Abnormalities of the peripheral blood as a presenting feature of immunodeficiency.
The predisposition of immunodeficient patients to the development of peripheral blood abnormalities is well documented. Less often recognized is the presence of immune defects in patients who initially present with "idiopathic" forms of thrombocytopenic purpura or autoimmune hemolytic anemia in the absence of symptomatology indicative of an immuno-deficiency. In this report we describe two children, each of whom had intermittent and at times severe hemolysis and thrombocytopenia secondary to formation of autoantibodies. Although the initial clinical impression was the presence of an "idiopathic" form of platelet or red cell destructive phenomenon, subsequent observations demonstrated abnormalities of the immune system which affected both B and T lymphocytes. In one of the patients there was a marked deficiency of IgA with a moderate but progressive decrease in IgM and IgG. The other patient had a moderate decrease in IgA and a failure to sensitize to dinitrochlorobenzene. Both exhibited dysmorphic features, including small stature, abnormal dentition, hyperelasticity of the skin, and hyperextensibility of the joints. Neither had significant problems with bacterial, fungal, or viral infections. These observations highlight the importance of evaluating the immune system in children with "idiopathic" forms of hemolytic anemia or thormbocytopenia. Demonstration of these abnormalities can have important therapeutic implications and may also provide information regarding the etiology of the blood abnormalities.


Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal.
BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.


A structured blood conservation program in pediatric cardiac surgery.
The limitation of alternative transfusion practices in infants increases the benefits of blood conservation. We analyzed the efficacy of a structured program to reduce transfusions and transfusion-associated complications in cardiac surgery PATIENTS AND METHODS: Our pediatric surgery database was reviewed retrospectively, comparing outcomes from two different time periods, after the implementation of an effective blood conservation program beginning in March 2014. A total of 214 infants (8.1±3.4 months) who underwent biventricular repair utilizing CPB (Group 1 - Blood conservation) were studied in a 12-month period (March 2014-February 2015) after the implementation of the new program, and compared with 250 infants (7.91±3.2 months) (Group 2 - Control-No blood conservation) of the previous 12-month period (March 2013-February 2014). The proportion of patients transfused with red blood cells was 75.2% (N=188) in control group and reduced by 16.4% in the study group (58.8% - 126 patients, p <0.01). The mean number of transfusions was 1.25 ± 0.5 units per patient in control group and decreased to 0.7 ± 0.5 units per patient after the start of the program (p = 0.035). Cerebral oximetry demonstrated better follow-up during the operative period confirming less hemodilution in Group 1. Respiratory support, inotropic need and ICU stay were significantly better in the study group. These findings, in addition to attendant risks and side effects of blood transfusion and the rising cost of safer blood products, justify blood conservation in pediatric cardiac operations. Circuit miniaturization, ultrafiltration, and reduced postoperative bleeding, presumably secondary to higher fibrinogen and other coagulation factor levels, contributed to this outcome.


Duration-dependent FMRI adaptation and distributed viewer-centered face representation in human visual cortex.
Two functional magnetic resonance imaging (fMRI) face viewpoint adaptation experiments were conducted to investigate whether fMRI adaptation in high-level visual cortex depends on the duration of adaptation and how different views of a face are represented in the human visual system. We found adaptation effects in multiple face-selective areas, which suggest a distributed, viewer-centered representation of faces in the human visual system. However, the nature of the adaptation effects was dependent on the length of adaptation. With long adaptation durations, face-selective areas along the hierarchy of the visual system gradually exhibited viewpoint-tuned adaptation. As the angular difference between the adapter and test stimulus increased, the blood oxygen level-dependent (BOLD) signal evoked by the test stimulus gradually increased as a function of the amount of 3-dimensional (3D) rotation. With short adaptation durations, however, face-selective areas in the ventral pathway, including the lateral occipital cortex and right fusiform area, exhibited viewpoint-sensitive adaptation. These areas showed an increase in the BOLD signal with a 3D rotation, but this signal increase was independent of the amount of rotation. Further, the right superior temporal sulcus showed little or very weak viewpoint adaptation with short adaptation durations. Our findings suggest that long- and short-term fMRI adaptations may reflect selective properties of different neuronal mechanisms.


Malignant perivascular epithelioid cell tumor of mesentery with lymph node involvement: a case report and review of literature.
Perivascular epithelioid cell tumor (PEComa) is a rare but distinct mesenchymal neoplasm composed of histologically and immunohistochemically unique perivascular epithelioid cells. Due to its relative rarity, little is known about the histogenesis and prognostic factors of this tumor. We describe a case of unusual mesenteric PEComa in a 38-year-old female patient with regional lymph node involvement. Histologically, the tumor was composed of sheet of epithelioid cells with abundant clear or eosinophillic cytoplasms. Extensive coagulative necrosis and a few mitotic figures (2/50 high power field) could be found in tumor. The epithelioid tumor cells were diffusely positive for HMB-45, Melan-A, and focally positive for calponin. One of enlarged mesenteric lymph nodes was observed to be involved by tumor. A diagnosis of malignant mesenteric PEComa with lymph node involvement was made. The patient received chemotherapy after total resection of tumor and segmental resection of involved jejunum. There was no sign of recurrence of tumor found in period of 6-month regular follow-up after chemotherapy. To our knowledge, this is the first case of malignant PEComa in mesentery accompanied with regional lymph node involvement. The literature on this rare tumor is reviewed and diagnostic criteria of malignant PEComa are discussed. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1309992178882788.


Monte Carlo calculation of imaging doses from diagnostic multidetector CT and kilovoltage cone-beam CT as part of prostate cancer treatment plans.
To calculate imaging doses to the rectum, bladder, and femoral heads as part of a prostate cancer treatment plans, assuming an image guided radiation therapy (IGRT) procedure involving either the multidetector CT (MDCT) or kilovoltage cone-beam CT (kV CBCT). This study considered an IGRT treatment plan for a prostate carcinoma patient involving 50.4 Gy from 28 initial fractions and a boost of 28.8 Gy from 16 fractions. A total of 45 CT imaging procedures, each involving a MDCT or a kV CBCT scan procedure, were carefully modeled using the MCNPX code version 2.5.0. The MDCT scanner model is based on the GE LightSpeed 16-MDCT scanner and the kV CBCT scanner model is based on the Varian On-Board Imager using parameters reported by the CT manufacturers and literatures. A patient-specific treatment planning CT data set was used to construct the phantom for the dose calculation. The target, organs-at-risk (OARs), and background voxels in the CT data set were categorized into six tissue types according to CT numbers for Monte Carlo calculations. For a total of 45 imaging procedures, it was found that the rectum received 78.4 and 76.7 cGy from MDCT and kV CBCT, respectively. The bladder received slightly greater doses of 82.4 and 77.9 cGy, while the femoral heads received much higher doses of 182.3 and 141.3 cGy from MDCT and kV CBCT, respectively. To investigate the impact of these imaging doses on treatment planning, OAR doses from MDCT or kV CBCT imaging procedures were added to the corresponding dose matrix reported by the original treatment plans to construct dose volume histograms. It was found that after the imaging dose is added, the rectum volumes irradiated to 75 and 70 Gy increased from 13.9% and 21.2%, respectively, in the original plan to 14.8% and 21.8%. The bladder volumes receiving 80 Gy increased to 4.6% from 4.1% in the original plan and the volume receiving 75 Gy increased to 7.9% from 7.5%. All values remained within the tolerance levels: V70<25%, V75 <15% for rectum and V75 < 25%, V80 < 15% for bladder. The irradiation of femoral heads was also acceptable with no volume receiving >45 Gy. IGRT procedures can irradiate the OARs to an imaging dose level that is great enough to require careful evaluation and perhaps even adjustment of original treatment planning in order to still satisfy the dose constraints. This study only considered one patient CT because the CT x rays cover a relatively larger volume of the body and the dose distribution is considerably more uniform than those associated with the therapeutic beams. As a result, the dose to an organ from CT imaging doses does not vary much from one patient to the other for the same CT settings. One factor that would potentially affect such CT dose level is the size of the patient body. More studies are needed to develop accurate and convenient methods of accounting for the imaging doses as part of treatment planning.


Neurocognitive outcomes in children with chronic kidney disease: Current findings and contemporary endeavors.
Given the rise in chronic kidney disease (CKD) in both children and adults, CKD has recently been targeted as a public health priority. Childhood onset kidney disease is generally a noncurable and progressive condition that leads to kidney failure by early adulthood. Fortunately, improved identification of kidney problems allows for early intervention, which is thought to slow progression toward end-stage renal disease. In addition, medical interventions for pediatric end-stage renal disease have also improved, allowing children to take advantage of lifesaving renal replacement treatments such as dialysis and kidney transplantation. In spite of improvements in identification and treatment, CKD causes both direct and indirect insults to a variety of organ systems. This paper reviews recently published studies pertaining to the neurocognitive and psychosocial impact of CKD on children of various ages and at various stages of kidney failure. Specific attention is focused on summarizing peer reviewed research that describes associations between kidney functioning and cognitive functioning, language acquisition, visual spatial abilities, memory, and executive functioning. In addition, peer reviewed research describing psychosocial outcomes associated with CKD related to academic achievement, social-behavioral functioning, and quality of life are summarized. The authors also identified disease-specific factors that likely mediate neurocognitive outcomes (e.g., anemia, hypertension, cardiovascular) and endorse the importance of continued interdisciplinary research collaborations that will provide a better understanding of the mechanisms responsible for improved neurocognitive functioning after transplantation. The authors conclude this review by describing a multicenter, prospective, longitudinal, National Institutes of Health funded study that is currently examining the developmental outcomes of children with mild to moderate CKD. The authors speculate that the Chronic Kidney Disease in Children Prospective Cohort Study (CKiD) findings will provide additional evidence-based guidance for clinicians and researchers working with children and adolescents with deteriorating kidney function to improve medical and developmental outcomes.


