Radial forces within muscle fibers in rigor.
Considering the widely accepted cross-bridge model of muscle contraction (Huxley. 1969. Science [Wash. D. C.]. 164:1356-1366), one would expect that attachment of angled cross-bridges would give rise to radial as well as longitudinal forces in the muscle fiber. These forces would tend, in most instances, to draw the myofilaments together and to cause the fiber to decrease in width. Using optical techniques, we have observed significant changes in the width of mechanically skinned frog muscle fibers when the fibers are put into rigor by deleting ATP from the bathing medium. Using a high molecular weight polymer polyvinylpyrrolidone (PVP-40; number average mol. wt. (Mn) = 40,000) in the bathing solution, we were able to estimate the magnitude of the radial forces by shrinking the relaxed fiber to the width observed with rigor induction. With rigor, fiber widths decreased up to approximately 10%, with shrinking being greater at shorter sarcomere spacing and at lower PVP concentrations. At higher PVP concentrations, some fibers actually swelled slightly. Radial pressures seen with rigor in 2 and 4% PVP ranged up to 8.9 x 10(3) N/m2. Upon rigor induction, fibers exerted a longitudinal force of approximately 1 x 10(5) N/m2 that was inhibited by high PVP concentrations (greater than or equal to 13%). In very high PVP concentrations (greater than or equal to 20%), fibers exerted an anomalous force, independent of ATP, which ranged up to 6 x 10(4) N/m2 at 60% PVP. Assuming that all the radial force is the result of cross-bridge attachment, we calculated that rigor cross-bridges exert a radial force of 0.2 x 1.2 x 10(-9) N per thick filament in sarcomeres near rest length. This force is of roughly the same order of magnitude as the longitudinal force per thick filament in rigor contraction or in maximal (calcium-activated) contraction of skinned fibers in ATP-containing solutions. Inasmuch as widths of fibers stretched well beyond overlap of thick and thin filaments decreased with rigor, other radially directed forces may be operating in parallel with cross-bridge forces.


Effects of the Level and Duration of Mobilization Therapy in the Surgical ICU on the Loss of the Ability to Live Independently: An International Prospective Cohort Study.
It is unclear whether early mobilization in the surgical ICU helps improve patients' functional recovery to a level that enables independent living. We assessed dose of mobilization (level + duration). We tested the research hypotheses that dose of mobilization predicts adverse discharge and that both duration of mobilization and maximum mobilization level predict adverse discharge. International, prospective cohort study. Study conducted in five surgical ICUs at four different institutions. One hundred fifty patients who were functionally independent before admission (Barthel Index ≥ 70) and who were expected to stay in the ICU for greater than or equal to 72 hours. None. Mobilization was quantified daily, and treatments from all healthcare providers were included. We developed and used the Mobilization Quantification Score that quantifies both level and duration of mobilization. We assessed the association between the dose of mobilization (level + duration; exposure) and adverse discharge disposition (loss of the ability to live independently; primary outcome). There was wide variability in the dose of mobilization across centers and patients, which could not be explained by patients' comorbidity or disease severity. Dose of mobilization was associated with reduced risk of adverse discharge (adjusted odds ratio, 0.21; 95%CI, 0.09-0.50; p < 0.001). Both level and duration explained variance of adverse discharge (adjusted odds ratio, 0.28; 95% CI, 0.12-0.65; p = 0.003; adjusted odds ratio, 0.14; 95% CI, 0.06-0.36; p < 0.001, respectively). Duration compared with the level of mobilization tended to explain more variance in adverse discharge (area under the curve duration 0.73; 95% CI, 0.64-0.82; area under the curve mobilization level 0.68; 95% CI, 0.58-0.77; p = 0.10). We observed wide variability in dose of mobilization treatment applied, which could not be explained by patients' comorbidity or disease severity. High dose of mobilization is an independent predictor of patients' ability to live independently after discharge. Duration of mobilization sessions should be taken into account in future quality improvement and research projects.


Prediction of in vivo short-chain fatty acid production in hindgut fermenting mammals: problems and pitfalls.
Short-chain fatty acids (SCFA) are considered to have important physiological functions. However, to prove this, SCFA must be determined, which is rather difficult as a lot of factors interfere with their production. This review focuses on the factors that influence the prediction of short-chain fatty acid formation in the large intestine of monogastric mammals. To mimic the in vivo situation, when predicting the amount of short-chain fatty acids produced from a certain substrate based on in vitro models, one has to estimate the amount of this substrate entering the large intestine, the retention time in the different parts of the large intestine, and the substrate fermentability. Instead of in vitro models, direct and indirect techniques may be used to measure short-chain fatty acid production in vivo. Direct techniques include the measurement of input and output or measuring differences in SCFA between portal and venous blood whereas indirect techniques measure the end products of fermentation. In this case, other factors have to be taken into account, including technical limitations and ethical considerations. In this review it is concluded that the choice for a method will rely on the purpose of the study taking into account the (dis)advantages of every method.


Endogenous opioids may protect the perinatal brain in hypoxia.
Endogenous opioids are released in great amounts in perinatal asphyxia. The role of this release has been unclear. In a study of cerebral blood flow and oxygen metabolism in 5 hypoxic newborn lambs, naloxone blocking of opioid receptors resulted in a proportional increase in telencephalic cerebral blood flow and oxygen metabolism. It is suggested that endogenous opioid release protects the neonatal brain in hypoxia by diminishing the cerebral metabolic rate of oxygen.


Awareness and Practices towards Vaccinating Their Children against COVID-19: A Cross-Sectional Study among Pakistani Parents.
There are typically lower COVID-19 vaccination rates among developing versus higher-income countries, which is exacerbated by greater vaccine hesitancy. However, despite the increasing evidence of safety, parents are still reluctant to vaccinate their children against COVID-19. This is a concern in countries experiencing successive waves, such as Pakistan. Consequently, the objective of this study was to gain better understanding and practice regarding parents vaccinating their children against COVID-19 in Pakistan. A cross-sectional study was conducted to measure parents' attitudes towards vaccinating their children. In total, 451 parents participated in the study, giving a response rate of 70.4%; 67.4% were female, 43.2% belonged to the 40-49 years age group, and 47.7% had three children, with 73% of parents fully immunized against COVID-19. We found that 84.7% of parents did not consider COVID-19 to be a very serious issue, and 53.9% considered that their children were not at high risk of COVID-19. Overall, only a quarter of the study participants had currently vaccinated their children and 11.8% were willing to vaccinate their children in the near future. Parents who had a better knowledge of COVID-19, secondary or higher education, children who had chronic illness, and those parents whose children had been infected with COVID-19 were more likely to have their children vaccinated. The most common reasons for vaccine hesitancy were "my child is not at high risk of COVID-19" (61%) and "I am afraid to put/inject a foreign object inside my child's body" (52.2%). Overall, vaccine acceptance was low among the parents of the children. Those parents with higher education, chronic illnesses, greater knowledge of COVID-19 and its vaccines, and those whose children had been infected with COVID-19 were significantly (p < 0.001) inclined towards vaccinating their children. Effective campaigns as well as awareness sessions are needed to address misinformation and reduce vaccine hesitancy.


Effectiveness of basic endoscopic surgical skill training for pediatric surgeons.
Pediatric surgeons require highly advanced skills when performing endoscopic surgery, but their experience with such cases tend to be limited in comparison to general surgeons. The aim of this study was to evaluate the effectiveness of basic endoscopic surgery training for less-experienced young pediatric surgeons and then compare their skills with those of general surgeons. The surgeons (n = 477) subjected to this study underwent a 2-day endoscopic skill training program, consisting of lectures, box training, VR simulator training, tissue training, and live tissue training. The trainees were divided into two groups: P (pediatric surgeons, n = 33) and G (general surgeons, n = 444). The trainees were required to make a continuous suture along a circle measuring 2.5 cm in diameter and the findings were evaluated both before and after training. A statistical analysis was conducted using the unpaired t test. The number of experienced cases totaled 20.8 ± 23.9 in P and 60.6 ± 80.5 in G (p < 0.001). The number of completed sutures before training was 1.4 ± 1.1 in P and 1.9 ± 1.5 in G (p < 0.05). The number of completed sutures after training was 4.1 ± 1.3 in P and 3.9 ± 1.9 in G (p > 0.05). The economy and speed of the forceps improved, however, the number of errors increased. Less-experienced pediatric surgeons improved their surgical skill and ability until reaching almost the same level as that observed in more experienced general surgeons during training, however, the number of errors after training increased in comparison to before training. As a result, this program needs to be modified to reduce the number of errors while enabling pediatric surgeons to master the safe and precise surgical techniques needed in this field.


