Differential density of normal renal parenchyma on nonenhanced CT: a new observation.
Nonenhanced CT scans through the kidneys commonly show a difference in radiopacity between the inner peripelvic portion of the renal parenchyma and the more peripheral regions of the renal parenchyma. This normal observation has not been described. We reviewed 50 nonenhanced CT scans. Renal parenchyma was evaluated by both visual inspection and density measurements of inner and outer aspects of the kidneys in 38 and visual inspection only in 12. A narrower window was used to better show density differences (100 W, 35 L). We recorded the indication for the CT, history, and recent blood chemistries. The inner parenchyma was of greater radiopacity than the outer parenchyma in 35 of 50 cases by visual inspection and in all densitometry cases (38 of 38). There was no correlation with clinical history or blood chemistry. A difference in density between the inner and outer portions of the renal parenchyma is very common and will often be seen if one looks for it. We have not shown an etiology for this difference, and indeed, it may be physiological. One must be aware of this finding to avoid mistaking it for pathology.


Viscosity Peak due to Shape Transition from Wormlike to Disklike Micelles: Effect of Dodecanoic Acid.
Here, we have investigated the synergistic growth of long wormlike micelles and their transformation into disklike micelles, which occurs in three-component solutions composed of sodium lauryl ether sulfate (SLES; anionic), cocamidopropyl betaine (CAPB; zwitterionic), and dodecanoic acid (HC12; nonionic). The solution rheology is characterized in terms of zero-shear viscosities and characteristic times for micellar breaking and reptation. Furthermore, the microstructure evolution, leading to the observed rheological behavior, is revealed by cryo-transmission electron microscopy (TEM) micrographs. In all cases, the CAPB-to-SLES ratio is fixed, whereas the fatty acid concentration is varied. At a certain HC12 concentration, the solution viscosity passes through a maximum. The cryo-TEM imaging indicates that wormlike micelles appear before the peak, grow further up to the peak, and finally transform into disklike aggregates (a very rare micellar structure) after the peak. The transformation of worms into disks leads to a drop in viscosity because the length-to-thickness aspect ratio of the disks is significantly lower than that of the worms. In this article, we elucidate the structure-rheology relations in micellar solutions that might be applied for the design of personal-care and household formulations.


A comparison of locked versus nonlocked Enders rods for length unstable pediatric femoral shaft fractures.
Stainless steel flexible Enders rods have been used for intramedullary fixation of pediatric femur fractures with good success. Despite intraoperative anatomic alignment, length unstable femur fractures can present postoperatively with fracture shortening. The purpose of this study was to review all length unstable pediatric femoral shaft fractures in which Enders rods were used and compare those that were locked to those that were not locked. A retrospective clinical and radiographic review of all patients at a single institution undergoing flexible intramedullary fixation for length unstable femoral shaft fractures from 2001 to 2008. A length unstable fracture was defined as either a comminuted fracture or a spiral fracture longer than twice the diameter of the femoral shaft. A total of 107 length unstable femoral shaft fractures fixed with Enders rods were identified, of which 37 cases (35%) had both Enders rods "locked" through the eyelet in the distal femur with a 2.7 mm fully threaded cortical screw. Patient demographics, clinical course, complications, fracture characteristics, and radiographic outcomes were compared for the locked and nonlocked groups. There were no statistical differences between the groups in demographic data, operative variables, fracture pattern, fracture location, time to union, femoral alignment, or major complications. Shortening of the femur and nail migration measured at 1 to 6 weeks postoperatively was significantly greater for the nonlocked cases. The medial and lateral locked Enders rods moved 1.3 and 1.9 mm, respectively, and the unlocked Enders each moved 12.1 mm (P < 0.05). At final follow-up there were significantly more (P < 0.05) clinical complaints in nonlocked group, including limp, clinical shortening, and painful palpable rods. Locking Enders rods for length unstable pediatric fractures is an excellent option to prevent shortening and resulted in no additional complications, added surgical time, or increased blood loss. Level III.


Enhancement of human adipose-derived stromal cell angiogenesis through knockdown of a BMP-2 inhibitor.
Previous studies have demonstrated the role of noggin, a bone morphogenetic protein-2 inhibitor, in vascular development and angiogenesis. The authors hypothesized that noggin suppression in human adipose-derived stromal cells would enhance vascular endothelial growth factor secretion and angiogenesis in vitro and in vivo to a greater extent than bone morphogenetic protein-2 alone. Human adipose-derived stromal cells were isolated from human lipoaspirate (n = 6) noggin was knocked down using lentiviral techniques. Knockdown was confirmed and angiogenesis was assessed by tubule formation and quantitative real-time polymerase chain reaction. Cells were seeded onto scaffolds and implanted into a 4-mm critical size calvarial defect. In vivo angiogenic signaling was assessed by immunofluorescence and immunohistochemistry. Human adipose-derived stromal cells with noggin suppression secreted significantly higher amounts of angiogenic proteins, expressed higher levels of angiogenic genes, and formed more tubules in vitro. In vivo, calvarial defects seeded with noggin shRNA human adipose-derived stromal cells exhibited a significantly higher number of vessels in the defect site than controls by immunohistochemistry (p < 0.05). In addition, bone morphogenetic protein-2-releasing scaffolds significantly enhanced vascular signaling in the defect site. Human adipose-derived stromal cells demonstrate significant increases in angiogenesis in vitro and in vivo with both noggin suppression and BMP-2 supplementation. By creating a cell with noggin suppressed and by using a scaffold with increased bone morphogenetic protein-2 signaling, a more angiogenic niche can be created.


Large-scale objective association of mouse phenotypes with human symptoms through structural variation identified in patients with developmental disorders.
Copy number variants (CNVs) are thought to underlie many human developmental abnormalities. However, it is unclear how many of these CNVs exert their pathogenic effects or, in particular, how distinct CNVs at dispersed loci can give rise to the same abnormality. We hypothesize that the mouse orthologs of genes whose copy number change gives rise to the same human abnormality might also yield a similar phenotype when disrupted in mice. Thus, by bringing together a large number of disparate CNVs, we may be able to identify an unusually overrepresented phenotype among the affected genes' mouse orthologs. We obtained 1,624 de novo CNVs identified in patients with developmental abnormalities from Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources and European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations database. Forming CNV sets for each of 1,088 distinct human abnormalities, we were able to associate a total of 143 (13%) human abnormalities with mouse model phenotypes. Although many mouse phenotypes are readily comparable to their associated human abnormality, others are less so, generating novel biological hypotheses. Of the 2,086 candidate genes that contribute to these associations, 65% have not been previously associated with human disease in Online Mendelian Inheritance in Man, and their distribution suggests both extensive pleiotropy and epistasis while also proposing a small number of simple additive consequences.


The predictive value of microalbuminuria in IDDM. A five-year follow-up study.
To investigate the predictive value of microalbuminuria and the annual increase of albumin excretion as risk factors for diabetic nephropathy. A 5-year follow-up of patients with microalbuminuria (urinary albumin excretion [UAE] = 30-299 mg/24 h) and matched patients with normoalbuminuria (UAE < 30 mg/24 h). The initial classification was based on one single 24-h urine collection. The annual increase in UAE was calculated by linear regression analysis of log-transformed UAE on time. This study was conducted at the outpatient clinic of the Steno Diabetes Center. The study subjects included 118 insulin-dependent diabetes mellitus (IDDM) patients between 18 and 50 years of age with microalbuminuria and 112 matched control patients with normal UAE with an age at diabetes onset of < 31 years. The main outcome measures were UAE, annual change in UAE rate (percentage per year), and the prevalence of retinopathy. After 5 years, 39 (33%, 24-42 CI [95% confidence interval]) patients with microalbuminuria had normoalbuminuria, 57 (48%, 38-57 CI) still had microalbuminuria, and 22 (19%, 12-27 CI) had developed diabetic nephropathy. Among the 112 patients with normoalbuminuria in 1985, 9 (8%, 4-15 CI) had developed microalbuminuria, and 2 (2%, 0-6 CI) had developed diabetic nephropathy. Of the 79 patients with persistent albuminuria, only 36 (46%, 34-57 CI) were progressors with a rate of progression of > 5%/year. Progressors had significantly higher HbAlc, higher mean blood pressure, and a higher incidence of proliferative retinopathy compared with nonprogressors. Multiple regression analysis only identified mean HbAlc as an independent predictor of the rate of progression. Smoking was significantly more prevalent in patients with persistent albuminuria. Microalbuminuria is a predictor of progression to diabetic nephropathy; however, not as strong as suggested previously. Calculation of the annual increase in UAE seems to be a more specific method of identifying patients who will develop diabetic nephropathy.


Determinants and outcome of unsuccessful referral after positive screening in a large birth-cohort study of population-based vision screening.
The efficacy of population-based vision screening is hampered by unsuccessful referral after a positive screening test. We studied the nature and causes of unsuccessful referral in a 7-year birth cohort study of vision screening in Rotterdam, the Netherlands. All parents of children who had been unsuccessfully referred were asked whether they recalled the referral. Reasons for noncompliance, if any, were identified using semi-structured interviews. Screening records were checked for written evidence of the referral. The parents' fluency in Dutch and their socioeconomic status were also assessed. Of the 561 screen-positive children, 129 (23%) had not been referred successfully. For the current study, 97 parents were successfully contacted. Of these, 14 parents had been willingly noncompliant and 83 said they were unaware of the referral, with 47% having poor to moderate fluency in Dutch. In 53 cases, the screening charts contained no written evidence of any referral. Amblyopia was identified in 3 of the unsuccessful referrals. In this population-based screening program, 1 of 4 positively screened children was not successfully referred. Apart from parental noncompliance, the unsuccessful referrals can be explained by miscommunication, deficient documentation, and physician noncompliance with screening guidelines. An effective monitoring feedback system may improve the efficacy of child vision screening.


