Comprehensive Review of Polymer and Polymer Gel Treatments for Natural Gas-Related Conformance Control.
Conformance problems often exist in natural gas-related activities, resulting in excessive water production from natural gas production wells and/or excessive natural gas production from oil production wells. Several mechanical and chemical solutions were reported in the literature to mitigate the conformance problems. Among the chemical solutions, two classes of materials, namely polymer gels and water-soluble polymers, have been mostly reported. These systems have been mainly reviewed in several studies for their applications as water shutoff treatments for oil production wells. Natural gas production wells exhibit different characteristics and have different properties which could impact the performance of the chemical solutions. However, there has not been any work done on reviewing the applications of these systems for the challenging natural gas-related shutoff treatments. This study provides a comprehensive review of the laboratory evaluation and field applications of these systems used for water control in natural gas production wells and gas shutoff in oil production wells, respectively. The first part of the paper reviews the in-situ polymer gel systems, where both organically and inorganically crosslinked systems are discussed. The second part presents the water-soluble polymers with a focus on their disproportionate permeability reduction feature for controlling water in gas production wells. The review paper provides insights into the reservoir conditions, treatment design and intervention, and the success rate of the systems applied. Furthermore, the outcomes of the paper will provide knowledge regarding the limitations of the existing technologies, current challenges, and potential paths forwards.


Drosophila circadian rhythms in seminatural environments: Summer afternoon component is not an artifact and requires TrpA1 channels.
Under standard laboratory conditions of rectangular light/dark cycles and constant warm temperature, Drosophila melanogaster show bursts of morning (M) and evening (E) locomotor activity and a "siesta" in the middle of the day. These M and E components have been critical for developing the neuronal dual oscillator model in which clock gene expression in key cells generates the circadian phenotype. However, under natural European summer conditions of cycling temperature and light intensity, an additional prominent afternoon (A) component that replaces the siesta is observed. This component has been described as an "artifact" of the TriKinetics locomotor monitoring system that is used by many circadian laboratories world wide. Using video recordings, we show that the A component is not an artifact, neither in the glass tubes used in TriKinetics monitors nor in open-field arenas. By studying various mutants in the visual and peripheral and internal thermo-sensitive pathways, we reveal that the M component is predominantly dependent on visual input, whereas the A component requires the internal thermo-sensitive channel transient receptor potential A1 (TrpA1). Knockdown of TrpA1 in different neuronal groups reveals that the reported expression of TrpA1 in clock neurons is unlikely to be involved in generating the summer locomotor profile, suggesting that other TrpA1 neurons are responsible for the A component. Studies of circadian rhythms under seminatural conditions therefore provide additional insights into the molecular basis of circadian entrainment that would otherwise be lost under the usual standard laboratory protocols.


AhrC and Eep are biofilm infection-associated virulence factors in Enterococcus faecalis.
Enterococcus faecalis is part of the human intestinal microbiome and is a prominent cause of health care-associated infections. The pathogenesis of many E. faecalis infections, including endocarditis and catheter-associated urinary tract infection (CAUTI), is related to the ability of clinical isolates to form biofilms. To identify chromosomal genetic determinants responsible for E. faecalis biofilm-mediated infection, we used a rabbit model of endocarditis to test strains with transposon insertions or in-frame deletions in biofilm-associated loci: ahrC, argR, atlA, opuBC, pyrC, recN, and sepF. Only the ahrC mutant was significantly attenuated in endocarditis. We demonstrate that the transcriptional regulator AhrC and the protease Eep, which we showed previously to be an endocarditis virulence factor, are also required for full virulence in murine CAUTI. Therefore, AhrC and Eep can be classified as enterococcal biofilm-associated virulence factors. Loss of ahrC caused defects in early attachment and accumulation of biofilm biomass. Characterization of ahrC transcription revealed that the temporal expression of this locus observed in wild-type cells promotes initiation of early biofilm formation and the establishment of endocarditis. This is the first report of AhrC serving as a virulence factor in any bacterial species.


Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression.
We employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons (HAHs). Female Harlan Sprague-Dawley rats were exposed for 13 weeks to toxicologically equivalent doses of four different HAHs based on the toxic equivalency factor of each chemical: TCDD (100 ng/kg/day), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF; 200 ng/kg/day), 3,3',4,4',5-pentachlorobiphenyl (PCB126; 1,000 ng/kg/day), or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153; 1,000 microg/kg/day). Global gene expression profiles for each exposure, which account for 8,799 gene probe sets contained on Affymetrix RGU34A GeneChips, were compared by principal components analysis. The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the nonAhR ligand PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver. Many genes were co-expressed during the 13-week TCDD, PeCDF, or PCB126 exposures, including classical AhR-regulated genes and some genes not previously characterized as being AhR regulated, such as carcinoembryonic-cell adhesion molecule 4 (C-CAM4) and adenylate cyclase-associated protein 2 (CAP2). Real-time reverse-transcriptase polymerase chain reaction confirmed the increased expression of these genes in TCDD-, PeCDF-, and PCB126-exposed rats as well as the up- or down-regulation of several other novel dioxin-responsive genes. In summary, DNA microarray successfully identified dioxin-responsive genes expressed after exposure to AhR ligands (TCDD, PeCDF, PCB126) but not after exposure to the non-AhR ligand PCB153. Together, these findings may help to elucidate some of the fundamental features of dioxin toxicity and may further clarify the biologic role of the AhR signaling pathway.


Designing a constructed wetland for the detention of agricultural runoff for water quality improvement.
The goal of this study was to construct a wetland that would detain runoff from a 162-ha watershed for the purposes of improving water quality. The volume of runoff that needed to be detained was determined to be that amount coming off the 162-ha watershed consisting of 146 ha of cultivated crop land and 16 ha of pasture that exceeded the amount that would have come off of the watershed in its natural, forested state. The Soil Conservation Service (now the Natural Resource Conservation Service [NRCS]) runoff curve number method was used to estimate runoff from the watershed in its natural, forested state and in its current state of cultivated crop land and pasture. The design of the constructed wetland was accomplished using the natural topography of the wetland site and the design criteria for a sediment containment system developed by NRCS. The SPAW (Soil-Plant-Atmosphere-Water Field & Pond Hydrology) computer model was used to model depth and volume in the wetland to determine if the constructed wetland design would accommodate typical runoff events. Construction of the wetland occurred over a 4-mo period. The capabilities of the system were verified when Hurricane Rita deposited above-normal rainfall to the wetland site area. The wetland was able to accommodate this event, allowing flow through the system for 9 d, followed by continued detention of remaining runoff for water quality improvement.


Changes in blood biochemical markers before, during, and after a 2-day ultramarathon.
We studied changes in blood markers of 18 nonprofessional, middle-aged runners of a 2-day, 130 km ultramarathon. Blood was sampled at baseline, after the goals on the first and second day, and at three time points (1, 3, and 5/6 days) after the race. Blood indices showed three patterns. First pattern indices showed essentially no changes after the two goals and after the race, including red blood cell indices, gamma-glutamyl transferase, and tumor necrosis factor-α. Second pattern markers, including the majority of indices, were elevated during the race (and also after the race for some parameters) and then returned to baseline afterward, including hemolysis/red blood cell destruction markers (indirect bilirubin) and an iron reservoir index (ferritin), muscle damage parameters (uric acid, creatine kinase, lactate dehydrogenase, and aspartate aminotransferase), renal function markers (creatinine and blood urea nitrogen), liver injury index (alanine aminotransferase), lipid metabolism indices (free fatty acid), reactive oxygen species and inflammation parameters (white blood cells, interleukin-6, and C-reactive protein), and energy production and catecholamines (adrenaline, noradrenaline, and dopamine). Third pattern index of a lipid metabolism marker - triglyceride - decreased during the race periods and started returning to baseline from then onward. Some hormonal markers such as insulin, leptin, and adiponectin showed unique patterns. These findings appeared informative for nonprofessional athletes to know about an optimal physical activity level, duration, and total exercise for elevating physical performance and monitoring physical/mental conditioning as well as for prevention of overtraining and physical injuries.


A new instrument for patients' ratings of physician performance in the hospital setting.
A new instrument to elicit patients' appraisals of physician performance has been developed from a previously-derived taxonomy of desired physician attitudes and behavior. The instrument allows patients to give ratings for their physicians' discrete, observable items of behavior, and also for complex, multidimensional attributes. When the instrument was administered to 131 randomly chosen medical inpatients, the results showed that technical competence and interpersonal (or humanistic) qualities were equally valued, and that physicians received high ratings for most features of performance. Except for less satisfaction in younger patients, clinical and demographic characteristics had little impact on the ratings. The performance characteristics of the instrument appear satisfactory, and its potential applications and proposals for further research are discussed.


The anti-allodynic alpha(2)delta ligand pregabalin inhibits the trafficking of the calcium channel alpha(2)delta-1 subunit to presynaptic terminals in vivo.
Neuropathic pain is caused by lesion or dysfunction of the peripheral sensory nervous system. Up-regulation of the voltage-gated Ca(2+) channel subunit alpha(2)delta-1 in DRG (dorsal root ganglion) neurons and the spinal cord correlates with the onset of neuropathic pain symptoms such as allodynia in several animal models of neuropathic pain. The clinically important anti-allodynic drugs gabapentin and pregabalin are alpha(2)delta-1 ligands, but how these drugs alleviate neuropathic pain is poorly understood. In the present paper, we review recent advances in our understanding of their molecular mechanisms.


