experience on milk energy output and lactation performance in the grey seal (Halichoerus grypus).
Although evidence from domestic and laboratory species suggests that reproductive experience plays a critical role in the development of aspects of lactation performance, whether reproductive experience may have a significant influence on milk energy transfer to neonates in wild populations has not been directly investigated. We compared maternal energy expenditures and pup growth and energy deposition over the course of lactation between primiparous and fully-grown, multiparous grey seal (Halichoerus grypus) females to test whether reproductive experience has a significant influence on lactation performance. Although there was no difference between primiparous females in milk composition and, thus, milk energy content at either early or peak lactation primiparous females had a significantly lower daily milk energy output than multiparous females indicating a reduced physiological capacity for milk secretion. Primiparous females appeared to effectively compensate for lower rates of milk production through an increased nursing effort and, thus, achieved the same relative rate of milk energy transfer to pups as multiparous females. There was no difference between primiparous and multiparous females in the proportion of initial body energy stores mobilised to support the costs of lactation. Although primiparous females allocated a greater proportion of energy stores to maternal maintenance versus milk production than multiparous females, the difference was not sufficient to result in significant differences in the efficiency of energy transfer to pups. Thus, despite a lower physiological capacity for milk production, primiparous females weaned pups of the same relative size and condition as multiparous females without expending proportionally more energy. Although reproductive experience does not significantly affect the overall lactation performance of grey seals, our results suggest that increases in mammary gland capacity with reproductive experience may play a significant role in the age-related increases in neonatal growth rates and weaning masses observed in other free-ranging mammals.


Genetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus: a systematic review protocol.
Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses. We will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger's test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. This review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person's response to metformin treatment and create personalized drugs with greater efficacy and safety. Registration number: PROSPERO, CRD42017079978.


Quinoline-2-carboimine copper complex immobilized on amine functionalized silica coated magnetite nanoparticles: a novel and magnetically retrievable catalyst for the synthesis of carbamates via C-H activation of formamides.
In the present study, we report the synthesis of a highly efficient and magnetically retrievable catalytic system (Cu-2QC@Am-SiO2@Fe3O4) through the covalent immobilization of quinoline-2-carboxaldehyde (2QC) on an amine functionalized silica coated ferrite nanosupport followed by metallation with copper acetate. The structure of the organic-inorganic hybrid nanomaterial has been confirmed using various physicochemical techniques such as Powder X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Energy Dispersive X-Ray Spectroscopy (EDS), Energy Dispersive X-Ray Fluorescence Spectroscopy (ED-XRF), Atomic Absorption Spectroscopy (AAS), Inductively Coupled Plasma Spectroscopy (ICP) and Vibrating Sample Magnetometry (VSM). The resulting nanocatalyst exhibits a remarkable catalytic efficacy in the synthesis of industrially and pharmaceutically significant carbamates via the C-H activation of formamides under solvent free conditions. The most important attribute of the present methodology is that the catalyst can be recovered simply through an external magnetic force and reused several times without any significant deterioration in its activity. Furthermore, the heterogeneity test has been carried out in order to ensure the intrinsic stability of the nanostructured catalyst. The activity of the Cu-2QC@Am-SiO2@Fe3O4 nanocatalyst has been found to be far more superior in comparison with the literature precedents in terms of the product yield, cost and reusability of the catalyst. Besides, ambient reaction conditions, simple workup procedure, wide substrate scope and cost effectiveness are some of the other outstanding features of this protocol that make it economical and sustainable.


Mothers' understanding of the term 'exclusive breastfeeding': a systematic review.
There is a lack of knowledge and understanding of the term exclusive breastfeeding (EBF) among health professionals. The purpose of this review was to examine the best available literature on mothers' understanding of the term EBF. A systematic search of eight electronic databases (Medline, Embase, CINAHL, CDSR, CENTRAL, Cab Abstracts, Scopus and African Index Medicus) was conducted (Protocol registration in PROSPERO: CRD42015019402). All study designs were eligible for inclusion. Studies were included if they: (1) involved mothers aged 18 years or older; (2) assessed mothers' knowledge/understanding/awareness of the term 'EBF'; (3) used the 1991 WHO definition of EBF and (4) were published between 1988 and 2015. Two reviewers retrieved articles, assessed study quality and performed data extraction. Of the 1700 articles identified, 21 articles met the inclusion criteria. Quantitative findings were pooled to calculate a proportion rate of 70.9% of mothers who could correctly define EBF, although the range varied between 3.1 and 100%. Qualitative findings revealed three themes: (1) EBF was understood by mothers as not mixing two milks; (2) the term 'exclusive' in EBF was incorrectly understood as not giving breast milk and (3) mothers believing that water can be given while exclusively breastfeeding. Research investigating aspects of self-reported EBF may consequently be unreliable. A standardised tool to assess mothers' knowledge of EBF could provide more accurate data. Public health campaigns should emphasise EBF to target mothers, while addressing the education of health professionals to ensure that they do not provide conflicting advice.


Participation of plasma membrane proteins in the formation of tight junctions by cultured epithelial cells.
Measurements of the transepithelial electrical resistance correlated with freeze-fracture observations have been used to study the process of tight junction formation under various experimental conditions in monolayers of the canine kidney epithelial cell line MDCK. Cells derived from previously confluent cultures and plated immediately after trypsin- EDTA dissociation develop a resistance that reaches its maximum value of several hundred ohms-cm(2) after approximately 24 h and falls to a steady-state value of 80-150 ohms- cm(2) by 48 h. The rise in resistance and the development of tight junctions can be completely and reversibly prevented by the addition of 10 mug/ml cycloheximide at the time of plating, but not when this inhibitor is added more than 10 h after planting. Thus tight junction formation consists of separable synthetic and assembly phases. These two phases can also be dissociated and the requirement for protein synthesis after plating eliminated if, following trypsinization, the cells are maintained in spinner culture for 24 h before plating. The requirement for protein synthesis is restored, however, if cells maintained in spinner culture are treated with trypsin before plating. Actinomycin D prevents development of resistance only in monolayers formed from cells derived from sparse rather than confluent cultures, but new mRNA synthesis is not required if cells obtained from sparse cultures are maintained for 24 h in spinner culture before plating. Once a steady-state resistance has been reached, its maintenance does not require either mRNA or protein synthesis; in fact, inhibition of protein synthesis causes a rise in the resistance over a 30-h period. Following treatments that disrupt the junctions in steady- state monolayers recovery of resistance also does not require protein synthesis. These observations suggest that proteins are involved in tight junction formation. Such proteins, which do not turn over rapidly under steady-state conditions, are destroyed by trypsinization and can be resynthesized in the absence of stable cell-cell or cell-substratum contact. Messenger RNA coding for proteins involved in tight junction formation is stable except when cells are sparsely plated, and can also be synthesized without intercellular contacts or cell-substratum attachment.


