Donor-specific portal blood transfusion in intestinal transplantation: a prospective, preclinical large animal study.
Unlike in kidney and heart transplantation, the role of pretransplant donor-specific blood transfusion (DST) has not been studied prospectively in a large animal model of bowel transplantation. We investigated the impact of portal versus systemic DST on overall survival, rejection, graft-versus-host disease (GVHD), and infection after total (small and large) bowel transplantation in pigs. Mixed lymphocyte culture-reactive, outbred pigs underwent total enterectomy and orthotopic total bowel transplantation with portal vein graft drainage. One unit of donor blood was transfused via the portal or systemic circulation (according to a randomization protocol) before graft implantation was begun. We studied six groups, all of which underwent at least a total bowel transplant: group 1 (n=5) comprised nonimmunosuppressed control pigs with portal DST; group 2 (n=6), nonimmunosuppressed control pigs with systemic DST; group 3 (n=5), cyclosporine (CsA)-treated pigs with portal DST; group 4 (n=5), CsA-treated pigs with systemic DST; group 5 (n=5), tacrolimus-treated pigs with portal DST; and group 6 (n=5), tacrolimus-treated pigs with systemic DST. All immunosuppressed pigs received prednisone (2 mg/kg/day) and either CsA (to maintain levels between 250 and 350 ng/ml) or tacrolimus (to maintain levels between 10 and 30 ng/ml). Stomal biopsies and autopsies were obtained to study the incidence of rejection, GVHD, and infection. Portal DST and tacrolimus-based immunosuppression resulted in the highest survival rates. At 7, 14, and 28 days after transplantation, survival rates in group 5 were 100%, 100%, and 80%; in group 6, 100%, 60%, and 40%; and in group 3, 100%, 0%, and 0%, respectively. Only the combination of portal DST and tacrolimus prevented the occurrence of, and death from, rejection. Death from rejection at 7, 14, and 28 days in group 5 was 0%, 0%, and 0%; in group 6, 0%, 33%, and 67%; and in group 3, 0%, 100%, and 100%, respectively. Of note, if immunosuppression was used, the groups with portal (versus systemic) DST had a higher risk of death from infection but a lower risk of death from GVHD. Simultaneous immunologic events were noted more frequently in groups with systemic (versus portal) DST. Long-term survival was noted only in groups with tacrolimus-based immunosuppression and was more common for those with portal (versus systemic) DST. Portal DST at the time of total bowel transplantation and posttransplant immunosuppression with tacrolimus prevent rejection and significantly increase graft survival. The combination of portal antigen presentation and tacrolimus needs to be studied in clinical bowel transplantation.


Occurrence and stability of lone pair-π and OH-π interactions between water and nucleobases in functional RNAs.
We identified over 1000 instances of water-nucleobase stacking contacts in a variety of RNA molecules from a non-redundant set of crystal structures with resolution ≤3.0 Å. Such contacts may be of either the lone pair-π (lp-π) or the OH-π type, in nature. The distribution of the distances of the water oxygen from the nucleobase plane peaks at 3.5 Å for A, G and C, and approximately at 3.1-3.2 Å for U. Quantum mechanics (QM) calculations confirm, as expected, that the optimal energy is reached at a shorter distance for the lp-π interaction as compared to the OH-π one (3.0 versus 3.5 Å). The preference of each nucleobase for either type of interaction closely correlates with its electrostatic potential map. Furthermore, QM calculations show that for all the nucleobases a favorable interaction, of either the lp-π or the OH-π type, can be established at virtually any position of the water molecule above the nucleobase skeleton, which is consistent with the uniform projection of the OW atoms over the nucleobases ring we observed in the experimental occurrences. Finally, molecular dynamics simulations of a model system for the characterization of water-nucleobase stacking contacts confirm the stability of these interactions also under dynamic conditions.


Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers.
Heterologous prime-boost vaccination has been shown to be an efficient way of inducing T cell responses in animals and in humans. We have used three vaccine vectors, naked DNA, modified vaccinia virus Ankara (MVA), and attenuated fowlpox strain, FP9, for prime-boost vaccination approaches against Plasmodium falciparum malaria in humans. In this study, we characterize, using two types of ELISPOT assays and FACS analysis, cell-mediated immune responses induced by different prime-boost combinations where all vectors encode a multiepitope string fused to the pre-erythrocytic Ag thrombospondin-related adhesion protein. We show that these different vectors need to be used in a specific order for an optimal ex vivo IFN-gamma response. From the different combinations, DNA priming followed by MVA boosting and FP9 priming followed by MVA boosting were most immunogenic and in both cases the IFN-gamma response was of broad specificity and cross-reactive against two P. falciparum strains (3D7 and T9/96). Immunization with all three vectors showed no improvement over optimal two vector regimes. Strong ex vivo IFN-gamma responses peaked 1 wk after the booster dose, but cultured ELISPOT assays revealed longer-lasting T cell memory responses for at least 6 mo. In the DNA-primed vaccinees the IFN-gamma response was mainly due to CD4(+) T cells, whereas in the FP9-primed vaccinees it was mainly due to CD4-dependent CD8(+) T cells. This difference may be of importance for the protective efficacy of these vaccination approaches against various diseases.


[Osteoporosis and chronic kidney disease: review and new therapeutic strategies].
Osteoporosis affects a segment of the population in which Chronic Kidney Disease is also greatly represented. Nephropathic patients may present peculiar biochemical abnormalities related to Chronic Kidney Disease, defining the Mineral and Bone Disorder. This kind of anomalies, in the worst scenarios, configure the typical histomorphology patterns of Renal Osteodystrophy. Scientific Societies of Endocrinology have established therapy guidelines for patients with osteoporosis only based on the glomerular filtration rate and recommend avoiding the use of some drugs for the more advanced classes of nephropathy. However, there is no clear therapeutic approach for patients with advanced nephropathy and bone abnormalities. In this paper we propose a systematic review of the literature and present our proposal for managing patients with advanced nephropathy, based on eGFR and on presence of Mineral and Bone Disorder.


Direct magnetic resonance detection of myelin and prospects for quantitative imaging of myelin density.
Magnetic resonance imaging has previously demonstrated its potential for indirectly mapping myelin density, either by relaxometric detection of myelin water or magnetization transfer. Here, we investigated whether myelin can be detected and possibly quantified directly. We identified the spectrum of myelin in the spinal cord in situ as well as in myelin lipids extracted via a sucrose gradient method, and investigated its spectral properties. High-resolution solution NMR spectroscopy showed the extract composition to be in agreement with myelin's known chemical make-up. The 400-MHz (1)H spectrum of the myelin extract, at 20 °C (room temperature) and 37 °C, consists of a narrow water resonance superimposed on a broad envelope shifted ∼3.5 ppm upfield, suggestive of long-chain methylene protons. Superimposed on this signal are narrow components resulting from functional groups matching the chemical shifts of the constituents making up myelin lipids. The spectrum could be modeled as a sum of super-Lorentzians with a T(2)* distribution covering a wide range of values (0.008-26 ms). Overall, there was a high degree of similarity between the spectral properties of extracted myelin lipids and those found in neural tissue. The normalized difference spectrum had the hallmarks of membrane proteins, not present in the myelin extract. Using 3D radially ramp-sampled proton MRI, with a combination of adiabatic inversion and echo subtraction, the feasibility of direct myelin imaging in situ is demonstrated. Last, the integrated signal from myelin suspensions is shown, both spectroscopically and by imaging, to scale with concentration, suggesting the potential for quantitative determination of myelin density.


Preventing photodarkening in ytterbium-doped high power fiber lasers; correlation to the UV-transparency of the core glass.
Photodarkening experiments are performed on ytterbium-doped silicate glass samples. A strong charge-transfer (CT) absorption band near 230nm in aluminosilicate glass is found to be correlated to the mechanism of induced color center formation. Excitation into the CT-absorption band generates similar color centers as observed in ytterbium-doped fiber lasers under 915nm high power diode pumping. The position of the CT-absorption band is compositional dependent and is shifted to shorter wavelengths in ytterbium doped phosphosilicate glass. Very low levels of photodarkening is observed for the ytterbium doped phosphosilicate glass composition under 915nm high power diode pumping. Possible excitation routes to reach the CT-absorption band under 915nm pumping are discussed.


Management of Cercospora Leaf Spot in Conventional and Organic Table Beet Production.
Cercospora leaf spot (CLS; Cercospora beticola) is the most important foliar disease affecting table beet. Epidemics occur annually and fungicides extend the survival of foliage to enable mechanized harvest. However, a high frequency of strobilurin-resistant C. beticola isolates necessitates the identification of fungicides with different modes of action for tactical rotation. There is also substantial demand for organically produced table beet, for which synthetic fungicides are prohibited. Five small-plot, replicated field trials were conducted over two years to evaluate conventional and Organic Materials Review Institute (OMRI)-listed products for CLS control in table beet cv. Ruby Queen at Geneva and Ithaca, New York. Benzovindiflupyr + difenoconazole significantly reduced temporal disease progress (measured by the area under the disease progress stairs; AUDPS) by 86.7 to 97.3% compared with nontreated plots, and mean survival time of leaves was significantly extended. The demethylation inhibitor, propiconazole, also provided significant disease control in two trials in 2016. Disease severity in plots treated with succinate dehydrogenase inhibitors (boscalid, fluxapyroxad + pyraclostrobin, and penthiopyrad) was significantly decreased compared with nontreated plots but less than other fungicides. Efficacious fungicides significantly increased the dry weight of foliage but did not significantly affect the dry weight of roots, and root shoulder diameter. The enhanced longevity of leaves and increased dry weight of foliage may extend opportunities for mechanized harvesting without deleteriously affecting root yield parameters which are strictly regulated for the processing markets. In two trials, copper octanoate + Bacillus amyloliquefaciens strain D747 (as Cueva + Double Nickel LC) resulted in significantly improved disease control in comparison with application of either product alone and provided comparable and reproducible disease control equivalent to conventional fungicides at both locations. The implications of these findings for CLS control in conventional and organic table beet production systems are discussed.


