Do male secondary sexual characters correlate with testis size and sperm length in the small hairy maggot blowfly?
The phenotype-linked fertility hypothesis proposes that secondary sexual characters (SSCs) advertise a male's fertility to prospective mates. However, findings from empirical studies attempting to test this hypothesis are often ambivalent or even contradictory, and few studies have simultaneously evaluated how both morphological and behavioural SSCs relate to ejaculate characteristics. Males of the small hairy maggot blowfly, Chrysomya varipes, possess conspicuous foreleg ornaments and display highly stereotyped courtship behaviour. These traits are favoured by females during pre-copulatory mate choice, but it remains unknown whether they correlate with post-copulatory traits expected to influence male fertility. The aim of this study was to investigate whether male courtship and ornamentation correlate with testis size and sperm length in C. varipes. We found that males investing more in courtship had bigger testes, and males with more extensive foreleg ornamentation released sperm with longer tails. Based on the assumption that larger testes enable males to produce more sperm, and that sperm with longer tails have greater propulsive force, our findings suggest that more vigorous and more ornamented males may be more fertile. These findings lend support to the phenotype-linked fertility hypothesis. However, a complete test of this hypothesis will require evaluating whether testis size and sperm length influence male fertilisation ability, as well as female fecundity and/or fertility.


Circulating Apolipoprotein E Concentration and Cardiovascular Disease Risk: Meta-analysis of Results from Three Studies.
The association of APOE genotype with circulating apolipoprotein E (ApoE) concentration and cardiovascular disease (CVD) risk is well established. However, the relationship of circulating ApoE concentration and CVD has received little attention. To address this, we measured circulating ApoE concentration in 9,587 individuals (with 1,413 CVD events) from three studies with incident CVD events: two population-based studies, the English Longitudinal Study of Ageing (ELSA) and the men-only Northwick Park Heart Study II (NPHSII), and a nested sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). We examined the association of circulating ApoE with cardiovascular risk factors in the two population-based studies (ELSA and NPHSII) and the relationship between ApoE concentration and coronary heart disease and stroke in all three studies. Analyses were carried out within study, and, where appropriate, pooled effect estimates were derived using meta-analysis. In the population-based samples, circulating ApoE was associated with systolic blood pressure (correlation coefficient 0.08, p < 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both p < 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both p < 0.001), high-density lipoprotein (correlation coefficient 0.16 and -0.14, respectively; both p < 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both p < 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, p = 0.001) and lipoprotein(a) (correlation coefficient -0.11, p < 0.001). In the pooled analysis of ASCOT, ELSA, and NPHSII, there was no association of ApoE with CVD events; the odds ratio (OR) for CVD events per 1-standard-deviation higher ApoE concentration was 1.02 (95% CI 0.96, 1.09). After adjustment for cardiovascular risk factors, the OR for CVD per 1-standard-deviation higher ApoE concentration was 0.97 (95% CI 0.82, 1.15). Limitations of these analyses include a polyclonal method of ApoE measurement, rather than isoform-specific measurement, a moderate sample size (although larger than any other study to our knowledge and with a long lag between ApoE measures), and CVD events that may attenuate an effect. In the largest study to date on this question, we found no evidence of an association of circulating ApoE concentration with CVD events. The established association of APOE genotype with CVD events may be explained by isoform-specific functions as well as other mechanisms, rather than circulating concentrations of ApoE.


When to refer a patient with a nerve injury to a specialist.
Nerve injury is a known and accepted risk of many oral surgical and dental procedures. Such injuries may occur despite the practitioner's providing the best of care. Taking proactive measures during evaluation and surgery may reduce the incidence of nerve injury. Injuries to the peripheral branches of the trigeminal nerve can cause unfavorable effects on orofacial sensation and related functions such as eating, drinking, washing, speaking, shaving and kissing. When nerve injuries secondary to dental or oral surgery procedures fail to resolve promptly and the resulting dysesthesia is unacceptable to the patient, timely treatment gives the patient the best chance of a favorable outcome. Treatment may involve surgical exploration and repair of the injured nerve. Recognition of and prompt referral for nerve injuries give the patient the best chance of achieving improvement or recovery of sensory function in the distribution of the injured nerve.


Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.
Necdin and Magel2 are related proteins inactivated in Prader-Willi syndrome (PWS), a sporadic chromosomal deletion disorder. We demonstrate that necdin and Magel2 bind to and prevent proteasomal degradation of Fez1, a fasciculation and elongation protein implicated in axonal outgrowth and kinesin-mediated transport, and also bind to the Bardet-Biedl syndrome (BBS) protein BBS4 in co-transfected cells. The interactions among necdin, Magel2, Fez1 and BBS4 occur at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS and may also be important in the features of PWS that overlap with BBS, such as learning disabilities, hypogonadism and obesity. Morphological abnormalities in axonal outgrowth and fasciculation manifest in several regions of the nervous system in necdin null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic and catecholaminergic neurons. These data demonstrate that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin impinges on axonal outgrowth. We further suggest that loss of necdin contributes to the neurological phenotype of PWS, and raise the possibility that co-deletion of necdin and the related protein Magel2 may explain the lack of single gene mutations in PWS.


Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation.
This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation. Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation. The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC0-24 in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups. The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC0-24. If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.


Absence of spontaneous central nervous system remyelination in class II-deficient mice infected with Theiler's virus.
We previously showed that Theiler's murine encephalomyelitis virus (TMEV)-infected major histocompatibility complex (MHC) class II-deficient mice develop both demyelination and neurologic deficits, whereas MHC class I-deficient mice develop demyelination but no neurologic deficits. The absence of neurologic deficits in the class I-deficient mice was associated with preserved sodium channel densities in demyelinated lesions, a relative preservation of axons, and extensive spontaneous remyelination. In this study, we investigated whether TMEV-infected class II-deficient mice, which have an identical genetic background (C57BL/6 x 129) as the class I-deficient mice, have preserved axons and spontaneous myelin repair following chronic TMEV-infection. Both class I- and class II-deficient mice showed similar extents of demyelination of the spinal cord white matter 4 months after TMEV infection. However, the class I-deficient mice demonstrated remyelination by oligodendrocytes, whereas class II-deficient mice showed minimal if any myelin repair. Demyelinated lesions, characterized by inflammatory infiltrates in both mutants, revealed disruption of axons in class II- but not class I-deficient mice. Further characterization revealed that even though class II-deficient mice lacked TMEV-specific IgG, they had virus-specific IgM, which, however, did not neutralize TMEV in vitro. In addition, class II-deficient mice developed TMEV-specific cytotoxic T-lymphocytes in the CNS during the acute (7 days) disease, but these cytotoxic lymphocytes were not present in the chronic stage of disease, despite a high titer of infectious virus throughout the disease. We envision that the presence of demyelination, high virus titer, absence of remyelination, and axonal disruption in chronically infected class II-deficient mice contributes to the development of paralytic disease.


Staphylococcal proteases aid in evasion of the human complement system.
Staphylococcus aureus is an opportunistic pathogen that presents severe health care concerns due to the prevalence of multiple antibiotic-resistant strains. New treatment strategies are urgently needed, which requires an understanding of disease causation mechanisms. Complement is one of the first lines of defense against bacterial pathogens, and S. aureus expresses several specific complement inhibitors. The effect of extracellular proteases from this bacterium on complement, however, has been the subject of limited investigation, except for a recent report regarding cleavage of the C3 component by aureolysin (Aur). We demonstrate here that four major extracellular proteases of S. aureus are potent complement inhibitors. Incubation of human serum with the cysteine proteases staphopain A and staphopain B, the serine protease V8 and the metalloproteinase Aur resulted in a drastic decrease in the hemolytic activity of serum, whereas two staphylococcal serine proteases D and E, had no effect. These four proteases were found to inhibit all pathways of complement due to the efficient degradation of several crucial components. Furthermore, S. aureus mutants lacking proteolytic enzymes were found to be more efficiently killed in human blood. Taken together, the major proteases of S. aureus appear to be important for pathogen-mediated evasion of the human complement system.


