The neglected burden of tuberculosis disease among health workers: a decade-long cohort study in South Africa.
Health workers (HWs) in resource-limited settings are at high-risk of exposure to tuberculosis (TB) at work. The aim of this study was to estimate the rate of TB disease among HWs in the Free State Province of South Africa between 2002 and 2012 and to compare demographic and clinical characteristics between HWs and the general population with TB. This study also explores the effect of occupational variables on risk of TB among HWs. Probabilistic record linkage was utilized to identify HWs who were also registered as TB patients. This historical prospective cohort study calculated incidence rate ratios (IRR) for TB disease among HWs in Free State from 2002 to 2012. Generalized linear mixed-effects regression was used to model the association between sex, race, facility type, occupation, duration of employment, and the rate of TB. There were 2677 cases of TB diagnosed among HWs from 2002 to 2012 and 1280 cases were expected. The overall TB incidence rate in HWs during the study period was 1496·32 per 100,000 compared to an incidence rate of 719·37 per 100,000 in the general population during the same time period. IRR ranged from 1·14 in 2012 to 3·12 in 2005. HWs who were male, black, coloured and employed less than 20 years had higher risk of TB. Facility type and occupation were not associated with increased risk of TB when adjusted for other covariates. HWs in South Africa have higher rates of TB than the general population. Improved infection prevention and control measures are necessary in all high-burden TB healthcare settings.


Inhibition of neural crest cell attachment by integrin antisense oligonucleotides.
Neural crest cell interactions with extracellular matrix molecules were analyzed with the use of antisense oligonucleotides to block synthesis of integrin subunits. When added to the culture medium of quail neural crest cells, selected antisense phosphorothiol oligonucleotides reduced the amounts of cell surface alpha 1 or beta 1 integrin subunits by up to 95 percent and inhibited neural crest cell attachment to laminin or fibronectin substrata. Differential effects on specific alpha integrins were noted after treatment with alpha-specific oligonucleotides. Cells recovered the ability to bind to substrata 8 to 16 hours after treatment with inhibitory oligonucleotides. The operation of at least three distinct alpha integrin subunits is indicated by substratum-selective inhibition of cell attachment.


Novel Biocontrol Methods for Listeria monocytogenes Biofilms in Food Production Facilities.
High mortality and hospitalization rates have seen Listeria monocytogenes as a foodborne pathogen of public health importance for many years and of particular concern for high-risk population groups. Food manufactures face an ongoing challenge in preventing the entry of L. monocytogenes into food production environments (FPEs) due to its ubiquitous nature. In addition to this, the capacity of L. monocytogenes strains to colonize FPEs can lead to repeated identification of L. monocytogenes in FPE surveillance. The contamination of food products requiring product recall presents large economic burden to industry and is further exacerbated by damage to the brand. Poor equipment design, facility layout, and worn or damaged equipment can result in Listeria hotspots and biofilms where traditional cleaning and disinfecting procedures may be inadequate. Novel biocontrol methods may offer FPEs effective means to help improve control of L. monocytogenes and decrease cross contamination of food. Bacteriophages have been used as a medical treatment for many years for their ability to infect and lyse specific bacteria. Endolysins, the hydrolytic enzymes of bacteriophages responsible for breaking the cell wall of Gram-positive bacteria, are being explored as a biocontrol method for food preservation and in nanotechnology and medical applications. Antibacterial proteins known as bacteriocins have been used as alternatives to antibiotics for biopreservation and food product shelf life extension. Essential oils are natural antimicrobials formed by plants and have been used as food additives and preservatives for many years and more recently as a method to prevent food spoilage by microorganisms. Competitive exclusion occurs naturally among bacteria in the environment. However, intentionally selecting and applying bacteria to effect competitive exclusion of food borne pathogens has potential as a biocontrol application. This review discusses these novel biocontrol methods and their use in food safety and prevention of spoilage, and examines their potential to control L. monocytogenes within biofilms in food production facilities.


Histopathology of experimental preretinal neovascularization.
Despite the morbidity resulting from abnormal retinal neovascularization, morphological events associated with its development have not been fully described. We therefore studied sequential morphologic events during preretinal neovascularization in an experimental model induced by injection of 250,000 homologous fibroblasts into the vitreous cavity of rabbits. Within 2 days following fibroblast injection, thickening of many venular and capillary endothelial cells resulted in partial obliteration of their lumina. 3H-thymidine incorporation occurred first in the nonvascular cells of the superficial medullary ray and thereafter in the preretinal vessels and extraretinal fibroblasts. Capillary budding was obvious within 3 days, with endothelial cells extending cytoplasmic processes into fragmented extracellular matrix (ECM). Endothelial cells, at the tips of budding vessels, and at more proximal sites in the parent vessel, incorporated 3H-thymidine and did not lose cell contact or migrate individually into the ECM. Lumina were present throughout the entire length of the buds and endothelial cells remained polarized. Neovascular events observed in this experimental model parallel those previously described in diabetic retinopathy and retinopathy of prematurity in humans.


Towards automatic pulmonary nodule management in lung cancer screening with deep learning.
The introduction of lung cancer screening programs will produce an unprecedented amount of chest CT scans in the near future, which radiologists will have to read in order to decide on a patient follow-up strategy. According to the current guidelines, the workup of screen-detected nodules strongly relies on nodule size and nodule type. In this paper, we present a deep learning system based on multi-stream multi-scale convolutional networks, which automatically classifies all nodule types relevant for nodule workup. The system processes raw CT data containing a nodule without the need for any additional information such as nodule segmentation or nodule size and learns a representation of 3D data by analyzing an arbitrary number of 2D views of a given nodule. The deep learning system was trained with data from the Italian MILD screening trial and validated on an independent set of data from the Danish DLCST screening trial. We analyze the advantage of processing nodules at multiple scales with a multi-stream convolutional network architecture, and we show that the proposed deep learning system achieves performance at classifying nodule type that surpasses the one of classical machine learning approaches and is within the inter-observer variability among four experienced human observers.


Early-auditory intervention in children with hearing loss and neurodevelopmental outcomes: cognitive, motor and language development.
To date, studies have mostly focused on the language outcome of early-auditory interventions including amplification for congenital hearing loss within the first 6 months. We aimed to examine the effect of early-auditory intervention in patients with congenital hearing loss on cognitive, motor and language outcomes, and determine the clinical variables that affect developmental outcomes. The medical records of 104 patients were retrospectively reviewed. Children were evaluated by the Bayley Scales of Infant and Toddler Development, Third Edition. The median ages of confirmation of hearing loss, amplification, starting auditory-verbal intervention and cochlear implantation were 9, 10, 13 and 19 months, respectively. Of the patients, 26% received a hearingaid fitting ≤6 months of age. Fifty-one children (49%) had additional disabilities. The median cognitive, language and motor scores of children with no additional disabilities were 95 (65-115), 68 (47-103) and 97 (58- 130), respectively and children with early-auditory intervention (≤6 months) demonstrated higher cognitive, receptive and expressive language subscale scores than late-auditory intervention group (p < 0.05) whereas there was no significant difference in motor scores (p > 0.05). A significant negative correlation was found between additional disability and cognitive, language and motor outcomes (r=-0.78, r=-0.54 and r=-0.75, respectively p < 0.01). There was a significant negative correlation between language outcomes and the degree of hearing loss (r=-0.20, p < 0.05). Multiple regression analyses revealed that additional disability and early-auditory intervention showed a significant amount of variance in cognitive and language scores. The early intervention did not make a significant, independent contribution on motor outcomes whereas additional disability did. Presence of additional disability was the strongest significant variable on developmental outcomes in hearing-impaired children. In children with no additional disability, significantly better cognitive and language scores were associated with the early-auditory intervention. Motor skills were not affected by the early-auditory intervention.


Protocol for the ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation) trial: a pragmatic multi-centre randomised controlled trial of surgical versus non-surgical treatment for proximal fracture of the humerus in adults.
Proximal humeral fractures, which occur mainly in older adults, account for approximately 4 to 5% of all fractures. Approximately 40% of these fractures are displaced fractures involving the surgical neck. Management of this group of fractures is often challenging and the outcome is frequently unsatisfactory. In particular it is not clear whether surgery gives better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform this decision. We aim to undertake a pragmatic UK-based multi-centre randomised controlled trial evaluating the effectiveness and cost-effectiveness of surgical versus standard non-surgical treatment for adults with an acute closed displaced fracture of the proximal humerus with involvement of the surgical neck. The choice of surgical intervention is left to the surgeon, who must use techniques that they are fully experienced with. This will avoid 'learning curve' problems. We will promote good standards of non-surgical care, similarly insisting on care-provider competence, and emphasize the need for comparable provision of rehabilitation for both groups of patients.We aim to recruit 250 patients from a minimum of 18 NHS trauma centres throughout the UK. These patients will be followed-up for 2 years. The primary outcome is the Oxford Shoulder Score, which will be collected via questionnaires completed by the trial participants at 6, 12 and 24 months. This is a 12-item condition-specific questionnaire providing a total score based on the person's subjective assessment of pain and activities of daily living impairment. We will also collect data for other outcomes, including general health measures and complications, and for an economic evaluation. Additionally, we plan a systematic collection of reasons for non-inclusion of eligible patients who were not recruited into the trial, and their baseline characteristics, treatment preferences and intended treatment. This article presents the protocol for a multi-centre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity. Current Controlled Trials ISRCTN50850043.