Scotopic threshold response (STR) of the human electroretinogram.
We recorded the human ERG using full-field stimuli at light intensities near absolute threshold to examine characteristics of the scotopic threshold response (STR). The human STR was seen below PII threshold and was the only component of the ERG evident near absolute rod psychophysical threshold. The human STR was detectable in the corneal ERG at stimulus intensities 0.6-1.0 log units above psychophysical threshold and had about a 2 log unit range to apparent saturation. Maximum STR amplitude was 12-20 microV. The STR latency ranged from 100-185 msec, depending on stimulus duration and intensity. The STR returned to baseline by 300 msec after onset, for very brief flashes, but it was prolonged with longer flashes. The spectral characteristics of the human STR matched rods and not cones. The STR followed Bloch's law and exhibited temporal integration for at least 80 msec. At 2.5-3 log units above visual threshold, corneal positive PII (b-wave and d.c. component) progressively obscured the negative STR. We propose that the human STR reflects post receptor processing in the retina. This is based on the similarity of the human STR to the STR of the cat and monkey, both of which originate at postreceptoral sites. Thus the human STR may find clinical use to evaluate the rod pathway in the proximal retina.


Hierarchical Representations of Aggression in a Hypothalamic-Midbrain Circuit.
Although the ventromedial hypothalamus ventrolateral area (VMHvl) is now well established as a critical locus for the generation of conspecific aggression, its role is complex, with neurons responding during multiple phases of social interactions with both males and females. It has been previously unclear how the brain uses this complex multidimensional signal and coordinates a discrete action: the attack. Here, we find a hypothalamic-midbrain circuit that represents hierarchically organized social signals during aggression. Optogenetic-assisted circuit mapping reveals a preferential projection from VMHvlvGlut2 to lPAGvGlut2 cells, and inactivation of downstream lPAGvGlut2 populations results in aggression-specific deficits. lPAG neurons are selective for attack action and exhibit short-latency, time-locked spiking relative to the activity of jaw muscles during biting. Last, we find that this projection conveys male-biased signals from the VMHvl to downstream lPAGvGlut2 neurons that are sensitive to features of ongoing activity, suggesting that action selectivity is generated by a combination of pre- and postsynaptic mechanisms.


Emergency cricothyrotomy: a reassessment.
The Medical College of Georgia Level I Trauma Center admitted 5603 adult trauma patients from January 1, 1989 through June 30, 1993. Cricothyrotomy was required in 66 of 525 patients who required emergency airway control but could not be intubated nonsurgically in an expeditious manner. There were three major complications (thyroid cartilage laceration, significant hemorrhage, and failure to obtain a surgical airway) involving two patients, but each resolved without sequelae. Twenty-six patients with cricothyrotomy survived their hospital course, of which seven had decannulation of the cricothyrotomy without further airway procedures, and 19 had conversion to tracheostomy. No patient had clinically significant morbidity from the cricothyrotomy, whether with or without a subsequent tracheostomy. Surgical cricothyrotomy remains an important technique with low morbidity for selected trauma victims needing emergency airway control.


The Gonadotropin-Releasing Hormone Analogue Therapy May Not Impact Final Height in Precocious Puberty of Girls With Onset of Puberty Aged 6 - 8 Years.
The effect on final height of gonadotropin-releasing hormone analogues (GnRHa) used in the treatment of precocious puberty is controversial. The aim of this study was to determine whether or not GnRHa therapy would make any contribution to final height in precocious puberty of girls with onset of pubertal characteristic development aged 6 - 8 years. Age at start of puberty, target height standard deviation score (SDS) presentation, follow-up height SDS, body mass index (BMI) SDS, bone age and predicted adult height of 34 female subjects who had reached their final height and with pubertal findings beginning at the ages of 6 - 8 were evaluated. These subjects were divided into two groups: treatment and non-treatment groups. The treatment group was further divided into two subgroups, receiving monthly or three-monthly depot GnRHa. Age at onset of puberty was 7.2 ± 0.9 years. Twenty-five cases were started on GnRHa and nine were followed-up without treatment. Fourteen cases received monthly 3.75 mg depot triptorelin acetate and 11 received three-monthly 11.25 mg depot. Mean age at start of treatment in the treatment group was 9.1 ± 1.2 years and mean bone age was 9.7 ± 2.3 years. Age at presentation in the non-treatment group was 8.4 ± 1.4 years and bone age was 10.3 ± 2.1 years. Target and final height SDS were similar in all the groups (P > 0.05). No difference was determined between the treatment groups in terms of initial height SDS, bone age, length of treatment, final height SDS or BMI SDS (P > 0.05). GnRHa therapy did not make a positive contribution to final height in precocious puberty of girls with onset of puberty aged 6 - 8 years.


Work related mortality among merchant seafarers employed in UK Royal Fleet Auxillary shipping from 1976 to 2005.
Over 2300 merchant seafarers are currently employed on board UK Royal Fleet Auxiliary (RFA) ships. However, little is known about work related mortality among these seafarers, and whether it is lower than among seafarers in merchant fleets. To establish the causes and circumstances of all work related deaths among seafarers who were employed in RFA ships from 1976 to 2005, to compare mortality rates with those in other merchant fleets, and to identify implications for maritime health. A population based study of work related mortality over 30 years. A total of 60 deaths among seafarers in RFA ships were caused by disease (30), accidents (19), suicide (6), homicide (one), and inconclusive causes (4). Six of the 19 fatal accidents were directly related to work duties (occupational accidents), 12 occurred during off-duty time and one resulted from a shipping disaster. The fatal accident rate was about one half, and the fatal work related accident rate was about one quarter, of corresponding rates in UK merchant shipping from 1976-2002; and they were much lower than those in merchant fleets internationally. The fatal accident rate in RFA shipping also fell by about 80% over the 30 year study period. The lower fatal accident rates in RFA shipping, particularly for work related accidents, presumably reflect a lower incidence of hazardous working practices, arising from better training and career pathways for seafarers in RFA shipping, as well as better maintained ships with higher manning levels than in merchant shipping.


Influence of vertical dimension on masseter muscle electromyographic activity in patients with mandibular dysfunction.
Occlusal splints were adjusted to different vertical heights and used to single out the influence of vertical dimension of occlusion in increments on BT-EMG activity of the masseter muscle in patients with mandibular dysfunction. The vertical dimension of least EMG activity was determined for each of 60 patients, who were randomly divided into three groups according to the vertical dimension at which the occlusal splint was adjusted: group No. 1, 1 mm from occlusal vertical dimension; group No. 2, mean vertical dimension, 4.25 mm; group No. 3, mean vertical dimension, 8.25 mm. Results showed a significant reduction of masseter BT-EMG activity (series A and B) at the end of the 3-week treatment period for patients in group Nos. 2 and 3 in comparison with group No. 1. Furthermore, the short-term use of occlusal splints with a vertical height that exceeded the so-called physiologic interocclusal distance did not result in an increase in masseter BT-EMG activity. This study suggests that an increase of vertical dimension of occlusion to or near the vertical dimension of least EMG activity by means of occlusal splints can be an effective way to obtain a reduction in masseteric muscle activity.


Aspiration pneumonia in pediatric age group: etiology, predisposing factors and clinical outcome.
Aspiration pneumonia in children is an important disease in terms of the morbidity and mortality associated with it. The objective of this study is to characterize the cases of aspiration pneumonia on the basis of the predisposing factors, types of aspiration syndromes, materials aspirated and their clinical outcome. A total of 107 patients diagnosed as having aspiration pneumonia, were included in this study. Cases were between 0-15 years of age, admitted to the Aga Khan University Hospital (AKUH) over five years. The most common form of aspiration syndrome seen was chemical pneumonitis (52.1%). The three most common factors predisposing to pulmonary aspiration were accidental ingestion (37.4%), altered consciousness (34.6%) and neurologic disorders (29%). Children who aspirated oropharyngeal flora were at higher odds to require mechanical ventilation than those aspirating inert fluids and particulate matter (OR = 6.4, 95% CI: 1.5-29.2, p = 0.003). Milk (31.8%), kerosene (21.5%) and oral secretions (19.6%) were the most common materials aspirated. Betel nuts were the most commonly aspirated foreign body. Patients aspirating oral secretions and milk were seen to have a relatively worse clinical outcome than those aspirating kerosene oil. Aspiration pneumonia is a relatively uncommon clinical entity at AKUH in children. However, it does cause significant morbidity and mortality.


Writing proposals for research funds.
In this paper, we provide generic guidelines for writing proposals for research funds. These guidelines apply to quantitative, qualitative and mixed methods research proposals. A proposal for research funding provides an overview of the planned research and is required by funding agencies. The proposal is submitted for evaluation and ranking by a review committee according to the criteria put forth by that particular agency. It may be necessary to submit proposals to more than one agency to acquire sufficient operating and infrastructure funding for a research project.