Increased ENaC activity during kidney preservation in Wisconsin solution.
The invention of an effective kidney preservation solution capable of prolonging harvested kidney viability is the core of kidney transplantation procedure. Researchers have been working on upgrading the preservation solution quality aiming at prolonging storage time while maintaining utmost organ viability and functionality. For many years, the University of Wisconsin (UW) solution has been considered the gold standard solution for kidney preservation. However, the lifespan of kidney preservation in the UW solution is still limited. Its impact on the epithelial Na+ channel (ENaC) activity and its mediated processes is unknown and the primary goal of this study. Kidneys harvested from 8 weeks old Sprague Dawley rats were divided into 4 groups depending upon the period of preservation in UW solution. Additional analysis was performed using dogs' kidneys. ENaC activity was measured using patch clamp technique; protein expression and mRNA transcription were tested through Western blot and RT-qPCR, respectively. A colorimetric LDH level estimation was performed at different time points during UW solution preservation. Kidney preservation in Wisconsin solution caused reduction of the kidney size and weight and elevation of LDH level. ENaC activity increased in both rat and dog kidneys preserved in the UW solution as assessed by patch clamp analysis. On the contrary, ENaC channel mRNA levels remained unchanged. ENaC activity is significantly elevated in the kidneys during preservation in UW solution, which might affect the immediate post-implantation allograft function and trajectory post-transplant.


Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal.
Fatty aldehyde dehydrogenase (EC 184.108.40.206) converts long-chain fatty aldehydes to the corresponding acids. Deficiency in this enzyme causes the Sjogren Larsson Syndrome, a rare inherited disorder characterized by ichthyosis, spasticity, and mental retardation. Using a fluorescent aldehyde, pyrenedecanal, and HPLC with fluorescence detection, we developed a novel method to monitor fatty aldehyde dehydrogenase activity by quantification of the product pyrenedecanoic acid together with the substrate pyrenedecanal and possible side products, such as aldehyde adducts. As shown with recombinant enzymes, pyrenedecanal showed a high preference for fatty aldehyde dehydrogenase compared with other aldehyde dehydrogenases. The method allowed detection of fatty aldehyde dehydrogenase activity in nanogram amounts of microsomal or tissue protein and microgram amounts of Sjogren Larsson syndrome patients' skin fibroblast protein. It could successfully be adapted for the analysis of fatty aldehyde dehydrogenase activity in gel slices derived from low-temperature SDS-PAGE, showing that fatty aldehyde dehydrogenase activity from solubilized rat liver microsomes migrates as a dimer. Thus, monitoring of pyrenedecanoic acid formation from pyrenedecanal by HPLC with fluorescence detection provides a robust and sensitive method for determination of fatty aldehyde dehydrogenase activity.


Women's perceptions of outcomes of prenatal case management.
Comprehensive case management is a multidisciplinary, community-based service often available to Medicaid-eligible women. The purpose of the study was to identify the variety of maternal outcomes, other than birth outcomes, attributable to comprehensive prenatal case management. This qualitative study used a social ecological approach. Twenty-four women were interviewed about the outcomes they experienced as a result of comprehensive prenatal case management. Ethnographic content analysis was used for data reduction. The participants' mean age was 25.4 (SD = 8.4) years, with an average parity of 1.9 (SD = 1.1). Fifteen participants (68%) had a 12th grade education or less. Ethnic minorities were included in the sample. Eleven participants (47%) worked at least part-time, although 23 (98%) were receiving Medicaid and 21 (88%) were receiving the Women, Infants, and Children's (WIC) supplementary nutrition program. The women attributed improvements of various types to the actions of the case manager, specifically in the areas of emotional well-being, learning, lifestyle behaviors, financial situation, services utilization, and maternal and infant physical health. Case management appeared to have immediate effects on the women, as well as intermediate effects, such as changes in lifestyle behaviors and services utilization. The women attributed those changes to having a healthy pregnancy.


Metaproteomic analysis of ratoon sugarcane rhizospheric soil.
The current study was undertaken to elucidate the mechanism of yield decline in ratoon sugarcane using soil metaproteomics combined with community level physiological profiles (CLPP) analysis. The available stalk number, stalk diameter, single stalk weight and theoretical yield of ratoon cane (RS) were found to be significantly lower than those of plant cane (NS). The activities of several carbon, nitrogen and phosphorus processing enzymes, including invertase, peroxidase, urease and phosphomonoesterase were found to be significantly lower in RS soil than in NS soil. BIOLOG analysis indicated a significant decline in average well-color development (AWCD), Shannon's diversity and evenness indices in RS soil as compared to NS soil. To profile the rhizospheric metaproteome, 109 soil protein spots with high resolution and repeatability were successfully identified. These proteins were found to be involved in carbohydrate/energy, amino acid, protein, nucleotide, auxin and secondary metabolisms, membrane transport, signal transduction and resistance, etc. Comparative metaproteomics analysis revealed that 38 proteins were differentially expressed in the RS soil as compared to the control soil or NS soil. Among these, most of the plant proteins related to carbohydrate and amino acid metabolism and stress response were up-regulated in RS soil. Furthermore, several microbial proteins related to membrane transport and signal transduction were up-regulated in RS soil. These proteins were speculated to function in root colonization by microbes. Our experiments revealed that sugarcane ratooning practice induced significant changes in the soil enzyme activities, the catabolic diversity of microbial community, and the expression level of soil proteins. They influenced the biochemical processes in the rhizosphere ecosystem and mediated the interactions between plants and soil microbes.


A community based stroke register in a high risk area for stroke in north west England.
To develop a community based stroke register to assess the magnitude of the problem of stroke in an entire health district in a high risk area for stroke. Community based stroke register from general practice data. East Lancashire Health Authority with a 1995 population of 534,287. The stroke register was developed and maintained for one calendar year in East Lancashire between 1 July 1994 and 30 June 1995. Efforts were made to include all patients who had a stroke during this period from participating general practices, using several sources of referral. Of the district's 118 general practices, 93 (79%) participated fully, covering a population of 405,272. A total of 932 strokes, including 642 first ever cases, were cross checked and confirmed, with only 50% from any single source, mainly the practices. The total stroke incidence rate was 1.60 per 1000 per year, adjusted for the England and Wales 1991 census population. The rate increased considerably with age from 0.88/1000 for ages 50-54 to 20.56/1000 for ages 85-89 years. From 50-74 years, the age specific incidence was higher in men, but overall it was higher in women (1.87; 95% confidence interval 1.67, 2.04 per 1000) than in men (1.31; 1.15, 1.47 per 1000), and slightly lower than in Oxford a decade earlier. The rate also varied in different localities, with higher rates in the central towns of Hyndburn (2.05/ 1000), Blackburn (1.63/1000), and Burnley (1.80/1000) and lowest values in rural areas (1.18/1000 in Pendle). Case fatality from stroke at 28 days was 34% and the hospital admission rate was high at 70%. The multiple source registration method is required for a stroke register. Stroke incidence in this area was still high and there was considerable variation across the district. Case fatality rates were similar to those in previous studies.


What is the true discharge rate and pattern of the striatal projection neurons in Parkinson's disease and Dystonia?
Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson's disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.


Thermal Stimulation Alters Cervical Spinal Cord Functional Connectivity in Humans.
The spinal cord has an active role in the modulation and transmission of the neural signals traveling between the body and the brain. Recent advancements in functional magnetic resonance imaging (fMRI) have made the in vivo examination of spinal cord function in humans now possible. This technology has been recently extended to the investigation of resting state functional networks in the spinal cord, leading to the identification of distinct patterns of spinal cord functional connectivity. In this study, we expand on the previous work and further investigate resting state cervical spinal cord functional connectivity in healthy participants (n = 15) using high resolution imaging coupled with both seed-based functional connectivity analyses and graph theory-based metrics. Within spinal cord segment functional connectivity was present between the left and right ventral horns (bilateral motor network), left and right dorsal horns (bilateral sensory network), and the ipsilateral ventral and dorsal horns (unilateral sensory-motor network). Functional connectivity between the spinal cord segments was less apparent with the connectivity centered at the region of interest and spanning <20 mm along the superior-inferior axis. In a subset of participants (n = 10), the cervical spinal cord functional network was demonstrated to be state-dependent as thermal stimulation of the right ventrolateral forearm resulted in significant disruption of the bilateral sensory network, increased network global efficiency, and decreased network modularity.


An epidemiological surveillance network of lumbar disc surgery to help prevention of and compensation for low back pain.
In the context of the establishment of a new surveillance system, the aim was to assess the proportion of cases of lumbar disc surgery (LDS) attributable to work according to occupation category and industry sector. The sociodemographic and socioeconomic data of 3150 inpatients living in a French region discharged in 2007-2008 from spine centers of the region following LDS were compared with those of the regional population. Occupational history was gathered using a mailed questionnaire. The attributable fraction of risk for exposed individuals (AFE) and population attributable fraction of risk (PAF) were calculated in relation to occupations and industries. Three occupational subcategories presented an AFE >50% for men (police and armed forces, unskilled agricultural and skilled craft blue-collar workers). There were eight subcategories for women, including material handlers and related equipment workers, and skilled industrial and unskilled agricultural blue-collar workers. The PAF for men was highest for construction and for women it was highest for wholesale and retail trades. The AFE and PAF are valuable for public policy. Although PAF could be used to help public health policy makers to implement preventive measures, the AFE could assist expert tribunals who take decisions about compensation for occupational diseases.


