Small interfering RNA-mediated suppression of Ccl2 in Müller cells attenuates microglial recruitment and photoreceptor death following retinal degeneration.
The recruitment and activation of inflammatory cells is thought to exacerbate photoreceptor death in retinal degenerative conditions such as age-related macular degeneration (AMD). We investigated the role of Müller cell-derived chemokine (C-C motif) ligand (Ccl)2 expression on monocyte/microglia infiltration and photoreceptor death in light-mediated retinal degeneration, using targeted small interfering (si)RNA. Adult Sprague-Dawley rats were injected intravitreally with 1 μg of either Ccl2 siRNA or scrambled siRNA, and were then exposed to 1000 lux of light for a period of 24 hours. The mice were given an overdose of barbiturate, and the retinas harvested and evaluated for the effects of bright-light exposure. Ccl2 expression was assessed by quantitative PCR, immunohistochemistry, and in situ hybridization. Monocytes/microglia were counted on retinal cryostat sections immunolabeled with the markers ED1 and ionized calcium binding adaptor (IBA)1, and photoreceptor apoptosis was assessed using terminal dUTP nick end labeling. Intravitreal injection of Ccl2 siRNA significantly reduced the expression of Ccl2 following light damage to 29% compared with controls. In retinas injected with Ccl2 siRNA, in situ hybridization and immunohistochemistry on retinal cryostat sections showed a substantial decrease in Ccl2 within Müller cells. Cell counts showed significantly fewer ED1-positive and IBA1-positive cells in the retinal vasculature and outer nuclear layer of Ccl2 siRNA-injected retinas, compared with controls. Moreover, there was significantly less photoreceptor apoptosis in Ccl2 siRNA-injected retinas compared with controls. Our data indicate that Ccl2 expression by Müller cells promotes the infiltration of monocytes/microglia, thereby contributing to the neuroinflammatory response and photoreceptor death following retinal injury. Modulation of exaggerated chemokine responses using siRNA may have value in reducing inflammation-mediated cell death in retinal degenerative disease such as AMD.


Vascular response of the dogfish and sculpin to angiotensin II.
The mechanism by which angiotensin II (AII) exerts its pressor effect was examined in a saltwater teleost and elasmobranch. In vivo application of AII failed to elicit any changes in dogfish (Squalus acanthias) mesenteric microcirculatory blood flow, but the sculpin (Myoxocephalus octodecimspinosus) mesentery bed showed consistent reversible decreases in blood flow following AII application. Topical treatment with 0.5 mg phentolamine did not attenuate the AII response. In vitro addition of AII did not alter the mean resting tension of the dogfish celiac artery or intestinal vein, but significantly contracted the sculpin aorta. Addition of chromaffin tissue to the dogfish arterial muscle bath imparted significant vasoaction to AII when compared to saline. Both in vivo and in vitro experiments demonstrate the absence of functional AII vascular receptors in dogfish and their presence in the sculpin. Additional evidence for the mediation of AII vascular action in the dogfish by catecholamine release has been demonstrated.


The effect of bee propolis on recurrent aphthous stomatitis: a pilot study.
Recurrent aphthous stomatitis (RAS) is a common, painful, and ulcerative disorder of the oral cavity of unknown etiology. No cure exists and medications aim to reduce pain associated with ulcers through topical applications or reduce outbreak frequency with systemic medications, many having serious side effects. The purpose of this pilot study was to evaluate the potential of a product to reduce the number of outbreaks of RAS ulcers. Propolis is a bee product used in some cultures as treatment for mouth ulcers. In this randomized, double-blind, placebo-controlled study, patients were assigned to take 500 mg of propolis or a placebo capsule daily. Subjects reported a baseline ulcer frequency and were contacted biweekly to record recurrences. Data were analyzed to determine if subjects had a decrease of 50% in outbreak frequency. The data indicated a statistically significant reduction of outbreaks in the propolis group (Fisher's exact test, one sided, p = 0.04). Patients in the propolis group also self-reported a significant improvement in their quality of life (p = 0.03). This study has shown propolis to be effective in decreasing the number of recurrences and improve the quality of life in patients who suffer from RAS. Propolis should be evaluated further in a larger sample clinical trial.