Bone anchor mesh fixation for complex laparoscopic ventral hernia repair.
Laparoscopic ventral hernia repair (LVHR) has gained wide acceptance by both surgeons and patients, but hernias that approach a bony prominence are more complex due to the difficulty of proper fixation. This study was conducted to evaluate the use of bone anchor mesh fixation for complex LVHR. A prospective study of patients having complex LVHR with bone anchors was conducted using patients from 2 academic institutions between July 2003 and December 2007. Patient demographic data, characteristics of the hernia, operative details, and postoperative outcomes were recorded. A total of 30 patients who had LVHR using bone anchors were evaluated (20 women, 10 men; mean age 60.9 years, range 41-83 years). In all, 17 suprapubic and 13 lateral hernias were included, requiring a mean of 2.8 and 3.2 bone anchors, respectively. The average hernia defect was 263 cm(2) (range 35-690 cm(2)), and the average mesh size was 663 cm(2) (range 255-1360 cm(2)). Mean operative time was 218 minutes (range 98-420 minutes), with an estimated blood loss of 46 mL (range 10-100 mL). The average length of stay was 5.2 days (range 1-26 days). Seven patients (23.3%) developed postoperative complications, and 1 patient in this study died (mortality 3.3%). During follow-up of 13.2 months (range 1-26 months), 2 patients (6.7%) developed a recurrent hernia. Bone anchors can be used successfully in the laparoscopic repair of complex ventral hernias, particularly with suprapubic and lateral hernias that approach a bony prominence. The complication rate is acceptable, with a short hospital stay and low recurrence rate.


What is the optimal duration of bisphosphonate therapy?
It is reasonable to stop bisphosphonates after 5 years of use and then to follow patients with markers of bone turnover. As long as the levels of these markers remain reduced, adding an antiresorptive drug does not make physiologic sense.


Limits to progressive reduction of resident skin bacteria by disinfection.
Antiseptic preparations used repeatedly to disinfect the skin caused a reduction in yield of resident flora to a low equilibrium level beyond which further reduction did not occur. This equilibrium varied with the antiseptic preparation used. In a comparison of three preparations, the lowest equilibrium level was obtained with 95% ethyl alcohol. The further reduction in yield of skin bacteria on using alcohol after repeated disinfection with an antiseptic detergent preparation ('two-phase' disinfection) was not paralleled by a further reduction when the preparations used in the two phases were reversed, the antiseptic detergent being used after repeated disinfection with ethyl alcohol. 'Two-phase' disinfection was therefore seen to be due to further reduction in skin bacteria from the low equilibrium obtained with the antiseptic detergent to the lower level obtainable by alcohol disinfection. When repeated disinfection to equilibrium with alcohol was followed by a 'second-phase' handwash with a non-antiseptic detergent and water, there was a large increase in the yield of skin bacteria. This finding supports the view that a low equilibrium level occurs when the reduction in density of accessible bacteria through disinfection is balanced by the emergence of bacteria drawn from deeper layers of the skin.


Conditional random slope: A new approach for estimating individual child growth velocity in epidemiological research.
Conditioning child growth measures on baseline accounts for regression to the mean (RTM). Here, we present the "conditional random slope" (CRS) model, based on a linear-mixed effects model that incorporates a baseline-time interaction term that can accommodate multiple data points for a child while also directly accounting for RTM. In two birth cohorts, we applied five approaches to estimate child growth velocities from 0 to 12 months to assess the effect of increasing data density (number of measures per child) on the magnitude of RTM of unconditional estimates, and the correlation and concordance between the CRS and four alternative metrics. Further, we demonstrated the differential effect of the choice of velocity metric on the magnitude of the association between infant growth and stunting at 2 years. RTM was minimally attenuated by increasing data density for unconditional growth modeling approaches. CRS and classical conditional models gave nearly identical estimates with two measures per child. Compared to the CRS estimates, unconditional metrics had moderate correlation (r = 0.65-0.91), but poor agreement in the classification of infants with relatively slow growth (kappa = 0.38-0.78). Estimates of the velocity-stunting association were the same for CRS and classical conditional models but differed substantially between conditional versus unconditional metrics. The CRS can leverage the flexibility of linear mixed models while addressing RTM in longitudinal analyses.


Environmental immune disruptors, inflammation and cancer risk.
An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.


Scientific basis for the design of small activated sludge systems.
The study presents an evaluation of the oxygen requirement and sludge production, modeled in terms of fundamental processes reflecting different biochemical transformations in activated sludge systems. Modern modeling concepts define substrate utilization and endogenous decay as major processes requiring final electron acceptors. Substrate and sludge components may be defined in terms of different parameters. Chemical oxygen demand (COD) and biochemical oxygen demand (BOD5) are the traditional substrate parameters. COD also serves to define biomass along with volatile suspended solids (VSS) parameter. Estimation of oxygen requirement and sludge production for aerobic activated sludge systems covering basic biochemical processes are defined for different substrate and sludge parameters, considering that each calculation is associated with a different stoichiometry on the basis of a selected parameter set. The German regulations are examined and the biochemical bases of the coefficients in the regulatory expressions are set in terms of fundamental model constants.


Lossy data compression of vibrotactile material-like textures.
Tactile content will be delivered over the Internet in the near future. Vibrotactile material-like textures that resemble the surfaces of wood, leather, etc., are representative of such content. We performed lossy compression of texture data for reducing the data size. We confirmed the effectiveness of two compression strategies: quantization and truncation of data beneath a shifted perceptual threshold curve. In the quantization strategy, the amplitude spectra of vibrotactile textures could be quantized in 14 steps. This reduced the data size to approximately one quarter without any noticeable quality deterioration. The method for truncating frequency components with amplitudes smaller than a shifted perceptual threshold curve was also effective, and it was preferable to the automatic deletion of subthreshold amplitudes. We reduced the data size of vibrotactile material textures to 10-20 percent of their original size by combining the lossy data compression strategy with Huffman coding, which is a lossless data compression method. Lossy compression algorithms will enhance the online delivery of vibrotactile material-like textures by decreasing their data size without significant loss of quality.


Evaluation of urine specific gravity and urine sediment as risk factors for urinary tract infections in cats.
It has been suggested that diseases that promote isosthenuria predispose to urinary tract infections because of a lack of the common bacteriostatic properties present in concentrated urine. The purpose of this study was to assess the clinicopathologic risk factors for positive urine culture outcome in cats with chronic kidney disease (CKD), diabetes mellitus (DM), uncontrolled hyperthyroidism (HT), or lower urinary tract disease (LUTD). For this retrospective study, medical records of all cats in which a urinalysis and aerobic bacterial urine culture were performed between January 1995 and December 2002 were reviewed. Signalment, body weight, and clinicopathologic data were recorded. Based on the medical records, cats were diagnosed with CKD, DM, HT, or LUTD. Prevalence odds ratios and 95% confidence intervals were calculated using logistic regression. Multivariate models were created for each variable of interest while controlling for the confounding effect of disease group. Six hundred fourteen cats met the criteria for inclusion in the study. Overall, positive urine cultures were identified in 16.9% of cats with CKD, 13.2% of cats with DM, 21.7% of cats with HT, and 4.9% of cats with clinical signs of LUTD. Decreasing urine specific gravity was not associated with positive urine culture when controlled for disease but pyuria, bacteriuria, and hematuria were all associated with positive urine culture outcome. Persians, females, increasing age, and decreasing body weight were all associated with positive urine culture outcome. Performing a urine culture sample based solely on the presence of isosthenuria does not seem warranted. Further studies are warranted to help identify host predisposing factors for urinary bacterial colonization in cats with these diseases.


Clove oil induces anaesthesia and blunts muscle contraction power in three Amazon fish species.
Clove oil is used as an anaesthetic for many species of fish worldwide; however, relatively few studies have assessed its effectiveness on Amazon fish species and no compelling evidence has ever been reported on the relaxant properties of this oil for skeletal muscle of fish. Thus, the objective of this study was to evaluate the latencies to deep anaesthesia and recovery, along with the myorelaxant effect of clove oil on three Amazon fish species: cardinal tetra, Paracheirodon axelrodi, banded cichlid, Heros severus and angelfish, Pterophyllum scalare, submitted to short-term anaesthetic baths. Fish were assayed in three groups of 60 fish each and individually anaesthetized in a completely randomized design with six clove oil concentrations using 10 fish/species/concentration. Electromyographic recordings from dorsal muscle were performed during stages of induction and recovery in which nine fish/species/stage were used. Deep anaesthesia was attained for all concentrations tested, and no mortalities were observed throughout the experiments and after a 48-h observation period. Concentration of 90 μL L-1 and above promoted fast deep anaesthesia (< 3 min) and calm recovery in angelfish and cardinal tetra, whereas the concentration of 60 μL L-1 sufficed to quickly anaesthetize banded cichlid. Times to full recovery were not significantly contrasting among species and occurred within appropriate time threshold (< 5 min). Clove oil exerted a conspicuous depression of muscle contraction power, and therefore can be effectively used as a muscle relaxant agent for P. scalare, P. axelrodi, H. severus and potentially, for other fish species.