Epileptic spasms in older pediatric patients: MEG and ictal high-frequency oscillations suggest focal-onset seizures in a subset of epileptic spasms.
To elucidate the pathophysiology of intractable epileptic spasms in older children by describing the interictal magnetoencephalography spike sources (MEGSSs), intracranial EEG ictal-onset zones (IOZs) and their ictal high-frequency oscillations (HFOs) and surgical outcomes. We studied five patients (4.5-14 years) who underwent surgery following intracranial video-EEG (VEEG) monitoring. We analyzed clinical profiles, MRIs, scalp and intracranial VEEGs, and MEGSSs. We localized ictal HFOs using a sampling rate of 1000 Hz and multiple band frequency analysis (MBFA). Seizure onset ranged from 0.4 to 8 years. Three patients presented with asymmetrical spasms. Interictal scalp VEEG recorded predominantly unilateral epileptiform discharges in four; generalized and multifocal in one. Ictal scalp VEEG showed generalized high-amplitude slow waves with superimposed fast waves in four patients; hemispheric electrodecremental episodes in one. MRI findings were normal in three, hemispheric polymicrogyria and periventricular heterotopia in one each. All patients had unilateral MEGSS clusters. Ictal HFOs, ranging from 150 to 250 Hz, localized over Rolandic and frontal regions in four, with one also having extensive temporo-occipital HFOs. After cortical resection, three patients were seizure free; one had >90% reduction in seizure frequency. One patient experienced residual seizures after resection of the hemispheric ictal HFO region. Unilateral clusters of MEGSSs overlapped regional IOZs in older patients with epileptic spasms. High spatio-temporal MBFA before and during spasms revealed the regional ictal HFOs. Seizure-free outcomes following resection of zone with MEGSS clusters and ictal HFOs suggested that a subset of epileptic spasms was focal-onset seizures.


Early life conditions, partnership histories, and mortality risk for Swedish men and women born 1915-1929.
This paper investigates the relationship between early life biological and social factors, partnership history, and mortality risk. Mortality risks for Swedish men and women over age 50 in the Uppsala Birth Cohort born 1915-1929 were estimated using survival analysis. Relative mortality risk was evaluated through nested multiplicative Gompertz models for 4348 men and 3331 women, followed from age 50 to the end of 2010. Being born to an unmarried mother was associated with higher mortality risk in later life for men and women, and relative to married individuals, being unmarried after age 50 was associated with elevated mortality risk. Single women and divorced men were the highest risk groups, and women were negatively impacted by a previous divorce or widowhood, while men were not. Both genders showed direct effects of early life variables on later life mortality and were vulnerable if unmarried in later life. However, in this study, previous marital disruptions appeared to have more (negative) meaning in the long-term for women.


The effects of superimposed tilt and lower body negative pressure on anterior and posterior cerebral circulations.
Steady-state tilt has no effect on cerebrovascular reactivity to increases in the partial pressure of end-tidal carbon dioxide (PETCO2). However, the anterior and posterior cerebral circulations may respond differently to a variety of stimuli that alter central blood volume, including lower body negative pressure (LBNP). Little is known about the superimposed effects of head-up tilt (HUT; decreased central blood volume and intracranial pressure) and head-down tilt (HDT; increased central blood volume and intracranial pressure), and LBNP on cerebral blood flow (CBF) responses. We hypothesized that (a) cerebral blood velocity (CBV; an index of CBF) responses during LBNP would not change with HUT and HDT, and (b) CBV in the anterior cerebral circulation would decrease to a greater extent compared to posterior CBV during LBNP when controlling PETCO2 In 13 male participants, we measured CBV in the anterior (middle cerebral artery, MCAv) and posterior (posterior cerebral artery, PCAv) cerebral circulations using transcranial Doppler ultrasound during LBNP stress (-50 mmHg) in three body positions (45°HUT, supine, 45°HDT). PETCO2 was measured continuously and maintained at constant levels during LBNP through coached breathing. Our main findings were that (a) steady-state tilt had no effect on CBV responses during LBNP in both the MCA (P = 0.077) and PCA (P = 0.583), and (b) despite controlling for PETCO2, both the MCAv and PCAv decreased by the same magnitude during LBNP in HUT (P = 0.348), supine (P = 0.694), and HDT (P = 0.407). Here, we demonstrate that there are no differences in anterior and posterior circulations in response to LBNP in different body positions.


Rivastigmine for dementia associated with Parkinson's disease.
Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.


JAK Kinases in Health and Disease: An Update.
Janus kinases (Jaks) are critical signaling elements for a large subset of cytokines. As a consequence they play pivotal roles in the patho-physiology of many diseases including neoplastic and autoimmune diseases. Small molecule Jak inhibitors as therapeutic agents have become a reality and the palette of such inhibitors will likely expand. This review will summarize our current knowledge on these key enzymes and their associated pharmaceutical inhibitors.


Color computer-generated holograms from projection images.
A novel method for the procurement of full-color three-dimensional (3-D) images of real objects has been developed. This method is based on extracting information from 3-D Fourier spectra, which are calculated from several projection images recorded using a white light source. 3-D Fourier spectra for three colors were obtained separately for projection images recorded with a color-CCD camera. Three computer-generated holograms (CGHs) were then synthesized from those Fourier spectra. The resulting numerically and optically reconstructed full-color images are presented.


Cognitive function and symptoms in adults and adolescents in relation to rf radiation from UMTS base stations.
There is widespread public concern about the potential adverse health effects of mobile phones in general and their associated base stations in particular. This study was designed to investigate the acute effects of radio frequency (RF) electromagnetic fields (EMF) emitted by the Universal Mobile Telecommunication System (UMTS) mobile phone base stations on human cognitive function and symptoms. Forty adolescents (15-16 years) and 40 adults (25-40 years) were exposed to four conditions: (1) sham, (2) a Continuous Wave (CW) at 2140 MHz, (3) a signal at 2140 MHz modulated as UMTS and (4) UMTS at 2140 MHz including all control features in a randomized, double blinded cross-over design. Each exposure lasted 45 min. During exposure the participants performed different cognitive tasks with the Trail Making B (TMB) test as the main outcome and completed a questionnaire measuring self reported subjective symptoms. No statistically significant differences between the UMTS and sham conditions were found for performance on TMB. For the adults, the estimated difference between UMTS and sham was -3.2% (-9.2%; 2.9%) and for the adolescents 5.5% (-1.1%; 12.2%). No significant changes were found in any of the cognitive tasks. An increase in 'headache rating' was observed when data from the adolescents and adults were combined (P = 0.027), an effect that may be due to differences at baseline. In conclusion, the primary hypothesis that UMTS radiation reduces general performance in the TMB test was not confirmed. However, we suggest that the hypothesis of subjective symptoms and EMF exposure needs further research.


Toxic Texts and Reading Remedies: Literary Medicine in Eighteenth-Century Print Cultures.
Today the idea of reading for health is perhaps most commonly associated with the term bibliotherapy. This seemingly new practice might be considered a significant shift of public and professional medical attitudes when compared with historical interpretations of the impact of reading on individuals' health. Much historiography concerning the reception of popular literature in eighteenth-century print culture has focused on the belief that readers of fiction, most often women, were at risk of corrupting their own minds and bodies through their reading choices. Yet, although popular, this view was not exclusively subscribed to by either medical practitioners or the wider public. This article reveals perspectives that warned against and celebrated the effects of reading on human health during the eighteenth century. Unlike what we see from much contemporary scholarship there is, in fact, a range of evidence which demonstrates that eighteenth-century medical practitioners were already engaging with the concept of reading as a therapeutic activity.


Relationship between perceived softness of bilayered skin models and their mechanical properties measured with a dual-sensor probe.
The development of a sensor system that can predict the subjective softness of human skin is an important goal for the cosmetics industry. Here, we first carried out a subjective softness evaluation test using 65 skin models consisting of polyurethane bilayers with different thickness of the superficial layer and different degree of cross-polymerization of the basal layer. The results showed that perceived softness was dependent on the mechanical properties of both the superficial and basal layers. Then, we used a recently developed tactile sensor system composed of a piezoelectric tactile sensor and a load cell to measure mechanical softness parameters of the superficial layer and the whole model, respectively. Statistical analysis showed that the data obtained from these two sensors were well correlated with the perceived softness of the prepared models. These results suggest that it may be feasible to predict the subjective softness of human skin in vivo from non-invasive mechanical softness measurements of the superficial skin layer and whole skin obtained with our new dual-probe sensor system.


Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians.
We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.


Is it all in the family? The effects of early social structure on neural-behavioral systems of prairie voles (Microtus ochrogaster).
The transition to parenthood is generally associated with a reduction in anxiety or anxiety-like behavior across a wide range of species. In some species, juveniles provide supplementary parental care for younger siblings, a behavior known as alloparenting. Although the fitness consequences of alloparenting behavior have been a focus of evolutionary research, less is known about how alloparenting behavior impacts affective states. In the socially monogamous prairie vole (Microtus ochrogaster), most juveniles exhibit alloparenting behavior, making the species an ideal model for examining the effects of alloparenting on future behavioral outcomes. We randomly assigned juvenile voles to alloparenting (AL) or no alloparenting (NoAL) groups and behaviorally phenotyped them for anxiety-like and social behaviors using the elevated plus maze (EPM), open field test (OFT), startle box, social interaction test, juvenile affiliation test, and partner preference test. AL voles displayed more anxiety-like and less exploratory behaviors than NoAL voles, spending significantly less time in the open arms of the EPM and center of an open field. We dissected the CA1 region of the hippocampus and the bed nucleus of the stria terminalis (BNST) from brains of behaviorally phenotyped voles and nontested siblings as well. Decreased brain-derived neurotrophic factor (BDNF) expression in CA1 has generally been associated with increased anxiety-like behavior in other rodents, while an anxiogenic role for BDNF in BNST is less established. Western blot analyses showed that alloparenting experience increased expression of BDNF in the BNST but decreased BDNF expression in the CA1 region of hippocampus (CA1) of nontested voles. There were similar differences in BNST BDNF of behaviorally phenotyped voles, and BDNF levels within this region were negatively correlated with exploratory behavior (i.e. time in center of OFT). Our results suggest that BDNF signaling in BNST and CA1 fluctuate with alloparenting experience, and they contribute to an increasingly complex "BDNF hypothesis" in which behavioral effects of this molecule are region-specific.


Brain abscess and dentistry: a review of the literature.
Brain abscess is a rare, extremely aggressive, life-threatening infection. A mortality rate of between 36% and 90% has been reported as recently as 1990. It is resistant to antibiotics and is one of the few bacterial infections whose morbidity and mortality statistics remain unaffected by the development of antimicrobial medications. Successful treatment appears to be dependent on early diagnosis, surgical intervention, and direct antibiotic irrigation of the surgical wound site, as well as intravenous administration of high doses of antibiotics throughout the crisis. It has been suggested that there is a relationship between dental infection or treatment and brain abscess. Dental infection and treatment have been found culpable in numerous cases reported in the literature. However, careful review of the articles reveals that dental infection or treatment has often been named as a causative factor (1) solely because an infection or treatment occurred within several months of brain abscess; (2) when nondental bacteria were cultured from the brain abscess; and (3) without culturing both the dental infection and the brain abscess to ascertain flora match.


Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations.
We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer.


Sleep, circadian rhythms and health.
At the core of human thought, for the majority of individuals in the developed nations at least, there is the tacit assumption that as a species we are unfettered by the demands imposed by our biology and that we can do what we want, at whatever time we choose, whereas in reality every aspect of our physiology and behaviour is constrained by a 24 h beat arising from deep within our evolution. Our daily circadian rhythms and sleep/wake cycle allow us to function optimally in a dynamic world, adjusting our biology to the demands imposed by the day/night cycle. The themes developed in this review focus upon the growing realization that we ignore the circadian and sleep systems at our peril, and this paper considers the mechanisms that generate and regulate circadian and sleep systems; what happens mechanistically when these systems collapse as a result of societal pressures and disease; how sleep disruption and stress are linked; why sleep disruption and mental illness invariably occur together; and how individuals and employers can attempt to mitigate some of the problems associated with working against our internal temporal biology. While some of the health costs of sleep disruption can be reduced, in the short-term at least, there will always be significant negative consequences associated with shift work and sleep loss. With this in mind, society needs to address this issue and decide when the consequences of sleep disruption are justified in the workplace.


Unraveling the sequence of cytosolic reactions in the export of GspB adhesin from Streptococcus gordonii.
Many pathogenic bacteria, including Streptococcus gordonii, possess a pathway for the cellular export of a single serine-rich-repeat protein that mediates the adhesion of bacteria to host cells and the extracellular matrix. This adhesin protein is O-glycosylated by several cytosolic glycosyltransferases and requires three accessory Sec proteins (Asp1-3) for export, but how the adhesin protein is processed for export is not well understood. Here, we report that the S. gordonii adhesin GspB is sequentially O-glycosylated by three enzymes (GtfA/B, Nss, and Gly) that attach N-acetylglucosamine and glucose to Ser/Thr residues. We also found that modified GspB is transferred from the last glycosyltransferase to the Asp1/2/3 complex. Crystal structures revealed that both Asp1 and Asp3 are related to carbohydrate-binding proteins, suggesting that they interact with carbohydrates and bind glycosylated adhesin, a notion that was supported by further analyses. We further observed that Asp1 also has an affinity for phospholipids, which is attenuated by Asp2. In summary, our findings support a model in which the GspB adhesin is sequentially glycosylated by GtfA/B, Nss, and Gly and then transferred to the Asp1/2/3 complex in which Asp1 mediates the interaction of the Asp1/2/3 complex with the lipid bilayer for targeting of matured GspB to the export machinery.


Probing the high-pressure viscosity of hydrocarbon mixtures using molecular dynamics simulations.
Computational predictions of the high-pressure viscosity of hydrocarbon mixtures could help to accelerate the development of fuels and lubricants with improved performance. In this study, we use molecular dynamics simulations to study the viscosity and density of methylcyclohexane, 1-methylnaphthalene, and their binary mixtures at 323 K and pressures of up to 500 MPa. The simulation results are in excellent agreement with previous experiments available up to 100 MPa for both pure compounds (200 MPa for 1-methylnaphthalene) and the binary mixtures. For 1-methylnaphthalene, the viscosity initially increases slower-than-exponential with pressure before it reaches an inflection point and then increases faster-than-exponential. The inflection point (300 MPa) occurs at a pressure slightly below the one at which 1-methylnaphthalene is expected to enter the supercooled phase (400 MPa). For methylcyclohexane, the increase in viscosity with pressure is slower-than-exponential over the entire pressure range studied. The binary mixtures show intermediate pressure-viscosity responses between the two pure cases. The applicability of equations commonly used to describe the pressure dependence of viscosity, as well as the viscosity of binary mixtures, is evaluated against the computational predictions.


Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder.
We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.


Patiromer Decreases Serum Potassium and Phosphate Levels in Patients on Hemodialysis.
Persistent hyperkalemia (serum potassium (K) ≥5.5 mEq/l) is a common condition in hemodialysis (HD) patients, is associated with increased mortality, and treatment options are limited. The effect of patiromer, a gastrointestinal K binder, on serum K was examined in HD patients. Six hyperkalemic HD patients (5 anuric) were admitted to clinical research units for 15 days (1 pretreatment week and 1 patiromer treatment week) and they received a controlled diet with identical meals on corresponding days of pretreatment and treatment weeks. Phosphate (P) binders were discontinued on admission. Patiromer, 12.6 g daily (divided 4.2 g TID with meals), was started on the Monday morning following the last pretreatment week blood sampling. Serum and 24-hour stool samples were collected daily. Mean ± SE serum K decreased (maximum change per corresponding day, 0.6 ± 0.2 mEq/l, p = 0.009) and fecal K increased 58% on patiromer compared with the pretreatment week. During the pretreatment week, 69.0, 47.6, and 11.9% of patients' serum K values were ≥5.5, ≥6.0, and ≥6.5 mEq/l, respectively. This was reduced to 38.1% (p = 0.009), 11.9% (p < 0.001), and 2.4% (p = 0.2) on patiromer. Following P binder discontinuation, the long interdialytic interval mean ± SE serum P numerically increased from 5.8 ± 0.4 to 7.0 ± 0.5 mg/dl (p = 0.06). On patiromer, P decreased from 7.0 ± 0.5 to 6.2 ± 0.5 mg/dl (p = 0.04). While on patiromer, fecal P numerically increased by 112 ± 72 mg/day (17%; p = 0.1792; range -148 to 344 mg/day). No patient discontinued patiromer because of adverse events (AEs); none had serious AEs. In 6 hyperkalemic HD patients, patiromer decreased serum K and P levels and increased fecal K.