The role of platelet-derived growth factor in the development of mouse molars.
Platelet-derived growth factor (PDGF) is a potent mitogen that functions in cytodifferentiation and wound healing. PDGF receptor-alpha (PDGFR-alpha) is required for the normal development of the dental ectomesenchyme (Stephenson et al., Proc. Natl. Acad. Sci. USA 88: 6-10, 1991). To investigate the regulatory potential of PDGF on tooth development, the expression of PDGF-AA was determined by reverse transcription-polymerase chain reaction (RT-PCR), the PDGF ligands and receptors were localized by immunohistochemistry. The growth-promoting effects of exogenous PDGF-AA on molar explants were determined by assaying for tritiated thymidine incorporation, the presence of type I collagen and amelogenin messenger RNA transcripts, and total DNA, RNA and protein accumulation. Based upon the temporal and spatial localization, PDGFs and their receptors are present in the enamel epithelia and pulpal mesenchyme of developing mouse molars. Exogenous PDGF-AA administration increased the total protein accumulation of mouse molar explants but produces no discernible effect on amelogenin and type I collagen expression.


How much do we know about constipation after surgery for anorectal malformation?
To evaluate the occurrence of constipation after anorectal malformations (ARM) repair and the results of laxative treatment. Between August 2012 and July 2017, the clinical data of patients with ARMs was prospectively collected. The patients were divided into two groups, good types and poor types. Good types included rectoperineal, rectovestibular, rectourethral bulbar, and no fistula. Risk factors were defined as spinal cord anomalies, sacral ratio <0.4, or cognitive impairment. Success was defined as that laxative could be tapered. Eighty-four patients were enrolled with mean age of 6.3 ± 7.8 (0.6-59.9) years. The mean age of onset of constipation was 12.8 ± 8.3 months and the mean interval was 5.9 ± 5.1 months after reconstructions. The interval was not significantly different between patients with good types and poor types. In 23 patients with severe constipation being treated for >6 months, 14 of 18 (77.8%) patients with good types were classified as success, whereas only 1 of 5 (20%) patients with poor types was (p = 0.02). In patients with good types, 9 of 9 (100%) patients with no risk factors were successful; however, only 5 out of 9 (55.6%) patients with risk factors were successful (p = 0.02). Constipation occurs shortly after operations. Patients with good types and no risk factors are susceptible to weaning laxatives.


A multi-centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2.
Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood. We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis. Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies. Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.


Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories.
In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphase plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered.


End-of-life planning in heart failure: it should be the end of the beginning.
Cardiovascular disease (CVD) is a chronic, progressive, incurable condition characterized by periods of apparent stability interspersed with acute exacerbations. Despite many important advances in its treatment, approximately one-third of deaths in Canada each year result from CVD. While this might lead one to assume that a comprehensive medical approach exists to the management of this inevitable outcome, the reality is much different. The current Canadian medical model emphasizes the management of acute exacerbations of CVD during which end-of-life issues figure frequently and prominently, although in a setting that is inappropriate to address the comprehensive needs of patients and their families.As a result, end-of-life care was made a theme of the recently reported Canadian Heart Health Strategy and Action Plan (www.chhs-scsc.ca). From this, several recommendations are made, central to which is the need to reframe CVD as a condition ideally suited to a chronic disease management approach. In addition, replacement of the term 'palliative care' with the term 'end-of-life planning and care' is proposed to foster earlier and more integrated comprehensive care, which, it is proposed, denotes the provision of advanced care planning, palliative care, hospice care and advanced directives, with a focus on decision making and planning. Finally, end-of-life planning and care should be a routine part of assessment of any patient with CVD, should be reassessed whenever important clinical changes occur and should be provided in a manner consistent with relevant CVD practice guidelines. Specifically, a Canadian strategy to improve end-of-life planning and care should focus on the following: * Integrated end-of-life planning and care across the health care system; * Facilitated communication and seamless care provision across all providers involved in end-of-life planning and care; * Adequate resources in the community for end-of-life planning and care; * Specialized training in sensitive communication and supportive care as part of core training for all members of the interdisciplinary care team; * Measurement of key performance indicators for end-of-life planning and care; and * Research into effective end-of-life planning and care.Heart failure is an advanced form of CVD with very high morbidity, mortality and burden of care, making it an ideal condition for implementation and testing of interventions to improve end-of-life planning and care.


Development of a Predictive Model for Common Bile Duct Stones in Patients With Clinical Suspicion of Choledocholithiasis: A Cohort Study.
Current choledocholithiasis guidelines heavily focus on patients with low or no risk, they may be inappropriate for populations with high rates of choledocholithiasis. We aimed to develop a predictive scoring model for choledocholithiasis in patients with relevant clinical manifestations. A multivariable predictive model development study based on a retrospective cohort of patients with clinical suspicion of choledocholithiasis was used in this study. The setting was a 700-bed public tertiary hospital. Participants were patients who had completed three reference tests (endoscopic retrograde cholangiography, magnetic resonance cholangiopancreatography, and intraoperative cholangiography) from January 2019 to June 2021. The model was developed using logistic regression analysis. Predictor selection was conducted using a backward stepwise approach. Three risk groups were considered. Model performance was evaluated by area under the receiver operating characteristic curve, calibration, classification measures, and decision curve analyses. Six hundred twenty-one patients were included; the choledocholithiasis prevalence was 59.9%. The predictors were age > 55 years, pancreatitis, cholangitis, cirrhosis, alkaline phosphatase level of 125 - 250 or > 250 U/L, total bilirubin level > 4 mg/dL, common bile duct size > 6 mm, and common bile duct stone detection. Pancreatitis and cirrhosis each had a negative score. The sum of scores was -4.5 to 28.5. Patients were categorized into three risk groups: low-intermediate (score ≤ 5), intermediate (score 5.5 - 14.5), and high (score ≥ 15). Positive likelihood ratios were 0.16 and 3.47 in the low-intermediate and high-risk groups, respectively. The model had an area under the receiver operating characteristic curve of 0.80 (95% confidence interval: 0.76, 0.83) and was well-calibrated; it exhibited better statistical suitability to the high-prevalence population, compared to current guidelines. Our scoring model had good predictive ability for choledocholithiasis in patients with relevant clinical manifestations. Consideration of other factors is necessary for clinical application, particularly regarding the availability of expert physicians and specialized equipment.


Intracranial pressure dose and outcome in traumatic brain injury.
Detecting and treating elevated intracranial pressure (ICP) is a cornerstone of management in patients with severe traumatic brain injury. The aim of this study was to determine the association between area under the curve measurement of elevated ICP and clinical outcome. Single center observational study using prospectively collected data at a University hospital, level one-trauma center. Sixty prospective patients with severe traumatic brain injury were prospectively enrolled over a 2-year period. Intracranial pressure measurements were captured using a real-time automated, high resolution vital signs data recording system. Mortality and functional outcome were assessed at 30 days, 3 and 6 months using Extended Glasgow Outcome Scale. Increasing elevated intracranial pressure time dose was associated with mortality (OR 1.08; 95 % confidence interval [CI], 1.01-1.15, p = 0.03) and poor functional outcome at 3 (OR 1.04; CI 1.00-1.07, p = 0.03) and 6 months (1.04; CI 1.01-1.08, p = 0.02). However, there was no association between episodic ICP data and outcome. These results suggest that pressure time dose measurement of intracranial pressure may be used to predict outcome in severe traumatic brain injury and may be a candidate biomarker in this disease.


