Silicon nanowire based radio-frequency spectrum analyzer.
We demonstrate a terahertz bandwidth silicon nanowire based radio-frequency spectrum analyzer using cross-phase modulation. We show that the device provides accurate characterization of 640Gbaud on-off-keyed data stream and demonstrate its potential for optical time-division multiplexing optimization and optical performance monitoring of ultrahigh speed signals on a silicon chip. We analyze the impact of free carrier effects on our device, and find that the efficiency of the device is not reduced by two-photon or free-carrier absorption, nor its accuracy compromised by free-carrier cross-chirp.


Comparing tongue shapes from ultrasound imaging using smoothing spline analysis of variance.
Ultrasound imaging of the tongue is increasingly common in speech production research. However, there has been little standardization regarding the quantification and statistical analysis of ultrasound data. In linguistic studies, researchers may want to determine whether the tongue shape for an articulation under two different conditions (e.g., consonants in word-final versus word-medial position) is the same or different. This paper demonstrates how the smoothing spline ANOVA (SS ANOVA) can be applied to the comparison of tongue curves [Gu, Smoothing Spline ANOVA Models (Springer, New York, 2002)]. The SS ANOVA is a technique for determining whether or not there are significant differences between the smoothing splines that are the best fits for two data sets being compared. If the interaction term of the SS ANOVA model is statistically significant, then the groups have different shapes. Since the interaction may be significant even if only a small section of the curves are different (i.e., the tongue root is the same, but the tip of one group is raised), Bayesian confidence intervals are used to determine which sections of the curves are statistically different. SS ANOVAs are illustrated with some data comparing obstruents produced in word-final and word-medial coda position.


Prevalence of antibodies to Toxoplasma gondii in woodchucks across an urban-rural gradient.
Increasing urbanization has important consequences for wildlife, including the potential for higher prevalence of diseases within "urban adapter" species exposed to spillover from domestic animals. We investigated whether prevalence of antibodies to Toxoplasma gondii in woodchucks (Marmota monax) was related to urbanization in a Midwestern landscape. We collected serum samples from adult woodchucks captured across an urban-rural gradient in Illinois, USA in May-November 2007. We used an indirect fluorescent antibody test (IFAT) on the serum samples to detect T. gondii antibodies. Five of 35 (14.3%) sera from woodchucks had detectable T. gondii antibodies. Prevalence was related positively to urbanization. All positive samples were from individuals inhabiting areas in which urban land cover exceeded 70%. Urban woodchucks are likely exposed to high levels of T. gondii oocysts in the environment due to habitat overlap with the definitive hosts for the parasite, domestic and feral cats, which reach high densities in urban areas.


Trial designs for chemotherapy-induced peripheral neuropathy prevention: ACTTION recommendations.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies.


Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute coronary syndrome in the emergency department.
Cardiac magnetic resonance (CMR) imaging permits early triage of patients presenting to the emergency department with acute chest pain but has been limited by the inability to differentiate new from old myocardial infarction. Our objective was to evaluate a CMR protocol that includes T2-weighted imaging and assessment of left ventricular wall thickness in detecting patients with acute coronary syndrome in the emergency department. In this prospective cohort observational study, we enrolled patients presenting to the emergency department with acute chest pain, negative cardiac biomarkers, and no ECG changes indicative of acute ischemia. The CMR protocol consisted of T2-weighted imaging, first-pass perfusion, cine function, delayed-enhancement magnetic resonance imaging, and assessment of left ventricular wall thickness. The clinical outcome (acute coronary syndrome) was defined by review of clinical charts by a consensus panel that used American Heart Association/American College of Cardiology guidelines. Among 62 patients, 13 developed acute coronary syndrome during the index hospitalization. The mean CMR time was 32+/-8 minutes. The new CMR protocol (with the addition of T2-weighted and left ventricular wall thickness) increased the specificity, positive predictive value, and overall accuracy from 84% to 96%, 55% to 85%, and 84% to 93%, respectively, compared with the conventional CMR protocol (cine, perfusion, and delayed-enhancement magnetic resonance imaging). Moreover, in a logistic regression analysis that contained information on clinical risk assessment (c-statistic=0.695) and traditional cardiac risk factors (c-statistic=0.771), the new CMR protocol significantly improved the c-statistic to 0.958 (P<0.0001). The present study indicates that a new CMR protocol improves the detection of patients with acute coronary syndrome in the emergency department and adds significant value over clinical assessment and traditional cardiac risk factors.


[Use of outpatient services in an urban area of Southern Brazil: place and frequency].
The objective was determine the use of health services by the adult population in Pelotas, RS, Brazil. A cross-sectional study was made on the basis of a population sample. One thousand six hundred and fifty-seven persons we interviewed during the months of March and June, 1992. A percentage of 9.7 of the sample was lost. Two dependents variables. One the type of service as determined by type of payment. The other the number of medical visits made during the previous year. The type of service was seen to be associated with the following social variables: social class, level of schooling and place of residence. The frequency of medical visits was associated with sex, risk factors and reasons for the visit. It was concluded that choice of the type of service depends more heavily in social class than other variables associated with the severity of the disease in question.


Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells.
Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4+ T cells mediated the autoimmune prevention but CD8+ T cells did not. CD4+ T cells also appeared to mediate the TLI-induced autoimmune disease because CD4+ T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells.


Geography and nursing: convergence in cyberspace?
During the last 3 years the interface between geography and nursing has provided fertile ground for research. Not only has a conceptual emphasis on space and place provided nurse researchers with a robust and subtly different way to deconstruct and articulate nursing environments, but also their studies have provided a much needed focus on certain areas of health-care, and in particular clinical practice, not currently prioritized by health geographers. We argue that, as something that is forcing fundamental re-considerations of the nature of both nursing and geography, cyberspace is a particularly important phenomenon that lies comparatively under-researched at this interface. To encourage some interest in researching nursing and cyberspace through a geographical lens, and at least to showcase a range of potentially useful and transportable concepts, we provide an overview of some of the key debates pertaining to cyberspace developed by human geographers, and make some initial and tentative connections to nursing.


Comparison of Media for Recovery of Verticillium dahliae from Soil.
Polygalacturonic acid (PGA) is an important constituent of Sorensen's NP-10 medium (NP-10) for estimating the population density of Verticillium dahliae in soil. Different types of PGA are available, but not all of them favor the growth of V. dahliae. Unavailability of PGA sodium salt from orange (P-1879) has created an unprecedented problem for the quantification of microscle-rotia (MS) of V. dahliae in soil. The PGA from orange (P-3889) that is now available does not support the growth of V. dahliae. Therefore, experiments were conducted to optimize the use of NP-10 prepared with P-3889 and various concentrations of NaOH. NP-10 with P-3889 amended with eight concentrations of NaOH were compared with NP-10 prepared from PGA sodium salt from orange (P-1879, now discontinued) and citrus (P-3850) along with cellophane and Na-pectate media for recovery of MS from soil and growth of V. dahliae on the media. Seven soils were assayed for MS, and eight isolates of V. dahliae were evaluated for growth and production of MS. Concentrations of NaOH >0.035N and <0.02N in NP-10 with P-3889 reduced mycelial growth, microsclerotial production, and recovery of MS from soils. Similarly, NP-10 with P-3850 alone, cellophane, and Na-pectate media had significantly reduced growth on media and recovery of V. dahliae from soils. The NP-10 with P-3889 and 0.025N NaOH consistently yielded numbers of V. dahliae MS from soil samples and supported the growth and production of MS similar to the NP-10 with P-1879. The medium developed in this study can serve as a direct replacement for the original NP-10 that was developed nearly three decades ago, an important component of which is no longer available.


Effects of fabrication, finishing, and polishing procedures on preload in prostheses using conventional "gold' and plastic cylinders.
This study reviews fundamental concepts related to the use of screws and presents data describing the effect of fabrication, finishing, and polishing procedures on as-received preload for implant cylinders. Specifically, this study measured and compared preload produced when using as-received gold cylinders (the reference or gold standard), and cast cylinders produced from premade gold and plastic cylinders in the as-cast condition and following postcast finishing and polishing manipulations. The results reveal that preload in the gold screw-gold cylinder-abutment joint can be affected by the casting process, and that the choice of cylinder type, casting alloy, investment, and finishing/polishing technique may affect the resultant preload as compared to as-received joint conditions. The data from this study indicate that when plastic patterns are used as part of the framework, finishing and polishing of implant cylinder components should provide an increased preload compared to no such manipulations. Also, if maximum preload is desired, the use of premade metal cylinders offers an advantage over plastic patterns in both preload magnitude and precision.


