Evaluating Weaknesses of "Perceptual-Cognitive Training" and "Brain Training" Methods in Sport: An Ecological Dynamics Critique.
The recent upsurge in "brain training and perceptual-cognitive training," proposing to improve isolated processes, such as brain function, visual perception, and decision-making, has created significant interest in elite sports practitioners, seeking to create an "edge" for athletes. The claims of these related "performance-enhancing industries" can be considered together as part of a process training approach proposing enhanced cognitive and perceptual skills and brain capacity to support performance in everyday life activities, including sport. For example, the "process training industry" promotes the idea that playing games not only makes you a better player but also makes you smarter, more alert, and a faster learner. In this position paper, we critically evaluate the effectiveness of both types of process training programmes in generalizing transfer to sport performance. These issues are addressed in three stages. First, we evaluate empirical evidence in support of perceptual-cognitive process training and its application to enhancing sport performance. Second, we critically review putative modularized mechanisms underpinning this kind of training, addressing limitations and subsequent problems. Specifically, we consider merits of this highly specific form of training, which focuses on training of isolated processes such as cognitive processes (attention, memory, thinking) and visual perception processes, separately from performance behaviors and actions. We conclude that these approaches may, at best, provide some "general transfer" of underlying processes to specific sport environments, but lack "specificity of transfer" to contextualize actual performance behaviors. A major weakness of process training methods is their focus on enhancing the performance in body "modules" (e.g., eye, brain, memory, anticipatory sub-systems). What is lacking is evidence on how these isolated components are modified and subsequently interact with other process "modules," which are considered to underlie sport performance. Finally, we propose how an ecological dynamics approach, aligned with an embodied framework of cognition undermines the rationale that modularized processes can enhance performance in competitive sport. An ecological dynamics perspective proposes that the body is a complex adaptive system, interacting with performance environments in a functionally integrated manner, emphasizing that the inter-relation between motor processes, cognitive and perceptual functions, and the constraints of a sport task is best understood at the performer-environment scale of analysis.


Crossing the arms confuses the clocks: sensory feedback and the bimanual advantage.
The bimanual advantage refers to the finding that tapping with two fingers on opposite hands exhibits reduced timing variability, as compared with tapping with only one finger. Two leading theories propose that the bimanual advantage results from the addition of either sensory (i.e., enhanced feedback) or cognitive (i.e., multiple timekeeper) processes involved in timing. Given that crossing the arms impairs perception of tactile stimuli and modulates cortical activation following tactile stimulation, we investigated the role of crossing the arms in the bimanual advantage. Participants tapped unimanually or bimanually with their arms crossed or uncrossed on a tabletop or in the air. With arms crossed, we expected increased interval timing variance. Similarly, for air tapping, we expected reduced bimanual advantage, due to reduced sensory feedback. A significant bimanual advantage was observed for the uncrossed, but not the crossed posture in tabletop tapping. Furthermore, removing tactile feedback from taps eliminated the bimanual advantage for both postures. Together, these findings suggest that crossing the arms likely impairs integration of internal (i.e., effector-specific) and external (i.e., environment-specific) information and that this multisensory integration is crucial to reducing timing variability during repetitive coordinated bimanual tasks.


Retrospective radiographic observational study of 1692 Straumann tissue-level dental implants over 10 years: I. Implant survival and loss pattern.
Implant dentistry is progressing based on extensive scientific results including preclinical and clinical studies. Researchers and clinicians have focused on implant designs and surface characteristics, which has resulted in various features being developed and introduced for enhancing osseointegration and reducing complications. The purpose of this study was to determine the cumulative survival rates of Straumann tissue-level dental implants over a 10-year period and identify the patterns of implant loss at a single research institution. In total, 1692 implants were installed in 881 patients who visited the Department of Periodontology, Dental Hospital, Yonsei University, Seoul from January 2003 to December 2009. Cases in which the implant was completely removed were defined as implant failures. Electronic or paper charts and radiographs were used to determine whether the implants failed. The survival rate of implants was analyzed using lifetime tables and Kaplan-Meier survival estimates. Log-rank test and Cox regression with shared frailty were used to analyze the risk factors and the types of implant failure. The 10-year cumulative survival rates were 98.23% and 95.70% at the implant and patient levels, respectively. Before installing a prosthesis (defined as the early stage), 13 implants in 10 patients were removed, while eight implants in seven patients were removed after completing a prosthesis (defined as the late stage). The cumulative survival rate was related to the implant diameter, length, site, and insertion torque. Most implant failures within 1 year were attributable to osseointegration failure. There were several cases of failure in the late stage without apparent marginal bone loss. Straumann tissue-level dental implants showed low failure rates and can be considered a useful long-term treatment option. The length, placement site, and insertion torque might affect implant survival.


Critical role of endoplasmic reticulum aminopeptidase 1 in determining the length and sequence of peptides bound and presented by HLA-B27.
HLA-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are the two strongest genetic factors predisposing to ankylosing spondylitis (AS). A key aminopeptidase in class I major histocompatibility complex presentation, ERAP1 potentially contributes to the pathogenesis of AS by altering HLA-B27 peptide presentation. The aim of this study was to analyze the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes (CTLs). ERAP1-silenced and -competent HeLa.B27 and C1R.B27 cells were isotope-labeled, mixed, lysed, and then immunoprecipitated using W6/32 or ME1 antibodies. Peptides bound to HLA-B27 were eluted and analyzed by tandem mass spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTLs was also studied. In both HeLa.B27 and C1R.B27 cells, the proportion of 9-mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentages of longer peptides (11-13 mer) were increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than were N-terminally extended peptides lacking an arginine at position 2. In both HeLa.B27 cells and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced peptide recognition by HLA-B27-restricted KK10-specific CTLs following infection with recombinant vaccinia virus or transfection with minigenes expressing KK10 precursors. Presence of an AS-protective variant of ERAP1, K528R, as compared to wild-type ERAP1, reduced the peptide recognition by KK10 CTLs following transfection with extended KK10 minigenes. These results show that ERAP1 directly alters peptide binding and presentation by HLA-B27, thus demonstrating a potential pathogenic mechanism in AS. Inhibition of ERAP1 could potentially be used for treatment of AS and other ERAP1-associated diseases.


18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis.
Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in combination with magnetic resonance imaging (MRI). MOG35-55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels.


Neural correlates of morphological decomposition during visual word recognition.
Considerable behavioral research has demonstrated that the visual word recognition system is sensitive to morphological structure. It has typically been assumed that analysis of morphologically complex words occurs only when the meaning of these words can be derived from the meanings of their constituents (e.g., hunter = hunt + er). However, results from recent behavioral research using the masked priming technique have demonstrated that morphological analysis can occur at an earlier orthographic level, in cases in which the meanings of complex words cannot be derived from their constituents (e.g., corner = corn + er). Here, we combine the logic of behavioral masked priming with the neurophysiological phenomenon of functional magnetic resonance imaging priming suppression to look for evidence of nonsemantic morphological priming at the neural level. Both behavioral and functional magnetic resonance imaging results indicated priming effects associated with the mere appearance of morphological structure (corner-CORN). In addition, these effects were distinguishable from lexical-semantic effects (bucket-PAIL) and orthographic effects (brothel-BROTH). Three left-lateralized occipito-temporal regions showed sensitivity to early morphological components of visual word recognition. Two of these regions also showed orthographic priming ( approximately BA 37, peak: -48 -60 -17; approximately BA 19, peak: -40 -77 -1), whereas one was sensitive only to morphological similarity between primes and targets ( approximately BA 19, peak: -37 -67 -7). These findings provide a neurobiological basis for a purely structural morphemic segmentation mechanism operating at early stages of visual word recognition.


Multi-parameter investigation of tandem mass spectrometry in a linear ion trap using response surface modelling.
The feasibility of experimental design in combination with subsequent response surface modelling was illustrated for the prediction and interpretation of tandem mass spectrometric (MS/MS) fragmentation data using a linear quadrupole ion trap under various experimental conditions. The instrumental parameters included were (i) the pressure of the collision gas, (ii) the collision energy, (iii) the fill time of the linear ion trap and (iv) the scan rate. The spectral intensity and width of five fragment ions of the doubly charged neuro-active peptide bombesin were used for evaluation, and all experiments were performed so as to resemble the results obtained from a liquid chromatographic peak. The reported results show how fairly simple mathematical tools can be utilized successfully to describe fundamental mechanisms associated with multiple collisional activation and collision-induced dissociation processes without an extensively controlled experimental environment. Most beneficial, using the suggested approach, is the ability to study interaction (synergistic) effects between various parameters. As was realized from the results, many interaction effects are indeed significant. For example, the effect on the signal intensity of different collision gas pressure settings is strongly dependent on the settings of the other parameters. The described approach can easily be adopted for optimization purposes of any MS/MS experiment.


Survey of water proton longitudinal relaxation in liver in vivo.
To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature. Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model. After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less. The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.