Gluten sensitivity and neuromyelitis optica: two case reports.
Neuromyelitis optica is a clinical syndrome characterised by acute transverse myelitis plus an acute or subacute optic neuritis with or without recovery. Although once believed to be a variant of multiple sclerosis, diagnostic criteria have recently been proposed for neuromyelitis optica, making it a clinically distinct syndrome. The term gluten sensitivity refers to a state of heightened immunological responsiveness to ingested gluten in genetically susceptible individuals, as indicated by circulating antibodies to gliadin. Several neurological complications have been described associated with gluten sensitivity ranging from peripheral neuropathy and cerebellar ataxia to an increased risk of epilepsy. Although myelopathy has been described in some case reports of coeliac disease, neuromyelitis optica has never been described in association with gluten sensitivity. We describe two cases of gluten sensitivity presenting as neuromyelitis optica with no previous history of significant gastrointestinal symptoms. Gluten sensitivity was confirmed by immunological and histological studies.


Cloning of the hsp70 (dnaK) genes from Rhizobium meliloti and Pseudomonas cepacia: phylogenetic analyses of mitochondrial origin based on a highly conserved protein sequence.
The genes for hsp70 (or dnaK) have been cloned and sequenced from Rhizobium meliloti and Pseudomonas cepacia, two bacterial species belonging to the alpha- and beta-subdivisions of gram-negative proteobacteria, respectively. On the basis of global alignment of HSP70 proteins, several sequence signatures have been identified that are distinctive of mitochondrial homologs and gram-negative proteobacteria on the one hand and the chloroplasts and cyanobacteria on the other. Detailed phylogenetic analyses of HSP70 sequences from various eubacteria and eukaryotic organellar and cytosolic homologs support the inference regarding the origin of mitochondria from a member of the alpha-proteobacteria and of chloroplasts from cyanobacteria. The analysis presented here also suggests a monophyletic origin of the mitochondrial homologs.


Further modified Taylor retractor for spinal surgery.
New techniques have minimized the incision length and thus required modifications of surgical instruments. The Taylor retractor is one of these instruments. We therefore designed several modifications of the classical Taylor retractor. The following structural modifications were made on the classical Taylor retractor: First, we provided detachable blades with three different lengths (60, 70, 80 mm). Second, we breached a slit wide enough to let the intervertebral disc rongeurs to nestle down in it. Third, instead of a single sharp tip at the end of the blade, an arched blade that had two smooth tips was designed. Adjustable blades allowed placing the retractor just on the skin without any space between the retractor and skin by sliding the retractor over its blade downwards, thus providing a low-profile surgical retraction. The slit facilitated reaching the other side of the disc by leaning against the retractor. Pressing slightly and lowering the retractor subsided the skin and the paravertebral muscle, consequently facilitated motion of rongeurs and provided better exposure owing to low profile retraction. The arched blade with two tips served better placement with less traumatization at the facet joint. The relevant modifications facilitated the surgical procedure. We believe one retractor with adjustable blades is enough for more comfortable surgery at any depth.


Fractionation of Biomolecules in Withania coagulans Extract for Bioreductive Nanoparticle Synthesis, Antifungal and Biofilm Activity.
Withania coagulans contains a complex mixture of various bioactive compounds. In order to reduce the complexity of the plant extract to purify its phytochemical biomolecules, a novel fractionation strategy using different solvent combination ratios was applied to isolate twelve bioactive fractions. These fractions were tested for activity in the biogenic synthesis of cobalt oxide nanoparticles, biofilm and antifungal activities. The results revealed that plant extract with bioactive fractions in 30% ratio for all solvent combinations showed more potent bioreducing power, according to the observed color changes and the appearance of representative absorption peaks at 500-510 nm in the UV-visible spectra which confirm the synthesis of cobalt oxide nanoparticles (Co3O4 NPs). XRD diffraction was used to define the crystal structure, size and phase composition of the products. The fractions obtained using 90% methanol/hexane and 30% methanol/hexane showed more effectiveness against biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus so these fractions could potentially be used to treat bacterial infections. The 90% hexane/H2O fraction showed excellent antifungal activity against Aspergillus niger and Candida albicans, while the 70% methanol/hexane fraction showed good antifungal activity for C. albicans, so these fractions are potentially useful for the treatment of various fungal infections. On the whole it was concluded that fractionation based on effective combinations of methanol/hexane was useful to investigate and study bioactive compounds, and the active compounds from these fractions may be further purified and tested in various clinical trials.


Saying "no" to temptation: Want-to motivation improves self-regulation by reducing temptation rather than by increasing self-control.
Self-regulation has been conceptualized as the interplay between controlled and impulsive processes; however, most research has focused on the controlled side (i.e., effortful self-control). The present studies focus on the effects of motivation on impulsive processes, including automatic preferences for goal-disruptive stimuli and subjective reports of temptations and obstacles, contrasting them with effects on controlled processes. This is done by examining people's implicit affective reactions in the face of goal-disruptive "temptations" (Studies 1 and 2), subjective reports of obstacles (Studies 2 and 3) and expended effort (Study 3), as well as experiences of desires and self-control in real-time using experience sampling (Study 4). Across these multiple methods, results show that want-to motivation results in decreased impulsive attraction to goal-disruptive temptations and is related to encountering fewer obstacles in the process of goal pursuit. This, in turn, explains why want-to goals are more likely to be attained. Have-to motivation, on the other hand, was unrelated to people's automatic reactions to temptation cues but related to greater subjective perceptions of obstacles and tempting desires. The discussion focuses on the implications of these findings for self-regulation and motivation.


Social network theory in the behavioural sciences: potential applications.
Social network theory has made major contributions to our understanding of human social organisation but has found relatively little application in the field of animal behaviour. In this review, we identify several broad research areas where the networks approach could greatly enhance our understanding of social patterns and processes in animals. The network theory provides a quantitative framework that can be used to characterise social structure both at the level of the individual and the population. These novel quantitative variables may provide a new tool in addressing key questions in behavioural ecology particularly in relation to the evolution of social organisation and the impact of social structure on evolutionary processes. For example, network measures could be used to compare social networks of different species or populations making full use of the comparative approach. However, the networks approach can in principle go beyond identifying structural patterns and also can help with the understanding of processes within animal populations such as disease transmission and information transfer. Finally, understanding the pattern of interactions in the network (i.e. who is connected to whom) can also shed some light on the evolution of behavioural strategies.


The effects of static and intermittent compression on nitric oxide production in articular cartilage explants.
Nitric oxide (NO) production and NO synthase (NOS) expression are increased in osteoarthritis and rheumatoid arthritis, suggesting that NO may play a role in the destruction of articular cartilage. To test the hypothesis that mechanical stress may increase NO production by chondrocytes, we measured the effects of physiological levels of static and intermittent compression on NOS activity, NO production, and NOS antigen expression by porcine articular cartilage explants. Static compression significantly increased NO production at 0.1 MPa stress for 24 h (P < 0.05). Intermittent compression at 0.5 Hz for 6 h followed by 18 h recovery also increased NO production and NOS activity at 1.0 MPa stress (P < 0.05). Intermittent compression at 0.5 Hz for 24 h at a magnitude of 0.1 or 0.5 MPa caused an increase in NO production and NOS activity (P < 0.05). Immunoblot analysis showed stress-induced upregulation of NOS2, but not NOS1 or NOS3. There was no loss in cell viability following any of the loading regimens. Addition of 2 mM 1400 W (a specific NOS2 inhibitor) reduced NO production by 51% with no loss of cell viability. These findings indicate that NO production by chondrocytes is influenced by mechanical compression in vitro and suggest that biomechanical factors may in part regulate NO production in vivo.


Thoracoscopic sympathectomy increases efferent cardiac vagal activity and baroreceptor sensitivity.
Thoracoscopic sympathectomy at levels T2 or T2-T3 is a treatment for focal hyperhidrosis and facial blushing. These levels of the sympathetic trunk innervate the heart, and consequently, the procedure is reported to change the heart rate variability due to changes in efferent cardiac autonomic activity. Our objective was to investigate the effects of thoracoscopic sympathectomy on global autonomic control, including baroreceptor sensitivity. Eight patients (6 F, median age 28 years [range 20-58 years]) were exposed to the tilt-table test and cardiopulmonary exercise test before, and 3 months after, thoracoscopic sympathectomy. Eight healthy age-, gender- and BMI-matched controls were used as controls and underwent the same tests once. During tilt-table testing electrocardiogram, blood pressure, impedance cardiography and respiration were measured continuously, and efferent cardiac autonomic balance was estimated. The heart rate measured during orthostatic stress test was lowered after thoracoscopic sympathectomy (between-group; P = 0.01) due to a change in autonomic tone, with increased vagal (high-frequency power n.u.; P = 0.001), and reduced sympathetic efferent cardiac activity (low-frequency power n.u.; P < 0.001). Baroreceptor sensitivity measured during rest was increased (26 ± 13 vs 44 ± 19 ms/mmHg; P = 0.01), and diastolic blood pressure reduced after surgery (P = 0.01). The increases in systolic blood pressure and the sympathetic marker CCV-LF in response to orthostatic stress were higher before sympathectomy, with almost no increases post-surgically (condition × group interaction; P = 0.01 and P = 0.001, respectively). We found no change in post-procedure exercise capacity, although patients had a lower peak VO2 and maximal cardiac index than controls. Thoracoscopic sympathectomy changes the autonomic tone towards increased vagal activity; this is potentially cardioprotective. To our knowledge, this is the first study to show increased baroreceptor sensitivity after thoracoscopic sympathectomy.