Sarcoidosis and membranous glomerulonephritis: a significant association.
Three patients were seen who had sarcoidosis associated with glomerulonephritis. Subsequent review of published reports of cases in which the two conditions occurred simultaneously showed a pattern of histological type of glomerulonephritis different from that seen in patients without associated disease. In sarcoidosis with glomerulonephritis there appeared to be a dearth of minimal-change disease and an excess of membranous glomerulonephritis compared with the prevalence that would be expected if the renal disease was merely a chance occurrence. These findings may provide evidence for an important relation between sarcoidosis and glomerulonephritis.


Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents.
Two major obstacles in the treatment of patients with central nervous system malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects of these three combinations against a panel of human tumor xenografts derived from central nervous system malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antitumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P < 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central nervous system malignancies.


Taurine prevents arsenic-induced cardiac oxidative stress and apoptotic damage: role of NF-kappa B, p38 and JNK MAPK pathway.
Cardiac dysfunction is a major cause of morbidity and mortality worldwide due to its complex pathogenesis. However, little is known about the mechanism of arsenic-induced cardiac abnormalities and the use of antioxidants as the possible protective agents in this pathophysiology. Conditionally essential amino acid, taurine, accounts for 25% to 50% of the amino acid pool in myocardium and possesses antioxidant properties. The present study has, therefore, been carried out to investigate the underlying mechanism of the beneficial role of taurine in arsenic-induced cardiac oxidative damage and cell death. Arsenic reduced cardiomyocyte viability, increased reactive oxygen species (ROS) production and intracellular calcium overload, and induced apoptotic cell death by mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. These changes due to arsenic exposure were found to be associated with increased IKK and NF-kappaB (p65) phosphorylation. Pre-exposure of myocytes to an IKK inhibitor (PS-1145) prevented As-induced caspase-3 and PARP cleavage. Arsenic also markedly increased the activity of p38 and JNK MAPKs, but not ERK to that extent. Pre-treatment with SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated NF-kappaB and IKK phosphorylation indicating that p38 and JNK MAPKs are mainly involved in arsenic-induced NF-kappaB activation. Taurine treatment suppressed these apoptotic actions, suggesting that its protective role in arsenic-induced cardiomyocyte apoptosis is mediated by attenuation of p38 and JNK MAPK signaling pathways. Similarly, arsenic intoxication altered a number of biomarkers related to cardiac oxidative stress and other apoptotic indices in vivo and taurine supplementation could reduce it. Results suggest that taurine prevented arsenic-induced myocardial pathophysiology, attenuated NF-kappaB activation via IKK, p38 and JNK MAPK signaling pathways and could possibly provide a protection against As-induced cardiovascular burden.


[Health policies and practices toward equity].
The text approaches the inequalities and the social exclusion in health establishing its social, historical, cultural and economic inter-relations and determinations. It points to the iniquities as consequence of the inequalities in the production and distribution of the wealth expressed by access to services and material goods. It discusses the practices of management, in the field of the health, as supporters of the equity, indicating the shared management as a tool that promotes the values of citizenship and respect to the diversity. It approaches the participation and the social control as practices that promote equity in the health services. It comments the experience of the Department of Social Politics and Health of Belo Horizonte with the work in geopolitical and social territories with practices of management, assistance and social control that contribute for equity. It concludes that, beyond the analyses and macro interventions, it is basic to take the spaces micro of the work for reflection and performance in the construction of equity.


Challenges in pain management at the end of life.
Effective pain management in the terminally ill patient requires an understanding of pain control strategies. Ongoing assessment of pain is crucial and can be accomplished using various forms and scales. It is also important to determine if the pain is nociceptive (somatic or visceral pain) or neuropathic (continuous dysesthesias or chronic lancinating or paroxysmal pain). Nociceptive pain can usually be controlled with nonsteroidal antiinflammatory drugs or corticosteroids, whereas neuropathic pain responds to tricyclic antidepressants or anticonvulsants. Relief of breakthrough pain requires the administration of an immediate-release analgesic medication. If a significant amount of medication for breakthrough pain is already being given, the baseline dose of sustained-release analgesic medication should be increased. If pain does not respond to one analgesic medication, physicians should use an equianalgesic dose chart when changing the medication or route of administration. Opioid rotation can be used if pain can no longer be controlled on a specific regimen. The impact of unresolved psychosocial or spiritual issues on pain management may need to be addressed.


Identification of hepatic niche harboring human acute lymphoblastic leukemic cells via the SDF-1/CXCR4 axis.
In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc (null) mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.


Cytoarchitecture and cortical connections of the posterior cingulate and adjacent somatosensory fields in the rhesus monkey.
The cytoarchitecture and connections of the caudal cingulate and medial somatosensory areas were investigated in the rhesus monkey. There is a stepwise laminar differentiation starting from retrosplenial area 30 towards the isocortical regions of the medial parietal cortex. This includes a gradational emphasis on supragranular laminar organization and general reduction of the infragranular neurons as one proceeds from area 30 toward the medial parietal regions, including areas 3, 1, 2, 5, 31, and the supplementary sensory area (SSA). This trend includes a progressive increase in layer IV neurons. Area 23c in the lower bank and transitional somatosensory area (TSA) in the upper bank of the cingulate sulcus appear as nodal points. From area 23c and TSA the architectonic progression can be traced in three directions: one culminates in areas 3a and 3b (core line), the second in areas 1, 2, and 5 (belt line), and the third in areas 31 and SSA (root line). These architectonic gradients are reflected in the connections of these regions. Thus, cingulate areas (30, 23a, and 23b) are connected with area 23c and TSA on the one hand and have widespread connections with parieto-temporal, frontal, and parahippocampal (limbic) regions on the other. Area 23c has connections with areas 30, 23a and b, and TSA as well as with medial somatosensory areas 3, 1, 2, 5, and SSA. Area 23c also has connections with parietotemporal, frontal, and limbic areas similar to areas 30, 23a, and 23b. Area TSA, like area 23c, has connections with areas 3, 1, 2, 5, and SSA. However, it has only limited connections with the parietotemporal and frontal regions and none with the parahippocampal gyrus. Medial area 3 is mainly connected to medial and dorsal sensory areas 3, 1, 2, 5, and SSA and to areas 4 and 6 as well as to supplementary (M2 or area 6m), rostral cingulate (M3 or areas 24c and d), and caudal cingulate (M4 or areas 23c and d) motor cortices. Thus, in parallel with the architectonic gradient of laminar differentiation, there is also a progressive shift in the pattern of corticocortical connections. Cingulate areas have widespread connections with limbic, parietotemporal, and frontal association areas, whereas parietal area 3 has more restricted connections with adjacent somatosensory and motor cortices. TSA is primarily related to the somatosensory-motor areas and has limited connections with the parietotemporal and frontal association cortices.


A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)


Quantum-dot-embedded silica nanotubes as nanoprobes for simple and sensitive DNA detection.
We have developed a new technique using fluorescent silica nanotubes for simple and sensitive DNA detection. The quantum-dot-embedded silica nanotubes (QD-SNTs) were fabricated by a sol-gel reaction using anodic aluminum silica oxide (AAO) as a template. The fluorescent QD-SNTs of different colors were then immobilized with single-stranded DNA and used as nanoprobes for DNA detection. The optical and structural properties of QD-SNT nanoprobes were examined using photoluminescence spectroscopy, confocal microscopy and transmission electron microscopy (TEM). The QD-SNT nanoprobes were applied to detect dye-labeled target DNA in a solution phase. The obvious color change of the QD-SNT nanoprobes was observed visually under a simple microscope after the successful detection with target DNA. The quantitative analyses indicated that ∼ 100 attomole of target DNA in one nanoprobe can generate a distinguishable and observable color change. The detection results also demonstrated that our assay exhibited high specificity, high selectivity and very low nonspecific adsorption. Our simple DNA assay based on QD-SNT nanoprobes is expected to be quite useful for the needs of fast DNA screening and detection applications.