Trophic Transfer and Accumulation of Multiwalled Carbon Nanotubes in the Presence of Copper Ions in Daphnia magna and Fathead Minnow (Pimephales promelas).
The increase in use of nanomaterials such as multiwalled carbon nanotubes (MWCNTs) presents a need to study their interactions with the environment. Trophic transfer was measured between Daphnia magna and Pimephales promelas (fathead minnow, FHM) exposed to MWCNTs with different outer diameter (OD) sizes (MWCNT1 = 8-15 nm OD and MWCNT2 = 20-30 nm OD) in the presence and absence of copper. Pristine FHM were fed D. magna, previously exposed for 3 d to MWCNT1 or MWCNT2 (0.1 mg/L) and copper (0.01 mg/L), for 7 d. D. magna bioaccumulated less MWCNT1 (0.02 μg/g) than MWCNT2 (0.06 μg/g), whereas FHM accumulated more MWCNT1 (0.81 μg/g) than MWCNT2 (0.04 μg/g). In the presence of copper, MWCNT bioaccumulation showed an opposite trend. Mostly MWCNT1 (0.03 μg/g) bioaccumulated in D. magna, however less MWCNT1 (0.21 μg/g) than MWCNT2 (0.32 μg/g) bioaccumulated in FHM. Bioaccumulation factors were higher for MWCNT1s than MWCNT2. However, an opposite trend was observed when copper was added. Plasma metallothionein-2 was measured among treatments; however concentrations were not statistically different from the control. This study demonstrates that trophic transfer of MWCNTs is possible in the aquatic environment and further exploration with mixtures can strengthen the understanding of MWCNT environmental behavior.


Comparison of diets of diabetic and nondiabetic women.
To assess the dietary habits of diabetic women. Participants in the Nurses Health Study, a cohort of 121,700 registered female nurses, were followed since 1976. We compared the usual dietary intakes of women who had been diagnosed with diabetes mellitus by 1980 and age-matched nondiabetic control women; diets of these women were assessed in 1980 and 1984 by a semiquantitative food frequency questionnaire. The study examined 162 IDDM women and 738 NIDDM women. Similar comparisons were made for 429 women who developed NIDDM between 1980 and 1984. Although differences were small, women with IDDM in 1984 and women with NIDDM in 1980 and 1984 consumed less energy from carbohydrates, especially from sucrose, and more energy from protein and fat than did control women. Similar results were also found in 1984 for the 429 women who developed NIDDM between 1980 and 1984. In 1980, energy from nonsucrose carbohydrate was slightly higher in both IDDM and NIDDM women than in the control women. However, in 1984, using a dietary questionnaire designed to assess more complete dietary intake, less consistent results were obtained. Diabetic women tended to avoid desserts and sweets, sugar-containing beverages, and alcoholic beverages but consumed more meat and meat products. Intakes of foods high in complex carbohydrates (e.g., bread, rice, pasta, and potatoes) were similar between diabetic and control women. The results suggest that these diabetic women did not consume the high-carbohydrate, low-fat diets that the American Diabetes Association has been recommending over the past decade.


[New ultrashort scheme for helicobacter pylori infection eradication using tetracyline, furazolidone and colloidal bismuth subcitrate in dyspeptic patients with or without peptic ulceration in the National Hospital Cayetano Heredia].
Helicobacter pylori (Hp) infection has been associated with the presence of duodenal ulcer, gastric ulcer and chronic active gastritis. It is also speculated that Hp may have a major role in gastric cancer development. Due to rising antibiotic resistance, probably lack of compliance and the expense of the currently used antimicrobial regimens, it's important to develop efficacious, short-duration and low cost therapies, especially for the treatment of low-income populations from underdeveloped countries. The goal of the present study is to asses the efficacy of two ultrashort antibiotic schemes against Hp infection. Patients with diagnosis of Hp infection, found in antral gastric biopsies, were included. They were randomly assigned to receive one of the following therapeutic schemes: tetracycline 500 mg qid, furazolidone 100 mg qid and colloidal bismuth subcitrate 120 mg qid for 3 days (Scheme I) or 4 days (Scheme II). Patients were instructed to come back for follow-up at least 8 weeks after starting medication. At the control visit, an upper endoscopy was performed and an average of 3 antral biopsies was taken. Biopsies were stained with hematoxylin-eosin for histological assessment and with Warthin-Starry silver staining for Hp diagnosis. A single experienced pathologist read all biopsies. In both, the initial biopsy and the control one, we evaluated: presence of Hp; presence, depth and grade of chronic gastritis; presence and grade of inflammatory activity; presence, grade and extent of mucinous damage; presence of glandular atrophy, intestinal metaplasia and lymphoid follicles. We also evaluated dyspeptic symptoms prior and after the treatment, and the presence of adverse events. 80 patients were enrolled, 2 were excluded because of intense nausea and vomits, 4 patients didn't follow the indications properly and 8 patients couldn't be contacted for the control visit. From the remaining 66 patients, 32 were assigned to Scheme I and 34 to Scheme II, both groups were comparable. Eradication rate was 68.8% (22/32) (CI = 52.1% - 82.7%) for Scheme I and 88.2% (30/34) (CI = 74.9% - 96.2%), significant higher, for Scheme II. There was decrease of dyspeptic symptoms and significant improvement of the histological pattern for both groups, except for presence of chronic gastritis, intestinal metaplasia, glandular atrophy and lymphoid follicles. Hp eradication was associated with significant symptoms decrease, normal endoscopy raising and improvement of all the histological parameters, except for presence of intestinal metaplasia and glandular atrophy. Treatment was well tolerated, 57.6% of the patients reported only mild adverse events, nausea was the most frequent (19.7%) and there was no difference between schemes. The triple ultrashort duration scheme including tetracycline, furazolidone and bismuth for 4 days is efficacious against Hp, with a high eradication rate (88.2%). The Hp disappearance is followed by improvement in every histological parameter that we evaluated, except for glandular atrophy and intestinal metaplasia; and it's also accompanied by a decrease in dyspeptic symptoms.


Carotid-cavernous fistula from the perspective of an ophthalmologist A Review.
Carotid-cavernous fistula (CCF) is an abnormal communication - vascular connection between arteries and veins in the cavernous sinus. Classification according to etiology is traumatic vs spontaneous. According to blood flow rate per high flow vs low flow fistula. According to anatomy of direct vs indirect: Direct (direct) CCF arises through direct communication between the internal carotid artery (ICA) and the cavernous sinus. Indirect CCF originates through indirect communication through the meningeal branches of ICA, external carotid artery and cavernous sinus (not directly with ICA) and Barrow type A, B, C, D division. Patients subjective complaints depend on the type of CCF. Most often it is pulsating tinnitus, synchronous with blood pulse. Typical findings include protrusion and pulsation of the eyeball, corkscrew vessels - arterialization of conjunctival and episleral vessels, increased intraocular pressure, not responding to local antiglaucomatous therapy, keratopathy a lagophthalmo, corneal ulcers. In the later untreated stages of CCF, secondary, venous stasis or central retinal vein occlusion can occur. Diagnostic procedures include B-scan and color Doppler ultrasonography, digital ophthamodynamometry, computer tomography, nuclear magnetic resonance and digital subtraction angiography. CCF can simulate orbitopathy, conjunctivitis symptoms, carotid occlusion, scleritis or cavernous sinus thrombosis. The ophthalmologist should recognize and indicate the necessary examinations in a timely manner. The therapy is ophthalmological, neuroradiological, sterotactic, surgical and conservative.


Proteolysis of cyclic AMP phosphodiesterase-II attenuates its ability to be inhibited by compounds which exert positive inotropic actions in cardiac tissue.
Extraction of frozen canine cardiac muscle rendered soluble over 90% of the cyclic AMP phosphodiesterase activity. The residual activity was membrane-bound. Ion exchange chromatography of the soluble activity on DE-52 allowed for the resolution of three distinct cyclic AMP phosphodiesterase fractions termed PDE-I, PDE-II and PDE-III in order of elution from the column by a linear NaCl gradient. The relative ratio of cyclic AMP phosphodiesterase activity exhibited by these three peaks was 1:0.65:0.82 and of cyclic GMP phosphodiesterase activity was 1:0.52:0.05 for PDE-I, PDE-II and PDE-III respectively. PDE-II and PDE-III were further purified by re-chromatography on DE-52. Fractions PDE-II and PDE-III were thermolabile at 50 degrees, decaying as single exponentials with half lives of 180 sec and 77 sec respectively. All three species exhibited non-linear Lineweaver-Burke plots for the hydrolysis of cyclic AMP, exhibiting both high and low affinity components. Hydrolysis of cyclic GMP by all three components obeyed normal kinetics, yielding linear plots. PDE-I was a Ca2+/calmodulin-activated species which exhibited a low Km for both cyclic AMP and cyclic GMP but hydrolysed cyclic GMP with a higher Vmax than for cyclic AMP. PDE-II exhibited a much lower Km for cyclic AMP than for cyclic GMP and a much higher Vmax for the hydrolysis of cyclic AMP. PDE-III exhibited a low Km for both cyclic AMP and cyclic GMP, however, its Vmax for cyclic AMP was about 40-fold higher than for cyclic GMP. Cyclic GMP acted as a potent inhibitor (IC50 = 6.3 microM) of cyclic AMP hydrolysis catalysed by PDE-III but not of the hydrolysis of cyclic AMP by PDE-II (IC50 = 33.2 microM). The phosphodiesterase inhibitors milrinone, CI-930, UK-35,493, carbazeran and buquineran acted as potent inhibitors of cyclic AMP hydrolysis catalysed by both PDE-II and PDE-III enzymes. They did not inhibit PDE-I activity. PDE-II, when prepared in the absence of protease inhibitors exhibited a reduced potency to inhibition by these compounds. Treatment of purified PDE-II with trypsin caused a reduction in enzyme activity and reduced dramatically the sensitivity of PDE-II activity to inhibition by these various compounds. The action of proteolysis in attenuating the inhibitory effect of these compounds on PDE-II was most dramatic with CI-930, milrinone, amrinone, buquineran and UK35,493 and least dramatic with carbazeran and IBMX.(ABSTRACT TRUNCATED AT 400 WORDS)


Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.
Cardiac transplantation is in decline, in contrast to other solid organs where the number of solid organ transplants from donors after circulatory death (DCD) is increasing. Hearts from DCD donors are not currently utilized due to concerns that they may suffer irreversible cardiac injury with resultant poor graft function. Using a large animal model, we tested the hypothesis that hearts from DCD donors would be suitable for transplantation. Donor pigs were subjected to hypoxic cardiac arrest (DCD) followed by 15 min of warm ischemia and resuscitation on cardiopulmonary bypass, or brainstem death (BSD) via intracerebral balloon inflation. Cardiac function was assessed through load-independent measures and magnetic resonance imaging and spectroscopy. After resuscitation, DCD hearts had near normal contractility, although stroke volume was reduced, comparable to BSD hearts. DCD hearts had a significant decline in phosphocreatine and increase in inorganic phosphate during the hypoxic period, with a return to baseline levels after reperfusion. After transplantation, cardiac function was comparable between BSD and DCD groups. Therefore, in a large animal model, the DCD heart maintains viability and recovers function similar to that of the BSD heart and may be suitable for clinical transplantation. Further study is warranted on optimal reperfusion strategies.


Is risk-taking in talented junior tennis players related to overuse injuries?
Overuse injuries are a serious problem in junior tennis. Gaining insight in age-specific risk factors can contribute to prevention. The developmental cognitive processes that take place during adolescence make talented players more inclined to take risks. This may be even more pronounced in the high performance culture in which they move. Therefore, this study focuses on the relationship between risk-taking and overuse injuries in talented tennis players. Seventy-three talented tennis players (45 boys and 28 girls, age 11-14 years) were monitored for 32 weeks, using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Risk-taking was measured at the start of the season with the Iowa Gambling Task. Linear regression analyses were executed to predict (a) overuse injuries, (b) time loss overuse injuries and (c) overuse severity, by risk-taking, exposure time, and injury history. In boys, risk-taking contributed significantly to time loss overuse injuries [F(1,39) = 7.764, P = 0.008, R2 = 0.15] and to overuse severity [F(1,39) = 5.683, P = 0.022, with an R2 of 0.13] In girls, time loss overuse injuries [F(1,23) = 6.889, P = 0.018, R2 = 0.20] and overuse severity [F(1,23) = 7.287, P = 0.013, R2 = 0.24] were predicted by exposure time. Coaches and trainers should be aware that talented male tennis players who are inclined to take risks, are more likely to maintain risky behavioral patterns related to overuse injuries.


Automated Pupillometry Using a Prototype Binocular Optical Coherence Tomography System.
To determine the test-retest reliability and diagnostic accuracy of a binocular optical coherence tomography (OCT) prototype (Envision Diagnostics, El Segundo, California, USA) for pupillometry. Assessment of diagnostic reliability and accuracy. Fifty participants with relative afferent pupillary defects (RAPDs) confirmed using the swinging flashlight method (mean age 49.6 years) and 50 healthy control subjects (mean age 31.3 years) were examined. Participants twice underwent an automated pupillometry examination using a binocular OCT system that presents a stimulus and simultaneously captures OCT images of the iris-pupil plane of both eyes. Participants underwent a single examination on the RAPDx (Konan Medical, Irvine, California, USA), an automated infrared pupillometer. Pupil parameters including maximum and minimum diameter, and anisocoria were measured. The magnitude of RAPD was calculated using the log of the ratio of the constriction amplitude between the eyes. A pathological RAPD was above ±0.5 log units on both devices. The intraclass correlation coefficient was >0.90 for OCT-derived maximum pupil diameter, minimum pupil diameter, and anisocoria. The RAPDx had a sensitivity of 82% and a specificity of 94% for detection of RAPD whereas the binocular OCT had a sensitivity of 74% and specificity of 86%. The diagnostic accuracy of the RAPDx and binocular OCT was 88% (95% confidence interval 80%-94%) and 80% (95% confidence interval 71%-87%) respectively. Binocular OCT-derived pupil parameters had excellent test-retest reliability. The diagnostic accuracy of RAPD was inferior to the RAPDx and is likely related to factors such as eye movement during OCT capture. As OCT becomes ubiquitous, OCT-derived measurements may provide an efficient method of objectively quantifying the pupil responses.


An in vitro system to silence mitochondrial gene expression.
The human mitochondrial genome encodes thirteen core subunits of the oxidative phosphorylation system, and defects in mitochondrial gene expression lead to severe neuromuscular disorders. However, the mechanisms of mitochondrial gene expression remain poorly understood due to a lack of experimental approaches to analyze these processes. Here, we present an in vitro system to silence translation in purified mitochondria. In vitro import of chemically synthesized precursor-morpholino hybrids allows us to target translation of individual mitochondrial mRNAs. By applying this approach, we conclude that the bicistronic, overlapping ATP8/ATP6 transcript is translated through a single ribosome/mRNA engagement. We show that recruitment of COX1 assembly factors to translating ribosomes depends on nascent chain formation. By defining mRNA-specific interactomes for COX1 and COX2, we reveal an unexpected function of the cytosolic oncofetal IGF2BP1, an RNA-binding protein, in mitochondrial translation. Our data provide insight into mitochondrial translation and innovative strategies to investigate mitochondrial gene expression.


A specific neural substrate for perceiving facial expressions of disgust.
Recognition of facial expressions is critical to our appreciation of the social and physical environment, with separate emotions having distinct facial expressions. Perception of fearful facial expressions has been extensively studied, appearing to depend upon the amygdala. Disgust-literally 'bad taste'-is another important emotion, with a distinct evolutionary history, and is conveyed by a characteristic facial expression. We have used functional magnetic resonance imaging (fMRI) to examine the neural substrate for perceiving disgust expressions. Normal volunteers were presented with faces showing mild or strong disgust or fear. Cerebral activation in response to these stimuli was contrasted with that for neutral faces. Results for fear generally confirmed previous positron emission tomography findings of amygdala involvement. Both strong and mild expressions of disgust activated anterior insular cortex but not the amygdala; strong disgust also activated structures linked to a limbic cortico-striatal-thalamic circuit. The anterior insula is known to be involved in responses to offensive tastes. The neural response to facial expressions of disgust in others is thus closely related to appraisal of distasteful stimuli.


Sex differences in the use of asthma drugs: cross sectional study.
To assess the use of asthma drugs by men and women with asthma and to identify sex specific predictors for the use of oral steroids. Cross sectional study. Six general practices in East Anglia. 103 men and 134 women aged 20-54 with asthma. Self reported use of agonists, inhaled steroids, and oral steroids. No sex difference was found in use of agonists or inhaled steroids. However a strong association existed between sex and oral steroid use. 40 (30%) women reported using oral steroids compared with nine (9%) men. Women were more than five times (odds ratio=5.5, 95% confidence interval 2.2 to 13.7) more likely to report use of oral steroids than men after asthma symptoms, age, visits to the general practitioner in previous six months, and time since diagnosis of asthma were controlled for. Women who had visited the general practitioner for asthma one or more times in the previous six months were four times (3.9, 1.6 to 9.5) as likely to report use of oral steroids. In addition, more frequent visits to the general practitioner for asthma were related in a dose-response manner to a greater likelihood of using oral steroids among women after asthma symptoms, age, and time since diagnosis were controlled for. This relation was not observed among men. Women used oral steroids more than men. The more frequent consultations with a doctor by women may result in more requests for oral steroids or doctors may preferentially prescribe oral steroids to women.


Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease.
Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis.


Physiological Changes in Portulacaria afra (L.) Jacq. during a Summer Drought and Rewatering.
The changes of titratable acidity, enzyme activity, water status, and pigment composition were studied in Portulacaria afra (L.) Jacq. during a normal summer drought and rewatering. Two groups of plants were grown outside under a clear plastic canopy with water stress initiated at 2-week intervals in May 1986. Drought resulted in a linear decrease of fresh weight for 80 days and there was no further fresh weight change for the next 65 days. Nocturnal CO(2) uptake remained measurable for 83 days. Cessation of exogenous CO(2) uptake corresponded to the point where the pressure potential (Psi(p)) became zero. Ribulose-1, 5-bisphosphate (RuBP) and phosphoenolpyruvate carboxylase were reduced to 50% of this activity by the end of the drought period. Phosphoenolpyruvate carboxykinase activity was undetectable after 120 to 140 days of drought. Chlorophyll (Chl) levels decreased with a preferential loss of Chl a over Chl b. Carotenoid content was relatively constant over the course of the drought period. After 145 days of drought, plants responded to rewatering within 24 hours; Psi(p) became positive and daytime CO(2) uptake resumed after 24 hours. After 3 days, RuBP carboxylase activity reached control levels. Activity of the CAM pathway recovered after 5 days, as noted by increased diurnal acid fluctuations. Phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase activity fully recovered within 6 days. Chl levels were greater than control levels within 5 days. Chl a/b ratios took 27 days to return to control levels. The results indicated that P. afra can withstand a normal summer drought by utilizing the CAM and CAM-idling pathway for 130 to 140 days. The plants respond rapidly to rewatering because of the conservation of enzyme activity and the quick recovery of Psi(p).


