Artificial discs for lumbar and cervical degenerative disc disease -update: an evidence-based analysis.
To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD). Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD. Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR. The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions: What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery?Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD) compared with spinal fusion?What is the rate of major complications (device failure, reoperation) with artificial discs compared with surgical spinal fusion?One reviewer evaluated the internal validity of the primary studies using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. The quality of concealment allocation was rated as: A, clearly yes; B, unclear; or C, clearly no. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A random effects model meta-analysis was conducted when data were available from 2 or more randomized controlled trials (RCTs) and when there was no statistical and or clinical heterogeneity among studies. Bayesian analyses were undertaken to do the following: Examine the influence of missing data on clinical success rates;Compute the probability that artificial discs were superior to spinal fusion (on the basis of clinical success rates);Examine whether the results were sensitive to the choice of noninferiority margin. The literature search yielded 140 citations. Of these, 1 Cochrane systematic review, 1 RCT, and 10 case series were included in this review. Unpublished data from an RCT reported in the grey literature were obtained from the manufacturer of the device. The search also yielded 8 health technology assessments evaluating ADR that are also included in this review. Six of the 8 health technology assessments concluded that there is insufficient evidence to support the use of either lumbar or cervical ADR. The results of the remaining 2 assessments (one each for lumbar and cervical ADR) led to a National Institute for Clinical Excellence guidance document supporting the safety and effectiveness of lumbar and cervical ADR with the proviso that an ongoing audit of all clinical outcomes be undertaken owing to a lack of long-term outcome data from clinical trials. Regarding lumbar ADR, data were available from 2 noninferiority RCTs to complete a meta-analysis. The following clinical, health systems, and adverse event outcome measures were synthesized: primary outcome of clinical success, Oswestry Disability Index (ODI) scores, pain VAS scores, patient satisfaction, duration of surgery, amount of blood loss, length of hospital stay, rate of device failure, and rate of reoperation. The meta-analysis of overall clinical success supported the noninferiority of lumbar ADR compared with spinal fusion at 24-month follow-up. Of the remaining clinical outcome measures (ODI, pain VAS scores, SF-36 scores [mental and physical components], patient satisfaction, and return to work status), only patient satisfaction and scores on the physical component scale of the SF-36 questionnaire were significantly improved in favour of lumbar ADR compared with spinal fusion at 24 months follow-up. Blood loss and surgical time showed statistical heterogeneity; therefore, meta-analysis results are not interpretable. Length of hospital stay was significantly shorter in patients receiving the ADR compared with controls. Neither the number of device failures nor the number of neurological complications at 24 months was statistically significantly different between the ADR and fusion treatment groups. However, there was a trend towards fewer neurological complications at 24 months in the ADR treatment group compared with the spinal fusion treatment group. Results of the Bayesian analyses indicated that the influence of missing data on the outcome measure of clinical success was minimal. The Bayesian model indicated that the probability for ADR being better than spinal fusion was 79%. The probability of ADR being noninferior to spinal fusion using a -10% noninferiority bound was 92%, and using a -15% noninferiority bound was 94%. The probability of artificial discs being superior to spinal fusion in a future trial was 73%. Six case series were reviewed, mainly to characterize the rate of major complications for lumbar ADR. The Medical Advisory Secretariat defined a major complication as any reoperation; device failure necessitating a revision, removal or reoperation; or life-threatening event. The rates of major complications ranged from 0% to 13% per device implanted. Only 1 study reported the rate of ASD, which was detected in 2 (2%) of the 100 people 11 years after surgery. There were no RCT data available for cervical ADR; therefore, data from 4 case series were reviewed for evidence of effectiveness and safety. Because data were sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time. The rate of major complications was assessed up to 2 years after surgery. It was found to range from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature. The total cost of a lumbar ADR procedure is $15,371 (Cdn; including costs related to the device, physician, and procedure). The total cost of a lumbar fusion surgery procedure is $11,311 (Cdn; including physicians' and procedural costs). Lumbar Artificial Disc Replacement Since the 2004 Medical Advisory Secretariat health technology policy assessment, data from 2 RCTs and 6 case series assessing the effectiveness and adverse events profile of lumbar ADR to treat DDD has become available. The GRADE quality of this evidence is moderate for effectiveness and for short-term (2-year follow-up) complications; it is very low for ASD.The effectiveness of lumbar ADR is not inferior to that of spinal fusion for the treatment of lumbar DDD. The rates for device failure and neurological complications 2 years after surgery did not differ between ADR and fusion patients. Based on a Bayesian meta-analysis, lumbar ADR is 79% superior to lumbar spinal fusion.The rate of major complications after lumbar ADR is between 0% and 13% per device implanted. The rate of ASD in 1 case series was 2% over an 11-year follow-up period.Outcome data for lumbar ADR beyond a 2-year follow-up are not yet available.Cervical Artificial Disc Replacement Since the 2004 Medical Advisory Secretariat health technology policy assessment, 4 case series have been added to the body of evidence assessing the effectiveness and adverse events profile of cervical ADR to treat DDD. The GRADE quality of this evidence is very low for effectiveness as well as for the adverse events profile. Sparse outcome data are available.Because data are sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.The rate of major complications was assessed up to 2 years after surgery; it ranged from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.


Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors.
Dolutegravir (DTG), elvitegravir (EVG) and raltegravir (RAL) are members of the latest class of antiretrovirals (ARVs) that have become available to treat human immunodeficiency virus (HIV) infection: integrase strand transfer inhibitors (INSTIs). INSTIs are potent inhibitors of the HIV integrase enzyme, with protein binding-adjusted concentration inhibiting viral replication by 90/95 % [IC90/95] values in the low nanogram per millilitre range, and they retain antiviral activity against strains of HIV with acquired resistance to other classes of ARVs. Each of the INSTIs has unique pharmacokinetic/pharmacodynamic properties, influencing its role in clinical use in specific subsets of patients. RAL and DTG have minimal drug-drug interaction profiles, as their metabolism has minimal cytochrome P450 (CYP) involvement. Conversely, EVG metabolism occurs primarily via CYP3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. EVG and DTG have the added benefit of availability of fixed-dose combination tablets, allowing for convenient and simplified ARV regimens. RAL is the only INSTI to be listed as a preferred agent in the current US perinatal treatment guidelines. All three INSTIs are recommended regimens for treatment-naïve individuals in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the INSTIs, and describes specific pharmacokinetic considerations for special patient conditions: hepatic impairment, renal dysfunction, pregnancy and co-infections.


Controlled assembly and plasmonic properties of asymmetric core-satellite nanoassemblies.
The assembly of noble metal nanoparticles offers an appealing means to control and enhance the plasmonic properties of nanostructures. However, making nanoassemblies with easily modifiable gap distances with high efficiency has been challenging. Here, we report a novel strategy to assemble gold nanoparticles (AuNPs) into Janus-type asymmetric core-satellite nanostructures. Markedly different desorption efficiency between large and small AuNPs in ethanol allows us to prepare the asymmetric core-satellite nanoassemblies in a dispersed colloidal state with near 100% purity. The resulting nanoassemblies have well-defined structures in which a core AuNP (51 nm) is covered by an average of 13 ± 3 satellite AuNPs (13 nm) with part of the core surfaces left unoccupied. Strong surface plasmon coupling is observed from these nanoassemblies as a result of the close proximity between the core and the satellites, which appears significantly red-shifted from the surface plasmon resonance frequencies of the constituting nanoparticles. The dependence of the surface plasmon coupling on a gap distance of less than 3 nm is systematically investigated by varying the length of the alkanedithiol linkers. The asymmetric core-satellite nanoassemblies also serve as an excellent surface-enhanced Raman scattering substrate with an enhancement factor of ~10(6). Finally, we demonstrate that the presented assembly method is extendible to the preparation of compositionally heterogeneous core-satellite nanoassemblies.


Complete inclusion of adaptive rowing only 1000 m ahead.
Adaptive rowing (AR) at the Paralympic level is accessible for rowers with physical disability. AR was included for the first time in the Beijing 2008 Paralympic Games. Racing distance for all AR events is currently 1000 m, which impedes public recognition of this sport and leads to many organisational challenges during the inclusive World Rowing Championships. The aim of this report was to discuss the feasibility of increasing AR race distance to 2000 m from a sports injury and athletic health perspective. As limited data on injury and illness risks exist in AR, knowledge and experiences had to be taken from other Paralympic sports. The anticipated duration of 2000 m AR competitions is either comparable or considerably lower than that of the other Paralympic disciplines with similar characteristics. AR has inherent injury and health risks especially within thorax, shoulders and low back region, but they are not expected to be significantly modified by increased racing times. Specific considerations need to be taken into account for athletes with a spinal cord injury, like in other sport disciplines. There are no distinctive contra-indications for AR events of 2000 m based on the current literature review and a 10-year experience in this sport. Long-term follow-ups are needed to understand fully the injury and health risk associated with AR and to develop appropriate prevention strategies.


An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution.
Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.


International Evolution of TIGER Informatics Competencies.
The TIGER Initiative aims to explain how to equip practicing nurses with informatics competencies. This chapter describes a collaborative effort to identify global informatics requirements in relation to core competencies and to match them with national and regional needs. Recommendations from the TIGER Informatics Competency Synthesis Project, described here, have implications for an international framework of informatics competencies for all types of health care professionals including nurses.