Etiology of inattention and hyperactivity/impulsivity in a community sample of twins with learning difficulties.
A community sample of 373 8 to 18 year-old twin pairs in which at least one twin in each pair exhibited a history of learning difficulties was utilized to examine the etiology of inattention and hyperactivity/impulsivity (hyp/imp). Symptoms of attention-deficit/hyperactivity disorder (ADHD) were assessed by the DSM-III Diagnostic Interview for Children and Adolescents. Inattention and hyp/imp composite scores were created based on results of a factor analysis. Results indicated that extreme ADHD scores were almost entirely attributable to genetic influences across several increasingly extreme diagnostic cutoff scores. Extreme inattention scores were also highly heritable whether or not the proband exhibited extreme hyp/imp. In contrast, the heritability of extreme hyp/imp increased as a linear function of the number of inattention symptoms exhibited by the proband. This finding suggests that extreme hyp/imp may be attributable to different etiological influences in individuals with and without extreme inattention. If this result can be replicated in other samples, it would provide evidence that the hyp/imp symptoms exhibited by individuals with Combined Type ADHD and Predominantly Hyp/Imp Type ADHD may be attributable to different etiological influences.


An AP-1 site in the nerve growth factor promoter is essential for 1, 25-dihydroxyvitamin D3-mediated nerve growth factor expression in osteoblasts.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D, induces nerve growth factor (NGF) synthesis in a variety of different cell lines. The mechanism by which 1,25(OH)2D3 induces NGF, however, is poorly understood. We used a series of full-length and truncated NGF promoter-human growth hormone (hGH) reporter gene plasmids to investigate the mechanism of 1,25(OH)2D3-induced NGF expression in osteoblasts. Untransfected rat osteosarcoma cells (ROS 17/2.8) treated with 1,25(OH)2D3 showed a 2-fold increase in NGF expression compared to control cells. ROS 17/2.8 osteosarcoma cells were transfected with the NGF-hGH reporter plasmids and treated with 10(-)8 M 1,25(OH)2D3. The full-length NGF promoter (-1800 to +120)-hGH reporter construct showed an approximately 2-fold increase in hGH release. Plasmids with successive 5'-deletions showed enhanced hGH expression in treated cells and control cells. A similar series of NGF promoter-hGH reporter gene constructs, lacking the AP-1 site located within the first intron of the NGF gene, were also transiently transfected into ROS 17/2.8 cells. When these cells were treated with the same dose of 1,25(OH)2D3, no increase in hGH expression was seen compared to control cells, demonstrating that this AP-1 site is essential for 1,25(OH)2D3-mediated NGF up-regulation. Since 1,25(OH)2D3 is known to activate the transcription of several genes through its interaction with the vitamin D receptor (VDR), we performed a series of gel electrophoretic mobility shift assays to determine if the VDR binds directly to the AP-1 sequence. No evidence of VDR binding, either as a homodimer or as a heterodimer, to the AP-1 sequence was observed. Treatment of ROS 17/2.8 cells with 1,25(OH)2D3, however, resulted in an increase in AP-1 binding activity; however, no significant changes in c-jun and c-fos levels were observed. Our data show that in osteoblasts, 1,25(OH)2D3 induces NGF expression indirectly by increasing AP-1 binding activity.


Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent.
The cysteine-modifying reagent N-ethylmaleimide (NEM) is known to augment currents from native M-channels in sympathetic neurons and cloned KCNQ2 channels. As a probe for channel function, we investigated the mechanism of NEM action and subunit specificity of cloned KCNQ2-5 channels expressed in Chinese hamster ovary cells at the whole-cell and single-channel levels. Biotinylation assays and total internal reflection fluorescence microscopy indicated that NEM action is not caused by increased trafficking of channels to the membrane. At saturating voltages, whole-cell currents of KCNQ2, KCNQ4, and KCNQ5 but not KCNQ3 were augmented threefold to fourfold by 50 microm NEM, and their voltage dependencies were negatively shifted by 10-20 mV. Unitary conductances of KCNQ2 and KCNQ3 (6.2 and 8.5 pS, respectively) were much higher that those of KCNQ4 and KCNQ5 (2.1 and 2.2 pS, respectively). Surprisingly, the maximal open probability (P(o)) of KCNQ3 was near unity, much higher than that of KCNQ2, KCNQ4, and KCNQ5. NEM increased the P(o) of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on their unitary conductances, suggesting that the increase in macroscopic currents can be accounted for by increases in P(o). Analysis of KCNQ3/4 chimeras determined the C terminus to be responsible for the differential maximal P(o), channel expression, and NEM action between the two channels. To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM, suggesting that NEM acts via alkylation of this residue.


The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes.
1. Ventricular myocytes demonstrate a steeply inwardly rectifying K(+) current termed I(K1). We investigated the molecular basis for murine I(K1) by removing the genes encoding Kir2.1 and Kir2.2. The physiological consequences of the loss of these genes were studied in newborn animals because mice lacking Kir2.1 have a cleft palate and die shortly after birth. 2. Kir2.1 (-/-) ventricular myocytes lack detectable I(K1) in whole-cell recordings in 4 mM external K(+). In 60 mM external K(+) a small, slower, residual current is observed. Thus Kir2.1 is the major determinant of I(K1). Sustained outward K(+) currents and Ba(2+) currents through L- and T-type channels were not significantly altered by the mutation. A 50 % reduction in I(K1) was observed in Kir2.2 (-/-) mice, raising the possibility that Kir2.2 can also contribute to the native I(K1). 3. Kir2.1 (-/-) myocytes showed significantly broader action potentials and more frequent spontaneous action potentials than wild-type myocytes. 4. In electrocardiograms of Kir2.1 (-/-) neonates, neither ectopic beats nor re-entry arrhythmias were observed. Thus the increased automaticity and prolonged action potential of the mutant ventricular myocytes were not sufficiently severe to disrupt the sinus pacing of the heart. The Kir2.1 (-/-) mice, however, had consistently slower heart rates and this phenotype is likely to arise indirectly from the influence of Kir2.1 outside the heart. 5. Thus Kir2.1 is the major component of murine I(K1) and the Kir2.1 (-/-) mouse provides a model in which the functional consequences of removing I(K1) can be studied at both cellular and organismal levels.


Different roles for Pax6 in the optic vesicle and facial epithelium mediate early morphogenesis of the murine eye.
Chimaeric mice were made by aggregating Pax6(-/-) and wild-type mouse embryos, in order to study the interaction between the optic vesicle and the prospective lens epithelium during early stages of eye development. Histological analysis of the distribution of homozygous mutant cells in the chimaeras showed that the cell-autonomous removal of Pax6(-/-) cells from the lens, shown previously at E12.5, is nearly complete by E9.5. Most mutant cells are eliminated from an area of facial epithelium wider than, but including, the developing lens placode. This result suggests a role for Pax6 in maintaining a region of the facial epithelium that has the tissue competence to undergo lens differentiation. Segregation of wild-type and Pax6(-/-) cells occurs in the optic vesicle at E9.5 and is most likely a result of different adhesive properties of wild-type and mutant cells. Also, proximo-distal specification of the optic vesicle (as assayed by the elimination of Pax6(-/-) cells distally), is disrupted in the presence of a high proportion of mutant cells. This suggests that Pax6 operates during the establishment of patterning along the proximo-distal axis of the vesicle. Examination of chimaeras with a high proportion of mutant cells showed that Pax6 is required in the optic vesicle for maintenance of contact with the overlying lens epithelium. This may explain why Pax6(-/-) optic vesicles are inefficient at inducing a lens placode. Contact is preferentially maintained when the lens epithelium is also wild-type. Together, these results demonstrate requirements for functional Pax6 in both the optic vesicle and surface epithelia in order to mediate the interactions between the two tissues during the earliest stages of eye development.


Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.
The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.