Resource competition and reproduction : The relationship between economic and parental strategies in the Krummhörn population (1720-1874).
A family reconstitution study of the Krummhörn population (Ostfriesland, Germany, 1720-1874) reveals that infant mortality and children's probabilities of marrying or emigrating unmarried are affected by the number of living same-sexed sibs in farmers' families but not in the families of landless laborers. We interpret these results in terms of a "local resource competition" model in which resource-holding families are obliged to manipulate the reproductive future of their offspring. In contrast, families that lack resources have no need to manipulate their offspring and are more likely to benefit from allowing their offspring to capitalize on whatever opportunities to reproduce present themselves.


Use of CA-125 Tests and Computed Tomographic Scans for Surveillance in Ovarian Cancer.
A 2009 randomized clinical trial demonstrated that using cancer antigen 125 (CA-125) tests for routine surveillance in ovarian cancer increases the use of chemotherapy and decreases patients' quality of life without improving survival, compared with clinical observation. The Society of Gynecologic Oncology guidelines categorize CA-125 testing as optional and discourage the use of radiographic imaging for routine surveillance. To date, few studies have examined the use of CA-125 tests in clinical practice. To examine the use of CA-125 tests and computed tomographic (CT) scans in clinical practice before and after the 2009 randomized clinical trial and to estimate the economic effect of surveillance testing. A prospective cohort of 1241 women with ovarian cancer in clinical remission after completion of primary cytoreductive surgery and chemotherapy at 6 National Cancer Institute-designated cancer centers between January 1, 2004, and December 31, 2011, was followed up through December 31, 2012, to study the use of CA-125 tests and CT scans before and after 2009. Data analysis was conducted from April 9, 2014, to March 28, 2016. The use of CA-125 tests and CT scans before and after 2009. Secondary outcomes included the time from CA-125 markers doubling to retreatment among women who experienced a rise in CA-125 markers before and after 2009, and the costs associated with surveillance testing using 2015 Medicare reimbursement rates. Among 1241 women (mean [SD] age 59 [12] years; 1112 white [89.6%]), the use of CA-125 testing and CT scans was similar during the study period. During 12 months of surveillance, the cumulative incidence of patients undergoing 3 or more CA-125 tests was 86% in 2004-2009 vs 91% in 2010-2012 (P = .95), and the cumulative incidence of patients undergoing more than 1 CT scan was 81% in 2004-2009 vs 78% in 2010-2012 (P = .50). Among women whose CA-125 markers doubled (n = 511), there was no significant difference in the time to retreatment with chemotherapy before and after 2009 (median, 2.8 vs 3.5 months; P = .40). During a 12-month period, there was a mean of 4.6 CA-125 tests and 1.7 CT scans performed per patient, resulting in a US population surveillance cost estimate of $1 999 029 per year for CA-125 tests alone and $16 194 647 per year with CT scans added. CA-125 tests and CT scans are still routinely used for surveillance testing in patients with ovarian cancer, although their benefit has not been proven and their use may have significant implications for patients' quality of life as well as costs.


"Don't give me that look" - overconfidence in false mental state perception in schizophrenia.
Dysfunctions in social cognition are implicated in the pathogenesis of schizophrenia and have been extensively replicated over the years. For memory research, the administration of cognitive tasks with metacognitive aspects like confidence ratings has deepened our insight into how impairments contribute to symptoms of the disorder. A total of 76 patients with schizophrenia or schizoaffective disorder and a sample of 30 healthy participants were tested with the Reading the Mind in the Eyes test (Eyes-test). The Eyes-test was complemented with a rating scale requesting response confidence and was administered along with paradigms tapping neuropsychological parameters and cognitive insight. Schizophrenia patients showed impaired abilities on mental state perception. In addition, they committed more high-confidence errors and at the same time made fewer high-confidence correct responses. Impairments were most pronounced in patients with formal thought disorder. The patients displayed a decreased metacognitive awareness for their deficits. The results suggest that adding confidence ratings to the investigation of social cognition promises to advance our understanding of social cognition in schizophrenia. Patients not only show severe impairments in social cognition, but are overconfident in their judgments and lack cognitive insight into their deficits. The results highlight the need for metacognitive therapeutic approaches for the treatment of this population.


Processing and intracellular targeting of prosomatostatin-derived peptides: the role of mammalian endoproteases.
Prosomatostatin is cleaved at dibasic and monobasic sites to produce somatostatin-14 and somatostatin-28 respectively. The mammalian pro-protein convertases comprising furin, PACE4 and PC1-6 have recently been identified and are believed to mediate endoproteolysis of prohormone precursors such as prosomatostatin. Furin is membrane bound, localized to the Golgi and mediates constitutive processing. PC1 and PC2 are soluble and are expressed solely in endocrine and neuroendocrine tissues suggesting a key role in prohormone processing. We have investigated the endogenous and heterologous synthesis and processing of rat prosomatostatin in 1027B2 rat islet somatostatinoma cells and in constitutive (COS-7, PC-12) and regulated (AtT-20, GH3/GH4C1) secretory cells. We have correlated processing efficiency with: secretion through the constitutive or regulated pathways; endogenous expression of furin, PC1 and PC2; and expression or overexpression of furin, PC1 and PC2. Pulse-chase studies showed that prosomatostatin is rapidly and independently processed to somatostatin-14 and somatostatin-28. Furin is capable of monobasic processing of prosomatostatin and is a candidate somatostatin-28 convertase. PC1 and PC2 both effect dibasic processing of prosomatostatin and qualify as putative somatostatin-14 convertases. PC1 is active in constitutive and regulated secretory cells, has a broader specificity and is overall more potent than PC2. Efficient processing of prosomatostatin begins in a Golgi or pre Golgi compartment. It requires the milieu of the secretory cell but not the secretory granule.


Fusion of green fluorescent protein to the C-terminus of granulysin alters its intracellular localization in comparison to the native molecule.
The engineering of green fluorescent protein (GFP) fusion constructs in order to visibly tag a protein of interest has become a commonly used cell biology technique. Although caveats to this approach are obvious, literature reports in which the chimeric molecule behaves differently than the native molecule are scant. This brief report describes one such case. Granulysin, a small lytic and antimicrobial protein produced by cytotoxic lymphocytes, traffics to the regulated secretory system and is subsequently released from cells upon proper stimulus. In an attempt to elucidate mechanisms by which it accumulates in and is released from cytolytic granules, GFP was fused to the C-terminus of granulysin and expressed in an NK cell line. A control construct expressing the native protein was similarly expressed. The data demonstrate that, while the fusion protein is expressed and secreted, its subcellular localization is altered in comparison to native granulysin. Thus, the addition of GFP to the C-terminus of granulysin obscures the signal(s) that cytotoxic lymphocytes use to sort it to the regulated secretory pathway despite its normal biosynthesis and secretion. This example is offered as a cautionary account for other researchers who contemplate using this technology.


Meditation-based training: a possible intervention for attention deficit hyperactivity disorder.
Recent studies suggest that training-based measures are effective in improving cognitive skills. Meditation-based training has produced lasting changes in brain and cognitive functions. This technique of mental training exhibits neuroplasticity in the attentional networks, exhibiting superior performance, especially in the domain of attention and executive control processing, which is impaired in attention deficit hyperactivity disorder (ADHD). Although intervention techniques for ADHD are well researched, many individuals continue to experience significant functional impairment despite the symptom improvement. This emphasizes a need for a comprehensive approach that requires an effective behavioral intervention. The present paper provides a converging review of meditation-based effects on the brain, dysfunctions of ADHD, and suggestions for enhancement of cognitive abilities in patients with ADHD using meditational training combined with existing measures of intervention. The idea proposed herein should be considered a step for initiation of empirical studies on meditation-based training intervention and outcome effects.


High levels of new neuron addition persist when the sensitive period for song learning is experimentally prolonged.
Socially reared zebra finch males imitate a song they hear during posthatching days 30-65; during this time, many new neurons are added to the high vocal center (HVC), a forebrain nucleus necessary for the production of learned song. New neuron addition drops sharply after day 65, and no new songs are imitated. In contrast, male zebra finches reared in isolation from other males have more variable songs at day 65 and thereafter can still imitate new sounds (Eales, 1985). We show that, in isolate birds, a greater number of new neurons continues to be added to HVC during the next 85 d, and this number correlates with syllable variability. We suggest that new neuron addition and turnover facilitate song change and that this effect lingers when an expected learning event is delayed.


Detecting causality in policy diffusion processes.
A universal question in network science entails learning about the topology of interaction from collective dynamics. Here, we address this question by examining diffusion of laws across US states. We propose two complementary techniques to unravel determinants of this diffusion process: information-theoretic union transfer entropy and event synchronization. In order to systematically investigate their performance on law activity data, we establish a new stochastic model to generate synthetic law activity data based on plausible networks of interactions. Through extensive parametric studies, we demonstrate the ability of these methods to reconstruct networks, varying in size, link density, and degree heterogeneity. Our results suggest that union transfer entropy should be preferred for slowly varying processes, which may be associated with policies attending to specific local problems that occur only rarely or with policies facing high levels of opposition. In contrast, event synchronization is effective for faster enactment rates, which may be related to policies involving Federal mandates or incentives. This study puts forward a data-driven toolbox to explain the determinants of legal activity applicable to political science, across dynamical systems, information theory, and complex networks.