Carrier frequency of HLA-DQB1*02 allele in patients affected with celiac disease: A systematic review assessing the potential rationale of a targeted allelic genotyping as a first-line screening.
Celiac Disease (CD) is an immune-mediated disorder, in which the HLA immunogenetic background (DQ2 and DQ8 heterodimers) and environmental trigger (gluten) are well established. Indeed, both factors are necessary - but not sufficient - to develop CD. However, it is very likely that CD is underdiagnosed in both developing and developed countries, due to several aspects, including the fact that a lot of patients present mild and/or atypical symptoms, without the presence of any recognized risk factors. Therefore, the possibility and feasibility of widened screening strategies to identify CD patients are debated. To provide further evidence of the main epidemiological importance of HLA-DQB1*02 allele in the population of CD patients. We performed a systematic search in PubMed, EMBASE, Cochrane, Web of Science and Scopus databases, in order to produce a systematic review assessing the carrier frequency of HLA-DQB1*02 allele in the celiac population. Following the PRISMA guidelines, we retrieved all the original articles describing CD patients' HLA-DQB1 genotype in such a way that could allow to assess the HLA-DQB1*02 carrier frequency among CD patients, along with the evidence of the appropriate diagnostic work-up to achieve a correct and final diagnosis of CD. The final output of this systematic search in the medical literature consisted of 38 studies providing the appropriate HLA-DQB1 genotype information of the respective CD population. According to this systematic review, including a pool of 4945 HLA-DQ genotyped CD patients, the HLA-DQB1*02 carrier frequency was 94.94%, meaning that only 5.06% of CD patients were completely lacking this allelic variant. Interestingly, if we consider only the studies whereby the prevalence of CD patients affected with type 1 diabetes mellitus was supposed or clearly established to be very low, the frequency of non-HLA-DQB1*02 carriers among CD patients dropped to 3.65%. Such a high carrier frequency of the HLA-DQB1*02 allelic variant (which is > 95%-96% in CD patients without risk factors, like type 1 diabetes mellitus comorbidity) might be exploited to consider a cost-effective and widened screening approach. If a sustainable strategy could be implemented through a low-cost targeted genetic test to detect the individual presence of HLA-DQB1*02 allele, an appropriate algorithm for serological screening in individuals resulting to be genetically predisposed to CD, might be considered.


Population densities, vegetation green-up, and plant productivity: impacts on reproductive success and juvenile body mass in reindeer.
Global warming is expected to cause earlier springs and increased primary productivity in the Arctic. These changes may improve food availability for Arctic herbivores, but may also have negative effects by generating a mismatch between the surge of high quality food in the spring and the timing of reproduction. We analyzed a 10 year dataset of satellite derived measures of vegetation green-up, population densities, calf body masses and female reproductive success in 19 reindeer (Rangifer tarandus) populations in Northern Norway. An early onset of spring and high peak plant productivity had positive effects on calf autumn body masses and female reproductive success. In addition, body masses and reproductive success were both negatively related to population density. The quantity of food available, as determined by the onset of vegetation green-up and plant productivity over the summer were the main drivers of body mass growth and reproductive success. We found no evidence for an effect of the speed of spring green-up. Nor did we detect a negative mismatch between early springs and subsequent recruitment. Effects of global warming on plant productivity and onset of spring is likely to positively affect sub-Arctic reindeer.


Socioeconomic background and war mortality during Vietnam's wars.
To understand the experience of North Vietnamese soldiers and civilians during the American war, I explore the paths leading Vietnamese men into battle by considering the relationship between socioeconomic status and war mortality. I use data obtained from retrospective information on kin survival and other socioeconomic characteristics given by respondents in the 1995 Vietnam Longitudinal Survey conducted in Vietnam's Red River Delta. My findings are opposite to those often cited to describe the experience of young Americans who fought in the Vietnam war. In Vietnam, sons of better-educated fathers bore the burden of war disproportionately in relation to sons of fathers with less education, both in proportion serving in the military and in diminished survival chances in combat. The Vietnamese experience during the American war testifies to the ability of a nation to reorder society temporarily and to persuade higher-status groups to contribute fully to the war effort. An appreciation of the meaning of this social reshuffling during the American war is critical for understanding the war, Vietnam, and that country's political outlook.


Quantitative analysis of Fuller's earth using laser-induced breakdown spectroscopy and inductively coupled plasma/optical emission spectroscopy.
Fuller's earth, most commonly known as Multani Matti (clay) in Urdu, among its various utilizations is traditionally used in skin care cosmetics, particularly for removing blackheads and to treat oily skin. It is also used for improving skin complexion. In this paper, laser-induced breakdown spectroscopy (LIBS) was effectively employed for the quantitative investigation of various clay samples for their special uses. To get the LIBS spectra with an optimal signal-to-noise as well as for a more robust and accurate analytical investigation, different experimental parameters (laser energy, gate delay time, and the distance between target and focusing lens) were optimized before the experiments on actual samples. The analysis of emission spectra revealed the presence of many different elements, including Al, Ca, Fe, Mg, Mn, Na, K, Li, S, Si, and Zn. The electron number density and plasma temperatures were determined using the Stark broadened line profile and Boltzmann plot method, respectively. To determine the relative concentration of observed elements, we used an integrated intensity ratio method, integrated intensity of every line from all elements, and calibration free (CF)-LIBS. The prevailing condition of local thermodynamic equilibrium during the experimental executions was verified with multiple criteria. The spectral lines used in CF-LIBS were characterized for the influence from the self-absorption phenomenon, but the same was found insignificant. The findings of our LIBS system were found to agree excellently with the outcomes of the inductively coupled plasma/optical emission spectroscopy, thereby yielding a high statistical correlation factor and hence enlighten the significance of LIBS as a safe and reliable tool for elemental analysis of clay samples.


Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice.
Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf-2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor.


Congenital dermal sinus with an infected dermoid cyst in the cervico-thoracic spinal cord.
Congenital dermal sinuses (CDS) are epithelium-lined tracts that result from incomplete separation of cutaneous ectoderm from the underlying neuroectoderm. CDS may be associated with dermoid cysts and can cause complications by mass effect and by functioning as a pathway for infection. Cervical and thoracic tracts are rare, making up 1 and 10% of all CDS, respectively. We present an unusual case of a cervico-thoracic CDS with concomitant infected dermoid leading to neurological dysfunction. A 1-year-old male with a normal developmental history presented with a several-week history of progressive weakness. Previous visits to two outside emergency departments diagnosed the patient with acute otitis media. After another episode of fever and worsening of neurological symptoms, the patient was correctly diagnosed as having CDS with an infected dermoid cyst. Antibiotics were initiated, the lesion was resected, and the patient improved neurologically. Although cervical and thoracic CDS with infected dermoids are rare, one should have a high index of suspicion when cutaneous stigmata of spinal dysraphism are identified. Due to the risk of neurological deterioration, the recommended treatment of CDS with or without a concomitant intraspinal dermoid is prompt administration of antibiotics and definitive surgical intervention.


Recording and reconstruction of a color holographic image by using digital lensless Fourier transform holography.
The numerical recording and reconstruction of a color holographic image are achieved by using digital lensless Fourier transform holography. Firstly, for a color object, three monochromatic digital holograms with different wavelengths (red, green, blue) are recorded by a black-white CCD, respectively. Then the reconstructed monochromatic holographic images (red, green, blue) are adjusted to be same in size through padding digital holograms with zeros, and the corresponding digital color holographic image is acquired by accurately syncretizing the resized reconstructed monochromatic images. One of the advantages using lensless Fourier transform holography is that it can well assure the precise superposition of the reconstructed images. By applying median filtering technique and superposing the speckle fields with different distributions, the speckle noises are well suppressed and the quality of the digital color holographic image is greatly improved. This digital color holography with high quality of reconstruction effect would have potential applications on digital holographic display of color objects.


Post-prostatectomy incontinence: Etiology, evaluation, and management.
Urinary incontinence after prostatectomy or radiation is a devastating problem in men and remains the most feared complication following the treatment of localized prostate cancer. With an increasing number of radical prostatectomies performed globally for prostate cancer, the impact of urinary incontinence on quality of life assumes an even greater importance. With the advent of male sling procedures, more men are now seeking treatment for incontinence. Since the introduction of the artificial urinary sphincter almost four decades ago, several surgical procedures have emerged to manage post-prostatectomy incontinence, including the male sling for milder forms of incontinence. Several of the newer procedures have shown promise in the United States; many others have been developed and utilized in other parts of the world, though they have not yet gained FDA approval in the United States. The present review seeks to illuminate the etiology, evaluation, and management of post-prostatectomy incontinence. An effort has been made to provide an algorithm to clinicians for appropriate surgical management. The surgical techniques of commonly performed procedures and their outcomes are described.