Type IV collagen is a novel DEJ biomarker that is reduced by radiotherapy.
The dental basement membrane (BM) is composed of collagen types IV, VI, VII, and XVII, fibronectin, and laminin and plays an inductive role in epithelial-mesenchymal interactions during tooth development. The BM is degraded and removed during later-stage tooth morphogenesis; however, its original position defines the location of the dentin-enamel junction (DEJ) in mature teeth. We recently demonstrated that type VII collagen is a novel component of the inner enamel organic matrix layer contiguous with the DEJ. Since it is frequently co-expressed with and forms functional complexes with type VII collagen, we hypothesized that type IV collagen should also be localized to the DEJ in mature human teeth. To identify collagen IV, we first evaluated defect-free erupted teeth from various donors. To investigate a possible stabilizing role, we also evaluated extracted teeth exposed to high-dose radiotherapy--teeth that manifest post-radiotherapy DEJ instability. We now show that type IV collagen is a component within the morphological DEJ of posterior and anterior teeth from individuals aged 18 to 80 yr. Confocal microscopy revealed that immunostained type IV collagen was restricted to the 5- to 10-µm-wide optical DEJ, while collagenase treatment or previous in vivo tooth-level exposure to > 60 Gray irradiation severely reduced immunoreactivity. This assignment was confirmed by Western blotting with whole-tooth crown and enamel extracts. Without reduction, type IV collagen contained macromolecular α-chains of 225 and 250 kDa. Compositionally, our results identify type IV collagen as the first macromolecular biomarker of the morphological DEJ of mature teeth. Given its network structure and propensity to stabilize the dermal-epidermal junction, we propose that a collagen-IV-enriched DEJ may, in part, explain its well-known fracture toughness, crack propagation resistance, and stability. In contrast, loss of type IV collagen may represent a biochemical rationale for the DEJ instability observed following oral cancer radiotherapy.


Unexpected Uptake by the Gallbladder in Post-Ablative I-131 Scan.
A 47-year-old woman was diagnosed as papillary thyroid carcinoma. I-131 ablation therapy was applied following total thyroidectomy, and the whole-body scan revealed a focus of increased uptake in the right upper quadrant. Lateral view images of the uptake site showed that the focus was located near the right liver lobe. The patient was referred to radiology department for correlative abdominal Computed Tomography (CT) and Ultrasonography (US) to rule out a possible liver metastasis. CT images detected a gallstone in the corresponding area, which was verified by US. These methods did not reveal any metastatic disease in the liver or in other abdominal organs. This is the first published case report documents a rare false-positive finding of I-131 scan that was associated with an asymptomatic gallstone, and emphasizes the importance of correlative imaging in gallbladder related I-131 uptake.


The sustained delivery of resveratrol or a defined grape powder inhibits new blood vessel formation in a mouse model of choroidal neovascularization.
The objective of this study was to determine whether resveratrol or a defined, reconstituted grape powder can attenuate the formation of new blood vessels in a mouse model of choroidal neovascularization (CNV). To accomplish this objective, C57BL/6J mice were randomized into control or treatment groups which received either resveratrol or grape powder by daily oral gavage, resveratrol or grape powder delivered ad libitum through the drinking water, or resveratrol by slow release via implanted osmotic pumps. A laser was used to rupture Bruch's membrane to induce CNV which was then detected in sclerochoroidal eyecups stained with antibodies against intercellular adhesion molecule-2. CNV area was measured using fluorescence microscopy and Image J software. Ad libitum delivery of both resveratrol and grape powder was shown to significantly reduce the extent of CNV by 68% and 57%, respectively. Parallel experiments conducted in vitro demonstrated that resveratrol activates p53 and inactivates Akt/protein kinase B in choroidal endothelial cells, contributing to its anti-proliferative and anti-migratory properties. In addition resveratrol was shown to inhibit the formation of endothelial cell networks, augmenting its overall anti-angiogenic effects. The non-toxic nature of resveratrol makes it an especially attractive candidate for the prevention and/or treatment of CNV.


Chimpanzees' flexible targeted helping based on an understanding of conspecifics' goals.
Humans extensively help others altruistically, which plays an important role in maintaining cooperative societies. Although some nonhuman animals are also capable of helping others altruistically, humans are considered unique in our voluntary helping and our variety of helping behaviors. Many still believe that this is because only humans can understand others' goals due to our unique "theory of mind" abilities, especially shared intentionality. However, we know little of the cognitive mechanisms underlying helping in nonhuman animals, especially if and how they understand others' goals. The present study provides the empirical evidence for flexible targeted helping depending on conspecifics' needs in chimpanzees. The subjects of this study selected an appropriate tool from a random set of seven objects to transfer to a conspecific partner confronted with differing tool-use situations, indicating that they understood what their partner needed. This targeted helping, (i.e., selecting the appropriate tool to transfer), was observed only when the helpers could visually assess their partner's situation. If visual access was obstructed, the chimpanzees still tried to help their partner upon request, but failed to select and donate the appropriate tool needed by their partner. These results suggest that the limitation in chimpanzees' voluntary helping is not necessarily due to failure in understanding others' goals. Chimpanzees can understand conspecifics' goals and demonstrate cognitively advanced targeted helping as long as they are able to visually evaluate their conspecifics' predicament. However, they will seldom help others without direct request for help.