Potential barriers to control of blood pressure.
Numerous studies, including the National Health and Nutrition Examination Survey, have suggested inadequate control in patients with hypertension. Few studies have investigated the factors that may contribute to inadequate blood pressure control. This study assesses adequacy of blood pressure control in patients treated at two osteopathic resident-training family practice centers and investigates potential barriers to adequate blood pressure control in this setting. The care of 127 hypertensive patients was studied for 9 months. The charts of these patients were examined for blood pressure readings, gender, number of missed visits, comorbid conditions, and changes in medications. The adequacy of blood pressure control was assessed by the standards promulgated by the sixth report of the Joint National Committee guidelines. Barriers to adequate control, including missed visits and changes in medications, were assessed. With the standard of control as a mean blood pressure of less than or equal to 140/80 mm Hg, 51.2% of the sample had controlled blood pressure. Factors that were associated with a significant reduction in the control of blood pressure were (1) patients new to the practice, (2) patients who missed follow-up visits for treatment of hypertension, and (3) patients who were undergoing changes in their medication profiles. Although rates of blood pressure control in this population are higher than those previously reported in the general population, they demonstrate room for improvement. Factors that are less under the control of physicians may be responsible for a large percentage of patients with uncontrolled hypertension. An understanding of the factors associated with poor blood pressure control is important in developing interventions to improve adequacy of blood pressure control.


Visuospatial attentional functioning in mice: interactions between cholinergic manipulations and genotype.
Attentional functioning in mice was assessed in an analogue of the five-choice serial reaction time task in which the requirement was to detect brief visual stimuli presented across five spatial locations. Two hybrid strains of mice were assessed; F1 C57Bl/6xDBA/2 and C57Bl/6x129sv. Both strains acquired the task to high levels of performance with, in particular, no problems due to premature responding. At performance, systematic manipulation of the task parameters indicated a pattern of effects consistent with the task, taxing aspects of visuospatial attention. There were some differential effects of task manipulations at baseline across strain. However, the pattern of effects suggested these were likely to be the result of effects on factors other than attentional functioning per se, such as behavioural reactivity and inhibition. There was evidence in both strains of specific, centrally mediated effects of scopolamine on attentional functioning, with the C57Bl/6xDBA/2 hybrid showing greater sensitivity to the drug manipulation. Specific effects on discriminative accuracy were observed at doses of 0.02 and 0.2 mg/kg scopolamine. At the 2 mg/kg dose, large reductions in accuracy were associated with large effects on other measures, including omissions and response latencies, suggestive of nonspecific effects on task performance. These data indicate, for the first time, the utility of operant methods in assessing visuospatial attentional functioning in mice. They confirm the importance of cholinergic mechanisms in attentional processes across species, and suggest interactions between cholinergic mechanisms and genotype in the expression of attentional phenotypes.


Patient safety and quality in laboratory and hemostasis testing: a renewed loop?
More than three decades ago, George Lundberg first introduced the concept of the brain-to-brain loop for laboratory diagnostics. According to this pioneering model, the first step in the loop involves the selection of laboratory tests in the brain of the physician caring for the patient, and the final step is the transmission of test results back to the ordering physician. There are several intermediary steps, some of which are preanalytical (e.g., identification of patient and blood samples, the process of blood collection, and specimen handling); some are analytical and relate to the actual performance of the test(s); whereas others are postanalytical and involve release of test results into the medical record and further steps such as the physician's reaction to laboratory information, their interpretation of these results, and subsequent appropriate clinical action. Hemostasis testing should also be viewed within such a paradigm, so that quality throughout the total testing process can be assured. For hemostasis testing, particular attention is required to ensure provision of appropriate test samples in the preanalytical phase. Nevertheless, the timeliness of testing and an appropriate interpretation of test results are also paramount. This article overviews the concept of quality testing within hemostasis as critical to ensuring patient safety and optimal clinical and therapeutic management.


Dense Array of Spikes on HIV-1 Virion Particles.
HIV-1 is rare among viruses for having a low number of envelope glycoprotein (Env) spikes per virion, i.e., ∼7 to 14. This exceptional feature has been associated with avoidance of humoral immunity, i.e., B cell activation and antibody neutralization. Virus-like particles (VLPs) with increased density of Env are being pursued for vaccine development; however, these typically require protein engineering that alters Env structure. Here, we used instead a strategy that targets the producer cell. We employed fluorescence-activated cell sorting (FACS) to sort for cells that are recognized by trimer cross-reactive broadly neutralizing antibody (bnAb) and not by nonneutralizing antibodies. Following multiple iterations of FACS, cells and progeny virions were shown to display higher levels of antigenically correct Env in a manner that correlated between cells and cognate virions (P = 0.027). High-Env VLPs, or hVLPs, were shown to be monodisperse and to display more than a 10-fold increase in spikes per particle by electron microscopy (average, 127 spikes; range, 90 to 214 spikes). Sequencing revealed a partial truncation in the C-terminal tail of Env that had emerged in the sort; however, iterative rounds of "cell factory" selection were required for the high-Env phenotype. hVLPs showed greater infectivity than standard pseudovirions but largely similar neutralization sensitivity. Importantly, hVLPs also showed superior activation of Env-specific B cells. Hence, high-Env HIV-1 virions, obtained through selection of producer cells, represent an adaptable platform for vaccine design and should aid in the study of native Env.IMPORTANCE The paucity of spikes on HIV is a unique feature that has been associated with evasion of the immune system, while increasing spike density has been a goal of vaccine design. Increasing the density of Env by modifying it in various ways has met with limited success. Here, we focused instead on the producer cell. Cells that stably express HIV spikes were screened on the basis of high binding by bnAbs and low binding by nonneutralizing antibodies. Levels of spikes on cells correlated well with those on progeny virions. Importantly, high-Env virus-like particles (hVLPs) were produced with a manifest array of well-defined spikes, and these were shown to be superior in activating desirable B cells. Our study describes HIV particles that are densely coated with functional spikes, which should facilitate the study of HIV spikes and their development as immunogens.


Efficient anisotropic refinement of macromolecular structures using FFT.
This paper gives the equations for the use of fast Fourier transformations in individual atomic anisotropic refinement. Restraints on bonded atoms, on the sphericity of each atom and between non-crystallographic symmetry related atoms are described. These have been implemented in the program REFMAC and its performance with several examples is analysed. All the tests show that anisotropic refinement not only reduces the R value and Rfree but also improves the fit to geometric targets, indicating that this parameterization is valuable for improving models derived from experimental data. The computer time taken is comparable to that for isotropic refinements.


A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation.
Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage-related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFκB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal.


Pain: A Review of Interleukin-6 and Its Roles in the Pain of Rheumatoid Arthritis.
Pain is a major and common symptom reported as a top priority in patients with rheumatoid arthritis (RA). Intuitively, RA-related pain is often considered to be a natural consequence of peripheral inflammation, so treatment of RA is expected to manage pain concurrently as part of inflammation control. However, pain in patients with RA can be poorly correlated with objective measures of inflammation, for example, in patients who are otherwise in remission. Joint damage appears to account for only a fraction of this residual pain. Emerging evidence suggests that alteration of peripheral and central pain processing contributes to RA-related pain; this is parallel to, but somewhat independent of, joint inflammation. Interleukin (IL)-6 is a proinflammatory cytokine that contributes to the pathogenesis of RA. It exerts systemic effects via signaling through soluble forms of the IL-6 receptor ("trans-signaling"). Evidence from preclinical studies demonstrates that intra-articular IL-6 can produce long-lasting peripheral sensitization to mechanical stimulation and suggests an important role for IL-6 in central pain sensitization. This may be partly explained by its ability to activate neurons through trans-signaling, affecting nociceptive plasticity and nerve fiber regrowth. Local activity at neuron endings may culminate in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons. Peripheral and central sensitization can promote the development of chronic pain, which can have a significant impact on patients' health and quality of life. A proportion of pain in RA may be more appropriately managed as an entity separate from inflammation. Both the peripheral and central nervous systems should be recognized as important potential systems targeted by RA. The substantial burden of RA-related chronic pain suggests that pain should be a key focus in RA management and should be assessed and addressed early and separately from the inflammatory component.


Supersaturable Solid Self-microemulsifying Delivery Systems of Astaxanthin via Spray Drying: Effects of Polymers and Solid Carriers.
This study aimed to develop the solid astaxanthin-encapsulated self-microemulsifying delivery system (S-AST SMEDS) spray-dried particles and investigate the effect of materials in formulations on product characteristics. The optimized liquid AST SMEDS incorporated with a polymeric precipitation inhibitor (PI) was solidified with a solid carrier by spray drying. Physicochemical properties of S-AST SMEDS spray-dried powders including morphology, particle size and distribution, flowability, solid-state characters, moisture content, yield, loading capacity of AST, and reconstitution properties were examined. Polymeric PIs seemed to have an impact on particles' size, surface smoothness, and flowability while solid carriers had an effect on the particles' moisture content and droplet size of microemulsions obtained after reconstitution. The amount of AST encapsulated in S-SMEDS powder was influenced by both polymer and solid carriers. Dissolution and short-term stability of S-AST SMEDS were also studied. Our developed spray-dried solid SMEDS particles helped enhance AST dissolution rate.