Cerebral lesions on 7 tesla MRI in patients with sickle cell anemia.
Patients with sickle cell anemia (SCA) are at a high risk to develop cerebral damage. Most common are silent cerebral infarctions (SCIs), visible as white matter hyperintensities (WMHs) on MRI in a patient without neurological deficits. The etiology of SCIs remains largely unclear. In addition, patients are at an increased risk for overt stroke, which is associated with large vessel disease. This classification based on the presence or absence of neurological deficits may not be the most fitting for research purposes, as it does not match the different underlying pathology. A classification based on imaging findings may therefore be a more straightforward approach for research purposes. We explored the feasibility to identify imaging features of SCIs in young, asymptomatic patients with SCA using ultra high-field 7 Tesla (7T) MRI. 7T MRI has a high resolution, which offers a unique chance to investigate small subclinical brain lesions in detail. To explore the superiority of 7T in identifying imaging abnormalities, we compared our results with 3T MRI. Ten young, neurologically asymptomatic patients with SCA underwent 7T and 3T MRI; 10 healthy, age-matched controls underwent 7T MRI. We used existing neuroimaging standards to classify the brain lesions. We scored 7T and 3T scans separately, blinded for all other results. Using 7T MRI, we identified more patients with intracerebral lesions (9/10 vs. 5/10), a higher total count of WMHs (203 vs. 190, p = 0.016) and more lacunes (5 vs. 4) compared to 3T MRI. Abnormalities seen on 7T, which could not be identified on 3T, were cortical hyperintensities (in 3/10) and a different aspect of irregular WMHs, closely associated with cortical hyperintensities in a patient with large vessel stenosis. In 7 controls, a total of 13 WMHs were present. Using 7T MRI, we identified more intracerebral lesions compared to 3T, and found several abnormalities not visible on 3T. 7T MRI in SCA seems of particular interest to study the cortical involvement and the relation between WMHs and the cortex. We found some imaging features that are thought to be representative for small vessel disease, including WMHs, lacunes and prominent perivascular spaces; to understand whether small vessel disease plays a role in SCA requires further research.


A Medicago truncatula SWEET transporter implicated in arbuscule maintenance during arbuscular mycorrhizal symbiosis.
Plants form a mutualistic symbiosis with arbuscular mycorrhizal (AM) fungi, which facilitates the acquisition of scarce minerals from the soil. In return, the host plants provide sugars and lipids to its fungal partner. However, the mechanism by which the AM fungi obtain sugars from the plant has remained elusive. In this study we investigated the role of potential SWEET family sugar exporters in AM symbiosis in Medicago truncatula. We show that M. truncatula SWEET1b transporter is strongly upregulated in arbuscule-containing cells compared to roots and localizes to the peri-arbuscular membrane, across which nutrient exchange takes place. Heterologous expression of MtSWEET1b in a yeast hexose transport mutant showed that it mainly transports glucose. Overexpression of MtSWEET1b in M. truncatula roots promoted the growth of intraradical mycelium during AM symbiosis. Surprisingly, two independent Mtsweet1b mutants, which are predicted to produce truncated protein variants impaired in glucose transport, exhibited no significant defects in AM symbiosis. However, arbuscule-specific overexpression of MtSWEET1bY57A/G58D , which are considered to act in a dominant-negative manner, resulted in enhanced collapse of arbuscules. Taken together, our results reveal a (redundant) role for MtSWEET1b in the transport of glucose across the peri-arbuscular membrane to maintain arbuscules for a healthy mutually beneficial symbiosis.


Anti-Chol-1 antigen, GQ1bα, antibodies are associated with Alzheimer's disease.
The interaction of amyloid β-proteins (Aβ) with membrane gangliosides has been reported to be an early event in Aβ fibril formation in Alzheimer's disease (AD). Neuronal degeneration in AD has been postulated to be associated with the presence of anti-ganglioside antibodies in patient sera. Using an enzyme-linked immunosorbent assay (ELISA) and high-performance thin-layer chromatography (HPTLC) immunostaining, sera from 27 individuals (10 with AD, 6 with vascular dementia (VD), and 11 non-demented age-matched pathological controls) were examined in order to detect anti-glycosphingolipid (GSL) antibodies, including anti-cholinergic-specific antigen (Chol-1α; GQ1bα) antibodies. All sera had natural antibodies against ganglio-N-tetraosyl gangliosides (brain-type gangliosides). However, sera of demented patients with AD and VD had significantly higher titers of anti-GSL antibodies than those in age-matched pathological controls. Although most serum antibodies, including anti- GM1, -GT1b, -GQ1b, -GQ1bα, were of the IgM type, the presence of the IgG type antibodies was also significantly elevated in the sera of demented patients with AD. Anti-GT1b antibodies of the IgG type were elevated in AD (90%, 9 of 10 cases) and VD (100%), respectively. Most surprisingly, anti-GQ1bα antibodies (IgM) were found in 90% (9/10) and 100% (6/6) in the sera of patients with AD and VD, respectively. Since GQ1bα is present in the cerebral cortex and hippocampus, the presence of anti-GQ1bα antibodies may play an important role in disrupting cholinergic synaptic transmission and may participate in the pathogenesis of dementia. We conclude that elevated anti-GSL antibody titers may be useful as an aid for clinical diagnosis of those dementias.


Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension.
Adipose tissue secretes vasoactive substances which may contribute to the development of obesity-related hypertension. The aim of this work was to study the expression of renin-angiotensin system genes in adipose tissue of obese hypertensive subjects and the hormonal regulation of these genes. Differential expression of renin-angiotensin system genes in subcutaneous abdominal adipocytes of 12 lean normotensive, eight obese normotensive, and 10 obese hypertensive women was determined in a cross-sectional study. In vitro hormonal regulation of these genes was studied in primary human adipocytes obtained by breast reduction from healthy women. In the clinical study, 24-h ambulatory blood pressure measurement and anthropometry were used to characterize the volunteers, and adipocytes were obtained by subcutaneous needle biopsy. The in vitro regulation of renin-angiotensin system genes by hydrocortisone, insulin, thyroxin, estradiol and angiotensin II on primary cultured human mammary adipocytes was studied by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). While expression of the angiotensinogen gene was significantly lower in adipocytes from both obese groups, the renin, angiotensin-converting enzyme and angiotensin II type 1 receptor genes were significantly upregulated in obese hypertensives. Hydrocortisone increased angiotensin II type 1 receptor gene and protein expression in a time- and dose-dependent manner in human adipocytes, but had no significant influence on other renin-angiotensin system genes. Expression of these genes was not significantly affected by any of the other tested hormones. Renin-angiotensin system genes are differentially regulated in human obesity and hypertension. The role of the adipose-tissue renin-angiotensin system in the development of obesity-associated hypertension or metabolic disease clearly warrants further study.


Nursing Practice With Transthoracic Intracardiac Catheters in Children: International Benchmarking Study.
Transthoracic intracardiac catheters are central catheters placed in the operating room at the conclusion of cardiac surgery for infants and children. Complications associated with these catheters (eg, bleeding, migration, premature removal, infection, leakage, and lack of function) have been described. However, no researchers have addressed the nursing management of these catheters in the intensive care unit, including catheter dressing and securement, mobilization of patients, and flushing the catheters, or the impact of these interventions on patients' outcomes. To internationally benchmark current nursing practice associated with care of infants and children with transthoracic intracardiac catheters. In a cross-sectional, descriptive study of nursing practice in infants and children with transthoracic intracardiac catheters, a convenience sample of bedside and advanced practice nurses was recruited to complete an online survey to benchmark current practice. The survey included questions on criteria for catheter insertion and removal, dressing care, flushing practice, securement, and mobilization of patients. Transthoracic intracardiac catheters are used by most centers that provide care for infants and children after open heart surgery. A wide range of practices was reported. Standardizing the use and care of transthoracic intracardiac catheters can improve the safety and efficacy of their use in infants and children and promote safe and early postoperative mobilization of patients.