Nanoparticle-Induced Augmentation of Neutrophils' Phagocytosis of Bacteria.
Despite the power of antibiotics, bacterial infections remain a major killer, due to antibiotic resistance and hosts with dysregulated immune systems. We and others have been developing drug-loaded nanoparticles that home to the sites of infection and inflammation via engineered tropism for neutrophils, the first-responder leukocytes in bacterial infections. Here, we examined how a member of a broad class of neutrophil-tropic nanoparticles affects neutrophil behavior, specifically questioning whether the nanoparticles attenuate an important function, bacterial phagocytosis. We found these nanoparticles actually augment phagocytosis of non-opsonized bacteria, increasing it by ∼50%. We showed this augmentation of phagocytosis is likely co-opting an evolved response, as opsonized bacteria also augment phagocytosis of non-opsonized bacteria. Enhancing phagocytosis of non-opsonized bacteria may prove particularly beneficial in two clinical situations: in hypocomplementemic patients (meaning low levels of the main bacterial opsonins, complement proteins, seen in conditions such as neonatal sepsis and liver failure) or for bacteria that are largely resistant to complement opsonization (e.g., Neisseria). Additionally, we observe that; 1) prior treatment with bacteria augments neutrophil uptake of neutrophil-tropic nanoparticles; 2) neutrophil-tropic nanoparticles colocalize with bacteria inside of neutrophils. The observation that neutrophil-tropic nanoparticles enhance neutrophil phagocytosis and localize with bacteria inside neutrophils suggests that these nanoparticles will serve as useful carriers for drugs to ameliorate bacterial diseases.


US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.
Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US, and 6 cases of CVST with thrombocytopenia had been identified among the recipients, resulting in a temporary national pause in vaccination with this product on April 13, 2021. To describe reports of CVST with thrombocytopenia following Ad26.COV2.S vaccine receipt. Case series of 12 US patients with CVST and thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up reported through April 21, 2021). Receipt of Ad26.COV2.S vaccine. Clinical course, imaging, laboratory tests, and outcomes after CVST diagnosis obtained from VAERS reports, medical record review, and discussion with clinicians. Patients' ages ranged from 18 to younger than 60 years; all were White women, reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6), hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days. Eleven patients initially presented with headache; 1 patient initially presented with back pain and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received heparin treatment. Platelet nadir ranged from 9 ×103/µL to 127 ×103/µL. All 11 patients tested for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA) screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]). As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued non-ICU hospitalization (n = 2), and discharged home (n = 4). The initial 12 US cases of CVST with thrombocytopenia after Ad26.COV2.S vaccination represent serious events. This case series may inform clinical guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.


Counterpoint: the case for immediate active treatment.
Active monitoring strategies recently have received attention as possible treatment options for men with low-risk prostate cancer who have a life expectancy of more than 10 years. However, no current criteria sufficiently predict outcomes for individuals with clinically localized disease and an otherwise long life expectancy who undergo either immediate or delayed treatment, or no treatment. This article describes the available evidence regarding treatment outcomes in men with low-risk prostate cancer and presents the case for immediate active treatment.


Role for regulated phosphatase activity in generating mitotic oscillations in Xenopus cell-free extracts.
Although current textbook explanations of cell-cycle control in eukaryotes emphasize the periodic activation of cyclin-dependent protein kinases (CDKs), recent experimental observations suggest a significant role for the periodic activation and inactivation of a CDK-counteracting protein phosphatase 2A with a B55δ subunit (PP2A:B55δ), during mitotic cycles in frog-egg extracts and early embryos. In this paper, we extend an earlier mathematical model of embryonic cell cycles to include experimentally motivated roles for PP2A:B55δ and its regulation by Greatwall kinase. Our model is consistent with what is already known about the regulation of CDK and PP2A:B55δ in frog eggs, and it suggests a previously undescribed role for the Greatwall-PP2A:B55δ interaction in creating a toggle switch for activation of the anaphase-promoting complex as embryonic cells exit mitosis and return to interphase.


beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.
Phosphorylation of the beta(2) adrenoreceptor (beta(2)AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (G(s)) to inhibitory guanine nucleotide regulatory protein (G(i)). beta-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the beta(2)AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the beta(2)AR. In human embryonic kidney 293 cells overexpressing a recombinant beta(2)AR, stimulation with isoprenaline recruits beta-arrestins 1 and 2 as well as both PDE4D3 and PDE4D5 to the receptor and stimulates receptor phosphorylation by PKA. The PKA phosphorylation status of the beta(2)AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)AR. Rolipram and PDE4D5-D556A also enhance beta(2)AR-mediated activation of extracellular signal-regulated kinases ERK12. This is consistent with a switch in coupling of the receptor from G(s) to G(i), because the ERK12 activation is sensitive to both inhibitors of PKA (H89) and G(i) (pertussis toxin). In cardiac myocytes, the beta(2)AR also switches from G(s) to G(i) coupling. Treating primary cardiac myocytes with isoprenaline induces recruitment of PDE4D3 and PDE4D5 to membranes and activates ERK12. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK12 activation. Thus, receptor-stimulated beta-arrestin-mediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the beta(2)AR in a physiological system, the cardiac myocyte.


Genetic and epigenetic regulation of stem cell homeostasis in plants.
Plants generate new organs through the activity of small populations of stem cells present in specialized niches called meristems. Stem cell homeostasis is attained by dynamic regulatory networks involving transcriptional regulators, hormones, and other intercellular signals that specify cell fate and convey positional information to the apical stem cells and the organizing center located immediately below. The balance between stem cell maintenance within the shoot apical meristem (SAM) and differentiation of cells that are displaced from the niche to form new organs involves the epigenetic silencing of stem cell regulatory genes. Recent advances have identified highly conserved chromatin remodeling factors as epigenetic regulators of stem cell fate that confer plasticity in plant development and ensure the stable inheritance of repressed expression states during organogenesis. These advances reveal that common mechanisms contribute to stem cell homeostasis in plants and animals.


A pre- post-evaluation of implementing an inpatient warfarin monitoring and education program.
The purpose of this study was to evaluate whether a new anticoagulation management program resulted in better monitoring of warfarin, increased warfarin patient education prior to discharge, and fewer bleeding complications associated with warfarin. A retrospective chart review was conducted of patients who were inpatients and received warfarin from April 1, 2008 to July 31, 2008 (control group) and from April 1, 2009 to July 31, 2009 (after implementation of the new anticoagulation program). The frequency of warfarin-related laboratory orders that included international normalized ratios (INRs), complete blood counts (CBCs), and documented patient education by pharmacy, nursing, and dietary services were determined before and after program implementation. Also, data was collected to determine frequencies of bleeding complications associated with warfarin. There were 112 patients in the pre- and 115 patients in the post-program group. After implementation of the inpatient warfarin management program, obtaining baseline INRs increased from 74% to 90% (p=0.001). Orders for baseline CBCs increased from 85% to 94% (p=0.026). Obtaining CBCs every 3 days increased from 54% to 74%, (p<0.001). However, there was no significant change in orders for daily INRs (p=0.055). Education by nursing increased from 54% to 80%, (p<0.001), by pharmacy increased from 8% to 76%, (p<0.001), and by dietary increased from 11% to 79%, (p<0.001). Documentation by all three disciplines in each patient increased from 3.6% to 59%, (p<0.001). Significantly fewer patients received vitamin K and/ or fresh frozen plasma for supratherapeutic INRs with bleeding complications after the program was initiated compared to baseline (p=0.009). The implementation of an inpatient warfarin management program led to better monitoring of patients receiving warfarin, and increased patient education. However, a larger and longer assessment is necessary to determine if these changes are maintained and how these changes affect long-term clinical outcomes.


Ecosystem-based management for military training, biodiversity, carbon storage and climate resiliency on a complex coastal land/water-scape.
The Defense Coastal/Estuarine Research Program (DCERP) was a 10-year multi-investigator project funded by the Department of Defense to improve understanding of ecosystem processes and their interactions with natural and anthropogenic stressors at the Marine Corps Base Camp Lejeune (MCBCL) located in coastal North Carolina. The project was aimed at facilitating ecosystem-based management (EBM) at the MCBCL and other coastal military installations. Because of its scope, interdisciplinary character, and duration, DCERP embodied many of the opportunities and challenges associated with EBM, including the need for explicit goals, system models, long-term perspectives, systems complexity, change inevitability, consideration of humans as ecosystem components, and program adaptability and accountability. We describe key elements of this program, its contributions to coastal EBM, and its relevance as an exemplar of EBM.