Persistent lung expansion after pleural talc poudrage in non-surgically resected malignant pleural mesothelioma.
To investigate the prognostic effect of persistent lung expansion after pleural talcage and other variables in non-surgically resected malignant pleural mesothelioma (MPM) patients. All consecutive patients submitted to video-assisted thoracoscopic (VAT) pleurodesis by talc poudrage for MPM between 2006 and 2011 were studied. The following parameters were prospectively recorded: age; sex; smoking history; asbestos exposure; C-reactive protein (CRP) levels; platelet (PLT) count; Eastern Cooperative Oncology Group performance status (ECOG PS); histologic subtype; clinical stage (cStage); chemotherapy; pleural fluid volume; and persistence of lung expansion at 3 months follow-up. Survival was assessed in June 2013. A total of 172 patients were considered; 146 of 172 patients demonstrated a complete lung expansion at discharge, whereas only 85 of 172 patients had persistent expanded lung on the affected side at the 3-month follow-up chest x-ray. Median survival was 11.5 months (95% confidence interval [CI], 10% to 14%) and 2-year disease-specific survival was 13% (95% CI, 7% to 24%) for the entire cohort. Multivariate analysis showed that non-epithelioid histology (hazard ratio [HR], 2.81; 95% CI, 1.82% to 5.09%), pleural fluid recurrence (HR 2.54; 95% CI, 1.73% to 4.40%), cStage greater than II (HR 2.36; 95% CI, 1.50% to 4.32%), ECOG PS greater than 1 (HR 2.19; 95% CI, 1.26% to 4.23%), CRP greater than 5 mg/L (HR 2.01; 95% CI, 1.18% to 4.12%), and PLT count greater than 400,000 (HR 1.76; 95% CI 1.14% to 3.92%) were independent predictors of poor prognosis. Persistent lung expansion after pleural talc poudrage and absence of fluid recurrence is demonstrated to be a stronger factor in predicting survival rather than clinical stage and other clinical variables in not surgically resected MPM patients.


Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.
EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.


The frustrations of adopting evidence-based medical education and how they can be overcome!
Evidence-based medical education has been widely promoted but our discussions with medical educators across different countries has highlighted that adopting this approach can be frustrating. There is often a lack of useful evidence that can inform the practical decisions that medical educators have to make about curriculum development or the way that they should teach, especially in relation to low and middle income countries. To overcome these challenges, we recommend that studies increase their reporting of the context and process of any interventions. We also recommend international collaborations with a common goal to answer a research question that is of importance across different contexts. Future research should also focus on understanding the challenges of implementing evidence-based medical education in different countries.


Deep Neural Network-Based Respiratory Pathology Classification Using Cough Sounds.
Intelligent systems are transforming the world, as well as our healthcare system. We propose a deep learning-based cough sound classification model that can distinguish between children with healthy versus pathological coughs such as asthma, upper respiratory tract infection (URTI), and lower respiratory tract infection (LRTI). To train a deep neural network model, we collected a new dataset of cough sounds, labelled with a clinician's diagnosis. The chosen model is a bidirectional long-short-term memory network (BiLSTM) based on Mel-Frequency Cepstral Coefficients (MFCCs) features. The resulting trained model when trained for classifying two classes of coughs-healthy or pathology (in general or belonging to a specific respiratory pathology)-reaches accuracy exceeding 84% when classifying the cough to the label provided by the physicians' diagnosis. To classify the subject's respiratory pathology condition, results of multiple cough epochs per subject were combined. The resulting prediction accuracy exceeds 91% for all three respiratory pathologies. However, when the model is trained to classify and discriminate among four classes of coughs, overall accuracy dropped: one class of pathological coughs is often misclassified as the other. However, if one considers the healthy cough classified as healthy and pathological cough classified to have some kind of pathology, then the overall accuracy of the four-class model is above 84%. A longitudinal study of MFCC feature space when comparing pathological and recovered coughs collected from the same subjects revealed the fact that pathological coughs, irrespective of the underlying conditions, occupy the same feature space making it harder to differentiate only using MFCC features.


Glycopeptide antibiotics: evolving resistance, pharmacology and adverse event profile.
The first glycopeptide antibiotic was vancomycin, isolated from the soil in the 1950s; since then, the class has expanded to include teicoplanin and the new semisynthetic glycopeptides dalbavancin, oritavancin and telavancin. They are bactericidal, active against most Gram-positive organisms, and in a concentration-dependent manner, inhibit cell wall synthesis. Resistance to vancomycin has emerged, especially among enterococci and Staphylococcus aureus through a variety of mechanisms. This emerging resistance to vancomycin makes proper dosing and monitoring of the area under the curve/MIC critically important. The chief adverse effect of vancomycin is nephrotoxicity, which is also intricately related to its dose. The efficacy of the semisynthetic glycopeptides has been demonstrated in skin and soft-tissue infections, but remains to be seen in serious methicillin-resistant Staphylococcus aureus infections.


Evaluation of plasma cytokines in patients with cocaine use disorders in abstinence identifies transforming growth factor alpha (TGFα) as a potential biomarker of consumption and dual diagnosis.
Cocaine use disorder (CUD) is a complex health condition, especially when it is accompanied by comorbid psychiatric disorders (dual diagnosis). Dual diagnosis is associated with difficulties in the stratification and treatment of patients. One of the major challenges in clinical practice of addiction psychiatry is the lack of objective biological markers that indicate the degree of consumption, severity of addiction, level of toxicity and response to treatment in patients with CUD. These potential biomarkers would be fundamental players in the diagnosis, stratification, prognosis and therapeutic orientation in addiction. Due to growing evidence of the involvement of the immune system in addiction and psychiatric disorders, we tested the hypothesis that patients with CUD in abstinence might have altered circulating levels of signaling proteins related to systemic inflammation. The study was designed as a cross-sectional study of CUD treatment-seeking patients. These patients were recruited from outpatient programs in the province of Malaga (Spain). The study was performed with a total of 160 white Caucasian subjects, who were divided into the following groups: patients diagnosed with CUD in abstinence (N = 79, cocaine group) and matched control subjects (N = 81, control group). Participants were clinically evaluated with the diagnostic interview PRISM according to the DSM-IV-TR, and blood samples were collected for the determination of chemokine C-C motif ligand 11 (CCL11, eotaxin-1), interferon gamma (IFNγ), interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-17α (IL-17α), macrophage inflammatory protein 1α (MIP-1α) and transforming growth factor α (TGFα) levels in the plasma. Clinical and biochemical data were analyzed in order to find relationships between variables. While 57% of patients with CUD were diagnosed with dual diagnosis, approximately 73% of patients had other substance use disorders. Cocaine patients displayed greater cocaine symptom severity when they were diagnosed with psychiatric comorbidity. Regarding inflammatory factors, we observed significantly lower plasma levels of IL-17α (p < 0.001), MIP-1α (p < 0.001) and TGFα (p < 0.05) in the cocaine group compared with the levels in the control group. Finally, there was a significant primary effect of dual diagnosis on the plasma concentrations of TGFα (p < 0.05) in the cocaine group, and these levels were lower in patients with dual diagnoses. IL-17α, MIP-1α and TGFα levels are different between the cocaine and control groups, and TGFα levels facilitate the identification of patients with dual diagnosis. Because TGFα reduction is associated with enhanced responses to cocaine in preclinical models, we propose TGFα as a potential biomarker of complex CUD in humans.


How mosquitoes see traps: role of visual responses.
The visual responses of female mosquitoes during appetitive and attraction flights to conspicuous features of their environment were reviewed. These studies showed for both flights long-range orientation (positive) could be followed by a short-range response (negative) to avoid the goal. In conjunction with the optomotor anemotactic response, appetitive flights are controlled by visual orientation toward more or less distant targets, which permits females to make a wider search than upwind flight along could accomplish. Most attraction flights are controlled primarily by visual and olfactory cues. The influence of visual targets upon mosquito flight behavior and the effect of this behavior upon trap catches is discussed.


Suppressor analysis of the MotB(D33E) mutation to probe bacterial flagellar motor dynamics coupled with proton translocation.
MotA and MotB form the stator of the proton-driven bacterial flagellar motor, which conducts protons and couples proton flow with motor rotation. Asp-33 of Salmonella enterica serovar Typhimurium MotB, which is a putative proton-binding site, is critical for torque generation. However, the mechanism of energy coupling remains unknown. Here, we carried out genetic and motility analysis of a slowly motile motB(D33E) mutant and its pseudorevertants. We first confirmed that the poor motility of the motB(D33E) mutant is due to neither protein instability, mislocalization, nor impaired interaction with MotA. We isolated 17 pseudorevertants and identified the suppressor mutations in the transmembrane helices TM2 and TM3 of MotA and in TM and the periplasmic domain of MotB. The stall torque produced by the motB(D33E) mutant motor was about half of the wild-type level, while those for the pseudorevertants were recovered nearly to the wild-type levels. However, the high-speed rotations of the motors under low-load conditions were still significantly impaired, suggesting that the rate of proton translocation is still severely limited at high speed. These results suggest that the second-site mutations recover a torque generation step involving stator-rotor interactions coupled with protonation/deprotonation of Glu-33 but not maximum proton conductivity.