A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice.
The commonly accepted diagnostic algorithm for hematuria includes excretory urography (IVP) and cystoscopy. Some have suggested that ultrasound of the upper urinary tract is adequate and that cystoscopy is not necessary in younger patients with microscopic hematuria. We ascertain whether a less intensive algorithm could be adopted while retaining diagnostic efficacy. A total of 1,930 patients were enrolled prospectively in the study at a hematuria clinic between October 1994 and March 1997. Evaluation consisted of basic demographics, history and examination, routine blood tests, urinalysis and cytology. All patients underwent plain abdominal radiography, renal ultrasound, IVP and flexible cystoscopy. A total of 1,194 males and 736 females with a mean age of 58 years (range 17 to 96) were included in the study. Overall, 61% of patients had no basis found for hematuria, 12% had bladder cancer, 13% had urinary tract infection and 2% had stones. Kidney and upper tract tumors were noted in 14 patients (0.7%), including 4 who presented with microscopic hematuria. If only ultrasound or IVP had been performed 4 of these cases would have been missed. Of 982 patients presenting with microscopic hematuria 51 had cancer. Bladder cancer was found in 7 patients younger than 40 years. Our findings suggest that cystoscopy cannot be safely avoided even in younger patients with microscopic hematuria. Only a combination of ultrasound and IVP detected all upper tract tumors.


Evolutionary analysis of whole-genome sequences confirms inter-farm transmission of Aleutian mink disease virus.
Aleutian mink disease virus (AMDV) is a frequently encountered pathogen associated with mink farming. Previous phylogenetic analyses of AMDV have been based on shorter and more conserved parts of the genome, e.g. the partial NS1 gene. Such fragments are suitable for detection but are less useful for elucidating transmission pathways while sequencing entire viral genomes provides additional informative sites and often results in better-resolved phylogenies. We explore how whole-genome sequencing can benefit investigations of AMDV transmission by reconstructing the relationships between AMDV field samples from a Danish outbreak. We show that whole-genome phylogenies are much better resolved than those based on the partial NS1 gene sequences extracted from the same alignment. Well-resolved phylogenies contain more information about the underlying transmission trees and are useful for understanding the spread of a pathogen. In the main case investigated here, the transmission path suggested by the tree structure was supported by epidemiological data. The use of molecular clock models further improved tree resolution and provided time estimates for the viral ancestors consistent with the proposed direction of spread. It was however impossible to infer transmission pathways from the partial NS1 gene tree, since all samples from the case farms branched out from a single internal node. A sliding window analysis showed that there were no shorter genomic regions providing the same phylogenetic resolution as the entire genome. Altogether, these results suggest that phylogenetic analyses based on whole-genome sequencing taking into account sampling dates and epidemiological data is a promising set of tools for clarifying AMDV transmission.


Liquid-Liquid Phase Separation As the Second Step of Complex Coacervation.
Liquid-liquid phase separation (LLPS) between tyrosine- and arginine-rich peptides are of biological importance. To understand the interactions between proteins in the condensed phase in close analogy to complex coacervation, we run multiple umbrella calculations between oligomers containing tyrosine (pY) and arginine (pR). We find pR-pY complexation to be energetically driven. Metadynamics simulations on monomers suggest that this energy of complexation is correlated with the number of π-cation bonds. Free energy calculations for the binding between pairs of poly glutamate-pR dimers show striking similarities between this process and LLPS. These calculations suggest that proteins containing arginine and tyrosine residues do not undergo complexation followed by coacervation. The mechanism, rather, is akin to phase separation of neutral polyion pairs.


Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.


Exploring motorcycle red-light violation in response to pedestrian green signal countdown device.
Literature has suggested that angle/rear-end collisions would arise from the reality that motorists and motorcyclists tended to accelerate aggressively in response to the remaining seconds of green signal countdown device (GSCD). One safety concern, while GSCD has gradually been removed for safety in Taiwan, is pedestrian green signal countdown device (PGSCD) that is used by approaching motorists and motorcyclists that may adopt the information to travel aggressively - an unintended consequence that is detrimental to safety. Research has reported that there appeared no negative effect of PGSCD on motorist behaviours but the effect on motorcyclists' behaviours has been rarely investigated. Using video/speed cameras, the current research investigates motorcyclists' RLV (red-light violation) behaviours. The descriptive analyses indicate that the percentage of RLV at PGSCD intersection is higher than that at typical intersection, and the violating motorcycles appear to have higher travelling speeds at PGSCD intersection. Several interaction terms were examined with the binary logit framework, and the results reveal that several factors are associated with RLV, notably male/young riders, moped/large motorcycle users, higher approaching speeds of motorcycles, those with tropical helmets, and lower traffic volume. Similar determinants of early-start behaviours (for those waiting at reds and could view the PGSCDs for the crossing pedestrians at the same time) were identified. Implications of the research findings, the concluding remarks, and recommendations for future research are finally provided.


Propagating free-space nonparaxial beams.
We use a method based on the simultaneous combination of the propagation operator and the Fourier transform with arbitrary index in propagating the transverse component of a nonparaxial beam in free space from an arbitrary initial transverse field structure. Being an iterative method, this approach can easily be implemented computationally. As an example of its efficiency, we derive the closed-form nonparaxial corrections to a Bessel-Gaussian beam, showing that our results differ strongly from those reported previously. The validity of our approach is supported by an analysis of the paraxiality estimator recently introduced in the literature.


Scattering based hyperspectral imaging of plasmonic nanoplate clusters towards biomedical applications.
A new optical scattering contrast-agent based on polymer-nanoparticle encapsulated silver nanoplates (PESNs) is presented. Silver nanoplates were chosen due to the flexibility of tuning their plasmon frequencies. The polymer coating preserves their physical and optical properties and confers other advantages such as controlled contrast agent delivery. Finite difference time domain (FDTD) simulations model the interaction of light with the nanoplates in different orientations in the cluster. Hyperspectral dark field microscopy (HYDFM) observes the scattering spectra of the PESNs. An unsupervised sequential maximum angle convex cone (SMACC) image analysis resolves spectral endmembers corresponding to different stacking orientations of the nanoplates. The orientation-dependent endmembers qualitatively agree with the FDTD results. For contrast enhancement, the uptake and spatial distribution of PESNs are demonstrated by an HYDFM study of single melanoma cells to result in an enhanced contrast of up to 400%. A supervised spatial mapping of the endmembers obtained by the unsupervised SMACC algorithm reveals spatial distributions of PESNs with various clustering orientations of encapsulated nanoplates. Our study demonstrates tunability in plasmonics properties in clustered metal nanoparticles and its utility for the development of scatter-based imaging contrast agents for a broad range of applications, including studies of single cells and other biomedical systems.


Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes.
Lipid rafts and caveolae are biochemically similar, specialized domains of the PM (plasma membrane) that cluster specific proteins. However, they are morphologically distinct, implying different, possibly complementary functions. Two-dimensional gel electrophoresis preceding identification of proteins by MS was used to compare the relative abundance of proteins in DRMs (detergent-resistant membranes) isolated from HUVEC (human umbilical-vein endothelial cells), and caveolae immunopurified from DRM fractions. Various signalling and transport proteins were identified and additional cell-surface biotinylation revealed the majority to be exposed, demonstrating their presence at the PM. In resting endothelial cells, the scaffold of immunoisolated caveolae consists of only few resident proteins, related to structure [CAV1 (caveolin-1), vimentin] and transport (V-ATPase), as well as the GPI (glycosylphosphatidylinositol)-linked, surface-exposed protein CD59. Further quantitative characterization by immunoblotting and confocal microscopy of well-known [eNOS (endothelial nitric oxide synthase) and CAV1], less known [SNAP-23 (23 kDa synaptosome-associated protein) and BASP1 (brain acid soluble protein 1)] and novel [C8ORF2 (chromosome 8 open reading frame 2)] proteins showed different subcellular distributions with none of these proteins being exclusive to either caveolae or DRM. However, the DRM-associated fraction of the novel protein C8ORF2 (approximately 5% of total protein) associated with immunoseparated caveolae, in contrast with the raft protein SNAP-23. The segregation of caveolae from lipid rafts was visually confirmed in proliferating cells, where CAV1 was spatially separated from eNOS, SNAP-23 and BASP1. These results provide direct evidence for the previously suggested segregation of transport and signalling functions between specialized domains of the endothelial plasma membrane.


Structure-based design of novel combinatorially generated NBTIs as potential DNA gyrase inhibitors against various Staphylococcus aureus mutant strains.
Although intercalating agents such as quinolones have had proven therapeutic success as antibacterial agents for more than 40 years, new forms of quinolone-based resistance in bacteria are continually emerging. To alleviate this problem, a new class of antibacterials is urgently needed; recently, novel bacterial topoisomerase inhibitors (NBTIs) have been found to be particularly important. Based on 67 experimentally evaluated NBTIs against wild-type (WT) DNA gyrase originating from Staphylococcus aureus, a predictive QSAR model was initially constructed and validated and was later used for in silico prediction of biological activities for an in house designed compound library of 548 novel drug-like NBTI combinatorial analogs. To evaluate the influence of gyrA alterations on NBTI resistance, various mutant homology models were constructed; meanwhile, their resistance profiles were assessed and validated relative to that of WT enzyme by structure-based virtual screening (VS) of known NBTIs. Surprisingly, the M121K mutant model was recognized as the most selective due to an additional established cation-π interaction between K121-NH3+ (not found in the WT) and the aromatic moiety of the NBTI right-hand site (RHS) fragment; this finding was additionally supported by VS of our combinatorially generated NBTIs. Moreover, we identified several attractive, synthetically feasible RHS building blocks that may enable the development of new NBTIs.


Age- and sex-specific pediatric reference intervals for biochemistry analytes as measured with the Ektachem-700 analyzer.
Using the Ektachem-700 multilayer film analyzer, we defined age- and sex-specific reference intervals for 20 analytes in sera from a healthy population of neonates and children ages one to 19 years. Upper and lower normal reference intervals for each analyte were determined by nonparametric methods as the 0.975 and 0.025 fractiles, respectively. Newborns have lower concentrations of total protein and albumin, and higher concentrations of phosphate, bilirubin, and enzymes in serum than older children do. Concentrations of urea, glucose, calcium, phosphate, and bilirubin change rapidly postnatally. Outside the neonatal period, no significant age- or sex-related difference was found for plasma glucose, serum amylase, conjugated or unconjugated bilirubin, or lipase. There was no sex-related difference in reference intervals for albumin, total protein, calcium, phosphate, or urea. However, concentrations of uric acid and creatine kinase are much higher in postpubertal boys than in girls. Alkaline phosphatase values peak later in boys. Except for lactate dehydrogenase and gamma-glutamyltransferase, the reference intervals defined here do not differ strikingly from data derived with use of other analyzers. The age- and sex-related trends are independent of method. However, each laboratory should determine the degree to which these reference ranges can be directly applied to analyses performed with another analyzer.


Effective use of TNF antagonists.
Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.


Psychological Distress in Patients with Coronary Artery Disease During the COVID-19 Pandemic and its Association with Coping Mechanisms.
Coronary artery disease (CAD) has been associated with increased stress both etiologically and as a consequence. The current pandemic of COVID-19 infection has impacted the personal, social, and occupational spheres of people's lives and has negatively affected mental health. People with existing chronic medical illnesses may be more vulnerable to the stressful effects of the ongoing pandemic.This study was conducted on patients with CAD during the COVID-19 pandemic to estimate the prevalence of psychological distress, the factors associated with distress, and their coping mechanisms. A cross-sectional study was conducted at a tertiary care teaching hospital in Kerala in the cardiology department. After informed consent was obtained from the patients with CAD, sociodemographic details were collected, Kessler Psychological Distress Scale (K-10 scale) was administered to assess psychological distress and the Brief COPE scale was administered to assess their coping mechanisms. Among 50 patients who participated, the prevalence of psychological distress was 50%. The factors associated with distress were female gender, semiskilled occupation, incomplete COVID-19 vaccination status, exposure of family to COVID-19, experiencing financial difficulties, and experiencing difficulty acquiring medications prescribed for CAD. Religion and acceptance were the most common coping strategies applied by the patients and acceptance was found to be a better coping strategy than religion. There is a high prevalence of psychological distress among patients with CAD during the pandemic, owing to the emotional, financial, and familial instability faced during the pandemic.


Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer.
The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27(kip1), the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27(kip1) expression, high (> or = 10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27(kip1), MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27(kip1) was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27(kip1) score is expected if the biopsy p27(kip1) score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27(kip1) assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27(kip1) expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27(kip1) in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.


Impact of light exposure on thyroid-stimulating hormone results using the Siemens Advia Centaur TSH-3Ultra assay.
Background Thyroid-stimulating hormone (TSH) is used as the first-line test of thyroid function. Siemens Healthcare Diagnostics recommend that Siemens Centaur reagents must be protected from light in the assay information and on reagent packaging. We have compared the effect of light exposure on results using Siemens TSH-3Ultra and follicle-stimulating hormone reagents. The thyroid-stimulating hormone reagent includes fluoroscein thiocyanate whereas the follicle-stimulating hormone reagent does not. Methods Three levels of quality controls were analysed using SiemensTSH-3Ultra and follicle-stimulating hormone reagent packs that had been kept protected from light or exposed to light at 6-h intervals for 48 h and then at 96 h. Results Thyroid-stimulating hormone results were significantly lower after exposure of TSH-3Ultra reagent packs to light. Results were >15% lower at all three levels of quality control following 18 h of light exposure and continued to decrease until 96 h. There was no significant difference in follicle-stimulating hormone results whether reagents had been exposed to or protected from light. Conclusions Thyroid-stimulating hormone results but not follicle-stimulating hormone results are lowered after exposure of reagent packs to light. Laboratories must ensure that TSH-3Ultra reagents are not exposed to light and analyse quality control samples on every reagent pack to check that there has not been light exposure prior to delivery. The labelling on TSH-3Ultra reagent packs should reflect the significant effect of light exposure compared with the follicle-stimulating hormone reagent. We propose that the effect of light exposure on binding of fluoroscein thiocyanate to the solid phase antibody causes the falsely low results.