Socio-economic determinants of micronutrient intake and status in Europe: a systematic review.
To provide the evidence base for targeted nutrition policies to reduce the risk of micronutrient/diet-related diseases among disadvantaged populations in Europe, by focusing on: folate, vitamin B12, Fe, Zn and iodine for intake and status; and vitamin C, vitamin D, Ca, Se and Cu for intake. MEDLINE and Embase databases were searched to collect original studies that: (i) were published from 1990 to 2011; (ii) involved >100 subjects; (iii) had assessed dietary intake at the individual level; and/or (iv) included best practice biomarkers reflecting micronutrient status. We estimated relative differences in mean micronutrient intake and/or status between the lowest and highest socio-economic groups to: (i) evaluate variation in intake and status between socio-economic groups; and (ii) report on data availability. Europe. Children, adults and elderly. Data from eighteen publications originating primarily from Western Europe showed that there is a positive association between indicators of socio-economic status and micronutrient intake and/or status. The largest differences were observed for intake of vitamin C in eleven out of twelve studies (5-47 %) and for vitamin D in total of four studies (4-31 %). The positive association observed between micronutrient intake and socio-economic status should complement existing evidence on socio-economic inequalities in diet-related diseases among disadvantaged populations in Europe. These findings could provide clues for further research and have implications for public health policy aimed at improving the intake of micronutrients and diet-related diseases.


Modeling and Characterization of Capacitive Elements With Tissue as Dielectric Material for Wireless Powering of Neural Implants.
This paper reports on the modeling and characterization of capacitive elements with tissue as the dielectric material, representing the core building block of a capacitive link for wireless power transfer to neural implants. Each capacitive element consists of two parallel plates that are aligned around the tissue layer and incorporate a grounded, guarded, capacitive pad to mitigate the adverse effect of stray capacitances and shield the plates from external interfering electric fields. The plates are also coated with a biocompatible, insulating, coating layer on the inner side of each plate in contact with the tissue. A comprehensive circuit model is presented that accounts for the effect of the coating layers and is validated by measurements of the equivalent capacitance as well as impedance magnitude/phase of the parallel plates over a wide frequency range of 1 kHz-10 MHz. Using insulating coating layers of Parylene-C at a thickness of and Parylene-N at a thickness of deposited on two sets of parallel plates with different sizes and shapes of the guarded pad, our modeling and characterization results accurately capture the effect of the thickness and electrical properties of the coating layers on the behavior of the capacitive elements over frequency and with different tissues.


Structure of the alpha and beta heavy chains of the outer arm dynein from Chlamydomonas flagella. Location of epitopes and protease-sensitive sites.
We describe here the pathways by which the alpha and beta heavy chains of the outer arm dynein from Chlamydomonas flagella are degraded by endoproteases. By probing the digestion products with monoclonal antibodies, we have located a number of protease-sensitive sites within both polypeptides and identified the regions of each molecule from which specific fragments are derived. These data also define the regions within each chain which contain the epitopes recognized by our monoclonal antibodies. The locations of the cleavage sites reveal both differences and similarities between the two molecules. The sites at which the beta chain is initially cleaved by elastase differ depending upon whether the particle is digested in situ or in solution, indicating that the beta chain undergoes a significant conformational change following extraction from the axoneme. Evidence was also obtained that heterogeneity exists among the purified alpha chain molecules. The possible arrangement of the different regions of the heavy chains within the alpha-beta dimer is discussed.


Incidental head and neck findings on MRI in young healthy volunteers: prevalence and clinical implications.
We determined the prevalence and clinical relevance of incidental brain and head and neck findings in young healthy volunteers with MR imaging. We retrospectively analyzed the MR images obtained from 203 healthy young adult volunteers (mean age, 21.9 years; range, 18-35 years). The prevalence of the categories of findings (no referral necessary, routine referral, urgent referral, and immediate referral) was scored by a head and neck radiologist or neuroradiologist. We found a high prevalence of incidental brain and head and neck abnormalities (9.4% and 36.7%, respectively); 4.4% of the brain findings and 5.5% of the head and neck findings were classified as in need of referral. Only 1 incidental finding classified as in need of referral (a skull lesion consistent with fibrous dysplasia) was actually referred at the time of the study (5.2%). These findings suggest that a high prevalence of incidental findings is common in healthy young volunteers, though the clinical implications are negligible.


Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients.
The clearance of midazolam (MDZ) in humans is principally due to metabolic biotransformation catalyzed by CYP3A isoforms. A study was conducted in patients who had undergone liver transplants that provides evidence that MDZ can be used as an in vivo probe of interindividual hepatic CYP3A variability. The clearance of MDZ and cyclosporine after i.v. administration were determined in 10 patients approximately 10 days after transplant surgery. Liver biopsy specimens were obtained within 24 hr of the pharmacokinetic study and CYP3A content and MDZ 1'-hydroxylation activity were measured in 13,000 x g tissue supernatants (S-13). The in vitro rate of 1'-hydroxy-MDZ formation was found to correlate significantly with the total CYP3A content in hepatic S-13 fractions (r = .84, P < .01). The total MDZ clearance measured in vivo was highly correlated with the hepatic CYP3A content measured in vitro (r = .93, P < .001) and with in vivo cyclosporine clearance (r = .81, P < .001). For five of the patients, the intrinsic clearance of midazolam to 1'-hydroxy-MDZ (Vmax/Km) in vitro measured in S-13 preparations was scaled for total liver mass and applied to the well stirred model of hepatic clearance to yield a prediction of MDZ clearance in vivo. The mean MDZ clearance predicted from in vitro 1'-hydroxylation data was identical to the mean clearance observed in vivo (0.60 +/- 0.24 versus 0.59 +/- 0.25 liter/min). Together, the results suggest that variability in hepatic CYP3A expression in liver transplant recipients, and possibly in other populations, can be determined by the measurement of MDZ metabolic clearance.


ShapeRotator: An R tool for standardized rigid rotations of articulated three-dimensional structures with application for geometric morphometrics.
The quantification of complex morphological patterns typically involves comprehensive shape and size analyses, usually obtained by gathering morphological data from all the structures that capture the phenotypic diversity of an organism or object. Articulated structures are a critical component of overall phenotypic diversity, but data gathered from these structures are difficult to incorporate into modern analyses because of the complexities associated with jointly quantifying 3D shape in multiple structures. While there are existing methods for analyzing shape variation in articulated structures in two-dimensional (2D) space, these methods do not work in 3D, a rapidly growing area of capability and research. Here, we describe a simple geometric rigid rotation approach that removes the effect of random translation and rotation, enabling the morphological analysis of 3D articulated structures. Our method is based on Cartesian coordinates in 3D space, so it can be applied to any morphometric problem that also uses 3D coordinates (e.g., spherical harmonics). We demonstrate the method by applying it to a landmark-based dataset for analyzing shape variation using geometric morphometrics. We have developed an R tool (ShapeRotator) so that the method can be easily implemented in the commonly used R package geomorph and MorphoJ software. This method will be a valuable tool for 3D morphological analyses in articulated structures by allowing an exhaustive examination of shape and size diversity.


Reversal sign on CT: effect of anoxic/ischemic cerebral injury in children.
A retrospective study was performed to determine the clinical and pathologic features, etiology, and outcome of children with the reversal sign. The reversal sign, a striking CT finding, probably represents a diffuse, anoxic/ischemic cerebral injury. CT features of the reversal sign are diffusely decreased density of cerebral cortical gray and white matter with a decreased or lost gray/white matter interface, or reversal of the gray/white matter densities and relatively increased density of the thalami, brainstem, and cerebellum. Twenty children with the reversal sign were retrospectively analyzed. We divided the patients into three groups: (1) acute reversal, (2) intermediate group, and (3) chronic reversal. There were nine cases of trauma (seven of child abuse); nine hypoxia/anoxia incidents (birth asphyxia, drowning, status epilepticus); one bacterial meningitis; and one degenerative encephalitis. All acute- and intermediate-group patients had respiratory problems requiring ventilator support and intensive care. In five of seven patients who died, autopsy findings were consistent with anoxic/ischemic encephalopathy. Surviving patients have profound neurologic deficits with severe developmental delay. The CT reversal sign carries a poor prognosis and indicates irreversible brain damage.


Angiographic features of transgenic mice with increased expression of human serine protease HTRA1 in retinal pigment epithelium.
Polypoidal choroidal vasculopathy (PCV) is characterized by a branching vascular network (BVN) of choroid that terminates in polypoidal dilations. We have previously reported the generation of the first PCV model by transgenically expressing human HTRA1 (hHTRA1(+)), a multifunctional serine protease, in mouse RPE. The purpose of this study was to perform a comprehensive examination of the PCV phenotypes (e.g., lesion type and distribution) of hHTRA1(+) mice by a variety of in vivo imaging techniques. We generated improved hHTRA1(+) mice with a more consistent phenotype. Transgenic mice were examined by indocyanine green angiography (ICGA), fluorescein angiography, funduscopy, and spectral-domain optical coherence tomography. In particular, we performed ICGA by tail vein injection of ICG to obtain high-quality ICGA comparable to human studies in terms of the three phases (early, middle, and late) of angiography. The polyps can be detected in the early "fill-in" phase of ICGA, and most lesions become visible in the middle phase and are more distinct in the late phase with the fading of surrounding vessels. In addition to the two key features of PCV (polypoidal dilations and BVNs), hHTRA1(+) mice exhibit other features of PCV (i.e., late geographic hyperfluorescence, pigment epithelial detachment, and hyperfluorescent plaque). Polypoidal lesions appear as reddish orange nodules on funduscopy. Transgenic hHTRA1(+) mice exhibit a rich spectrum of "clinical" features that closely mimic human PCV. This animal model will serve as an invaluable tool for future mechanistic and translational studies of PCV and other forms of choroidal vasculopathies.


Metabolic Flexibility: Hibernation, Torpor, and Estivation.
Many environmental conditions can constrain the ability of animals to obtain sufficient food energy, or transform that food energy into useful chemical forms. To survive extended periods under such conditions animals must suppress metabolic rate to conserve energy, water, or oxygen. Amongst small endotherms, this metabolic suppression is accompanied by and, in some cases, facilitated by a decrease in core body temperature-hibernation or daily torpor-though significant metabolic suppression can be achieved even with only modest cooling. Within some ectotherms, winter metabolic suppression exceeds the passive effects of cooling. During dry seasons, estivating ectotherms can reduce metabolism without changes in body temperature, conserving energy reserves, and reducing gas exchange and its inevitable loss of water vapor. This overview explores the similarities and differences of metabolic suppression among these states within adult animals (excluding developmental diapause), and integrates levels of organization from the whole animal to the genome, where possible. Several similarities among these states are highlighted, including patterns and regulation of metabolic balance, fuel use, and mitochondrial metabolism. Differences among models are also apparent, particularly in whether the metabolic suppression is intrinsic to the tissue or depends on the whole-animal response. While in these hypometabolic states, tissues from many animals are tolerant of hypoxia/anoxia, ischemia/reperfusion, and disuse. These natural models may, therefore, serve as valuable and instructive models for biomedical research.