Structural analysis of replication protein A recruitment of the DNA damage response protein SMARCAL1.
SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1 (SMARCAL1) is a recently identified DNA damage response protein involved in remodeling stalled replication forks. The eukaryotic single-strand DNA binding protein replication protein A (RPA) recruits SMARCAL1 to stalled forks in vivo and facilitates regression of forks containing leading strand gaps. Both activities are mediated by a direct interaction between an RPA binding motif (RBM) at the N-terminus of SMARCAL1 and the C-terminal winged-helix domain of the RPA 32 kDa subunit (RPA32C). Here we report a biophysical and structural characterization of the SMARCAL1-RPA interaction. Isothermal titration calorimetry and circular dichroism spectroscopy revealed that RPA32C binds SMARCAL1-RBM with a Kd of 2.5 μM and induces a disorder-to-helix transition. The crystal structure of RPA32C was refined to 1.4 Å resolution, and the SMARCAL1-RBM binding site was mapped on the structure on the basis of nuclear magnetic resonance chemical shift perturbations. Conservation of the interaction surface to other RBM-containing proteins allowed construction of a model for the RPA32C/SMARCAL1-RBM complex. The implications of our results are discussed with respect to the recruitment of SMARCAL1 and other DNA damage response and repair proteins to stalled replication forks.


"If you don't abstain, you will die of AIDS": AIDS education in Kenyan public schools.
We explored constraints of implementing AIDS education in public schools in Kenya. Sixty interviews with teachers and 60 focus group discussions with students were conducted in 21 primary and nine secondary schools. System/school-level constraints included lack of time in the curriculum, limited reach of secondary-school students (because AIDS education is embedded in biology, which is not compulsory), and disapproval of openness about sex and condoms by the Ministry of Education and parents. Alternative strategies to teach about AIDS had their own constraints. Teachers lacked training and support and felt uncomfortable with the topic. They were not used to interactive teaching methods and sometimes breached confidentiality. Teachers' negative attitudes constrained students from seeking information. Training interventions should be provided to teachers to increase their self-confidence, foster more positive attitudes, and stimulate interactive teaching methods. The Ministry of Education needs to have a clear policy toward the promotion of condoms.


Role of Dietary Nutrients in the Modulation of Gut Microbiota: A Narrative Review.
Understanding how dietary nutrients modulate the gut microbiome is of great interest for the development of food products and eating patterns for combatting the global burden of non-communicable diseases. In this narrative review we assess scientific studies published from 2005 to 2019 that evaluated the effect of micro- and macro-nutrients on the composition of the gut microbiome using in vitro and in vivo models, and human clinical trials. The clinical evidence for micronutrients is less clear and generally lacking. However, preclinical evidence suggests that red wine- and tea-derived polyphenols and vitamin D can modulate potentially beneficial bacteria. Current research shows consistent clinical evidence that dietary fibers, including arabinoxylans, galacto-oligosaccharides, inulin, and oligofructose, promote a range of beneficial bacteria and suppress potentially detrimental species. The preclinical evidence suggests that both the quantity and type of fat modulate both beneficial and potentially detrimental microbes, as well as the Firmicutes/Bacteroides ratio in the gut. Clinical and preclinical studies suggest that the type and amount of proteins in the diet has substantial and differential effects on the gut microbiota. Further clinical investigation of the effect of micronutrients and macronutrients on the microbiome and metabolome is warranted, along with understanding how this influences host health.


Dual-lifetime referencing (DLR): a powerful method for on-line measurement of internal pH in carrier-bound immobilized biocatalysts.
Industrial-scale biocatalytic synthesis of fine chemicals occurs preferentially as continuous processes employing immobilized enzymes on insoluble porous carriers. Diffusional effects in these systems often create substrate and product concentration gradients between bulk liquid and the carrier. Moreover, some widely-used biotransformation processes induce changes in proton concentration. Unlike the bulk pH, which is usually controlled at a suitable value, the intraparticle pH of immobilized enzymes may deviate significantly from its activity and stability optima. The magnitude of the resulting pH gradient depends on the ratio of characteristic times for enzymatic reaction and on mass transfer (the latter is strongly influenced by geometrical features of the porous carrier). Design and selection of optimally performing enzyme immobilizates would therefore benefit largely from experimental studies of the intraparticle pH environment. Here, a simple and non-invasive method based on dual-lifetime referencing (DLR) for pH determination in immobilized enzymes is introduced. The technique is applicable to other systems in which particles are kept in suspension by agitation. The DLR method employs fluorescein as pH-sensitive luminophore and Ru(II) tris(4,7-diphenyl-1,10-phenantroline), abbreviated Ru(dpp), as the reference luminophore. Luminescence intensities of the two luminophores are converted into an overall phase shift suitable for pH determination in the range 5.0-8.0. Sepabeads EC-EP were labeled by physically incorporating lipophilic variants of the two luminophores into their polymeric matrix. These beads were employed as carriers for immobilization of cephalosporin C amidase (a model enzyme of industrial relevance). The luminophores did not interfere with the enzyme immobilization characteristics. Analytical intraparticle pH determination was optimized for sensitivity, reproducibility and signal stability under conditions of continuous measurement. During hydrolysis of cephalosporin C by the immobilizate in a stirred reactor with bulk pH maintained at 8.0, the intraparticle pH dropped initially by about 1 pH unit and gradually returned to the bulk pH, reflecting the depletion of substrate from solution. These results support measurement of intraparticle pH as a potential analytical processing tool for proton-forming/consuming biotransformations catalyzed by carrier-bound immobilized enzymes. Fluorescein and Ru(dpp) constitute a useful pair of luminophores in by DLR-based intraparticle pH monitoring. The pH range accessible by the chosen DLR system overlaps favorably with the pH ranges at which enzymes are optimally active and stable. DLR removes the restriction of working with static immobilized enzyme particles, enabling suspensions of particles to be characterized also. The pH gradient developed between particle and bulk liquid during reaction steady state is an important carrier selection parameter for enzyme immobilization and optimization of biocatalytic conversion processes. Determination of this parameter was rendered possible by the presented DLR method.


Identification and molecular characterization of oat peptides implicated on coeliac immune response.
Oats provide important nutritional and pharmacological properties, although their safety in coeliac patients remains controversial. Previous studies have confirmed that the reactivity of the anti-33-mer monoclonal antibody with different oat varieties is proportional to the immune responses in terms of T-cell proliferation. Although the impact of these varieties on the adaptive response has been studied, the role of the dendritic cells (DC) is still poorly understood. The aim of this study is to characterize different oat fractions and to study their effect on DC from coeliac patients. Protein fractions were isolated from oat grains and analyzed by SDS-PAGE. Several proteins were characterized in the prolamin fraction using immunological and proteomic tools, and by Nano-LC-MS/MS. These proteins, analogous to α- and γ-gliadin-like, showed reactive sequences to anti-33-mer antibody suggesting their immunogenic potential. That was further confirmed as some of the newly identified oat peptides had a differential stimulatory capacity on circulating DC from coeliac patients compared with healthy controls. This is the first time, to our knowledge, where newly identified oat peptides have been shown to elicit a differential stimulatory capacity on circulating DC obtained from coeliac patients, potentially identifying immunogenic properties of these oat peptides.


The deformation behavior and mechanical properties of chondrocytes in articular cartilage.
Chondrocytes in articular cartilage utilize mechanical signals to regulate their metabolic activity. A fundamental step in determining the role of various biophysical factors in this process is to characterize the local mechanical environment of the chondrocyte under physiological loading. A combined experimental and theoretical approach was used to quantify the in-situ mechanical environment of the chondrocyte. The mechanical properties of enzymatically-isolated chondrocytes and their pericellular matrix (PCM) were determined using micropipette aspiration. The values were used in a finite element model of the chondron (the chondrocyte and its PCM) within articular cartilage to predict the stress-strain and fluid flow microenvironment of the cell. The theoretical predictions were validated using three-dimensional confocal microscopy of chondrocyte deformation in situ. Chondrocytes were found to behave as a viscoelastic solid material with a Young's modulus of approximately 0.6 kPa. The elastic modulus of the PCM was significantly higher than that of the chondrocyte, but several orders of magnitude lower than that of the extracellular matrix. Theoretical modeling of cell-matrix interactions suggests the mechanical environment of the chondrocyte is highly non-uniform and is dependent on the viscoelastic properties of the PCM. Excellent agreement was observed between the theoretical predictions and the direct measurements of chondrocyte deformation, but only if the model incorporated the PCM. These findings imply that the PCM plays a functional biomechanical role in articular cartilage, and alterations in PCM properties with aging or disease will significantly affect the biophysical environment of the chondrocyte.