SU-E-T-167: Comprehensive Evaluation of EPID Image Acquisition for Integrating and Temporal Dosimetry of Fixed-Gantry IMRT and ArcIMRT.
To evaluate EPID for dosimetry applications of arc and static-gantry IMRT with sliding window (SW) and/or step-and-shoot (SS) deliveries Methods: IMRT beams (SW & SS) were designed that generate beam hold-offs and dose rate modulation due to MLC motion under 10 × 10 cm jaw. An arcIMRT beam was designed by adding gantry movement to the SW field. A 10 cm × 10 cm open beam was also used. Despite differences in delivered dose rates/pulse characteristics, the four beams should deliver the same total dose. For each beam, various MUs with 6 MV beam at 300MU/min were irradiated on EPID which operated in image acquisition of integration mode (IM), continuous scanning mode with synchronization (CMs) and without (CMn) to beam pulses. Acquired images were evaluated in repeatability, dose linearity, and reproducibility (reproduce open beam output in IM). In IM, repeatability, dose linearity, and reproducibility were within 1% for all dose levels and beams. In CMs, they were within 1-2% if dose rate was maintained steady (1) for SW beam (needed a minimum 1.3 MU/cm MLC motion) and (2) arcIMRT beam (needed a minimum 1 MU/degree and 2.8 MU/cm MLC motion) and (3) if a minimum of 38-40 MU per shoot was used for SS beam. Nonlinearity was observed for fewer MUs. This is due to the response of EPID to pulse-length reduction for fixed-gantry therapy and pulse dropping for arc therapy. The latter produces in-planar non-uniformity making EPID unsuitable for temporal dosimetry of arcIMRT. Sacrifice in temporal resolution then became necessary such as multi-frames per image (eg. ∼1 sec/image). In CMn the results were similar to those of CMs. However, they showed artifacts, thus this mode was not preferred. We found conditions under which integrating and temporal EPID dosimetry can be used for IMRT and arcIMRT dose deliveries.


Neurofilaments as biomarkers in neurological disorders.
Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.


The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.
Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.


Neuromechanical principles underlying movement modularity and their implications for rehabilitation.
Neuromechanical principles define the properties and problems that shape neural solutions for movement. Although the theoretical and experimental evidence is debated, we present arguments for consistent structures in motor patterns, i.e., motor modules, that are neuromechanical solutions for movement particular to an individual and shaped by evolutionary, developmental, and learning processes. As a consequence, motor modules may be useful in assessing sensorimotor deficits specific to an individual and define targets for the rational development of novel rehabilitation therapies that enhance neural plasticity and sculpt motor recovery. We propose that motor module organization is disrupted and may be improved by therapy in spinal cord injury, stroke, and Parkinson's disease. Recent studies provide insights into the yet-unknown underlying neural mechanisms of motor modules, motor impairment, and motor learning and may lead to better understanding of the causal nature of modularity and its underlying neural substrates.


NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications.
Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world's adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.


Differential patterns of human immunoglobulin G subclass responses to distinct regions of a single protein, the merozoite surface protein 1 of Plasmodium falciparum.
Comparisons of immunoglobulin G (IgG) subclass responses to the major polymorphic region and to a conserved region of MSP-1 in three cohorts of African villagers exposed to Plasmodium falciparum revealed that responses to Block 2 are predominantly IgG3 whereas antibodies to MSP-1(19) are mainly IgG1. The striking dominance of IgG3 to Block 2 may explain the short duration of this response and also the requirement for continuous stimulation by malaria infection to maintain clinical immunity.


Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease.
Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.


Carbon monoxide overproduced by heme oxygenase-1 causes a reduction of vascular resistance in perfused rat liver.
This study aimed to examine whether livers overexpressing heme oxygenase (HO)-1 could alter the vascular resistance through the vasorelaxing action of carbon monoxide (CO). The relationship among HO-1 expression, CO generation, and the vascular resistance was assessed in perfused rat livers pretreated with hemin, an inducer of HO-1. At 18 h after the hemin treatment, livers displayed marked increases in HO-1 expression in hepatocytes and venous CO flux and a reduction of the basal resistance. The reduction of the resistance in hemin-treated livers was canceled by administration of oxyhemoglobin, a reagent trapping both CO and nitric oxide (NO), but not by methemoglobin, which captures NO but not CO. Liposome-encapsulated oxyhemoglobin, which cannot access the space of Disse, did not cause vasoconstriction. Furthermore, these livers became less sensitive to endothelin-1, a vasoconstrictive peptide, than the untreated controls through mechanisms involving CO. On the other hand, at 12 or 24 h after the treatment when the HO-1 induction was not accompanied by CO overproduction, neither a decrease in the basal resistance nor vascular hyporeactivity to endothelin-1 was observed. These results suggest that CO overproduced in the extrasinusoidal compartment is a determinant of the HO-1-mediated vasorelaxation in the liver.


Prophylactic cranial irradiation in extensive small-cell lung cancer.
We conducted a randomized trial of prophylactic cranial irradiation in patients with extensive small-cell lung cancer who had had a response to chemotherapy. Patients between the ages of 18 and 75 years with extensive small-cell lung cancer were randomly assigned to undergo prophylactic cranial irradiation (irradiation group) or receive no further therapy (control group). The primary end point was the time to symptomatic brain metastases. Computed tomography or magnetic resonance imaging of the brain was performed when any predefined key symptom suggestive of brain metastases was present. The two groups (each with 143 patients) were well balanced regarding baseline characteristics. Patients in the irradiation group had a lower risk of symptomatic brain metastases (hazard ratio, 0.27; 95% confidence interval [CI], 0.16 to 0.44; P<0.001). The cumulative risk of brain metastases within 1 year was 14.6% in the irradiation group (95% CI, 8.3 to 20.9) and 40.4% in the control group (95% CI, 32.1 to 48.6). Irradiation was associated with an increase in median disease-free survival from 12.0 weeks to 14.7 weeks and in median overall survival from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4 to 35.5) in the irradiation group and 13.3% (95% CI, 8.1 to 19.9) in the control group. Irradiation had side effects but did not have a clinically significant effect on global health status. Prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs disease-free and overall survival. (ClinicalTrials.gov number, NCT00016211 [ClinicalTrials.gov].).


Developing digital applications for tailored communication in orthopaedics using a Research through Design approach.
Tailored communication and information provision is expected to contribute to patient-centred care (PCC) in total hip arthroplasty (THA). In previous research, three subgroups of THA patients were identified that are similar in their clinical, psychological and communication characteristics. Preliminary subgroup-specific design guidelines were also formulated. Using these insights as a starting point, a theoretical framework was developed for tailored information provision and communication using digital applications. This study aims to refine the framework as well as subgroup-specific design guidelines for digital applications. This study uses a Research through Design (RtD) approach, generating insights both from the development and evaluation of prototypes in the early design stage. Paper-based prototypes will be made for each subgroup and evaluated with patients and care providers. Semi-structured interviews are held with participants exploring their experiences with the prototype. A quasi-experiment with a non-random control cohort is used to validate the qualitative findings. Post-surgery consultations with and without prototype are videotaped and scored using a structured instrument. A design diary will be used to summarize design decisions and considerations. Feedback from participants is analysed inductively. Adaptations in subgroup-specific guidelines will be based on comparison of verbal feedback and descriptive statistics from consultations with and without prototype. Although mixed-method feasibility studies of digital health interventions are common, this protocol also considers the utility of the early design process and the designer's perspective for realizing PCC and tailored care.


Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study.
Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification. This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH. The DLCN score was applied on a sample of 1377 adults (mean age 42.9 ± 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3-5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score. Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects.


Effect of reduced food intake on toxicokinetics of halogenated organic contaminants in herring gull (Larus argentatus) chicks.
The aim of the present study was to investigate how contaminant exposure and reduced food intake affect tissue distribution and biotransformation of halogenated organic contaminants (HOCs) in Arctic seabirds using herring gull (Larus argentatus) as a model species. Herring gull chicks were exposed for 44 d to cod liver oil containing a typical mixture of contaminants. Following exposure, food intake was reduced for a one-week period in a subgroup of the chicks. Polyclorinated biphenyls, organochlorine pesticides, and brominated flame retardants, as well as a wide range of hydroxy, methyl sulfone, and methoxy compounds were measured in liver, brain, and plasma samples. Additionally, phase I biotransformation enzyme activities and phase I and II messenger ribonucleic acid (mRNA) expression were investigated in the liver, brain, or both. Both contaminant exposure and reduced food intake had an increasing effect on the concentrations of HOCs and their metabolites. The HOC exposure and reduced food intake also led to increased 7-ethoxyresorufin-O-deethylation (EROD) activity, whereas mRNA expression of the biotransformation enzymes increased only following the reduced food intake. Tissue distribution of HOCs and their metabolites was not affected by either contaminant exposure or reduced food intake. In conclusion, the results indicate that biotransformation capacity and formation of HOC metabolites increase during reduced food intake. This finding supports the hypothesis that reduced food intake increases the susceptibility of Arctic animals to the effects of lipophilic HOCs.


Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy.
Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.


Effectiveness of screening hospital admissions to detect asymptomatic carriers of Clostridium difficile: a modeling evaluation.
Both asymptomatic and symptomatic Clostridium difficile carriers contribute to new colonizations and infections within a hospital, but current control strategies focus only on preventing transmission from symptomatic carriers. Our objective was to evaluate the potential effectiveness of methods targeting asymptomatic carriers to control C. difficile colonization and infection (CDI) rates in a hospital ward: screening patients at admission to detect asymptomatic C. difficile carriers and placing positive patients into contact precautions. We developed an agent-based transmission model for C. difficile that incorporates screening and contact precautions for asymptomatic carriers in a hospital ward. We simulated scenarios that vary according to screening test characteristics, colonization prevalence, and type of strain present at admission. In our baseline scenario, on average, 42% of CDI cases were community-onset cases. Within the hospital-onset (HO) cases, approximately half were patients admitted as asymptomatic carriers who became symptomatic in the ward. On average, testing for asymptomatic carriers reduced the number of new colonizations and HO-CDI cases by 40%-50% and 10%-25%, respectively, compared with the baseline scenario. Test sensitivity, turnaround time, colonization prevalence at admission, and strain type had significant effects on testing efficacy. Testing for asymptomatic carriers at admission may reduce both the number of new colonizations and HO-CDI cases. Additional reductions could be achieved by preventing disease in patients who are admitted as asymptomatic carriers and developed CDI during the hospital stay.


Cardiac Autonomic Modulation Response Before, During, and After Submaximal Exercise in Older Adults With Intellectual Disability.
The analysis of the heart rate variability (HRV) consists of changes in the time intervals between consecutive R waves. It provides information on the autonomic nervous system regulation and it is a predictor of adverse cardiovascular events. Several studies analyzed this parameter in youth and adults with Intellectual Disability (ID). Nevertheless, there is a lack of information regarding the HRV before, during, and after exercise in older adults with ID. Therefore, we aimed to describe and compare the cardiac autonomic modulation before, during, and after the six-minute walk test (6MWT) in older adults with and without ID. Twenty-four volunteers with ID and 24 without ID (non-ID) participated in this study. HRV was assessed by R-R intervals at rest, during and after the 6MWT. At rest and recovery periods, the participants remained sited. The symbolic analysis was used to evaluate non-linear HRV components. The recovery HR kinetics was assessed by the mean response time, which is equivalent to time constant (τ)+time delay (TD). Between groups differences in HRV variables were not significant. During the recovery period, HR kinetics time variables showed significant better results in non-ID participants (TD: 6±5s vs. 15±11s; τ: 19±10s vs. 35±17s; and MRT: 25±9s vs. 50±11s, all p<0.050). In conclusion, our results suggest that the HRV in older adults with and without ID is similar during rest, exercise, and recovery. Recovery HR kinetics after the 6MWT was slower in older adults with ID. The reason for these results may be a reduced post-exercise vagal rebound in older adults with ID.


Improvement in signs and symptoms in psoriasis patients with Pycnogenol® supplementation.
The aim of the study was the evaluation of supplementation with Pycnogenol®, French maritime pine bark extract (registered trademark of Horphag Research Ltd.) to improve the effects of the management of psoriasis and reduce the need for treatments. Patients (age range 30-45) with moderate/severe plaque psoriasis were included in a 12-week registry study that did not interfere with 'standard management'. The minimum Psoriasis Area Severity Index (PASI) score at inclusion was 10. Subjects with 10-29% (grade 2) and 30-49% (grade 3) of involved area were included. Oxidative stress (plasma free radicals) was measured. Patient-reported measures included the Dermatology Life Quality Index (DLQI). The supplement was used at a dosage of 150 mg/day (50 mg three times daily). The two registry groups (standard management and standard management+supplementation) were comparable. Dropouts were due to logistical problems. Single PASI items were evaluated: a decrease in the affected body area in boths groups was observed. The decrease in affected areas was more pronounced in the Pycnogenol group in all body regions. The severity score (erythema, induration, desquamation) improved more significantly with Pycnogenol. Considering the water content of skin in all areas, the increase was higher with Pycnogenol. The quantity of exfoliating cells (score from -5 to +5) was significantly reduced in both groups, with a better action using Pycnogenol. Skin moisture improved with treatment in all subjects, with better effects using Pycnogenol. Using a modified (12 items) DLQI indicating how much psoriasis had affected the patient's life in the previous week, Pycnogenol-supplemented subjects performed better for each single parameter in comparison with standard management. Improvement in the treatment time (-32% in comparison with standard management) and costs (decreased on average 36.4% in comparison with standard management) were observed in the supplement group. A decrease in consumption of other drugs was observed with the supplement. Oxidative stress was significantly lower in the supplement group at 12 weeks. These results indicate the efficacy of Pycnogenol supplementation in improving control of the most common clinical aspects of psoriasis and in reducing oxidative stress. Further studies may indicate the possible systemic or local use of Pycnogenol and its role in controlling side effects and costs of standard management.


Neural representations of faces and body parts in macaque and human cortex: a comparative FMRI study.
Single-cell studies in the macaque have reported selective neural responses evoked by visual presentations of faces and bodies. Consistent with these findings, functional magnetic resonance imaging studies in humans and monkeys indicate that regions in temporal cortex respond preferentially to faces and bodies. However, it is not clear how these areas correspond across the two species. Here, we directly compared category-selective areas in macaques and humans using virtually identical techniques. In the macaque, several face- and body part-selective areas were found located along the superior temporal sulcus (STS) and middle temporal gyrus (MTG). In the human, similar to previous studies, face-selective areas were found in ventral occipital and temporal cortex and an additional face-selective area was found in the anterior temporal cortex. Face-selective areas were also found in lateral temporal cortex, including the previously reported posterior STS area. Body part-selective areas were identified in the human fusiform gyrus and lateral occipitotemporal cortex. In a first experiment, both monkey and human subjects were presented with pictures of faces, body parts, foods, scenes, and man-made objects, to examine the response profiles of each category-selective area to the five stimulus types. In a second experiment, face processing was examined by presenting upright and inverted faces. By comparing the responses and spatial relationships of the areas, we propose potential correspondences across species. Adjacent and overlapping areas in the macaque anterior STS/MTG responded strongly to both faces and body parts, similar to areas in the human fusiform gyrus and posterior STS. Furthermore, face-selective areas on the ventral bank of the STS/MTG discriminated both upright and inverted faces from objects, similar to areas in the human ventral temporal cortex. Overall, our findings demonstrate commonalities and differences in the wide-scale brain organization between the two species and provide an initial step toward establishing functionally homologous category-selective areas.


Manganese Porphyrin and Radiotherapy Improves Local Tumor Response and Overall Survival in Orthotopic Murine Mammary Carcinoma Models.
Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.