Incidence of Second ACL Injuries 2 Years After Primary ACL Reconstruction and Return to Sport.
The incidence of second anterior cruciate ligament (ACL) injuries in the first 12 months after ACL reconstruction (ACLR) and return to sport (RTS) in a young, active population has been reported to be 15 times greater than that in a previously uninjured cohort. There are no reported estimates of whether this high relative rate of injury continues beyond the first year after RTS and ACLR. The incidence rate of a subsequent ACL injury in the 2 years after ACLR and RTS would be less than the incidence rate reported within the first 12 months after RTS but greater than the ACL injury incidence rate in an uninjured cohort of young athletes. Cohort study; Level of evidence, 2. Seventy-eight patients (mean age, 17.1 ± 3.1 years) who underwent ACLR and were ready to return to a pivoting/cutting sport and 47 controls (mean age, 17.2 ± 2.6 years) who also participated in pivoting/cutting sports were prospectively enrolled. Each participant was followed for injury and athlete exposure (AE) data for a 24-month period after RTS. Twenty-three ACLR and 4 control participants suffered an ACL injury during this time. Incidence rate ratios (IRRs) were calculated to compare the rates (per 1000 AEs) of ACL injury in athletes in the ACLR and control groups. For the ACLR group, similar comparisons were conducted for side of injury by sex. The overall incidence rate of a second ACL injury within 24 months after ACLR and RTS (1.39/1000 AEs) was nearly 6 times greater (IRR, 5.71; 95% CI, 2.0-22.7; P = .0003) than that in healthy control participants (0.24/1000 AEs). The rate of injury within 24 months of RTS for female athletes in the ACLR group was almost 5 times greater (IRR, 4.51; 95% CI, 1.5-18.2; P = .0004) than that for female controls. Although only a trend was observed, female patients within the ACLR group were twice as likely (IRR, 2.43; 95% CI, 0.8-8.6) to suffer a contralateral injury (1.13/1000 AEs) than an ipsilateral injury (0.47/1000 AEs). Overall, 29.5% of athletes suffered a second ACL injury within 24 months of RTS, with 20.5% sustaining a contralateral injury and 9.0% incurring a retear injury of the ipsilateral graft. There was a trend toward a higher proportion of female participants (23.7%) who suffered a contralateral injury compared with male participants (10.5%) (P = .18). Conversely, for ipsilateral injuries, the incidence proportion between female (8.5%) and male (10.5%) participants was similar. These data support the hypothesis that in the 24 months after ACLR and RTS, patients are at a greater risk to suffer a subsequent ACL injury compared with young athletes without a history of ACL injuries. In addition, the contralateral limb of female patients appears at greatest risk.


Microbial diversity and population dynamics of activated sludge microbial communities participating in electricity generation in microbial fuel cells.
In this study, we performed microbial community analysis to examine microbial diversity and community structure in microbial fuel cells (MFCs) seeded with activated sludge from a municipal wastewater treatment plant in South Korea. Because anode-attached biofilm populations are particularly important in electricity transfer, the ecological characteristics of anode-attached biofilm microbes were explored and compared with those of microbes grown in suspension in an anode chamber. 16S rDNA-based community analysis showed that the degree of diversity in anode-attached biofilms was greater than that of the originally seeded activated sludge as well as that of the suspension-grown microbes in the anode bottle. In addition, Bacteroidetes and Clostridia grew preferentially during MFC electricity generation. Further phylogenetic analysis revealed that the anode biofilm populations described in this work are phylogenetically distant from previously characterized MFC anode biofilm microbes. These findings suggest that a phylogenetically diverse set of microbes can be involved in the electricity generation of MFC anode compartments, and that increased microbial diversity in anode biofilms may help to stabilize electricity production in the MFC.


Developing a Tool for Evaluation of Causes of Futile Care in Intensive Care Units.
In Iran, futile care has become a challenge for intensive care nurses. The aim of the study was to develop a tool for assessing the reasons of futile care at intensive care units (ICUs). A sequential mixed method in three stages was applied. In the first stage, a phenomenological study was performed with van Manen's method by interviewing 25 nurses at ICUs of 11 hospitals in Qazvin. To extract the items of the tool in the second stage, the concept of futile care in ICUs and its reasons were defined. Ultimately, the psychometric properties of the questionnaire were evaluated with face validity, content validity (quantitative and qualitative), construct validity (exploratory factor analysis), internal consistency (Cronbach's alpha), and test-retest reliability. The initial tool had 119 questions. After validation, 39 items remained in the final questionnaire. Five extracted factors were as follows: professional competence (14 items), organizational policy (9 items), socio-cultural factors (7 items), personal beliefs and values (4 items), and legal issues (5 items). Cronbach's alpha for the whole questionnaire was 0.91 (range: 0.71-0.96). The test-retest reliability was 0.87 (p < 0.001). Nursing managers and clinical nurses can use this tool to identify the causes of futile care and reduce it in their clinical settings. Policy makers can use this tool for improving the management of ICUs.


Women's occupations, energy expenditure, and cardiovascular risk factors.
The purpose of this study was to examine the cardiovascular risk factors and energy expenditure of women from occupations that differ by physical activity level and socioeconomic level. Participants included 171 women randomly selected from employee lists at 10 employment sites. Measures included blood pressure, body mass index, levels of total and high-density lipoprotein (HDL) cholesterol, a submaximal aerobic fitness test on a bicycle ergometer, and a 12-month retrospective self-report of occupational, leisure time, and household energy expenditure. Women in active occupations had lower total cholesterol and higher HDL cholesterol than women in sedentary occupations. Women with higher occupational energy expenditure scores had higher HDL cholesterol and lower total cholesterol than women with lower occupational energy scores. Findings suggest that cardiovascular benefits, particularly for lipid profiles, may be derived from even small increases in occupational physical activity. The workplace may offer an environment for initiating policies to facilitate increased physical activity among women.


Comparisons of the cost-effectiveness among hospital chronic care, nursing home placement, home nursing care and family care for severe stroke patients.
This study compared the cost and effectiveness of long-term institutional care and home care for stroke patients with severe physical disabilities. Whether home care is more economical or effective than institutional care for patients with chronic illnesses remains controversial when the cost of family labour is considered. Thus, decisions concerning the appropriate type of care setting for patients with severe chronic illness remain difficult. From November 1995 to March 1996, 313 hospitalized stroke patients with severe physical disabilities treated at one of five hospitals in the Taipei metropolitan area were followed from the day of hospital discharge until the third month after discharge. These 313 patients were divided into four groups as follows: (1) 106 who were admitted to a chronic care unit in a hospital, (2) 60 who were admitted to nursing homes, (3) 60 who received professional home nursing care and (4) 87 who returned home without receiving professional care. The change of physical functional status in the patient was examined as the difference between activities of daily living (ADL) scores measured at discharge and at the end of the third month after discharge. Information on family costs for caregiving, including pay for long-term services utilized, labour costs for caregiving and out-of-pocket expenditures for miscellaneous materials was obtained during a weekly telephone interview. The results indicated that caring for patients in their own homes was not only more expensive but was also less effective in improving ADL scores than caring for patients in nursing homes and in chronic care units of hospitals. The results suggest that caring for patients with severe physical disabilities in institutions is more appropriate than caring of them at home.


Dietary fiber and amyotrophic lateral sclerosis: results from 5 large cohort studies.
Amyotrophic lateral sclerosis (ALS) is a fast-progressing neurodegenerative disease with a median survival time from diagnosis of 1.5-3 years. The cause of ALS is unknown, but inflammation may play a role. Fiber has been shown to lower inflammatory markers, and a high fiber intake was associated with a lower risk of ALS in a case-control study; however, prospective studies are lacking. We explored the relation between dietary intake of fiber and the risk of ALS in 5 large prospective cohort studies comprising over 1,050,000 US citizens who contributed 1,133 ALS cases during a mean of 15 years of follow-up (1980-2008). Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. We found that intakes of total fiber, cereal fiber, vegetable fiber, and fruit fiber were not associated with ALS risk when comparing the highest quintile of intake with the lowest (for total fiber, pooled multivariable relative risk (RR) = 0.99, 95% confidence interval (CI): 0.80, 1.24; for cereal fiber, RR = 1.13, 95% CI: 0.94, 1.37; for vegetable fiber, RR = 0.97, 95% CI: 0.77, 1.23; and for fruit fiber, RR = 1.05, 95% CI: 0.86, 1.29). These findings do not support the hypothesis that fiber intake is a major determinant of ALS risk.


Function of the Plant DNA Polymerase Epsilon in Replicative Stress Sensing, a Genetic Analysis.
Faithful transmission of the genetic information is essential in all living organisms. DNA replication is therefore a critical step of cell proliferation, because of the potential occurrence of replication errors or DNA damage when progression of a replication fork is hampered causing replicative stress. Like other types of DNA damage, replicative stress activates the DNA damage response, a signaling cascade allowing cell cycle arrest and repair of lesions. The replicative DNA polymerase ε (Pol ε) was shown to activate the S-phase checkpoint in yeast in response to replicative stress, but whether this mechanism functions in multicellular eukaryotes remains unclear. Here, we explored the genetic interaction between Pol ε and the main elements of the DNA damage response in Arabidopsis (Arabidopsis thaliana). We found that mutations affecting the polymerase domain of Pol ε trigger ATR-dependent signaling leading to SOG1 activation, WEE1-dependent cell cycle inhibition, and tolerance to replicative stress induced by hydroxyurea, but result in enhanced sensitivity to a wide range of DNA damaging agents. Using knock-down lines, we also provide evidence for the direct role of Pol ε in replicative stress sensing. Together, our results demonstrate that the role of Pol ε in replicative stress sensing is conserved in plants, and provide, to our knowledge, the first genetic dissection of the downstream signaling events in a multicellular eukaryote.