Immunization against Schistosoma mansoni in rhesus monkeys and the requirement of activation of both cell-mediated and humoral mechanisms.
When groups of rhesus monkeys were pretreated with BCG plus hyperimmune serum from monkeys with chronic schistosomiasis or with dialyzable transfer factor from uninfected monkeys plus hyperimmune serum and were challenged with 1,500 cercariae of Schistosoma mansoni, the mean worm burdens were significantly lower than that of untreated controls. Pretreatment with neither BCG alone nor Corynebacterium parvum plus a membrane antigen of adult worms of S. mansoni affected susceptibility. Neither lymphocyte proliferation in the presence of mitogens or schistosome antigen nor serological responsiveness (as measured by gel diffusion, Cercarienhüllenreaktion, circumoval precipitation, or enzyme-linked immunoabsorbent assay) correlated with the degree of resistance of the animals to S. mansoni. The pretreatment procedures used did not cause any abnormal histopathological responses and did not alter the characteristic host response to schistosome eggs in the lungs, liver, mesenteric lymph nodes, and colon.


The nuclear envelope can control gene expression and cell cycle progression via miRNA regulation.
The nuclear envelope can regulate gene expression through its interaction with chromatin and by the sequestration of specific transcription factors. In this study, we show that such regulation can be achieved via microRNA regulation. We identify a set of miRNAs that are dysregulated in the absence of a fully functional nuclear lamina. We then focus on miRNA-31 and experimentally confirm its targets. The target set identified is significantly enriched in genes involved in controlling progress through the cell cycle such as Cdkn2a. Normalizing miRNA-31 levels, either using a specific inhibitor or by restoration of the nuclear lamina, also normalizes cell cycle distribution and cell proliferation rates. We show that the 3'UtR of p16(Ink4a)/p19(Arf) has a functional miRNA-31 binding site which contributes to the observed regulation of cell cycle progression. Our findings are the first demonstration that the nuclear envelope can control gene expression by regulating specific miRNA levels, and that miRNA-31 is involved in the regulation of cell proliferation and progress through the cell cycle at least in part by regulating the levels of p16(Ink4a)/p19(Arf).


The temporal dynamics of cognitive reactivity and their association with the depression risk: an exploratory study.
Cognitive reactivity is the change in depressive thinking in response to negative mood. Previous research indicates that cognitive reactivity is an important variable in the etiology and course of depression. The present study tested which time interval after a negative mood induction is critical for the prediction of the depression risk. Participants suffering from a major depressive disorder were recruited when entering inpatient treatment. At the end of inpatient treatment they completed an experimental procedure to assess their depressive thinking once before and twice after a negative mood induction. Subsequently, patients were followed up for 26 weeks. The immediate change in depressive thinking in response to the negative mood induction was negatively associated with future depression. The delayed change did not predict the depression risk. The negative association between the immediate change in depressive thinking and the depression risk is not in line with results from previous studies on cognitive reactivity. Previous research on emotion context insensitivity and the avoidance of negative thoughts offers hypotheses which could account for this result. Further research is needed to shed light on the processes underlying cognitive reactivity.


Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal.
A cannabinoid antagonist, SR 141716A, dose dependently precipitated a behavioral withdrawal syndrome in rats continuously infused i.p. for only 4 days with relatively low-dose regimens of delta 9-tetrahydrocannabinol. The following dose regimens, expressed as mg/kg/24 hr, were used for days 1 through 4: high-12.5, 25, 50 and 100; medium-2.5, 5, 10 and 20; and low-0.5, 1, 2 and 4. The major withdrawal signs of the syndrome were scratching, rubbing face with paws, licking, wetdog shakes, arched back and ptosis (at least 50% closure of eyelids). At the highest dose regimen, other signs noted in fewer subjects were biting, tongue rolling, retropulsion, head shakes, extended limbs or high stepping, ataxia, myoclonic spasms and front paw treading. During abrupt withdrawal (delta 9 tetrahydrocannabinol was discontinued and vehicle substituted) abstinence signs were also noted; however, except during a 48-hr observation period, withdrawal was not sufficiently robust to achieve statistical significance. The results of this study provide evidence that a modest course of delta 9-tetrahydrocannabinol can produce physical dependence. Hence, the risk and incidence of marijuana dependence in humans may be greater than previously projected.