Expanding the scope of aromatic polyketides by combinatorial biosynthesis.
Combinatorial biosynthesis is a technology for mixing genes responsible for the biosynthesis of secondary metabolites, in order to generate products for compound libraries serendipitously or to cause desired modifications to natural products. Both of these approaches are extremely useful in drug discovery. Streptomyces and related species are abundant in bioactive secondary metabolites and were therefore the first microbes to be used for combinatorial biosynthesis. Polyketides are the most abundant medicinal agents among natural products. Structural diversity and a wide scope of bioactivities are typical of the group. However, the common feature of polyketides is a biosynthetic process from simple carboxylic acid residues. In molecular genetics, polyketides are sub-classified as types I and II, called modular and aromatic polyketides respectively. The best-known bioactivities of aromatic polyketides are their antibacterial and antitumor effects. Genetic analysis of aromatic polyketides has resulted in almost 30 cloned and identified biosynthetic gene clusters. Several biosynthetic enzymes are flexible enough to allow their use in combinatorial biosynthesis to create high diversity compound libraries. This review describes the state of the art of combinatorial biosynthesis, giving anthracyclines as examples. Contiguous DNA sequences for antibiotics, cloned from four different anthracycline producers, provide tools for rapid lead optimization or other structural modification processes, and not only for anthracyclines. Two gene cassettes enabling fast and flexible structural modification of polyketides are introduced in this paper.


Pain relief as an opponent process: a psychophysical investigation.
Relief from pain in humans is frequently measured by computing the reduction on an 11-point pain intensity scale. However, this definition of relief may be insufficient to capture the utility of pain relief for the individual. Based on pain literature and evidence from studies examining relief and reward, it is clear that pain relief is a broad concept comprising several factors, only one of which is pain intensity reduction. According to opponent process theory, all sensations consist of a primary process and a slow 'opponent process' of opposite valence, the purpose of which is to reduce the deviation from homeostatic balance. Here, opponent process theory provided a framework to explore the interaction between pain, relief and reward. We devised three psychophysical studies examining the temporal (Experiment I) and magnitude (Experiments I and II) relationships between pain severity and its subsequent relief. In Experiment III, we further manipulated the magnitude and pleasantness of relief experienced by applying innocuous cooling following noxious heat stimulation of capsaicin-sensitized skin. Results confirmed predictions from opponent process theory and showed that pain intensity reduction was significantly stronger than relief intensity ratings. Furthermore, continuous relief ratings appeared to reflect the speed of pain intensity reduction. Varying pain intensity parametrically confirmed that relief increases with pain intensity. That innocuous cooling following primary hyperalgesia intervention significantly increased the intensity, pleasantness and duration of relief provides further evidence that pain relief encapsulates more than a reduction in pain intensity. Importantly, the high relief pleasantness ratings confirmed the hypothesized link between relief and reward.


Fine needle aspiration cytology of male breast lesions - a retrospective study over a six year period.
Fine needle aspiration cytology (FNAC) has a well-established role in the management of palpable breast lumps. However breast masses in males are rarely aspirated and hence there is limited cytopathologic experience. The aim of our study was to determine the efficacy of FNAC in the diagnosis of male breast lesions and also we attempted to describe the cytomorphological features of some of these lesions. Data on male breast FNAC done between 2008 to 2013 were retrieved from the records of the cytopathology laboratory. FNAC diagnosis were categorized as benign, malignant, suspicious for malignancy and inadequate or unsatisfactory. Cytohistologic correlation was done with data from histopathology records. Sensitivity, specificity and diagnostic accuracy were calculated using standard statistical methods. Forty out of 1098 patients undergoing breast FNAC were males. Histopathology was available in 8 (20%) out of 40 cases. There were no false positive or false negative diagnoses. FNAC had a sensitivity, specificity and diagnostic accuracy of 100% for male breast lesions. FNAC is a very accurate tool for the diagnosis of male breast lesions. It is highly sensitive and specific with good cytohistologic correlation. To reduce the high rate of surgical biopsies of benign male breast masses, we conclude that FNAC should be performed as a standard procedure in the clinical evaluation of male breast lesions.


A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study.
The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide-cisplatin in this patient population. Patients were randomized to receive ifosfamide (1.5 g/m(2)/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m(2)/day) times 5 days. No patient had received previous chemotherapy. Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin-ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide-cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for "other" metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test). The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.


Residential trajectories of street youth-the Montréal Cohort Study.
Little is known about the course of homelessness among youth between the ages of 18 and 25 despite the many characteristics distinguishing them from adolescents and from older street-involved populations. We examined the residential trajectories of homeless young adults in Montréal over a 21-month period and identified determinants of various trajectory profiles. The 365 study participants (79 % men, mean age 21.9 years) were followed for an average of 515 days (range 81-630 days). We assessed housing status with a questionnaire based on the residential follow-back calendar designed by the New Hampshire Dartmouth Research Center. Using latent growth analysis to examine achievement of residential stability over time, we observed three different trajectories: group 1 presented a low probability of housing throughout the entire study period; group 2 showed a high probability of early and stable housing; group 3 displayed a fluctuating pattern. Protective correlates of residential stability included high school education, birth in Canada, and presence of mental health problems. Drug abuse or dependence was associated with a decreased probability of housing.


Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.
A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported. To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci. Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design. Inpatients and screened control subjects. The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively. Blood or saliva samples were collected from each participant for DNA extraction and genotyping. Associations of SNPs in BDNF and NTRK2 with SA and MDD. Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10(-7) for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes. Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.


A system for delivering mechanical stimulation and robot-assisted therapy to the rat whisker pad during facial nerve regeneration.
Functional recovery is typically poor after facial nerve transection and surgical repair. In rats, whisking amplitude remains greatly diminished after facial nerve regeneration, but can recover more completely if the whiskers are periodically mechanically stimulated during recovery. Here we present a robotic "whisk assist" system for mechanically driving whisker movement after facial nerve injury. Movement patterns were either preprogrammed to reflect natural amplitudes and frequencies, or movements of the contralateral (healthy) side of the face were detected and used to control real-time mirror-like motion on the denervated side. In a pilot study, 20 rats were divided into nine groups and administered one of eight different whisk assist driving patterns (or control) for 5-20 minutes, five days per week, across eight weeks of recovery after unilateral facial nerve cut and suture repair. All rats tolerated the mechanical stimulation well. Seven of the eight treatment groups recovered average whisking amplitudes that exceeded controls, although small group sizes precluded statistical confirmation of group differences. The potential to substantially improve facial nerve recovery through mechanical stimulation has important clinical implications, and we have developed a system to control the pattern and dose of stimulation in the rat facial nerve model.


Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA.
Early initiation of combination antiretroviral therapy (ART) during primary HIV-1 infection may prevent the establishment of large viral reservoirs, possibly resulting in improved control of plasma viraemia rebound after ART cessation. Levels of cell-associated HIV-1 DNA and plasma HIV-1 RNA were measured longitudinally in 32 acutely and recently infected patients, who started ART ≤120 days after the estimated date of infection, and interrupted ART after 18 months (median) of continuous therapy. Averages of HIV-1 DNA and RNA concentrations present in blood 30-365 days after therapy interruption (median duration 300 days, range 195-358) were compared between patients who started ART ≤60 days after the estimated date of infection (early starters), those who started between 61 and 120 days (later starters), and, for HIV-1 RNA only, with 89 untreated participants of the Swiss HIV Cohort Study with documented seroconversion and longitudinal measurements collected 90-455 days after the first positive HIV test. In early ART starters, average levels of plasma HIV-1 RNA and cell-associated HIV-1 DNA after treatment interruption were 1 log(10) (P=0.008) and 0.4 log(10) (P=0.03) lower compared with later starters. Average post-treatment plasma HIV-1 RNA levels in early starters were significantly lower, respectively, compared with untreated controls (-1.2 log(10); P<0.0004). Early treatment initiation within 2 months after HIV infection compared with later therapy initiation resulted in reduced levels of plasma viraemia and proviral HIV-1 DNA for ≥1 year after subsequent ART cessation. Plasma HIV-1 RNA levels in early starters were also significantly lower than in untreated controls.


Radiofrequency ablation of small renal cortical tumours in healthy adults: renal function preservation and intermediate oncological outcome.
To present the glomerular filtration rate (GFR) and oncological outcomes in a series of patients with cT1a renal cortical tumours treated with radiofrequency ablation (RFA), a non-ischaemic minimally invasive ablative method, as nephron-sparing surgery gives excellent oncological outcomes and preserves renal function. Healthy (American Society of Anesthesiologists, ASA, I and II) patients with cT1a renal masses were identified, and clinical and radiographic data were reviewed to assess indications, complications, radiological evidence of disease recurrence, and renal function. Changes in GFR were calculated. Radiological recurrence was defined as any new enhancement (>10 Hounsfield units) after absence of enhancement on initial 6-week computed tomography. Four patients were ASA I and 59 were ASA II; the median (range) age was 58 (20-84.6) years and the lesion diameter 2.1 (1-4.0) cm. Preoperative needle biopsy was diagnostic in 89% of patients, including 75% diagnostic of renal cell carcinoma (RCC). At a median (range) follow-up of 34 (1.0-80) months the renal preservation rate was 97%. One patient had a nephrectomy for biopsy-confirmed recurrence of RCC at 55 months; a second had a nephrectomy at 24 months for suspected radiographic recurrence, but had no evidence of disease on final pathology. A fifth (20%) of the patients had chronic kidney disease at the time of diagnosis. The median GFR before and after RFA was 76.3 and 74.3 mL/min/m(2) (difference 2.0 mL/min/m(2)). RFA might be a reasonable treatment choice for the healthy patient, with appropriate informed consent. Intermediate results suggest excellent oncological outcomes and preservation of renal function.