Expression of acidic fibroblast growth factor and basic fibroblast growth factor in nasal polyps.
Up-regulated expression of acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) in nasal polyps may be related to epithelial proliferation and neoangiogenesis associated with nasal polyp growth. aFGF and bFGF are polypeptides that effect mitogenesis, neoangiogenesis and tissue repair. The purpose of this study was to investigate the expression of aFGF and bFGF at both the mRNA and protein levels in nasal polyps. Tissue samples of nasal polyp and inferior turbinate mucosae were obtained. Reverse transcriptase (RT)-PCR, in situ hybridization, and Western blotting for aFGF and bFGF were performed in nasal polyp and nasal inferior turbinate. RT-PCR showed 50% aFGF and 29% bFGF expression positivity in 14 nasal polyps; however, 13 turbinates revealed no PCR products. aFGF and bFGF expression was localized to some inflammatory cells of nasal polyps by in situ hybridization. Western blotting identified aFGF and bFGF molecular masses of 18 kDa and 24 kDa, respectively, in nasal polyps, and these levels were higher than those observed in nasal turbinates. aFGF and bFGF proteins were also localized in some inflammatory cells of nasal polyps by immunostaining.


Stochastic Image Registration with User Constraints.
Constrained registration is an active area of research and is the focus of this work. This note describes a non-rigid image registration framework for incorporating landmark constraints. Points that must remain stationary are selected, the user chooses the spatial extent of the inputs, and an automatic step computes the deformable registration, respecting the constraints. Parametrization of the deformation field is by an additive composition of a similarity transformation and a set of Gaussian radial basis functions. The bases' centers, variances, and weights are determined with a global optimization approach that is introduced. This approach is based on the particle filter for performing constrained optimization; it explores a series of states defining a deformation field that is physically meaningful (i.e., invertible) and prevents chosen points from moving. Results on synthetic two dimensional images are presented.


Accounting for uncertainty in model-based prevalence estimation: paratuberculosis control in dairy herds.
A common approach to the application of epidemiological models is to determine a single (point estimate) parameterisation using the information available in the literature. However, in many cases there is considerable uncertainty about parameter values, reflecting both the incomplete nature of current knowledge and natural variation, for example between farms. Furthermore model outcomes may be highly sensitive to different parameter values. Paratuberculosis is an infection for which many of the key parameter values are poorly understood and highly variable, and for such infections there is a need to develop and apply statistical techniques which make maximal use of available data. A technique based on Latin hypercube sampling combined with a novel reweighting method was developed which enables parameter uncertainty and variability to be incorporated into a model-based framework for estimation of prevalence. The method was evaluated by applying it to a simulation of paratuberculosis in dairy herds which combines a continuous time stochastic algorithm with model features such as within herd variability in disease development and shedding, which have not been previously explored in paratuberculosis models. Generated sample parameter combinations were assigned a weight, determined by quantifying the model's resultant ability to reproduce prevalence data. Once these weights are generated the model can be used to evaluate other scenarios such as control options. To illustrate the utility of this approach these reweighted model outputs were used to compare standard test and cull control strategies both individually and in combination with simple husbandry practices that aim to reduce infection rates. The technique developed has been shown to be applicable to a complex model incorporating realistic control options. For models where parameters are not well known or subject to significant variability, the reweighting scheme allowed estimated distributions of parameter values to be combined with additional sources of information, such as that available from prevalence distributions, resulting in outputs which implicitly handle variation and uncertainty. This methodology allows for more robust predictions from modelling approaches by allowing for parameter uncertainty and combining different sources of information, and is thus expected to be useful in application to a large number of disease systems.


Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon.
The neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) were compared for their effects in promoting the survival and/or regulation of expression of phenotypic markers of dopaminergic and GABAergic neurons in cultures derived from embryonic rat ventral mesencephalon. Dopaminergic neuron number and phenotypic expression were monitored by tyrosine hydroxylase (TH) immunocytochemistry, and measurement of high-affinity dopamine uptake activity and dopamine content, respectively. High-affinity GABA uptake, glutamic acid decarboxylase (GAD) activity, and endogenous GABA content were used to detect GABAergic neurons. Seven days of treatment with either BDNF or NT-3 resulted in dose-dependent increases in the number of TH-positive neurons, with maximal responses of 3-fold and 2.3-fold, respectively. Dopamine uptake activity and dopamine content were similarly increased. The effects of BDNF and NT-3 on dopamine uptake activity showed no additivity. NT-4/5 treatment elicited the greatest increase (7-fold) in the number of TH-positive neurons, as well as a 2.6-fold increase in dopamine content. In marked contrast to BDNF or NT-3, NT-4/5 had no effect on dopamine uptake capacity. BDNF, NT-3, or NT-4/5 also produced dose-dependent elevations of 2-3-fold in GABA uptake activity. These effects were not additive. GAD activity was increased by BDNF (1.8-fold) and NT-3 (threefold) treatment, but not by NT-4/5, whereas GABA content was increased to a similar extent by all three neurotrophins. NGF had no effect on any of the parameters measured in this study. Northern analyses indicated that the mRNAs encoding TrkB and TrkC, the functional high-affinity receptors for BDNF and NT-4/5, and NT-3, respectively, are expressed in the substantia nigra of adult rat brain, as well as in cultures of developing ventral mesencephalon. Taken together, our results indicate that BDNF and NT-3 have broadly similar effects in promoting the survival and differentiated phenotype of both dopaminergic and GABAergic neurons of the developing substantia nigra. Although BDNF and NT-4/5 are thought to act through the same high-affinity receptor, TrkB, it is evident that these two neurotrophins have distinct as well as overlapping actions toward mesencephalic dopaminergic or GABAergic neurons.


Cryptococcosis as an emerging systemic mycosis in dogs.
To review the etiology, pathogenesis, and clinical presentations of canine cryptococcosis that are of relevance to veterinary emergency and critical care veterinarians. Diagnosis, treatment, and public health considerations of the disease will also be discussed. Cryptococcosis is a multisystemic disease of dogs, with a predilection for the CNS, caused by encapsulated yeast species of the genus Cryptococcus. The 2 main pathogenic species are Cryptococcus neoformans and Cryptococcus gattii (previously known as C. neoformans var. gattii). Cryptococcosis is an emerging disease in North America, with C. gattii gaining prominence as a cause of serious veterinary and human disease. Definitive diagnosis is made by serologic (antigen) testing, culture, and identification of the organism using light microscopy. False negatives and false positives, while uncommon, can occur in dogs using commercially available antigen tests. Cytological examination demonstrates the organism in a majority of cases, although culture is more sensitive. Specific media are required to differentiate between C. neoformans and C. gattii. The most commonly used antifungal drugs to treat canine cryptococcosis are azole antifungals and amphotericin B. Some strains of Cryptococcus are resistant to antifungal drugs, especially fluconazole. Cautious use of glucocorticoids in critically affected dogs with CNS presentations can improve outcome. Prognosis is variable and depends on the severity of disease, underlying host immunocompetence, and financial constraints of the owner. Altered mental status in dogs with CNS cryptococcosis is a negative prognostic indicator.


Ancillary study management systems: a review of needs.
The valuable clinical data, specimens, and assay results collected during a primary clinical trial or observational study can enable researchers to answer additional, pressing questions with relatively small investments in new measurements. However, management of such follow-on, "ancillary" studies is complex. It requires coordinating across institutions, sites, repositories, and approval boards, as well as distributing, integrating, and analyzing diverse data types. General-purpose software systems that simplify the management of ancillary studies have not yet been explored in the research literature. We have identified requirements for ancillary study management primarily as part of our ongoing work with a number of large research consortia. These organizations include the Center for HIV/AIDS Vaccine Immunology (CHAVI), the Immune Tolerance Network (ITN), the HIV Vaccine Trials Network (HVTN), the U.S. Military HIV Research Program (MHRP), and the Network for Pancreatic Organ Donors with Diabetes (nPOD). We also consulted with researchers at a range of other disease research organizations regarding their workflows and data management strategies. Lastly, to enhance breadth, we reviewed process documents for ancillary study management from other organizations. By exploring characteristics of ancillary studies, we identify differentiating requirements and scenarios for ancillary study management systems (ASMSs). Distinguishing characteristics of ancillary studies may include the collection of additional measurements (particularly new analyses of existing specimens); the initiation of studies by investigators unaffiliated with the original study; cross-protocol data pooling and analysis; pre-existing participant consent; and pre-existing data context and provenance. For an ASMS to address these characteristics, it would need to address both operational requirements (e.g., allocating existing specimens) and data management requirements (e.g., securely distributing and integrating primary and ancillary data). The scenarios and requirements we describe can help guide the development of systems that make conducting ancillary studies easier, less expensive, and less error-prone. Given the relatively consistent characteristics and challenges of ancillary study management, general-purpose ASMSs are likely to be useful to a wide range of organizations. Using the requirements identified in this paper, we are currently developing an open-source, general-purpose ASMS based on LabKey Server (http://www.labkey.org) in collaboration with CHAVI, the ITN and nPOD.