Evolution of the Toroidal Flux of CME Flux Ropes during Eruption.
Coronal mass ejections (CMEs) are large-scale explosions of the coronal magnetic field. It is believed that magnetic reconnection significantly builds up the core structure of CMEs, a magnetic flux rope, during the eruption. However, the quantitative evolution of the flux rope, particularly its toroidal flux, is still unclear. In this paper, we study the evolution of the toroidal flux of the CME flux rope for four events. The toroidal flux is estimated as the magnetic flux in the footpoint region of the flux rope, which is identified by a method that simultaneously takes the coronal dimming and the hook of the flare ribbon into account. We find that the toroidal flux of the CME flux rope for all four events shows a two-phase evolution: a rapid increasing phase followed by a decreasing phase. We further compare the evolution of the toroidal flux with that of the Geostationary Operational Environmental Satellites soft X-ray flux and find that they are basically synchronous in time, except that the peak of the former is somewhat delayed. The results suggest that the toroidal flux of the CME flux rope may be first quickly built up by the reconnection mainly taking place in the sheared overlying field and then reduced by the reconnection among the twisted field lines within the flux rope, as enlightened by a recent 3D magnetohydrodynamic simulation of CMEs.


Nondepleting anti-CD4 monoclonal antibody enhances the ability of oral alloantigen delivery to induce indefinite survival of cardiac allografts: oral tolerance to alloantigen.
We examined whether oral administration of alloantigen could induce the prolonged survival of cardiac allografts. Hearts from CBK (H2k+Kb) transgenic or (C57BL/10xCBA)F1 (H2bxH2k) mice were transplanted into CBA (H2k) recipients pretreated orally with 1 x 10(7) donor splenocytes in the presence or absence of a nondepleting anti-CD4 (YTS 177, 200 microg/dose). Modest prolongation of CBK cardiac grafts was induced in CBA mice fed with multiple doses of CBK splenocytes (MST 42 days compared with controls fed with syngeneic CBA splenocytes, 12 days). When the CD4 monoclonal antibody, YTS177, was administered for 2 days before the first oral delivery of CBK splenocytes, all mice accepted their grafts indefinitely (MST > 100 days versus mice treated with anti-CD4 alone, 11.5 days). To determine if feeding multiple doses of alloantigen was essential, CBA mice were given CBK splenocytes orally on a single occasion in combination with the anti-CD4. The majority of the grafts survived indefinitely (MST >100 days). This oral treatment regimen also induced indefinite prolongation of (C57BL/10xCBA)F1 cardiac grafts. The induction of unresponsiveness by oral administration of alloantigen can be augmented by a nondepleting anti-CD4, YTS177, when given before the first oral delivery of allogeneic cells.


Sequence of the Saccharomyces GAL region and its transcription in vivo.
In Saccharomyces, the enzymes used to convert galactose to glucose are specified by three coordinately expressed, tightly linked genes, GAL7, GAL10, and GAL1. These genes are induced by galactose and are controlled by the positive regulator gene gal4 and the negative regulator gene gal80. GAL81 mutations, which are known to alter the gal4 protein, produce a constitutive phenotype. We have cloned fragments of Saccharomyces carlsbergensis DNA that span 26.3 kilobases surrounding the three clustered GAL genes. About 5 kilobases of the sequence was determined, which includes the entire GAL1 gene, the two intercistronic regions, and portions of the coding sequences of GAL10 and GAL7. Some amino acid homology between the GAL1 gene product, galactokinase, and the Escherichia coli galactokinase was detected. By using various Saccharomyces DNA fragments, the accumulation of GAL1 and GAL10 RNA in yeast cells after induction with galactose was studied. Our results, using wild-type, gal4-, gal80-, and GAL81-1- yeast cells, support the hypothesis that control is exerted at the transcriptional level.


Inhibition of RAGE signaling through the intracellular delivery of inhibitor peptides by PEI cationization.
The receptor for advanced glycation end products (RAGE) is a multi-ligand cell surface receptor and a member of the immunoglobulin superfamily. RAGE is involved in a wide range of inflammatory, degenerative and hyper-proliferative disorders which span over different organs by engaging diverse ligands, including advanced glycation end products, S100 family proteins, high-mobility group protein B1 (HMGB1) and amyloid β. We previously demonstrated that the cytoplasmic domain of RAGE is phosphorylated upon the binding of ligands, enabling the recruitment of two distinct pairs of adaptor proteins, Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) and myeloid differentiation protein 88 (MyD88). This engagement allows the activation of downstream effector molecules, and thereby mediates a wide variety of cellular processes, such as inflammatory responses, apoptotic cell death, migration and cell growth. Therefore, inhibition of the binding of TIRAP to RAGE may abrogate intracellular signaling from ligand-activated RAGE. In the present study, we developed inhibitor peptides for RAGE signaling (RAGE-I) by mimicking the phosphorylatable cytosolic domain of RAGE. RAGE-I was efficiently delivered into the cells by polyethylenimine (PEI) cationization. We demonstrated that RAGE-I specifically bound to TIRAP and abrogated the activation of Cdc42 induced by ligand-activated RAGE. Furthermore, we were able to reduce neuronal cell death induced by an excess amount of S100B and to inhibit the migration and invasion of glioma cells in vitro. Our results indicate that RAGE-I provides a powerful tool for therapeutics to block RAGE-mediated multiple signaling.


Radiofrequency ablation of hepatocellular carcinoma.
Radiofrequency ablation (RFA), usually performed under percutaneous ultrasound guidance, is considered the gold standard among minimally invasive therapies. On the strength of some recent randomized trials, its indications include operable patients with small hepatocellular carcinoma and inoperable patients with more advanced disease also in combination with other therapies. RFA has lower complication rates and costs less than surgery.


In vivo detection of PARACEST agents with relaxation correction.
Several pulse sequences have been used to detect paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents in animals to quantify the uptake over time following a bolus injection. The observed signal change is a combination of relaxation effects and PARACEST contrast. The purpose of the current study was to isolate the PARACEST effect from the changes in bulk water relaxation induced by the PARACEST agent in vivo for the fast low-angle shot pulse sequence. A fast low-angle shot-based pulse sequence was used to acquire continuous images on a 9.4-T MRI of phantoms and the kidneys of mice following PARACEST agent (Tm(3+)-DOTAM-Gly-Lys) injection. A WALTZ-16 pulse was applied before every second image to generate on-resonance paramagnetic chemical exchange effects. Signal intensity changes of up to 50% were observed in the mouse kidney in the control images (without a WALTZ-16 preparation pulse) due to altered bulk water relaxation induced by the PARACEST agent. Despite these changes, a clear on-resonance paramagnetic chemical exchange effect of 4-7% was also observed. A four-pool exchange model was used to describe image signal intensity. This study demonstrates that in vivo on-resonance paramagnetic chemical exchange effect contrast can be isolated from tissue relaxation time constant changes induced by a PARACEST agent that dominate the signal change.


B-type natriuretic peptide as a biomarker beyond heart failure: speculations and opportunities.
Cardiac secretion of B-type natriuretic peptide (BNP) Increases with the progression of heart failure (HF), and plasma measurement of BNP has emerged recently as a useful, cost-effective biomarker for the diagnosis and prognosis of HF. The diagnostic utility of BNP is complemented by its therapeutic use in decompensated HF. Although clinical use of BNP as a biomarker in HF is Increasing, the specificity of BNP for HF is not robust, suggesting that other mechanisms beyond simple ventricular stretch stimulate BNP release. Several studies have shown that BNP levels Increase in other cardiovascular disease states including ischemia, arrhythmias, fibrosis, cardiac hypertrophy, and coronary endothelial dysfunction. Furthermore, 2 important studies revealed recently that moderate elevations In BNP level, well below the HF range, have prognostic value for future cardiovascular events. Specifically, BNP levels greater than 20 pg/mL were associated with significantly Increased risk of HF and atrial fibrillation. These observations increase speculation that elevated BNP levels represent a final common pathway for many cardiovascular pathologic states and that BNP can be used as a biomarker for non-HF mechanisms, preclinical disease, and other pathologic states of myocardial disease.


Single Tablet Regimen Usage and Efficacy in the Treatment of HIV Infection in Australia.
Single tablet regimens (STRs) for HIV infection improve patient satisfaction, quality of life, medication adherence, and virological suppression compared to multitablet regimens (MTRs). This is the first study assessing STR uptake and durability in Australia. This retrospective audit of all patients receiving an STR (n = 299) at a large Sydney HIV clinic (January 2012-December 2013) assessed patient demographics, treatment prior to STR, HIV RNA load and CD4 during MTR and STR dosing, and reasons for STR switch. 206 patients switched from previous antiretroviral treatment to an STR, of which 88% switched from an MTR. Reasons for switching included desire to simplify treatment (57%), reduced side effects or toxicity (18%), and cost-saving for the patient. There was no switching for virological failure. Compared to when on an MTR, patients switching to an STR had significantly lower HIV RNA counts (p < 0.001) and significantly higher CD4 counts (p < 0.001). The discontinuation rate from STR was very low and all patients who switched to an STR maintained virological suppression throughout the study duration, although the study is limited by the absence of a control group.