Heterogeneity of breast cancer subtypes and survival among Hispanic women with invasive breast cancer in California.
There are limited data regarding breast cancer subtypes among Hispanic women. The current study assessed the distribution and prognosis of molecular subtypes defined by joint expression of the hormone receptors (HR; estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2). Using California Cancer Registry data, we identified Hispanic women diagnosed with invasive breast cancer from 2005 to 2010. Breast cancer subtypes were defined as HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- (triple negative). We estimated breast cancer subtype frequencies and used polytomous logistic regression, Kaplan-Meier survival plots and Cox regression to examine differences in relation to demographic and clinical characteristics. Among 16,380 Hispanic women with breast cancer, HR+/HER- subtype was the most common (63 %), followed by triple negative (16 %), HR+/HER2+ (14 %), and HR-/HER2+ (8 %). Women in lower SES neighborhoods had greater risk of triple negative and HR-/HER2+ subtypes relative to HR+/HER2- (p < 0.05). Hispanic women with triple negative and HR-/HER2+ tumors experienced poorer survival than those with HR+/HER- tumors. Breast cancer-specific mortality increased with decreasing SES, relative to the highest SES quintile, from HR = 1.38 for quintile 4 to HR = 1.76 for quintile 1 (lowest SES level). Our findings indicate that Hispanic women residing in low SES neighborhoods had significantly increased risk of developing and dying from HR- than HR+ breast cancers. Similar patterns of subtype frequency and prognosis among California Hispanic women and studies of other racial/ethnic groups underscore the need to better understand the impact of SES on risk factor exposures that increase the risk of breast cancer subtypes with poor prognosis.


A QSPR-approach to the estimation of the pK(HB) of six-membered nitrogen-heterocycles using quantum mechanically derived descriptors.
Descriptors derived from semiempirical (AM1) molecular orbital calculations have been used to construct a quantitative structure-property relationship (QSPR) for the thermodynamic hydrogen-bond basicity, p K(HB), of a series of six-membered aromatic nitrogen-heterocycles. The resulting model uses four-descriptors (the Coulson charge on the nitrogen atom, the energy of the localized nitrogen lone-pair orbital, the p-orbital contribution to this MO and an accessibility angle). The model gives r2(cv)=0.95 for 51 compounds with a standard deviation between calculation and experiment of 0.13 log units.


Versatile robotic probe calibration for position tracking in ultrasound imaging.
Within the field of ultrasound-guided procedures, there are a number of methods for ultrasound probe calibration. While these methods are usually developed for a specific probe, they are in principle easily adapted to other probes. In practice, however, the adaptation often proves tedious and this is impractical in a research setting, where new probes are tested regularly. Therefore, we developed a method which can be applied to a large variety of probes without adaptation. The method used a robot arm to move a plastic sphere submerged in water through the ultrasound image plane, providing a slow and precise movement. The sphere was then segmented from the recorded ultrasound images using a MATLAB programme and the calibration matrix was computed based on this segmentation in combination with tracking information. The method was tested on three very different probes demonstrating both great versatility and high accuracy.


Embodied Conversational Agents in Clinical Psychology: A Scoping Review.
Embodied conversational agents (ECAs) are computer-generated characters that simulate key properties of human face-to-face conversation, such as verbal and nonverbal behavior. In Internet-based eHealth interventions, ECAs may be used for the delivery of automated human support factors. We aim to provide an overview of the technological and clinical possibilities, as well as the evidence base for ECA applications in clinical psychology, to inform health professionals about the activity in this field of research. Given the large variety of applied methodologies, types of applications, and scientific disciplines involved in ECA research, we conducted a systematic scoping review. Scoping reviews aim to map key concepts and types of evidence underlying an area of research, and answer less-specific questions than traditional systematic reviews. Systematic searches for ECA applications in the treatment of mood, anxiety, psychotic, autism spectrum, and substance use disorders were conducted in databases in the fields of psychology and computer science, as well as in interdisciplinary databases. Studies were included if they conveyed primary research findings on an ECA application that targeted one of the disorders. We mapped each study's background information, how the different disorders were addressed, how ECAs and users could interact with one another, methodological aspects, and the study's aims and outcomes. This study included N=54 publications (N=49 studies). More than half of the studies (n=26) focused on autism treatment, and ECAs were used most often for social skills training (n=23). Applications ranged from simple reinforcement of social behaviors through emotional expressions to sophisticated multimodal conversational systems. Most applications (n=43) were still in the development and piloting phase, that is, not yet ready for routine practice evaluation or application. Few studies conducted controlled research into clinical effects of ECAs, such as a reduction in symptom severity. ECAs for mental disorders are emerging. State-of-the-art techniques, involving, for example, communication through natural language or nonverbal behavior, are increasingly being considered and adopted for psychotherapeutic interventions in ECA research with promising results. However, evidence on their clinical application remains scarce. At present, their value to clinical practice lies mostly in the experimental determination of critical human support factors. In the context of using ECAs as an adjunct to existing interventions with the aim of supporting users, important questions remain with regard to the personalization of ECAs' interaction with users, and the optimal timing and manner of providing support. To increase the evidence base with regard to Internet interventions, we propose an additional focus on low-tech ECA solutions that can be rapidly developed, tested, and applied in routine practice.


The treatment of zinc-cyanide electroplating rinse water using an electrocoagulation process.
This paper investigates the treatment of zinc-cyanide electroplating rinse water using an electrocoagulation process (ECP). The effects of operating parameters such as electrode material, current density (2.5-40 A/m(2)), operating time (0-60 min), initial pH (5-12) and electrode connection mode (monopolar parallel (MP-P), monopolar series and bipolar series) on the ECP were evaluated to find the optimum operating conditions. At 20 A/m(2), 60 min, the highest removal efficiencies were obtained with 85 and 99% for Fe and 64 and 33% for Al electrodes, for cyanide and zinc, respectively. The optimum operating conditions were found to be 30 A/m(2) and 40 min, for the Fe electrode at the original pH (9.5) of the rinse water. Considering efficiency and economy, the MP-P connection mode was determined as the optimum connection mode.