Biomechanics of brain edema in acute cerebral ischemia in cats.
We studied whether the biomechanical properties of brain play an important role in the development of early ischemic brain edema in cats with middle cerebral artery occlusion. Brain tissue pressure, tissue compliance, and tissue resistance were measured from the gray matter in the core and the periphery of the middle cerebral artery territory for 6 hours after occlusion. Regional cerebral blood flow and water content were also measured from the same areas. Ventricular fluid pressure was recorded. Tissue pressure rose gradually in the core, where flow was 6 ml/100 g/min, over 4 hours and then stabilized. The pressure gradient measured between edematous tissue and ventricular fluid was 5.3 mm Hg. Tissue resistance increased 1 hour after occlusion when water content increased to 10 mg/g. Later, when water content increased by 40 mg/g, tissue resistance decreased and tissue compliance increased significantly. In the periphery, where flow was 17.6 ml/100 g/min, tissue pressure rose slightly while tissue compliance and tissue resistance did not change within 6 hours. Our data indicate that as ischemic injury progresses, edema fluid accumulates in highly compliant brain parenchyma, then migrates through highly conductive tissue into the cerebrospinal fluid spaces, driven by the hydrostatic pressure gradient between the edematous tissue and the cerebrospinal fluid.


Measuring coral calcification under ocean acidification: methodological considerations for the 45Ca-uptake and total alkalinity anomaly technique.
As the oceans become less alkaline due to rising CO2 levels, deleterious consequences are expected for calcifying corals. Predicting how coral calcification will be affected by on-going ocean acidification (OA) requires an accurate assessment of CaCO3 deposition and an understanding of the relative importance that decreasing calcification and/or increasing dissolution play for the overall calcification budget of individual corals. Here, we assessed the compatibility of the 45Ca-uptake and total alkalinity (TA) anomaly techniques as measures of gross and net calcification (GC, NC), respectively, to determine coral calcification at pHT 8.1 and 7.5. Considering the differing buffering capacity of seawater at both pH values, we were also interested in how strongly coral calcification alters the seawater carbonate chemistry under prolonged incubation in sealed chambers, potentially interfering with physiological functioning. Our data indicate that NC estimates by TA are erroneously ∼5% and ∼21% higher than GC estimates from 45Ca for ambient and reduced pH, respectively. Considering also previous data, we show that the consistent discrepancy between both techniques across studies is not constant, but largely depends on the absolute value of CaCO3 deposition. Deriving rates of coral dissolution from the difference between NC and GC was not possible and we advocate a more direct approach for the future by simultaneously measuring skeletal calcium influx and efflux. Substantial changes in carbonate system parameters for incubation times beyond two hours in our experiment demonstrate the necessity to test and optimize experimental incubation setups when measuring coral calcification in closed systems, especially under OA conditions.


The change in ratio of convex and concave lung volume in adolescent idiopathic scoliosis: a 3D CT scan based cross sectional study of effect of severity of curve on convex and concave lung volumes in 99 cases.
To study the effect of the degree of scoliosis, degree of hypokyphosis/lordosis and rotation of apical vertebra on individual lung volume (measured with CT scan) in asymptomatic adolescent idiopathic scoliosis (AIS) patients. Individual (right and left) lung volume, angle of kyphosis and rotation of apical vertebra, were measured in 77 asymptomatic AIS patients having right thoracic curve, using modern computed tomography (CT) scan. To compare, lung volumes were measured in 22 normal persons (control group). The ratio of "right to left lung volume (convex to concave side)" was obtained and compared among these groups. With increased Cobb's angle, ratio of convex to concave lung volume increased. For Cobb's angle more than 40 degrees, it was increased significantly (P = 0.0042). A significant degree of correlation was found between axial rotation angle of apical vertebra and right to left lung volume ratio (P = 0.0067, r = 0.271). A significant inverse correlation was found between the angle of kyphosis and right to left lung volume ratio, i.e., as the angle of kyphosis decreased the convex to concave lung volume ratio increased (P = 0.0109, r = -0.255). In asymptomatic, AIS patients, with increase in degree of curvature, and rotation of apical vertebra, the ratio of convex to concave side lung volume increases; indicating concave side lung volume is comparatively more affected (decreased) than convex side lung volume. On the other hand with decrease in the angle of kyphosis the convex to concave lung volume ratio increases indicating kyphotic angle has an inverse relation to convex to concave lung volume ratio.