Therapeutic applications of whey protein.
Whey, a protein complex derived from milk, is being touted as a functional food with a number of health benefits. The biological components of whey, including lactoferrin, beta-lactoglobulin, alpha-lactalbumin, glycomacropeptide, and immunoglobulins, demonstrate a range of immune-enhancing properties. In addition, whey has the ability to act as an antioxidant, antihypertensive, antitumor, hypolipidemic, antiviral, antibacterial, and chelating agent. The primary mechanism by which whey is thought to exert its effects is by intracellular conversion of the amino acid cysteine to glutathione, a potent intracellular antioxidant. A number of clinical trials have successfully been performed using whey in the treatment of cancer, HIV, hepatitis B, cardiovascular disease, osteoporosis, and as an antimicrobial agent. Whey protein has also exhibited benefit in the arena of exercise performance and enhancement.


Asymmetric hybridization between non-native winter moth, Operophtera brumata (Lepidoptera: Geometridae), and native Bruce spanworm, Operophtera bruceata, in the Northeastern United States, assessed with novel microsatellites and SNPs.
The European winter moth, Operophtera brumata, is a non-native pest in the Northeastern USA causing defoliation of forest trees and crops such as apples and blueberries. This species is known to hybridize with O. bruceata, the Bruce spanworm, a native species across North America, although it is not known if there are hybrid generations beyond F1. To study winter moth population genetics and hybridization with Bruce spanworm, we developed two sets of genetic markers, single nucleotide polymorphisms (SNPs) and microsatellites, using genomic approaches. Both types of markers were validated using samples from the two species and their hybrids. We identified 1216 SNPs and 24 variable microsatellite loci. From them we developed a subset of 95 species-diagnostic SNPs and ten microsatellite loci that could be used for hybrid identification. We further validated the ten microsatellite loci by screening field collected samples of both species and putative hybrids. In addition to confirming the presence of F1 hybrids reported in previous studies, we found evidence for multi-generation asymmetric hybridization, as suggested by the occurrence of hybrid backcrosses with the winter month, but not with the Bruce spanworm. Laboratory crosses between winter moth females and Bruce spanworm males resulted in a higher proportion of viable eggs than the reciprocal cross, supporting this pattern. We discuss the possible roles of population demographics, sex chromosome genetic incompatibility, and bacterial symbionts as causes of this asymmetrical hybridization and the utility of the developed markers for future studies.


gamma-diketone central neuropathy: quantitative morphometric analysis of axons in rat spinal cord white matter regions and nerve roots.
A quantitative analytical method was used to measure myelinated axon morphometric parameters (e.g., axon area, ratio of axon area/fiber area, and index of circularity) in rat nervous tissue during intoxication with 2,5-hexanedione (HD). Parameters were assessed in nerve roots (dorsal and ventral) and in ascending (gracile fasciculus and spinocerebellar tract) and descending (corticospinal and rubrospinal tracts) spinal cord white matter tracts (L4-L5) of rats intoxicated with HD at two different daily dose-rates (175 or 400 mg HD/kg/day, gavage). For each dose-rate, tissue was sampled at four neurological endpoints: unaffected, slight, moderate, and severe toxicity, as determined by gait analysis and measurements of grip strength. Results indicate that, regardless of the HD dose-rate, axon atrophy (reduced axon area) was a widespread, abundant effect that developed in concert with neurological deficits. The atrophy response occurred contemporaneously in both ascending and descending spinal tracts, which suggests that loss of caliber developed simultaneously along the proximodistal axon axis. In contrast, swollen axons were a numerically small component and were present in nerve roots and spinal tracts only during subchronic intoxication at the lower HD dose-rate (i.e., 175 mg/kg/day). Intoxication at the higher dose-rate (400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. These observations in conjunction with our previous studies of HD-induced peripheral neuropathy (Toxicol. Appl. Pharmacol. 135 (1995) 58; and Toxicol. Appl. Pharmacol. 165 (2000) 127) indicate that axon atrophy, and not axonal swelling, is a primary neuropathic phenomenon.


Machine Learning: Deepest Learning as Statistical Data Assimilation Problems.
We formulate an equivalence between machine learning and the formulation of statistical data assimilation as used widely in physical and biological sciences. The correspondence is that layer number in a feedforward artificial network setting is the analog of time in the data assimilation setting. This connection has been noted in the machine learning literature. We add a perspective that expands on how methods from statistical physics and aspects of Lagrangian and Hamiltonian dynamics play a role in how networks can be trained and designed. Within the discussion of this equivalence, we show that adding more layers (making the network deeper) is analogous to adding temporal resolution in a data assimilation framework. Extending this equivalence to recurrent networks is also discussed. We explore how one can find a candidate for the global minimum of the cost functions in the machine learning context using a method from data assimilation. Calculations on simple models from both sides of the equivalence are reported. Also discussed is a framework in which the time or layer label is taken to be continuous, providing a differential equation, the Euler-Lagrange equation and its boundary conditions, as a necessary condition for a minimum of the cost function. This shows that the problem being solved is a two-point boundary value problem familiar in the discussion of variational methods. The use of continuous layers is denoted "deepest learning." These problems respect a symplectic symmetry in continuous layer phase space. Both Lagrangian versions and Hamiltonian versions of these problems are presented. Their well-studied implementation in a discrete time/layer, while respecting the symplectic structure, is addressed. The Hamiltonian version provides a direct rationale for backpropagation as a solution method for a certain two-point boundary value problem.


The new reckoning: The Combat Casualty Care Research Program responds to real and present challenges in military operational projections.
This issue of the Journal of Trauma and Acute Care Surgery features topics from the 2017 Military Health System Research Symposium and starts a second decade of partnership between the Combat Casualty Care Research Program (CCCRP) and the journal. This publication comes at a time of significant change for the CCCRP, as it responds to military planning for the future multidomain battlefield (MDB). The projected MDB portends markedly different operational scenarios than those conducted over the past 17 years. Emerging threats around the globe have the Department of Defense preparing for more complex battlefields that are larger in size and scope and which pit the United States against better equipped and more sophisticated adversaries. As the CCCRP navigates this new reckoning associated with trauma care on the MDB, its research investments will need to be robust and enabled to plan, program, and budget for agile and closer-term solutions. To accomplish this, the program will need to expand on its strong foundation of lessons learned and assets developed over the past 20 years.


Transparency of informed consent in pilot and feasibility studies is inadequate: a single-center quality assurance study.
Pilot and feasibility studies (PAFS) often have complex objectives aimed at assessing feasibility of conducting a larger study. These may not be clear to participants in pilot studies. Here, we aimed to assess the transparency of informed consent in PAFS by investigating whether researchers communicate, through patient information leaflets and consent forms, key features of the studies. We collected this data from original versions of these documents submitted for ethics approval and the final approved documents for PAFS submitted to the Hamilton Integrated Research Ethics Board, Canada. One hundred eighty-four PAFS, submitted for ethics approval from 2004 to 2020, were included, and we found that of the approved consent documents which were provided to participants, 83.2% (153) stated the terms "pilot" or "feasibility" in their title, 12% (22) stated the definition of a pilot/feasibility study, 42.4% (78) of the studies stated their intent to assess feasibility, 19.6% (36) stated the specific feasibility objectives, 1.6% (3) stated the criteria for success of the pilot study, and 0.5% (1) stated all five of these criteria. After ethics review, a small increase in transparency occurred, ranging from 1.6 to 2.8% depending on the criteria. By extracting data from the protocols of the PAFS, we found that 73.9% (136) stated intent to assess feasibility, 71.2% (131) stated specific feasibility objectives, and 33.7% (62) stated criteria for success of the study to lead to a larger study. The transparency of informed consent in PAFS is inadequate and needs to be specifically addressed by research ethics guidelines. Research ethics boards and researchers ought to be made aware and mindful of best practices of informed consent in the context of PAFS.