Resting heart rate changes after endurance training in older adults: a meta-analysis.
Question remains regarding endurance training and changes in resting heart rate (HR) among older individuals. The objective of this meta-analysis was to determine the effects of controlled aerobic training on resting HR among sedentary older adults. Studies were identified by a systematic computer database search, hand article search, and cross-reference. The inclusion criteria were (i) controlled clinical trials, (ii) endurance exercise as the only intervention, (iii) a nonexercise control group, (iv) within-group mean ages of subjects > or = 60 yr, (v) a measure of changes in resting HR, (vi) studies published in English journals. Outcome was derived from 13 studies with a total of 651 individuals in 14 control (N = 241) and 16 exercise groups (N = 410). The pooled standardized effect size by a fixed-effect model showed an upper moderate effect of -0.58 +/- 0.08 (mean +/- SEM, 95% CI = -0.74 to -0.42). This homogeneity effect was statistically significant (P = 0.001). The magnitude of net change averaged -6 bpm (-2 to -12 bpm), representing an 8.4% reduction. Greater and statistically significant decrease of resting HR among the elderly was found in the studies with training length more than 30 wk. This meta-analytic investigation supports the efficacy of endurance exercise training in decreasing HR at rest in older adults. This training induced adaptation may have protective benefits for cardiovascular aging. A longer exercise training length, probably more than 30 wk, may be needed for older individuals to be more effective in terms of resting HR reduction.


Concentrated stress effects of contoured and non-contoured high Tibial osteotomy plates: A finite-element study.
The TomoFix plate has been extensively used in high tibial osteotomy surgery to stabilize the distracted tibial bones. However, distal pain related to plate irritation was considered one of the most relevant complications for this fixation device. This study aimed to correlate reports of distal pain with the profiles of the distracted tibia and initial plate and plate contour. This study used the finite-element method to investigate the profile-, distraction-, and contour-induced effects on stress distribution of the distal tibia-plate contact. The associations of two tibia profiles (normal and concave), distraction angles, and two plate profiles (contoured and non-contoured) were discussed in this study. The areas and stresses of the distal tibia-plate contact were chosen as comparison indices. Before weight-bearing, the non-contoured plates of the normal and concave tibia profiles consistently showed less contact area at the distal tibia-plate region. Consequently, the physiological loads make the non-contoured plate subject to more concentrated bone stresses and thus may induce more pain at the distal tibia-plate region than a contoured plate. When the distraction angle decreases, the tibia-plate gap increases. Prior to fixation, the tibia-plate gap can be evaluated by the profiles of the distracted tibia and non-contoured plate by use of anteroposterior radiograph and computer-aided simulation. In the situations of a lower distraction angle or a large tibia-plate gap, the use of a plate bender or a lag screw is recommended in order to contour the plate for reducing the concentrated stress at the distal tibia-plate region.


Role of gender in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation.
Heterotopic ossification most commonly occurs after burn injury, joint arthroplasty, and trauma. Male gender has been identified as a risk factor for the development of heterotopic ossification. It remains unclear why adult male patients are more predisposed to this pathologic condition than adult female patients. In this study, the authors use their validated tenotomy/burn model to explore differences in heterotopic ossification between male and female mice. The authors used their Achilles tenotomy and burn model to evaluate the osteogenic potential of mesenchymal stem cells of male and female injured and noninjured mice. Groups consisted of injured male (n = 3), injured female (n = 3), noninjured male (n = 3), and noninjured female (n = 3) mice. The osteogenic potential of cells harvested from each group was assessed through RNA and protein levels and quantified using micro-computed tomographic scan. Histomorphometry was used to verify micro-computed tomographic findings, and immunohistochemistry was used to assess osteogenic signaling at the site of heterotopic ossification. Mesenchymal stem cells of male mice demonstrated greater osteogenic gene and protein expression than those of female mice (p < 0.05). Male mice in the burn group formed 35 percent more bone than female mice in the burn group. This bone formation correlated with increased pSmad and insulin-like growth factor 1 signaling at the heterotopic ossification site in male mice. The authors demonstrate that male mice form quantitatively more bone compared with female mice using their burn/tenotomy model. These findings can be explained at least in part by differences in bone morphogenetic protein and insulin-like growth factor 1 signaling.


Constitutive expression of human hsp27, Drosophila hsp27, or human alpha B-crystallin confers resistance to TNF- and oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts.
Hyperthermia and other forms of stress that induce and/or stimulate heat shock or stress protein (hsp) expression enhance the cellular resistance to TNF-alpha. One of the stress proteins, hsp70, has been shown to participate in the molecular mechanisms that regulate this phenomenon. Here we have tested the capability of small hsps from different species to protect against this cytokine in the TNF-sensitive L929 fibrosarcoma cells. The genes that encode human hsp27, Drosophila hsp27, and human alpha B-crystallin were placed under the control of the constitutive SV40 early promoter and were stably introduced into L929 cells. We observed that all clones that constitutively expressed the exogenous small hsps exhibited a strong protection against TNF-mediated killing, which was proportional to the level of the expressed proteins. This phenomenon did not correlate with altered binding of TNF-alpha to its receptors, and no protection was observed as a consequence of the transfection or selection procedures. In addition, the overexpression of the exogenous small hsps did not modify the level of the endogenous stress proteins in the transfected clones. Remarkably, the small hsps also induced a protection against oxidative stresses generated by either hydrogen peroxide or menadione. In L929 cells, the killing induced by TNF-alpha and oxidative stress is thought to occur through the accumulation of intracellular reactive oxygen intermediates. Hence, our data suggest that the small hsps from different species share the property to protect L929 cells against the deleterious effects of reactive oxygen intermediates generated by either TNF-alpha or oxidative stress.


Substrate tRNA recognition mechanism of a multisite-specific tRNA methyltransferase, Aquifex aeolicus Trm1, based on the X-ray crystal structure.
Archaeal and eukaryotic tRNA (N(2),N(2)-guanine)-dimethyltransferase (Trm1) produces N(2),N(2)-dimethylguanine at position 26 in tRNA. In contrast, Trm1 from Aquifex aeolicus, a hyper-thermophilic eubacterium, modifies G27 as well as G26. Here, a gel mobility shift assay revealed that the T-arm in tRNA is the binding site of A. aeolicus Trm1. To address the multisite specificity, we performed an x-ray crystal structure study. The overall structure of A. aeolicus Trm1 is similar to that of archaeal Trm1, although there is a zinc-cysteine cluster in the C-terminal domain of A. aeolicus Trm1. The N-terminal domain is a typical catalytic domain of S-adenosyl-l-methionine-dependent methyltransferases. On the basis of the crystal structure and amino acid sequence alignment, we prepared 30 mutant Trm1 proteins. These mutant proteins clarified residues important for S-adenosyl-l-methionine binding and enabled us to propose a hypothetical reaction mechanism. Furthermore, the tRNA-binding site was also elucidated by methyl transfer assay and gel mobility shift assay. The electrostatic potential surface models of A. aeolicus and archaeal Trm1 proteins demonstrated that the distribution of positive charges differs between the two proteins. We constructed a tRNA-docking model, in which the T-arm structure was placed onto the large area of positive charge, which is the expected tRNA-binding site, of A. aeolicus Trm1. In this model, the target G26 base can be placed near the catalytic pocket; however, the nucleotide at position 27 gains closer access to the pocket. Thus, this docking model introduces a rational explanation of the multisite specificity of A. aeolicus Trm1.


Chrysin attenuates cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity.
Chrysin (CHR) is a natural flavonoid and is present in high concentration in honey, propolis and many plant extracts. The aim of the present study was to evaluate the effects of CHR to reduce cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity. Morphology of the cardiomyocytes was determined by optic and transmission electron microscopy and biochemistry methods. The expression of Bcl-2, Bax and Caspase-3 were assessed by immunofluorecence. Tunel assay was used to assess apoptosis in cardiomyocytes. In addition, the distribution of desmin protein was evaluated using immunohistochemistry. Our results show that MTX treatment significantly increased serum levels of creatine kinase isoenzyme (CK-MB), indicator of cardiac injury and withdrawn under CHR protection. Expression levels of Bcl-2 decreased, while those of Bax and caspase-3 increased following MTX treatment. 50 mg/kg of daily CHR intake reduced Bax and caspase-3 immunopositivity and restored Bcl-2 levels to a value comparable to the control. TUNEL (+) cardiomyocyte nuclei of MTX group showed typical signs of apoptosis which almost completely disappeared in response to 50 mg/kg CHR treatment. In parallel, an irregular distribution and a weak expression of desmin is associated with MTX induced cardiotoxic effects which was also restored by CHR treatment. In conclusion chrysin inhibits MTX-triggered cardiomyocyte apoptosis via multiple pathways, including decrease of the Bax/Bcl-2 ratio and caspase-3 expression along with preservation of the desmin disarray.


Long-term follow-up of asymptomatic healthy subjects with frequent and complex ventricular ectopy.
From 1973 to 1983 we followed 73 asymptomatic healthy subjects who were discovered to have frequent and complex ventricular ectopy. Ventricular ectopy in these subjects was measured by 24-hour ambulatory electrocardiography, which showed a mean frequency of 566 ventricular ectopic beats per hour (range, 78 to 1994), with multiform ventricular ectopic beats in 63 per cent, ventricular couplets in 60 per cent, and ventricular tachycardia in 26 per cent. Asymptomatic healthy status was confirmed by extensive noninvasive cardiologic examination, although cardiac catheterization of a subsample of subjects disclosed serious coronary artery disease in 19 per cent. Follow-up for 3.0 to 9.5 years (mean, 6.5) was accomplished in 70 subjects (96 per cent) and documented one sudden death and one death from cancer. Calculation of a standardized mortality ratio (Monson's U.S. data, 8th revision) for 448 person-years of follow-up indicated that 7.4 deaths were expected, whereas 2 occurred (standardized mortality ratio, 27; P less than 0.05). A comparison of survival of the study cohort with that of persons without coronary artery disease or with mild disease, patients with moderate disease, and men with unrecognized myocardial infarction showed a favorable prognosis for the study cohort over 10 years. We conclude that the long-term prognosis in asymptomatic healthy subjects with frequent and complex ventricular ectopy is similar to that of the healthy U.S. population and suggests no increased risk of death.