Psychotic-like experiences in the general community: the correlates of CIDI psychosis screen items in an Australian sample.
Apart from individuals with clinical psychosis, community surveys have shown that many otherwise well individuals endorse items designed to identify psychosis. The aim of this study was to characterize the demographic correlates of individuals who endorse psychosis screening items in a large general community sample. The National Survey of Mental Health and Wellbeing interviewed 10641 individuals living in private dwellings in Australia. As part of a diagnostic interview (the CIDI), respondents were asked between three and six items originally designed to screen for potential psychosis. We examined the impact of selected demographic variables on endorsement of these items including sex, age, marital status, migrant status, urban/rural status, employment, education, and socio-economic status. An estimated 11.7% of the Australian population endorsed at least one psychosis-screening item. Significantly higher endorsement was associated with younger age, migrants from non-English-speaking backgrounds, those who had never married or who were divorced/separated or unemployed, those living in urban regions and those from the lowest socio-economic levels. Many of the correlates of endorsement of psychosis-screen items are also associated with psychosis. Unravelling the factors that contribute to this broader non-clinical phenotype will aid our understanding of psychosis.


Do the Adaptations of Venice and Miami to Sea Level Rise Offer Lessons for Other Vulnerable Coastal Cities?
Both Venice and Miami are high-density coastal cities that are extremely vulnerable to rising sea levels and climate change. Aside from their sea-level location, they are both characterized by large populations, valuable infrastructure and real estate, and economic dependence on tourism, as well as the availability of advanced scientific data and technological expertize. Yet their responses have been quite different. We examine the biophysical environments of the two cities, as well as their socio-economic features, administrative arrangements vulnerabilities, and responses to sea level rise and flooding. Our study uses a qualitative approach to illustrate how adaptation policies have emerged in these two coastal cities. Based on this information, we critically compare the different adaptive responses of Venice and Miami and suggest what each city may learn from the other, as well as offer lessons for other vulnerable coastal cities. In the two cases presented here it would seem that adaptation to SLR has not yet led to a reformulation of the problem or a structural transformation of the relevant institutions. Decision-makers must address the complex issue of rising seas with a combination of scientific knowledge, socio-economic expertize, and good governance. In this regard, the "hi-tech" approach of Venice has generated problems of its own (as did the flood control projects in South Florida over half a century ago), while the increasing public mobilization in Miami appears more promising. The importance of continued long-term adaptation measures is essential in both cities.


Elevated JNK activation contributes to the pathogenesis of human brain tumors.
The ERK pathway is typically associated with activation of the EGF receptor and has been shown to play a major role in promoting several tumor phenotypes. An analogous signaling module, the JNK pathway, has not been shown to be consistently activated by the EGF receptor but is instead more uniformly stimulated by cellular stresses and cytokines. The function of the JNK pathway in primary tumors is unclear as it has been implicated in both promoting apoptosis and cell growth in vitro, which may be a reflection of the cell lines chosen. Primary human brain tumors frequently show overexpression of the EGF receptor. To clarify the role of JNK in tumorigenesis, we have investigated the role of JNK in a large panel of primary human brain tumors and tumor derived cell lines. Here we present evidence that JNK has a major role in promoting tumorigenesis both in vivo and in vitro. Western blot analysis demonstrated that 86% (18 of 21) of primary brain tumors showed evidence of JNK activation but only 38% (8 of 21) showed evidence of ERK activation. Kinase assays revealed that 77% of brain tumor cell lines activated JNK in response to EGF (7 of 13) or had high levels of basal activity (3 of 13), whereas none of six normal cell lines analysed, including astrocytes, had these properties. Of several growth factors examined, EGF produced the highest level of JNK induction in tumor cell lines and the duration of activation was greater than that seen for ERK. Expression of a dominant-negative (dn) form of JNK potently inhibited EGF mediated anchorage independent growth and protection from cell death in two glial tumor cell lines. These findings demonstrate that enhanced JNK activation is frequently found in primary brain tumors and that this activation contributes to phenotypes related to transformation.