Parsing the neural correlates of moral cognition: ALE meta-analysis on morality, theory of mind, and empathy.
Morally judicious behavior forms the fabric of human sociality. Here, we sought to investigate neural activity associated with different facets of moral thought. Previous research suggests that the cognitive and emotional sources of moral decisions might be closely related to theory of mind, an abstract-cognitive skill, and empathy, a rapid-emotional skill. That is, moral decisions are thought to crucially refer to other persons' representation of intentions and behavioral outcomes as well as (vicariously experienced) emotional states. We thus hypothesized that moral decisions might be implemented in brain areas engaged in 'theory of mind' and empathy. This assumption was tested by conducting a large-scale activation likelihood estimation (ALE) meta-analysis of neuroimaging studies, which assessed 2,607 peak coordinates from 247 experiments in 1,790 participants. The brain areas that were consistently involved in moral decisions showed more convergence with the ALE analysis targeting theory of mind versus empathy. More specifically, the neurotopographical overlap between morality and empathy disfavors a role of affective sharing during moral decisions. Ultimately, our results provide evidence that the neural network underlying moral decisions is probably domain-global and might be dissociable into cognitive and affective sub-systems.


The directed mutation controversy and neo-Darwinism.
According to neo-Darwinian theory, random mutation produces genetic differences among organisms whereas natural selection tends to increase the frequency of advantageous alleles. However, several recent papers claim that certain mutations in bacteria and yeast occur at much higher rates specifically when the mutant phenotypes are advantageous. Various molecular models have been proposed that might explain these directed mutations, but the models have not been confirmed. Critics contend that studies purporting to demonstrate directed mutation lack certain controls and fail to account adequately for population dynamics. Further experiments that address these criticisms do not support the existence of directed mutations.


NCCN Guidelines implementation in the multidisciplinary Merkel Cell Carcinoma Program at the University of Michigan.
Merkel cell carcinoma (MCC) is a rare malignancy of the skin, and prospective randomized clinical studies on management and treatment are very limited. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MCC provide up-to-date, best evidence-based, and consensus-driven management pathways with the purpose of providing best care and outcomes. Multidisciplinary management with consensus treatment recommendations to individualize patient care within the framework of these guidelines is optimal. The University of Michigan multidisciplinary MCC program uses NCCN Guidelines in the management and treatment of its patients. This article discusses 4 patient presentations to highlight the implementation of the NCCN Guidelines for MCC at the University of Michigan.


Polarization division multiplexed 4 × 10 Gbps simultaneous transmissions in 1.0-µm waveband and C-waveband over a 14.4-km-long holey fiber using an ultra-broadband photonic transport system.
Polarization division multiplexing (PDM) and wavelength division multiplexing (WDM) are essential techniques for enhancing the capacity of photonic networks and facilitating the efficient use of optical frequency resources. 2 PDM × 2 WDM × 10 Gbps error-free simultaneous transmissions in the 1.0-µm waveband and C-waveband are successfully demonstrated for the first time using an ultra-broadband photonic transport system over a 14.4-km-long holey fiber transmission line.


Geographical distribution of the health crisis of war in the Tigray region of Ethiopia.
War destroys health facilities and displaces health workers. It has a devastating impact on population health, especially in vulnerable populations. We assess the geographical distribution of the impact of war on healthcare delivery by comparing the pre-November 2020 and the November to June 2021 status of health facilities in the Tigray region of Ethiopia. Data were collected from February 2021 to June 2021, during an active civil war and an imposed communication blackout in Tigray. Primary data were collected and verified by multiple sources. Data include information on health facility type, geocoding and health facility status (fully functional (FF), partially functional (PF), not functional, no communication). Only 3.6% of all health facilities (n=1007), 13.5% of all hospitals and health centres (n=266), and none of the health posts (n=741), are functional. Destruction varies by geographic location; only 3.3% in Western, 3.3% in South Eastern, 6.5% in North Western, 8% in Central, 14.6% in Southern, 16% in Eastern and 78.6% in Mekelle are FF. Only 9.7% of health centres, 43.8% of general hospitals and 21.7% of primary hospitals are FF. None of the health facilities are operating at prewar level even when classified as FF or PF due to lack of power and water or essential devices looted or destroyed, while they still continue operating. The war in Tigray has clearly had a direct and devastating impact on healthcare delivery. Restoration of the destroyed health facilities needs to be a priority agenda of the international community.


An exploratory study on scientific investigations in homeopathy using medical analyzer.
The action of homeopathic medicines, in ultra-high dilution, is not directly observable. An attempt was made to explore autonomic response of selective homeopathic medicines, in healthy persons, using Medical Analyzer System (Electronics Division, Bhabha Atomic Research Centre, Mumbai, India). The objective of the study was to observe the action of homeopathic medicines on physiologic variability of heart rate and blood flow. Pre- and postinterventional variability spectra of heart rate and blood flow of 77 subjects were recorded with the Medical Analyzer System, administering homeopathic preparations of Aconitum napellus (6c, 10M), Arsenicum album (200c, 1M), Gelsemium sempervirens (200c, 1M), Phosphorus (200c, 1M), Pulsatilla nigricans (200c) and Sulphur (200c, 1M) versus placebo control. The amplitude of the peaks viz. low-frequency, medium-frequency, and high-frequency was measured for postintervention analysis. An increase in the amplitude of any valid peak by 100% or a decrease by 50% was considered as significant change. Aconitum napellus produced a response in heart rate variability (HRV) with 30c potency and in blood flow variability with 1M potency. Sulphur 200c and 1M, Gelsemium 200c and Pulsatilla 200c, produced a 62.5% response in HRV against the placebo response of 16.6%. Gelsemium, Phosphorus, and Sulphur produced a response in blood flow variability with a 1M potency, similar to the response of Aconitum napellus 1M. These data suggest that it is possible to record the response of homeopathic medicines on physiologic parameters of the autonomic nervous system.


Regulation of Cripto-1 signaling and biological activity by caveolin-1 in mammary epithelial cells.
Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. In this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null(-/-)/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1(+/-)/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis.


Herbal remedy clinical trials in the media: a comparison with the coverage of conventional pharmaceuticals.
This study systematically compares newspaper coverage of clinical trials for herbal remedies, a popular type of complementary and alternative medicine, with clinical trials for pharmaceuticals using a comparative content analysis. This is a timely inquiry given the recognized importance of the popular press as a source of health information, the complex and significant role of complementary and alternative medicine in individual health-care decisions, and the trend toward evidence-based research for some complementary and alternative medical therapies. We searched PubMed for clinical trials, Lexis/Nexis for newspaper articles in the UK, US, Australia/New Zealand, and Factiva for Canadian newspaper articles from 1995 to 2005. We used a coding frame to analyze and compare 48 pharmaceutical and 57 herbal remedy clinical trials as well as 201 pharmaceutical and 352 herbal remedy newspaper articles. Herbal remedy clinical trials had similar Jadad scores to pharmaceutical trials but were significantly smaller and of shorter duration. The trials were mostly studies from Western countries and published in high-ranking journals. The majority of pharmaceutical (64%) and herbal remedy (53%) clinical trials had private sector funding involvement. A minority declared further author conflicts of interest. Newspaper coverage of herbal remedy clinical trials was more negative than for pharmaceutical trials; a result only partly explained by the greater proportion of herbal remedy clinical trials reporting negative results (P = 0.0201; (2) = 7.8129; degrees of freedom = 2). Errors of omission were common in newspaper coverage, with little reporting of dose, sample size, location, and duration of the trial, methods, trial funding, and conflicts of interest. There was an under-reporting of risks, especially for herbal remedies. Our finding of negative coverage of herbal remedy trials is contrary to the positive trends in most published research based primarily on anecdotal accounts. Our results highlight how media coverage is not providing the public with the information necessary to make informed decisions about medical treatments. Most concerning is the lack of disclosure of trial funding and conflicts of interest that could influence the outcome or reporting of trial results. This lack of reporting may impact the medical research community, which has the most to lose by way of public trust and respect.


Tomographic method for measurement of the gradient refractive index of the crystalline lens. II. The rotationally symmetrical lens.
In the first part of this paper we presented a tomographic method to reconstruct the refractive index profile of spherically symmetrical lenses. Here we perform the generalization to lenses that are rotationally symmetrical around the optical axis, as is the ideal human lens. Analysis of the accuracy and versatility of this method is carried out by performing numerical simulations in which different magnitudes of experimental errors and two extreme case scenarios for the likely shape of the refractive index distribution of the human lens are considered. Finally, experimental results for a porcine lens are shown. Conceptually simple and computationally swift, this method could prove to be a valuable tool for the accurate retrieval of the gradient index of a broad spectrum of rotationally symmetrical crystalline lenses.