A New Pneumococcal Capsule Type, 10D, is the 100th Serotype and Has a Large cps Fragment from an Oral Streptococcus.
Streptococcus pneumoniae (pneumococcus) is a major human pathogen producing structurally diverse capsular polysaccharides. Widespread use of highly successful pneumococcal conjugate vaccines (PCVs) targeting pneumococcal capsules has greatly reduced infections by the vaccine types but increased infections by nonvaccine serotypes. Herein, we report a new and the 100th capsule type, named serotype 10D, by determining its unique chemical structure and biosynthetic roles of all capsule synthesis locus (cps) genes. The name 10D reflects its serologic cross-reaction with serotype 10A and appearance of cross-opsonic antibodies in response to immunization with 10A polysaccharide in a 23-valent pneumococcal vaccine. Genetic analysis showed that 10D cps has three large regions syntenic to and highly homologous with cps loci from serotype 6C, serotype 39, and an oral streptococcus strain (S. mitis SK145). The 10D cps region syntenic to SK145 is about 6 kb and has a short gene fragment of wciNα at the 5' end. The presence of this nonfunctional wciNα fragment provides compelling evidence for a recent interspecies genetic transfer from oral streptococcus to pneumococcus. Since oral streptococci have a large repertoire of cps loci, widespread PCV usage could facilitate the appearance of novel serotypes through interspecies recombination.IMPORTANCE The polysaccharide capsule is essential for the pathogenicity of pneumococcus, which is responsible for millions of deaths worldwide each year. Currently available pneumococcal vaccines are designed to elicit antibodies to the capsule polysaccharides of the pneumococcal isolates commonly causing diseases, and the antibodies provide protection only against the pneumococcus expressing the vaccine-targeted capsules. Since pneumococci can produce different capsule polysaccharides and therefore reduce vaccine effectiveness, it is important to track the appearance of novel pneumococcal capsule types and how these new capsules are created. Herein, we describe a new and the 100th pneumococcal capsule type with unique chemical and serological properties. The capsule type was named 10D for its serologic similarity to 10A. Genetic studies provide strong evidence that pneumococcus created 10D capsule polysaccharide by capturing a large genetic fragment from an oral streptococcus. Such interspecies genetic exchanges could greatly increase diversity of pneumococcal capsules and complicate serotype shifts.


Comment On: Maintenance of Remission in Inflammatory Bowel Disease Using Omega-3 Fatty Acids (Fish Oil): A Systematic Review and Meta-Analyses.
The objective was to systematically review the efficacy and safety of n-3 (omega-3 fatty acids, fish oil) for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Electronic databases were searched systematically for randomized controlled trials of n-3 for maintenance of remission in inflammatory bowel disease (IBD). Studies of patients of any age group who were in remission at the time of recruitment and were followed for at least 6 months were included. The primary outcome was relapse rate at the end of the follow-up period. Nine studies were eligible for inclusion; six studies of CD (n = 1039) and three of UC (n = 138). There was a statistically significant benefit for n-3 in CD (relative risk [RR] 0.77; 95% confidence interval [CI] 0.61-0.98); however, the studies were heterogeneous (I 2 = 58%). The absolute risk reduction was -0.14 (95% CI: -0.25 to -0.02). Opinions may vary on whether this is a clinically significant effect. Two well-done studies with a larger sample size reported no benefit. A sensitivity analysis excluding a small pediatric study resulted in the pooled RR being no longer statistically significant. A funnel plot analysis suggested publication bias for the smaller studies. For UC, there was no difference in the relapse rate between the n-3 and control groups (RR 1.02; 95% CI: 0.51-2.03). The pooled analysis showed a higher rate of diarrhea (RR 1.36; 95% CI: 1.01-1.84) and symptoms of the upper gastrointestinal tract (RR 1.96; 95% CI: 1.37-2.80) in the n-3 treatment group. There are insufficient data to recommend the use of omega-3 fatty acids for maintenance of remission in CD and UC. ( Inflamm Bowel Dis. 2011;17:336-345).


Construction of longitudinal prediction targets using semisupervised learning.
In establishing prognostic models, often aided by machine learning methods, much effort is concentrated in identifying good predictors. However, the same level of rigor is often absent in improving the outcome side of the models. In this study, we focus on this rather neglected aspect of model development. We are particularly interested in the use of longitudinal information as a way of improving the outcome side of prognostic models. This involves optimally characterizing individuals' outcome status, classifying them, and validating the formulated prediction targets. None of these tasks are straightforward, which may explain why longitudinal prediction targets are not commonly used in practice despite their compelling benefits. As a way of improving this situation, we explore the joint use of empirical model fitting, clinical insights, and cross-validation based on how well formulated targets are predicted by clinically relevant baseline characteristics (antecedent validators). The idea here is that all these methods are imperfect but can be used together to triangulate valid prediction targets. The proposed approach is illustrated using data from the longitudinal assessment of manic symptoms study.


Nuclear export of microRNA precursors.
MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.


Micro-scaffold array chip for upgrading cell-based high-throughput drug testing to 3D using benchtop equipment.
Cell-based high throughput drug screening accelerates the pace of drug discovery which is routinely operated on planar high-density multi-well plates with sophisticated robotic liquid-dispensing systems for cell seeding and drug administration. Considerable efforts have been made to upgrade in vitro cellular models from 2D to a more biomimetic 3D configuration. For instance, in anti-cancer drug screening, tumor spheroids are increasingly applied as a gold-standard 3D model exhibiting cellular behaviors and drug responses distinguishable from the 2D counterpart. However, translation of spheroids to high throughput drug screening is challenging since pre-formation of spheroids and subsequent translocation to multi-well plates for drug testing are usually uncontrollable and time/reagent consuming and cell loss is inevitable during medium exchange for drug testing. Here we present an off-the-shelf micro-scaffold array chip which enables high throughput 3D cell culture, drug administration and quantitative in situ assays entirely on the same chip. The sponge-like micro-scaffolds functioned both as absorbents to realize parallel auto-loading of cells or drugs and as barriers to prevent cell loss during medium exchange via centrifugation. Rapid manual loading of cell suspensions or drugs into the 96 isolated micro-scaffolds on the chip was achieved in the timescale of several seconds, meanwhile with total medium consumption reduced to the order of microliters. Proof of concept demonstration of drug cytotoxicity testing was performed on multiple cancer cells using common benchtop equipment, making it accessible to most biomedical labs with basic cell culture setups. Higher cellular drug resistance was constantly obtained with this platform compared to the planar cultures, which was partially attributed to the malignant phenotype of cancer cells yielded by enhanced cell-matrix interactions in the micro-scaffolds. Interestingly, the high drug resistance of 3D cultured cells in the micro-scaffold was shown to be density-independent in contrast to the density-dependent drug response for 2D cultured cells, indicating intrinsic differences between the two culture models. This platform is expected to facilitate upgrade of the current cell-based high throughput drug testing to the 3D level and be widely applicable across various disciplines.


Lower back pain as a manifestation of acute gouty sacroiliitis: Utilization of dual-energy computed tomography (DECT) in establishing a diagnosis.
Gout is the most common inflammatory arthritis which initially presents as a monoarthritis that usually favours peripheral joints namely the 1st MTP. It was reported in the literature to rarely involve the axial joint, such as the sacroiliac joint, and often mimics seronegative spondyloarthritis (SpA). Gout is a male disease and after menopause the risk in females is equal to males. Previous reports describe male patients developing gout involving the SI joint. We report a lady with a history of gout presenting with acute onset lower back pain. MRI of the sacroiliac joints revealed unilateral sacroilitis. With the help of Dual-Energy Computed Tomography (DECT) which is a newer imaging technique, a diagnosis of gout involving the sacroiliac joint was established. Gout involving the sacroiliac joints is rare, however it should be considered in the differential diagnosis in patients with unilateral sacroilitis given the similarity in presentation to SpA. Utilization of newer imaging modalities including DECT can highly guide in establishing a diagnosis and providing the correct treatment.


Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, double-dummy, placebo-controlled, crossover trial.
Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) "off" motor score of ≥ 25 in a 2-day, single-dose, double-blind, double-dummy, crossover study. Patients arrived in the morning in the practically defined "off" state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5-minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to "on" and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to "on," latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit.


SimAmph: an agent-based simulation model for exploring the use of psychostimulants and related harm amongst young Australians.
Computer simulations provide a useful tool for bringing together diverse sources of information in order to increase understanding of the complex aetiology of drug use and related harm, and to inform the development of effective policies. In this paper, we describe SimAmph, an agent-based simulation model for exploring how individual perceptions, peer influences and subcultural settings shape the use of psychostimulants and related harm amongst young Australians. We present the conceptual architecture underpinning SimAmph, the assumptions we made in building it, the outcomes of sensitivity analysis of key model parameters and the results obtained when we modelled a baseline scenario. SimAmph's core behavioural algorithm is able to produce social patterns of partying and recreational drug use that approximate those found in an Australian national population survey. We also discuss the limitations involved in running closed-system simulations and how the model could be refined to include the social, as well as health, consequences of drug use. SimAmph provides a useful tool for integrating diverse data and exploring drug policy scenarios. Its integrated approach goes some way towards overcoming the compartmentalisation that characterises existing data, and its structure, parameters and values can be modified as new data and understandings emerge. In a companion paper (Dray et al., 2011), we use the model outlined here to explore the possible consequences of two policy scenarios.


Mohs micrographic surgery.
Mohs micrographic surgery is a precise method of skin cancer removal that offers the highest cure rate and conserves the maximal amount of normal tissue. It is indicated for recurrent tumors and certain primary basal cell and squamous cell carcinomas, but not for small, nonrecurrent, well-defined lesions. The fresh tissue technique permits the use of horizontal frozen sections for the complete microscopic examination of lateral and deep margins.


Large bowel myoelectrical activity in man.
The myoelectrical activity of human colon and rectum has been studied by three types of electrode in man--intraluminal (suction), serosal and cutaneous. The patterns obtained indicate a high degree of consistency between the methods and the value of surface electrodes is emphasized. Gradient along the large bowel of both frequency and percentage electrical activity have been observed and possible physiological roles are postulated for them. By correlating the features of regular electrical and corresponding regular motor waves an alteration in the myoelectrical pattern is observed in the region of the rectosigmoid junction.