Porphyrin Production and Regulation in Cutaneous Propionibacteria.
Porphyrins are intermediate metabolites in the biosynthesis of vital molecules, including heme, cobalamin, and chlorophyll. Bacterial porphyrins are known to be proinflammatory, with high levels linked to inflammatory skin diseases. Propionibacterium species are dominant skin commensals and play essential roles in defending against pathogens and in triggering an inflammatory response. To better understand how the inflammatory potential of the skin microbiome may vary depending on its propionibacterial composition, we compared the production levels of porphyrins among Propionibacterium acnes, Propionibacterium granulosum, Propionibacterium avidum, and Propionibacterium humerusii strains. We found that porphyrin production varied among these species, with P. acnes type I strains producing significantly larger amounts of porphyrins than P. acnes type II and III strains and other Propionibacterium species. P. acnes strains that are highly associated with the common skin condition acne vulgaris responded to vitamin B12 supplementation with significantly higher porphyrin production. In contrast, vitamin B12 supplementation had no effect on the porphyrin production of health-associated P. acnes strains and other propionibacteria. We observed low-level porphyrin production in most Propionibacterium strains harboring the deoR repressor gene, with the exception of P. acnes strains belonging to type I clades IB-3 and IC. Our findings shed light on the proinflammatory potential of distinct phylogenetic lineages of P. acnes as well as other resident skin propionibacteria. We demonstrate that the overall species and strain composition is important in determining the metabolic output of the skin microbiome in health and disease.IMPORTANCE Porphyrins are a group of metabolites essential to the biosynthesis of heme, cobalamin, and chlorophyll in living organisms. Bacterial porphyrins can be proinflammatory, with high levels linked to human inflammatory diseases, including the common skin condition acne vulgaris. Propionibacteria are among the most abundant skin bacteria. Variations in propionibacteria composition on the skin may lead to different porphyrin levels and inflammatory potentials. This study characterized porphyrin production in all lineages of Propionibacterium acnes, the most dominant skin Propionibacterium, and other resident skin propionibacteria, including P. granulosum, P. avidum, and P. humerusii We revealed that P. acnes type I strains produced significantly more porphyrins than did type II and III strains and other Propionibacterium species. The findings from this study shed light on the proinflammatory potential of the skin microbiome and can be used to guide the development of effective acne treatments by modulating the skin microbiome and its metabolic activities.


Liriodendron genome sheds light on angiosperm phylogeny and species-pair differentiation.
The genus Liriodendron belongs to the family Magnoliaceae, which resides within the magnoliids, an early diverging lineage of the Mesangiospermae. However, the phylogenetic relationship of magnoliids with eudicots and monocots has not been conclusively resolved and thus remains to be determined1-6. Liriodendron is a relict lineage from the Tertiary with two distinct species-one East Asian (L. chinense (Hemsley) Sargent) and one eastern North American (L. tulipifera Linn)-identified as a vicariad species pair. However, the genetic divergence and evolutionary trajectories of these species remain to be elucidated at the whole-genome level7. Here, we report the first de novo genome assembly of a plant in the Magnoliaceae, L. chinense. Phylogenetic analyses suggest that magnoliids are sister to the clade consisting of eudicots and monocots, with rapid diversification occurring in the common ancestor of these three lineages. Analyses of population genetic structure indicate that L. chinense has diverged into two lineages-the eastern and western groups-in China. While L. tulipifera in North America is genetically positioned between the two L. chinense groups, it is closer to the eastern group. This result is consistent with phenotypic observations that suggest that the eastern and western groups of China may have diverged long ago, possibly before the intercontinental differentiation between L. chinense and L. tulipifera. Genetic diversity analyses show that L. chinense has tenfold higher genetic diversity than L. tulipifera, suggesting that the complicated regions comprising east-west-orientated mountains and the Yangtze river basin (especially near 30° N latitude) in East Asia offered more successful refugia than the south-north-orientated mountain valleys in eastern North America during the Quaternary glacial period.


HIV/SIV infection primes monocytes and dendritic cells for apoptosis.
Subversion or exacerbation of antigen-presenting cells (APC) death modulates host/pathogen equilibrium. We demonstrated during in vitro differentiation of monocyte-derived macrophages and monocyte-derived dendritic cells (DCs) that HIV sensitizes the cells to undergo apoptosis in response to TRAIL and FasL, respectively. In addition, we found that HIV-1 increased the levels of pro-apoptotic Bax and Bak molecules and decreased the levels of anti-apoptotic Mcl-1 and FLIP proteins. To assess the relevance of these observations in the context of an experimental model of HIV infection, we investigated the death of APC during pathogenic SIV-infection in rhesus macaques (RMs). We demonstrated increased apoptosis, during the acute phase, of both peripheral blood DCs and monocytes (CD14(+)) from SIV(+)RMs, associated with a dysregulation in the balance of pro- and anti-apoptotic molecules. Caspase-inhibitor and death receptors antagonists prevented apoptosis of APCs from SIV(+)RMs. Furthermore, increased levels of FasL in the sera of pathogenic SIV(+)RMs were detected, compared to non-pathogenic SIV infection of African green monkey. We suggest that inappropriate apoptosis of antigen-presenting cells may contribute to dysregulation of cellular immunity early in the process of HIV/SIV infection.


Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase.
The metabolic regulator AMP-activated protein kinase (AMPK) maintains cellular homeostasis through regulation of proteins involved in energy-producing and -consuming pathways. Although AMPK phosphorylation targets include cytoplasmic and nuclear proteins, the precise mechanisms that regulate AMPK localization, and thus its access to these substrates, are unclear. We identify highly conserved carboxy-terminal hydrophobic amino acids that function as a leptomycin B-sensitive, CRM1-dependent nuclear export sequence (NES) in the AMPK catalytic subunit (AMPKα). When this sequence is modified AMPKα shows increased nuclear localization via a Ran-dependent import pathway. Cytoplasmic localization can be restored by substituting well-defined snurportin-1 or protein kinase A inhibitor (PKIA) CRM1-binding NESs into AMPKα. We demonstrate a functional requirement in vivo for the AMPKα carboxy-terminal NES, as transgenic Drosophila expressing AMPKα lacking this NES fail to rescue lethality of AMPKα null mutant flies and show decreased activation loop phosphorylation under heat-shock stress. Sequestered to the nucleus, this truncated protein shows highly reduced phosphorylation at the key Thr172 activation residue, suggesting that AMPK activation predominantly occurs in the cytoplasm under unstressed conditions. Thus, modulation of CRM1-mediated export of AMPKα via its C-terminal NES provides an additional mechanism for cells to use in the regulation of AMPK activity and localization.


8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging.
Age-associated changes in lung structure and function are some of the most important predictors of overall health, cognitive activities and longevity. Common to all aging cells is an increase in oxidatively modified DNA bases, primarily 8-oxo-7,8-dihydroguanine (8-oxoG). It is repaired via DNA base excision repair pathway driven by 8-oxoguanine DNA glycosylase-1 (OGG1-BER), whose role in aging has been the focus of many studies. This study hypothesizes that signaling and consequent gene expression during cellular response to OGG1-BER "wires" senescence/aging processes. To test OGG1-BER was mimicked by repeatedly exposing diploid lung fibroblasts cells and airways of mice to 8-oxoG base. Results showed that repeated exposures led to G1 cell cycle arrest and pre-matured senescence of cultured cells in which over 1000 genes were differentially expressed -86% of them been identical to those in naturally senesced cells. Gene ontology analysis of gene expression displayed biological processes driven by small GTPases, phosphoinositide 3-kinase and mitogen activated kinase cascades both in cultured cells and lungs. These results together, points to a new paradigm about the role of DNA damage and repair by OGG1 in aging and age-associated disease processes.


Headache and transient focal neurological symptoms during pregnancy, a prospective cohort.
The main purpose of the present prospective study was to evaluate the course of migraine and non-migrainous headache during pregnancy and to estimate the occurrence of self-reported transient focal neurological symptoms. In total 1631 (77%) pregnant women completed the study and were followed-up during pregnancy. The first questionnaire (Q1) was sent together with the appointment letter and delivered at the time of ultrasound screening. The second questionnaire (Q2), to be filled in during pregnancy, was delivered at the time of birth. Q1 and Q2 covered questions about headache, transient neurological symptoms, and other background and demographic data. Subjects reporting transient sensory, motor or visual disturbances were also interviewed by phone in order to achieve a more precise description of the symptoms. A total of 58% subjects with migraine reported not having migraine or no headache at all during pregnancy. Among individuals with non-migrainous headache 25% reported not having any headaches, while 1.9% of the subjects without headache experienced headache attacks during pregnancy that fulfilled the criteria for migraine. Individuals without headache or with non-migrainous headache reported significantly less sensory, motor and visual disturbances during pregnancy compared with migraine subjects. More than 60% of those with possible aura phenomenon were migraine patients, while symptoms of peripheral or non-neurological origin were more common among headache free or those with non-migrainous headache. Transient neurological symptoms were less common among individuals without or with non-migrainous headache compared with migraine. This may indicate that there is an increased susceptibility of unknown cause for these symptoms among migraine patients during pregnancy.


International fertility change: new data and insights from the developmental idealism framework.
Many scholars have offered structural and ideational explanations for the fertility changes occurring around the world. This paper focuses on the influence of developmental idealism-a schema or set of beliefs endorsing development, fertility change, and causal connections between development and fertility. Developmental idealism is argued to be an important force affecting both population policy and the fertility behavior of ordinary people. We present new survey data from ordinary people in six countries-Argentina, China, Egypt, Iran, Nepal, and the United States-about the extent to which developmental idealism is known and believed. We ask individuals if they believe that fertility and development are correlated, that development is a causal force in changing fertility levels, and that fertility declines enhance the standard of living and intergenerational relations. We also ask people about their expectations concerning future trends in fertility in their countries and whether they approve or disapprove of the trends they expect. The data show widespread linkage in the minds of ordinary people between fertility and development. Large fractions of people in these six settings believe that fertility and development are correlated, that development reduces fertility, and that declines in fertility foster development. Many also expect and endorse future declines in fertility.


Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan).
The literature has consistently reported no association between low to moderate alcohol consumption and pancreatic cancer; however, a few studies have shown that high levels of intake may increase risk. Most single studies have limited power to detect associations even in the highest alcohol intake categories or to examine associations by alcohol type. We analyzed these associations using 1,530 pancreatic cancer cases and 1,530 controls from the Pancreatic Cancer Cohort Consortium (PanScan) nested case-control study. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression, adjusting for potential confounders. We observed no significant overall association between total alcohol (ethanol) intake and pancreatic cancer risk (OR = 1.38, 95% CI = 0.86-2.23, for 60 or more g/day vs. >0 to <5 g/day). A statistically significant increase in risk was observed among men consuming 45 or more grams of alcohol from liquor per day (OR = 2.23, 95% CI = 1.02-4.87, compared to 0 g/day of alcohol from liquor, P-trend = 0.12), but not among women (OR = 1.35, 95% CI = 0.63-2.87, for 30 or more g/day of alcohol from liquor, compared to none). No associations were noted for wine or beer intake. Overall, no significant increase in risk was observed, but a small effect among heavy drinkers cannot be ruled out.


Reactivity of the mutagen 1,4-dinitro-2-methylpyrrole as an alkylating agent.
The formation of chemical species with DNA-damaging and mutagenic activity for bacterial test systems was detected in sorbic acid-nitrite mixtures. 1,4-Dinitro-2-methylpyrrole (NMP), one the main products resulting from the reaction between sorbic acid and nitrite, has mutagenic properties, and here its alkylating capacity was investigated. The conclusions drawn are as follows: (i) In aqueous medium, after the addition of a hydroxide ion and the subsequent loss of nitrite, NMP affords 5-methyl-3-nitro-1H-pyrrol-2-ol. This species is in equilibrium with 5-methyl-3-nitro-1H-pyrrol-2(5H)-one, the effective alkylating agent responsible for the genotoxic capacity of NMP; (ii) 5-methyl-3-nitro-1H-pyrrol-2(5H)-one alkylates 4-(p-nitrobenzyl)pyridine (NBP), a molecule with nucleophilic characteristics similar to those of DNA bases, forming an adduct (AD; epsilon = 1.14 x 10(4) M(-1) cm(-1)); (iii) The calculated energy barrier for the alkylation of NBP for NMP and the value of the fraction of alkylating agent forming the adduct are consistent with the observed mutagenicity of NMP; (iv) The reactivity of NMP can be explained in terms of the instability of the N-NO(2) bond as well as the effect of this group on aromaticity.


Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects.
One hundred consecutive patients aged up to 75 with newly diagnosed cancer of the prostate suitable for hormonal treatment were included in a controlled study of the cardiovascular effects of oestrogen versus orchidectomy. In all cases pre-existing cardiovascular morbidity was excluded. Of the 100 patients, 91 were strictly randomised to receive either oestrogen (n = 47) or orchidectomy (n = 44) and 9 (6 given oestrogen, 3 orchidectomy) either chose their own treatment (five cases) or had it selected for them by the urologist (four). Oestrogen was given in the lowest recommended dosage in Sweden--namely, as 160 mg polyestradiol phosphate intramuscularly every month for the first three months, then 80 mg monthly, plus ethinyloestradiol 1 mg by mouth daily for the first two weeks, then 150 micrograms daily. At entry to the study the two treatment groups showed no difference in demographic characteristics or conventional risk factors for cardiovascular disease. During the first year, however, 13 (25%) of the patients given oestrogen suffered major cardiovascular events as compared with none of the patients after orchidectomy. Patients in the oestrogen treatment group who did not have minor signs of atherosclerosis at entry to the study suffered a similar incidence of cardiovascular complications to those who did have these signs at entry. The substantially increased risk of cardiovascular complications in patients given oestrogen for prostatic cancer warrants careful consideration when choosing treatment for this disorder.


Differential use of autophagy by primary dendritic cells specialized in cross-presentation.
Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed "cross-presentation." The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.


Effects of Shear Stress Gradients on Ewing Sarcoma Cells Using 3D Printed Scaffolds and Flow Perfusion.
In this work, we combined three-dimensional (3D) scaffolds with flow perfusion bioreactors to evaluate the gradient effects of scaffold architecture and mechanical stimulation, respectively, on tumor cell phenotype. As cancer biologists elucidate the relevance of 3D in vitro tumor models within the drug discovery pipeline, it has become more compelling to model the tumor microenvironment and its impact on tumor cells. In particular, permeability gradients within solid tumors are inherently complex and difficult to accurately model in vitro. However, 3D printing can be used to design scaffolds with complex architecture, and flow perfusion can simulate mechanical stimulation within the tumor microenvironment. By modeling these gradients in vitro with 3D printed scaffolds and flow perfusion, we can identify potential diffusional limitations of drug delivery within a tumor. Ewing sarcoma (ES), a pediatric bone tumor, is a suitable candidate to study heterogeneous tumor response due to its demonstrated shear stress-dependent secretion of ligands important for ES tumor progression. We cultured ES cells under flow perfusion conditions on poly(propylene fumarate) scaffolds, which were fabricated with a distinct pore size gradient via extrusion-based 3D printing. Computational fluid modeling confirmed the presence of a shear stress gradient within the scaffolds and estimated the average shear stress that ES cells experience within each layer. Subsequently, we observed enhanced cell proliferation under flow perfusion within layers supporting lower permeability and increased surface area. Additionally, the effects of shear stress gradients on ES cell signaling transduction of the insulin-like growth factor-1 pathway elicited a response dependent upon the scaffold gradient orientation and the presence of flow-derived shear stress. Our results highlight how 3D printed scaffolds, in combination with flow perfusion in vitro, can effectively model aspects of solid tumor heterogeneity for future drug testing and customized patient therapies.


Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes.
Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline's psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents' self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen's d range 0.7 - 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.


Evidence of validity for the Japanese version of the foot and ankle ability measure.
The Foot and Ankle Ability Measure (FAAM) is a valid, reliable, and self-reported outcome instrument for the foot and ankle region. To provide evidence for translation, cross-cultural adaptation, validity, and reliability of the Japanese version of the FAAM (FAAM-J). Cross-sectional study. Collegiate athletic training/sports medicine clinical setting. Eighty-three collegiate athletes. All participants completed the Activities of Daily Living and Sports subscales of the FAAM-J and the Physical Functioning and Mental Health subscales of the Japanese version of the Short Form-36v2 (SF-36). Also, 19 participants (23%) whose conditions were expected to be stable completed another FAAM-J 2 to 6 days later for test-retest reliability. We analyzed the scores of those subscales for convergent and divergent validity, internal consistency, and test-retest reliability. The Activities of Daily Living and Sports subscales of the FAAM-J had correlation coefficients of 0.86 and 0.75, respectively, with the Physical Functioning section of the SF-36 for convergent validity. For divergent validity, the correlation coefficients with Mental Health of the SF-36 were 0.29 and 0.27 for each subscale, respectively. Cronbach α for internal consistency was 0.99 for the Activities of Daily Living and 0.98 for the Sports subscale. A 95% confidence interval with a single measure was ±8.1 and ±14.0 points for each subscale. The test-retest reliability measures revealed intraclass correlation coefficient values of 0.87 for the Activities of Daily Living and 0.91 for the Sports subscales with minimal detectable changes of ±6.8 and ±13.7 for the respective subscales. The FAAM was successfully translated for a Japanese version, and the FAAM-J was adapted cross-culturally. Thus, the FAAM-J can be used as a self-reported outcome measure for Japanese-speaking individuals; however, the scores must be interpreted with caution, especially when applied to different populations and other types of injury than those included in this study.


[Research on social support in health: current status and new challenges].
On the borderline between sociology and psychology, the concept of social support has made it possible to develop a whole research tradition aimed at explaining some of the differences existing in the distribution of mental and physical disease. The concept of social support itself, however, still presents some ambiguities which must be clarified. These problems are discussed and it is showed and shows that the topic can be enriched with the contribution of the social sciences. Different definitions of the concept itself, are briefly analysed and the complexity and multidimensional character of social support are highlighted. The association between social support and health is discussed. The differences and implications of the direct effect model and the buffering effect model are addressed, and the relevance of the construct of social support is enhanced. The need to study social support not only as a likely determinant of some forms of disease, but also as a dependent variable, is brought out. Some recent developments in the study of factors associated with the availability of social support are discussed. It is shown that social support is a product of certain social factors which can be clearly identified by sociological analysis. In order to illustrate this point, the structural determinants of a specific dimension of social support-attention-are discussed. The importance of structural variables like social class and gender in attempting to explain the differential distribution of certain forms of social support is emphasized. It is proposed, on the theoretical level, that the intersection between two related autonomous constructs-social class and social support-may better explain those aspects of these concepts that are of importance to observed heterogeneity in the distribution of mental and physical health. Different theoretical and methodological approaches to the understanding of the determinants of social support and its effect on health are suggested.