The antimicrobial peptide sublancin ameliorates necrotic enteritis induced by Clostridium perfringens in broilers.
Sublancin is an antimicrobial peptide produced by 168 containing 37 amino acids. The objective of this study was to investigate its inhibitory efficacy against both in vitro and in vivo. In the in vitro study, we determined that sublancin had a minimum inhibitory concentration of 8 μM against , which was much higher than the antibiotic lincomycin (0.281 μM). Scanning electron microscopy showed that sublancin damaged the morphology of . The in vivo study was conducted on broilers for a 28-d period using a completely randomized design. A total of 252 chickens at 1 d of age were randomly assigned to 1 of 6 treatments including an uninfected control; an infected control; 3 infected groups supplemented with sublancin at 2.88, 5.76, or 11.52 mg activity/L of water; and an infected group supplemented with lincomycin at 75 mg activity/L of water (positive control). Necrotic enteritis was induced in the broilers by oral inoculation of on d 15 through 21. Thereafter, the sublancin or lincomycin were administered fresh daily for a period of 7 days. The challenge resulted in a significant decrease in ADG ( < 0.05) and a remarkable deterioration in G:F ( < 0.05) during d 15 to 21 of the experiment. There was a sharp increase of numbers in the cecum ( < 0.05). The addition of sublancin or lincomycin reduced caecal counts ( < 0.05). The counts had a tendency to decrease in the lincomycin treatment ( = 0.051) but were the highest in the sublancin treatment (5.76 mg activity/L of water). A higher villus height to crypt depth ratio in the duodenum and jejunum as well as a higher villus height in the duodenum were observed in broilers treated with sublancin or lincomycin ( < 0.05) compared with infected control broilers. It was observed that sublancin and lincomycin decreased IL-1β, IL-6, and tumor necrosis factor-α levels ( < 0.05) in the ileum compared with the infected control. In conclusion, although sublancin's minimum inhibitory concentration is much higher than lincomycin in vitro, less sublancin is needed to control necrotic enteritis induced by in vivo than lincomycin. These novel findings indicate that sublancin could be used as a potential antimicrobial agent to control necrotic enteritis.


Abstinence from drugs of abuse in community-based members of Narcotics Anonymous.
Narcotics Anonymous (NA) is an abstinence-based fellowship with more than 58,000 groups worldwide. There has, however, been little research reported on its members. This study was designed to clarify the nature of the participants in NA who are primarily abstinent, long-term members. A protocol was implemented to survey members at 10 NA group meetings in three different states, through the cooperation of the NA World Service Office. A 51-item self-administered questionnaire, addressing key aspects of substance use and recovery, was anonymously completed by 396 respondents. Respondents were 71.5% male; the mean age was 38.1 years; 68.2% were White; and the principal drug problems comprised cocaine (28.5%), heroin (27.5%), other opiates (13.4%), methamphetamine (12.9%), alcohol (8.6%), marijuana (6.6%), and other stimulants (2.5%). Eighty-seven percent had prior treatment for a substance use disorder. On average respondents had first encountered NA at age 26.9, they had been abstinent an average of 5.7 years at the time they filled out the questionnaire, and 47.5% had served as sponsors. Ninety-four percent designated themselves as spiritual, and only 29.6% designated themselves as religious. NA offers support for long-term abstinence from diverse misuse of drugs among users of different backgrounds.


Balance training using an interactive game to enhance the use of the affected side after stroke.
[Purpose] Stroke and other cerebrovascular diseases are major causes of adult mobility problems. Because stroke immobilizes the affected body part, balance training uses the healthy body part to complete the target movement. The muscle utilization rate on the stroke affected side is often reduced which further hinders affected side functional recovery in rehabilitation. [Subjects and Methods] This study tested a newly-developed interactive device with two force plates to measuring right and left side centers of pressure, to establish its efficacy in the improvement of the static standing ability of patients with hemiplegia. An interactive virtual reality game with different side reaction ratios was used to improve patient balance. The feasibility of the proposed approach was experimentally demonstrated. [Results] Although the non-affected-side is usually used to support the body weight in the standing position, under certain circumstances the patients could switch to using the affected side. A dramatic improvement in static standing balance control was achieved in the eyes open condition. [Conclusion] The proposed dual force plate technique used in this study separately measured the affected and non-affected-side centers of pressure. Based on this approach, different side ratio integration was achieved using an interactive game that helped stroke patients improve balance on the affected side. Only the patient who had suffered stroke relatively recently benefited significantly. The proposed technique is of little benefit for patients whose mobility has stagnated to a certain level.


Enhancement and control of the selectivity in light-driven ketone versus water reduction using aminopyridine cobalt complexes.
Cobalt(ii) complexes with the general structure [CoII(OTf)(Y,XPy2Tstacn)](OTf) (1R, where Y,XPy2Tstacn is 1,4-di(p-Y,m-X-picolyl)-7-R-1,4,7-triazacyclononane; 1H, 1CO2Et, 1DMM) and [CoII(OTf)2(Y,XPyMetacn)] (2R, where Y,XPyMetacn is 1-(p-Y,m-X-picolyl)-7,4-di-methyl-1,4,7-triazacyclononane; 2CO2Et, 2Cl, 2H, 2DMM, 2NMe2) were active in both light-driven acetophenone (3a) and water reduction. Competition studies show that aromatic ketone/water reduction selectivity ranks from 0.2 to 8.0. Nevertheless, considering the concentrations of water and ketone in catalysis (ratio H2O/3a ∼ 2000) the highest selectivity obtained is greater than 15 000. The selectivity correlates well with the CoI/II redox potential within the same cobalt catalyst series (span 240 mV (1R) and 290 mV (2R)), with electron donating ligands favoring ketone reduction over H2 evolution. Based on this finding, the operative mechanism for the reduction of aromatic ketones is consistent with a single electron transfer (SET) followed by a hydrogen atom transfer (HAT) mechanism. This new insight will be a guide to develop selective catalytic systems to produce fine solar chemicals in water.


Molecular mechanisms of pancreatic injury.
Despite being a subject of much scientific scrutiny, the pathogenesis of acute pancreatitis is still not well understood. This article reviews recent advances in our understanding of acute pancreatitis. Zymogen activation, observed within acini early during acute pancreatitis for a long time, was shown to be sufficient to induce acute pancreatitis. Another key early event, NFκB activation, has previously been shown to induce acute pancreatitis. The relationship between these two key early steps is beginning to be clarified. Mechanisms of zymogen activation - pathologic calcium signaling, pH changes, colocalization and autophagy, and of NFκB activation have been investigated intensively along with potential therapeutic targets both upstream and downstream of these key events. Additional key findings have been elucidation of the role of bioenergetics and the dual role of oxidative stress in acute pancreatitis, recognition of endoplasmic reticulum stress as an early step and the status of duct cells as important entities in pancreatic injury. Current findings have provided further insight into the roles and mechanisms of zymogen activation and inflammatory pathways in pancreatic injury. Future studies, which will be of great importance in identifying therapeutic targets, are being undertaken to establish the relative contributions of these pathways during acute pancreatitis.


Application of jackknife procedures to inter-experiment comparisons of parameter estimates for the Michaelis-Menten equation.
The jackknife procedure is introduced as a means of making comparisons among Michaelis-Menten parameter estimates for six different experimental conditions. In addition to providing a solution to the general inter-experimental comparison problem, the jackknife procedure will provide valid parameter estimates even when some of the assumptions usually required for statistical analysis are violated, e.g., the random errors are not normally distributed and the variances are not homogeneous. Other recent variations of the jackknife have also been introduced and briefly investigated: (i) the linear jackknife, which is more efficient computationally, and (ii) the weighted jackknife, which reduces the influence of design points (substrate concentrations) that have an excessive influence on the precision of parameter estimates.


Do instrumental activities of daily living predict dementia at 1- and 2-year follow-up? Findings from the Development of Screening guidelines and diagnostic Criteria for Predementia Alzheimer's disease study.
To investigate whether problems in instrumental activities of daily living (IADL) can add to conventionally used clinical measurements in helping to predict a diagnosis of dementia at 1- and 2-year follow-up. Multicenter prospective cohort study. Memory clinics in Europe. Individuals aged 55 and older without dementia. IADLs were measured using pooled activities from five informant-based questionnaires. Structural equation modeling (SEM) was used to investigate the relation between IADLs and dementia. Age, sex, education, depression, and cognitive measures (Mini-Mental State Examination and verbal memory) were included in the model. Five hundred thirty-one participants had baseline and 1-year follow-up assessments; 69 (13.0%) of these had developed dementia at 1-year follow-up. At 2-year follow-up, 481 participants were seen, of whom 100 (20.8%) had developed dementia. Participants with IADL disabilities at baseline had a higher conversion rate (24.4%) than participants without IADL disabilities (16.7%) (chi-square = 4.28, degrees of freedom = 1, P = .04). SEM showed that IADL disability could help predict dementia in addition to the measured variables at 1-year follow-up (odds ratio (OR) = 2.20, 95% confidence interval (CI) = 1.51-3.13) and 2-year follow-up (OR = 2.11, 95% CI = 1.33-3.33). IADL disability is a useful addition to the diagnostic process in a memory clinic setting, indicating who is at higher risk of developing dementia at 1- and 2-year follow-up.


Synthesis of regiospecifically fluorinated conjugated dienamides.
Modular synthesis of regiospecifically fluorinated 2,4-diene Weinreb amides, with defined stereochemistry at both double bonds, was achieved via two sequential Julia-Kocienski olefinations. In the first step, a Z-a-fluorovinyl Weinreb amide unit with a benzothiazolylsulfanyl substituent at the allylic position was assembled. This was achieved via condensation of two primary building blocks, namely 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (a Julia-Kocienski olefination reagent) and 2-(benzo[d]thiazol-2-ylthio)acetaldehyde (a bifunctional building block). This condensation was highly Z-selective and proceeded in a good 76% yield. Oxidation of benzothiazolylsulfanyl moiety furnished a second-generation Julia-Kocienski olefination reagent, which was used for the introduction of the second olefinic linkage via DBU-mediated condensations with aldehydes, to give (2Z,4E/Z)-dienamides in 50%-74% yield. Although olefinations were 4Z-selective, (2Z,4E/Z)-2-fluoro-2,4-dienamides could be readily isomerized to the corresponding 5-substituted (2Z,4E)-2-fluoro-N-methoxy-N-methylpenta-2,4-dienamides in the presence of catalytic iodine.