Renal Stones and Risk Factors in Jeddah and Riyadh.
Saudi Arabia has extremely hot climate for most of the year; this is associated with the risk of developing nephrolithiasis. This retrospective research aimed to investigate the current prevalence, manifestation, mode of treatment, and risk factors of renal stones in Jeddah and Riyadh, Saudi Arabia. A cross-sectional study was conducted from November 2018 to June 2019 at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. This study included 1031 participants aged ≥18 years from Jeddah (n=652, 63.3%) and Riyadh (n=379, 36.8%). Data were expressed as mean ± standard deviation (minimum-maximum) or number (%). Comparisons between patients with and without renal stones were made using the Chi-square test and unpaired Student's t-test as appropriate. The odds ratio (OR) with a 95% confidence interval (95% CI) was determined for the risk factors of renal stones. The prevalence of renal stones was 16.9% among the participants. A significantly high risk for renal stones was associated with male sex (2.96; 95% CI: 2.08-4.20, P = 0.0001) and age group of 34-40 years (OR: 1.44; 95% CI: 1.005-2.103, P = 0.047). Hypertension was more common in patients with renal stones than those without renal stones (9.5% vs.4.6%, P = 0.013). The percentage of patients who took diuretics was significantly higher among those with renal stones than among those without renal stones (11.2% vs. 3.5%, P = 0.001). Of the 169 patients with renal stones, 58.0% had a positive family history of renal stones, and 23.7% had a history of urinary tract infections (UTIs). The symptoms of renal stones were pain (86.4%), hematuria (11.2%), fever (2.4%), and others (0.6%). Of all the patients, 43.8% took medication. For most patients, the stones passed spontaneously (67.5%), while 23.7% underwent lithotripsy, and 1.5% received stents. In this study, we found a higher prevalence of renal stones two major cities in Saudi Arabia in Jeddah and Riyadh, at 16.4%. Risk factors included male sex and age group of 34-40 years. A significant number of patients with renal stones have a family history of renal stones and a history of UTI. Loin pain and hematuria were the two major clinical presenting symptoms for renal stones. In the majority of patients, the renal stones passed spontaneously without the need for lithotripsy or surgery.


Identification of the CAD gene from Eucalyptus urophylla GLU4 and its functional analysis in transgenic tobacco.
Cinnamyl alcohol dehydrogenase (CAD) catalyzes the final step in lignin biosynthesis. The genus Eucalyptus belongs to the family Myrtaceae, which is the main cultivated species in China. Eucalyptus urophylla GLU4 (GLU4) is widely grown in Guangxi. It is preferred for pulping because of its excellent cellulose content and fiber length. Based on GLU4 and CAD gene expression, a Eucalyptus variety low in lignin content should be obtained using transgenic technology, which could reduce the cost of pulp and improve the pulping rate, and have favorable prospects for application. However, the role and function of CAD in GLU4 is still unclear. In the present study, EuCAD was cloned from GLU4 and identified using bioinformatic tools. Subsequently, in order to evaluate its impact on lignin synthesis, a full-length EuCAD RNAi vector was constructed, and transgenic tobacco was obtained via Agrobacterium-mediated transformation. A significant decrease in CAD expression and lignin content in transgenic tobacco demonstrated a key role for EuCAD in lignin biosynthesis and established a regulatory role for RNAi. In our study, the direct molecular basis of EuCAD expression was determined, and the potential regulatory effects of this RNAi vector on lignin biosynthesis in E. urophylla GLU4 were demonstrated. Our results provide a theoretical basis for the study of lignin biosynthesis in Eucalyptus.


Associations of supermarket accessibility with obesity and fruit and vegetable consumption in the conterminous United States.
Limited access to supermarkets may reduce consumption of healthy foods, resulting in poor nutrition and increased prevalence of obesity. Most studies have focused on accessibility of supermarkets in specific urban settings or localized rural communities. Less is known, however, about how supermarket accessibility is associated with obesity and healthy diet at the national level and how these associations differ in urban versus rural settings. We analyzed data on obesity and fruit and vegetable (F/V) consumption from the Behavioral Risk Factor Surveillance System for 2000-2006 at the county level. We used 2006 Census Zip Code Business Patterns data to compute population-weighted mean distance to supermarket at the county level for different sizes of supermarket. Multilevel logistic regression models were developed to test whether population-weighted mean distance to supermarket was associated with both obesity and F/V consumption and to determine whether these relationships varied for urban (metropolitan) versus rural (nonmetropolitan) areas. Distance to supermarket was greater in nonmetropolitan than in metropolitan areas. The odds of obesity increased and odds of consuming F/V five times or more per day decreased as distance to supermarket increased in metropolitan areas for most store size categories. In nonmetropolitan areas, however, distance to supermarket had no associations with obesity or F/V consumption for all supermarket size categories. Obesity prevalence increased and F/V consumption decreased with increasing distance to supermarket in metropolitan areas, but not in nonmetropolitan areas. These results suggest that there may be a threshold distance in nonmetropolitan areas beyond which distance to supermarket no longer impacts obesity and F/V consumption. In addition, obesity and food environments in nonmetropolitan areas are likely driven by a more complex set of social, cultural, and physical factors than a single measure of supermarket accessibility. Future research should attempt to more precisely quantify the availability and affordability of foods in nonmetropolitan areas and consider alternative sources of healthy foods besides supermarkets.


Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.
Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.


Oligomerization and activity of the helicase domain of the tobacco mosaic virus 126- and 183-kilodalton replicase proteins.
A protein-protein interaction within the helicase domain of the Tobacco mosaic virus (TMV) 126- and 183-kDa replicase proteins was previously implicated in virus replication (S. Goregaoker, D. Lewandowski, and J. Culver, Virology 282:320-328, 2001). To further characterize the interaction, polypeptides covering the interacting portions of the TMV helicase domain were expressed and purified. Biochemical characterizations demonstrated that the helicase domain polypeptides hydrolyzed ATP and bound both single-stranded and duplexed RNA in an ATP-controlled fashion. A TMV helicase polypeptide also was capable of unwinding duplexed RNA, confirming the predicted helicase function of the domain. Biochemically active helicase polypeptides were shown by gel filtration to form high-molecular-weight complexes. Electron microscopy studies revealed the presence of ring-like oligomers that displayed six-sided symmetry. Taken together, these data demonstrate that the TMV helicase domain interacts with itself to produce hexamer-like oligomers. Within the context of the full-length 126- and 183-kDa proteins, these findings suggest that the TMV replicase may form a similar oligomer.


Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking.
Distinct populations of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1- and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1- or D2-MSNs. Because D1- and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1- versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A μ opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic μ opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTDGABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking. More than 90% of ventral striatum is composed of two cell types, those expressing dopamine D1 or D2 receptors, which exert opposing roles on motivated behavior. Both cell types send GABAergic projections to the ventral pallidum and were found to differentially promote cue-induced reinstatement of cocaine seeking via the ventral pallidum. Furthermore, after cocaine self-administration, synaptic plasticity was selectively lost in D2, but not D1 inputs to the ventral pallidum. The selective impairment in D2 afferents may promote the influence of D1 inputs to drive relapse to cocaine seeking.


[Determinants of early sexual initiation in the Pelotas birth cohort from 1982 to 2004-5, Southern Brazil].
To analyze social determinants of early sexual initiation among young adults from a birth cohort. Individuals from the 1982 birth cohort (N=4,297) were interviewed in 2004-5, city of Pelotas, Southern Brazil. Early sexual initiation (<13 years of age) was the outcome. Descriptive and stratified analyses were performed according to sex. Variables analyzed were family income in 1982, ethnicity, young adult's level of education and change in income (between 1982 and 2004-5). Ethnographic data were used to complement result analysis. Prevalence of early sexual initiation was higher among black and mixed men, and those with low level of education and low family income in 1982 and 2004-5. More traditional male sexual role requirements, such as virility and sexual initiative, showed more repercussion and adherence from an early age among men. Young family women with higher income and level of education tended to delay their sexual initiation. Imposition of traditional values was found to influence early sexual initiation among men and women with lower level of education and income. Results found re-established the economic factor as a determinant of behavior or uses of sexuality for both sexes. To focus on political efforts that help the economically disadvantaged to have opportunities and egalitarian future perspectives is an important strategy for health outcomes.


'Everything takes too long and nobody is listening': Developing theory to understand the impact of advice on stress and the ability to cope.
Shrinking state spending in the UK has been accompanied by a profound restructuring of the welfare system, leading to financial insecurity for many people, culminating in extreme stress and serious deterioration of physical and mental health. Theory surrounding the impact of welfare advice on stress is lacking; this paper undertakes an in depth exploration of the experiences of stress among welfare advice seekers, considering these in light of existing substantive theories of stress and coping to generate new insight. A thematic analysis explored the experiences of stress in welfare advice seekers. Four overarching themes and twelve subthemes emerged. They are further understood utilising traditional theories of stress (Transactional Model of Stress and Coping and the Conservation of Resources theory), which then underpin the development of a 'Stress Support Matrix' and a holistic theory related specifically to welfare, stress and coping.