Yule-Nielsen based recto-verso color halftone transmittance prediction model.
The transmittance spectrum of halftone prints on paper is predicted thanks to a model inspired by the Yule-Nielsen modified spectral Neugebauer model used for reflectance predictions. This model is well adapted for strongly scattering printing supports and applicable to recto-verso prints. Model parameters are obtained by a few transmittance measurements of calibration patches printed on one side of the paper. The model was verified with recto-verso specimens printed by inkjet with classical and custom inks, at different halftone frequencies and on various types of paper. Predictions are as accurate as those obtained with a previously developed reflectance and transmittance prediction model relying on the multiple reflections of light between the paper and the print-air interfaces. Optimal n values are smaller in transmission mode compared with the reflection model. This indicates a smaller amount of lateral light propagation in the transmission mode.


[Violence, ethnic groups and skin color: a study on differences in the metropolitan region of Salvador, Bahia, Brazil].
The objective of this study was to analyze the distribution of various forms of violence--structural, institutional, interpersonal, and crime-related--in the three most common color groups of Bahian society: mulattos, whites, and blacks. The study compared the levels of victimization of mulatto, white, and black individuals with their assessments of the efficiency of crime-control institutions, in order to ascertain how that relates to those same citizens' acceptance of authoritarian attitudes and norms. The data analyzed came from the multicenter project on Attitudes and Cultural Standards about Violence (ACTIVA) project, from a sample of 1,384 residents of the Salvador metropolitan region. The study was designed as a cross-sectional survey, with interviews done in the people's homes between September and December of 1996. The sample selection was done in three stages: first, residential areas were chosen at random; then, a systematic selection was made from the homes in each of the selected areas; finally, the persons to be interviewed were chosen at random. To collect the data the researchers used a pretested questionnaire that had been designed for the ACTIVA study. The results showed an unequal distribution of structural violence that mainly affected blacks. There were no differences by color group for interpersonal and institutional violence. Criminal violence impacted whites and blacks to the same degree. Distrust in the efficiency of the civil and military police and in the justice and penal systems was very high among all three color groups. Moreover, few differences were found among the groups with regard to authoritarian attitudes and norms. Based on the results, it is possible to conclude that public order is threatened if the dissatisfaction with institutions for crime prevention and reduction continues at a high level at the same time that individuals tend to support violence to resolve conflicts.


Ligand recognition by alpha beta T cell receptors.
While still incomplete, the first data concerning the biochemistry of T cell receptor-ligand interactions in cell-free systems seem to have considerable predictive value regarding whether a T cell response is strong or weak or suppressive. This data will help considerably in elucidating the mechanisms behind T cell responsiveness. Also of great interest are the first structures of T cell receptor molecules and, particularly, TCR-ligand complexes. These appear to confirm earlier suggestions of a fixed orientation for TCR engagement with peptide/MHC and should form the basis for understanding higher oligomers, evidence for which has also just emerged. We conclude with an analysis of the highly diverse CDR3 loops found in all antigen receptor molecules and suggest that such regions form the core of both TCR and antibody specificity.


Mode field patterns and preferential mode coupling in planar waveguide-coupled square microcavities.
We report a numerical and analytical study of mode field patterns and mode coupling in planar waveguide-coupled square microcavities, using two-dimensional (2-D) finite-difference time-domain (FDTD) method and k-space representation. Simulated mode field patterns can be identified by k-space modes. We observe that different mode number parities permit distinctly different mode field patterns and spectral characteristics. Simulation results suggest that k-space modes that nearly match the waveguide propagation mode have a relatively high coupling efficiency. Such preferential mode coupling can be modified by the mode number parity.


Cell cycle dependence of retroviral transduction: An issue of overlapping time scales.
Recombinant retroviruses are currently used as gene delivery vehicles for the purpose of gene therapy. It is generally believed that the efficiency of retroviral transduction depends on the cell cycle status of the target cells. However, it has been reported that this is not the case for the transduction of human and murine fibroblasts, in contrast to other cell types such as lymphocytes. The predictions of a mathematical model that we constructed, offer an explanation of this contradiction, based on the dynamics of the underlying processes of target cell growth and the intracellular decay of retroviral vectors. The model suggests that the utility of synchronization experiments, that are usually employed to study cell cycle specificity, is severely limited when the time scales of the above kinetic events are comparable to each other. The predictions of the model also suggest the use of retroviral vectors as cell cycle markers, as an alternative way to detect cell cycle dependence of retroviral transduction. This method obviates the need for cell synchronization and therefore, it does not perturb the cell cycle or interfere with the life cycle of retroviral vectors. Moreover, it does not depend on the intracellular stability of retroviral vectors. Our results show that in contrast to previously reported results, transduction of murine fibroblasts is cell cycle dependent, and they are consistent with the current notion that mitosis is the phase that confers transduction susceptibility.


Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa.
To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.


Association between Egg Consumption and Cholesterol Concentration: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
The association of egg consumption and serum cholesterol concentrations in healthy people has been discussed for a long time. In this study, we aimed to explore association of egg consumption with on low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) concentrations and the LDL-c/HDL-c ratio through meta-analysis. This systematic review only included randomized controlled trials (RCTs) investigating egg consumption in healthy populations without combination therapy. We extracted mean and standard deviation for LDL-c/HDL-c ratio, LDL-c/HDL-c. The extracted data were pooled in a random-effects model and were presented as mean difference (MD) with 95% confidence interval (CI). Moreover, subgroup analyses were conducted for understanding effects of more egg consumption (MEC) on different intervention periods, egg-consumption levels, classification of responders. Overall, 17 RCTs met the eligibility criteria and pooled results showed MEC group had a higher LDL-c/HDL-c ratio than the control group (MD = 0.14, p = 0.001, I2 = 25%). The MEC group also had higher LDL-c than the control group (MD = 8.14, p < 0.0001, I2 = 18%). Moreover, for the subset of intervention over two months, the MEC group seemed to have a larger effect size than the subset of intervention within two months. This synthesis, the largest meta-analysis on this topic, shows the impact of egg consumption on lipid profiles among healthy subjects. Notably, longer time with MEC may lead to higher LDL-c/HDL-c ratio and LDL-c. However, RCTs with long tern follow-up are needed to guarantee the association between egg consumption and human health.


Early morphogenesis of the Caenorhabditis elegans pharynx.
We investigated the cellular behaviors that accompany the early stages of pharyngeal morphogenesis in Caenorhabditis elegans. The embryonic pharynx develops from a ball of cells into a linear tube connected anteriorly to the buccal cavity and posteriorly to the midgut. By using GFP reporters localized to discrete subcellular regions, we show that pharyngeal morphogenesis can be divided into three stages: (1) lengthening of the nascent pharyngeal lumen by reorientation of apicobasal polarity of anterior pharyngeal cells ("Reorientation"), (2) formation of an epithelium by the buccal cavity cells, which mechanically couples the buccal cavity to the pharynx and anterior epidermis ("Epithelialization"), and (3) a concomitant movement of the pharynx anteriorly and the epidermis of the mouth posteriorly to bring the pharynx, buccal cavity, and mouth into close apposition ("Contraction"). Several models can account for these cellular behaviors, and we distinguish between them by physically or genetically ablating cells within the digestive tract. These studies provide the first description of how the pharynx primordium develops into an epithelial tube, and reveal that pharyngeal morphogenesis resembles aspects of mammalian kidney tubulogenesis.


Timing of GP end-of-life recognition in people aged ≥75 years: retrospective cohort study using data from primary healthcare records in England.
High-quality, personalised palliative care should be available to all, but timely recognition of end of life may be a barrier to end-of-life care for older people. To investigate the timing of end-of-life recognition, palliative registration, and the recording of end-of-life preferences in primary care for people aged ≥75 years. Retrospective cohort study using national primary care record data, covering 34% of GP practices in England. ResearchOne data from electronic healthcare records (EHRs) of people aged ≥75 years who died in England between 1 January 2015 and 1 January 2016 were examined. Clinical codes relating to end-of-life recognition, palliative registration, and end-of-life preferences were extracted, and the number of months that elapsed between the code being entered and death taking place were calculated. The timing for each outcome and proportion of relevant EHRs were reported. Death was recorded for a total of 13 149 people in ResearchOne data during the 1-year study window. Of those, 6303 (47.9%) records contained codes suggesting end of life had been recognised at a point in time prior to the month of death. Recognition occurred ≥12 months before death in 2248 (17.1%) records. In total, 1659 (12.6%) people were on the palliative care register and 457 (3.5%) were on the register for ≥12 months before death; 2987 (22.7%) records had a code for the patient's preferred place of care, and 1713 (13.0%) had a code for the preferred place of death. Where preferences for place of death were recorded, a care, nursing, or residential home (n = 813, 47.5%) and the individual's home (n = 752, 43.9%) were the most common. End-of-life recognition in primary care appears to occur near to death and for only a minority of people aged ≥75 years. The findings suggest that older people's deaths may not be anticipated by health professionals, compromising equitable access to palliative care.