Diffuse Leptomeningeal Glioneuronal Tumor Presented with Language Developmental Delay.
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a new central nervous system tumor defined by the WHO in 2016 characterized mainly by hydrocephalus, headache, and epilepsy. We reported the case of a patient diagnosed with DLGNT who presented with language developmental delay and positive but subtle changes in imaging two years before the emergence of typical clinical symptoms. Few studies were conducted on early tumor symptoms due to the limited number of cases. We hypothesized that with the existence of pre-tumor symptoms, language developmental delay may be related to tumor.


Cellular morphology of leg musculature in the water bear Hypsibius exemplaris (Tardigrada) unravels serial homologies.
Tardigrades (water bears) are microscopic, segmented ecdysozoans with four pairs of legs. Lobopodous limbs that are similar to those seen in tardigrades are hypothesized to represent the ancestral state of Panarthropoda (Tardigrada + Onychophora + Arthropoda), and their evolutionary history is important to our understanding of ecdysozoan evolution. Equally important is our understanding of the functional morphology of these legs, which requires knowledge of their musculature. Tardigrade musculature is well documented but open questions remain. For example, while the muscular organization of each trunk segment and its legs is unique, three of the four trunk segments are nevertheless relatively homonomous. To what extent, then, do leg muscles show segmental patterns? Specifically, which leg muscles are serially repeated and which are unique? The present study addresses these questions using a combination of techniques intended to visualize both the overall layout and fine structure of leg muscles in the eutardigrade Hypsibius exemplaris. In doing so, we propose serial homologies for all leg muscles in each of the four legs and reveal new details of their cellular structure and attachment sites. We compare our results to those of previous studies and address the functional implications of specialized muscle cell morphologies.


Inhibition of artificial secondary caries in root by fluoride-releasing restorative materials.
This investigation evaluated the fluoride-releasing properties of various fluoride-releasing restorative materials, including resin-modified glass-ionomer cements (Fuji ionomer TypeII LC, Photac-Fil Aplicap, Vitremer), compomers (Ionosit FIL, Compoglass, Dyract) and fluoride-releasing resin composites (Heliomolar radiopaque, Degufill mineral). The study also estimated the effects of those materials on the inhibition of artificial secondary caries around restorations using a bacterial caries-inducing system. The amount of fluoride released from the materials in deionized water was measured every one week for 10 weeks. Class V cavities with the gingival margin located in the root were prepared in extracted human premolars and restored with each of the materials. The restored teeth were incubated in the bacterial artificial caries chamber, and the artificial lesion created around the restoration was observed microradiographically. The resin-modified glass-ionomer cements released the largest amount of fluoride and created a thick radio-opaque zone in the artificial lesion along the restoration-dentin interface. These results indicated that the fluoride-releasing restorative materials have the potential to inhibit secondary caries formation around restorations. Resin-modified glass-ionomer cements presented a particularly strong effect, compared with compomers and fluoride-releasing resin composites.


A tunnel in the large ribosomal subunit revealed by three-dimensional image reconstruction.
A better understanding of the molecular mechanism of protein biosynthesis depends on the availability of a reliable model for the ribosome particle. The application of a diffraction technique, namely, three-dimensional image reconstruction from two-dimensional sheets of the large ribosomal subunits of Bacillus stearothermophilus at a resolution of 30 angstroms is described. The resulting three-dimensional model shows at least four projecting arms, arranged radially near the presumed interface with the 30S subunit. The projecting arms are positioned around a cleft, which turns into a tunnel with a length of 100 to 120 angstroms and a diameter of up to 25 angstroms. This tunnel spans the particle and may provide the path taken by the nascent polypeptide chain.


An ISO 9001 quality management system in a hospital: bureaucracy or just benefits?
To describe how The Red Cross Hospital in Beverwijk, The Netherlands implemented an ISO 9000 quality management system throughout the entire organisation, obtained an ISO 9002:1994 and subsequently an ISO 9001:2000 certificate. First, a global implementation plan was written concerning the process obtaining in each department. Once improved, each process was subjected to a procedure, and specific protocols effected. On completion the Quality Manual was put together. Quality management was completed by implementing an internal audit system involving 50 co-workers. A number of advantages are found from using ISO. The focus on patients has been re-established. All processes are identified and subject to continuous improvement. Performance measurements were introduced and give an integrated picture of results. Measurements subsequently lead to improvement of quality of care and to quality system improvements. The documentation system serves the organization's needs without leading to bureaucracy. Positive effects on patient safety could be demonstrated compared with ten other hospitals. Given the need for adequate quality management tools in health care and the need for demonstrating quality, the positive effects reported in this article show how ISO is expected to become more prevalent in health-care organisations.


Hypoxia-reoxygenation treatment attenuates gestational diabetes mellitus.
Oxidative stress leads to insulin resistance and gestational diabetes mellitus (GDM). The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling is an important anti-oxidative stress pathway, which can be activated by hypoxia-reoxygenation (H/R) treatment. We aimed to demonstrate the effects of H/R treatment on GDM symptoms as well as reproductive outcomes. Pregnant C57BL/KsJ db/+ mice were used as a genetic GDM model. Plasma insulin and other biochemical indexes of plasma, insulin sensitivity, glucose intolerance, blood glucose and liver biochemical indexes were evaluated. Protein abundance of HO-1 and Nrf2 were assessed with Western blot. H/R treatment markedly ameliorated β-cell insufficiency and glucose intolerance, suppressed oxidative stress in vivo, stimulated the activities of anti-oxidant enzymes, and led to improved reproductive outcomes. The beneficial effects of H/R treatment were mechanistically mediated via the restoration of Nrf2/HO-1 anti-oxidant signaling pathway in the liver of GDM mice. Our study, for the first time, suggests that H/R treatment is a potentially novel therapeutic approach against GDM symptoms, by activating the Nrf2/HO-1 signaling pathway and inhibiting oxidative stress.