Immunoproteomics: the key to discovery of new vaccine antigens against bacterial respiratory infections.
The increase in antibiotic resistance and the shortage of new antimicrobials to prevent difficult bacterial infections underlines the importance of prophylactic therapies to prevent infection by bacterial pathogens. Vaccination has reduced the incidence of many serious diseases, including respiratory bacterial infections. However, there are many pathogens for which no vaccine is available and some vaccines are not effective among all age groups or among immunocompromised individuals. Immunoproteomics is a powerful technique which has been used to identify potential vaccine candidates to protect against pathogenic bacteria. The combination of proteomics with the detection of immunoreactive antigens using serum highlights immunogenic proteins that are expressed during infection. This is particularly useful when patient serum is used as the antigens that promote a humoral response during human infection are identified. This review outlines examples of vaccine candidates that have been identified using immunoproteomics and have successfully protected animals against challenge when tested in immunisation studies. Many immunoreactive proteins are common to several unrelated pathogens, however some of these are not always protective in animal immunisation and challenge studies. Furthermore, examples of well-established immunogens, including Bordetella pertussis antigen FHA were not detected in immunoproteomics studies, indicating that this technology may underrepresent the immunoreactive proteins in a pathogen. Although only one step in the pathway towards an efficacious approved vaccine, immunoproteomics is an important technology in the identification of novel vaccine antigens.


Hesperidin protects against IL-1β-induced inflammation in human osteoarthritis chondrocytes.
Hesperidin is a vitamin P flavonoid compound primarily present in citrus fruits, which possesses an anti-inflammatory effect. The functional role of hesperidin in interleukin (IL)-1β-stimulated human osteoarthritis (OA) chondrocytes is still unknown. In the present study, anti-inflammatory effects of hesperidin in IL-1β-stimulated chondrocytes were investigated. The results demonstrated that hesperidin treatment markedly decreased nitric oxide and prostaglandin E2 production and markedly downregulated inducible nitric oxide synthase and cyclooxygenase-2 expression in IL-1β-stimulated OA chondrocytes. In addition, hesperidin markedly reduced IL-1β-induced matrix metalloproteinase (MMP)-3 and MMP-13 expression in human OA chondrocytes. Furthermore, hesperidin markedly decreased the activation of nuclear factor (NF)-κB in human OA chondrocytes. In conclusion, it was revealed for the first time that hesperidin inhibited inflammatory responses in IL-1β-stimulated human chondrocytes, potentially through inhibiting the activation of the NF-κB signaling pathway. These data suggest that hesperidin may be a potential agent for the treatment of OA.


The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.
Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM ), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.


Phrasal recognition.
In this paper, we introduce visual phrases, complex visual composites like "a person riding a horse." Visual phrases often display significantly reduced visual complexity compared to their component objects because the appearance of those objects can change profoundly when they participate in relations. We introduce a dataset suitable for phrasal recognition that uses familiar PASCAL object categories, and demonstrate significant experimental gains resulting from exploiting visual phrases. We show that a visual phrase detector significantly outperforms a baseline which detects component objects and reasons about relations, even though visual phrase training sets tend to be smaller than those for objects. We argue that any multiclass detection system must decode detector outputs to produce final results; this is usually done with nonmaximum suppression. We describe a novel decoding procedure that can account accurately for local context without solving difficult inference problems. We show this decoding procedure outperforms the state of the art. Finally, we show that decoding a combination of phrasal and object detectors produces real improvements in detector results.


A comparison between patients treated at a combat support hospital in Iraq and a Level I trauma center in the United States.
Combat support hospitals (CSHs) function under adverse operational conditions, delivering care to diverse patients. Appropriate allocation of resources and training are dependent on accurate assessments of the populations' needs. This study compared two patient populations treated between December 2004 and November 2005, one from a CSH in Iraq, the other at a civilian Level I trauma center. The trauma registry at Oregon Health & Science University was queried to evaluate all trauma patients admitted during the study period. The medical databases of the CSH were retrospectively reviewed. Coalition (Co) patients were US soldiers, their allies, and support staff. Noncoalition (Non-Co) patients were Iraqi Army, Iraqi National Guard, enemy forces, and Iraqi civilians. One thousand fifty-four patients were admitted to the CSH. Four hundred sixty-five of 696 (67%) Co patients versus 143 of 358 (40%) Non-Co patients had disease-related diagnoses (p < 0.01). The remaining 446 patients had traumatic diagnoses; 231 (52%) of these were Co patients. The incidence of battle injury was 59% in Co patients versus 90% in Non-Co patients (p < 0.01). One thousand three hundred thirty-nine trauma patients were admitted to Oregon Health & Science University. Civilian patients were older, less likely to be men, and had higher Injury Severity Scale scores than Co and Non-Co patients. Non-Co patients had higher Injury Severity Scale score, longer lengths of stay, and underwent 2.5 times as many operations as Co patients. Of the civilian patients, 93% were injured by blunt mechanisms compared with 20% of combat victims (p < 0.01). Percentages of abdominal, thoracic, and vascular procedures were similar between the three groups, but combat victims had more soft tissue procedures and dressing changes. There were no differences in mortality. Although CSHs and civilian trauma centers treat significantly different patient populations, the operations performed and outcomes are similar. Non-Co patients consumed 2.5 times more operative resources than did Co patients at the CSH.


Thrombospondin 1 in hypoxia-conditioned media blocks the growth of human microvascular endothelial cells and is increased in systemic sclerosis tissues.
Systemic sclerosis (SSc) is a chronic inflammatory autoimmune disease characterised by vascular dysfunction and damage, excess collagen deposition and subsequent organ manifestations. Vasculopathy is an early feature of the disease which leads to a chronic hypoxic environment in the tissues. Paradoxically, there is a lack of angiogenesis. We hypothesised that this may in part be due to a nonphysiological, overriding upregulation in antiangiogenic factors produced by the hypoxic tissues. We considered thrombospondin 1 (TSP-1) as a candidate antiangiogenic factor. Conditioned media from human microvascular endothelial cells cultured in both normoxic and hypoxic environments were able to block endothelial cell proliferation, with the latter environment having a more profound effect. Filtration to remove > 100-kDa proteins or heparin-binding proteins from the conditioned media eliminated their antiproliferative effect. TSP-1 was expressed in high concentrations in the hypoxic media, as was vascular endothelial growth factor (VEGF). Depletion of TSP-1 from the media by immunoprecipitation reduced the antiproliferative effect. We then show that, in a dose-dependent fashion, recombinant TSP-1 blocks the proliferation of endothelial cells. Immunohistochemistry of skin biopsy material revealed that TSP-1 expression was significantly higher throughout the skin of patients with SSc compared with healthy controls. Despite the environment of chronic tissue hypoxia in SSc, there is a paradoxical absence of angiogenesis. This is thought to be due in part to aberrant expression of antiangiogenic factors, including TSP-1. We have demonstrated that TSP-1 is released in high concentrations by hypoxic endothelial cells. The conditioned media from these cells is able to block proliferation and induce apoptosis in microvascular endothelial cells, an effect that is reduced when TSP-1 is immunoprecipitated out. Further, we have shown that recombinant TSP-1 is able to block proliferation and induce apoptosis at concentrations consistent with those found in the plasma of patients with SSc and that its effect occurs in the presence of elevated VEGF levels. Taken together, these data are consistent with a model wherein injured microvascular cells in SSc fail to repair because of dysregulated induction of TSP-1 in the hypoxic tissues.


Is There a Role for an 18F-fluorodeoxyglucose-derived Biological Boost in Squamous Cell Anal Cancer?
To investigate the potential role for a biological boost in anal cancer by assessing whether subvolumes of high 18F-fluorodeoxyglucose (FDG) avidity, identified at outset, are spatially consistent during a course of chemoradiotherapy (CRT). FDG-positron emission tomography (FDG-PET) scans from 21 patients enrolled into the ART study (NCT02145416) were retrospectively analysed. In total, 29 volumes including both primary tumours and involved nodes >2 cm were identified. FDG-PET scans were carried out before treatment and on day 8 or 9 of CRT. FDG subvolumes were created using a percentage of maximum FDG avidity at thresholds of 34%, 40%, 50%, on the pre-treatment scans, and 70% and 80% on the subsequent scans. Both FDG-PET scans were deformably registered to the planning computed tomography scan. The overlap fraction and the vector distance were calculated to assess spatial consistency. FDG subvolumes for further investigation had an overlap fraction >0.7, as this has been defined in previous publications as a 'good' correlation. The median overlap fractions between the diagnostic FDG-PET subvolumes 34%, 40% and 50% of maximum standardised uptake value (SUVmax) and subsequent FDG-PET subvolumes of 70% of SUVmax were 0.97, 0.92 and 0.81. The median overlap fraction between the diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 1.00, 1.00 and 0.92. The median (range) vector distance values between diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 0.74 mm (0.19-2.94) 0.74 mm (0.19-3.39) and 0.71 mm (0.2-3.29), respectively. Twenty of 29 volumes (69.0%) achieved a threshold > 0.7 between the FDG 50% subvolume on the diagnostic scan and the FDG 80% subvolume on the subsequent scan. FDG-avid subvolumes identified at baseline were spatially consistent during a course of CRT treatment. The subvolume of 50% of SUVmax on the pre-treatment scan could be considered as a potential target for dose escalation.