Novel presentations of periodic fever syndromes: Discrepancies between genetic and clinical diagnoses.
The Periodic fever syndromes (PFS) are a group of disorders of the innate immune system. We investigated patients diagnosed with PFS at the Dartmouth Hitchcock Pediatric Rheumatology Clinic. Case acquisition was performed by reviewing ICD 9/10 coded records for familial Mediterranean fever (ICD 9 277.31), laboratory test records for PFS genetic screening, and clinic records between 1/1/2011 and 12/31/2017. Twenty-seven cases had clinical evaluations including PFS genetic screening. Clinical diagnoses included familial Mediterranean fever (FMF) (10 cases), Muckle-Wells (2 cases), tumor necrosis factor receptor associated periodic syndrome (TRAPS) (4 cases), hyper IgD syndrome (HIDS) (1 case), Crohn's Disease (1 case), systemic onset juvenile idiopathic arthritis (SoJIA) (1 case), fever of unknown origin (FUO) (1 case), periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) (6 cases), and cold-induced urticaria (1 case). Fifteen cases were associated with a genetic cause. Seven of the 10 FMF cases were confirmed genetically and were either heterozygous or compound heterozygotes. Both cases of Muckle-Wells had either a compound heterozygote for CIAS 1 or a NOD gene mutation. Both TRAPS cases presented atypically with patients developing systemic lupus erythematosus (SLE) or being asymptomatic. Two patients had novel syndromes. One FMF patient had a TRNT1 gene mutation who responded to intravenous immunoglobulin (IVIg) and colchicine after failing multiple treatments. The other had SoJIA with a LPIN 2 gene mutation but responded to colchicine. Only one of the 15 genetically proven cases had classical presentation and genetics (HIDS secondary to a mevalonate kinase (MVK) gene mutation). PFS screening was helpful in over half of the cases to develop therapeutic treatment plans. Given the atypical clinical presentations seen with genetically determined PFS, extensive genetic testing is indicated for all patients presenting with a PFS, excluding classical PFAPA syndrome.


Immature Neurons and Radial Glia, But Not Astrocytes or Microglia, Are Altered in Adult Cntnap2 and Shank3 Mice, Models of Autism.
Autism spectrum disorder (ASD) is often associated with cognitive deficits and excessive anxiety. Neuroimaging studies have shown atypical structure and neural connectivity in the hippocampus, medial prefrontal cortex (mPFC), and striatum, regions associated with cognitive function and anxiety regulation. Adult hippocampal neurogenesis is involved in many behaviors that are disrupted in ASD, including cognition, anxiety, and social behaviors. Additionally, glial cells, such as astrocytes and microglia, are important for modulating neural connectivity during development, and glial dysfunction has been hypothesized to be a key contributor to the development of ASD. Cells with astroglial characteristics are known to serve as progenitor cells in the developing and adult brain. Here, we examined adult neurogenesis in the hippocampus, as well as astroglia and microglia in the hippocampus, mPFC, and striatum of two models that display autism-like phenotypes, Cntnap2-/- and Shank3+/ΔC transgenic mice. We found a substantial decrease in the number of immature neurons and radial glial progenitor cells in the ventral hippocampus of both transgenic models compared with wild-type controls. No consistent differences were detected in the number or size of astrocytes or microglia in any other brain region examined. Future work is needed to explore the functional contribution of adult neurogenesis to autism-related behaviors as well as to temporally characterize glial plasticity as it is associated with ASD.


Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial.
To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.


[Obsessive compulsive disorder and the internet. An evaluation of Dutch-language websites and quality indicators].
The Internet is an important source of information about health matters. The quality of the information about Obsessive Compulsive Disorder (OCD) has not been investigated. Possible indicators of quality are the DISCERN rating tool, Google PageRank and cooperation from health care professionals. To investigate the quality of the information given on Dutch-language websites relating to OCD and to determine whether the quality of the contents is correlated with site characteristics, scores on DISCERN and Google PageRank. We selected 27 Dutch-language websites via Google and Ixquick and investigated the correlation between the quality of the contents measured by 4 parameters and the presence of incorrect information, site characteristics, the DISCERN score and Google PageRank. The quality of the information was generally poor. The only investigated site characteristic that was found to be associated with basic criteria relating to symptoms and diagnosis was the size of the site. The DISCERN score was significantly correlated with the quality of the information. The occurrence of incorrect information was independent of the quality of the content, site characteristics, Google PageRank and DISCERN scores. The quality of Dutch-language websites on the subject of OCD is inadequate. Site characteristics and Google PageRank are not good predictors of the quality of information. The DISCERN rating tool is a potentially valuable indicator of content quality with regard to treatment options.


Are "by-stander" female Sprague-Dawley rats affected by experimental procedures?
The objective of this study was to test the hypotheses that female rats are stressed by being in the same room as animals subjected to common husbandry and experimental procedures and that the level of stress is affected by housing density. Two commonly used indices of stress, heart rate (HR) and mean arterial blood pressure (MAP), were determined by using radiotelemetry for 2 h before and 3 h after rats witnessed the following procedures: decapitation, simulated decapitation, cage change, simulated cage change, restraint and subcutaneous injection, removal of rats to another room for injection, restraint and tail-vein injection, handling and weighing, and handling and vaginal lavage. In addition, home cage behaviors (sleeping, awake, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the procedures. Witnessing decapitation of six other rats induced small, but significant, increases in HR above undisturbed baseline values in animals housed alone, whereas responses in animals housed with one or three cage mates were slightly greater than those of rats housed alone. Witnessing a routine cage change induced significant increases in HR in rats which were equal to or greater than those induced by witnessing decapitations; however, housing density had little effect on the responses to cage change. HR did not significantly increase above baseline values in rats witnessing restraint and a subcutaneous or tail-vein injection of other rats or when witnessing other rats being handled and weighed. However, rats housed alone showed significant increases in HR when witnessing a vaginal lavage of other rats. Active behaviors (moving, rearing, grooming) in the home cage were significantly altered only in rats housed alone and then only when witnessing a cage change or a tail-vein injection. Considering primarily increased HR, we conclude that female Sprague-Dawley rats may be marginally stressed when present in the same room in which decapitation is being performed, but similar stress-like responses are induced by common husbandry and experimental procedures. Finally, group housing often, but not always, reduces the stress-like responses that can occur in female by-stander rats.


Intravitreal gentamicin-induced macular infarction: SD-OCT features.
A 75-year-old woman developed acute-onset endophthalmitis following phacoemulsification in the left eye. She was treated with intravitreal injections of vancomycin, ceftazidime, and gentamicin. The patient had persistent visual loss in the left eye after treatment. Her best-corrected visual acuity was 2/200 in the left eye and examination revealed a pale disc, retinal hemorrhages, and multiple nerve fiber layer infarcts. Fluorescein angiography showed retinal vascular non-perfusion in the macula. On spectral-domain optical coherence tomography (SD-OCT), there was diffuse retinal thinning, absence of the foveal depression, and increased reflectivity of the nerve fiber and ganglion cell layers, but with an intact inner segment/outer segment junction. This case demonstrates SD-OCT features in macular infarction following intravitreal gentamicin, specifically changes involving the inner retina with a relatively intact outer retina.


Informatics implementation in the Veterans Health Administration (VHA) healthcare system to improve quality of care.
We describe VHA's information technology (IT) implementation from the providers' perspective, and identify factors influencing its effective implementation to improve care. We surveyed a stratified random national sample of 4227 clinicians from three VHA primary care provider groups: 1) physicians; 2) nurse practitioners, physician assistants; and 3) nurses. Facility-level IT support availability was rated across six dimensions: 1) access to literature/evidence, 2) computerized decision support, 3) computerized clinical data, 4) error reduction, 5) provider communication, and 6) patient communication. Factor analysis identified a 5-item scale (IT clinical support, á = 0.76). Generalized estimating equation models identified factors influencing IT clinical support. Complete data from 123 hospitals (1777 providers) were included. IT clinical support was higher in urban hospitals (p<0.05) and those with cooperative cultures (p<0.01). Opportunities exist to enhance effective use of IT to support clinical decision making, electronic communication with patients and access to recommendations while delivering care.


Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.
Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.


Prevention of cisplatin-induced hearing loss by administration of a thiosulfate-containing gel to the middle ear in a guinea pig model.
Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary.


Low renal papillary plasma flow in both Dahl and Kyoto rats with spontaneous hypertension.
Abnormally low plasma flow to renal papilla characterizes Dahl hypertension. When eating a normal Na diet (0.3% NaCl) both hypertension-sensitive (S) rats and hypertension-resistant (R) rats, 16 weeks old, have fairly normal blood pressure (BP), averaging 144 and 129 mm Hg, respectively. However, even in this barely hypertensive state, 18 S rats had a 31% lower papillary plasma flow (Lilienfield method) than 22 R rats, 19.2 ml/100 g of papilla per min compared to 25.6 (P less than 0.001). When a high (8%) NaCl diet was fed for 7 days, R rats increased papillary plasma flow from 25.6 on 0.3% NaCl to 33.8 on 8% NaCl, a 32% rise (P less than 0.001). S rats increased papillary flow from 20.4 to 24.8, a 22% rise (P less than 0.05). When a high (8%) NaCl diet was fed for 4 weeks, R rats increased papillary plasma flow from 25.7 ml/100 g per min on 0.3% NaCl to 29.5 ml/100 g per min on 8% NaCl, a 15% rise (P less than 0.025). S rats increased papillary flow from 17.7 to 20.0 ml/100 g per min (not significant). S rats on 8% NaCl had a papillary flow 32% lower than R rats on 8% NaCl (P less than 0.001). BP of S rats rose to 162 mm Hg after 4 weeks on 8% NaCl; in R rats, BP did not rise at all. S rats on 0.3% NaCl have a low papillary flow even in a borderline hypertensive state. When challenged with 8% NaCl, R rats increased papillary flow, an adaptation possibly important for the natriuresis. S rats failed to achieve this same high papillary flow. Lacking this adaptation, hypertension may then conceivably occur in S rats to accomplish natriuresis through a "pressure natriuresis" mechanism. Papillary flow also decreased by 11% in 26 Kyoto 17-week-old spontaneously hypertensives (BP, 182 mm Hg) compared to 24 Kyoto normotensives (BP, 118 mm Hg), 29.5 vs 33.2 ml/100 g per min (P less than 0.001). Thus, low papillary flow exists in both hypertensions.


Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade.
Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.


Targeting of Helicobacter pylori thymidylate synthase ThyX by non-mitotoxic hydroxy-naphthoquinones.
ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the functionally analogous human enzyme, thus providing means for selective inhibition of bacterial growth. To identify novel compounds with anti-bacterial activity against the human pathogenic bacterium Helicobacter pylori, based on our earlier biochemical and structural analyses, we designed a series of eighteen 2-hydroxy-1,4-naphthoquinones (2-OH-1,4-NQs) that target HpThyX. Our lead-like molecules markedly inhibited the NADPH oxidation and 2'-deoxythymidine-5'-monophosphate-forming activities of HpThyX enzyme in vitro, with inhibitory constants in the low nanomolar range. The identification of non-cytotoxic and non-mitotoxic 2-OH-1,4-NQ inhibitors permitted testing their in vivo efficacy in a mouse model for H. pylori infections. Despite the widely assumed toxicity of naphthoquinones (NQs), we identified tight-binding ThyX inhibitors that were tolerated in mice and can be associated with a modest effect in reducing the number of colonizing bacteria. Our results thus provide proof-of-concept that targeting ThyX enzymes is a highly feasible strategy for the development of therapies against H. pylori and a high number of other ThyX-dependent pathogenic bacteria. We also demonstrate that chemical reactivity of NQs does not prevent their exploitation as anti-microbial compounds, particularly when mitotoxicity screening is used to prioritize these compounds for further experimentation.


Exploring assistance in Sweden and the United States.
Few international comparisons of health services are performed using microlevel data. Using such data, this paper compares the need for and receipt of assistance with activities of daily living (ADLs) in comparable samples in the United States and Sweden, a country with a universal system of community-based services. Data from national surveys of community residents completed at approximately the same time in each nation are used to create comparable measures of need and assistance. Descriptive and logistic regression analyses compare need and assistance patterns across the nations and identify individual factors that explain receipt of assistance and unmet needs. Our results indicate that a simple story of greater use of paid formal services in Sweden and more unpaid informal use in the United States masks a more complex relationship. Assistance with ADLs seems to be more targeted in Sweden; narrow differences in assistance widen considerably when the analysis is limited to those reporting need. Although these two different health systems result in similar levels of overall ADL assistance, a detailed microlevel comparison reveals key distinctions. Further microlevel comparisons of access, cost, and quality in cross-national data can further aid our understanding of the consequences of health policy.


Spontaneous diameter oscillations of the radial artery in humans.
In this study we investigated whether there exists a periodic contractile activity of the radial artery, and we evaluated the impact of such an oscillatory behavior on the mechanical properties of this medium-sized muscular vessel. The internal diameter of the right radial artery was measured noninvasively in six healthy male volunteers aged 18-42 yr using a high-precision ultrasonic echo-tracking device. Blood pressure was simultaneously recorded on the same side at the middle finger by photoplethysmography. The electrical activity of the heart was monitored during the entire experiment by electrocardiography. The frequency components of the arterial diameter, blood pressure, and heart rate were obtained using spectral analysis. Under resting conditions, the radial arterial diameter exhibited a spontaneous oscillation with a period ranging from 45 to 70 s and an amplitude of 80 +/- 14 microns (+/- SE). No very low-frequency mode (< or = 0.02 Hz) was identified in either heart rate or blood pressure. These diameter oscillations affected the distensibility-pressure curves acquired simultaneously. Thus the 3-4% oscillatory variation in arterial diameter was paralleled by a 1.5- to 2-fold change in distensibility. These low-frequency oscillations of large arteries seem to be mediated by an intrinsic vascular mechanism.


Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha.
Interleukin 12 (IL-12) produced by macrophages immediately after infection is considered essential for activation of a protective immune response against intracellular pathogens. In the murine Mycobacterium bovis Bacillus Calmette-Guérin (BCG) model we assessed whether early IL-12 production by macrophages depends on other cytokines. In vitro, murine bone marrow-derived macrophages produced IL-12 after infection with viable M. bovis BCG or stimulation with LPS, however, priming with recombinant interferon gamma (rIFN-gamma) was necessary. In addition, IL-12 production by these macrophages was blocked by specific anti-tumor necrosis factor alpha (TNF-alpha) antiserum. Macrophages from gene deletion mutant mice lacking either the IFN-gamma receptor or the TNF receptor 1 (p55) failed to produce IL-12 in vitro after stimulation with rIFN-gamma and mycobacterial infection. In vivo, IL-12 production was induced in spleens of immunocompetent mice early during M. bovis BCG infection but not in those of mutant mice lacking the receptors for IFN-gamma or TNF. Our results show that IL-12 production by macrophages in response to mycobacterial infection depends on IFN-gamma and TNF. Hence, IL-12 is not the first cytokine produced in mycobacterial infections.


Determinants in Adolescence of Stroke-Related Hospital Stay Duration in Men: A National Cohort Study.
Physical and psychological characteristics in adolescence are associated with subsequent stroke risk. Our aim is to investigate their relevance to length of hospital stay and risk of second stroke. Swedish men born between 1952 and 1956 (n=237 879) were followed from 1987 to 2010 using information from population-based national registers. Stress resilience, body mass index, cognitive function, physical fitness, and blood pressure were measured at compulsory military conscription examinations in late adolescence. Joint Cox proportional hazards models estimated the associations of these characteristics with long compared with short duration of stroke-related hospital stay and with second stroke compared with first. Some 3000 men were diagnosed with nonfatal stroke between ages 31 and 58 years. Low stress resilience, underweight, and higher systolic blood pressure (per 1-mm Hg increase) during adolescence were associated with longer hospital stay (compared with shorter) in ischemic stroke, with adjusted relative hazard ratios (and 95% confidence intervals) of 1.46 (1.08-1.89), 1.41 (1.04-1.91), and 1.01 (1.00-1.02), respectively. Elevated systolic and diastolic blood pressures during adolescence were associated with longer hospital stay in men with intracerebral hemorrhage: 1.01 (1.00-1.03) and 1.02 (1.00-1.04), respectively. Among both stroke types, obesity in adolescence conferred an increased risk of second stroke: 2.06 (1.21-3.45). Some characteristics relevant to length of stroke-related hospital stay and risk of second stroke are already present in adolescence. Early lifestyle influences are of importance not only to stroke risk by middle age but also to recurrence and use of healthcare resources among stroke survivors.


Patterns of dental caries severity in Chinese kindergarten children.
The dental caries status of a population group is traditionally described by mean values of decayed, missing and filled teeth or surfaces (DMFT or S). Because of the limitations of the DMF values alone, additional measures of dental caries become important. A system of describing the pattern of dental caries attack hierarchically according to severity of caries was suggested by Poulsen & Horowitz (Community Dent Oral Epidemiol 1974;2:7-11). The purpose of the present study was to analyze caries data from a group of 3-6-year-old Chinese kindergarten children according to this hierarchical system, assess the hierarchical assumptions of the system with deciduous teeth and evaluate its usefulness as an additional caries description for a kindergarten population. As part of a longitudinal field trial, baseline caries data were collected from 452 children. Caries was registered by tooth surface without the use of radiographs. Each child was assigned to one of six mutually exclusive zones of increasing caries severity, from zone 0=caries free through zone 5, the most severe, assuming that once a child was classified into a given zone it automatically belonged to all zones of lesser severity (except zone 0). On the basis of the original six zones, 61% of the children were classified correctly according to the hierarchical concept, but different alternative models which merged one or more zones together demonstrated varying percentages of correct classification, the cariologically most acceptable one placing 83% correctly. For each age group there was a close correlation between mean dmfs and increasing severity. The hierarchical model provides a valuable additional description of the caries status in deciduous teeth and is consistent with professional and epidemiological knowledge of caries attack patterns.