Regulation of CFTR Cl- conductance in secretion by cellular energy levels.
Recent studies suggested dual regulation of the Cl- conductance (GCl) affected in cystic fibrosis, one by protein kinase A-dependent phosphorylation and a second by low-affinity ATP binding. We proposed that ATP binding may couple the transport demands to the energy level of the cell. In the present study we examined this hypothesis further in a purely secretory function using the epithelial cell line T84. We used a depletion-permeabilization protocol on cells grown on permeable supports to deplete the cells of endogenous ATP and to provide access to the intracellular compartment for the impermeable nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and ATP. In contrast to non-depleted permeabilized cells, which responded to 0.1 mM cAMP with an increase in transepithelial potential (delta Vt = 29.8 +/- 3.0 mV, n = 4) and conductance (delta Gt = 1.23 +/- 0.54 mS/cm2, n = 4), addition of cAMP to ATP-depleted cells resulted in insignificant changes in Vt (delta Vt = 0.7 +/- 0.2 mV, n = 26; P < 0.05) and Gt (delta Gt = 0.020 +/- 0.003 mS/cm2, n = 26; P < 0.05). However, the cAMP response was restored by addition of 5 mM ATP (delta Vt = 21.7 +/- 1.5 mV, n = 26; delta Gt = 0.59 +/- 0.06 mS/cm2, n = 26). ATP dose-response experiments, taken together with the effect of cAMP with and without ATP, suggest that phosphorylation is necessary, but not sufficient, for activation. The data provide evidence for a second level of regulation of GCl, which requires high concentrations of ATP.(ABSTRACT TRUNCATED AT 250 WORDS)


Cyclic AMP suppresses fibronectin expression in the rabbit aorta in vitro.
The effect of cAMP on the in vitro expression of rabbit aortic fibronectin was examined using a previously characterized organ culture system. Elevation of intracellular cAMP in incubated aortic rings by use of forskolin or dibutyryl cAMP (dbcAMP) inhibited the normally observed increase in fibronectin mRNA to levels below that found in unincubated tissue. The effect of dbcAMP on fibronectin mRNA was dose dependent and reversible. dbcAMP did not affect overall protein biosynthesis or the changes in collagen or elastin mRNAs that normally occurred during in vitro incubation, suggesting a selective regulatory effect on fibronectin. The inhibitory effect of dbcAMP on steady-state fibronectin mRNA levels was independent of the dibutyrate moiety, was not a result of cytotoxicity, did not require de novo protein synthesis, and did not appear to occur through a protein kinase A pathway. The data suggested that suppression of fibronectin mRNA levels potentially occurred via an indirect mechanism that may have involved a dbcAMP-induced reduction in intracellular calcium ([Ca2+]i) levels. The resultant decrease in [Ca2+]i may have affected fibronectin expression via a reduction in protein kinase C activity but did not depend on a calmodulin or calmodulin kinase I or II mechanism.


Presentation of SLE in UK primary care using the Clinical Practice Research Datalink.
To describe the presenting symptoms of SLE in primary care using the Clinical Practice Research Database (CPRD) and to calculate the time from symptom presentation to SLE diagnosis. Incident cases of SLE were identified from the CPRD between 2000 and 2012. Presenting symptoms were identified from the medical records of cases in the 5 years before diagnosis and grouped using the British Isles Lupus Activity Group (BILAG) symptom domains. The time from the accumulation of one, two and three BILAG domains to SLE diagnosis was investigated, stratified by age at diagnosis (<30, 30-49 and ≥50 years). We identified 1426 incident cases (170 males and 1256 females) of SLE. The most frequently recorded symptoms and signs prior to diagnosis were musculoskeletal, mucocutaneous and neurological. The median time from first musculoskeletal symptom to SLE diagnosis was 26.4 months (IQR 9.3-43.6). There was a significant difference in the time to diagnosis (log rank p<0.01) when stratified by age and disease severity at baseline, with younger patients <30 years and those with severe disease having the shortest times and patients aged ≥50 years and those with mild disease having the longest (6.4 years (IQR 5.8-6.8)). The time from symptom onset to SLE diagnosis is long, especially in older patients. SLE should be considered in patients presenting with flaring or chronic musculoskeletal, mucocutaneous and neurological symptoms.


Cotton dust, endotoxin and cancer mortality among the Shanghai textile workers cohort: a 30-year analysis.
Although occupational exposure to cotton dust and endotoxin is associated with adverse respiratory health, associations with cancer are unclear. We investigated cancer mortality in relation to cotton dust and endotoxin exposure in the Shanghai textile workers cohort. We followed 444 cotton textile and a reference group of 467 unexposed silk workers for 30 years (26 777 person-years). HRs for all cancers combined (with and without lung cancer) and gastrointestinal cancer were estimated in Cox regression models as functions of cotton textile work and categories of cumulative exposure (low, medium, high), after adjustment for covariates including pack-years smoked. Different lag years accounted for disease latency. Risks of mortality from gastrointestinal cancers and all cancers combined, with the exclusion of lung cancer, were increased in cotton workers relative to silk workers. When stratified by category of cumulative cotton exposure, in general, risks were greatest for 20-year lagged medium exposure (all cancers HR=2.7 (95% CI 1.4 to 5.2); cancer excluding lung cancer HR=3.4 (1.7-7.0); gastrointestinal cancer HR=4.1 (1.8-9.7)). With the exclusion of lung cancer, risks of cancer were more pronounced. When stratified by category of cumulative endotoxin exposure, consistent associations were not observed for all cancers combined. However, excluding lung cancer, medium endotoxin exposure was associated with all cancers and gastrointestinal cancer in almost all lag models. Cotton dust may be associated with cancer mortality, especially gastrointestinal cancer, and endotoxin may play a causative role. Findings also indirectly support a protective effect of endotoxin on lung cancer.


1H,13C and 15N chemical shift assignments of the SUD domains of SARS-CoV-2 non-structural protein 3c: "The SUD-M and SUD-C domains".
SARS-CoV-2 RNA, nsP3c (non-structural Protein3c) spans the sequence of the so-called SARS Unique Domains (SUDs), first observed in SARS-CoV. Although the function of this viral protein is not fully elucidated, it is believed that it is crucial for the formation of the replication/transcription viral complex (RTC) and of the interaction of various viral "components" with the host cell; thus, it is essential for the entire viral life cycle. The first two SUDs, the so-called SUD-N (the N-terminal domain) and SUD-M (domain following SUD-N) domains, exhibit topological and conformational features that resemble the nsP3b macro (or "X") domain. Indeed, they are all folded in a three-layer α/β/α sandwich structure, as revealed through crystallographic structural investigation of SARS-CoV SUDs, and they have been attributed to different substrate selectivity as they selectively bind to oligonucleotides. On the other hand, the C-terminal SUD (SUD-C) exhibit much lower sequence similarities compared to the SUD-N & SUD-M, as reported in previous crystallographic and NMR studies of SARS-CoV. In the absence of the 3D structures of SARS-CoV-2, we report herein the almost complete NMR backbone and side-chain resonance assignment (1H,13C,15N) of SARS-CoV-2 SUD-M and SUD-C proteins, and the NMR chemical shift-based prediction of their secondary structure elements. These NMR data will set the base for further understanding at the atomic-level conformational dynamics of these proteins and will allow the effective screening of a large number of small molecules as binders with potential biological impact on their function.


Impact of Dehazing on Underwater Marker Detection for Augmented Reality.
Underwater augmented reality is a very challenging task and amongst several issues, one of the most crucial aspects involves real-time tracking. Particles present in water combined with the uneven absorption of light decrease the visibility in the underwater environment. Dehazing methods are used in many areas to improve the quality of digital image data that is degraded by the influence of the environment. This paper describes the visibility conditions affecting underwater scenes and shows existing dehazing techniques that successfully improve the quality of underwater images. Four underwater dehazing methods are selected for evaluation of their capability of improving the success of square marker detection in underwater videos. Two reviewed methods represent approaches of image restoration: Multi-Scale Fusion, and Bright Channel Prior. Another two methods evaluated, the Automatic Color Enhancement and the Screened Poisson Equation, are methods of image enhancement. The evaluation uses diverse test data set to evaluate different environmental conditions. Results of the evaluation show an increased number of successful marker detections in videos pre-processed by dehazing algorithms and evaluate the performance of each compared method. The Screened Poisson method performs slightly better to other methods across various tested environments, while Bright Channel Prior and Automatic Color Enhancement shows similarly positive results.


Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models.
Intraportal transplantation of islets has successfully treated select patients with type 1 diabetes. However, intravascular infusion and the intrahepatic site contribute to significant early and late islet loss, yet a clinical alternative has remained elusive. We investigated non-encapsulating, porous, biodegradable polymer scaffolds as a vehicle for islet transplantation into extrahepatic sites, using syngeneic mouse and allogeneic porcine models. Scaffold architecture was modified to enhance cell infiltration leading to revascularization of the islets with minimal inflammatory response. In the diabetic mouse model, 125 islets seeded on scaffolds implanted into the epididymal fat pad restored normoglycemia within an average of 1.95 days and transplantation of only 75 islets required 12.1 days. Increasing the pore size to increase islet-islet interactions did not significantly impact islet function. The porcine model was used to investigate early islet engraftment. Increasing the islet seeding density led to a greater mass of engrafted islets, though the efficiency of islet survival decreased. Transplantation into the porcine omentum provided greater islet engraftment than the gastric submucosa. These results demonstrate scaffolds support murine islet transplantation with high efficiency, and feasibility studies in large animals support continued pre-clinical studies with scaffolds as a platform to control the transplant microenvironment.


Naming a giraffe but not an animal: Base-level but not superordinate naming in a patient with impaired semantics.
We report data on patient FK, who presented with a marked deficit in accessing semantic knowledge about objects when tested across a range of input and output modalities. FK also showed a high degree of item-specific consistency in object identification, over and above effects due to object familiarity. We show that, despite being better at naming some objects than others, FK was equally poor at discriminating the superordinate categories of the stimuli. Also, he tended to be better at matching nameable items to a base-level label than to a superordinate-level label. We discuss the implications of the data for models of semantic memory.


Cortical morphometry in narcolepsy with cataplexy.
The sleep-wake disorder narcolepsy with cataplexy is associated with the loss of hypocretin-(orexin-) producing neurons in the lateral hypothalamus. Several studies have reported abnormal cerebral activation in patients with narcolepsy with cataplexy. It remains unclear, however, whether these functional changes are related to structural alterations, particularly at the cortical level. To quantify structural brain changes associated with narcolepsy with cataplexy, we used high-resolution T1-weighted magnetic resonance imaging (MRI) in 12 patients compared with 12 healthy participants matched for age and gender. Subcortical and regional cortical volumes were measured using a method unbiased by non-linear registration. Further whole-brain analyses were conducted, measuring cortical characteristics, such as cortical thickness and gyrification, at thousands of points across each hemisphere using validated algorithms. Statistical analyses accounted for an effect of age and gender. We observed decreased cortical volume in the left paracentral lobule and increased cortical volume in the left caudal part of the middle frontal gyrus in narcoleptic patients compared with controls. Cortical thickness in prefrontal areas was inversely correlated with the severity of narcolepsy. Further, we observed several clusters of cortical thinning in patients with childhood or adolescent onset of narcolepsy compared with patients with adult onset of the disease. Our results suggest that specific anatomical changes may differentiate subgroups of narcolepsy patients with different clinical profiles (such as varying symptom severity or different age at onset). Future studies with larger groups of sleepy patients are required to assess whether distinct patterns of anatomical changes may distinguish narcolepsy from non-hypocretin-deficient hypersomnia disorders.


The role of UCP 1 in production of reactive oxygen species by mitochondria isolated from brown adipose tissue.
We provide evidence that ablation or inhibition of, uncoupling protein 1 increases the rate of reactive oxygen containing species production by mitochondria from brown adipose tissue, no matter what electron transport chain substrate is used (succinate, glycerol-3-phosphate or pyruvate/malate). Consistent with these data are our observations that (a) the mitochondrial membrane potential is maximal when uncoupling protein 1 is ablated or inhibited and (b) oxygen consumption rates in mitochondria from uncoupling protein 1 knock-out mice, are significantly lower than those from wild-type mice, but equivalent to those from wild-type mice in the presence of GDP. In summary, we show that uncoupling protein 1 can affect reactive oxygen containing species production by isolated mitochondria from brown adipose tissue.


Multi-photon patterning of photoactive o-nitrobenzyl ligands bound to gold surfaces.
We quantitatively investigate lithographic patterning of a thiol-anchored self-assembled monolayer (SAM) of photocleavable o-nitrobenzyl ligands on gold through a multi-photon absorption process at 1.7 eV (730 nm wavelength). The photocleaving rate increases faster than the square of the incident light intensity, indicating a process more complex than simple two-photon absorption. We tentatively ascribe this observation to two-photon absorption that triggers the formation of a long-lived intermediate aci-nitro species whose decomposition yield is partially determined either by absorption of additional photons or by a local temperature that is elevated by the incident light. At the highest light intensities, thermal processes compete with photoactivation and lead to damage of the SAM. The threshold is high enough that this destructive process can largely be avoided, even while power densities are kept sufficiently large that complete photoactivation takes place on time scales of tens of seconds to a few minutes. This means that this type of ligand can be activated at visible and near infrared wavelengths where plasmonic resonances can easily be engineered in metal nanostructures, even though their single-photon reactivity at these wavelengths is negligible. This will allow selective functionalization of plasmon hotspots, which in addition to high resolution lithographic applications would be of benefit to applications such as Surface Enhanced Raman Spectroscopy and plasmonic photocatalysis as well as directed bottom-up nanoassembly.


Adherence by midwives to the Dutch national guidelines on threatened miscarriage in general practice: a prospective study.
To determine the feasibility for midwives to adhere to Dutch national guidelines on threatened miscarriage in general practice. Prospective recording of appointments by midwives who agreed to adhere to the guidelines on threatened miscarriage. Interviews with the midwives after they had recorded appointments for one year. Midwifery practices in The Netherlands. 56 midwives who agreed to adhere to the guidelines; 43 midwives actually made records from 156 clients during a period of 12 months. Adherence to each recommendation and reasons for non-adherence. The recommendation that a physical examination should take place on the first and also on the follow up appointment was not always adhered to. Reasons for non-adherence were the midwives' criticism of this recommendation, their lack of knowledge or skills, and the specific client situation. Adherence to a follow up appointment after 10 days, a counselling consultation after six weeks, and not performing an ultrasound scan was low. Reasons for non-adherence were mainly based on the midwives' criticism of these recommendations and reluctance on the part of the client. Furthermore, many midwives did not give information and instructions to the client. It is noteworthy that in 13% of the cases the midwife's policy was overridden by the obstetrician taking control of the situation after the midwife had requested an ultrasound scan. Those recommendations in the guidelines on threatened miscarriage that are most often not adhered to should be reviewed. To reduce conflicts about ultrasound scans and referrals, agreement on the policy on threatened miscarriage should be mutually established between midwives and obstetricians.


HMGB1 accelerates alveolar epithelial repair via an IL-1β- and αvβ6 integrin-dependent activation of TGF-β1.
High mobility group box 1 (HMGB1) protein is a danger-signaling molecule, known to activate an inflammatory response via TLR4 and RAGE. HMGB1 can be either actively secreted or passively released from damaged alveolar epithelial cells. Previous studies have shown that IL-1β, a critical mediator acute lung injury in humans that is activated by HMGB1, enhances alveolar epithelial repair, although the mechanisms are not fully understood. Herein, we tested the hypothesis that HMGB1 released by wounded alveolar epithelial cells would increase primary rat and human alveolar type II cell monolayer wound repair via an IL-1β-dependent activation of TGF-β1. HMGB1 induced in primary cultures of rat alveolar epithelial cells results in the release of IL-1β that caused the activation of TGF-β1 via a p38 MAPK-, RhoA- and αvβ6 integrin-dependent mechanism. Furthermore, active TGF-β1 accelerated the wound closure of primary rat epithelial cell monolayers via a PI3 kinase α-dependent mechanism. In conclusion, this study demonstrates that HMGB1 released by wounded epithelial cell monolayers, accelerates wound closure in the distal lung epithelium via the IL-1β-mediated αvβ6-dependent activation of TGF-β1, and thus could play an important role in the resolution of acute lung injury by promoting repair of the injured alveolar epithelium.


Wavelength-division-multiplexing method of polarized low-coherence interferometry for fiber Fabry-Perot interferometric sensors.
We propose a new wavelength-division-multiplexing method for extrinsic fiber Fabry-Perot interferometric (EFPI) sensing in a polarized low-coherence interferometer configuration. In the proposed method, multiple LED sources are used with different center wavelengths, and each LED is used by a specific sensing channel, and therefore the spatial frequency of the low-coherence interferogram of each channel can be separated. A bandpass filter is used to extract the low-coherence interferogram of each EFPI channel, and thus the cavity length of each EFPI channel can be identified through demultiplexing. We successfully demonstrate the simultaneous demodulation of EFPI sensors with same nominal cavity length while maintaining high measurement precision.