Accurate automated protein NMR structure determination using unassigned NOESY data.
Conventional NMR structure determination requires nearly complete assignment of the cross peaks of a refined NOESY peak list. Depending on the size of the protein and quality of the spectral data, this can be a time-consuming manual process requiring several rounds of peak list refinement and structure determination. Programs such as Aria, CYANA, and AutoStructure can generate models using unassigned NOESY data but are very sensitive to the quality of the input peak lists and can converge to inaccurate structures if the signal-to-noise of the peak lists is low. Here, we show that models with high accuracy and reliability can be produced by combining the strengths of the high-resolution structure prediction program Rosetta with global measures of the agreement between structure models and experimental data. A first round of models generated using CS-Rosetta (Rosetta supplemented with backbone chemical shift information) are filtered on the basis of their goodness-of-fit with unassigned NOESY peak lists using the DP-score, and the best fitting models are subjected to high resolution refinement with the Rosetta rebuild-and-refine protocol. This hybrid approach uses both local backbone chemical shift and the unassigned NOESY data to direct Rosetta trajectories toward the native structure and produces more accurate models than AutoStructure/CYANA or CS-Rosetta alone, particularly when using raw unedited NOESY peak lists. We also show that when accurate manually refined NOESY peak lists are available, Rosetta refinement can consistently increase the accuracy of models generated using CYANA and AutoStructure.


Reconstruction versus conservative treatment after rupture of the anterior cruciate ligament: cost effectiveness analysis.
The decision whether to treat conservatively or reconstruct surgically a torn anterior cruciate ligament (ACL) is an ongoing subject of debate. The high prevalence and associated public health burden of torn ACL has led to continuous efforts to determine the best therapeutic approach. A critical evaluation of benefits and expenditures of both treatment options as in a cost effectiveness analysis seems well-suited to provide valuable information for treating physicians and healthcare policymakers. A literature review identified four of 7410 searched articles providing sufficient outcome probabilities for the two treatment options for modeling. A transformation key based on the expert opinions of 25 orthopedic surgeons was used to derive utilities from available evidence. The cost data for both treatment strategies were based on average figures compiled by Orthopaedic University Hospital Balgrist and reinforced by Swiss national statistics. A decision tree was constructed to derive the cost-effectiveness of each strategy, which was then tested for robustness using Monte Carlo simulation. Decision tree analysis revealed a cost effectiveness of 16,038 USD/0.78 QALY for ACL reconstruction and 15,466 USD/0.66 QALY for conservative treatment, implying an incremental cost effectiveness of 4,890 USD/QALY for ACL reconstruction. Sensitivity analysis of utilities did not change the trend. ACL reconstruction for reestablishment of knee stability seems cost effective in the Swiss setting based on currently available evidence. This, however, should be reinforced with randomized controlled trials comparing the two treatment strategies.


Metabolic oxidation of pyruvate and lactate during early myocardial reperfusion.
We have previously described the rates of oxidation for long-chain fatty acids and glucose in stunned myocardium during early reflow after moderately severe regional ischemia. The purpose of these studies was to characterize the rates of pyruvate and lactate oxidation during comparable periods of reflow. In the main protocol, pyruvate oxidation was defined at two conditions of coronary flow and at two levels of fatty acids in the coronary perfusate. Twenty animals were prepared using the extracorporeally perfused, working swine heart model. In five control (group 1) hearts, flow in the left anterior descending coronary artery was maintained at aerobic levels during a 115-minute perfusion trial. In 15 hearts (groups 2 and 3), flow was held at aerobic levels for 30 minutes, reduced acutely by 60% for 45 minutes, and restored again to aerobic levels for the final 40-minute reflow. In the five control hearts and in 10 of the reperfused hearts (group 2), 20% Intralipid (KabiVitrum, Alameda, California) with heparin was infused to raise serum fatty acids to an average of 0.95 +/- 0.08 mumol/ml, whereas in the five remaining nonsupplemented group 3 hearts, serum levels of fatty acids were 0.49 +/- 0.10 mumol/ml. Ischemia in supplemented and nonsupplemented hearts caused a decline in regional mechanical performance (-40 delta % and -39 delta % below aerobic values in active shortening) that failed to recover completely (-16 delta % and -25 delta % below aerobic values in active shortening) during reflow.(ABSTRACT TRUNCATED AT 250 WORDS)


Degradable double hydrophilic block copolymers and tripartite polyionic complex micelles thereof for small interfering ribonucleic acids (siRNA) delivery.
Polymer vectors for gene therapy have been largely investigated as an alternative to viral vectors. In particular, double hydrophilic block copolymers (DHBCs) have shown potential in this domain, but to date studies mainly focus on non-degradable copolymers, which may be a restriction for further development. To overcome this limitation, we synthesized a DHBC (PEG43-b-PCL12(COOH)6.5) composed of a poly(ethylene glycol) (PEG) non-ionic and bioeliminable block and a degradable carboxylic acid-functionalized poly(ε-caprolactone) (PCL) block. The potential of this DHBC as an original vector for small interfering ribonucleic acids (siRNA) to formulate tripartite polyionic complex (PIC) micelles with poly(lysine) (PLL) was evaluated. We first studied the impact of the charge ratio (R) on the size and the zeta potential of the resulting micelles. With a charge ratio R = 1, one formulation with optimized physico-chemical properties showed the ability to complex 75% of siRNA. We showed a stability of the micelles at pH 7.4 and a disruption at pH 5, which allowed a pH-triggered siRNA release and proved the pH-stimuli responsive character of the tripartite micelles. In addition, the tripartite PIC micelles were shown to be non-cytotoxic below 40 µg/mL. The potential of these siRNA vectors was further evaluated in vitro: it was found that the tripartite PIC micelles allowed siRNA internalization to be 3 times higher than PLL polyplexes in murine mesenchymal stem cells, and were able to transfect human breast cancer cells. Overall, this set of data pre-validates the use of degradable DHBC as non-viral vectors for the encapsulation and the controlled release of siRNA, which may therefore constitute a sound alternative to non-degradable and/or cytotoxic polycationic vectors.


Promise-based management: the essence of execution.
Critical initiatives stall for a variety of reasons--employee disengagement, a lack of coordination between functions, complex organizational structures that obscure accountability, and so on. To overcome such obstacles, managers must fundamentally rethink how work gets done. Most of the challenges stem from broken or poorly crafted commitments. That's because every company is, at its heart, a dynamic network of promises made between employees and colleagues, customers, outsourcing partners, or other stakeholders. Executives can overcome many problems in the short-term and foster productive, reliable workforces for the long-term by practicing what the authors call "promise-based management," which involves cultivating and coordinating commitments in a systematic way. Good promises share five qualities: They are public, active, voluntary, explicit, and mission based. To develop and execute an effective promise, the "provider" and the "customer" in the deal should go through three phases of conversation. The first, achieving a meeting of minds, entails exploring the fundamental questions of coordinated effort: What do you mean? Do you understand what I mean? What should I do? What will you do? Who else should we talk to? In the next phase, making it happen, the provider executes on the promise. In the final phase, closing the loop, the customer publicly declares that the provider has either delivered the goods or failed to do so. Leaders must weave and manage their webs of promises with great care-encouraging iterative conversation and making sure commitments are fulfilled reliably. If they do, they can enhance coordination and cooperation among colleagues, build the organizational agility required to seize new business opportunities, and tap employees' entrepreneurial energies.


Adverse Drug reactions in an Ageing PopulaTion (ADAPT) study protocol: a cross-sectional and prospective cohort study of hospital admissions related to adverse drug reactions in older patients.
Older people experience greater morbidity with a corresponding increase in medication use resulting in a potentially higher risk of adverse drug reactions (ADRs). The aim of this study is to determine the prevalence and characteristics of ADR-related hospital admissions among older patients (≥65 years) and their associated health and cost outcomes. The proposed study will include a cross-sectional study of ADR prevalence in all patients aged ≥65 years admitted acutely to a large tertiary referral hospital in Ireland over a 9-month period (2016-2017) and a prospective cohort study of patient-reported health outcomes and costs associated with ADR-related hospital admissions. All acute medical admissions will be screened for a suspected ADR-related hospital admission. A number of validated algorithms will be applied to assess the type, causative medications, preventability and severity of each ADR. ADRs will be determined, using a consensus method, by an expert panel. Patients who provide consent will be followed up 3 months post-discharge to establish patient-reported health outcomes (health service use, health-related quality of life, adherence) and costs associated with ADR-related hospital admissions. A random sample of patients admitted to hospital without a suspected ADR will be invited to take part in the study as a control group. Ethical approval was obtained from Beaumont Hospital Ethics Committee. Findings will be disseminated through presentations and peer-reviewed publications.


Mesenchymal stem cells alleviate atherosclerosis by elevating number and function of CD4(+)CD25 (+)FOXP3 (+) regulatory T-cells and inhibiting macrophage foam cell formation.
Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaques inside arteries, leading to narrowing and blockage. Potential therapeutic strategies include expanding the population of regulatory T-cells (Tregs) to enhance atheroprotective immunity, and inhibiting the formation of macrophage foam cells. Here, we studied the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on atherosclerotic plaque formation in Apolipoprotein E(-/-) (ApoE-KO) mice, and elucidated the underlying mechanism. BM-MSCs isolated from 4 week-old ApoE-KO mice were evaluated by flow cytometry for expression of MSC-specific markers. Thirty eight week-old ApoE-KO mice were randomly divided into three experimental groups (n = 10 per group): 1. MSC group-received BM-MSCs intravenously; 2. Vehicle group-received DMEM; 3. Control group-did not receive any treatment. Administration of MSCs resulted in a marked decrease in the size of atherosclerotic plaques 3 months after treatment. In addition, the number and function of CD4(+)CD25(+)FOXP3(+) regulatory T-cells (Tregs) in cultured splenocytes, and the expression of FOXP3 at both mRNA and protein levels, was significantly increased in the MSC group. In vitro experiments further indicated that the formation of macrophage foam cells was inhibited by treatment with MSCs, accompanied by a significant downregulation in CD36 and scavenger receptor A (SRA). Our findings suggest that MSCs play an atheroprotective role by enhancing the number and function of Tregs and inhibiting the formation of macrophage foam cells. Hence, administration of MSCs to atherosclerotic patients might have significant clinical benefits.