Bilateral Versus Single Internal Mammary Artery Use in Coronary Artery Bypass Grafting: A Propensity Matched Analysis.
Bilateral internal mammary artery (BIMA) grafts have demonstrated superior long-term outcomes compared with single internal mammary artery (SIMA) grafts. Despite this, BIMA remains widely underutilised due to perceived technical challenges and concerns regarding wound healing. We sought to examine the morbidity and mortality associated with BIMA use in a propensity-matched cohort of patients. From 2009 to 2016, 3,594 consecutive patients underwent coronary artery bypass surgery at three affiliated institutions. Thirty-day (30) mortality and morbidity data were collected prospectively. Propensity-score matched analyses were performed for BIMA versus SIMA use controlling for a number of preoperative characteristics. Overall, 29% of procedures were performed off pump, with a greater proportion in the BIMA group (43% vs. 21%, p<0.001). In the propensity-score analysis consisting of 820 matched pairs, there were similar rates of 30-day mortality (1.3% BIMA vs. 0.9% SIMA, p=0.48) and deep sternal wound infection (1.1% BIMA vs. 0.9% SIMA, p=0.84). The rate of superficial sternal wound infection trended towards being higher in the BIMA group (2.6% vs. 1.3%, p=0.077). The rates of red blood cell transfusions (27.4% vs. 27%, p=0.217), other blood product transfusions (18% vs. 20%, p=0.217), and reoperation for bleeding (2.9% vs. 2.1%, p=0.349) were similar. Bilateral internal mammary artery use was associated with similar rates of deep sternal wound infection compared to SIMA use, with a preponderance of superficial sternal wound infections that did not result in increased mortality or transfusion requirements. The use of BIMA should be more widely considered for coronary artery bypass surgery.


Inequities in childhood immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics in Kenya.
The global Immunisation Agenda 2030 highlights coverage and equity as a strategic priority goal to reach high equitable immunisation coverage at national levels and in all districts. We estimated inequities in full immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics among children aged 12-23 months in Kenya. We analysed full immunisation coverage (1-dose BCG, 3-dose DTP-HepB-Hib (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B), 3-dose polio, 1-dose measles, and 3-dose pneumococcal vaccines) of 3943 children aged 12-23 months from the 2014 Kenya Demographic and Health Survey. We disaggregated mean coverage by socioeconomic (household wealth, religion, ethnicity), geographic (place of residence, province), maternal (maternal age at birth, maternal education, maternal marital status, maternal household head status), child (sex of child, birth order), and place of birth characteristics, and estimated inequities in full immunisation coverage using bivariate and multivariate logistic regression. Immunisation coverage ranged from 82% [81-84] for the third dose of polio to 97.4% [96.7-98.2] for the first dose of DTP-HepB-Hib, while full immunisation coverage was 68% [66-71] in 2014. After controlling for other background characteristics through multivariate logistic regression, children of mothers with primary school education or higher have at least 54% higher odds of being fully immunised compared to children of mothers with no education. Children born in clinical settings had 41% higher odds of being fully immunised compared to children born in home settings. Children in the Coast, Western, Central, and Eastern regions had at least 74% higher odds of being fully immunised compared to children in the North Eastern region, while children in urban areas had 26% lower odds of full immunisation compared to children in rural areas. Children in the middle and richer wealth quintile households were 43-57% more likely to have full immunisation coverage compared to children in the poorest wealth quintile households. Children who were sixth born or higher had 37% lower odds of full immunisation compared to first-born children. Children of mothers with no education, born in home settings, in regions with limited health infrastructure, living in poorer households, and of higher birth order are associated with lower rates of full immunisation. Targeted programmes to reach under-immunised children in these subpopulations will lower the inequities in childhood immunisation coverage in Kenya.


Effect of urodilatin infusion on renal haemodynamics, tubular function and vasoactive hormones.
1. The renal efficacy of urodilatin in humans has only been partly investigated. It is unknown whether intravenously infused urodilatin has an effect on sodium reabsorption in both the proximal and distal part of the nephron. 2. Twelve healthy subjects participated in this double-blind, placebo-controlled study in a cross-over design. They received, in a randomized order, a short term (60 min) infusion of urodilatin in three different doses (10, 20 and 40 ng min-1 kg-1 of body weight) and placebo. Renal haemodynamics were estimated by clearance technique with radioactive tracers, and proximal tubular handling of sodium was evaluated by lithium clearance. 3. The 20 ng min-1 kg-1 dose increased the urinary sodium excretion and urinary flow rate compared with the effects of placebo. It increased the glomerular filtration rate and decreased the effective renal plasma flow. In addition, the dose increased the lithium clearance compared with placebo, but did not significantly change the fractional excretion of lithium. On the other hand, it markedly decreased the distal fractional reabsorption of sodium. It also had a suppressive effect on renin secretion. The systemic arterial blood pressure was unchanged, but the dose increased the pulse rate and the haematocrit. The highest dose (40 ng min-1 kg-1) induced a wide variation in the natriuretic and diuretic responses, probably due to a blood-pressure-lowering effect. 4. We conclude, that the urodilatin dose of 20 ng min-1 kg-1 of body weight was most efficacious in this short-term infusion study, and that it had potent natriuretic and diuretic qualities, probably due to stimulation of the glomerular filtration rate and inhibition of sodium reabsorption in the distal part of the nephron.