Differential gene expression between juvenile and adult dura mater: a window into what genes play a role in the regeneration of membranous bone.
Although reossification of large calvarial defects is possible in children, adults lack this tissue engineering capacity. In this study, the authors compared the differences in gene expression between juvenile and adult dura mater using a mouse cDNA microarray with 42,000 unique elements. Non-suture-associated parietal bone was harvested from 6-day-old and 60-day-old mice. The dura mater was carefully dissected from the calvarial disk and snap-frozen. RNA was extracted from pooled dura mater for microarray analysis. The 25 most differentially expressed genes were listed, as were selected bone-related genes. In addition, quantitative real-time reverse-transcriptase polymerase chain reaction confirmation of selected genes-BMP-2, BMP-4, and BMP-7; and osteopontin (OP), osteocalcin (OC), and FGFR-1-was performed. Juvenile dura mater expressed significantly greater amounts of BMP-2 and OP. Minimal difference in OC expression was observed between juvenile and adult dura mater. Extracellular matrix proteins (Col3a1, 5a1, 6a1, and fibronectin 1), osteoblast differentiation markers (Runx2/Cbfa1, Itm2a, and FGFR-1), and the growth factor Ptn were among other genes with greater expression in juvenile dura mater. Markers of osteoclasts (Acp5, MMP9, Ctsk) and the multiple candidate gene Ntrk2 were also expressed at higher levels in the juvenile dura mater. These findings suggest a more differentiated osteoprogenitor population to exist along with a greater presence of osteoclasts in the juvenile dura mater relative to adults. In addition to establishing a baseline difference in gene expression between juvenile and adult dura mater, new genes potentially critical to the regenerative potential of juvenile calvaria were identified.


Cut to the Quick: The Consequences of Youth Violent Victimization for the Timing of Dating Debut and First Union Formation.
Concentrated in adolescence, violent victimization is developmentally disruptive. It undermines physical, mental, and socioemotional well-being and compromises youths' transitions into and progression through key life course tasks. Youth violent victimization (YVV) has been linked to precocious exits from adolescence and premature entries into adulthood. This includes early entry into coresidential romantic unions, which is but one stage of a relationship sequence generally beginning via dating debut. Using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) and Cox regression, we examine the effects of YVV on the timing of dating debut and progression to first coresidential unions during adolescence and the transition to adulthood. We pay particular attention to how these effects may be structured by age and gender. Overall, we find that victims begin dating sooner and progress more quickly from dating to first unions than do non-victims. However, youths victimized in early adolescence withdraw from dating and union formation, whereas late adolescent victims appear to overinvest in relationships-at least temporarily-displaying accelerated entry into dating and rapid progression to first unions. We conclude by discussing the implication of these age-graded patterns for intervention efforts and youth well-being more broadly.


Microdeletions of chromosome 7p21, including TWIST1, associated with significant microcephaly, facial dysmorphism, and short stature.
Saethre-Chotzen syndrome due to TWIST1 mutations is characterized by coronal synostosis, facial dysmorphism and additional variable anomalies. Small deletions comprising the whole TWIST1 account for a small proportion of patients with Saethre-Chotzen syndrome. Here we describe 3 patients with facial dysmorphism, marked microcephaly, short stature (2/3 patients), and overlapping 7p21 microdeletions. Molecular karyotyping identified small deletions of chromosome 7p21 including TWIST1 with a size of 526 kb, 9.2 Mb, and 11.7 Mb, respectively. The clinical manifestations of these patients do not resemble the typical phenotype of Saethre-Chotzen syndrome. In the two patients with larger microdeletions, severe mental retardation and significant short stature are present. Facial dysmorphism of patient 3 includes also signs of blepharophimosis-ptosis-epicanthus inversus syndrome.


Computational model-informed design and bioprinting of cell-patterned constructs for bone tissue engineering.
Three-dimensional (3D) bioprinting is a rapidly advancing tissue engineering technology that holds great promise for the regeneration of several tissues, including bone. However, to generate a successful 3D bone tissue engineering construct, additional complexities should be taken into account such as nutrient and oxygen delivery, which is often insufficient after implantation in large bone defects. We propose that a well-designed tissue engineering construct, that is, an implant with a specific spatial pattern of cells in a matrix, will improve the healing outcome. By using a computational model of bone regeneration we show that particular cell patterns in tissue engineering constructs are able to enhance bone regeneration compared to uniform ones. We successfully bioprinted one of the most promising cell-gradient patterns by using cell-laden hydrogels with varying cell densities and observed a high cell viability for three days following the bioprinting process. In summary, we present a novel strategy for the biofabrication of bone tissue engineering constructs by designing cell-gradient patterns based on a computational model of bone regeneration, and successfully bioprinting the chosen design. This integrated approach may increase the success rate of implanted tissue engineering constructs for critical size bone defects and also can find a wider application in the biofabrication of other types of tissue engineering constructs.


Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG.
Several guidelines have been reported for bone-directed treatment in women with early breast cancer (EBC) for averting fractures, particularly during aromatase inhibitor (AI) therapy. Recently, a number of studies on additional fracture related risk factors, new treatment options as well as real world studies demonstrating a much higher fracture rate than suggested by randomized clinical controlled trials (RCTs). Therefore, this updated algorithm was developed to better assess fracture risk and direct treatment as a position statement of several interdisciplinary cancer and bone societies involved in the management of AI-associated bone loss (AIBL). A systematic literature review identified recent advances in the management of AIBL. Results with individual agents were assessed based on trial design, size, follow-up, and safety. Several fracture related risk factors in patients with EBC were identified. Although, the FRAX algorithm includes fracture risk factors (RF) in addition to BMD, it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL. In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score<-2.0 or with a T-score of <-1.5 SD with one additional RF, or with ≥2 risk factors (without BMD) for the duration of AI treatment. Patients with T-score>-1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12 - 24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.


Genomic and epidemiological monitoring of yellow fever virus transmission potential.
The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.


Non-invasively visualizing cell-matrix interactions in two-photon excited supramolecular hydrogels.
Visualizing the role of extracellular matrix (ECM) in cell bioactivities in three-dimensional (3D) view is highly important for in-depth understanding of fundamental physiological issues in various in vitro experiments. Using current designs it is difficult to produce 3D biomimetic ECM with intrinsic fluorescence under non-invasive near-infrared excitation. Herein, we have designed and synthesized a series of non-conventional coumarin-derived hydrogelators, which can self-assemble to form nanofibrous 3D supramolecular hydrogels through C-HO bonds and be excited by two-photon absorption, ensuring the direct and dynamic visualization of cell-matrix interactions with high resolution images in a 3D environment. Real-time monitoring of ECM-regulated dynamic cell behaviours is highly desirable for future basic and applied research.


Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.
Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.


Surgical site infections: epidemiology, microbiology and prevention.
Surgical site infections (SSIs) are defined as infections occurring up to 30 days after surgery (or up to one year after surgery in patients receiving implants) and affecting either the incision or deep tissue at the operation site. Despite improvements in prevention, SSIs remain a significant clinical problem as they are associated with substantial mortality and morbidity and impose severe demands on healthcare resources. The incidence of SSIs may be as high as 20%, depending on the surgical procedure, the surveillance criteria used, and the quality of data collection. In many SSIs, the responsible pathogens originate from the patient's endogenous flora. The causative pathogens depend on the type of surgery; the most commonly isolated organisms are Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus spp. and Escherichia coli. Numerous patient-related and procedure-related factors influence the risk of SSI, and hence prevention requires a 'bundle' approach, with systematic attention to multiple risk factors, in order to reduce the risk of bacterial contamination and improve the patient's defences. The Centers for Disease Control and Prevention guidelines for the prevention of SSIs emphasise the importance of good patient preparation, aseptic practice, and attention to surgical technique; antimicrobial prophylaxis is also indicated in specific circumstances. Emerging technologies, such as microbial sealants, offer the ability to seal and immobilise skin flora for the duration of a surgical procedure; a strong case therefore exists for evaluating such technologies and implementing them into routine clinical practice as appropriate.


Enhanced catalytic activity for CO oxidation by the metal-oxide perimeter of TiO2/nanostructured Au inverse catalysts.
We report the effect of metal-oxide interfaces on CO oxidation catalytic activity with inverse TiO2-nanostructured Au catalysts. The inverse nanocatalysts were prepared by depositing TiO2via the liquid-phase immersion method on electrochemically synthesized Au nanostructure supports. The catalytic performance for CO oxidation was investigated using various amounts of Ti (i.e. 0.1-1.0 wt%) on two different morphologies of Au nanostructures (i.e. nanoporous and nanorod). In comparing the different Au morphologies, we found an overall higher TOF and lower activation energy for the TiO2/nanoporous Au than those for the TiO2/nanorod Au. In addition, the CO oxidation activity increased as the Ti content increased up to 0.5 wt% probably due to active TiO2-Au interface sites enhancing CO oxidation via the supply of adsorption sites or charge transfer from TiO2 to Au. However, a higher titania content (i.e. 1.0 wt% TiO2) resulted in decreased activity caused by high surface coverage of TiO2 decreasing the number of TiO2-Au interface sites. These results implied that the perimeter area of the metal-oxide interface played a significant role in determining the catalytic performance for CO oxidation.