Daily hassles and uplifts: a diary study on understanding relationship quality.
In this investigation, we use the Conservation of Resources (CoR) theory as a guide to examine how both uplifts and hassles are associated with positive (e.g., satisfaction, commitment) and negative (ambivalence, conflict) relational quality on a daily basis. In previous studies of hassles and uplifts, the focus has been primarily on negative outcomes at the individual level (e.g., affect). Here, we build on this previous research in examining both positive and negative events (i.e., uplifts and hassles) in associations with positive and negative relational qualities. Further, we focus on examining social and nonsocial events that are external to the relationship (i.e., do not involve the romantic partner) and how they are linked with relational qualities. Finally, we examine which patterns are confined to the same day and which carry over to subsequent days (i.e., lagged effects). Contrary to previous literature, we find that both social and nonsocial hassles are largely unrelated to relationship quality after accounting for the effects of social and nonsocial uplifts. In contrast, nonsocial uplifts bolster positive feelings about the relationship on that day. Results also show that hassles and uplifts may work together to explain relational commitment. Finally, we find that nonsocial uplifts experienced on one day are associated with trend-level declines in next day positive feelings about the relationship. Our findings suggest that preserving relationship quality through daily experiences is best achieved by equipping couples to recognize the benefits of uplifts to the relationship, especially uplifts that are nonsocial, in tandem with managing hassles.


Acute stress rapidly decreases plasma testosterone in a free-ranging male songbird: potential site of action and mechanism.
We used a free-ranging, seasonally breeding adult male songbird, the rufous-winged sparrow, Aimophila carpalis, to investigate the effects of acute stress-induced by capture followed by restraint, on the hypothalamo-pituitary-testicular axis. Intra- and interindividual comparisons revealed that males decreased their plasma testosterone (T) by 37-52% in response to acute stress. The decrease occurred within 15 min of capture and persisted for at least another 15 min. Within 15 min, the decrease in plasma T was not associated with a reduction in plasma luteinizing hormone (LH). Thirty minutes after capture and restraint, the decrease in plasma T either was likewise not associated with decreased plasma LH (intraindividual comparison) or concurred with a reduction in plasma LH (interindividual comparison). These observations indicate that effects of stress may have been mediated at the pituitary gland and also directly at the testicular levels. To address this question, we measured the hormonal response to an injection of the glutamate receptor agonist N-methyl-d,l-aspartate (NMA) to stimulate to stimulate the release of gonadotropin-releasing hormone (GnRH) or of GnRH to stimulate the release of LH. Treatment with NMA did not change plasma LH, presumably because the birds were in breeding condition and already secreting GnRH at a maximum rate. Administration of GnRH increased plasma LH equally in birds that were or were not stressed before the treatment. An injection of purified ovine LH (oLH) increased plasma T equally in birds that were or were not acutely stressed before the hormone injection. Thus, the observed acute stress-induced decrease in plasma T was apparently not mediated by decreased responsiveness of the pituitary gland to GnRH or of the testes to LH. Decreased plasma T following stress may involve a direct impairment of the testicular endocrine function.


P-glycoprotein acts as an immunomodulator during neuroinflammation.
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which autoreactive myelin-specific T cells cause extensive tissue damage, resulting in neurological deficits. In the disease process, T cells are primed in the periphery by antigen presenting dendritic cells (DCs). DCs are considered to be crucial regulators of specific immune responses and molecules or proteins that regulate DC function are therefore under extensive investigation. We here investigated the potential immunomodulatory capacity of the ATP binding cassette transporter P-glycoprotein (P-gp). P-gp generally drives cellular efflux of a variety of compounds and is thought to be involved in excretion of inflammatory agents from immune cells, like DCs. So far, the immunomodulatory role of these ABC transporters is unknown. Here we demonstrate that P-gp acts as a key modulator of adaptive immunity during an in vivo model for neuroinflammation. The function of the DC is severely impaired in P-gp knockout mice (Mdr1a/1b-/-), since both DC maturation and T cell stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b -/- mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines. Our data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherapy.


Retinoblastoma in Mongolia: Clinical characteristics and survival from 1987 to 2014.
This study aims to describe the clinical characteristics and treatment outcome of retinoblastoma in Mongolian children. Data of all children diagnosed with retinoblastoma at the National Center for Maternal and Child Health of Mongolia from 1987 to January 2014 were reviewed retrospectively. The ICRB classification was used. Survival characteristics of the cohort were analyzed. Retinoblastoma was diagnosed in 79 eyes of 64 cases during the study period. Median age of diagnosis was 24.5 ± 15.8 months. There were no differences in sex ratio, and 15 cases (23%) were bilateral. Forty-three (67%) patients were from rural areas. The more frequent clinical presentations were leukocoria in 50 (78%) patients, strabismus in 24 (38%) patients, and glaucoma in 21 (33%) patients. Sixty-one (95%) patients were diagnosed with Classification D or worse when presented to us. Due to late diagnosis in the majority of cases, unilateral and bilateral enucleations were performed in 48 (61%) eyes and 24 (30%) eyes, respectively; exenteration was done in three (4%) eyes. Fifty-two (81%) patients received chemotherapy and 13 (8.3%) patients underwent external beam radiation after enucleation. At the time of last follow-up, 52 (81%) patients were alive, five (8%) patients were dead, and seven (11%) patients had lost to follow-up or unknown vital status. The mean follow-up period was 121.5 months (range, 12-360 months). In five cases with immunohistochemistry analysis in the eye specimen, neuron-specific enolase-, Ki-67 protein-, and B-cell lymphoma 2-positive cells were found in all five (100%) cases and Rb protein was detected in three (60%) cases. Retinoblastoma in Mongolia is frequently diagnosed at late stages and has a poor outcome. These data show the importance of early pediatric eye examinations and better treatment of retino-blastoma in children younger than 3 years in Mongolia.


Molecular genetics of Alzheimer's disease.
The part that genetics plays in the origin of Alzheimer's disease (AD) is a complex problem that is only now, in the last few years, beginning to be understood. Progress in the study of the epidemiology of AD, discovery of multiple AD loci, and interpreting how mutations affect and produce the AD phenotype have been the initial keys to unlocking the mysteries of this disease. We now know of the existence of at least three AD loci on chromosomes 14, 19, and 21 and are beginning to understand the role that one of these loci, APP, and its mutations plays in the progression of AD. On future studies using animal modeling and the positional cloning of the other AD loci, a definite model for AD should become evident within the next few years.


Reasons for interrupting colleagues during emergency department work - A qualitative study.
Emergency department team members frequently need to interact with each other, a circumstance causing multiple interruptions. However, information is lacking about the motives underlying these interruptions and this study aimed to explore clinicians' reasons to interrupt colleagues during emergency department work. Semi-structured interviews with 10 physicians and 10 registered nurses at two Swedish emergency departments. The interviews were analyzed inductively using content analysis. The working conditions to some extent sustained the clinicians' need to interrupt, for example different routines. Another reason to interrupt was to improve the initiator's work process, such as when the initiators perceived that the interruption had high clinical relevance. The third reason concerns the desire to influence the work process of colleagues in order to prevent mistakes and provide information for the person being interrupted to improve patient care. The three identified categories for why emergency department clinicians interrupt their colleagues were related to working conditions and a wish to improve/influence the work processes for both initiators and recipients. Several of the reasons given for interrupting colleagues were done in order to improve patient care. Interruptions perceived as negative to the recipient were mostly related to the working conditions.


Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: a hypothesis for the mechanism of action and a potential biomarker for outcomes.
OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising therapy for refractory epilepsy. Unfortunately, the variability in outcomes from ANT DBS is not fully understood. In this pilot study, the authors assess potential differences in functional connectivity related to the volume of tissue activated (VTA) in ANT DBS responders and nonresponders as a means for better understanding the mechanism of action and potentially improving DBS targeting. METHODS This retrospective analysis consisted of 6 patients who underwent ANT DBS for refractory epilepsy. Patients were classified as responders (n = 3) if their seizure frequency decreased by at least 50%. The DBS electrodes were localized postoperatively and VTAs were computationally generated based on DBS programming settings. VTAs were used as seed points for resting-state functional MRI connectivity analysis performed using a control dataset. Differences in cortical connectivity to the VTA were assessed between the responder and nonresponder groups. RESULTS The ANT DBS responders showed greater positive connectivity with the default mode network compared to nonresponders, including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobule, and precuneus. Interestingly, there was also a consistent anticorrelation with the hippocampus seen in responders that was not present in nonresponders. CONCLUSIONS Based on their pilot study, the authors observed that successful ANT DBS in patients with epilepsy produces increased connectivity in the default mode network, which the authors hypothesize increases the threshold for seizure propagation. Additionally, an inhibitory effect on the hippocampus mediated through increased hippocampal γ-aminobutyric acid (GABA) concentration may contribute to seizure suppression. Future studies are planned to confirm these findings.