DNA helicase Srs2 disrupts the Rad51 presynaptic filament.
Mutations in the Saccharomyces cerevisiae gene SRS2 result in the yeast's sensitivity to genotoxic agents, failure to recover or adapt from DNA damage checkpoint-mediated cell cycle arrest, slow growth, chromosome loss, and hyper-recombination. Furthermore, double mutant strains, with mutations in DNA helicase genes SRS2 and SGS1, show low viability that can be overcome by inactivating recombination, implying that untimely recombination is the cause of growth impairment. Here we clarify the role of SRS2 in recombination modulation by purifying its encoded product and examining its interactions with the Rad51 recombinase. Srs2 has a robust ATPase activity that is dependent on single-stranded DNA (ssDNA) and binds Rad51, but the addition of a catalytic quantity of Srs2 to Rad51-mediated recombination reactions causes severe inhibition of these reactions. We show that Srs2 acts by dislodging Rad51 from ssDNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the Rad51 presynaptic filament efficiently. Our findings have implications for the basis of Bloom's and Werner's syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated ageing.


Role of rpoS in the development of cell envelope resilience and pressure resistance in stationary-phase Escherichia coli.
This work investigated the role of rpoS in the development of increased cell envelope resilience and enhanced pressure resistance in stationary-phase cells of Escherichia coli. Loss of both colony-forming ability and membrane integrity, measured as uptake of propidium iodide (PI), occurred at lower pressures in E. coli BW3709 (rpoS) than in the parental strain (BW2952). The rpoS mutant also released much higher concentrations of protein under pressure than the parent. We propose that RpoS-regulated functions are responsible for the increase in membrane resilience as cells enter stationary phase and that this plays a major role in the development of pressure resistance. Strains from the Keio collection with mutations in two RpoS-regulated genes, cfa (cyclopropane fatty acyl phospholipid synthase) and osmB (outer membrane lipoprotein), were significantly more pressure sensitive and took up more PI than the parent strain, with cfa having the greatest effect. Mutations in the bolA morphogene and other RpoS-regulated lipoprotein genes (osmC, osmE, osmY, and ybaY) had no effect on pressure resistance. The cytoplasmic membranes of the rpoS mutant failed to reseal after pressure treatment, and strains with mutations in osmB and nlpI (new lipoprotein) were also somewhat impaired in the ability to reseal their membranes. The cfa mutant, though pressure sensitive, was unaffected in membrane resealing, implying that the initial transient permeabilization event is critical for loss of viability rather than the failure to reseal. The enhanced pressure sensitivity of polA, recA, and xthA mutants suggested that DNA may be a target of oxidative stress in pressure-treated cells.


Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of stroke recurrence and longitudinal progression of white matter lesions and silent brain infarcts on MRI (CEREBRAL study): rationale, design, and methodology.
Patients with a history of ischemic stroke are known to develop new ischemic stroke. While asymptomatic, the presence and progression of silent brain infarcts and white matter lesions on magnetic resonance imaging are associated with an increased risk of future strokes. Both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are recommended for the primary and secondary prevention of stroke, but there are no direct comparisons of angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers regarding their cerebroprotective effects, including their effect on asymptomatic cerebral lesions detected by magnetic resonance imaging. Elderly (65 years or older) patients with essential hypertension who underwent cerebral magnetic resonance imaging and were found to have any cerebral ischemic lesions, such as cerebral infarction, silent brain infarct, or white matter lesion, were enrolled in this CEREBRAL study. Patients who agreed to participate were enrolled in the randomized controlled trial portion. Patients who did not agree to participate in the randomized controlled trial were enrolled in the cohort study portion. After two-years of angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers treatment, follow-up magnetic resonance imaging examination will be performed. The primary end-point is the composite of (1) occurrence of a fatal or nonfatal cerebrovascular event or (2) progression of cerebrovascular lesions as evaluated by magnetic resonance imaging, including white matter lesions or silent brain infarcts. After enrollment, cognitive function was evaluated, if possible, using the Mini-Mental State Examination. Our study will clarify whether angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are more effective for preventing primary and recurrence of ischemic stroke, including the progression of asymptomatic cerebral lesions on magnetic resonance imaging, in elderly hypertensive patients.


Porcine Collagen-Bone Composite Induced Osteoblast Differentiation and Bone Regeneration In Vitro and In Vivo.
Due to autogenous bone limitations, some substitute bone grafts were developed. Collagenated porcine graft (CPG) is able to regenerate new bone, although the number of studies is insufficient, highlighting the need for future studies to better understand the biomaterial. In order to understand better CPG's possible dental guided bone regeneration indications, the aim of this work was to determine CPG's biological capacity to induce osteoblast differentiation in vitro and guided bone regeneration in vivo, whilst being compared with commercial hydroxyapatite and beta tricalcium phosphate (HA/β-TCP) and porcine graft alone. Cell cytotoxicity (WST-1), alkaline phosphatase activity (ALP), and real-time polymerase chain reaction (qPCR) were assessed in vitro. Critical size defects of New Zealand white rabbits were used for the in vivo part, with critical size defect closures and histological analyses. WST-1 and ALP indicated that CPG directly stimulated a greater proliferation and confluency of cells with osteoblastic differentiation in vitro. Gene sequencing indicated stable bone formation markers, decreased resorption makers, and bone remodeling coupling factors, making the transition from osteoclast to osteoblast expression at the end of seven days. CPG resulted in the highest new bone regeneration by osteoconduction in critical size defects of rabbit calvaria at eight weeks. Nonetheless, all biomaterials achieved nearly complete calvaria defect closure. CPG was found to be osteoconductive, like porcine graft and HA/β-TCP, but with higher new bone formation in critical size defects of rabbit calvaria at eight weeks. CPG can be used for different dental guided bone regeneration procedures; however, further studies are necessary.


Responsibility without legal authority? Tackling alcohol-related health harms through licensing and planning policy in local government.
The power to influence many social determinants of health lies within local government sectors that are outside public health's traditional remit. We analyse the challenges of achieving health gains through local government alcohol control policies, where legal and professional practice frameworks appear to conflict with public health action. Current legislation governing local alcohol control in England and Wales is reviewed and analysed for barriers and opportunities to implement effective population-level health interventions. Case studies of local government alcohol control practices are described. Addressing alcohol-related health harms is constrained by the absence of a specific legal health licensing objective and differences between public health and legal assessments of the relevance of health evidence to a specific place. Local governments can, however, implement health-relevant policies by developing local evidence for alcohol-related health harms; addressing cumulative impact in licensing policy statements and through other non-legislative approaches such as health and non-health sector partnerships. Innovative local initiatives-for example, minimum unit pricing licensing conditions-can serve as test cases for wider national implementation. By combining the powers available to the many local government sectors involved in alcohol control, alcohol-related health and social harms can be tackled through existing local mechanisms.


Osler Centenary Papers: Management of pleural infection: Osler's final illness and recent advances.
Sir William Osler's great work and achievements are extensively documented. Less well known is his prolonged battle with postinfluenza pneumonia, lung abscess and pleural infection that eventually led to his demise. At the age of 70, he was a victim of the global Spanish influenza epidemic, and subsequently developed pneumonia. In the era before antibiotics, he received supportive care and opium for symptom control. The infection extended to the pleura and he required repeated thoracentesis which failed to halt his deterioration. He proceeded to open surgical drainage involving rib resection. Unfortunately, he died shortly after the operation from massive pleuropulmonary haemorrhage. In this article, we review the events leading up to Osler's death and contrast his care 100 years ago with contemporary state-of-the-art management in pleural infection.


Perceived support among families deciding about organ donation for their loved ones: donor vs nondonor next of kin.
Families' experiences in the hospital influence their decisions about donating organs of brain-dead relatives. Meeting families' support needs during this traumatic time is an obligation and a challenge for critical care staff. (1) To elicit family members' accounts of various types of support received and perceived quality of care for themselves and their loved ones when they made the donation decision, and (2) to examine the relationship between these factors and the families' donation decision. Retrospective telephone interviews of 199 families from different regions of the country were completed. Aside from demographic data, the survey addressed perceptions of informational, emotional, and instrumental support and quality of care. One hundred fifty-four study participants consented to donation; 45 declined. White next of kin were significantly more likely than African Americans to consent. Specific elements of reported support were significantly associated with consent to donate. Donor and nondonor families had differing perceptions of quality care for themselves and their loved ones. Receiving understandable information about organ donation was the strongest predictor of consent. Specific supportive behaviors by staff as recounted by family members of potential donors were significantly associated with consent to donation. These behaviors lend themselves to creative training and educational programs for staff. Such interventions are essential not only for next of kin of brain-dead patients, but also for staff and ultimately for the public as a whole.