Addiction Potential of Cigarettes With Reduced Nicotine Content in Populations With Psychiatric Disorders and Other Vulnerabilities to Tobacco Addiction.
A national policy is under consideration to reduce the nicotine content of cigarettes to lower nicotine addiction potential in the United States. To examine how smokers with psychiatric disorders and other vulnerabilities to tobacco addiction respond to cigarettes with reduced nicotine content. A multisite, double-blind, within-participant assessment of acute response to research cigarettes with nicotine content ranging from levels below a hypothesized addiction threshold to those representative of commercial cigarettes (0.4, 2.3, 5.2, and 15.8 mg/g of tobacco) at 3 academic sites included 169 daily smokers from the following 3 vulnerable populations: individuals with affective disorders (n = 56) or opioid dependence (n = 60) and socioeconomically disadvantaged women (n = 53). Data were collected from March 23, 2015, through April 25, 2016. After a brief smoking abstinence, participants were exposed to the cigarettes with varying nicotine doses across fourteen 2- to 4-hour outpatient sessions. Addiction potential of the cigarettes was assessed using concurrent choice testing, the Cigarette Purchase Task (CPT), and validated measures of subjective effects, such as the Minnesota Nicotine Withdrawal Scale. Among the 169 daily smokers included in the analysis (120 women [71.0%] and 49 men [29.0%]; mean [SD] age, 35.6 [11.4] years), reducing the nicotine content of cigarettes decreased the relative reinforcing effects of smoking in all 3 populations. Across populations, the 0.4-mg/g dose was chosen significantly less than the 15.8-mg/g dose in concurrent choice testing (mean [SEM] 30% [0.04%] vs 70% [0.04%]; Cohen d = 0.40; P < .001) and generated lower demand in the CPT (α = .027 [95% CI, 0.023-0.031] vs α = .019 [95% CI, 0.016-0.022]; Cohen d = 1.17; P < .001). Preference for higher over lower nicotine content cigarettes could be reversed by increasing the response cost necessary to obtain the higher dose (mean [SEM], 61% [0.02%] vs 39% [0.02%]; Cohen d = 0.40; P < .001). All doses reduced Minnesota Nicotine Withdrawal Scale total scores (range of mean decreases, 0.10-0.50; Cohen d range, 0.21-1.05; P < .001 for all), although duration of withdrawal symptoms was greater at higher doses (η2 = 0.008; dose-by-time interaction, P = .002). Reducing the nicotine content of cigarettes may decrease their addiction potential in populations that are highly vulnerable to tobacco addiction. Smokers with psychiatric conditions and socioeconomic disadvantage are more addicted and less likely to quit and experience greater adverse health impacts. Policies to reduce these disparities are needed; reducing the nicotine content in cigarettes should be a policy focus.


A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography.
Female BRCA1/2 mutation carriers develop in up to 50% breast cancer (BC) before age 50 years. We investigated whether the specific histologic features of BRCA1/2-associated breast cancer influence imaging. We correlated the mammographic results with the histology of 34 BC in BRCA1/2 mutation carriers and 34 sporadic cancers in patients, matched for age and year of diagnosis. Mammography was significantly more frequently false-negative in carriers than controls (62% vs. 29% p = 0.01), despite comparable tumor size (mean solidus in circle 1.51 vs. 1.75) and breast density (high 41% vs. 53%). The image in carriers was significantly less as spiculated mass (6 vs. 18 p = 0.01). Cancers of BRCA1/2 mutation carriers had frequently higher mitotic counts (p < 0.0001) and prominent pushing margins around the tumor (p = 0.08) (p = 0.05 for 32 BRCA1). We also observed that prominent "pushing margins" correlated significantly with a false-negative mammography (p = 0.005) and with a mammographic image of a smooth, not a spiculated, mass (p = 0.01). False-negative mammography correlated independently with: BRCA1/2 mutation (p = 0.02), prominent pushing margins (p = 0.03) and high breast density (p = 0.01). MRI was carried out in 12 carriers, had 100% sensitivity and detected 5 cancers, still occult at physical examination and mammography. A BRCA1/2 mutation and high breast density at mammography contribute independently to false-negative mammography results. In mutation carriers any mammographic mass must be regarded with suspicion. Pushing margins of the tumor partly explain these results. For early BC detection in mutation carriers additional methods like MRI may be needed. This may not be necessary in other young women with breast symptoms.


Photorefractive materials for nonvolatile volume holographic data storage
Optically gated recording and nonvolatile readout in a digital volume holographic data storage system that uses a pair of mutually incoherent light sources during recording and only one for readout were demonstrated recently. This approach used stoichiometric lithium niobate, which after post-growth processing gave rise to an at least two orders of magnitude improvement in sensitivity over the best materials reported previously. It is also shown that by adding certain dopants (iron and manganese) to near-stoichiometric lithium niobate, the dark storage time and gating efficiency can be increased compared with previous work. The underlying physical mechanisms of gated recording and the effectiveness of the gating process responsible for this manifold improved performance are discussed, and bipolarons and small polarons are identified as the responsible photorefractive species.


Quantitative trait loci affecting atherosclerosis at the aortic root identified in an intercross between DBA2J and 129S6 apolipoprotein E-null mice.
Apolipoprotein E-null mice on a DBA/2J genetic background (DBA-apoE) are highly susceptible to atherosclerosis in the aortic root area compared with those on a 129S6 background (129-apoE). To explore atherosclerosis-responsible genetic regions, we performed a quantitative trait locus (QTL) analysis using 172 male and 137 female F2 derived from an intercross between DBA-apoE and 129-apoE mice. A genome-wide scan identified two significant QTL for the size of lesions at the root: one is Ath44 on Chromosome (Chr) 1 at 158 Mb, and the other Ath45 on Chr 2 at 162 Mb. Ath44 co-localizes with but appears to be independent of a previously reported QTL, Ath1, while Ath45 is a novel QTL. DBA alleles of both Ath44 and Ath45 confer atherosclerosis-susceptibility. In addition, a QTL on Chr 14 at 73 Mb was found significant only in males, and 129 allele conferring susceptibility. Further analysis detected female-specific interactions between a second QTL on Chr 1 at 73 Mb and a QTL on Chr 3 at 21 Mb, and between Chr 7 at 84 Mb and Chr 12 at 77 Mb. These loci for the root atherosclerosis were independent of QTLs for plasma total cholesterol and QTLs for triglycerides, but a QTL for HDL (Chr 1 at 126 Mb) overlapped with the Ath44. Notably, haplotype analysis among 129S6, DBA/2J and C57BL/6 genomes and their gene expression data narrowed the candidate regions for Ath44 and Ath45 to less than 5 Mb intervals where multiple genome wide associations with cardiovascular phenotypes have also been reported in humans. SNPs in or near Fmo3, Sele and Selp for Ath44, and Lbp and Pkig for Ath45 were suggested for further investigation as potential candidates underlying the atherosclerosis susceptibility.


Functional interactions of p53 with poly(ADP-ribose) polymerase (PARP) during apoptosis following DNA damage: covalent poly(ADP-ribosyl)ation of p53 by exogenous PARP and noncovalent binding of p53 to the M(r) 85,000 proteolytic fragment.
We have examined the domain-specific interactions between p53 and poly(ADP-ribose)polymerase (PARP) (E.C. 184.108.40.206) in apoptotic HeLa cells. Apoptosis was induced by exposing cells to 50 microM N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for increasing lengths of time and was confirmed by: (a) oligonucleosomal fragmentation of chromatin; (b) increase in p53 levels; and (c) degradation of PARP into the characteristic M(r) 85,000 (COOH-terminal catalytic domain) and M(r) 29,000 (DNA-binding domain) peptide fragments. We also immunodetected p53 in immunoprecipitates obtained with a PARP-specific antibody. However, intact PARP coimmunoprecipitated with a p53-specific antibody during the initial 30 min of MNNG treatment. After 60 min, only the COOH-terminal fragment coimmunoprecipitated with p53, indicating that PARP noncovalently binds p53 via its M(r) 85,000 catalytic domain. Therefore, we next examined p53 as a covalent target for poly(ADP-ribosyl)ation. Although p53 was not endogenously poly (ADP-ribosyl)ated in situ, incubation of cell extracts with full-length PARP from calf thymus and [32P]beta NAD+ resulted in its time-dependent poly(ADP-ribosyl)ation. In summary, our results are consistent with the conclusion that PARP and p53 are activated with nonoverlapping kinetics during apoptosis.


The Top 50 Most Cited Articles in Cartilage Regeneration.
The aim of this study was to identify and analyze the top 50 most cited articles in cartilage regeneration. The impact of a scientific journal can be gauged by the total number of citations it has accrued. The top 50 most cited articles involving cartilage regeneration represent the most quoted level of evidence among this new subspecialty. This study aims to identify and analyze the 50 most cited articles in cartilage regeneration. The Web of Science™ citation indexing service was utilized to determine the most frequently cited articles published after 1956 containing "cartilage regeneration" in the "topic" or "title." The 50 most cited articles were included. The number of citations, year of publication, country of article origin, article institution, journal of publication, publication format, and authorship were then calculated for each article. The span of citations ranged from 1287 to 203 citations, with a mean of 361.02 citations per article in question. The articles originated from 11 countries, with the United States contributing 34 articles, followed by Japan with 5 articles. The articles were distributed across 34 high-impact journals. Biomaterials was the journal with the highest number of publications (seven articles) followed by the Journal of Orthopaedic Research (three articles). Of the 50 articles, 2 were clinical observational studies, 47 concerned basic science, and 1 was review article. The most cited articles involving cartilage regeneration are detected in both experimental and clinical research fields. The high ratio of basic science to clinical articles reflects the infancy of this relatively new specialty and that further clinical research is required in this area.