High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors.
Collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis, is induced in DBA/1 (H-2q) mice following immunization with type II collagen (CII) in CFA. Since we have previously shown that IFN-gamma exerts a biphasic effect during the evolution of CIA in DBA/1 mice, we analyzed the development of this disease in mice with a disruption of the IFN-gamma receptor gene (IFN-gammaR(0/0)). Mutant mice were interbred with the DBA/1 strain to yield IFN-gammaR(0/0) mice expressing the H-2q haplotype. In three consecutive experiments, IFN-gammaR(0/0) male mice were found to exhibit severe clinical and histologic arthritis with an average incidence of 88.5 vs 94.1% for the wild DBA/1 strain. Notably, onset of clinical symptoms occurred significantly earlier than in DBA/1 mice. Although of a lower magnitude than in males, CIA also developed early in IFN-gammaR(0/0) female mice and with higher clinical severity than in control DBA/1 females. Immunization of knockout mice with CII resulted in the generation of CII-specific T cells belonging to the Th1 phenotype that recognize the same immunodominant peptides as do DBA/1 mice. CIA in IFN-gammaR(0/0) mice was associated with a down-regulation of the CII-specific IgG response, and this impairment was essentially due to a strong reduction of Abs of the IgG2a isotype. Taken together, our findings provide evidence that IFN-gammaR deficiency in DBA/1 mice leads to the occurrence of severe CIA with an accelerated onset compared with that in wild-type mice, indicating that the proinflammatory action of IFN-gamma has been bypassed in the IFN-gammaR(0/0) mice.


Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route.
In this study, curcumin loaded chitin nanogels (CCNGs) were developed using biocompatible and biodegradable chitin with an anticancer curcumin drug. Chitin, as well as curcumin, is insoluble in water. However, the developed CCNGs form a very good and stable dispersion in water. The CCNGs were analyzed by DLS, SEM and FTIR and showed spherical particles in a size range of 70-80 nm. The CCNGs showed higher release at acidic pH compared to neutral pH. The cytotoxicity of the nanogels were analyzed on human dermal fibroblast cells (HDF) and A375 (human melanoma) cell lines and the results show that CCNGs have specific toxicity on melanoma in a concentration range of 0.1-1.0 mg mL(-1), but less toxicity towards HDF cells. The confocal analysis confirmed the uptake of CCNGs by A375. The apoptotic effect of CCNGs was analyzed by a flow-cytometric assay and the results indicate that CCNGs at the higher concentration of the cytotoxic range showed comparable apoptosis as the control curcumin, in which there was negligible apoptosis induced by the control chitin nanogels. The CCNGs showed a 4-fold increase in steady state transdermal flux of curcumin as compared to that of control curcumin solution. The histopathology studies of the porcine skin samples treated with the prepared materials showed loosening of the horny layer of the epidermis, facilitating penetration with no observed signs of inflammation. These results suggest that the formulated CCNGs offer specific advantage for the treatment of melanoma, the most common and serious type of skin cancer, by effective transdermal penetration.


Is Seeing Believing? Perceptions of Wildfire Risk Over Time.
Ongoing challenges to understanding how hazard exposure and disaster experiences influence perceived risk lead us to ask: Is seeing believing? We approach risk perception by attending to two components of overall risk perception: perceived probability of an event occurring and perceived consequences if an event occurs. Using a two-period longitudinal data set collected from a survey of homeowners living in a fire-prone area of Colorado, we find that study participants' initial high levels of perceived probability and consequences of a wildfire did not change substantially after extreme wildfire events in the intervening years. More specifically, perceived probability of a wildfire changed very little, whereas the perceived consequences of a wildfire went up a bit. In addition, models of risk perceptions show that the two components of overall risk perception are correlated with somewhat different factors, and experience is not found to be one of the strongest correlates with perceived risk. These results reflect the importance of distinguishing the components of overall risk and modeling them separately to facilitate additional insights into the complexities of risk perceptions, factors related to perceived risk, and change in risk perceptions over time.