Measuring hospital use without claims: a comparison of patient and provider reports.
We compared the validity of hospital admission and length of stay reports from patients, outpatient providers, and hospitals, and we examined possible sources of error. Data were collected from people enrolled in a randomized trial of treatment for severe mental illness and substance use disorders, from community mental health centers (CMHCs), and from hospitals. Reports for each of the 74 study participants covered two-year time periods beginning and ending at various times between 1989 and 1993. We compared reports from the various sources and constructed a hybrid with data from all three sources. Using parametric and non-parametric statistics, we compared patient, CMHC, and hospital reports with each other and with the hybrid source. In subsequent regression analyses we explored correlates of reporting accuracy. Single-source reports underestimated hospital use, but when patient and CMHC reports were combined, results were very similar to those obtained by the more laborious hybrid method. Patient reports became less accurate as the time between discharge and reporting increased; people with bipolar disorders reported admissions with greater accuracy than did people with schizophrenia. CMHC reporting accuracy decreased as the distance to the admitting hospital increased and were less accurate for people with more severe psychiatric symptoms. Reports from single sources are likely to underestimate hospital use for different reasons. Combining carefully collected data from patients and outpatient providers produces estimates of hospital use that are substantially the same as those developed through methods that are more laborious and costly.


Lipoic acid based core cross-linked micelles for multivalent platforms: design, synthesis and application in bio-imaging and drug delivery.
Natural lipoic acid derived small-molecule amphiphiles self-assemble into micelles in water. The presence of numerous disulfides accumulated in the core makes the micelles readily cross-linked to achieve the establishment of core cross-linked micelles (CCMs). Thanks to the inherent biocompatibility, the resulting lipoic acid based CCMs (LA-CCMs) are good multivalent platforms for biomedical applications.


Assessment of immunological parameters following a qigong training program.
Qigong is a type of Chinese psychosomatic exercise that integrates meditation, slow physical movements, and breathing, and to which numerous physical as well as mental benefits have been classically ascribed. The aim of the present study was to analyze the effects of a qigong program on various immunological parameters. 29 naive subjects participated in the study, of whom 16 were allocated to the experimental group and the rest to the control group. The experimental subjects underwent a qigong training program, conducted by a qualified instructor, consisting of half an hour of daily practice for one month. The day before the experiment commenced and the day after it finished, blood samples were drawn from all subjects for the quantification of immunological parameters (leukocytes, immunoglobulins, and complement). As statistical analysis, analysis of covariance (ANCOVA) was carried out. Statistically significant differences were found between the control and experimental groups, with the experimental group showing lower numbers of total leukocytes and eosinophils, number and percentage of monocytes, as well as complement C3 concentration. In addition, a similar result with a trend towards significance was observed in the number of eosinophils. These findings demonstrate that after one month of practicing qigong, significant immunological changes occurred between the experimental and control groups, with a consistently lower and broadly significant profile of these measures within the qigong practitioner group.


Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway.
Large conductance, calcium- and voltage-gated potassium (BK) channels are ubiquitous and critical for neuronal function, immunity, and smooth muscle contractility. BK channels are thought to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP(2)) only through phospholipase C (PLC)-generated PIP(2) metabolites that target Ca(2+) stores and protein kinase C and, eventually, the BK channel. Here, we report that PIP(2) activates BK channels independently of PIP(2) metabolites. PIP(2) enhances Ca(2+)-driven gating and alters both open and closed channel distributions without affecting voltage gating and unitary conductance. Recovery from activation was strongly dependent on PIP(2) acyl chain length, with channels exposed to water-soluble diC4 and diC8 showing much faster recovery than those exposed to PIP(2) (diC16). The PIP(2)-channel interaction requires negative charge and the inositol moiety in the phospholipid headgroup, and the sequence RKK in the S6-S7 cytosolic linker of the BK channel-forming (cbv1) subunit. PIP(2)-induced activation is drastically potentiated by accessory beta(1) (but not beta(4)) channel subunits. Moreover, PIP(2) robustly activates BK channels in vascular myocytes, where beta(1) subunits are abundantly expressed, but not in skeletal myocytes, where these subunits are barely detectable. These data demonstrate that the final PIP(2) effect is determined by channel accessory subunits, and such mechanism is subunit specific. In HEK293 cells, cotransfection of cbv1+beta(1) and PI4-kinaseIIalpha robustly activates BK channels, suggesting a role for endogenous PIP(2) in modulating channel activity. Indeed, in membrane patches excised from vascular myocytes, BK channel activity runs down and Mg-ATP recovers it, this recovery being abolished by PIP(2) antibodies applied to the cytosolic membrane surface. Moreover, in intact arterial myocytes under physiological conditions, PLC inhibition on top of blockade of downstream signaling leads to drastic BK channel activation. Finally, pharmacological treatment that raises PIP(2) levels and activates BK channels dilates de-endothelized arteries that regulate cerebral blood flow. These data indicate that endogenous PIP(2) directly activates vascular myocyte BK channels to control vascular tone.


Species association of hepatitis B virus (HBV) in non-human apes; evidence for recombination between gorilla and chimpanzee variants.
Hepatitis B virus (HBV) infections are widely distributed in humans, infecting approximately one third of the world's population. HBV variants have also been detected and genetically characterised from Old World apes; Gorilla gorilla (gorilla), Pan troglodytes (chimpanzee), Pongo pygmaeus (orang-utan), Nomascus nastusus and Hylobates pileatus (gibbons) and from the New World monkey, Lagothrix lagotricha (woolly monkey). To investigate species-specificity and potential for cross species transmission of HBV between sympatric species of apes (such as gorillas and chimpanzees in Central Africa) or between humans and chimpanzees or gorillas, variants of HBV infecting captive wild-born non-human primates were genetically characterised. 9 of 62 chimpanzees (11.3%) and two from 11 gorillas (18%) were HBV-infected (15% combined frequency), while other Old world monkey species were negative. Complete genome sequences were obtained from six of the infected chimpanzee and both gorillas; those from P. t .ellioti grouped with previously characterised variants from this subspecies. However, variants recovered from P. t. troglodytes HBV variants also grouped within this clade, indicative of transmission between sub-species, forming a paraphyletic clade. The two gorilla viruses were phylogenetically distinct from chimpanzee and human variants although one showed evidence for a recombination event with a P.t.e.-derived HBV variant in the partial X and core gene region. Both of these observations provide evidence for circulation of HBV between different species and sub-species of non-human primates, a conclusion that differs from the hypothesis if of strict host specificity of HBV genotypes.


Association of Hormonal Contraception With Depression.
Millions of women worldwide use hormonal contraception. Despite the clinical evidence of an influence of hormonal contraception on some women's mood, associations between the use of hormonal contraception and mood disturbances remain inadequately addressed. To investigate whether the use of hormonal contraception is positively associated with subsequent use of antidepressants and a diagnosis of depression at a psychiatric hospital. This nationwide prospective cohort study combined data from the National Prescription Register and the Psychiatric Central Research Register in Denmark. All women and adolescents aged 15 to 34 years who were living in Denmark were followed up from January 1, 2000, to December 2013, if they had no prior depression diagnosis, redeemed prescription for antidepressants, other major psychiatric diagnosis, cancer, venous thrombosis, or infertility treatment. Data were collected from January 1, 1995, to December 31, 2013, and analyzed from January 1, 2015, through April 1, 2016. Use of different types of hormonal contraception. With time-varying covariates, adjusted incidence rate ratios (RRs) were calculated for first use of an antidepressant and first diagnosis of depression at a psychiatric hospital. A total of 1 061 997 women (mean [SD] age, 24.4 [0.001] years; mean [SD] follow-up, 6.4 [0.004] years) were included in the analysis. Compared with nonusers, users of combined oral contraceptives had an RR of first use of an antidepressant of 1.23 (95% CI, 1.22-1.25). Users of progestogen-only pills had an RR for first use of an antidepressant of 1.34 (95% CI, 1.27-1.40); users of a patch (norgestrolmin), 2.0 (95% CI, 1.76-2.18); users of a vaginal ring (etonogestrel), 1.6 (95% CI, 1.55-1.69); and users of a levonorgestrel intrauterine system, 1.4 (95% CI, 1.31-1.42). For depression diagnoses, similar or slightly lower estimates were found. The relative risks generally decreased with increasing age. Adolescents (age range, 15-19 years) using combined oral contraceptives had an RR of a first use of an antidepressant of 1.8 (95% CI, 1.75-1.84) and those using progestin-only pills, 2.2 (95% CI, 1.99-2.52). Six months after starting use of hormonal contraceptives, the RR of antidepressant use peaked at 1.4 (95% CI, 1.34-1.46). When the reference group was changed to those who never used hormonal contraception, the RR estimates for users of combined oral contraceptives increased to 1.7 (95% CI, 1.66-1.71). Use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.


Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.
In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.


Clinical predictors of recurrent Clostridium difficile infection in out-patients.
Clostridium difficile infection (CDI) recurs in 20-30% of patients. To describe the predictors of recurrence in out-patients with CDI. Out-patient cases of CDI in Olmsted County, MN residents diagnosed between 28 June 2007 and 25 June 2010 were identified. Recurrent CDI was defined as recurrence of diarrhoea with a positive C. difficile PCR test from 15 to 56 days after the initial diagnosis with interim resolution of symptoms. Patients who had two positive tests within 14 days were excluded. Cox proportional hazard models were used to assess the association of clinical variables with time to recurrence of CDI. The cohort included 520 out-patients; 104 had recurrent CDI (cumulative incidence of 17.5% by 30 days). Univariate analysis identified increasing age and antibiotic use to be associated with recurrent CDI. Severe CDI, peripheral leucocyte count and change in serum creatinine >1.5-fold were not. In a multiple variable model, concomitant antibiotic use was associated with risk of recurrent CDI (HR = 5.4, 95% CI 1.6-17.5, P = 0.005), while age (HR per 10 year increase = 1.1, 95% CI 0.9-1.3, P = 0.22); peripheral leucocyte count >15 × 10(9) /L (HR = 1.0, 95% CI 0.5-2.1, P = 0.92); and change in serum creatinine greater than 1.5-fold (HR = 0.8, 95% CI 0.4-1.5, P = 0.44) were not. Antibiotic use was independently associated with a dramatic risk of recurrent Clostridium difficile infection in an out-patient cohort. It is important to avoid unnecessary systemic antibiotics in patients with Clostridium difficile infection, and patients with ongoing antibiotic use should be monitored closely for recurrent infection.


Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase.
There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two "druggable" pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.


Selective excitation of parabolic-index optical fibers by Gaussian beams.
Excitation coefficients of the guided modes of a parabolic-index optical fiber by narrow input Gaussian beams are calculated. The effects of beam offset, tilt, width, and wave-front curvature are examined. A wave-optical procedure for optimizing the input Gaussian beamwidth (to excite as few mode groups as possible) as a function of beam offset is presented and shown to be in agreement with a simple Fourier-optics optimization.


A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1.
ATP-sensitive potassium (KATP) channels are major regulators of glucose-induced insulin secretion in pancreatic beta cells. We have described a dominant heterozygous mutation--E1506K--in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of K(ATP)-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0.07 in those without diabetes and 0.05 in those with the disorder; not significantly different from controls). Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes.


Neural mechanism of activity spread in the cat motor cortex and its relation to the intrinsic connectivity.
Motor cortical points are linked by intrinsic horizontal connections having a recurrent network topology. However, it is not known whether neural activity can propagate over the area covered by these intrinsic connections and whether there are spatial anisotropies of synaptic strength, as opposed to synaptic density. Moreover, the mechanisms by which activity spreads have yet to be determined. To address these issues, an 8 × 8 microelectrode array was inserted in the forelimb area of the cat motor cortex (MCx). The centre of the array had a laser etched hole ∼500 μm in diameter. A microiontophoretic pipette, with a tip diameter of 2-3 μm, containing bicuculline methiodide (BIC) was inserted in the hole and driven to a depth of 1200-1400 μm from the cortical surface. BIC was ejected for ∼2min from the tip of the micropipette with positive direct current ranging between 20 and 40 nA in different experiments. This produced spontaneous nearly periodic bursts (0.2-1.0 Hz) of multi-unit activity in a radius of about 400 μm from the tip of the micropipette. The bursts of neural activity spread at a velocity of 0.11-0.24 ms⁻¹ (mean=0.14 mm ms⁻¹, SD=0.05)with decreasing amplitude.The area activated was on average 7.22 mm² (SD=0.91 mm²), or ∼92% of the area covered by the recording array. The mode of propagation was determined to occur by progressive recruitment of cortical territory, driven by a central locus of activity of some 400 μm in radius. Thus, activity did not propagate as a wave. Transection of the connections between the thalamus and MCx did not significantly alter the propagation velocity or the size of the recruited area, demonstrating that the bursts spread along the routes of intrinsic cortical connectivity. These experiments demonstrate that neural activity initiated within a small motor cortical locus (≤ 400 μm in radius) can recruit a relatively large neighbourhood in which a variety of muscles acting at several forelimb joints are represented. These results support the hypothesis that the MCx controls the forelimb musculature in an integrated and anticipatory manner based on a recurrent network topology


Daily physical activity in patients with chronic obstructive pulmonary disease: a systematic review.
Patients with chronic obstructive pulmonary disease (COPD) are often limited in their daily physical activity. However, the level, type and intensity of daily physical activity are not known, nor there is a clear insight in the contributing factors. The aim of this review is to describe daily physical activity of COPD patients, and to examine its relationship with demographic factors, pulmonary function, physical fitness, systemic inflammation and quality of life. A systematic literature search was conducted, including studies assessing daily physical activity in all stages of COPD by various different types of measurement techniques. In total, 47 studies were selected; 17 performance-, 20 questionnaire-, and 12 interview-based. Two studies used both a performance- and questionnaire-based method. Overall, COPD patients have a lower level and intensity of daily physical activity compared to healthy controls. This was reported by performance- as well as questionnaire-based studies, yet with a large variation (42-86% and 28-97%, respectively). Reduced daily physical activity is associated with higher levels of airway obstruction, higher levels of systemic inflammation, and lower levels of physical fitness. The association between daily physical activity and quality of life is less clear. In conclusion, this is the first review that examined the level, type and determinants of daily physical activity in COPD. It demonstrates that reduced daily physical activity frequently occurs in COPD patients, yet with a large variation. Methods of measuring and reporting daily physical activity should be more standardized.


Deficiency of niemann-pick type C-1 protein impairs release of human immunodeficiency virus type 1 and results in Gag accumulation in late endosomal/lysosomal compartments.
Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C-1 (NPC1)-deficient (NPCD) cells, wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments. We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release. Further, NPCD Epstein-Barr virus-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly compared to normal cells. Infection of the NPCD fibroblasts with a vesicular stomatitis virus G-pseudotyped strain of HIV-1 produced similar results, suggesting a postentry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release. Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.


A Retrospective Study of Neurological Complications in Pediatric Patients With Moyamoya Disease Undergoing General Anesthesia.
Moyamoya disease is a condition with potentially devastating and permanent neurological sequelae. Adequate volume status and blood pressure, tight control of carbon dioxide to achieve normocarbia, and providing postoperative analgesia to prevent hyperventilation are typical goals that are used during anesthetic care in these patients. The purpose of this study was to assess postanesthesia neurological complications in moyamoya patients undergoing general anesthesia for imaging studies and surgical procedures excluding neurosurgical revascularization. We performed a retrospective cohort study examining moyamoya patients who received general anesthesia for imaging studies and nonneurosurgical-revascularization procedures between January 1, 2001 and December 1, 2016 at our quaternary care pediatric hospital. A general anesthetic encounter was excluded if it occurred within 30 days after a revascularization surgery. The electronic medical records of study patients were analyzed for perioperative management, and neurological outcomes within 30 days of an anesthetic were assessed. A total of 58 patients undergoing 351 anesthesia exposures were included in the study. Three patients experienced neurological complications, which included focal neurological weakness, seizure, and altered mental status. The incidence of complications during anesthesia encounters was 0.85% (3/351) with a 95% confidence interval of 0.28-2.62. Over a 16-year period at our hospital, 3 children with moyamoya disease who underwent anesthesia for nonneurosurgical-revascularization purposes demonstrated postanesthesia neurological symptoms. The symptoms were consistent with transient ischemic attacks and all resolved without long-term sequelae.