Phenotype of frailty: characterization in the women's health and aging studies.
"Frailty" is an adverse, primarily gerontologic, health condition regarded as frequent with aging and having severe consequences. Although clinicians claim that the extremes of frailty can be easily recognized, a standardized definition of frailty has proved elusive until recently. This article evaluates the cross-validity, criterion validity, and internal validity in the Women's Health and Aging Studies (WHAS) of a discrete measure of frailty recently validated in the Cardiovascular Health Study (CHS). The frailty measure developed in CHS was delineated in the WHAS data sets. Using latent class analysis, we evaluated whether criteria composing the measure aggregate into a syndrome. We verified the criterion validity of the measure by testing whether participants defined as frail were more likely than others to develop adverse geriatric outcomes or to die. The distributions of frailty in the WHAS and CHS were comparable. In latent class analyses, the measures demonstrated strong internal validity vis à vis stated theory characterizing frailty as a medical syndrome. In proportional hazards models, frail women had a higher risk of developing activities of daily living (ADL) and/or instrumental ADL disability, institutionalization, and death, independently of multiple potentially confounding factors. The findings of this study are consistent with the widely held theory that conceptualizes frailty as a syndrome. The frailty definition developed in the CHS is applicable across diverse population samples and identifies a profile of high risk of multiple adverse outcomes.


Antioxidant activities of chokeberry extracts and the cytotoxic action of their anthocyanin fraction on HeLa human cervical tumor cells.
The present study evaluates the antioxidant activity of two Aronia melanocarpa cultivars-Viking and Aron-and of Aronia prunifolia hybrid in relationship with their phytochemical composition regarding the contents of total phenolics, flavonoids, procyanidins, and monomeric anthocyanins. The antioxidant capacity of the mentioned extracts of chokeberries was evaluated through five complementary assays: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), H(2)O(2) scavenging potential, oxygen radical absorbance capacity, ferric reducing antioxidant power, and cupric ion reducing antioxidant capacity. A. prunifolia hybrid was found to have the highest antioxidant activity and to be the richest in polyphenols, procyanidins, and anthocyanins compared with the A. melanocarpa cultivars. A good correlation was observed between antioxidant activity and total procyanidin and anthocyanin content. Cyanidin glycosides inhibited HeLa human cervical tumor cell proliferation and increased generation of reactive oxygen species after 48 h of treatment, suggesting that they could be responsible for the antiproliferative activity. These results may be significant for industry concerning food quality and disease prevention.


Photonic band gap filter for wavelength division multiplexer.
An optical multiplexer-demultiplexer based on an index-confined photonic band gap waveguide is proposed. The dropping of electromagnetic waves having a given frequency or a certain frequency band is obtained via a phase-shifted grating obtained by breaking the uniform period sequence to include a defect layer. The selective filtering properties of the proposed structure are simulated by means of a computer code relying on a bi-directional beam propagation method based on the method of lines.


Interplay between hydrogen bonding and n→π* interaction in an analgesic drug salicin.
The competition and cooperation between weak intermolecular interactions are important in determining the conformational preferences of molecules. Understanding the relative strengths of these effects in the context of potential drug candidates is therefore essential. We use a combination of gas-phase spectroscopy and quantum-chemical calculations to elucidate the nature of such interactions for the analgesic salicin [2-(hydroxymethyl)phenyl β-d-glucopyranoside], an analog of aspirin found in willow bark. Of several possible conformers, only three are observed experimentally, and these are found to correspond with the three lowest energy conformers obtained from density functional theory calculations and simulated Franck-Condon spectra. Natural bond orbital analyses show that these are characterized by a subtle interplay between weak n→π* interaction and conventional strong hydrogen bond, with additional insights into this interaction provided by analysis of quantum theory of atoms in molecules and symmetry-adapted perturbation theory calculations. In contrast, the higher energy conformers, which are not observed experimentally, are mostly stabilized by the hydrogen bond with negligible contribution of n→π* interaction. The n→π* interaction results in a preference for the benzyl alcohol group of salicin to adopt a gauche conformation, a characteristic also found when salicin is bound to the β-glucosidase enzyme. As such, understanding the interplay between these weak interactions has significance in the rationalization of protein structures.


ADIPOSITY-BASED CHRONIC DISEASE AS A NEW DIAGNOSTIC TERM: THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT.
The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) have created a chronic care model, advanced diagnostic framework, clinical practice guidelines, and clinical practice algorithm for the comprehensive management of obesity. This coordinated effort is not solely based on body mass index as in previous models, but emphasizes a complications-centric approach that primarily determines therapeutic decisions and desired outcomes. Adiposity-Based Chronic Disease (ABCD) is a new diagnostic term for obesity that explicitly identifies a chronic disease, alludes to a precise pathophysiologic basis, and avoids the stigmata and confusion related to the differential use and multiple meanings of the term "obesity." Key elements to further the care of patients using this new ABCD term are: (1) positioning lifestyle medicine in the promotion of overall health, not only as the first algorithmic step, but as the central, pervasive action; (2) standardizing protocols that comprehensively and durably address weight loss and management of adiposity-based complications; (3) approaching patient care through contextualization (e.g., primordial prevention to decrease obesogenic environmental risk factors and transculturalization to adapt evidence-based recommendations for different ethnicities, cultures, and socio-economics); and lastly, (4) developing evidence-based strategies for successful implementation, monitoring, and optimization of patient care over time. This AACE/ACE blueprint extends current work and aspires to meaningfully improve both individual and population health by presenting a new ABCD term for medical diagnostic purposes, use in a complications-centric management and staging strategy, and precise reference to the obesity chronic disease state, divested from counterproductive stigmata and ambiguities found in the general public sphere. AACE = American Association of Clinical Endocrinologists ABCD = Adiposity-Based Chronic Disease ACE = American College of Endocrinology BMI = body mass index CPG = clinical practice guidelines HCP = health care professionals.


Significance of Lipid-Derived Reactive Aldehyde-Specific Immune Complexes in Systemic Lupus Erythematosus.
Even though systemic lupus erythematosus (SLE) is associated with high morbidity and mortality rates among young and middle-aged women, the molecular mechanisms of disease pathogenesis are not fully understood. Previous studies from our laboratory suggested an association between oxidative stress and SLE disease activity (SLEDAI). To further assess the role of reactive oxygen species (ROS) in SLE, we examined the contribution of lipid-derived reactive aldehydes (LDRAs)-specific immune complexes in SLE. Sera from 60 SLE patients with varying SLEDAI and 32 age- and gender- matched healthy controls were analyzed for oxidative stress and related markers. Patients were divided into two groups based on their SLEDAI scores (<6 and ≥ 6). Both SLEDAI groups showed higher serum 4-hydroxynonenal (HNE)-/malondialdehyde (MDA)-protein adducts and their specific immune complexes (HNE-/MDA-specific ICs) together with IL-17 than the controls, but the levels were significantly greater in the high SLEDAI (≥ 6) group. Moreover, the serum levels of anti-oxidant enzymes Cu/Zn superoxide dismutase (SOD) and catalase (CAT) were significantly reduced in both patient groups compared to controls. Remarkably, for the first time, our data show that increased HNE-/MDA-specific ICs are positively associated with SLEDAI and elevated circulating immune complexes (CICs), suggesting a possible causal relationship among oxidative stress, LDRA-specific ICs and the development of SLE. Our findings, apart from providing firm support to an association between oxidative stress and SLE, also suggest that these oxidative stress markers, especially the HNE-/MDA-specific ICs, may be useful in evaluating the prognosis of SLE as well as in elucidating the mechanisms of disease pathogenesis.