Seaweed Secondary Metabolites with Beneficial Health Effects: An Overview of Successes in In Vivo Studies and Clinical Trials.
Macroalgae are increasingly viewed as a source of secondary metabolites with great potential for the development of new drugs. In this development, in vitro studies are only the first step in a long process, while in vivo studies and clinical trials are the most revealing stages of the true potential and limitations that a given metabolite may have as a new drug. This literature review aims to give a critical overview of the secondary metabolites that reveal the most interesting results in these two steps. Phlorotannins show great pharmaceutical potential in in vivo models and, among the several examples, the anti-dyslipidemia activity of dieckol must be highlighted because it was more effective than lovastatin in an in vivo model. The IRLIIVLMPILMA tridecapeptide that exhibits an in vivo level of activity similar to the hypotensive clinical drug captopril should still be stressed, as well as griffithsin which showed such stunning results over a variety of animal models and which will probably move onto clinical trials soon. Regarding clinical trials, studies with pure algal metabolites are scarce, limited to those carried out with kahalalide F and fucoxanthin. The majority of clinical trials currently aim to ascertain the effect of algae consumption, as extracts or fractions, on obesity and diabetes.


The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma.
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) histological features. It is almost impossible to obtain an accurate, preoperative noninvasive diagnosis of cHCC-CC with tumor markers or cross-sectional abdominal imaging due to the mixed histological features. Despite these difficulties, accurate cHCC-CC diagnosis remains an important goal with prognostic significance. In our study, we retrospectively reviewed the tumor markers: AFP and CA 19-9, and cross-sectional liver imaging, in light of liver explant findings, to identify and characterize cHCC-CC features followed by liver transplantation (LT) outcome analysis. The results from this 12 patient cohort failed to identify characteristic features for cHCC-CC. None of the imaging features helped to identify the cHCC-CC tumor and they mimicked either HCC or CC, depending on the degree of glandular differentiation expressed histologically. In our cHCC-CC LT recipients, the 1-, 3- and 5-year cumulative survival probabilities were 79%, 66% and 16%, respectively with a 5-year survival comparable to or better than LT for intrahepatic CC but poorer than LT for HCC following the Milan criteria. Conceivably explained by its cholangiocarcinoma component the LT outcome for this rare and hard to diagnose tumor appears poor.


Caffeine enhances sustained attention among adolescents.
Despite the growing interest in caffeine use and its effects among adolescents, and a large literature on caffeine and attention among adults, there is a lack of experimental work examining the impact of caffeine on sustained attention among adolescents. We evaluated the acute effects of caffeine (vs. placebo) during a long (33-min) classic vigilance task among 31 adolescents (aged 12-17; 15 female; median caffeine use = 28 mg/day). We predicted a dose-dependent effect of caffeine, which would attenuate declines in target detection over time (i.e., a vigilance decrement). In each of 3 visits, participants completed an identical pairs continuous performance task beginning ∼25 min after consumption of noncaloric flavored water containing placebo, 1 mg/kg, or 3 mg/kg caffeine (order counterbalanced). Percent hits for low probability targets across 12 100-trial blocks was the primary outcome measure. As predicted, the linear decline in hits across trial blocks was attenuated by caffeine (Caffeine vs. Placebo × Block Linear, p = .01), with significant improvements in Blocks 9-12 (ps < .03). Compared to 1 mg/kg, 3 mg/kg caffeine resulted in earlier improvement in target detection (Drug Dose × Block Quadratic, p = .001). This study demonstrated that caffeine acutely and dose-dependently improves sustained attention among adolescents. These results were likely due to the attention-enhancing effect of caffeine, rather than withdrawal reversal, as our sample was characterized by light to moderate caffeine use. This study provides the foundation for further work on the impact of chronic caffeine consumption on cognitive function during adolescence. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets.
These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any gender-related differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 micromol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 micromol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25. 3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2. 1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 micromol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels.


Binaural interactions in primary auditory cortex of the awake macaque.
The functional organization of primary auditory cortex in non-primates is generally modeled as a tonotopic gradient with an orthogonal representation of independently mapped binaural interaction columns along the isofrequency contours. Little information is available regarding the validity of this model in the primate brain, despite the importance of binaural cues for sound localization and auditory scene analysis. Binaural and monaural responses of A1 to pure tone stimulation were studied using auditory evoked potentials, current source density and multiunit activity. Key findings include: (i) differential distribution of binaural responses with respect to best frequency, such that 74% of the sites exhibiting binaural summation had best frequencies below 2000 Hz; (ii) the pattern of binaural responses was variable with respect to cortical depth, with binaural summation often observed in the supragranular laminae of sites showing binaural suppression in thalamorecipient laminae; and (iii) dissociation of binaural responses between the initial and sustained action potential firing of neuronal ensembles in A1. These data support earlier findings regarding the temporal and spatial complexity of responses in A1 in the awake state, and are inconsistent with a simple orthogonal arrangement of binaural interaction columns and best frequency in A1 of the awake primate.