Elevated levels of methylmalonate and homocysteine in Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis.
Increasing evidence suggests that elevated levels of homocysteine (Hcy) and methylmalonate (MMA) may be involved in the pathogenesis of neurodegenerative diseases. The urine levels of MMA and serum levels of Hcy as well as folic acid and vitamin B(12) were measured in patients suffering from the distinct neurodegenerative diseases progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), and compared to age- and gender-matched control subjects. We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8, ALS 13.9, control 11.2 micromol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7, control 1.8 mg/g) in all patient groups in comparison with controls. Levels of Hcy and MMA did not differ significantly between the neurodegenerative diseases. Our findings might imply that Hcy and MMA are released as a consequence of neurodegeneration regardless of the underlying cause and serve as surrogate markers of neurodegeneration. Alternatively they might be directly implicated in the pathogenesis of these diseases. Since elevated levels of both Hcy and MMA are neurotoxic, further studies might investigate the effect of vitamin therapy on disease progression.


The performance of Orma Boran and Maasai Zebu crossbreeds in a trypanosomosis endemic area of Nguruman, south western Kenya.
Studies on the trypanotolerance of Orma Boran X Maasai Zebu (Orma Zebu) crossbred cattle (F1 progeny) and pure-bred Maasai Zebu contemporaries were carried out in Nguruman, south western Kenya. The two groups were monitored from birth for a period of 2 years. The incidence of trypanosomosis, parasitaemia, packed cell volume (PCV), body mass and average daily mass gain were monitored. During the study period, overall trypanosomosis incidence was low (3%). The crossbred cattle had a higher incidence of infection (61% vs 39%). The mean PCV and mean mass gain for the crossbred cattle was higher than that of the Maasai Zebu. The mean calf body mass at weaning (8 months) for the Orma Zebu and Maasai Zebu was 72 kg and 64 kg, respectively, while at 18 months of age their mean body mass was 164 kg and 123 kg, respectively. During the rainy season significant differences in average daily mass gains were noted (P < 0.05). The superior mass gain of the Orma Zebu observed during the rainy season, despite higher infection rates, indicate an enhanced trypanotolerance. Moreover, the better performance of the Orma Zebu is an attribute that could be exploited in the adoption of the trypanotolerance genotype, as a sustainable trypanosomosis control strategy.


Comparing the Cost of Treatment with Octreotide Long-Acting Release versus Lanreotide in Patients with Metastatic Gastrointestinal Neuroendocrine Tumors.
The 2 somatostatin analogs currently recommended by the National Comprehensive Cancer Network for the treatment of gastrointestinal (GI) neuroendocrine tumors (NETs) include octreotide long-acting release (Sandostatin LAR) for injectable suspension and lanreotide (Somatuline Depot) injection for subcutaneous use. To estimate the costs to payers associated with 30-mg octreotide LAR and 120-mg lanreotide treatment among patients with metastatic GI-NETs. The costs to payers associated with the 2 drugs were estimated by including the costs of each drug, drug administration, and adverse events. The unit drug costs for octreotide LAR and for lanreotide were obtained from ReadyPrice Wholesale Acquisition Cost; the doses were obtained from published studies. The adverse event rates were obtained from 2 phase 3 clinical trials, PROMID and CLARINET. Deterministic one-way sensitivity analyses were used to assess the impact of modifying assumptions and inputs on the results, including the 2017 Average Sales Price (ASP). All costs were estimated in 2016 US dollars, with a constant discount of 3%. The costs to payers associated with the treatment of GI-NETs during 1-, 3-, and 5-year horizons were $74,566, $180,082, and $262,344, respectively, for octreotide LAR and $84,856, $205,562, and $299,667, respectively, for lanreotide. Thus, octreotide LAR was associated with lower costs by $10,290 (1 year), $25,480 (3 years), and $37,323 (5 years) compared with lanreotide. Over a 5-year horizon, the costs of adverse events and administration accounted for 0.72% of the total cost for octreotide LAR and 0.51% of the total cost for lanreotide. Sensitivity analyses confirmed that the main factor affecting the cost difference was the price of the drugs; analyses using the ASP yielded similar results. For the management of metastatic GI-NETs, the cost to payers of treatment with 30-mg octreotide LAR is considerably lower than with 120-mg lanreotide over 1-, 3-, and 5-year horizons. In the presence of healthcare resource constraints, these findings may support decision-making when considering the care of patients with metastatic GI-NETs.


Crystal structure of deoxycytidylate hydroxymethylase from bacteriophage T4, a component of the deoxyribonucleoside triphosphate-synthesizing complex.
Bacteriophage T4 deoxycytidylate hydroxymethylase (EC 184.108.40.206), a homodimer of 246-residue subunits, catalyzes hydroxymethylation of the cytosine base in deoxycytidylate (dCMP) to produce 5-hydroxymethyl-dCMP. It forms part of a phage DNA protection system and appears to function in vivo as a component of a multienzyme complex called deoxyribonucleoside triphosphate (dNTP) synthetase. We have determined its crystal structure in the presence of the substrate dCMP at 1.6 A resolution. The structure reveals a subunit fold and a dimerization pattern in common with thymidylate synthases, despite low (approximately 20%) sequence identity. Among the residues that form the dCMP binding site, those interacting with the sugar and phosphate are arranged in a configuration similar to the deoxyuridylate binding site of thymidylate synthases. However, the residues interacting directly or indirectly with the cytosine base show a more divergent structure and the presumed folate cofactor binding site is more open. Our structure reveals a water molecule properly positioned near C-6 of cytosine to add to the C-7 methylene intermediate during the last step of hydroxymethylation. On the basis of sequence comparison and crystal packing analysis, a hypothetical model for the interaction between T4 deoxycytidylate hydroxymethylase and T4 thymidylate synthase in the dNTP-synthesizing complex has been built.


High Chromaticity Aluminum Plasmonic Pixels for Active Liquid Crystal Displays.
Chromatic devices such as flat panel displays could, in principle, be substantially improved by incorporating aluminum plasmonic nanostructures instead of conventional chromophores that are susceptible to photobleaching. In nanostructure form, aluminum is capable of producing colors that span the visible region of the spectrum while contributing exceptional robustness, low cost, and streamlined manufacturability compatible with semiconductor manufacturing technology. However, individual aluminum nanostructures alone lack the vivid chromaticity of currently available chromophores because of the strong damping of the aluminum plasmon resonance in the visible region of the spectrum. In recent work, we showed that pixels formed by periodic arrays of Al nanostructures yield far more vivid coloration than the individual nanostructures. This progress was achieved by exploiting far-field diffractive coupling, which significantly suppresses the scattering response on the long-wavelength side of plasmonic pixel resonances. In the present work, we show that by utilizing another collective coupling effect, Fano interference, it is possible to substantially narrow the short-wavelength side of the pixel spectral response. Together, these two complementary effects provide unprecedented control of plasmonic pixel spectral line shape, resulting in aluminum pixels with far more vivid, monochromatic coloration across the entire RGB color gamut than previously attainable. We further demonstrate that pixels designed in this manner can be used directly as switchable elements in liquid crystal displays and determine the minimum and optimal numbers of nanorods required in an array to achieve good color quality and intensity.


Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses.
Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.