Perovskite as light harvester: a game changer in photovoltaics.
It is not often that the scientific community is blessed with a material, which brings enormous hopes and receives special attention. When it does, it expands at a rapid pace and its every dimension creates curiosity. One such material is perovskite, which has triggered the development of new device architectures in energy conversion. Perovskites are of great interest in photovoltaic devices due to their panchromatic light absorption and ambipolar behavior. Power conversion efficiencies have been doubled in less than a year and over 15% is being now measured in labs. Every digit increment in efficiency is being celebrated widely in the scientific community and is being discussed in industry. Here we provide a summary on the use of perovskite for inexpensive solar cells fabrication. It will not be unrealistic to speculate that one day perovskite-based solar cells can match the capability and capacity of existing technologies.


RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation.
The Flavivirus genus contains several arthropod-borne viruses that pose global health threats, including dengue viruses (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). In order to understand how these viruses replicate in human cells, we previously conducted genome-scale RNA interference screens to identify candidate host factors. In these screens, we identified ribosomal proteins RPLP1 and RPLP2 (RPLP1/2) to be among the most crucial putative host factors required for DENV and YFV infection. RPLP1/2 are phosphoproteins that bind the ribosome through interaction with another ribosomal protein, RPLP0, to form a structure termed the ribosomal stalk. RPLP1/2 were validated as essential host factors for DENV, YFV, and ZIKV infection in two human cell lines: A549 lung adenocarcinoma and HuH-7 hepatoma cells, and for productive DENV infection of Aedes aegypti mosquitoes. Depletion of RPLP1/2 caused moderate cell-line-specific effects on global protein synthesis, as determined by metabolic labeling. In A549 cells, global translation was increased, while in HuH-7 cells it was reduced, albeit both of these effects were modest. In contrast, RPLP1/2 knockdown strongly reduced early DENV protein accumulation, suggesting a requirement for RPLP1/2 in viral translation. Furthermore, knockdown of RPLP1/2 reduced levels of DENV structural proteins expressed from an exogenous transgene. We postulate that these ribosomal proteins are required for efficient translation elongation through the viral open reading frame. In summary, this work identifies RPLP1/2 as critical flaviviral host factors required for translation. Flaviviruses cause important diseases in humans. Examples of mosquito-transmitted flaviviruses include dengue, yellow fever and Zika viruses. Viruses require a plethora of cellular factors to infect cells, and the ribosome plays an essential role in all viral infections. The ribosome is a complex macromolecular machine composed of RNA and proteins and it is responsible for protein synthesis. We identified two specific ribosomal proteins that are strictly required for flavivirus infection of human cells and mosquitoes: RPLP1 and RPLP2 (RPLP1/2). These proteins are part of a structure known as the ribosomal stalk and help orchestrate the elongation phase of translation. We show that flaviviruses are particularly dependent on the function of RPLP1/2. Our findings suggest that ribosome composition is an important factor for virus translation and may represent a regulatory layer for translation of specific cellular mRNAs.


Use of preventive services by managed care enrollees: an updated perspective.
We examined whether enrollees in managed care plans received more preventive services than enrollees in non-managed care plans did, by conducting an updated literature synthesis of studies published between 1990 and 1998. We found that 37 percent of comparisons indicated that managed care enrollees were significantly more likely to obtain preventive services; 3 percent indicated that they were significantly less likely to do so; and 60 percent found no difference. Enrollees in group/staff-model health maintenance organizations (HMOs) were more likely to receive preventive services, but there was little evidence, outside of Medicaid managed care, that managed care plans are worse at providing preventive services. However, most of the evidence is equivocal: Provision of preventive services was neither better nor worse in managed versus non-managed care plans. Because of the blurred distinctions among types of health plans, more research is needed to identify which plan characteristics are most likely to encourage appropriate utilization.


Isolation of the pandemic (H1N1) 2009 virus and its reassortant with an H3N2 swine influenza virus from healthy weaning pigs in Thailand in 2011.
A total of 300 nasal swabs were collected from 5 pig farms in two provinces in the Eastern part of Thailand in February 2011 and were subjected to viral isolation of influenza A viruses. Two H3N2 and 6 H1N1 influenza A viruses were isolated from swabs collected from clinically healthy weaning pigs on farms in Chonburi and Chachoengsao provinces, respectively. The H3N2 isolates consisted of the hemagglutinin (HA) and neuraminidase (NA) genes closely related to Thai SIVs and derived from a cluster of human seasonal H3N2 strains circulating around 1996-1997. The remaining gene segments of the isolates originated from the Pandemic (H1N1) 2009 (A (H1N1) pdm09) virus. Antigenicity of the H3N2 isolates was distinguishable from a human seasonal vaccine strain in the 1996-1998 seasons that represented antigenicity of the seasonal strains around 1996-1998. Nasal swabs from a Chachoengsao farm yielded A (H1N1) pdm09 viruses in chicken embryonated eggs and MDCK cells. A (H1N1) pdm09 viruses isolated in this study grew poorly in MDCK cells. Deduced amino acid sequences of the HA1 region of the HA protein of egg isolated viruses were identical to the sequences directly amplified from original swab samples. Our result demonstrated that the A (H1N1) pdm09 virus has been established in the Thai pig population and this has resulted in genetic reassortment with Thai SIV that previously circulated among pigs.


Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: insights on the relation between mesiotemporal connectivity and cortical atrophy.
Temporal lobe epilepsy (TLE) is considered primarily a limbic disorder. Our purpose was to map limbic network organization in TLE and to statistically relate it to neocortical atrophy. We performed MRI-based cortical thickness analysis in 110 TLE patients (including 68 patients with hippocampal atrophy and 42 patients with normal hippocampal volume) and 46 healthy controls. Limbic connectivity was statistically inferred by correlating mean thickness of the entorhinal cortex (EC) with thickness at each vertex across the entire neocortex. The EC was chosen as seed region since it is the link between the neocortex and the hippocampal formation. Patients showed cortical thinning mainly in temporal and fronto-central neocortices, with a prevalence of atrophy in up to 35%. In controls, EC networks corresponded closely to known anatomical connections. In TLE the pattern of correlations was similar to controls, suggesting that pathological processes in the EC affect the same networks that co-vary with the EC in the healthy brain. Nevertheless, we found decreases in correlations mainly in the temporal lobe and increases mainly in orbitofrontal cortices. Although our analysis indicated alterations in the temporo-limbic network in TLE, there was no association between mesiotemporal connectivity and atrophy across the entire cortical surface. This divergence underlines the complexity of the pathophysiological mechanisms leading to neocortical atrophy in TLE.


Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection.
Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions.


The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer.
Lamin A/C (LMNA), lamin B1 (LMNB1) and lamin B receptor (LBR) have key roles in nuclear structural integrity and chromosomal stability. In this study, we have studied the relationships between the mRNA expressions of A-type lamins, LMNB1 and LBR and the clinicopathological parameters in human breast cancer. Samples of breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT; n = 30) were assessed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher levels of A-type lamins and LMNB1 mRNA expression were seen in ANCT. Higher lamin A/C expression was associated with the early clinical stage (TNM1 vs. TNM3 - 13 vs. 0.21; p = 0.0515), with better clinical outcomes (disease-free survival vs. mortality - 11 vs. 1; p = 0.0326), and with better overall (p = 0.004) and disease-free survival (p = 0.062). The expression of LMNB1 declined with worsening clinical outcome (disease-free vs. mortalities - 0.0011 vs. 0.000; p = 0.0177). LBR mRNA expression was directly associated with tumor grade (grade 1 vs. grade 3 - 0.00 vs. 0.00; p = 0.0479) and Nottingham Prognostic Index (NPI1 vs. NPI3 - 0.00 vs. 0.00; p = 0.0551). To the best of our knowledge, this is the first study to suggest such a role for A-type lamins, lamin B1 and LBR in human breast cancer, identifying an important area for further research.