Sample-based surface coloring.
In this paper, we present a sample-based approach for surface coloring, which is independent of the original surface resolution and representation. To achieve this, we introduce the Orthogonal Fragment Buffer (OFB)-an extension of the Layered Depth Cube-as a high-resolution view-independent surface representation. The OFB is a data structure that stores surface samples at a nearly uniform distribution over the surface, and it is specifically designed to support efficient random read/write access to these samples. The data access operations have a complexity that is logarithmic in the depth complexity of the surface. Thus, compared to data access operations in tree data structures like octrees, data-dependent memory access patterns are greatly reduced. Due to the particular sampling strategy that is employed to generate an OFB, it also maintains sample coherence, and thus, exhibits very good spatial access locality. Therefore, OFB-based surface coloring performs significantly faster than sample-based approaches using tree structures. In addition, since in an OFB, the surface samples are internally stored in uniform 2D grids, OFB-based surface coloring can efficiently be realized on the GPU to enable interactive coloring of high-resolution surfaces. On the OFB, we introduce novel algorithms for color painting using volumetric and surface-aligned brushes, and we present new approaches for particle-based color advection along surfaces in real time. Due to the intermediate surface representation we choose, our method can be used to color polygonal surfaces as well as any other type of surface that can be sampled.


Reducing late maternal death due to cardiovascular disease - A pragmatic pilot study.
Late maternal mortality (up-to 1-year postpartum) is poorly reported globally and is commonly due to cardiovascular disease (CVD). We investigated targeted interventions aiming at reducing peripartum heart failure admission and late maternal death. Prospective single-centre study of 269 peripartum women presenting with CVD in pregnancy, or within 6-months postpartum. Both cardiac disease maternity (CDM) Group-I and Group-II were treated by a dedicated cardiac-obstetric team. CDM Group-II received additional interventions: 1. Early (2-6 weeks) postpartum follow-up at the CDM clinic and immediate referral to dedicated CVD specialist clinics. 2. Beta-blocker therapy was continued in women with LVEF<45% while pregnant, or immediately started postpartum. Of 269 consecutive women (mean age 28.6 ± 5.9), 213 presented prepartum, 22% in NYHA groups III-IV and 79% in modified WHO groups III-IV. Patients were diagnosed with congenital heart disease (30%), valvular heart disease (25%) and cardiomyopathy (31%). The groups were similar in age, diagnosis, NYHA, modified WHO, BP and HIV, but Group-II had a higher rate of previously known CVD (p < 0.001) and a lower rate of being nulliparous (p < 0.0005). Of Group-I patients 9 died within the 12-month follow-up period versus one death in Group-II (p = 0.047). Heart failure leading to admission was 32% in Group-I versus 14% in Group-II (p = 0.0008), with Group-II having a higher beta-blocker use peripartum (p = 0.009). Perinatal mortality rate was 22/1000 live births with no differences between groups. Early follow-up in a dedicated CDM clinic with targeted pharmacological interventions led to a significant reduction in peripartum heart failure admission and mortality.


Genomic differentiation tracks earth-historic isolation in an Indo-Australasian archipelagic pitta (Pittidae; Aves) complex.
Allopatric speciation has played a particularly important role in archipelagic settings where populations evolve in isolation after colonizing different islands. The Indo-Australasian island realm is an unparalleled natural laboratory of biotic diversification. Here we explore how the level of earth-historic isolation has influenced genetic differentiation across the region by investigating phylogeographic patterns in the Pitta sordida species complex. We generated a de novo genome and compared population genomics of 29 individuals of Pitta sordida from the entire distributional range and we reconstructed phylogenetic relationship using mitogenomes, a multi-nuclear gene dataset and single nucleotide polymorphisms (SNPs). We found deep divergence between an eastern and a western group of taxa across Indo-Australasia. Within both groups we have identified major lineages that are geographically separated into Philippines, Borneo, western Sundaland, and New Guinea, respectively. Although these lineages are genetically well-differentiated, suggesting a long-term isolation, there are signatures of extensive gene flow within each lineage throughout the Pleistocene, despite the wide geographic range occupied by some of them. We found little evidence of hybridization or introgression among the studied taxa, but forsteni from Sulawesi makes an exception. This individual, belonging to the eastern clade, is genetically admixed between the western and eastern clades. Geographically this makes sense as Sulawesi is not far from Borneo that houses a population of hooded pittas that belongs to the western clade. We found that geological vicariance events cannot explain the current genetic differentiation in the Pitta sordida species complex. Instead, the glacial-interglacial cycles may have played a major role therein. During glacials the sea level could be up to 120 m lower than today and land bridges formed within both the Sunda Shelf and the Sahul Shelf permitting dispersal of floral and faunal elements. The geographic distribution of hooded pittas shows the importance of overwater, "stepping-stone" dispersals not only to deep-sea islands, but also from one shelf to the other. The most parsimonious hypothesis is an Asian ancestral home of the Pitta sordida species complex and a colonization from west to east, probably via Wallacea.


The Podmore case.
On January 10, 1929, in Southampton, England, two men examining the interior of a long-padlocked garage that had been previously used as a storeroom by a local agent of the Wolf's Head Oil Company found the decomposing body of its missing agent, Vivian Messiter. The assistance of Scotland Yard was obtained. Sir Bernard Spilsbury's autopsy revealed that Messiter had died from several severe blunt force craniocerebral injuries, the murder weapon apparently being a blood-encrusted hammer found nearby. Suspicion immediately centered on William Podmore, alias William Thomas, who had been employed by Messiter for 3 days in late October 1928, immediately prior to Messiter's being declared missing. Podmore, who was wanted for fraud and robbery elsewhere in England, was questioned and told a self-serving story. Meanwhile, it had been suspected that he had reported to Messiter sales of oil to fictitious customers, collecting commissions on same, and this was eventually reinforced by the finding of traces of writing in a receipt book. Two fellow prisoners of Podmore stated that he had confessed in their presence. Almost 14 months after the murder, Podmore was charged with it. He was later convicted, and was hanged after some public outcry against the verdict.


Circulating ceramide ratios and risk of vascular brain aging and dementia.
We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample. We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.


Economic Evaluation in Global Perspective: A Bibliometric Analysis of the Recent Literature.
We present a bibliometric analysis of recently published full economic evaluations of health interventions and reflect critically on the implications of our findings for this growing field. We created a database drawing on 14 health, economic, and/or general literature databases for articles published between 1 January 2012 and 3 May 2014 and identified 2844 economic evaluations meeting our criteria. We present findings regarding the sensitivity, specificity, and added value of searches in the different databases. We examine the distribution of publications between countries, regions, and health areas studied and compare the relative volume of research with disease burden. We analyse authors' country and institutional affiliations, journals and journal type, language, and type of economic evaluation conducted. More than 1200 economic evaluations were published annually, of which 4% addressed low-income countries, 4% lower-middle-income countries, 14% upper-middle-income countries, and 83% high-income countries. Across country income levels, 53, 54, 86, and 100% of articles, respectively, included an author based in a country within the income level studied. Biomedical journals published 74% of economic evaluations. The volume of research across health areas correlates more closely with disease burden in high-income than in low-income and middle-income countries. Our findings provide an empirical basis for further study on methods, research prioritization, and capacity development in health economic evaluation.


State- and bond-selected unimolecular reactions.
Unimolecular reactions are crucial chemical events that have been the focus of increasingly sophisticated investigation in the past decade. Unraveling their details is one fundamental goal of experimental and theoretical studies of chemical dynamics. New techniques are revealing the possibilities, and challenges, of eigenstate- and bondspecific unimolecular reactions. These experiments clearly demonstrate the intimate connection between intramolecular processes and unimolecular reaction dynamics and suggest means of exploiting molecular properties to study and control reactions at the level of individual quantum states.


Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide.
Activation of interleukin-1 (IL-1) receptor (IL-1R), Toll-like receptor 2 (TLR2), and TLR4 triggers NF-kappaB and mitogen-activated protein kinase (MAPK)-dependent signaling, thereby initiating immune responses. Tollip has been implicated as a negative regulator of NF-kappaB signaling triggered by these receptors in in vitro studies. Here, deficient mice were used to determine the physiological contribution of Tollip to immunity. NF-kappaB, as well as MAPK, signaling appeared normal in Tollip-deficient cells stimulated with IL-1beta or the TLR4 ligand lipopolysaccharide (LPS). Similarly, IL-1beta- and TLR-driven activation of dendritic cells and lymphocytes was indistinguishable from wild-type cells. In contrast, the production of the proinflammatory cytokines, IL-6 and tumor necrosis factor alpha was significantly reduced after IL-1beta and LPS treatment at low doses but not at lethal doses of LPS. Tollip therefore controls the magnitude of inflammatory cytokine production in response to IL-1beta and LPS.