A distance-based block searching algorithm.
We present in this paper an algorithm for the multiple comparison of a set of protein sequences. Our approach is that of peptide matching and consists in looking for all the words that occur approximatively in at least q of the sequences in the set, where q is a parameter. Words are compared by using a reference object called a model, that is itself a word over the alphabet of the amino acids, and the comparison between a model and a word is based on w-length words instead of single symbols. This idea is similar to the one used in the Blast program in the case of pairwise comparisons. Two w-length words are considered to be related if an alignment without gaps of the two using a similarity matrix has a score greater than a certain threshold value t. In our case, we say that a k-length word u is an occurrence of a model m of the same length if every w-length subword of u is related to the corresponding subword of m in the sense given above. If a model m has occurrences in at least q of the sequences of the set, m is said to occur in the set. In percentage terms, the value of q may correspond to something as small as 5% of the sequences (search for recurrent words in a set of non homologous proteins) or as high as 70-100% (establishment of a list of all similar words as a first step in a multiple alignment program). The algorithm presented here is an efficient and exact way of looking for all the models, of a fixed length k or of the greatest possible length kmax, that occur in a set of sequences. It can work with any kind of scoring matrix and an extension of the algorithm allows for the introduction of gaps between a model and its occurrences.


Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.
Striated muscle-specific disruption of the dystroglycan (DAG1) gene results in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis. We find that satellite cells, expressing dystroglycan, support continued efficient regeneration of skeletal muscle along with transient expression of dystroglycan in regenerating muscle fibers. We demonstrate a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing. Thus, maintenance of regenerative capacity by satellite cells expressing dystroglycan is likely responsible for mild disease progression in mice and possibly humans. Therefore, inadequate repair of skeletal muscle by satellite cells represents an important mechanism affecting the pathogenesis of muscular dystrophy.


Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions employing dialkylbiaryl phosphine ligands.
The cores of many types of polymers, ligands, natural products, and pharmaceuticals contain biaryl or substituted aromatic structures, and efficient methods of synthesizing these structures are crucial to the work of a broad spectrum of organic chemists. Recently, Pd-catalyzed carbon-carbon bond-forming processes, particularly the Suzuki-Miyaura cross-coupling reaction (SMC), have risen in popularity for this purpose. The SMC has many advantages over other methods for constructing these moieties, including mild conditions, high tolerance toward functional groups, the commercial availability and stability of its reagents, and the ease of handling and separating byproducts from its reaction mixtures. Until 1998, most catalysts for the SMC employed triarylphosphine ligands. More recently, new bulky and electron-rich phosphine ligands, which can dramatically improve the efficiency and selectivity of such cross-coupling reactions, have been introduced. In the course of our studies on carbon-nitrogen bond-forming reactions, we found that the use of electron-rich and bulky phosphines enhanced the rate of both the oxidative addition and reductive elimination processes; this was the beginning of our development of a new family of ligands, the dialkylbiarylphosphines L1-L12. These ligands can be used for a wide variety of palladium-catalyzed carbon-carbon, carbon-nitrogen, and carbon-oxygen bond-forming processes as well as serving as supporting ligands for a number of other reactions. The enhanced reactivity of these catalysts has expanded the scope of cross-coupling partners that can be employed in the SMC. With use of such dialkylbiarylphosphine ligands, the coupling of unactivated aryl chlorides, aryl tosylates, heteroaryl systems, and very hindered substrate combinations have become routine. The utility of these ligands has been successfully demonstrated in a wide number of synthetic applications, including industrially relevant processes. In this Account, we provide an overview of the use and impact of dialkylbiarylphosphine ligands in the SMC. We discuss our studies on the mechanistic framework of the reaction, which have allowed us to rationally modify the ligand structures in order to tune their properties. We also describe selected applications in the synthesis of natural products and new materials to illustrate the utility of these dialkylbiarylphosphine ligands in various "real-world" synthetic applications.


Multidrug resistance in Salmonella enterica serotype Typhimurium from humans in France (1993 to 2003).
The aim of this study was to determine the distribution of the antimicrobial resistance phenotypes (R types), the phage types and XbaI-pulsed-field gel electrophoresis (PFGE) types, the genes coding for resistance to beta-lactams and to quinolones, and the class 1 integrons among a representative sample of Salmonella enterica serotype Typhimurium isolates collected from humans in 2002 through the French National Reference Center for Salmonella (NRC-Salm) network. The trends in the evolution of antimicrobial resistance of serotype Typhimurium were reviewed by using NRC-Salm data from 1993, 1997, 2000, and 2003. In 2002, 3,998 isolates of serotype Typhimurium were registered at the NRC-Salm among 11,775 serotyped S. enterica isolates (34%). The most common multiple antibiotic resistance pattern was resistance to amoxicillin, chloramphenicol, streptomycin and spectinomycin, sulfonamides, and tetracycline (ACSSpSuTe R type), with 156 isolates (48.8%). One isolate resistant to extended-spectrum cephalosporins due to the production of TEM-52 extended-spectrum beta-lactamase was detected (0.3%), and one multidrug-resistant isolate was highly resistant to ciprofloxacin (MIC > 32 mg/liter). We found that 57.2% of the isolates tested belonged to the DT104 clone. The main resistance pattern of DT104 isolates was R type ACSSpSuTe (83.2%). However, evolutionary changes have occurred within DT104, involving both loss (variants of Salmonella genomic island 1) and acquisition of genes for drug resistance to trimethoprim or to quinolones. PFGE profile X1 was the most prevalent (74.5%) among DT104 isolates, indicating the need to use a more discriminatory subtyping method for such isolates. Global data from the NRC-Salm suggested that DT104 was the main cause of multidrug resistance in serotype Typhimurium from humans from at least 1997 to 2003, with a roughly stable prevalence during this period.


Paraxial localized waves in free space.
Subluminal, luminal and superluminal localized wave solutions to the paraxial pulsed beam equation in free space are determined. A clarification is also made to recent work on pulsed beams of arbitrary speed which are solutions of a narrowband temporal spectrum version of the forward pulsed beam equation.


The happy personality: a meta-analysis of 137 personality traits and subjective well-being.
This meta-analysis used 9 literature search strategies to examine 137 distinct personality constructs as correlates of subjective well-being (SWB). Personality was found to be equally predictive of life satisfaction, happiness, and positive affect, but significantly less predictive of negative affect. The traits most closely associated with SWB were repressive-defensiveness, trust, emotional stability, locus of control-chance, desire for control, hardiness, positive affectivity, private collective self-esteem, and tension. When personality traits were grouped according to the Big Five factors, Neuroticism was the strongest predictor of life satisfaction, happiness, and negative affect. Positive affect was predicted equally well by Extraversion and Agreeableness. The relative importance of personality for predicting SWB, how personality might influence SWB, and limitations of the present review are discussed.


In vitro whole-blood analysis of cellular immunity in patients with active coccidioidomycosis by using the antigen preparation T27K.
Measurement of cellular immunity in human coccidioidomycosis has important diagnostic and prognostic implications. The coccidioidin skin test has been the standard for the measurement of this, but it is not available in the United States. We examined the utility of measuring surface expression of CD69 on T lymphocytes in whole blood incubated with the coccidioidal antigen preparation T27K as an alternative to the skin test. Seventy donors with active coccidioidomycosis were studied. The mean fluorescent intensity (MFI) of CD69 expression on CD3 lymphocytes in response to T27K was 28.61 +/- 1.77, significantly greater than the control response of 11.45 +/- 0.78 (P < 0.001). The MFI CD69 response to T27K above that for the control (MFI CD69 above control) was 6.35 +/- 2.18 for seven subjects with disseminated coccidioidomycosis who were studied within 5 months of diagnosis. This was significantly below the value of 20.17 +/- 3.17 for 18 subjects with pulmonary coccidioidomycosis studied within 5 months of diagnosis and the value of 19.58 +/- 2.91 for 27 subjects with disseminated coccidioidomycosis studied after 5 months of diagnosis (for both, P < 0.05). There was an inverse correlation between coccidioidal clinical score and MFI CD69 above control for all 34 subjects with disseminated coccidioidomycosis (r = 0.362; P = 0.036) but not for the 36 subjects with pulmonary disease (r < 0.001; P = 0.993). Among 30 subjects for whom data were available, there was a highly significant association between the MFI CD69 above control and the supernatant concentrations of gamma interferon, interleukin-2 (IL-2), and tumor necrosis factor alpha (for all, P < 0.001), but not for IL-4, IL-5, or IL-10. These data indicate that in vitro assessment of CD69 expression on T lymphocytes by using T27K may be a useful measure of cellular immune response among subjects with active coccidioidomycosis.