I want to break free - macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape.
Candida albicans is a major cause of fungal nosocomial infections. Host defense against disseminated infections caused by this yeast strongly relies on myeloid cells of the innate immune system. Recently, several breakthroughs have been made that significantly improved our understanding of the role of macrophages during candidiasis and how C. albicans and macrophages interact. Resident tissue macrophages and macrophages derived from monocytes that infiltrate infected tissues are essential for the initiation of the antifungal immune response, as well as elimination of C. albicans from the bloodstream and infected organs. These cells engulf and try to eliminate the invading fungi through specialized mechanisms. Concurrently, C. albicans tries to survive the stresses imposed by the macrophage, acquires nutrients, and can break free from their captive environment. This review focuses on the most recent insights into the strategies of macrophages to eliminate C. albicans and the fungal counterstrategies to overcome these threats.


The effect of human platelet lysate on the differentiation ability of human adipose-derived stem cells cultured on ECM-coated surfaces.
Human mesenchymal stem cells (hMSCs), such as human adipose-derived stem cells (hADSCs), present heterogeneous characteristics, including varying differentiation abilities and genotypes. hADSCs isolated under different conditions exhibit differences in stemness. We isolated hADSCs from human fat tissues via culture on different cell culture biomaterials including tissue culture polystyrene (TCPS) dishes and extracellular matrix protein (ECM)-coated dishes in medium supplemented with 5% or 10% serum-converted human platelet lysate (hPL) or 10% fetal bovine serum (FBS) as a control. Currently, it is not clear whether xeno-free hPL in the cell culture medium promotes the ability of hMSCs such as hADSCs to differentiate into several cell lineages compared to the xenomaterial FBS. We investigated whether a synchronized effect of ECM (Matrigel, fibronectin, and recombinant vitronectin) coatings on TCPS dishes for efficient hADSC differentiation could be observed when hADSCs were cultured in hPL medium. We found that Matrigel-coated dishes promoted hADSC differentiation into osteoblasts and suppressed differentiation into chondrocytes in 10% hPL medium. Recombinant vitronectin- and fibronectin-coated dishes greatly promoted hADSC differentiation into osteoblasts and chondrocytes in 5% and 10% hPL media. hPL promoted hADSC differentiation into osteoblasts and chondrocytes compared to FBS on the fibronectin-coated surface and recombinant vitronectin-coated surface.


Chemoreceptor drives and short sleep-wake cycles during hypoxia: a simulation study.
We used a Grodins-type mathematical model of the cardio-pulmonary system to investigate the cycling behaviour of the respiratory system during hypoxia in response to changes of state between waking and sleeping, namely a diminution of respiratory chemosensitivity during sleep. Shifts between waking and sleeping were triggered by various combinations of threshold values for PAO2. Mild or moderate hypoxia was simulated by values of inspired O2 concentration between 13% and 16% (normal 21%). In mild or moderate hypoxia, reductions of overall respiratory gain from about 2 to 0.8 l.min-1 mmHg-1 at sleep onset will produce falls in PAO2 likely to cause sleep-wake cycles with oscillations in PAO2. The higher the arousal threshold (in relation to steady-state PAO2 during sleep), the shorter and more stable the sleep-wake cycles. As the arousal threshold is raised, and as hypoxia is exacerbated from mild (FIO2 = 16%) to moderate (FIO2 = 13%), the sleep-wake cycle length tends to converge to a value around one minute. The level and determinants of the "back-to-sleep" threshold are hard to define from presently available experimental data, but the level is not important in determining the length of the sleep-wake cycle compared to the arousal threshold. Alinearities in chemoreceptor feedback were introduced first by incorporating "drive" thresholds, to simulate central or obstructive apnoea. This produced larger oscillations in respiratory variables, but no change in cycle length. Chemoreceptor thresholds for PCO2 at the level of 38-39 mmHg did produce shorter ventilation cycles, down to about 20 s in length, but these were not related in any simple way to the resulting sleep-wake cycles. The combination of sleep state changes and chemoreceptor feedback alinearities can produce short sleep-wake cycles despite the diminution in chemoreceptor gain occurring in sleep.


A novel strategy for thermometry based on the temperature-induced red shift of the charge transfer band edge.
We report a novel strategy for optical temperature sensing using the temperature-induced red shift of the charge transfer band (CTB) edge of the VO43- groups in GdVO4:5% Sm3+. Excitation spectra were recorded at a series of temperatures ranging from 300 to 480 K. It is demonstrated that an excitation intensity of around 360 nm corresponding to the tail of the CTB and an excitation intensity of 407.6 nm corresponding to the 6H5/2 → 4F7/2 transition of Sm3+ exhibit opposite temperature dependence. Based on this, the relative sensitivity was obtained to be 3313/T2 in our investigated temperature range, which is remarkable progress compared with the optical temperature sensors reported previously. We believe that this work broadens the pathway for the design of highly sensitive temperature sensing materials.


Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells.
Epoxyeicosatrienoic acids (EETs) are polyunsaturated fatty acids synthesized from arachidonic acid by CYP2J2 epoxygenase and inactivated by soluble epoxide hydrolase (sEH or Ephx2) to dihydroxyeicosatrienoic acids. Mitochondrial function following ischemic insult is a critical determinant of reperfusion-induced cell death in the myocardium. The objectives of the current study were to investigate the protective role of EETs in mitochondrial function. Mice with the targeted disruption of the Ephx2 gene, cardiomyocyte-specific overexpression of CYP2J2 or perfused with EETs all have improved postischemic LVDP recovery compared to wild-type (WT). Perfusion with the mPTP opener, atractyloside, abolished the improved postischemic functional recovery observed in CYP2J2 Tr, sEH null and EET perfused hearts. Electron micrographs demonstrated WT hearts to have increased mitochondrial fragmentation and T-tubule swelling compared to CYP2J2 Tr hearts following 20 min global ischemia and 20 min reperfusion. Direct effects of EETs on mitochondria were assessed in isolated rat cardiomyocytes and H9c2 cells. Laser-induced loss of mitochondrial membrane potential (DeltaPsi(m)) and mPTP opening was significantly reduced in cells treated with 14, 15-EET (1 microM). The EET protective effect was blocked by the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (1 muM, 14, 15-EEZE), paxilline (10 microM, BK(Ca) inhibitor) and 5HD (100 microM, K(ATP) inhibitor). Our studies show that EETs can limit mitochondrial dysfunction following cellular stress via a K(+) channel-dependent mechanism.


A cerium-based MOFzyme with multi-enzyme-like activity for the disruption and inhibition of fungal recolonization.
A cerium-based metal-organic framework (Ce-MOF, denoted as AU-1) was synthesized using a solvothermal method by employing 4,4',4''-nitrilotribenzoic acid (H3NTB) as the linker and cerium clusters as the metal center. The material was considered as a MOFzyme based on the peroxidase-like activity of Ce-MOF that could eliminate and kill fungi, such as Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, and Rhodotorula glutinis. Ce-MOF showed high antifungal activity against airborne opportunistic human pathogens isolated from the outside of a hospital. The antifungal activity of CeMOF was evaluated using the colony-forming units, dry mass method, soluble proteins, and microscopic imaging. It exhibited an inhibition efficiency of 93.3-99.3% based on the colony-forming unit method. The Ce-MOF caused extensive deformation of the conidiophores, vesicles, and phialides with growth inhibition between 7.55-77.41% (based on the dry mass method). Ce-MOF showed different efficiencies in inhibiting the different fungal species. The biological activity of Ce-MOF was due to its enzymatic activity, such as those of antioxidants, catalase, superoxide dismutase, and peroxidase. Ce-MOF exhibited excellent enzymatic activity towards the fungal cells. Our results may facilitate the design of a MOFzyme system and pave the way for more profound applications of nanozymes.


A survey of stakeholder knowledge, experience, and opinions of advance directives for mental health in Virginia.
An innovative Virginia health care law enables competent adults with serious mental illness to plan for treatment during incapacitating crises using an integrated advance directive with no legal distinction between psychiatric or other causes of decisional incapacity. This article reports results of a survey of 460 individuals in five stakeholder groups during the initial period of the law's implementation. All respondents held favorable views of advance directives for mental health care. Identified barriers to completing and using advance directives varied by group. We conclude that relevant stakeholders support implementation of advance directives for mental health, but level of baseline knowledge and perception of barriers vary. A multi-pronged approach will be needed to achieve successful implementation of advance directives for mental health.