From cradle to early grave: juvenile mortality in European shags Phalacrocorax aristotelis results from inadequate development of foraging proficiency.
In most long-lived animal species, juveniles survive less well than adults. A potential mechanism is inferior foraging skills but longitudinal studies that follow the development of juvenile foraging are needed to test this. We used miniaturized activity loggers to record daily foraging times of juvenile and adult European shags Phalacrocorax aristotelis from fledging to the following spring. Juveniles became independent from their parents 40 days post-fledging. They compensated for poor foraging proficiency by foraging for approximately 3 h d(-1) longer than adults until constrained by day length in early November. Thereafter, juvenile foraging time tracked shortening day length up to the winter solstice, when foraging time of the two age classes converged and continued to track day length until early February. Few individuals died until midwinter and mortality peaked in January-February, with juvenile mortality (including some of the study birds) five times that of adults. In their last two weeks of life, juveniles showed a marked decline in foraging time consistent with individuals becoming moribund. Our results provide compelling evidence that juveniles compensate for poor foraging proficiency by increasing foraging time, a strategy that is limited by day length resulting in high winter mortality.


Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis.
In humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f5 -/- mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities.


Glucocorticoid Therapy of Multiple Sclerosis Patients Induces Anti-inflammatory Polarization and Increased Chemotaxis of Monocytes.
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by the infiltration of mononuclear cells into the CNS and a subsequent inflammation of the brain. Monocytes are implicated in disease pathogenesis not only in their function as potential antigen-presenting cells involved in the local reactivation of encephalitogenic T cells but also by independent effector functions contributing to structural damage and disease progression. However, monocytes also have beneficial effects as they can exert anti-inflammatory activity and promote tissue repair. Glucocorticoids (GCs) are widely used to treat acute relapses in MS patients. They act on a variety of cell types but their exact mechanisms of action including their modulation of monocyte function are not fully understood. Here we investigated effects of the therapeutically relevant GC methylprednisolone (MP) on monocytes from healthy individuals and MS patients in vitro and in vivo. The monocyte composition in the blood was different in MS patients compared to healthy individuals, but it was only marginally affected by MP treatment. In contrast, application of MP caused a marked shift toward an anti-inflammatory monocyte phenotype in vitro and in vivo as revealed by an altered gene expression profile. Chemotaxis of monocytes toward CCL2, CCL5, and CX3CL1 was increased in MS patients compared to healthy individuals and further enhanced by MP pulse therapy. Both of these migration-promoting effects were more pronounced in MS patients with an acute relapse than in those with a progressive disease. Interestingly, the pro-migratory GC effect was independent of chemokine receptor levels as exemplified by results obtained for CCR2. Collectively, our findings suggest that GCs polarize monocytes toward an anti-inflammatory phenotype and enhance their migration into the inflamed CNS, endowing them with the capacity to suppress the pathogenic immune response.


Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects.
Low-grade brain tumors (pilocytic astrocytomas) that result from a genomic rearrangement in which the BRAF kinase domain is fused to the amino terminal of the KIAA1549 gene (KIAA1549:BRAF fusion; f-BRAF) commonly arise in the cerebellum of young children. To model this temporal and spatial specificity in mice, we generated conditional KIAA1549:BRAF strains that coexpresses green fluorescent protein (GFP). Although both primary astrocytes and neural stem cells (NSCs) from these mice express f-BRAF and GFP as well as exhibit increased MEK activity, only f-BRAF-expressing NSCs exhibit increased proliferation in vitro. Using Cre driver lines in which KIAA1549:BRAF expression was directed to NSCs (f-BRAF; BLBP-Cre mice), astrocytes (f-BRAF; GFAP-Cre mice), and NG2 progenitor cells (f-BRAF; NG2-Cre mice), increased glial cell numbers were observed only in the cerebellum of f-BRAF; BLBP-Cre mice in vivo. The availability of this unique KIAA1549:BRAF conditional transgenic mouse strain will enable future mechanistic studies aimed at defining the developmentally-regulated temporal and spatial determinants that underlie low-grade astrocytoma formation in children.


Functional Connectivity Substrates for tDCS Response in Minimally Conscious State Patients.
Transcranial direct current stimulation (tDCS) is a non-invasive technique recently employed in disorders of consciousness, and determining a transitory recovery of signs of consciousness in almost half of minimally conscious state (MCS) patients. Although the rising evidences about its possible role in the treatment of many neurological and psychiatric conditions exist, no evidences exist about brain functional connectivity substrates underlying tDCS response. We retrospectively evaluated resting state functional Magnetic Resonance Imaging (fMRI) of 16 sub-acute and chronic MCS patients (6 tDCS responders) who successively received a single left dorsolateral prefrontal cortex (DLPFC) tDCS in a double-blind randomized cross-over trial. A seed-based approach for regions of left extrinsic control network (ECN) and default-mode network (DMN) was performed. tDCS responders showed an increased left intra-network connectivity for regions co-activated with left DLPFC, and significantly with left inferior frontal gyrus. Non-responders (NR) MCS patients showed an increased connectivity between left DLPFC and midline cortical structures, including anterior cingulate cortex and precuneus. Our findings suggest that a prior high connectivity with regions belonging to ECN can facilitate transitory recovery of consciousness in a subgroup of MCS patients that underwent tDCS treatment. Therefore, resting state-fMRI could be very valuable in detecting the neuronal conditions necessary for tDCS to improve behavior in MCS.


Distributed-feedback-laser-based NICE-OHMS in the pressure-broadened regime.
A compact noise-immune cavity-enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) system based on a narrow linewidth distributed-feedback laser and fiber-coupled acousto-optic and electro-optic modulators has been developed. Measurements of absorption and dispersion signals have been performed at pressures up to 1/3 atmosphere on weak acetylene transitions at 1551 nm. Multiline fitting routines were implemented to obtain transition parameters, i.e., center frequencies, linestrengths, and pressure broadening coefficients. The signal strength was shown to be linear with pressure and concentration, and independent of detection phase. The minimum detectable on-resonance absorption with a cavity with a finesse of 460 was 2 × 10(-10) cm(-1) for 1 minute of integration time.


Nucleosome structure incorporated histone acetylation site prediction in Arabidopsis thaliana.
Acetylation is a crucial post-translational modification for histones, and plays a key role in gene expression regulation. Due to limited data and lack of a clear acetylation consensus sequence, a few researches have focused on prediction of lysine acetylation sites. Several systematic prediction studies have been conducted for human and yeast, but less for Arabidopsis thaliana. Concerning the insufficient observation on acetylation site, we analyzed contributions of the peptide-alignment-based distance definition and 3D structure factors in acetylation prediction. We found that traditional structure contributes little to acetylation site prediction. Identified acetylation sites of histones in Arabidopsis thaliana are conserved and cross predictable with that of human by peptide based methods. However, the predicted specificity is overestimated, because of the existence of non-observed acetylable site. Here, by performing a complete exploration on the factors that affect the acetylability of lysines in histones, we focused on the relative position of lysine at nucleosome level, and defined a new structure feature to promote the performance in predicting the acetylability of all the histone lysines in A. thaliana. We found a new spacial correlated acetylation factor, and defined a ε-N spacial location based feature, which contains five core spacial ellipsoid wired areas. By incorporating the new feature, the performance of predicting the acetylability of all the histone lysines in A. Thaliana was promoted, in which the previous mispredicted acetylable lysines were corrected by comparing to the peptide-based prediction.


Angiomyolipoma with minimal fat on MDCT: can counts of negative-attenuation pixels aid diagnosis?
The purpose of this study was to determine whether counts of pixels with subzero attenuation on CT scans can aid in the diagnosis of renal angiomyolipoma with minimal fat. Of 33 angiomyolipomas identified among 719 renal masses resected from 702 patients over 4 years, 15 masses in 15 patients were prospectively diagnosed on the basis of the presence of fat at MDCT. The 18 patients with minimal-fat angiomyolipoma and a matched (age, sex, tumor size) cohort of patients with renal cell carcinoma were included in this study. Three radiologists independently counted the number of pixels with attenuation less than -10, -20, and -30 HU. Receiver operating characteristic analysis of the number of pixels at each cutoff was used to calculate sensitivity, specificity, and positive predictive value with the following criteria: 1, more than 10 pixels less than -20 HU; 2, more than 20 pixels less than -20 HU; 3, more than 5 pixels less than -30 HU. Using criterion 1, reader A identified six angiomyolipomas; reader B, five; and reader C, two. The combined sensitivity was 24%; specificity, 98%; and positive predictive value, 69%. Using criterion 2, reader A identified three angiomyolipomas; reader B, four; and reader C, two. The combined sensitivity was 17%; specificity, 100%; and positive predictive value, 100%. Using criterion 3, reader A identified four angiomyolipomas; reader B, four; and reader C, two. The combined sensitivity was 18%; specificity, 100%; and positive predictive value, 100%. CT findings of more than 20 pixels with attenuation less than -20 HU and more than 5 pixels with attenuation less than -30 HU have a positive predictive value of 100% in detection of angiomyolipoma, but most angiomyolipomas with minimal fat cannot be reliably identified on the basis of an absolute pixel count.