Magnetically guided capsule endoscopy.
Wireless capsule endoscopy (WCE) is a powerful tool for medical screening and diagnosis, where a small capsule is swallowed and moved by means of natural peristalsis and gravity through the human gastrointestinal (GI) tract. The camera-integrated capsule allows for visualization of the small intestine, a region which was previously inaccessible to classical flexible endoscopy. As a diagnostic tool, it allows to localize the sources of bleedings in the middle part of the gastrointestinal tract and to identify diseases, such as inflammatory bowel disease (Crohn's disease), polyposis syndrome, and tumors. The screening and diagnostic efficacy of the WCE, especially in the stomach region, is hampered by a variety of technical challenges like the lack of active capsular position and orientation control. Therapeutic functionality is absent in most commercial capsules, due to constraints in capsular volume and energy storage. The possibility of using body-exogenous magnetic fields to guide, orient, power, and operate the capsule and its mechanisms has led to increasing research in Magnetically Guided Capsule Endoscopy (MGCE). This work shortly reviews the history and state-of-art in WCE technology. It highlights the magnetic technologies for advancing diagnostic and therapeutic functionalities of WCE. Not restricting itself to the GI tract, the review further investigates the technological developments in magnetically guided microrobots that can navigate through the various air- and fluid-filled lumina and cavities in the body for minimally invasive medicine.


Correlation Between the Revised Trauma Score and Injury Severity Score: Implications for Prehospital Trauma Triage.
Prehospital triage of the seriously injured patient is fraught with challenges, and trauma scoring systems in current triage guidelines warrant further investigation. The primary objective of this study was to assess the correlation of the physiologically based Revised Trauma Score (RTS) and MGAP score (mechanism of injury, Glasgow Coma Scale, age, blood pressure) with the anatomically based Injury Severity Score (ISS). The secondary objectives for this study were to compare the accuracy of the MGAP score and the RTS for the prediction of in-hospital mortality for trauma patients. This study was a retrospective cohort including 10 years of patient data in a large single-center trauma registry at a primary adult resource center (Level I) for trauma patients. Participants included adults (age ≥18 years). The primary outcome measure was injury severity (measured by ISS) and a secondary analysis compared the RTS and MGAP for the prediction of patient mortality. Descriptive statistics were used to describe the cohort and correlation methods were employed. Each score's accuracy for the prediction of mortality was calculated using the area under receiver operating characteristic (AUROC) curves. In total, 43,082 trauma patient records were reviewed; 32,798 patients had complete RTS data available and 32,371 patients had complete data available for MGAP analyses. The correlation between scene RTS and ISS was poor (-.29), as was the correlation between MGAP and ISS (-.28). For the prediction of mortality, admission MGAP demonstrated the highest sensitivity and specificity for mortality (AUROC 0.96; 95% CI, 0.95-0.96). While elements of the RTS remain the first criterion recommended to quantify the totality of physiological injury severity, the composite RTS score derived from this system correlates poorly with actual anatomical injury severity. The MGAP scoring system demonstrated higher sensitivity and specificity for mortality but was not superior to the RTS for predicting anatomical injury severity. In the future development of national and international field triage guidelines for trauma patients, the findings from this study may be considered in order to improve the accuracy of prehospital triage. The findings in this analysis complement a growing body of evidence that suggests that MGAP may be a superior and more easily calculable prehospital scoring system for the prediction of mortality in trauma patients.


Metabolic Profiling of Interspecies Interactions During Sessile Bacterial Cultivation Reveals Growth and Sporulation Induction in Paenibacillus amylolyticus in Response to Xanthomonas retroflexus.
The toolbox available for microbiologists to study interspecies interactions is rapidly growing, and with continuously more advanced instruments, we are able to expand our knowledge on establishment and function of microbial communities. However, unravelling molecular interspecies interactions in complex biological systems remains a challenge, and interactions are therefore often studied in simplified communities. Here we perform an in-depth characterization of an observed interspecies interaction between two co-isolated bacteria, Xanthomonas retroflexus and Paenibacillus amylolyticus. Using microsensor measurements for mapping the chemical environment, we show how X. retroflexus promoted an alkalization of its local environment through degradation of amino acids and release of ammonia. When the two species were grown in proximity, the modified local environment induced a morphological change and growth of P. amylolyticus followed by sporulation. 2D spatial metabolomics enabled visualization and mapping of the degradation of oligopeptide structures by X. retroflexus and morphological changes of P. amylolyticus through e.g. the release of membrane-associated metabolites. Proteome analysis and microscopy were used to validate the shift from vegetative growth towards sporulation. In summary, we demonstrate how environmental profiling by combined application of microsensor, microscopy, metabolomics and proteomics approaches can reveal growth and sporulation promoting effects resulting from interspecies interactions.


[Pathomorphology of experimental pneumocystosis and cytogenesis of the pathogen Pneumocystis carinii].
A lung pneumocystosis model has been developed in white non-inbred rats (83 animals). The pathological process develops during 1 month versus 2-3 months in other models. Pathomorphology is in principle similar to human pneumocystosis. Bauer's method appeared to be the simplest and adequate for the detection of mature pneumocysts in the lung sections among many other methods used.


Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.


The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved?
The conceptualisation of autistic spectrum disorder and Alzheimer's disease has undergone something of a paradigm shift in recent years and rather than being viewed as single illnesses with a unitary pathogenesis and pathophysiology they are increasingly considered to be heterogeneous syndromes with a complex multifactorial aetiopathogenesis, involving a highly complex and diverse combination of genetic, epigenetic and environmental factors. One such environmental factor implicated as a potential cause in both syndromes is aluminium, as an element or as part of a salt, received, for example, in oral form or as an adjuvant. Such administration has the potential to induce pathology via several routes such as provoking dysfunction and/or activation of glial cells which play an indispensable role in the regulation of central nervous system homeostasis and neurodevelopment. Other routes include the generation of oxidative stress, depletion of reduced glutathione, direct and indirect reductions in mitochondrial performance and integrity, and increasing the production of proinflammatory cytokines in both the brain and peripherally. The mechanisms whereby environmental aluminium could contribute to the development of the highly specific pattern of neuropathology seen in Alzheimer's disease are described. Also detailed are several mechanisms whereby significant quantities of aluminium introduced via immunisation could produce chronic neuropathology in genetically susceptible children. Accordingly, it is recommended that the use of aluminium salts in immunisations should be discontinued and that adults should take steps to minimise their exposure to environmental aluminium.


Risk of primary infection and reinfection with respiratory syncytial virus.
Respiratory syncytial virus is the most important cause of serious lower respiratory tract infection in children. For children followed up from birth in the Houston Family Study, the infection rate was 68.8/100 children less than 12 months of age and 82.6/100 during the second year of life. Virtually all children had been infected at least once by 24 months of age, and about one half had experienced two infections. Although lower respiratory tract disease (LRD) was common (22.4/100 during year 1 and 13.0/100 during year 2), most children had only one LRD illness. The risk of reinfection was inversely related to the level of neutralizing antibodies in the serum. Reinfection illnesses were generally mild, and risk of reinfection decreased to only 33.3/100 during year 4. Studies of children with LRD and surveys of hospitalizations provide the basis for an estimate of the number of children hospitalized each year during the respiratory syncytial virus epidemics. Almost 100,000 children in the United States experience an illness of sufficient severity to require hospitalization.


The behavioral and linguistic interactions of specifically language-delayed and normal boys with their mothers.
3 studies were based on subgroups selected from larger pools of either normal children or children with delays in the expression and/or comprehension of language but normal nonverbal abilities. In Study 1, younger (28-50 months) and older (51-68 months) normal (N = 27) and language-delayed (N = 33) boys were observed interacting with their mothers in free play and structured task situations. Although language-delayed children initiated fewer interactions, their responsiveness to maternal interactions, questions, and commands did not differ from that of normal children. Mothers questioned language-delayed children less frequently during tasks but did not differ from mothers of normal children on other measures of interaction, responsiveness, control, or reward strategies. In Study 2, the complexity of maternal speech directed to normal (N = 11) and expressively delayed (N = 11) boys who were matched on the basis of comprehensive skills did not differ. Maternal speech to boys with delays in both language expression and comprehension (N = 11) was significantly less complex. In Study 3, the discrepancy between the speech complexity of mothers and that of their language-delayed children (N = 47) was greatest in younger children with greater expression and comprehension delays, who initiated fewer interactions and proved less responsive to maternal interactions and questions.