Clinical effectiveness and cost-effectiveness of second- and third-generation left ventricular assist devices as either bridge to transplant or alternative to transplant for adults eligible for heart transplantation: systematic review and cost-effectiveness model.
Advanced heart failure (HF) is a debilitating condition for which heart transplant (HT) offers the best treatment option. However, the supply of donor hearts is diminishing and demand greatly exceeds supply. Ventricular assist devices (VADs) are surgically implanted pumps used as an alternative to transplant (ATT) or as a bridge to transplant (BTT) while a patient awaits a donor heart. Surgery and VADs are costly. For the NHS to allocate and deliver such services in a cost-effective way the relative costs and benefits of these alternative treatments need to be estimated. To investigate for patients aged ≥ 16 years with advanced HF eligible for HT: (1) the clinical effectiveness and cost-effectiveness of second- and third-generation VADs used as BTT compared with medical management (MM); and (2) the clinical effectiveness and cost-effectiveness of second- and third-generation VADs used as an ATT in comparison with their use as BTT therapy. Searches for clinical effectiveness studies covered years from 2003 to March 2012 and included the following data bases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases [NHS Centre for Reviews and Dissemination (CRD)], Science Citation Index and Conference Proceedings (Web of Science), UK Clinical Research Network (UKCRN) Portfolio Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and National Library of Medicine (NLM) Gateway, Cochrane Central Register of Controlled Trials (CENTRAL), Current Controlled Trials and ClinicalTrials.gov. Reference lists of relevant articles were checked, and VAD manufacturers' websites interrogated. For economic analyses we made use of individual patient data (IPD) held in the UK Blood and Transplant Database (BTDB). Systematic reviews of evidence on clinical effectiveness and cost-effectiveness of second- and third-generation US Food and Drug Administration (FDA) and/or Conformité Européenne (CE) approved VADs. Publications from the last 5 years with control groups, or case series with 50 or more patients were included. Outcomes included survival, functional capacity (e.g. change in New York Heart Association functional classification), quality of life (QoL) and adverse events. Data from the BTDB were obtained. A discrete-time, semi-Markov, multistate model was built. Deterministic and probabilistic methods with multiple sensitivity analyses varying survival, utilities and cost inputs to the model were used. Model outputs were incremental cost-effectiveness ratios (ICERs), cost/quality-adjusted life-years (QALYs) gained and cost/life-year gained (LYG). The discount rate was 3.5% and the time horizon varied over 3 years, 10 years and lifetime. Forty publications reported clinical effectiveness of VADs and one study reported cost-effectiveness. We found no high-quality comparative empirical studies of VADs as BTT compared with MM or as ATT compared with BTT. Approximately 15-25% of the patients receiving a device had died by 12 months. Studies reported the following wide ranges for adverse events: 4-27% bleeding requiring transfusion; 1.5-40% stroke; 3.3-48% infection; 1-14% device failure; 3-30% HF; 11-32% reoperation; and 3-53% renal failure. QoL and functional status were reported as improved in studies of two devices [HeartMate II (HMII; Thoratec Inc., Pleasanton, CA, USA) and HeartWare (HW; HeartWare Inc., Framingham, MA, USA)]. At 3 years, 10 years and lifetime, the ICERs for VADs as BTT compared with MM were £122,730, £68,088 and £55,173 respectively. These values were stable to changes in survival of the MM group. Both QoL and costs were reduced by VADs as ATT compared with VADs as BTT giving ICERs in south-west quadrant of the cost effectiveness plain (cost saving/QALY sacrificed) of £353,467, £31,685 and £20,637 over the 3 years, 10 years and lifetime horizons respectively. Probabilistic analyses yielded similar results for both research questions. Conclusions about the clinical effectiveness were limited by the lack of randomised controlled trials (RCTs) comparing the effectiveness of different VADs for BTT or comparing BTT with any alternative treatment and by the overlapping populations in published studies. Although IPD from the BTDB was used to estimate the cost-effectiveness of VADs compared with MM for BTT, the lack of randomisation of populations limited the interpretation of this analysis. At 3 years, 10 years and lifetime the ICERs for VADs as BTT compared with MM are higher than generally applied willingness-to-pay thresholds in the UK, but at a lifetime time horizon they approximate threshold values used in end of life assessments. VADs as ATT have a reduced cost but cause reduced QALYs relative to BTT. Future research should direct attention towards two areas. First, how any future evaluations of second- or third-generation VADs might be conducted. For ethical reasons a RCT offering equal probability of HT for each group would not be feasible; future studies should fully assess costs, long-term patient survival, QoL, functional ability and adverse events, so that these may be incorporated into economic evaluation agreement on outcomes measures across future studies. Second, continuation of accurate data collection in the UK database to encompass QoL data and comparative assessment of performance with other international centres. The National Institute for Health Research Health Technology Assessment programme.


Where is your arm? Variations in proprioception across space and tasks.
The sense of limb position is crucial for movement control and environmental interactions. Our understanding of this fundamental proprioceptive process, however, is limited. For example, little is known about the accuracy of arm proprioception: Does it vary with changes in arm configuration, since some peripheral receptors are engaged only when joints move toward extreme angles? Are these variations consistent across different tasks? Does proprioceptive ability change depending on what we try to localize (e.g., fingertip position vs. elbow angle)? We used a robot exoskeleton to study proprioception in 14 arm configurations across three tasks, asking healthy subjects to 1) match a pointer to elbow angles after passive movements, 2) match a pointer to fingertip positions after passive movements, and 3) actively match their elbow angle to a pointer. Across all three tasks, subjects overestimated more extreme joint positions; this may be due to peripheral sensory signals biasing estimates as a safety mechanism to prevent injury. We also found that elbow angle estimates were more precise when used to judge fingertip position versus directly reported, suggesting that the brain has better access to limb endpoint position than joint angles. Finally, precision of elbow angle estimates improved in active versus passive movements, corroborating work showing that efference copies of motor commands and alpha-gamma motor neuron coactivation contribute to proprioceptive estimates. In sum, we have uncovered fundamental aspects of normal proprioceptive processing, demonstrating not only predictable biases that are dependent on joint configuration and independent of task but also improved precision when integrating information across joints.


Joints and their relations as critical features in action discrimination: evidence from a classification image method.
Classifying an action as a runner or a walker is a seemingly effortless process. However, it is difficult to determine which features are used with hypothesis-driven research, because biological motion stimuli generally consist of about a dozen joints, yielding an enormous number of potential relationships among them. Here, we develop a hypothesis-free approach based on a classification image method, using experimental data from relatively few trials (∼1,000 trials per subject). Employing ambiguous actions morphed between a walker and a runner, we identified three types of features that play important roles in discriminating bipedal locomotion presented in a side view: (a) critical joint feature, supported by the finding that the similarity of the movements of feet and wrists to prototypical movements of these joints were most reliably used across all participants; (b) structural features, indicated by contributions from almost all other joints, potentially through a form-based analysis; and (c) relational features, revealed by statistical correlations between joint contributions, specifically relations between the two feet, and relations between the wrists/elbow and the hips. When the actions were inverted, only critical joint features remained to significantly influence discrimination responses. When actions were presented with continuous depth rotation, critical joint features and relational features associated strongly with responses. Using a double-pass paradigm, we estimated that the internal noise is about twice as large as the external noise, consistent with previous findings. Overall, our novel design revealed a rich set of critical features that are used in action discrimination. The visual system flexibly selects a subset of features depending on viewing conditions.