Enhancement of platelet response to immune complexes and IgG aggregates by lipid A-rich bacterial lipopolysaccharides.
The effect of the common lipid moiety of bacterial LPS on secretion from washed human platelets has been studied. The lipid A-rich LPS of S. minnesota R595 and a lipid A preparation both potentiated platelet serotonin secretion in response to IgG aggregates or immune complexes up to 50-fold but had little effect in the absence of IgG. Lipid A has been shown to bind immune aggregates, raising the possibility that its mechanism of action involved effective enlargement or insolubilization of the aggregates. IgG aggregates of dimer to tetramer size were shown to be platelet simuli, equivalent on a weight basis to larger soluble aggregates. The effect of both sizes of aggregates on platelets were equally enhanced by the LPS, indicating that increased size of aggregates alone could not account for the effect of LPS. Similarly, because lipid A-rich LPS enhanced platelet response to already insoluble immune complexes, its mechanism of action cannot simply be insolubilization of immune aggregates. These LPS did not enhance platelet stimulation by antiplatelet antibody, monosodium urate crystals, or thrombin and only slightly enhanced stimulation by insoluble human skin collagen. This indicates some stimulus specificity in the ability of LPS to increase platelet secretion. The enhancement of cell response to immune complexes by the common lipid region of LPS may represent a mechanism for the diverse effects of LPS in vivo and in vitro.


A complex endeavour: an ethnographic study of the implementation of the Sepsis Six clinical care bundle.
Implementation of the 'Sepsis Six' clinical care bundle within an hour of recognition of sepsis is recommended as an approach to reduce mortality in patients with sepsis, but achieving reliable delivery of the bundle has proved challenging. There remains little understanding of the barriers to reliable implementation of bundle components. We examined frontline clinical practice in implementing the Sepsis Six. We conducted an ethnographic study in six hospitals participating in the Scottish Patient Safety Programme Sepsis collaborative. We conducted around 300 h of non-participant observation in emergency departments, acute medical receiving units and medical and surgical wards. We interviewed a purposive sample of 43 members of hospital staff. Data were analysed using a constant comparative approach. Implementation strategies to promote reliable use of the Sepsis Six primarily focused on education, engaging and motivating staff, and providing prompts for behaviour, along with efforts to ensure that equipment required was readily available. Although these strategies were successful in raising staff awareness of sepsis and engagement with implementation, our study identified that completing the bundle within an hour was not straightforward. Our emergent theory suggested that rather than being an apparently simple sequence of six steps, the Sepsis Six actually involved a complex trajectory comprising multiple interdependent tasks that required prioritisation and scheduling, and which was prone to problems of coordination and operational failures. Interventions that involved allocating specific roles and responsibilities for completing the Sepsis Six in ways that reduced the need for coordination and task switching, and the use of process mapping to identify system failures along the trajectory, could help mitigate against some of these problems. Implementation efforts that focus on individual behaviour change to improve uptake of the Sepsis Six should be supplemented by an understanding of the bundle as a complex trajectory of work in which improving reliability requires attention to coordination of workflow, as well as addressing the mundane problems of interruptions and operational failures that obstruct task completion.


Immunization registries in the EMR Era.
The CDC established a national objective to create population-based tracking of immunizations through regional and statewide registries nearly 2 decades ago, and these registries have increased coverage rates and reduced duplicate immunizations. With increased adoption of commercial electronic medical records (EMR), some institutions have used unidirectional links to send immunization data to designated registries. However, access to these registries within a vendor EMR has not been previously reported. To develop a visually integrated interface between an EMR and a statewide immunization registry at a previously non-reporting hospital, and to assess subsequent changes in provider use and satisfaction. A group of healthcare providers were surveyed before and after implementation of the new interface. The surveys addressed access of the California Immunization Registry (CAIR), and satisfaction with the availability of immunization information. Information Technology (IT) teams developed a "smart-link" within the electronic patient chart that provides a single-click interface for visual integration of data within the CAIR database. Use of the tool has increased in the months since its initiation, and over 20,000 new immunizations have been exported successfully to CAIR since the hospital began sharing data with the registry. Survey data suggest that providers find this tool improves workflow and overall satisfaction with availability of immunization data. (p=0.009). Visual integration of external registries into a vendor EMR system is feasible and improves provider satisfaction and registry reporting.


Association of PTP-PEST with the SH3 domain of p130cas; a novel mechanism of protein tyrosine phosphatase substrate recognition.
The protein tyrosine phosphatase PTP-PEST displays remarkable substrate specificity, in vitro and in vivo for p130cas a signalling intermediate implicated in mitogenic signalling, cell-adhesion induced signalling, and in transformation by a variety of oncogenes. We have identified a high affinity interaction between the SH3 domain of p130cas and a proline-rich sequence (P335PPKPPR) within the C-terminal segment of PTP-PEST. Mutation of proline 337 within this sequence to alanine significantly impairs the ability of PTP-PEST to recognise tyrosine phosphorylated p130cas as a substrate, without qualitatively affecting the selectivity of the interaction. Thus the highly specific nature of the interaction between PTP-PEST and p130cas appears to result from a combination of two distinct substrate recognition mechanisms; the catalytic domain of PTP-PEST contributes specificity to the interaction with p130cas, whereas the SH3 domain-mediated association of p130cas and PTP-PEST dramatically increases the efficiency of the interaction. Furthermore, our results indicate that one important function of the p130cas SH3 domain is to associate with PTP-PEST and thereby facilitate the dephosphorylation of p130cas, resulting in the termination of tyrosine phosphorylation-dependent signalling events downstream of p130cas.


Observations of light-induced structural changes of retinal within rhodopsin.
Photo-isomerization of the 11-cis retinal chromophore activates the mammalian light-receptor rhodopsin, a representative member of a major superfamily of transmembrane G-protein-coupled receptor proteins (GPCRs) responsible for many cell signal communication pathways. Although low-resolution (5 A) electron microscopy studies confirm a seven transmembrane helix bundle as a principal structural component of rhodopsin, the structure of the retinal within this helical bundle is not known in detail. Such information is essential for any theoretical or functional understanding of one of the fastest occurring photoactivation processes in nature, as well as the general mechanism behind GPCR activation. Here we determine the three-dimensional structure of 11-cis retinal bound to bovine rhodopsin in the ground state at atomic level using a new high-resolution solid-state NMR method. Significant structural changes are observed in the retinal following activation by light to the photo-activated M(I) state of rhodopsin giving the all-trans isomer of the chromophore. These changes are linked directly to the activation of the receptor, providing an insight into the activation mechanism of this class of receptors at a molecular level.


Synthesis and nephrotoxicity of 6-bromo-2,5-dihydroxy-thiophenol.
The formation of potentially reactive thiols has been postulated to play a role in the nephrotoxicity caused by a number of glutathione and/or cysteine conjugates. However, the inherent reactivity of such compounds has precluded both their identification in biological systems and a determination of their actual toxicity. To this end we have synthesized 6-bromo-2,5-dihydroxy-thiophenol as a putative metabolite of nephrotoxic 2-bromohydroquinone-glutathione conjugates. The compound was prepared by the addition of sodium thiosulfate to 2-bromo-1,4-benzoquinone followed by reduction of the S-arylthiosulfate to the thiophenol. 2,5-Dihydroxy-thiophenol was similarly prepared. Structural identification was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy. Administration of 6-bromo-2,5-dihydroxy-thiophenol to rats (0.35 mmol/kg; intraperitoneally) caused an increase in blood urea nitrogen and histological alterations similar to those observed after 2-bromo-(diglutathion-S-yl)hydroquinone administration. 2,5-Dihydroxy-thiophenol was also nephrotoxic but at a dose of 0.6 mmol/kg. In contrast, no effects on liver pathology were observed after administration of either 6-bromo-2,5-dihydroxy-thiophenol or 2,5-dihydroxy-thiophenol and serum glutamate pyruvate transaminase levels were normal. Neither 2-, 3-, nor 4-bromothiophenol had any effect on blood urea nitrogen at doses between 0.2 and 0.8 mmol/kg (intraperitoneally) and no apparent alterations were seen in kidney slices prepared from bromothiophenol-treated rats. These findings suggest that the quinone function of 6-bromo-2,5-dihydroxy-thiophenol is necessary for the expression of toxicity. In this respect, the lower activity of NAD(P)H quinone oxidoreductase (EC 220.127.116.11) in renal cortex may be of toxicological significance.


A porcine adenovirus with low human seroprevalence is a promising alternative vaccine vector to human adenovirus 5 in an H5N1 virus disease model.
Human adenovirus 5 (AdHu5) vectors are robust vaccine platforms however the presence of naturally-acquired neutralizing antibodies may reduce vector efficacy and potential for re-administration. This study evaluates immune responses and protection following vaccination with a replication-incompetent porcine adenovirus 3 (PAV3) vector as an alternative vaccine to AdHu5 using an avian influenza H5N1 disease model. Vaccine efficacy was evaluated in BALB/c mice following vaccination with different doses of the PAV3 vector expressing an optimized A/Hanoi/30408/2005 H5N1 hemagglutinin antigen (PAV3-HA) and compared with an AdHu5-HA control. PAV3-HA rapidly generated antibody responses, with significant neutralizing antibody titers on day 21, and stronger cellular immune responses detected on day 8, compared to AdHu5-HA. The PAV3-HA vaccine, administered 8 days before challenge, demonstrated improved survival and lower virus load. Evaluation of long-term vaccine efficacy at 12 months post-vaccination showed better protection with the PAV3-HA than with the AdHu5-HA vaccine. Importantly, as opposed to AdHu5, PAV3 vector was not significantly neutralized by human antibodies pooled from over 10,000 individuals. Overall, PAV3-based vector is capable of mediating swift, strong immune responses and offer a promising alternative to AdHu5.