ICD-10-CM/PCS: transferring knowledge from ICD-9-CM.
The transition to ICD-10-CM/PCS has expanded educational opportunities for educators and trainers who are taking on the responsibility of training coders on the new system. Coding education currently faces multiple challenges in the areas of how to train the new workforce, what might be the most efficient method of providing that training, how much retraining of the current workforce with ICD-9-CM training will be required, and how to meet the national implementation deadline of 2014 in the most efficacious manner. This research sought to identify if there was a difference between a group of participants with no knowledge of ICD-9-CM and those with some knowledge of ICD-9-CM in scores on an ICD-10-CM/PCS quiz. Results indicate a difference, supporting the idea of knowledge transfer between the systems and providing additional insight into coding education.


Pharmacological characterization of mammalian D1 and D2 dopamine receptors expressed in Drosophila Schneider-2 cells.
Mammalian D1 and D2 dopamine receptors were stably expressed in Drosophila Schneider-2 (S2) cells and screened for their pharmacological properties. Saturable, dose-dependent, high affinity binding of the D1-selective antagonist [3H]SCH-23390 was detected only in membranes from S2 cells induced to express rat dopamine D1 receptors, while saturable, dose-dependent, high affinity binding of the D2-selective antagonist [3H]methylspiperone was detected only in membranes from S2 cells induced to express rat dopamine D2 receptors. No specific binding of either radioligand could be detected in membranes isolated from uninduced or untransfected S2 cells. Both dopamine D1 and D2 receptor subtypes displayed the appropriate stereoselective binding of enantiomers of the nonselective antagonist butaclamol. Each receptor subtype also displayed the appropriate agonist stereoselectivities. The dopamine D1 receptor bound the (+)-enantiomer of the D1-selective agonist SKF38393 with higher affinity than the (-)-enantiomer, while the dopamine D2 receptor bound the (-)-enantiomer of the D2-selective agonist norpropylapomorphine with higher affinity than the (+)-enantiomer. At both receptor subtypes, dopamine binding was best characterized as occurring to a single low affinity site. In addition, the low affinity dopamine binding was also found to be insensitive to GTPgammaS and magnesium ions. Overall, the pharmacological profiles of mammalian dopamine D1 and D2 receptors expressed in Drosophila S2 cells is comparable to those observed for these same receptors when they are expressed in mammalian cell lines. A notable distinction is that there is no evidence for the coupling of insect G proteins to mammalian dopamine receptors. These results suggest that the S2 cell insect G system may provide a convenient source of pharmacologically active mammalian D1 and D2 dopamine receptors free of promiscuous G protein contaminants.


Alone at last! New functions for Ca2+ channel beta subunits?
New functions for voltage-gated Ca(2+) channel auxiliary beta subunits have recently been identified. These functions appear to be regulated by the beta subunit alone, independently of any effects on the Ca(2+) influx; hence, the beta subunit may not be truly "auxiliary" and may play more fundamental roles in Ca(2+) homeostasis or gene regulation. These new findings raise important questions and open new, exciting research avenues.


Synthetic-aperture radar autofocus by maximizing sharpness.
To focus a synthetic-aperture radar image that is suffering from phase errors, a phase-error estimate is found that, when it is applied, maximizes the sharpness of the image. Closed-form expressions are derived for the gradients of a sharpness metric with respect to phase-error parameters, including both a point-by-point (nonparametric) phase function and coefficients of a polynomial expansion. Use of these expressions allows for a highly efficient gradient-search algorithm for high-order phase errors. The effectiveness of the algorithm is demonstrated with an example.


Tracheobronchial rupture: a considerable risk for young teenagers.
Tracheobronchial (TB) ruptures are ten times lower in children than in adults. Despite its rarity in the literature, we found that it is as common as in adults in our series. We investigated TB ruptures in childhood regarding age, trauma presentation, injury localization and treatment options. From 1994 through 2001, eight children (six male, two female) were admitted to our department with TB injury. All patients were healthy prior to trauma. The average and median ages were 9.8 and 11, respectively. All patients except one (iatrogenic) were suffering from blunt thoracic trauma. There were seven main bronchial (five right, two left) and one tracheal wounds. Six of the ruptures were circumferential. Urgent (n=6) and delayed (n=2) thoracotomies were performed; 'end-to-end' anastomosis (n=4), pneumonectomy (n=2) and 'primary suturing' (n=2) were applied. We had no mortality. Main bronchus rupture was overlooked in two patients as one of them had almost totally normal clinical appearance, and the other one had negative endoscopic findings. Both of these patients were successfully operated within 3 months. Our limited experience showed us that these kinds of injuries threaten school age population as well. False negative bronchoscopic results increase when additional injuries accompany. TB ruptures should be always taken into consideration after blunt chest trauma. Early or late repair of the lesion should be decided depending on the patient's clinical course.


Outcomes for implementation science: an enhanced systematic review of instruments using evidence-based rating criteria.
High-quality measurement is critical to advancing knowledge in any field. New fields, such as implementation science, are often beset with measurement gaps and poor quality instruments, a weakness that can be more easily addressed in light of systematic review findings. Although several reviews of quantitative instruments used in implementation science have been published, no studies have focused on instruments that measure implementation outcomes. Proctor and colleagues established a core set of implementation outcomes including: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, sustainability (Adm Policy Ment Health Ment Health Serv Res 36:24-34, 2009). The Society for Implementation Research Collaboration (SIRC) Instrument Review Project employed an enhanced systematic review methodology (Implement Sci 2: 2015) to identify quantitative instruments of implementation outcomes relevant to mental or behavioral health settings. Full details of the enhanced systematic review methodology are available (Implement Sci 2: 2015). To increase the feasibility of the review, and consistent with the scope of SIRC, only instruments that were applicable to mental or behavioral health were included. The review, synthesis, and evaluation included the following: (1) a search protocol for the literature review of constructs; (2) the literature review of instruments using Web of Science and PsycINFO; and (3) data extraction and instrument quality ratings to inform knowledge synthesis. Our evidence-based assessment rating criteria quantified fundamental psychometric properties as well as a crude measure of usability. Two independent raters applied the evidence-based assessment rating criteria to each instrument to generate a quality profile. We identified 104 instruments across eight constructs, with nearly half (n = 50) assessing acceptability and 19 identified for adoption, with all other implementation outcomes revealing fewer than 10 instruments. Only one instrument demonstrated at least minimal evidence for psychometric strength on all six of the evidence-based assessment criteria. The majority of instruments had no information regarding responsiveness or predictive validity. Implementation outcomes instrumentation is underdeveloped with respect to both the sheer number of available instruments and the psychometric quality of existing instruments. Until psychometric strength is established, the field will struggle to identify which implementation strategies work best, for which organizations, and under what conditions.


Feedback in the rabbit's central circadian system, revealed by the changes in its free-running food intake pattern induced by blinding, cervical sympathectomy, pinealectomy, and melatonin administration.
Long-term records of the number of food approaches per 30 min were obtained from 16 rabbits in constant light and after blinding. Optic nerve sectioning usually resulted in a shortening of the free-running period (tau; mean reduction = -0.26 hr) of the oscillator governing the rabbit's food intake pattern. Subsequent resection of both superior cervical ganglia always reduced this tau (mean = -0.41 hr), and it could be further shortened (mean = -0.24 hr) by chronic administration of melatonin. These observations led to experiments in which the food intake of 15 blinded rabbits was recorded before and after pinealectomy. This always resulted in a lengthening of tau (mean = +0.27 hr), which was never seen after subtotal or sham pinealectomy in 10 other blinded animals (mean = -0.05 hr). Sympathectomy also reduced tau (mean = -0.50 hr) in the pinealectomized rabbits, whereas it induced a smaller reduction (mean = -0.29 hr) after sham pinealectomy. These results, together with previous observations on the effect of sympathectomy on the retinal "dark" discharge and on the influence of the latter upon the food intake pattern, indicate that the cervical sympathetic nerves may form part of three feedback loops for the rabbit's central circadian system. These have separate postganglionic pathways; there are also differences in the circadian phasing of their activities and in their effects on tau.


Cellular requirements for building a retinal neuropil.
How synaptic neuropil is formed within the CNS is poorly understood. The retinal inner plexiform layer (IPL) is positioned between the cell bodies of amacrine cells (ACs) and retinal ganglion cells (RGCs). It consists of bipolar cell (BC) axon terminals that synapse on the dendrites of ACs and RGCs intermingled with projections from Müller glia (MG). We examined whether any of these cellular processes are specifically required for the formation of the IPL. Using genetic and pharmacological strategies, we eliminated RGCs, ACs, and MG individually or in combination. Even in the absence of all of these partner cells, an IPL-like neuropil consisting of only BC axon terminals still forms, complete with presynaptic specializations and sublaminar organization. Previous studies have shown that an IPL can form in the complete absence of BCs; therefore, we conclude that neither presynaptic nor postsynaptic processes are individually essential for the formation of this synaptic neuropil.