"Blue flags", development of a short clinical questionnaire on work-related psychosocial risk factors - a validation study in primary care.
Working conditions substantially influence health, work ability and sick leave. Useful instruments to help clinicians pay attention to working conditions are lacking in primary care (PC). The aim of this study was to test the validity of a short "Blue flags" questionnaire, which focuses on work-related psychosocial risk factors and any potential need for contacts and/or actions at the workplace. From the original"The General Nordic Questionnaire" (QPSNordic) the research group identified five content areas with a total of 51 items which were considered to be most relevant focusing on work-related psychosocial risk factors. Fourteen items were selected from the identified QPSNordic content areas and organised in a short questionnaire "Blue flags". These 14 items were validated towards the 51 QPSNordic items. Content validity was reviewed by a professional panel and a patient panel. Structural and concurrent validity were also tested within a randomised clinical trial. The two panels (n = 111) considered the 14 psychosocial items to be relevant. A four-factor model was extracted with an explained variance of 25.2%, 14.9%, 10.9% and 8.3% respectively. All 14 items showed satisfactory loadings on all factors. Concerning concurrent validity the overall correlation was very strong rs = 0.87 (p < 0.001).). Correlations were moderately strong for factor one, rs = 0.62 (p < 0.001) and factor two, rs = 0.74 (p < 0.001). Factor three and factor four were weaker, bur still fair and significant at rs = 0.53 (p < 0.001) and rs = 0.41 (p < 0.001) respectively. The internal consistency of the whole "Blue flags" was good with Cronbach's alpha of 0.76. The content, structural and concurrent validity were satisfactory in this first step of development of the "Blue flags" questionnaire. In summary, the overall validity is considered acceptable. Testing in clinical contexts and in other patient populations is recommended to ensure predictive validity and usefulness.


Stereotactic radiosurgery improves locomotor recovery after spinal cord injury in rats.
Currently, because of the precision of stereotactic radiosurgery, radiation can now be delivered by techniques that shape the radiation beam to the tissue target for a variety of clinical applications. This avoids unnecessary and potentially damaging irradiation of surrounding tissues inherent in conventional irradiation, so that irradiation of the minimum volume of tissue necessary for optimal therapeutic benefit can be achieved. Although conventional x-irradiation has been shown to improve recovery from spinal cord injury in animals, the efficacy of targeted irradiation of the injured spinal cord has not been demonstrated previously. The purpose of these studies was to determine whether stereotactic x-irradiation of the injured spinal cord can enhance locomotor function and spare spinal cord tissue after contusion injury in a standard experimental model of spinal cord injury. Contusion injury was produced in rats at the level of T10 with a weight-drop device, and doses of x-irradiation were delivered 2 hours after injury via a Novalis, 6-MeV linear accelerator shaped beam radiosurgery system (BrainLAB USA, Westchester, IL) in 4 sequential fractions, with beam angles 60 to 70 degrees apart, at a rate of 6.4 Gy/minute. The target volume was a 4 x 15-mm cylinder along the axis of the spinal cord, with the isocenter positioned at the contusion epicenter. Locomotor function was determined for 6 weeks after injury with the 21-point Basso, Beattie, and Bresnahan (BBB) locomotor scale and tissue sparing in histological sections of the spinal cord. Locomotor function recovered progressively during the 6-week postinjury observation period. BBB scores were significantly greater in the 10-Gy x-irradiated group compared with controls (9.4 versus 7.3; P < 0.05), indicating hind limb weight support or dorsal stepping in contrast to hind limb joint mobility without weight bearing. Doses in the range of 2 to 10 Gy increased BBB scores progressively, whereas greater doses of 15 to 25 Gy were associated with lower BBB scores. The extent of locomotor recovery after treatment with x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. These results suggest a beneficial role for stereotactic radiosurgery in a rat model of acute spinal cord contusion injury and raise hopes for human treatment strategies. Additional animal studies are needed to further define potential benefits.


Bereavement services for family caregivers: how often used, why, and why not.
Bereavement services are central to high-quality end-of-life care, however, little is known about how frequently and why such bereavement services are used and not used. We examined family caregiver reports about how often they used bereavement services, predictors of their use, and reported reasons for not using bereavement services. Prospective cohort study of family caregivers (n = 161) of patients with cancer enrolled with hospice between October 1999 and September 2001. We conducted bivariate and multivariable analyses to determine predictors of bereavement service use, adjusted for a broad range of factors including caregiving experiences, major depressive disorder (MDD), relationship with the deceased, and demographic factors. We used content analysis to summarize responses to open-ended questions concerning why individuals did not use bereavement services. We found that approximately 30% of family caregivers used bereavement services in the year postloss, and the majority of these caregivers used services in the first 6 months postloss. Even among bereaved caregivers with MDD, less than half (47.6%) used bereavement services. Factors associated with using bereavement services included being a spouse caregiver, younger age, having MDD at study enrollment, witnessing highly distressing events pertaining to the patient's death, having assisted the patient with more Instrumental Activities of Daily Living (IADLs) prior to the patient's death, having greater availability of instrumental support for oneself, and physician communication with the caregiver about the patient's prognosis before the patient's death. The most common given reason for nonuse was the perception that bereavement services were not needed or would not help. Addressing caregiver receptivity to bereavement services will be an important aspect of increasing appropriate use of such services. Future studies might examine specific interventions for reducing barriers and increasing receptivity to bereavement service use.


Development of a web-based intervention for the indicated prevention of depression.
To reduce the large public health burden of the high prevalence of depression, preventive interventions targeted at people at risk are essential and can be cost-effective. Web-based interventions are able to provide this care, but there is no agreement on how to best develop these applications and often the technology is seen as a given. This seems to be one of the main reasons that web-based interventions do not reach their full potential. The current study describes the development of a web-based intervention for the indicated prevention of depression, employing the CeHRes (Center for eHealth Research and Disease Management) roadmap. The goals are to create a user-friendly application which fits the values of the stakeholders and to evaluate the process of development. The employed methods are a literature scan and discussion in the contextual inquiry; interviews, rapid prototyping and a requirement session in the value specification stage; and user-based usability evaluation, expert-based usability inspection and a requirement session in the design stage. The contextual inquiry indicated that there is a need for easily accessible interventions for the indicated prevention of depression and web-based interventions are seen as potentially meeting this need. The value specification stage yielded expected needs of potential participants, comments on the usefulness of the proposed features and comments on two proposed designs of the web-based intervention. The design stage yielded valuable comments on the system, content and service of the web-based intervention. Overall, we found that by developing the technology, we successfully (re)designed the system, content and service of the web-based intervention to match the values of stakeholders. This study has shown the importance of a structured development process of a web-based intervention for the indicated prevention of depression because: (1) it allows the development team to clarify the needs that have to be met for the intervention to be of use to the target audience; and (2) it yields feedback on the design of the application that is broader than color and buttons, but encompasses comments on the quality of the service that the application offers.


Satisfaction with life after burn: A Burn Model System National Database Study.
While mortality rates after burn are low, physical and psychosocial impairments are common. Clinical research is focusing on reducing morbidity and optimizing quality of life. This study examines self-reported Satisfaction With Life Scale scores in a longitudinal, multicenter cohort of survivors of major burns. Risk factors associated with Satisfaction With Life Scale scores are identified. Data from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) Burn Model System (BMS) database for burn survivors greater than 9 years of age, from 1994 to 2014, were analyzed. Demographic and medical data were collected on each subject. The primary outcome measures were the individual items and total Satisfaction With Life Scale (SWLS) scores at time of hospital discharge (pre-burn recall period) and 6, 12, and 24 months after burn. The SWLS is a validated 5-item instrument with items rated on a 1-7 Likert scale. The differences in scores over time were determined and scores for burn survivors were also compared to a non-burn, healthy population. Step-wise regression analysis was performed to determine predictors of SWLS scores at different time intervals. The SWLS was completed at time of discharge (1129 patients), 6 months after burn (1231 patients), 12 months after burn (1123 patients), and 24 months after burn (959 patients). There were no statistically significant differences between these groups in terms of medical or injury demographics. The majority of the population was Caucasian (62.9%) and male (72.6%), with a mean TBSA burned of 22.3%. Mean total SWLS scores for burn survivors were unchanged and significantly below that of a non-burn population at all examined time points after burn. Although the mean SWLS score was unchanged over time, a large number of subjects demonstrated improvement or decrement of at least one SWLS category. Gender, TBSA burned, LOS, and school status were associated with SWLS scores at 6 months; scores at 12 months were associated with LOS, school status, and amputation; scores at 24 months were associated with LOS, school status, and drug abuse. In this large, longitudinal, multicenter cohort of burn survivors, satisfaction with life after burn was consistently lower than that of non-burn norms. Furthermore mean SWLS scores did not improve over the two-year follow-up period. This study demonstrates the need for continued efforts to improve patient-centered long term satisfaction with life after burn.