Relationship between stress factor and periodontal disease in a rural area population in Japan.
Several studies conducted in Western countries have shown significant associations between stress factors and periodontal disease. However, there have been only a few studies conducted in Asian countries. The present study was designed to identify possible relationship between stress and periodontal disease in residents of a rural area in Japan. - Data were collected from 1,089 adults with at least six natural teeth in a typical farming district of Japan. Subjects were asked to complete a questionnaire on daily stresses in various aspects of life. Data on gender, occupation, smoking, alcohol drinking habits, dental health behavior and systemic disease status were obtained from the questionnaires. Periodontal disease status was assessed using clinical attachment loss (CAL), and the subjects were dichotomized according to mean CAL<1.5 mm (control group) and>/=1.5 mm (diseased group). Logistic regression was applied to assess the associations between stress and other factors with periodontal disease, and odds ratios (ORs) as well as 95% confidence intervals were calculated. In bivariate analysis, significant relationships were found between periodontal disease and stress within 1 month (P<0.001), job stress (P<0.001), self-health-related stress (P<0.001) and family health-related stress (P<0.01). Logistic regression analysis revealed that subjects who felt job stress (OR=1.71, P<0.05) and those who felt stress due to self health (OR=1.72, P<0.05) were more prone to have periodontal disease than were those who never or only rarely felt such stress. Significant correlations were also found between periodontal disease and smoking habit, frequency of dental clinic visits and hyperlipidemia (OR=1.8, P<0.05, OR=2.0, P<0.001, OR=2.1, P<0.05, respectively). - The results suggest that stress related to self health and job might be potential risk indicators for development of periodontal diseases. Intervention measures including stress reduction may provide adjunctive approaches for preventing and treating periodontal disease.


Characteristics of Unruptured Compared to Ruptured Intracranial Aneurysms: A Multicenter Case-Control Study.
Only a minority of intracranial aneurysms rupture to cause subarachnoid hemorrhage. To test the hypothesis that unruptured aneurysms have different characteristics and risk factor profiles compared to ruptured aneurysms. We recruited patients with unruptured aneurysms or aneurysmal subarachnoid hemorrhages at 22 UK hospitals between 2011 and 2014. Demographic, clinical, and imaging data were collected using standardized case report forms. We compared risk factors using multivariable logistic regression. A total of 2334 patients (1729 with aneurysmal subarachnoid hemorrhage, 605 with unruptured aneurysms) were included (mean age 54.22 yr). In multivariable analyses, the following variables were independently associated with rupture status: black ethnicity (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.29-4.56, compared to white) and aneurysm location (anterior cerebral artery/anterior communicating artery [OR 3.21; 95% CI 2.34-4.40], posterior communicating artery [OR 3.92; 95% CI 2.67-5.74], or posterior circulation [OR 3.12; 95% CI 2.08-4.70], compared to middle cerebral artery). The following variables were inversely associated with rupture status: antihypertensive medication (OR 0.65; 95% CI 0.49-0.84), hypercholesterolemia (0.64 OR; 95% CI 0.48-0.85), aspirin use (OR 0.28; 95% CI 0.20-0.40), internal carotid artery location (OR 0.53; 95% CI 0.38-0.75), and aneurysm size (per mm increase; OR 0.76; 95% CI 0.69-0.84). We show substantial differences in patient and aneurysm characteristics between ruptured and unruptured aneurysms. These findings support the hypothesis that different pathological mechanisms are involved in the formation of ruptured aneurysms and incidentally detected unruptured aneurysms. The potential protective effect of aspirin might justify randomized prevention trials in patients with unruptured aneurysms.


Differentiation of lymphoid cells: B cell as a direct target and T cell as a regulator in lipopolysaccharide-enhanced induction of immunoglobulin production.
The cells involved in the stimulatory effect of bacterial lipopolysaccharide (LPS) on the induction of immunoglobulin (Ig) production by rabbit spleen cells cultured in the absence of antigen has been analyzed. Addition of LPS caused a several-fold enhancement of both DNA synthesis and Ig production. These enhanced activities were not significantly affected by depletion of adherent cells in the spleen cell population. Although inactivation of splenic T cells by anti-thymocyte serum (ATS) treatment did not affect the enhancement of DNA synthesis due to LPS, such treatment did adversely affect the enhancement of Ig production by LPS. Furthermore, the enhancement of Ig production of ATS-treated spleen cells by LPS was found to be dependent on the number of thymocytes added. In addition, the prior incubation of ATS-treated spleen cells with LPS resulted in effective enhancement of Ig production when such ATS-treated spleen cells and thymocytes were combined after removal of LPS. An identical experiment, except that thymocytes instead of ATS-treated spleen cells received the prior incubation with LPS, did not result in enhancement of Ig production. Finally, the enhanced Ig production due to LPS was inhibited by hydroxyurea, a known inhibitor of cellular DNA synthesis. The relationship between the mitogenic activity of LPS on B cells, the regulatory function of T cells, and the enhancement of Ig production by LPS is discussed in relation to the contrasting reports concerning the cellular target of LPS.


[Absenteeism of nursing workers in a school hospital].
Absenteeism in the nursing team worries the institutions' managers, because they reflect on the human resources quantitative aspects, interfering in the quality of healthcare provided to the clientele. This descriptive, retrospective study identified the percentage and the types of expected and non-expected absences of nursing workers in a school hospital, between April, 2001 and March, 2002. Data were collected by consultating the schedules and the monthly attendance reports in the Human Resources Center. Expected absences reached 40% for weekly days off, 3.9% for holidays and 9% for vacations. The percentage of non-expected absences for the nursing category varied from 0 to 46.3%, predominantly due to maternity leaves and occupational accidents. For nursing technicians and auxiliaries, percentages varied from 0.5% to 11.6%. In this case, the absences were due to sick and medical leaves approved by the National Institute of Social Security.


Encapsulation of epigallocatechin gallate in zein/chitosan nanoparticles for controlled applications in food systems.
The objective of this study was to prepare chitosan nanoparticles (CS NPs) coated with zein as a promising encapsulation and delivery system for epigallocatechin gallate (EGCG). The factors influencing the nanoparticle fabrication, including zein concentration, zein/chitosan weight ratio and EGCG encapsulation percentage, were systematically investigated. The physicochemical and structural analysis showed that the electrostatic interactions and hydrogen bonds were the major forces responsible for nanoparticles formation. The transmission electron microscopy study revealed the spherical nature with smooth surface of obtained nanoparticles. The release profile of EGCG showed a burst effect, followed by slow release. EGCG release was relatively higher from zein/chitosan nanoparticles (zein/CS NPs) with higher DPPH scavenging activity, than that of NPs without zein coating in 95% ethanol fatty simulant. These results indicated that controlled-release of EGCG from zein/CS NPs and its corresponding antioxidant activities in 95% ethanol fatty simulant may provide long-term protection against oxidation for fatty foods.


A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells.
Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, n-arachidonoyl dopamine, n-oleoyldopamine (OLDA), and n-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types.


Respiratory Tract Infections in Diabetes - Lessons From Tuberculosis and Influenza to Guide Understanding of COVID-19 Severity.
Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups. Several mechanisms have been proposed for this increased susceptibility, including pre-existing immune dysfunction, a lack of metabolic flexibility due to insulin resistance, inadequate dietary quality or adverse interactions with antidiabetic treatments or common comorbidities. Some mechanisms that predispose patients with T2D to severe COVID-19 may indeed be shared with other previously characterized respiratory tract infections. Accordingly, in this review, we give an overview of response to Influenza A virus and to Mycobacterium tuberculosis (Mtb) infections. Similar risk factors and mechanisms are discussed between the two conditions and in the case of COVID-19. Lastly, we address emerging approaches to address research needs in infection and metabolic disease, and perspectives with regards to deployment or repositioning of metabolically active therapeutics.


The impact of Telephonic Health Coaching on Health Outcomes in a High-risk Population.
Health coaching is a client-centric process to increase motivation and self-efficacy that supports sustainable lifestyle behavior changes and active management of health conditions. This study describes an intervention offered as a benefit to health plan members and examines health and behavioral outcomes of participants. High-risk health plan enrollees were invited to participate in a telephonic health coaching intervention addressing the whole person and focusing on motivating health behavior changes. Outcomes of self-reported lifestyle behaviors, perceived health, stress levels, quality of life, readiness to make changes, and patient activation levels were reported at baseline and upon program completion. Retrospectively, these data were extracted from administrative and health coaching records of participants during the first 2 full years of the program. Less than 7% of the 114 615 potential candidates self-selected to actively participate in health coaching, those with the highest chronic disease load being the most likely to participate. Of 6940 active participants, 1082 fully completed health inventories, with 570 completing Patient Activation Measure (PAM). The conditions most often represented in the active participants were depression, congestive heart failure, diabetes, hyperlipidemia, hypertension, osteoporosis, asthma, and low back pain. In 6 months or less, 89% of participants met at least one goal. Significant improvements occurred in stress levels, healthy eating, exercise levels, and physical and emotional health, as well as in readiness to make change and PAM scores. The types of client-selected goals most often met were physical activity, eating habits, stress management, emotional health, sleep, and pain management, resulting in improved overall quality of life regardless of condition. Positive shifts in activation levels and readiness to change suggest that health coaching is an intervention deserving of future prospective research studies to assess the utilization, efficacy, and potential cost-effectiveness of health coaching programs for a range of populations.