Surgical and chemotherapeutic experience regarding a urachal carcinoma with repeated relapse: case report and literature review.
Urachal carcinoma is a rare tumor that is usually associated with a poor prognosis, especially the pathological type, urachal mucinous adenocarcinoma. Surgery remains the primary treatment in prolonging the overall survival time of patients. We report on a 41-year-old woman with urachal mucinous adenocarcinoma who underwent three surgeries and several courses of chemotherapy over a 42-month period. The first surgery, involving en-bloc excision of the urachal mass, partial urinary bladder, urachal ligament, and umbilicus was performed in May 2007. It is well known that the correct surgical scheme plays a key role in preventing recurrence or metastasis. However, a second debulking surgery with only a single salpingo-oophorectomy may have contributed directly to the patient's subsequent left ovarian metastasis. Therefore, we strongly recommend performing a bilateral salpingo-oophorectomy once ovarian metastasis has been detected, even if the metastasis is only present on one side. Although postoperative adjuvant chemotherapy regimens, first with Taxol, carboplatin, gemcitabine, and cisplatin, and then with IFO, EPI, and mesna were consecutively administered after the first and second surgeries, they seemed less effective, since recurrence and metastasis occurred shortly after each surgical treatment. After a third debulking surgery in June 2009, docetaxel, oxaliplatin, and capecitabine were administered. This chemotherapy regimen was chosen based on an immunohistochemical test that involved the multidrug resistance gene; this test indicated that the urachal mucinous adenocarcinoma was resistant to the two chemotherapy regimens used previously. Surprisingly, the patient exhibited a marker response to the new regimen and the metastatic foci entered into a stable disease stage. However, the patient still died of diffuse metastatic disease 1.5 years later. During the whole period of treatment, we found that serum tumor markers including CA724, CA125, CA19-9, and CEA were elevated in a linear pattern, with parallel increases in line with peritoneal carcinomatosis and parallel reductions in line with response to personalized chemotherapy. Personalized treatment can be given to those patients who experience a poor response to initial therapy. Moreover, an immunohistochemical test for the multidrug resistance gene and serum tumor markers may supply key information in the choice of reasonable chemotherapeutics.


Quantification of the natural history of visceral leishmaniasis and consequences for control.
Visceral leishmaniasis has been targeted for elimination as a public health problem (less than 1 case per 10,000 people per year) in the Indian sub-continent by 2017. However, there is still a high degree of uncertainty about the natural history of the disease, in particular about the duration of asymptomatic infection and the proportion of asymptomatically infected individuals that develop clinical visceral leishmaniasis. Quantifying these aspects of the disease is key for guiding efforts to eliminate visceral leishmaniasis and maintaining elimination once it is reached. Data from a detailed epidemiological study in Bangladesh in 2002-2004 was analysed to estimate key epidemiological parameters. The role of diagnostics in determining the probability and rate of progression to clinical disease was estimated by fitting Cox proportional hazards models. A multi-state Markov model of the natural history of visceral leishmaniasis was fitted to the data to estimate the asymptomatic infection period and the proportion of asymptomatic individuals going on to develop clinical symptoms. At the time of the study, individuals were taking several months to be diagnosed with visceral leishmaniasis, leading to many opportunities for ongoing transmission. The probability of progression to clinical disease was strongly associated with initial seropositivity and even more strongly with seroconversion, with most clinical symptoms developing within a year. The estimated average durations of asymptomatic infection and symptomatic infection for our model of the natural history are 147 days (95 % CI 130-166) and 140 days (95 % CI 123-160), respectively, and are significantly longer than previously reported estimates. We estimate from the data that 14.7 % (95 % CI 12.6-20.0 %) of asymptomatic individuals develop clinical symptoms-a greater proportion than previously estimated. Extended periods of asymptomatic infection could be important for visceral leishmaniasis transmission, but this depends critically on the relative infectivity of asymptomatic and symptomatic individuals to sandflies. These estimates could be informed by similar analysis of other datasets. Our results highlight the importance of reducing times from onset of symptoms to diagnosis and treatment to reduce opportunities for transmission.


Beyond busyness: creating slack in the organization.
Human beings are not machines. The patient safety literature documents the price we pay for excessive overtime, long hours, and no breaks. Disengaged staff, high vacancy rates, and turnover are the products of cultures that do not support a professional environment where nurses are seen as knowledge workers. At his retirement dinner, a factory worker accepted accolades for his years of dedicated service. In his farewell speech, he noted that for 40 years the factory used his hands but never his brains. His expertise and knowledge were never acknowledged or solicited. Consequently he watched in silence for years as directives came down from managers and leaders that were totally unrealistic and bore no relevance to the reality in which he worked. And he watched the initiatives fail. Unfortunately we in health care can create that exact situation if we do not incorporate time (slack) into the schedules of our knowledge workers so they can unleash their genius, reinvent health care, and fix health care from the inside out. Nurse leaders must be the architects of participation and allow this to happen.


The role of tyrosine kinase inhibitor "Lapatinib" in pulmonary hypertension.
Pulmonary Arterial Hypertension (PAH) and cancer share growth factor and protein kinase signaling pathways that result in smooth muscle cell proliferation and vasculopathy. There is little known about the impact of Lapatinib on the pulmonary vasculature. After reporting a case of Lapatinib-induced PAH we investigated the association of Lapatinib with the development of PAH in our institution. We reviewed charts for all patients treated with Lapatinib at our institution between 2008 and 2013. Patients who had undergone 2D-echocardiogram both prior to and after treatment were included in the analysis. Increase in Pulmonary artery systolic pressure (PASP) was assessed. Patients were also evaluated in terms of risk factors for non-Group 1 PAH. A total of 27 patients were found to have 2-D echo done before and after starting treatment with Lapatinib. Six patients were found to have significant increase in their PASP after starting treatment. Right heart catheterization before and after stopping the medication was available in three patient, confirming the diagnosis of PAH with complete resolution after stopping the medication. The median pre-treatment and post treatment PASP in those 6 patients was 29 mmHg and 65.5 mmHg respectively (N = 6; p = 0.027). Lapatinib might be associated with the development of PAH. PASP should be evaluated in patients who become short of breath while on treatment, and stopping the drug in cases where no other reasons are identified could be associated with reversibility of the elevated pulmonary artery pressure.


Nutrient distribution and metabolism in the intervertebral disc in the unloaded state: a parametric study.
A 2-D finite element model for the intervertebral disc in which quadriphasic theory is coupled to the transport of solutes involved in cellular nutrition was developed for investigating the main factors contributing to disc degeneration. Degeneration is generally considered to result from chronic disc cell nutrition insufficiency, which prevents the cells from renewing the extracellular matrix and thus leads to the loss of proteoglycans. Hence, the osmotic power of the disc is decreased, causing osmomechanical impairments. Cellular metabolism depends strongly on the oxygen, lactate and glucose concentrations and on pH in the disc. To study the diffusion of these solutes in a mechanically or osmotically loaded disc, the osmomechanical and diffusive effects have to be coupled. The intervertebral disc is modeled here using a plane strain formulation at the equilibrium state under physiological conditions after a long rest period (called unloaded state). The correlations between solute distribution and various properties of healthy and degenerated discs are investigated. The numerical simulation shows that solute distribution in the disc depends very little on the elastic modulus or the proteoglycan concentration but greatly on the porosity, diffusion coefficient and endplate diffusion area. This coupled model therefore opens new perspectives for investigating intervertebral disc degeneration mechanisms.


Granulocyte Colony-Stimulating Factor Alleviates Bacterial-Induced Neuronal Apoptotic Damage in the Neonatal Rat Brain through Epigenetic Histone Modification.
Bacterial meningitis during the perinatal period may cause long-term neurological deficits. The study investigated whether bacterial lipopolysaccharide (LPS) derived from E. coli. led to neuronal apoptosis with an impaired performance of long-term cognitive function involving the activation of histone modification in the TNF-α gene promoter. Further, we looked into the therapeutic efficacy of granulocyte colony-stimulating factor (G-CSF) in a neonatal brain suffering from perinatal bacterial meningitis. We applied the following research techniques: neurobehavioral tasks, confocal laser microscopy, chromatin immunoprecipitation, and Western blotting. At postnatal day 10, the animals were subjected to LPS and/or G-CSF. The target brain tissues were then collected at P17. Some animals (P45) were studied using neurobehavioral tasks. The LPS-injected group revealed significantly increased expression of NF-κB phosphorylation and trimethylated H3K4 in the TNFA gene promoter locus. Furthermore, the caspase-3, neuronal apoptosis expression, and an impaired performance in cognitive functions were also found in our study. Such deleterious outcomes described above were markedly alleviated by G-CSF therapy. This study suggests that selective therapeutic action sites of G-CSF through epigenetic regulation in the TNFA gene promoter locus may exert a potentially beneficial role for the neonatal brain suffering from perinatal bacterial-induced meningitis.


Actions of sex steroids on kisspeptin expression and other reproduction-related genes in the brain of the teleost fish European sea bass.
Kisspeptins are well known as mediators of the coordinated communication between the brain-pituitary axis and the gonads in many vertebrates. To test the hypothesis that gonadal steroids regulate kiss1 and kiss2 mRNA expression in European sea bass (a teleost fish), we examined the brains of gonad-intact (control) and castrated animals, as well as castrated males (GDX) and ovariectomized females (OVX) that received testosterone (T) and estradiol (E2) replacement, respectively, during recrudescence. In GDX males, low expression of kiss1 mRNA is observed by in situ hybridization in the caudal hypothalamus (CH) and the mediobasal hypothalamus (MBH), although hypothalamic changes in kiss1 mRNA levels were not statistically different among the groups, as revealed by real-time PCR. However, T strongly decreased kiss2 expression levels in the hypothalamus, which was documented in the MBH and the nucleus of the lateral recess (NRLd) in GDX T-treated sea bass males. Conversely, it appears that E2 evokes low kiss1 mRNA in the CH, while there were cells expressing kiss2 in the MBH and NRLd in these OVX females. These results demonstrate that kisspeptin neurons are presumably sensitive to the feedback actions of sex steroids in the sea bass, suggesting that the MBH represents a major site for sex steroid actions on kisspeptins in this species. Also, recent data provide evidence that both positive and negative actions occur in key factors involved in sea bass reproductive function, including changes in the expression of gnrh-1/gonadotropin, cyp19b, er and ar genes and sex steroid and gonadotropin plasma levels in this teleost fish.