Cooperation between myogenic regulatory factors and SIX family transcription factors is important for myoblast differentiation.
Precise regulation of gene expression is crucial to myogenesis and is thought to require the cooperation of various transcription factors. On the basis of a bioinformatic analysis of gene regulatory sequences, we hypothesized that myogenic regulatory factors (MRFs), key regulators of skeletal myogenesis, cooperate with members of the SIX family of transcription factors, known to play important roles during embryonic skeletal myogenesis. To this day little is known regarding the exact molecular mechanism by which SIX factors regulate muscle development. We have conducted a functional genomic study of the role played by SIX1 and SIX4 during the differentiation of skeletal myoblasts, a model of adult muscle regeneration. We report that SIX factors cooperate with the members of the MRF family to activate gene expression during myogenic differentiation, and that their function is essential to this process. Our findings also support a model where SIX factors function not only 'upstream' of the MRFs during embryogenesis, but also 'in parallel' to them during myoblast differentiation. We have identified new essential nodes that depend on SIX factor function, in the myogenesis regulatory network, and have uncovered a novel way by which MRF function is modulated during differentiation.


Coherent optical spectroscopy of a hybrid nanocrystal complex embedded in a nanomechanical resonator.
We have theoretically investigated a hybrid nanocrystal complex consisted of a metal nanoparticle (MNP) and a semiconductor quantum dot (SQD) embedded in a nanomechanical resonator in the simultaneous presence of a strong control field and a weak probe field. It is shown that the resonance amplification peak of the probe spectrum will enhance dramatically due to the coupling of the plasmon, exciton and nanomechanical resonator. The enhancement increases significantly with decreasing the distance between the metal nanoparticle and a quantum dot, which implies the strong plasmon enhancement effect in this coupled system. The results obtained here may have the potential applications such as tunable Raman lasers and bio-sensors.


Myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.


Association of anthropometric measures across the life-course with refractive error and ocular biometry at age 15 years.
A recent Genome-wide association meta-analysis (GWAS) of refractive error reported shared genetics with anthropometric traits such as height, BMI and obesity. To explore a potential relationship with refractive error and ocular structure we performed a life-course analysis including both maternal and child characteristics using data from the Avon Longitudinal Study of Parents and Children cohort. Measures collected across the life-course were analysed to explore the association of height, weight, and BMI with refractive error and ocular biometric measures at age 15 years from 1613children. The outcome measures were the mean spherical equivalent (MSE) of refractive error (dioptres), axial length (AXL; mm), and radius of corneal curvature (RCC; mm). Potential confounding variables; maternal age at conception, maternal education level, parental socio-economic status, gestational age, breast-feeding, and gender were adjusted for within each multi-variable model. Maternal height was positively associated with teenage AXL (0.010 mm; 95% CI: 0.003, 0.017) and RCC (0.005 mm; 95% CI: 0.003, 0.007), increased maternal weight was positively associated with AXL (0.004 mm; 95% CI: 0.0001, 0.008). Birth length was associated with an increase in teenage AXL (0.067 mm; 95% CI: 0.032, 0.10) and flatter RCC (0.023 mm; 95% CI: 0.013, 0.034) and increasing birth weight was associated with flatter RCC (0.005 mm; 95% CI: 0.0003, 0.009). An increase in teenage height was associated with a lower MSE (- 0.007 D; 95% CI: - 0.013, - 0.001), an increase in AXL (0.021 mm; 95% CI: 0.015, 0.028) and flatter RCC (0.008 mm; 95% CI: 0.006, 0.010). Weight at 15 years was associated with an increase in AXL (0.005 mm; 95% CI: 0.001, 0.009). At each life stage (pre-natal, birth, and teenage) height and weight, but not BMI, demonstrate an association with AXL and RCC measured at age 15 years. However, the negative association between refractive error and an increase in height was only present at the teenage life stage. Further research into the growth pattern of ocular structures and the development of refractive error over the life-course is required, particularly at the time of puberty.


Differential changes in impulsivity and sensation seeking and the escalation of substance use from adolescence to early adulthood.
Recent evidence suggests that impulsivity and sensation seeking are not stable risk factors for substance use among adolescents and early adults but rather that they undergo significant developmental maturation and change. Further, developmental trends of both personality facets may vary across individuals. In the current investigation, we used longitudinal data from ages 15 to 26 on 5,632 individuals drawn from the offspring generation of the National Longitudinal Survey of Youth to examine whether interindividual differences in intraindividual change in impulsivity and sensation seeking predicted the escalation of alcohol, marijuana, and cigarette use in adolescence and early adulthood. Latent growth curve models revealed significant individual differences in rates of change in both personality and substance use. Age-related changes in personality were positively associated with individual differences in substance-use change. Individuals who declined more slowly in impulsivity increased in alcohol, marijuana, and cigarette more rapidly, whereas individuals who declined more slowly in sensation seeking increased more rapidly in alcohol use only. Although risk for substance use across the population may peak during adolescence and early adulthood, this risk may be highest among those who decline more gradually in impulsivity.


The methionine-homocysteine cycle and its effects on cognitive diseases.
Homocysteine, a sulfur-containing amino acid, is a metabolite of the essential amino acid methionine, and exists at a critical biochemical intersection in the methionine cycle - between S-adenosylmethionine, the indispensable ubiquitous methyl donor, and vitamins B12 and folic acid. High blood levels of homocysteine signal a breakdown in this vital process, resulting in far-reaching biochemical and life consequences. The link between homocysteine and cardiovascular disease is well established, and decreasing plasma total homocysteine by providing nutritional cofactors for its metabolism has been shown to reduce the risk of cardiovascular events. Information has been emerging regarding a connection between homocysteine metabolism and cognitive function, from mild cognitive decline (age-related memory loss) to vascular dementia and Alzheimer's disease. Significant deficiencies in the homocysteine re-methylation cofactors cobalamin (B12) and folate, as well as the trans-sulfuration cofactor vitamin B6, are commonly seen in the elderly population, with a resultant increase in homocysteine with advancing age. Hyperhomocysteinemia has been shown to be an independent risk factor for cognitive dysfunction. Indirect and direct vascular damage can be caused by homocysteine, which has been implicated in vascular dementia, with an increased risk of multiple brain infarcts and dementia as homocysteine levels rise. A significant correlation has been found between risk of Alzheimer's disease and high plasma levels of homocysteine, as well as low levels of folic acid, and vitamins B6 and B12. All of these disease associations are thought to be interrelated via increased homocysteine and S-adenosylhomocysteine and subsequent hypomethylation of numerous substances, including DNA and proteins, that render vascular structures and neurons more susceptible to damage and apoptosis. Providing the nutritional cofactors for proper functioning of the methionine cycle may improve methylation and protect the brain from damage. Further studies need to be performed to assess whether this will also reduce the risk of cognitive diseases and/or improve cognitive functioning.


Optimising minimal building blocks for addressable self-assembly.
Addressable structures are characterised by the set of unique components from which they are built and by the specific location that each component occupies. For an addressable structure to self-assemble, its constituent building blocks must be encoded with sufficient information to define their positions with respect to each other and to enable them to navigate to those positions. DNA, with its vast scope for encoding specific interactions, has been successfully used to synthesise addressable systems of several hundred components. In this work we examine the complementary question of the minimal requirements for building blocks to undergo addressable self-assembly driven by a controlled temperature quench. Our testbed is an idealised model of cubic particles patterned with attractive interactions. We introduce a scheme for optimising the interactions using a variant of basin-hopping and a negative design principle. The designed building blocks are tested dynamically in simple target structures to establish how their complexity affects the limits of reliable self-assembly.


Expression of protein C inhibitor (PCI) in benign and malignant prostatic tissues.
Protein C inhibitor (PCI) occurs at high concentration in seminal plasma, and inhibits human glandular kallikrein-2 and, less readily, prostate-specific antigen. Previous studies have localized PCI in the male genital tract. Here we have performed a detailed investigation of PCI expression in the prostatic tissues, metastases, and cell lines. Immunohistochemistry, in situ hybridization, and Western blotting were used to study prostatic tissues, metastases, and PC-3, DU-145, and LNCaP cells. PCI was immunolocalized in tissue microarray spots with BPH epithelium (detection rate 100%), PIN lesions (100%), tumors (96%), metastases (88%), and in all cell lines. ISH and WB supported the findings. PCI is widely expressed in benign prostatic epithelium, and may act as a local regulator of enzymatic activity in seminal fluid, of importance for normal sperm function. Lack of PCI expression in a subpopulation of high-grade tumor cells in combination with maintained protease expression may facilitate invasive growth patterns.