Results of an efficacy trial with an outer membrane vesicle vaccine against systemic serogroup B meningococcal disease in Norway.
A placebo controlled, double blind efficacy trial with a new outer membrane vesicle vaccine against systemic meningococcal disease of serogroup B, has been conducted in Norwegian secondary schools. The study was randomized at school level (1335 schools) and 171,800 students volunteered. The study started in October 1988 and the code was opened in June 1991. Out of the thirty-six proven cases of acute, severe, systemic disease caused by serogroup B meningococci among the participants, twelve occurred in eleven schools given vaccine, twenty-four in twenty-four schools given placebo. twenty-four cases were recorded among secondary school students who did not participate in the study. The protection rate was calculated to 57.4% with a p-value of 1.2% and lower limit of confidence (95%) to 27.7%. The results have initiated research towards an improved outer membrane vesicle vaccine against this disease.


Dual-mode refractive index and charge sensing to investigate complex surface chemistry on nanostructures.
This work presents a novel dual-mode charge and refractive index sensitive device integrated with nanoplasmonic islands, for the first time, on insulator-semiconductor junctions. The developed nano-metal-insulator semiconductor (nMIS) sensor facilitates simultaneous detection of charge and mass changes on the nanoislands due to the binding of biomolecules. The charging of the nanoislands is traced by using the capacitive field-effect electrolyte-metal-insulator-semiconductor structure and the refractive index changes are quantified by measuring the change in the localized surface plasmon resonances of the nanoislands. To demonstrate the performance of our dual-mode sensor we study the effect of oxygen plasma on immobilized biomolecules. As a case study biotinylated aptamers specific to interleukin 6 (IL-6) were chosen to conduct the immunoassay studies. We confirm that the adsorbed aptamers on the nanoislands do not lose their functionality after exposure to low energy oxygen plasma (<600 J). This finding is critical for the development of 'ready-to-use' microfluidic immunoassay platforms (glass-PDMS based) where immobilizing biomolecules on one of the substrates is often required prior to the bonding of glass and PDMS. Our results also open new opportunities for utilizing plasma to encapsulate biomolecules in polymers and hydrogels. More significantly, nMIS sensors can readily be adopted for multiplexed and high throughput label free immunoassay systems, further driving innovations in biomedical and healthcare research.


Poorly differentiated squamous cell carcinoma arising in tattooed skin.
Introduction. Tattoos have increasingly become accepted by mainstream Western society. As a result, the incidence of tattoo-associated dermatoses is on the rise. The presence of a poorly differentiated squamous cell carcinoma in an old tattooed skin is of interest as it has not been previously documented. Case Presentation. A 79-year-old white homeless man of European descent presented to the dermatology clinic with a painless raised nodule on his left forearm arising in a tattooed area. A biopsy of the lesion revealed a poorly differentiated squamous cell carcinoma infiltrating into a tattoo. The lesion was completely excised and the patient remains disease-free one year later. Conclusion. All previous reports of squamous cell carcinomas arising in tattoos have been well-differentiated low-grade type or keratoacanthoma-type and are considered to be coincidental rather than related to any carcinogenic effect of the tattoo pigments. Tattoo-associated poorly differentiated invasive carcinoma appears to be extremely rare.


Different epidemic potentials of the HIV-1B and C subtypes.
HIV, the cause of AIDS in humans, is characterized by great genetic heterogeneity. In particular, HIV-1 group M subtypes are responsible for most of the infections worldwide. We investigate the demographic history of HIV-1B and HIV-1C subtypes in South Africa and Brazil using both a parametric and a nonparametric approach based on coalescent theory. Our results show that although both subtypes are spreading exponentially in Brazil, the HIV-1C growth rate is about twice that of Brazilian HIV-1B or South African HIV-1C, providing evidence, for the first time, of a different epidemic potential between two HIV-1 subtypes. The present study not only may have important consequences for devising future vaccination and therapeutic strategies, but also offers additional evidence that skyline plots are indeed a simple and powerful tool for monitoring and predicting the behavior of viral epidemics.


The impact of genome-wide association studies on biomedical research publications.
The past decade has seen major investment in genome-wide association studies (GWAS). Among the many goals of GWAS, a major one is to identify and motivate research on novel genes involved in complex human disease. To assess whether this goal is being met, we quantified the effect of GWAS on the overall distribution of biomedical research publications and on the subsequent publication history of genes newly associated with complex disease. We found that the historical skew of publications toward genes involved in Mendelian disease has not changed since the advent of GWAS. Genes newly implicated by GWAS in complex disease do experience additional publications compared to control genes, and they are more likely to become exceptionally studied. But the magnitude of both effects has declined over the past decade. Our results suggest that reforms to encourage follow-up studies may be needed for GWAS to most successfully guide biomedical research toward the molecular mechanisms underlying complex human disease.


Hepatitis A virus infections in travelers, 1988-2004.
Uncertainty exists about the current risk of hepatitis A virus infection in nonimmune travelers to destinations with high or intermediate risk of transmission. We analyzed recent epidemiological data on imported hepatitis A to determine region-specific attack rates and incidences. Surveillance data on hepatitis A virus infections diagnosed during 1988-2004 were evaluated on the basis of notification by laboratories, additional reports of physicians, and traveler's statistics. This study focuses on international travelers with hepatitis A virus infection detected after their return to Switzerland. The rate of imported hepatitis A virus infections decreased 75% from 1988 to 2004 and accounted overall for 42% of all hepatitis A cases reported in Switzerland. The actual incidence of hepatitis A in travelers to countries of high or intermediate risk of transmission was 3.0-11.0 per 100,000 person-months abroad for all travelers and 6.0-28.0 per 100,000 for those presumed to be nonimmune. The actual proportion of those visiting friends and relatives among patients with hepatitis A has increased to 28.2%, with children aged 0-14 years predominating. Reductions in the incidence by hepatitis A vaccination were estimated to vary between 35.0% and 61.8% for different destinations. The risk of hepatitis A virus infections has decreased by a factor of 10-50-fold over time, compared with findings from older studies. The risk, however, remains very considerable at many destinations, including frequently visited places, such as Mexico. Children of immigrants are a high-risk population. Strategies are needed to reach those at highest risk.


How best to assess quality of life in informal carers of people with dementia; A systematic review of existing outcome measures.
In the UK, there are currently 800 000 people living with dementia. This number is expected to double in the next 20 years. Two-thirds of people with dementia live in the community supported by informal carers. Caring for a person with dementia has adverse effects on psychological, physical, social wellbeing and quality of life. The measurement of quality of life of carers of people with dementia is increasingly of interest to health and social care practitioners and commissioners, policymakers, and carers themselves. However, there is lack of consensus on the most suitable instrument(s) for undertaking this. A systematic review of the literature using COSMIN methodology. Searching of electronic databases (Medline, PsycINFO, CINAHL and Web of Science), reference list and citation searching of key papers was undertaken. COSMIN methodology was used to simultaneously extract data from and assess methodological quality of included studies, and make a recommendation for the instrument with the most high quality evidence for its measurement properties. Ten instruments were suitable for inclusion in this review. The Carer well-being and support questionnaire (CWS) has the best quality evidence for the greatest number of measurement of properties. The Caregiver Well-Being Scale is also worthy of consideration. There is not presently a measure which could be recommended for use in economic evaluations, however the Impact of Alzheimer's Disease on the Caregiver questionnaire (IADCQ) could potentially be used following further investigation of its measurement properties in a representative population. The CWS is the most appropriate instrument to recommend for the assessment of quality of life in informal carers of people with dementia at present. All instruments included in this review would benefit from more rigorous evaluation of their measurement properties.