Physical limits to biomechanical sensing in disordered fibre networks.
Cells actively probe and respond to the stiffness of their surroundings. Since mechanosensory cells in connective tissue are surrounded by a disordered network of biopolymers, their in vivo mechanical environment can be extremely heterogeneous. Here we investigate how this heterogeneity impacts mechanosensing by modelling the cell as an idealized local stiffness sensor inside a disordered fibre network. For all types of networks we study, including experimentally-imaged collagen and fibrin architectures, we find that measurements applied at different points yield a strikingly broad range of local stiffnesses, spanning roughly two decades. We verify via simulations and scaling arguments that this broad range of local stiffnesses is a generic property of disordered fibre networks. Finally, we show that to obtain optimal, reliable estimates of global tissue stiffness, a cell must adjust its size, shape, and position to integrate multiple stiffness measurements over extended regions of space.


RAD18 transmits DNA damage signalling to elicit homologous recombination repair.
To maintain genome stability, cells respond to DNA damage by activating signalling pathways that govern cell-cycle checkpoints and initiate DNA repair. Cell-cycle checkpoint controls should connect with DNA repair processes, however, exactly how such coordination occurs in vivo is largely unknown. Here we describe a new role for the E3 ligase RAD18 as the integral component in translating the damage response signal to orchestrate homologous recombination repair (HRR). We show that RAD18 promotes homologous recombination in a manner strictly dependent on its ability to be recruited to sites of DNA breaks and that this recruitment relies on a well-defined DNA damage signalling pathway mediated by another E3 ligase, RNF8. We further demonstrate that RAD18 functions as an adaptor to facilitate homologous recombination through direct interaction with the recombinase RAD51C. Together, our data uncovers RAD18 as a key factor that orchestrates HRR through surveillance of the DNA damage signal.


Oncoplastic Breast Conserving Surgery: Aesthetic Satisfaction and Oncological Outcomes.
Oncoplastic breast conserving surgery (BCS) involves radical excision of tumors while maintaining the natural breast contours. In this study, we present the results of the oncoplastic BCS surgeries performed in our clinic. 13 breast cancer patients who had undergone oncoplastic BCS were included in this retrospective study. Postoperative photographs and retrospective chart reviews were used to evaluate the results. Aesthetic satisfaction level was verbally obtained from the patients. Oncoplastic BCS was performed using superomedial, superolateral, superior and inferior pedicles. All the patients were highly satisfied with the final aesthetic results and tumor free at the postoperative 12 months. Oncoplastic BCS can achieve favorable results regarding the final aesthetic appearance and tumor control.


Effectiveness of Telehealth Cardiac Rehabilitation Programs on Health Outcomes of Patients With Coronary Heart Diseases: AN UMBRELLA REVIEW.
The aim of this study was to conduct an umbrella review summarizing the evidence from existing systematic reviews of telehealth cardiac rehabilitation (CR) on health outcomes of patients with coronary heart disease (CHD). An umbrella review of systematic reviews was undertaken in accordance with the PRISMA and JBI guidelines. A systematic search was conducted in Medline, APA PsycINFO, Embase, CINAHL, Web of Science, Cochrane database of systematic reviews, JBI evidence synthesis, Epistemonikos, and PROSPERO, searching for systematic reviews published from 1990 to current and was limited to the language source of English and Chinese. Outcomes of interest were health behaviors and modifiable CHD risk factors, psychosocial outcomes, and other secondary outcomes. Study quality was appraised using the JBI checklist for systematic reviews. A narrative analysis was conducted, and meta-analysis results were synthesized. From 1301 identified reviews, 13 systematic reviews (10 meta-analyses) comprised 132 primary studies conducted in 28 countries. All the included reviews have high quality, with scores ranging 73-100%. Findings to the health outcomes remained inconclusive, except solid evidence was found in the significant improvement in physical activity (PA) levels and behaviors from telehealth interventions, exercise capacity from mobile health (m-health) only and web-based only interventions, and medication adherence from m-health interventions. Telehealth CR programs, work adjunct or in addition to traditional CR and standard care, are effective in improving health behaviors and modifiable CHD risk factors, particularly in PA. In addition, it does not increase the incidence in terms of mortality, adverse events, hospital readmission, and revascularization.


Low-Dose Acetylsalicylic Acid Treatment and Impact on Short-Term Mortality in Staphylococcus aureus Bloodstream Infection: A Propensity Score-Matched Cohort Study.
Staphylococcus aureus bloodstream infection is associated with considerable mortality. Experimental models suggest a direct antistaphylococcal effect of acetylsalicylic acid, but evidence from human studies is scarce. We aimed to estimate the effect of low-dose acetylsalicylic acid therapy on mortality in bloodstream infections caused by S. aureus compared with Escherichia coli. Retrospective cohort study based on observational data from 838 and 602 episodes of S. aureus and E. coli bloodstream infection, respectively. Swiss tertiary referral center. Adult patients with S. aureus and E. coli bloodstream infection, respectively, categorized according to low-dose acetylsalicylic acid therapy as outpatient or inpatient before bacteremia. None. Thirty-day all-cause mortality was analyzed in a total of 314 propensity score-matched S. aureus bloodstream infection and in 268 E. coli bloodstream infection patients, respectively (1:1 match of low-dose acetylsalicylic acid users and nonusers). S. aureus bloodstream infection cases and controls were equally matched for relevant confounders except treatment with statins, which was strongly associated with a low-dose acetylsalicylic acid use (p < 0.001). At day 30, 12.1% of cases and 27.4% of controls had died (hazard ratio, 0.40; p < 0.001). Low-dose acetylsalicylic acid use was associated with a reduced 30-day all-cause mortality in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; p = 0.001) of matched patients and also of the entire cohort (n = 689) after adjustment for the propensity score (hazard ratio, 0.58, 95% CI, 0.34-0.98; p = 0.04). In contrast, low-dose acetylsalicylic acid use was not associated with the primary endpoint in patients with E. coli bloodstream infection (hazard ratio, 0.78; 95% CI, 0.40-1.55; p = 0.8). Low-dose acetylsalicylic acid at the time of bloodstream infection was strongly associated with a reduced short-term mortality in patients with S. aureus bloodstream infection. Future studies are required to investigate if early low-dose acetylsalicylic acid is a suitable treatment in patients with S. aureus bloodstream infection.


New developmental evidence supports a homeotic frameshift of digit identity in the evolution of the bird wing.
The homology of the digits in the bird wing is a high-profile controversy in developmental and evolutionary biology. The embryonic position of the digits cartilages with respect to the primary axis (ulnare and ulna) corresponds to 2, 3, 4, but comparative-evolutionary morphology supports 1, 2, 3. A homeotic frameshift of digit identity in evolution could explain how cells in embryonic positions 2, 3, 4 began developing morphologies 1, 2, 3. Another alternative is that no re-patterning of cell fates occurred, and the primary axis shifted its position by some other mechanism. In the wing, only the anterior digit lacks expression of HoxD10 and HoxD12, resembling digit 1 of other limbs, as predicted by 1, 2, 3. However, upon loss of digit 1 in evolution, the most anterior digit 2 could have lost their expression, deceitfully resembling a digit 1. To test this notion, we observed HoxD10 and HoxD12 in a limb where digit 2 is the most anterior digit: The rabbit foot. We also explored whether early inhibition of Shh signalling in the embryonic wing bud induces an experimental homeotic frameshift, or an experimental axis shift. We tested these hypotheses using DiI injections to study the fate of cells in these experimental wings. We found strong transcription of HoxD10 and HoxD12 was present in the most anterior digit 2 of the rabbit foot. Thus, we found no evidence to question the use of HoxD expression as support for 1, 2, 3. When Shh signalling in early wing buds is inhibited, our fate maps demonstrate that an experimental homeotic frameshift is induced. Along with comparative morphology, HoxD expression provides strong support for 1, 2, 3 identity of wing digits. As an explanation for the offset 2, 3, 4 embryological position, the homeotic frameshift hypothesis is consistent with known mechanisms of limb development, and further proven to be experimentally possible. In contrast, the underlying mechanisms and experimental plausibility of an axis shift remain unclear.


Repeated survey on changes in musculoskeletal complaints relative to age and work demands.
To examine changes in musculoskeletal complaints over four years in groups of employees relative to age and work demands. Repeated questionnaire data of male employees in heavy physical work (exposed group, n = 7324) and mental work (control group, n = 4686), stratified for age (20-9, 30-9, 40-9, 50-9), were analysed. For each employee, data on the occurrence of musculoskeletal complaints from two surveys with a mean interval of around four years were available. Changes in prevalences over the follow up interval were analysed. Proportions of new, recovered, and chronic cases as well as those free of complaints at both surveys were studied. For most complaints, there were significantly greater increases in prevalences in the exposed group compared with the control group over the follow up interval particularly within the group aged 40-9 for back, neck, and several sites of the upper and lower limbs. The 20-9 year age group also had significantly greater changes for several musculoskeletal complaints. Within the oldest age group (50-9) exposure to heavy physical work demands only affected changes in prevalences of neck and upper arm complaints. After four years in the cohort free of complaints at the start of the follow up the group aged 40-9 had the highest prevalence of complaints of the back, neck, and the upper and lower limbs. Middle aged and younger employees develop musculoskeletal complaints as a result of exposure to heavy physical work. In the oldest age group health related selection seems to mask the occupational health risks under study. To prevent the expected increase in musculoskeletal disorders and related work disability in our aging workforce, preventive measures should be taken at all stages of a working life.