Association of diabetes with age-related macular degeneration in the EUREYE study.
To examine the association between self-reported diabetes history and early or late age-related macular degeneration (AMD) in the European population. Participants aged 65 years and over in the cross-sectional population-based EUREYE study underwent an eye examination including digital retinal photography. The images were graded at a single centre. A structured questionnaire was administered by trained field workers for putative risk factors for AMD including history of diabetes mellitus. Logistic regression models were used to examine the association between diabetes and stages of AMD, taking account of potential demographic, behavioural, dietary and medical (history of cardiovascular disease) confounders. Photographic images were graded according to the modified International Classification System for AMD and stratified into five exclusive stages from no signs of AMD (AMD stage 0), early AMD (Stages 1-3) and late AMD (Stage 4). Late AMD was subdivided in neovascular AMD (NV-AMD) or geographic atrophy (GA). Data on diabetes history and potential confounders were available in 2117 control subjects without AMD, 2182 with early AMD, 49 with GA and 101 with NV-AMD. Of all participants, 13.1% reported a history of diabetes. After adjusting for potential confounders, subjects with neovascular AMD compared with controls had increased odds for diabetes (odds ratio 1.81; 95% confidence interval, 1.10 to 2.98, p = 0.02). Subjects with AMD grades 1 to 3 or GA had no increased odds for diabetes compared with those without AMD. In the EUREYE study, after multiple adjustments, positive association of diabetes mellitus with neovascular AMD was found. The hypothesis that diabetes is associated with neovascular AMD but not with geographic atrophy may suggest a different pathogenesis of the two advanced forms of the disease and needs to be further evaluated.


Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies.
Free radical chain oxidation of highly oxidizable 7-dehydrocholesterol (7-DHC), initiated by 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), was carried out at 37 degrees C in benzene for 24 h. Fifteen oxysterols derived from 7-DHC were isolated and characterized with 1D and 2D NMR spectroscopy and mass spectrometry. A mechanism that involves abstraction of hydrogen atoms at C-9 and/or C-14 is proposed to account for the formation of all of the oxysterols and the reaction progress profile. In either the H-9 or H-14 mechanism, a pentadienyl radical intermediate is formed after abstraction of H-9 or H-14 by a peroxyl radical. This step is followed by the well-precedented transformations observed in peroxidation reactions of polyunsaturated fatty acids such as oxygen addition, peroxyl radical 5-exo cyclization, and S(H)i carbon radical attack on the peroxide bond. The mechanism for peroxidation of 7-DHC also accounts for the formation of numerous oxysterol natural products isolated from fungal species, marine sponges, and cactaceous species. In a cell viability test, the oxysterol mixture from 7-DHC peroxidation was found to be cytotoxic to Neuro2a neuroblastoma cells in the micromolar concentration range. We propose that the high reactivity of 7-DHC and the oxysterols generated from its peroxidation may play important roles in the pathogenesis of Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata, and cerebrotendinous xanthomatosis, all of these being metabolic disorders characterized by an elevated level of 7-DHC.


A controlled comparison of involuntarily hospitalized medication refusers and acceptors.
Involuntarily hospitalized psychiatric patients consecutively admitted over a six-month period who successfully refused medication (n = 37) are compared with a randomly selected group of medication-accepting patients committed during the same time period (n = 37). The overall refusal rate was 15.6 percent during the study period. Acceptors and refusers did not differ on age, sex, diagnosis, ethnicity, marital status, or preadmission living status. Differences between the groups indicate that refusers are sicker and lower functioning, are more behaviorally acute on the ward, and stay in the hospital twice as long as acceptors. Refusers also have a significantly negative impact on the overall ward milieu. The impact of institutional factors on the rate and outcome from mediation refusal are discussed.


The Canadian Dementia Imaging Protocol: Harmonization validity for morphometry measurements.
The harmonized Canadian Dementia Imaging Protocol (CDIP) has been developed to suit the needs of a number of co-occurring Canadian studies collecting data on brain changes across adulthood and neurodegeneration. In this study, we verify the impact of CDIP parameters compliance on total brain volume variance using 86 scans of the same individual acquired on various scanners. Data included planned data collection acquired within the Consortium pour l'identification précoce de la maladie Alzheimer - Québec (CIMA-Q) and Canadian Consortium on Neurodegeneration in Aging (CCNA) studies, as well as opportunistic data collection from various protocols. For images acquired from Philips scanners, lower variance in brain volumes were observed when the stated CDIP resolution was set. For images acquired from GE scanners, lower variance in brain volumes were noticed when TE/TR values were within 5% of the CDIP protocol, compared to values farther from that criteria. Together, these results suggest that a harmonized protocol like the CDIP may help to reduce neuromorphometric measurement variability in multi-centric studies.


The role of chondrocytes in intramembranous and endochondral ossification during distraction osteogenesis in the rabbit.
We have used a rabbit leg-lengthening model for detailed studies of the histology of distraction osteogenesis. Some unusual features of the endochondral ossification that occurs during the rapid transition of cartilage to bone in the regenerate were observed. Histological staining techniques together with immunohistochemistry and nonradioactive in situ mRNA hybridization for cartilage and bone-related molecules have been used to document the presence of an overlapping cartilage-bone phenotype in cells of the cartilage-bone transitional region. In those particular areas, some chondrocytes appeared to be directly transformed into newly formed bone trabeculae which are surrounded by bone matrix. Acid phosphatases were found within the cartilage matrix in some of the cartilage/bone transitional regions and type I collagen mRNA and type II collagen protein were found together in some of the marginal hypertrophic chondrocytes. This study indicates an unusual role of chondrocytes in the process of ossification at a distraction rate of 1.3 mm/day in the rabbit. Further direct evidence is required to prove the hypothesis that the hypertrophic chondrocytes may transdifferentiate into bone cells in this model.