Identification of two [4Fe-4S]-cluster-containing hydro-lyases from Pyrococcus furiosus.
The hyperthermophilic archaeon Pyrococcus furiosus is a strict anaerobe. It is therefore not expected to use the oxidative tricarboxylic acid (TCA) cycle for energy transduction. Nonetheless, its genome encodes more putative TCA cycle enzymes than the closely related Pyrococcus horikoshii and Pyrococcus abyssi, including an aconitase (PF0201). Furthermore, a two-subunit fumarase (PF1755 and PF1754) is encoded on the Pyr. furiosus genome. In the present study, these three genes were heterologously overexpressed in Escherichia coli to enable characterization of the enzymes. PF1755 and PF1754 were shown to form a [4Fe-4S]-cluster-containing heterodimeric enzyme, able to catalyse the reversible hydratation of fumarate. The aconitase PF0201 also contained an Fe-S cluster, and catalysed the conversion from citrate to isocitrate. The fumarase belongs to the class of two-subunit, [4Fe-4S]-cluster-containing fumarate hydratases exemplified by MmcBC from Pelotomaculum thermopropionicum; the aconitase belongs to the aconitase A family. Aconitase probably plays a role in amino acid synthesis when the organism grows on carbohydrates. However, the function of the seemingly metabolically isolated fumarase in Pyr. furiosus has yet to be established.


A liquid-like organelle at the root of motile ciliopathy.
Motile ciliopathies are characterized by specific defects in cilia beating that result in chronic airway disease, subfertility, ectopic pregnancy, and hydrocephalus. While many patients harbor mutations in the dynein motors that drive cilia beating, the disease also results from mutations in so-called dynein axonemal assembly factors (DNAAFs) that act in the cytoplasm. The mechanisms of DNAAF action remain poorly defined. Here, we show that DNAAFs concentrate together with axonemal dyneins and chaperones into organelles that form specifically in multiciliated cells, which we term DynAPs, for dynein axonemal particles. These organelles display hallmarks of biomolecular condensates, and remarkably, DynAPs are enriched for the stress granule protein G3bp1, but not for other stress granule proteins or P-body proteins. Finally, we show that both the formation and the liquid-like behaviors of DynAPs are disrupted in a model of motile ciliopathy. These findings provide a unifying cell biological framework for a poorly understood class of human disease genes and add motile ciliopathy to the growing roster of human diseases associated with disrupted biological phase separation.


[Testicular leukemic infiltration].
To remind that despite its low incidence, leukemic relapse in the testicles worsens the prognosis of this haematopoietic neoplasia. We report the case of a 20-year-old male suffering from acute lymphoblastic leukemia in complete remission after induction and maintenance treatment, who suffered a leukemic relapse in both testicles. Diagnosis was made by ultrasound and confirmed after bilateral testicular biopsies. The patient died due to fungal infection after new treatment with systemic chemotherapy and bone marrow transplantation. It is necessary to suspect the existence of leukemic cells within the testicles in patients with this disease, mainly acute lymphoblastic leukemia, who present with acute testicular symptoms. Testicular biopsy confirms the diagnosis. Treatment is systemic, with testicular radiation to eradicate the leukemic reservoir. Despite the achievement of local disease control, this situation worsens the prognosis.


Mobile phone intervention and weight loss among overweight and obese adults: a meta-analysis of randomized controlled trials.
We conducted a meta-analysis of randomized controlled trials to examine the association of mobile phone intervention with net change in weight-related measures among overweight and obese adults. We searched electronic databases and conducted a bibliography review to identify articles published between the inception date of each database and March 27, 2014. Fourteen trials (including 1,337 participants in total) that met the eligibility criteria were included. Two investigators independently abstracted information on study characteristics and study outcomes. Net change estimates comparing the intervention group with the control group were pooled across trials using random-effects models. Compared with the control group, mobile phone intervention was associated with significant changes in body weight and body mass index (weight (kg)/height (m)(2)) of -1.44 kg (95% confidence interval (CI): -2.12, -0.76) and -0.24 units (95% CI: -0.40, -0.08), respectively. Subgroup analyses revealed that the associations were consistent across study-duration and intervention-type subgroups. For example, net body weight changes were -0.92 kg (95% CI: -1.58, -0.25) and -1.85 kg (95% CI: -2.99, -0.71) in trials of shorter (<6 months) and longer (≥6 months) duration, respectively. These findings provide evidence that mobile phone intervention may be a useful tool for promoting weight loss among overweight and obese adults.


CHOROIDEREMIA: Retinal Degeneration With an Unmet Need.
Choroideremia is an incurable, X-linked, recessive retinal dystrophy caused by loss of function mutations in the CHM gene. It is estimated to affect approximately 1 in 50,000 male patients. It is characterized by progressive degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. There is an unmet need in choroideremia, because currently, there are no approved treatments available for patients with the disease. We review the patient journey, societal impact, and emerging treatments for patients with choroideremia. Its relative rarity and similarities with other retinal diseases in early years mean that diagnosis of choroideremia can often be delayed. Furthermore, its impact on affected individuals, and wider society, is also likely underestimated. AAV2-mediated gene therapy is an investigational treatment that aims to replace the faulty CHM gene. Early-phase studies reported potentially important visual acuity gains and maintenance of vision in some patients, and a large Phase 3 program is now underway. Choroideremia is a disease with a significant unmet need. Interventions that can treat progression of the disease and improve visual and functional outcomes have the potential to reduce health care costs and enhance patient quality of life.


[Functional study of the hypophyseal-thyroid and adrenal systems in physiological pregnancy and late toxicosis].
A comprehensive study was conducted in 30 healthy nonpregnant women, 115 healthy pregnant women and in 38 pregnant women with late toxicosis as well as in 25 healthy infants and 29 infants born to mothers with late toxicosis. A radioimmunoassay was used to measure serum thyrotropin (TSH), somatotropin (STH), adrenocorticotropin (ACTH), thyroxine (T4), triiodothyronine (T3), cortisol (CORT) and aldosterone (ALDO) levels. A catecholamine (CA) level was determined dy fluorimetry. Elevated ACTH, TSH, CORT and ALDO levels were noted in normal pregnancy. The above data indicated that the pituitary-thyroid and pituitary-adrenal systems of pregnant women formed adaptive reactions to the body demand for hormones. The reduction of ACTH and T3 levels and rise of CORT, ALDO, T4 levels and the serum protein thyroxine-binding capacity were noted in the pregnant women with late toxicosis. These hormonal differences may be indicative of a decrease in the reserves of women with late toxicosis. It is concluded that the pituitary-thyroid and pituitary-adrenal systems in newborns are capable of maintaining homeostasis by the moment of birth.


Young-onset dementia: scoping review of key pointers to diagnostic accuracy.
Routine psychiatric assessments tailored to older patients are often insufficient to identify the complexity of presentation in younger patients with dementia. Significant overlap between psychiatric disorders and neurodegenerative disease means that high rates of prior incorrect psychiatric diagnosis are common. Long delays to diagnosis, misdiagnosis and lack of knowledge from professionals are key concerns. No specific practice guidelines exist for diagnosis of young-onset dementia (YOD). The review evaluates the current evidence about best practice in diagnosis to guide thorough assessment of the complex presentations of YOD with a view to upskilling professionals in the field. A comprehensive search of the literature adopting a scoping review methodology was conducted regarding essential elements of diagnosis in YOD, over and above those in current diagnostic criteria for disease subtypes. This methodology was chosen because research in this area is sparse and not amenable to a traditional systematic review. The quality of evidence identified is variable with the majority provided from expert opinion and evidence is lacking on some topics. Evidence appears weighted towards diagnosis in frontotemporal dementia and its subtypes and young-onset Alzheimer's disease. The literature demonstrates that a clinically rigorous and systematic approach is necessary in order to avoid mis- or underdiagnosis for younger people. The advent of new disease-modifying treatments necessitates clinicians in the field to improve knowledge of new imaging techniques and genetics, with the goal of improving training and practice, and highlights the need for quality indicators and alignment of diagnostic procedures across clinical settings. None.


Enchanted by the earliest stages of human life.
Editors' note: The Ogawa-Yamanaka Stem Cell Prize recognizes groundbreaking work in translational regenerative medicine using reprogrammed cells. The prize is supported by Gladstone Institutes, in partnership with Cell Press. Magdalena Zernicka-Goetz, recipient of the 2023 Ogawa-Yamanaka Stem Cell Prize, has created self-assembling embryo-like models that are advancing regenerative medicine.