Linking bovine tuberculosis on cattle farms to white-tailed deer and environmental variables using Bayesian hierarchical analysis.
Bovine tuberculosis is a bacterial disease caused by Mycobacterium bovis in livestock and wildlife with hosts that include Eurasian badgers (Meles meles), brushtail possum (Trichosurus vulpecula), and white-tailed deer (Odocoileus virginianus). Risk-assessment efforts in Michigan have been initiated on farms to minimize interactions of cattle with wildlife hosts but research on M. bovis on cattle farms has not investigated the spatial context of disease epidemiology. To incorporate spatially explicit data, initial likelihood of infection probabilities for cattle farms tested for M. bovis, prevalence of M. bovis in white-tailed deer, deer density, and environmental variables for each farm were modeled in a Bayesian hierarchical framework. We used geo-referenced locations of 762 cattle farms that have been tested for M. bovis, white-tailed deer prevalence, and several environmental variables that may lead to long-term survival and viability of M. bovis on farms and surrounding habitats (i.e., soil type, habitat type). Bayesian hierarchical analyses identified deer prevalence and proportion of sandy soil within our sampling grid as the most supported model. Analysis of cattle farms tested for M. bovis identified that for every 1% increase in sandy soil resulted in an increase in odds of infection by 4%. Our analysis revealed that the influence of prevalence of M. bovis in white-tailed deer was still a concern even after considerable efforts to prevent cattle interactions with white-tailed deer through on-farm mitigation and reduction in the deer population. Cattle farms test positive for M. bovis annually in our study area suggesting that the potential for an environmental source either on farms or in the surrounding landscape may contributing to new or re-infections with M. bovis. Our research provides an initial assessment of potential environmental factors that could be incorporated into additional modeling efforts as more knowledge of deer herd factors and cattle farm prevalence is documented.


Quantifying auditory impressions in dreams in order to assess the relevance of dreaming as a model for psychosis.
A long noted hypothesis is that mechanisms of dreaming play a role in psychotic hallucinations. One challenge for this hypothesis is that while psychotic hallucinations primarily are auditory, dreaming most characteristically is visual. At the same time, previous studies have not explicitly examined auditory impressions in dreaming. Here, we mapped the prevalence and characteristics of auditory impressions in 130 dreams reported after spontaneous awakenings from sleep in 13 normal, healthy people. We instructed participants to report any dream they could recall and to pay particular attention to possible auditory impressions. The participants reported auditory impressions in 93.9% of their dreams on average. The most prevalent auditory type was other people speaking (83.9% of participants' dreams), followed by the dreamer speaking (60.0%), and other types of sounds (e.g. music, 33.1%). Of altogether 407 instances of auditory impressions in the 130 dreams, auditory quality was judged comparable to waking in 46.4%, indeterminate in 50.6%, and absent or only thought-like in 2.9%. The results suggest that also internally generated auditory (verbal) sensations are a central component of dreaming, typically occurring several times every night in normal, healthy people.


Direct visualization of the interfacial position of colloidal particles and their assemblies.
A method for direct visualization of the position of nanoscale colloidal particles at air-water interfaces is presented. After assembling hard (polystyrene, poly(methyl methacrylate), silica) or soft core-shell gold-hydrogel composite (Au@PNiPAAm) colloids at the air-water interface, butylcyanoacrylate is introduced to the interface via the gas phase. Upon contact with water, an anionic polymerization reaction of the monomer is initiated and a film of poly(butylcyanoacrylate) (PBCA) is generated, entrapping the colloids at their equilibrium position at the interface. We apply this method to investigate the formation of complex, binary assembly structures directly at the interface, to visualize soft, nanoscale hydrogel colloids in the swollen state, and to visualize and quantify the equilibrium position of individual micro- and nanoscale colloids at the air-water interface depending of the amount of charge present on the particle surface. We find that the degree of deprotonation of the carboxyl group shifts the air-water contact angle, which is further confirmed by colloidal probe atomic force microscopy. Remarkably, the contact angles determined for individual colloidal particles feature a significant distribution that greatly exceeds errors attributable to the size distribution of the colloids. This finding underlines the importance of accessing soft matter on an individual particle level.


Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or 4-week schedule?
Chemotherapy with gemcitabine and cisplatin (GC) is an active regimen in advanced transitional cell carcinoma (TCC). Traditionally, GC has been administered as a 4-week schedule. However, an alternative 3-week schedule may be more feasible. Long-term survival data for the alternative 3-week schedule and comparisons of the feasibility and toxicity between the two schedules have not previously been published. We performed a retrospective analysis of patients with stage IV TCC, treated with GC by a standard 4-week or by an alternative 3-week schedule. A total of 212 patients received GC (3-week; n = 151, 4-week; n = 61). We found no statistical differences in overall survival between the two schedules (hazard ratio 1.15, 95% CI 0.83-1.59), p = 0.40). Five-year survival rates were 14.9% and 11.8% for the 3- and 4-week schedule, respectively (p = 0.94). Response rates were 59.7% and 55.6%, respectively (p = 0.61). Toxicity was less pronounced in the 3-week schedule with regards to neutropenia, thrombocytopenia, and transfusion rates. Hematologic toxicity at day 15 in the 4-week schedule was common, leading to dose omissions in 47% of cycles. Dose intensity for gemcitabine was accordingly lower in the 4 week-schedule. The higher dose intensity of cisplatin in the 3-week schedule, did not lead to increased renal toxicity. In 13 patients with impaired renal function, cisplatin was split into 2 days, which was feasible and efficient. Efficacy parameters for the GC 3-week schedule were comparable to those for the 4-week schedule, whereas toxicity was less pronounced. The 3-week schedule may be an effective and feasible alternative GC-schedule.


Associations of circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade.
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with prostate specific antigen-detected prostate cancer in a case-control study nested within the prostate testing for cancer and treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs. localized) and Gleason grade (high-grade (≥7) vs. low-grade (<7)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20-<30 ng/mL; insufficient: 12-<20 ng/mL; deficient: <12 ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a 2-fold increased risk of advanced versus localized cancer (OR for deficient vs. adequate total 25(OH)D=2.33, 95% CI: 1.26, 4.28) and high-grade versus low-grade cancer (OR for deficient vs. adequate total 25(OH)D=1.78, 95% CI: 1.15, 2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low-Gleason grade), but there was no evidence of an association with overall prostate cancer risk.


The proBAM and proBed standard formats: enabling a seamless integration of genomics and proteomics data.
On behalf of The Human Proteome Organization (HUPO) Proteomics Standards Initiative, we introduce here two novel standard data formats, proBAM and proBed, that have been developed to address the current challenges of integrating mass spectrometry-based proteomics data with genomics and transcriptomics information in proteogenomics studies. proBAM and proBed are adaptations of the well-defined, widely used file formats SAM/BAM and BED, respectively, and both have been extended to meet the specific requirements entailed by proteomics data. Therefore, existing popular genomics tools such as SAMtools and Bedtools, and several widely used genome browsers, can already be used to manipulate and visualize these formats "out-of-the-box." We also highlight that a number of specific additional software tools, properly supporting the proteomics information available in these formats, are now available providing functionalities such as file generation, file conversion, and data analysis. All the related documentation, including the detailed file format specifications and example files, are accessible at http://www.psidev.info/probam and at http://www.psidev.info/probed .


Two-photon continuous flow lithography.
A new approach for microfluidics-based production of polymeric particles, namely two-photon continuous flow lithography, is reported. This technique takes advantage of two-photon lithography to create objects with sub-micrometer and 3D features, and overcomes the traditional process limitations of two-photon lithography by using multiple beam production under continuous flow. Polymeric fibers, helical and bow-tie particles with sub-diffraction resolution and surface roughness as low as 10 nm are demonstrated.


Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts < 100/mm3. Multicenter AIDS Cohort Study.
Incidence rates of AIDS illnesses are described among patients with < or = 100 CD4 cells/mm3 grouped by use of antiretrovirals and chemoprophylaxis. Data were obtained from 2646 homosexual men infected with human immunodeficiency virus type 1. Participants were in the Multicenter AIDS Cohort Study during 1985-1993. The incidence rates per 100 person-years for Pneumocystis carinii pneumonia were 47.4 without treatment, 21.5 with antiretrovirals alone, and 12.8 with antiretrovirals combined with chemoprophylaxis. For Kaposi's sarcoma these rates were 23.2, 11.3, and 15.1, respectively. The incidence of some opportunistic infections, including Mycobacterium avium complex, nonretinitis cytomegalovirus disease, and cytomegalovirus retinitis, increased among persons receiving P. carinii pneumonia prophylaxis, because of reduction of this pneumonia and extension of life span. The incidence pattern of AIDS-defining illnesses in patients receiving treatment points to the changing AIDS epidemic and the need for new therapies. The data are particularly relevant to the development and planning of clinical trials and to health care providers.


Constructive thinking, rational intelligence and irritable bowel syndrome.
To evaluate rational and experiential intelligence in irritable bowel syndrome (IBS) sufferers. We recruited 100 subjects with IBS as per Rome II criteria (50 consulters and 50 non-consulters) and 100 healthy controls, matched by age, sex and educational level. Cases and controls completed a clinical questionnaire (including symptom characteristics and medical consultation) and the following tests: rational-intelligence (Wechsler Adult Intelligence Scale, 3rd edition); experiential-intelligence (Constructive Thinking Inventory); personality (NEO personality inventory); psychopathology (MMPI-2), anxiety (state-trait anxiety inventory) and life events (social readjustment rating scale). Analysis of variance was used to compare the test results of IBS-sufferers and controls, and a logistic regression model was then constructed and adjusted for age, sex and educational level to evaluate any possible association with IBS. No differences were found between IBS cases and controls in terms of IQ (102.0 +/- 10.8 vs 102.8 +/- 12.6), but IBS sufferers scored significantly lower in global constructive thinking (43.7 +/- 9.4 vs 49.6 +/- 9.7). In the logistic regression model, global constructive thinking score was independently linked to suffering from IBS [OR 0.92 (0.87-0.97)], without significant OR for total IQ. IBS subjects do not show lower rational intelligence than controls, but lower experiential intelligence is nevertheless associated with IBS.