Potential predictive markers of chemotherapy resistance in stage III ovarian serous carcinomas.
Chemotherapy resistance remains a major obstacle in the treatment of women with ovarian cancer. Establishing predictive markers of chemoresponse would help to individualize therapy and improve survival of ovarian cancer patients. Chemotherapy resistance in ovarian cancer has been studied thoroughly and several non-overlapping single genes, gene profiles and copy number alterations have been suggested as potential markers. The objective of this study was to explore genetic alterations behind chemotherapy resistance in ovarian cancer with the ultimate aim to find potential predictive markers. To create the best opportunities for identifying genetic alterations of importance for resistance, we selected a homogenous tumor material concerning histology, stage and chemotherapy. Using high-resolution whole genome array comparative genomic hybridization (CGH), we analyzed the tumor genomes of 40 fresh-frozen stage III ovarian serous carcinomas, all uniformly treated with combination therapy paclitaxel/carboplatin. Fisher's exact test was used to identify significant differences. Subsequently, we examined four genes in the significant regions (EVI1, MDS1, SH3GL2, SH3KBP1) plus the ABCB1 gene with quantitative real-time polymerase chain reaction (QPCR) to evaluate the impact of DNA alterations on the transcriptional level. We identified gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1 to be significantly associated with chemotherapy resistance. In the gene expression analysis, EVI1 expression differed between samples with gain versus without gain, exhibiting higher expression in the gain group. In conclusion, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian serous carcinomas. Thus, further studies are required to validate these findings in an independent ovarian tumor series.


Use of temperature to improve West Nile virus forecasts.
Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs.


Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?
Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).


Dose enhancement in radiotherapy of small lung tumors using inline magnetic fields: A Monte Carlo based planning study.
To report on significant dose enhancement effects caused by magnetic fields aligned parallel to 6 MV photon beam radiotherapy of small lung tumors. Findings are applicable to future inline MRI-guided radiotherapy systems. A total of eight clinical lung tumor cases were recalculated using Monte Carlo methods, and external magnetic fields of 0.5, 1.0, and 3 T were included to observe the impact on dose to the planning target volume (PTV) and gross tumor volume (GTV). Three plans were 6 MV 3D-CRT plans while 6 were 6 MV IMRT. The GTV's ranged from 0.8 to 16 cm(3), while the PTV's ranged from 1 to 59 cm(3). In addition, the dose changes in a 30 cm diameter cylindrical water phantom were investigated for small beams. The central 20 cm of this phantom contained either water or lung density insert. For single beams, an inline magnetic field of 1 T has a small impact in lung dose distributions by reducing the lateral scatter of secondary electrons, resulting in a small dose increase along the beam. Superposition of multiple small beams leads to significant dose enhancements. Clinically, this process occurs in the lung tissue typically surrounding the GTV, resulting in increases to the D98% (PTV). Two isolated tumors with very small PTVs (3 and 6 cm(3)) showed increases in D98% of 23% and 22%. Larger PTVs of 13, 26, and 59 cm(3) had increases of 9%, 6%, and 4%, describing a natural fall-off in enhancement with increasing PTV size. However, three PTVs bounded to the lung wall showed no significant increase, due to lack of dose enhancement in the denser PTV volume. In general, at 0.5 T, the GTV mean dose enhancement is around 60% lower than that at 1 T, while at 3 T, it is 5%-60% higher than 1 T. Monte Carlo methods have described significant and predictable dose enhancement effects in small lung tumor plans for 6 MV radiotherapy when an external inline magnetic field is included. Results of this study indicate that future clinical inline MRI-guided radiotherapy systems will be able to deliver a dosimetrically superior treatment to small (PTV < 15 cm(3)), isolated lung tumors over non-MRI-Linac systems. This increased efficacy coincides with the reimbursement in the United States of lung CT screening and the likely rapid growth in the number of patients with small lung tumors to be treated with radiotherapy.


Asian American adolescents' first sexual intercourse: gender and acculturation differences.
Interventions aimed at adolescents need to be culturally specific. The dearth of data on Asian American adolescents has made it difficult to meet their needs. Data from the National Longitudinal Study of Adolescent Health were used, with a sample of 323 Asian American female adolescents and 366 Asian American male adolescents. Logistic regression analysis was used to assess the association between acculturation at Wave 1 (1995) and sexual experience at Wave 2 (1996), controlling for demographic, psychosocial and family variables. Overall, 24% of young women and 20% of young men had had sexual intercourse. Among young women, the most acculturated were more likely to have had sexual intercourse than the least acculturated (odds ratio, 4.9); acculturation was not associated with sexual intercourse for young men. Medium and high levels of parental attachment were associated with decreased odds of sexual experience for young women (0.4 and 0.2), but not for young men. Binge drinking was associated with an increased risk of sexual experience for young women (6.4), and tobacco use was associated with increased risk for young men (3.0). Like all adolescents, Asian Americans are at high risk for the consequences of sexual activity. For this fast-growing population, there is a crucial need for preventive programs that are culturally sensitive, inclusive of family and gender-specific.


CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations.
CAG repeat expansion in exon 1 of the androgen receptor (AR) gene has been reported to be associated with male infertility in some but not all populations. Until now, studies have not been carried out to examine this among Indian populations. For the first time, we have analyzed the CAG repeat motif in the AR gene in 280 men with azoospermia and in 201 men with normal fertility. The mean number of CAG repeats in the AR gene of men with azoospermia was 21.7 +/- 0.18, with a high incidence of repeat number 22. Among fertile-control men, the mean number of CAG repeats was 22.4 +/- 0.19, with a predominance of repeat number 23. The highest number of CAG repeats (32) was found with low frequency in both fertile and azoospermic groups. Comparison of fertile men and those with azoospermia on the basis of CAG repeats revealed that the number of CAG repeats in both groups were similar, as revealed with a paired t test (t = 0.04; P =.967). Expansion of the CAG repeat in the AR gene is therefore not associated with male infertility in Indian populations. This suggests that what is true for one population may not be true for other populations.


In vitro characterization of multivalent adhesion molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel.
Treatment of wounded military personnel at military medical centers is often complicated by colonization and infection of wounds with pathogenic bacteria. These include nosocomially transmitted, often multidrug-resistant pathogens such as Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa and extended spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. We analyzed the efficacy of multivalent adhesion molecule (MAM) 7-based anti-adhesion treatment of host cells against aforementioned pathogens in a tissue culture infection model. Herein, we observed that a correlation between two important hallmarks of virulence, attachment and cytotoxicity, could serve as a useful predictor for the success of MAM7-based inhibition against bacterial infections. Initially, we characterized 20 patient isolates (five from each pathogen mentioned above) in terms of genotypic diversity, antimicrobial susceptibility and important hallmarks of pathogenicity (biofilm formation, attachment to and cytotoxicity toward cultured host cells). All isolates displayed a high degree of genotypic diversity, which was also reflected by large strain-to-strain variability in terms of biofilm formation, attachment and cytotoxicity within each group of pathogen. Using non-pathogenic bacteria expressing MAM7 or latex beads coated with recombinant MAM7 for anti-adhesion treatment, we showed a decrease in cytotoxicity, indicating that MAM7 has potential as a prophylactic agent to attenuate infection by multidrug-resistant bacterial pathogens.


Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence.
Hypothermia has been used for medicinal purposes since ancient times. This paper reviews the current potential clinical applications for mild hypothermia (32-35 degrees C). Induced hypothermia is used mostly to prevent or attenuate neurological injury, and has been used to provide neuroprotection in traumatic brain injury, cardiopulmonary resuscitation, stroke, and various other disorders. The evidence for each of these applications is discussed, and the mechanisms underlying potential neuroprotective effects are reviewed. Some of this evidence comes from animal models, and a brief overview of these models and their limitations is included in this review. The duration of cooling and speed of re-warming appear to be key factors in determining whether hypothermia will be effective in preventing or mitigating neurological injury. Some other potential usages of hypothermia, such as its use in the peri-operative setting and its application to mitigate cardiac injury following ischemia and reperfusion, are also discussed. Although induced hypothermia appears to be a highly promising treatment, it should be emphasized that it is associated with a number of potentially serious side effects, which may negate some or all of its potential benefits. Prevention and/or early treatment of these complications are the key to successful use of hypothermia in clinical practice. These side effects, as well as various physiological changes induced by cooling, are discussed in a separate review.


Arginine methylation of CRTC2 is critical in the transcriptional control of hepatic glucose metabolism.
Fasting glucose homeostasis is maintained in part through cAMP (adenosine 3',5'-monophosphate)-dependent transcriptional control of hepatic gluconeogenesis by the transcription factor CREB (cAMP response element-binding protein) and its coactivator CRTC2 (CREB-regulated transcriptional coactivator 2). We showed that PRMT6 (protein arginine methyltransferase 6) promotes fasting-induced transcriptional activation of the gluconeogenic program involving CRTC2. Mass spectrometric analysis indicated that PRMT6 associated with CRTC2. In cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme-encoding genes. In mice, ectopic expression of PRMT6 promoted higher blood glucose concentrations, which were associated with increased expression of genes encoding gluconeogenic factors, whereas knockdown of hepatic PRMT6 decreased fasting glycemia and improved pyruvate tolerance. The abundance of hepatic PRMT6 was increased in mouse models of obesity and insulin resistance, and adenovirus-mediated depletion of PRMT6 restored euglycemia in these mice. We propose that PRMT6 is involved in the regulation of hepatic glucose metabolism in a CRTC2-dependent manner.