Alternative Reproductive Tactics Arising from a Continuous Behavioral Trait: Callers versus Satellites in Field Crickets.
Alternative reproductive tactics may arise when natural enemies use sexual signals to locate the signaler. In field crickets, elevated costs to male calling due to acoustically orienting parasitoid flies create opportunity for an alternative tactic, satellite behavior, where noncalling males intercept females attracted to callers. Although the caller-satellite system in crickets that risk detection by parasitoids resembles distinct behavioral phenotypes, a male's propensity to behave as caller or satellite can be a continuously variable trait over several temporal scales, and an individual may pursue alternate tactics at different times. We modeled a caller-satellite-parasitoid system as a spatially explicit interaction among male and female crickets using individual-based simulation. Males varied in their propensity to call versus behave as a satellite from one night to the next. We varied mortality, density, sex ratio, and female mating behavior, and recorded lifetime number of mates as a function of a male's probability of calling (vs. acting as a satellite) along a gradient in parasitism risk. Frequently, the optimal behavior switched abruptly from being pure caller (call every night) to pure satellite (never call) as parasitism rate increased. However, mixed strategies prevailed even with high parasitism risk under conditions of higher background mortality rate, decreasing density, increasing female-biased sex ratio, and increasing female choosiness. In natural populations, high parasitoid pressure alone would be unlikely to yield fixation of pure satellite behavior.


The efficacy of prospective memory rehabilitation plus metacognitive skills training for adults with traumatic brain injury: study protocol for a randomized controlled trial.
Impairment of prospective memory (PM) is common following traumatic brain injury (TBI) and negatively impacts on independent living. Compensatory approaches to PM rehabilitation have been found to minimize the impact of PM impairment in adults with TBI; however, poor self-awareness after TBI poses a major barrier to the generalization of compensatory strategies in daily life. Metacognitive skills training (MST) is a cognitive rehabilitation approach that aims to facilitate the development of self-awareness in adults with TBI. This paper describes the protocol of a study that aims to evaluate the efficacy of a MST approach to compensatory PM rehabilitation for improving everyday PM performance and psychosocial outcomes after TBI. This randomized controlled trial has three treatment groups: compensatory training plus metacognitive skills training (COMP-MST), compensatory training only (COMP), and waitlist control. Participants in the COMP-MST and COMP groups will complete a 6-week intervention consisting of six 2-h weekly training sessions. Each 1.5-h session will involve compensatory strategy training and 0.5 h will incorporate either MST (COMP-MST group) or filler activity as an active control (COMP group). Participants in the waitlist group receive care as usual for 6 weeks, followed by the COMP-MST intervention. Based on the sample size estimate, 90 participants with moderate to severe TBI will be randomized into the three groups using a stratified sampling approach. The primary outcomes include measures of PM performance in everyday life and level of psychosocial reintegration. Secondary outcomes include measures of PM function on psychometric testing, strategy use, self-awareness, and level of support needs following TBI. Blinded assessments will be conducted pre and post intervention, and at 3-month and 6-month follow-ups. This study seeks to determine the efficacy of COMP-MST for improving and maintaining everyday PM performance and level of psychosocial integration in adults with moderate to severe TBI. The findings will advance theoretical understanding of the role of self-awareness in compensatory PM rehabilitation and skills generalization. COMP-MST has the potential to reduce the cost of rehabilitation and lifestyle support following TBI because the intervention could enhance generalization success and lifelong application of PM compensatory strategies. New Zealand Clinical Trials Registry, ACTRN12615000996561 . Registered on 23 September 2015; retrospectively registered 2 months after commencement.


Three-dimensional angiography fused with CT/MRI for multimodal imaging of nanoparticles based on Ba4Yb3F17:Lu3+,Gd3+ .
Designing nanosized multi-modality contrast agents for high-resolution imaging is challenging since most agents are only useful for single-mode imaging. In this work, we successfully synthesized biocompatible polyethylene glycol (PEG-) and l-glutamine (GLN-) modified Ba4Yb3F17:Lu3+,Gd3+ nanoparticles (LNPs@PEG@GLN) that can be employed as a multi-modality contrast agent. Fluorescence dye-modified LNPs@PEG@GLN nanoparticles can be used for computed tomography (CT), magnetic resonance imaging (MRI), and fluorescence imaging (FI). They display high X-ray absorption, outstanding T2-weighted imaging capability, and good fluorescence uptake. Furthermore, LNPs@PEG@GLN enhances contrast efficiencies for different imaging modalities in vivo. Interestingly, LNPs@PEG@GLN is a promising agent for CT angiography. These nanoparticles could be a promising contrast agent for multi-modality imaging and diagnosing vascular diseases.


Thermally induced birefringence in Nd:YAG slab lasers.
We study thermally induced birefringence in crystalline Nd:YAG zigzag slab lasers and the associated depolarization losses. The optimum crystallographic orientation of the zigzag slab within the Nd:YAG boule and photoelastic effects in crystalline Nd:YAG slabs are briefly discussed. The depolarization is evaluated using the temperature and stress distributions, calculated using a finite element model, for realistically pumped and cooled slabs of finite dimensions. Jones matrices are then used to calculate the depolarization of the zigzag laser mode. We compare the predictions with measurements of depolarization, and suggest useful criteria for the design of the gain media for such lasers.


Streptococcal pyrogenic exotoxin B inhibits apoptotic cell clearance by macrophages through protein S cleavage.
Clearance of apoptotic cells by macrophages plays an important role in maintaining tissue homeostasis. Previous study indicated that streptococcal pyrogenic exotoxin B (SPE B) reduces phagocytic activity in group A streptococcus (GAS) infection. Here, we demonstrate that SPE B causes an inhibitory effect on protein S-mediated phagocytosis. In the presence of SPE B, serum- and purified protein S-mediated phagocytosis of apoptotic cells were significantly inhibited. The binding abilities of protein S to apoptotic cells were decreased by treatment with SPE B. Bacterial culture supernatants from GAS NZ131 strain also caused a reduction of protein S binding to apoptotic cells, but speB mutant strain did not. SPE B directly cleaved protein S in vitro and in vivo, whereas a lower level of cleavage occurred in mice infected with a speB isogenic mutant strain. SPE B-mediated initial cleavage of protein S caused a disruption of phagocytosis, and also resulted in a loss of binding ability of protein S-associated C4b-binding protein to apoptotic cells. Taken together, these results suggest a novel pathogenic role of SPE B that initiates protein S degradation followed by the inhibition of apoptotic cell clearance by macrophages.


GPs' perceptions of workload in England: a qualitative interview study.
GPs report the lowest levels of morale among doctors, job satisfaction is low, and the GP workforce is diminishing. Workload is frequently cited as negatively impacting on commitment to a career in general practice, and many GPs report that their workload is unmanageable. To gather an in-depth understanding of GPs' perceptions and attitudes towards workload. All GPs working within NHS England were eligible. Advertisements were circulated via regional GP e-mail lists and national social media networks in June 2015. Of those GPs who responded, a maximum-variation sample was selected until data saturation was reached. Semi-structured, qualitative interviews were conducted. Data were analysed thematically. In total, 171 GPs responded, and 34 were included in this study. GPs described an increase in workload over recent years, with current working days being long and intense, raising concerns over the wellbeing of GPs and patients. Full-time partnership was generally not considered to be possible, and many participants felt workload was unsustainable, particularly given the diminishing workforce. Four major themes emerged to explain increased workload: increased patient needs and expectations; a changing relationship between primary and secondary care; bureaucracy and resources; and the balance of workload within a practice. Continuity of care was perceived as being eroded by changes in contracts and working patterns to deal with workload. This study highlights the urgent need to address perceived lack of investment and clinical capacity in general practice, and suggests that managing patient expectations around what primary care can deliver, and reducing bureaucracy, have become key issues, at least until capacity issues are resolved.


Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities.
Tools to reliably measure Plasmodium falciparum (Pf) exposure in individuals and communities are needed to guide and evaluate malaria control interventions. Serologic assays can potentially produce precise exposure estimates at low cost; however, current approaches based on responses to a few characterized antigens are not designed to estimate exposure in individuals. Pf-specific antibody responses differ by antigen, suggesting that selection of antigens with defined kinetic profiles will improve estimates of Pf exposure. To identify novel serologic biomarkers of malaria exposure, we evaluated responses to 856 Pf antigens by protein microarray in 186 Ugandan children, for whom detailed Pf exposure data were available. Using data-adaptive statistical methods, we identified combinations of antibody responses that maximized information on an individual's recent exposure. Responses to three novel Pf antigens accurately classified whether an individual had been infected within the last 30, 90, or 365 d (cross-validated area under the curve = 0.86-0.93), whereas responses to six antigens accurately estimated an individual's malaria incidence in the prior year. Cross-validated incidence predictions for individuals in different communities provided accurate stratification of exposure between populations and suggest that precise estimates of community exposure can be obtained from sampling a small subset of that community. In addition, serologic incidence predictions from cross-sectional samples characterized heterogeneity within a community similarly to 1 y of continuous passive surveillance. Development of simple ELISA-based assays derived from the successful selection strategy outlined here offers the potential to generate rich epidemiologic surveillance data that will be widely accessible to malaria control programs.