In-chern-hau-tang and genipin reduces acute urinary bladder distension evoked sympathetic activation-induced hepatic dysfunction in rats.
Increased norepinephrine production by acute urine retention (AUR) induced sympathetic activation may contribute to acute liver injury (ALI) via the action of hepatic vasoconstriction and increased reactive oxygen species (ROS) production. We evaluated whether In-Chern-Hau-Tang, a hepatoprotective herb medicine, and its major ingredient genipin, may ameliorate norepinephrine-induced liver injury in the rat. We determined the effects of In-Chern-Hau-Tang and genipin on norepinephrine-induced oxidative stress in the Kupffer and endothelial cells and AUR-induced ALI in the rat via a chemiluminescence analyzer, physiologic and biochemical determination and western blot. The results of in vitro study showed that genipin with efficient H(2)O(2) and HOCl scavenging activities decreased norepinephrine-enhanced ROS production in the Kupffer cell and endothelial cell cultures. AUR activated hepatic sympathetic nervous activity lead to a hepatic hypoxia/hypoperfusion, and a reduction in bile flow. AUR increased intercellular adhesion molecular 1 (ICAM-1) protein expression, and hepatic ROS production from the activated leukocyte NADPH oxidase activity subsequently leading to plasma aspartate aminotransferase (AST) elevation. Hepatic sympathetic denervation, or oral pretreatment of In-Chern-Hau-Tang or genipin for 1 week ameliorated the level in AUR-induced hepatic hypoxia/hypoperfusion, and bile stasis. Hepatic denervation, In-Chern-Hau-Yang and genipin inhibited AUR-enhanced hepatic ICAM-1 expression, hepatic ROS production, leukocyte NADPH oxidase activity and plasma AST activity. In conclusion, In-Chern-Hau-Tang along with its active component, genipin, can ameliorate AUR-induced ALI via the alleviation of oxidative stress possibly by the inhibition of sympathetic induced hypoxia/hypoperfusion and leukocyte NADPH oxidase activity.


Human and entomological surveillance of Toscana virus in the Emilia-Romagna region, Italy, 2010 to 2012.
Toscana virus (TOSV), transmitted by phlebotomine sandflies, is recognised as one of the most important causes of viral meningitis in summer in Mediterranean countries. A surveillance plan based on both human and entomological surveys was started in 2010 in the Emilia-Romagna region, Italy. Clinical samples from patients with neurological manifestations were collected during 2010 to 2012. The surveillance protocol was improved during these years, allowing the detection of 65 human infections. Most of these infections were recorded in hilly areas, where sandflies reach the highest density. Entomological sampling around the homes of the patients resulted in a low number of captured sandflies, while later sampling in a hilly area with high number of human cases (n=21) resulted in a larger number of captured sandflies. Using this approach, 25,653 sandflies were sampled, of which there were 21,157 females, which were sorted into 287 pools. TOSV RNA was detected by real-time PCR in 33 of the pools. The results highlighted the role of Phlebotomus perfiliewi as the main vector of TOSV and a potential link between vector density and virus circulation. This integrated system shows that an interdisciplinary approach improves the sensitiveness and effectiveness of health surveillance.


Monoclonal antibodies directed against human FcRn and their applications.
The MHC class I-like Fc receptor (FcRn) is an intracellular trafficking Fc receptor that is uniquely responsible for the extended serum half-life of antibodies of the IgG subclass and their ability to transport across cellular barriers. By performing these functions, FcRn affects numerous facets of antibody biology and pathobiology. Its critical role in controlling IgG pharmacokinetics has been leveraged for the design of therapeutic antibodies and related biologics. FcRn also traffics serum albumin and is responsible for the enhanced pharmacokinetic properties of albumin-conjugated therapeutics. The understanding of FcRn and its therapeutic applications has been limited by a paucity of reliable serological reagents against human FcRn. Here, we describe the properties of a new panel of highly specific monoclonal antibodies (mAbs) directed against human FcRn with diverse epitope specificities. We show that this antibody panel can be used to study the tissue expression pattern of human FcRn, to selectively block IgG and serum albumin binding to human FcRn in vitro and to inhibit FcRn function in vivo. This mAb panel provides a powerful resource for probing the biology of human FcRn and for the evaluation of therapeutic FcRn blockade strategies.


Hormonal therapy and risk of breast cancer in mexican women.
The use of hormonal therapies, including hormonal contraceptives (HC) and postmenopausal hormone replacement therapy (HRT) have been shown to influence breast cancer (BC) risk. However, the variations of these effects among populations and ethnic groups are not completely documented, especially among Hispanic women. We evaluated the association between HC and premenopausal BC risk, and between HRT and postmenopausal BC risk in Mexican women. Data from a Mexican multi-center population-based case-control study ofwomen aged 35 to 69 years were analysed. A total of 1000 cases and 1074 matched controls were recruited between 2004 and 2007. Information on hormonal therapy was collected through a structured questionnaire. Results were analysed using conditional logistic regression models. Overall, HC were used by 422/891 (47.3%) premenopausal women and HRT was used by 220/1117 (19.7%) postmenopausal women. For HC, odds ratios (ORs) for BC were 1.11 (95% confidence interval (CI): 0.82, 1.49) for current users and 1.68 (95% CI: 0.67, 4.21) for ever-users. No clear effect of duration of use was observed. For HRT, the OR for BC was significantly increased in ever users (OR: 1.45; 95% CI: 1.01, 2.08). A non-significant increased risk was observed for combined estrogen/progestin, (OR = 1.85; 95% CI: 0.84, 4.07) whereas no effect was observed for the use of estrogen alone (OR = 1.14; 95% CI: 0.68, 1.91). Our results indicate that, HC had a non-significant effect on the risk of pre-menopausal BC, but suggested that injected contraceptives may slightly increase the risk, whereas HRT had a significant effect on post-menopausal BC in this population. This study provides new information about the effects of HC and HRT on BC risk in a Mexican population, which may be of relevance for the population of Latin America as a whole.


Microassay for nuclear binding of steroid receptors with use of intact cells from small samples of avian and human tissue.
A micro version of a nuclear binding assay to assess the biological activity of receptors for steroid hormones was developed for application to small (needle) biopsies of human tumors for the purpose of predicting responses to steroid therapy. This easier assay requires 10-fold less tissue than the original nuclear binding assay described for progesterone receptors in the avian oviduct, endometrium, and endometrial carcinomas (Spelsberg TC, et al., Endocrinology 1987;121:631). We describe the application of this micro assay to normal avian oviduct and cancers of the human breast, and we demonstrate a tissue specificity and saturation of nuclear binding. The micro assay reliably measured as little as 0.5 mg equivalents of tissue per assay tube. Results for breast tumors determined to be estrogen-receptor-positive by the standard dextran-coated charcoal method were also determined with this nuclear binding assay. As described previously for progesterone receptors in endometrial carcinomas, some receptor-positive breast biopsies displayed negligible capacity for nuclear binding. Therefore, with the present assay we have identified nonfunctional receptors in these biopsies, which may be useful for accurate prediction of patients' responses to therapy with hormones.


Evaluation of In Silico Multifeature Libraries for Providing Evidence for the Presence of Small Molecules in Synthetic Blinded Samples.
The current gold standard for unambiguous molecular identification in metabolomics analysis is comparing two or more orthogonal properties from the analysis of authentic reference materials (standards) to experimental data acquired in the same laboratory with the same analytical methods. This represents a significant limitation for comprehensive chemical identification of small molecules in complex samples. The process is time consuming and costly, and the majority of molecules are not yet represented by standards. Thus, there is a need to assemble evidence for the presence of small molecules in complex samples through the use of libraries containing calculated chemical properties. To address this need, we developed a Multi-Attribute Matching Engine (MAME) and a library derived in part from our in silico chemical library engine (ISiCLE). Here, we describe an initial evaluation of these methods in a blinded analysis of synthetic chemical mixtures as part of the U.S. Environmental Protection Agency's (EPA) Non-Targeted Analysis Collaborative Trial (ENTACT, Phase 1). For molecules in all mixtures, the initial blinded false negative rate (FNR), false discovery rate (FDR), and accuracy were 57%, 77%, and 91%, respectively. For high evidence scores, the FDR was 35%. After unblinding of the sample compositions, we optimized the scoring parameters to better exploit the available evidence and increased the accuracy for molecules suspected as present. The final FNR, FDR, and accuracy were 67%, 53%, and 96%, respectively. For high evidence scores, the FDR was 10%. This study demonstrates that multiattribute matching methods in conjunction with in silico libraries may one day enable reduced reliance on experimentally derived libraries for building evidence for the presence of molecules in complex samples.


[Reliability and validity of a self-administered questionnaire of patient health care behavior and satisfaction].
The reliability of a self-administered questionnaire of health care behavior and patient satisfaction, and also the validity of measuring patient satisfaction by a single question, were investigated on 754 outpatients and 204 inpatients. In order to assess the reliability and the validity, the questionnaire was administrated twice. Subjects for reliability tests were 194 outpatients and 91 inpatients and validity tests were performed with 280 outpatients and 84 inpatients. To assess the validity of patient satisfaction, supplementary questions about satisfaction (outpatients 22 items, inpatients 14 items) were included in the questionnaire. Reliability was assessed using kappa coefficient and proportion of agreement. To assess validity, principal component analysis was performed, and the correlation between principal-components and the score of patient satisfaction was analyzed. With the exception of patient understanding of the doctor's explanation and patient satisfaction, kappa coefficient and proportion of agreement were high (kappa: 0.4 approximately 0.82), indicating that question contents were objective and easily understood. By making the question categories simple, a higher kappa coefficient and proportion of agreement in patient understanding about doctor's explanation and patient satisfaction were achieved. This suggests that in questionnaire, similar question category must be made simple or similar categories should be put together in analysis. Spearman's correlation coefficient between the question about patient satisfaction and the first principal component (which summarizes all of the questions about patient satisfaction) was high (outpatients: 0.63, inpatients: 0.67). Therefore the validity of measuring general information about patient satisfaction by using a single question is suggested.