Soy intake and breast cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population.
We reviewed epidemiological studies of soy intake and breast cancer among Japanese women. This report is one among a series of articles by our research group, which is evaluating the existing evidence concerning the association between health-related lifestyles and cancer. Original data were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database, complemented with manual searches. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility. Five cohort studies and six case-control studies were identified. Among the cohort studies, two studies observed that total soy intake (in terms of total amounts of soy foods or soy isoflavones) was associated with a moderate (0.5 ≤ relative risk ≤ 0.67 with statistical significance) or strong (relative risk ≤ 0.5 with statistical significance) risk reduction of breast cancer in postmenopausal women. Among the case-control studies, two studies reported a weak (0.67 ≤ odds ratio ≤ 1.5 with statistical significance or 0.5 ≤ odds ratio ≤ 0.67 without statistical significance) inverse association between total soy intake and the risk of breast cancer. In the former, this association was observed in all women combined-premenopausal and postmenopausal women-but in the latter, the association was confined to postmenopausal women. The associations of intakes of individual soy foods with the risk of breast cancer were generally null. There is some evidence that supports the biological plausibility of a protective effect of isoflavones on breast cancer risk. We conclude that soy intake possibly decreases the risk of breast cancer among Japanese women.


Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study.
The glucagon-like peptide-1 analog liraglutide increases heart rate and may be associated with more cardiac events in chronic heart failure (CHF) patients. We studied whether this could be ascribed to effects on myocardial glucose uptake (MGU), myocardial blood flow (MBF) and MBF reserve (MFR). CHF patients with left ventricular ejection fraction ≤45% and without type 2 diabetes were randomized to liraglutide (N = 18) 1.8 mg once daily or placebo (N = 18) for 24 weeks in a double-blinded design. Changes in MGU during an oral glucose tolerance test (OGTT) and changes in MBF and MFR from baseline to follow-up were measured quantitatively by 18F-FDG and 15O-H2O positron emission tomography. Compared with placebo, liraglutide reduced weight (P = 0.03), HbA1c (P = 0.03) and the 2-hour glucose value during the OGTT (P = 0.004). Despite this, changes in MGU (P = 0.98), MBF (P = 0.76) and MFR (P = 0.89) from baseline to follow-up did not differ between groups. Furthermore, there was no association between the level of insulin resistance at baseline and changes in MGU in patients treated with liraglutide. Liraglutide did not affect MGU, MBF, or MFR in non-diabetic CHF patients. Any potential increase in cardiac events in these patients seems not to involve changes in MGU, MBF, or MFR. Trial registry: http://www.ClinicalTrials.org . Identifier: NCT01472640. Url: https://clinicaltrials.gov/ct2/show/NCT01472640?term=NCT01472640&rank=1.


Single visual neurons code opposing motion independent of direction.
Cells in intermediate and deeper layers of the pigeon optic tectum respond best when a textured background pattern is moved in the opposite direction to a moving test spot. Complete inhibition occurs when the background moves in the same direction as the test stimulus. Most noteworthy is the invariance of this relationship over a wide range of test spot directions. These cells represent a higher level of abstraction in a motion-detecting system and may play a role in figure-ground segregation or the discrimination of the motion of an object from self-induced optical motion.


COX-2 in brain and spinal cord implications for therapeutic use.
Following the discovery of inducible COX-2 in arthritic joint fluid and immunocompetent cells a revolution in the field of antiinflammatory treatment was expected. The detection of a constitutive COX-2 in the kidney, in stomach and central nervous system destroyed this hypotheses. Further experiments in animal models were done to elucidate the role of the constitutive COX-2 in different physiological and pathophysiological states. In central nervous system was shown that the constitutive COX-2 is the predominant isoform of cyclooxygenases in brain and spinal cord and is highly regulated by different mediators. After experimental induction of peripheral inflammation a significant induction of COX-2 gene, protein expression and synthesis of prostaglandins in the spinal cord was detected. It was concluded that COX-2 is strongly involved in pain mediation processing in the spinal cord. The detection of COX-2 in the brain endothelial cells and its role in fever led to new insights of development and time course of temperature elevation. Probably, the use of selective COX-2 inhibitors decreases fever more effective than classical antipyretics. Furthermore, newer results show a role of COX-2 in differentiation and maturation processes in brain. These findings implicate new ways for the treatment of Alzheimer's disease and other degenerative brain disorders. Clinical and experimental results with selective COX-2 inhibitors show a better safety profile than non-selective COX inhibitors. The clinical use after drug registration will be decide on the further role of this new class of drugs in analgesic/antiinflammatory therapy and on new fields of clinical use.


The Impact of Low-Dose Cranial Boost on the Long-Term Outcomes of Adult Patients with High-Risk Acute Lymphoblastic Leukemia Undergoing Total Body Irradiation and Allogeneic Hematopoietic Stem Cell Transplantation.
Total body irradiation (TBI) is an integral part of the conditioning regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic, hematopoietic, cell transplantation (allo-HCT). There are conflicting data in the literature regarding the utility of a cranial irradiation boost in high-risk adult ALL without evidence of preexisting central nervous system (CNS) involvement. This study investigates the posttransplant clinical outcomes of patients with high-risk adult ALL undergoing TBI conditioning for allo-HCT with or without a whole-brain boost, without overt CNS involvement at the time of diagnosis. A retrospective cohort study was conducted using a medical record analysis. We identified 58 patients who were treated between January 1998 and December 2016, and met our preset inclusion criteria of adults (age >18 years old) who carried a pathologically confirmed diagnosis of CNS-negative, high-risk ALL, who underwent hematopoietic stem cell transplantation with TBI conditioning. A multivariate analysis of correlation between patient outcomes and collected categorical variables was assessed with stepwise Cox logistic regression. Survival analyses were assessed using the Kaplan-Meier technique with a log-rank test. With a median follow-up time of 5.3 years, there was a statistically significant improvement in actuarial 7-year CNS relapse-free survival (100% vs 76.4%; P = .043) in favor of patients undergoing a cranial boost. There was no statistically significant improvement in 7-year progression-free survival (78.3% vs 62.5%; P = .076) or overall survival (49.4% vs 43.5%; P = .921) with versus without a cranial boost. On multivariate analysis, the presence of a cranial boost was the only identified variable with an independent relationship to CNS relapse-free survival. Adult patients with high-risk, CNS-negative ALL were found to have a statistically significant improvement in CNS relapse-free survival and a trend toward improved progression-free survival with the inclusion of a cranial boost with TBI pretransplant conditioning. Our data indicate that further investigation into the use of cranial boost in this patient population is warranted.


Nanoparticles for imaging and tumor gene delivery.
Molecular imaging of receptors expressed on the surface of tumor cells is becoming a major field of investigation in clinical oncology, especially for the detection of cancer at its earliest stages. Nowadays, MRI, microcomputed tomography (microCT), ultrasound, positron emission tomography (PET), optical coherence tomography (OCT), and other major imaging systems are available to scientists and clinicians. Each technique has advantages and limitations, thus making them complementary. We report herein our investigations on the synthesis and use of new probes for small animal imaging as well as on the preparation and use of targeting complexes to deliver specific gene in tumors cells.


High-Performance Flexible InAs Thin-Film Photodetector Arrays with Heteroepitaxial Growth Using an Abruptly Graded InxAl1-xAs Buffer.
Current infrared thermal image sensors are mainly based on planar firm substrates, but the rigid form factor appears to restrain the versatility of their applications. For wearable health monitoring and implanted biomedical sensing, transfer of active device layers onto a flexible substrate is required while controlling the high-quality crystalline interface. Here, we demonstrate high-detectivity flexible InAs thin-film mid-infrared photodetector arrays through high-yield wafer bonding and a heteroepitaxial lift-off process. An abruptly graded InxAl1-xAs (0.5 < x < 1) buffer was found to drastically improve the lift-off interface morphology and reduce the threading dislocation density twice, compared to the conventional linear grading method. Also, our flexible InAs photodetectors showed excellent optical performance with high mechanical robustness, a peak room-temperature specific detectivity of 1.21 × 109 cm-Hz1/2/W at 3.4 μm, and excellent device reliability. This flexible InAs photodetector enabled by the heteroepitaxial lift-off method shows promise for next-generation thermal image sensors.


Does vitamin D intake during infancy promote the development of atopic allergy?
The active metabolite of vitamin D, 1,25-(OH)2D3, has immunomodulatory properties in addition to its more established action on bone and calcium metabolism. Recently vitamin D has been proposed as one of several environmental factors responsible for the increase in atopic diseases during the last decades. The objective of this study was to determine whether the estimated dose of dietary vitamin D3 during the first year of life is associated with atopic diseases up to the age of 6 years. In a prospective birth cohort study 123 six-year-old children were investigated for the cumulative incidence of atopic dermatitis, allergic rhinitis or asthma by means of a postal questionnaire. Their vitamin D3 intake during infancy was recorded in a previous study and the relationship between lower or higher vitamin D3 intake and atopic illness later in childhood was assessed. Atopic manifestations were more prevalent in the group with higher intake of vitamin D3. Although small, this study supports previous investigations suggesting a role of vitamin D intake during infancy in the development of atopic allergy later in childhood. If these findings are confirmed in prospective controlled clinical trials, prevention through modified vitamin D3 supplementation in infancy could be discussed to reduce the burden of atopic illnesses.


Soluble α-synuclein is a novel modulator of Alzheimer's disease pathophysiology.
Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.