The impact of gender, puberty, and pregnancy in patients with POLG disease.
To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.


Differential effects of atrial natriuretic peptide and dopamine on urinary protein excretion in chronic glomerulonephritis.
1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.


Full-length sequence of an ethiopian human immunodeficiency virus type 1 (HIV-1) isolate of genetic subtype C.
Genetic subtype C of the human immunodeficiency virus type-1 (HIV-1) has established foci of infection in India and in at least eight African countries, and is expected to contribute significantly to the global pandemic. Here we report the first almost full-length sequence of a subtype C HIV-1 from Ethiopia. Clone C2220, 9031 nt in length, was derived by long PCR amplification of proviral DNA from virus cultured on primary peripheral blood mononuclear cells, and contains all but 74 nt of the unique sequence information of the HIV-1 genome. This clone resembles HIV-1 isolates of subtypes A, B, and D in its genome organization with one notable exception: the core promoter contains not two, but three potential binding sites for the transcription factor NF-kB. The extra NF-kB site was found in all other Ethiopian strains analyzed, as well as in subtype C viruses from Zambia, suggesting it is typical for the C-subtype of HIV-1. The phylogenetic relationship of C2220 to other HIV-1 isolates is also presented. Subtype C viruses circulating in Ethiopia exhibit the low interisolate diversity typical of other, newly established HIV-1 epidemics, and C2220 is both representative of Ethiopian subtype C viruses and a suitable prototype for the development of vaccines against HIV-1 subtype C.


Complications, Risk Factors, and Staffing Patterns for Noncardiac Surgery in Patients with Left Ventricular Assist Devices.
Patients with left ventricular assist devices presenting for noncardiac surgery are increasingly commonplace; however, little is known about their outcomes. Accordingly, the authors sought to determine the frequency of complications, risk factors, and staffing patterns. The authors performed a retrospective study at their academic tertiary care center, investigating all adult left ventricular assist device patients undergoing noncardiac surgery from 2006 to 2015. The authors described perioperative profiles of noncardiac surgery cases, including patient, left ventricular assist device, surgical case, and anesthetic characteristics, as well as staffing by cardiac/noncardiac anesthesiologists. Through univariate and multivariable analyses, the authors studied acute kidney injury as a primary outcome; secondary outcomes included elevated serum lactate dehydrogenase suggestive of left ventricular assist device thrombosis, intraoperative bleeding complication, and intraoperative hypotension. The authors additionally studied major perioperative complications and mortality. Two hundred and forty-six patients underwent 702 procedures. Of 607 index cases, 110 (18%) experienced postoperative acute kidney injury, and 16 (2.6%) had elevated lactate dehydrogenase. Of cases with complete blood pressure data, 176 (27%) experienced intraoperative hypotension. Bleeding complications occurred in 45 cases (6.4%). Thirteen (5.3%) patients died within 30 days of surgery. Independent risk factors associated with acute kidney injury included major surgical procedures (adjusted odds ratio, 4.4; 95% CI, 1.1 to 17.3; P = 0.03) and cases prompting invasive arterial line monitoring (adjusted odds ratio, 3.6; 95% CI, 1.3 to 10.3; P = 0.02) or preoperative fresh frozen plasma transfusion (adjusted odds ratio, 1.7; 95% CI, 1.1 to 2.8; P = 0.02). Intraoperative hypotension and acute kidney injury were the most common complications in left ventricular assist device patients presenting for noncardiac surgery; perioperative management remains a challenge.


A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of an Adjuvanted HIV-1 Gag-Pol-Nef Fusion Protein and Adenovirus 35 Gag-RT-Int-Nef Vaccine in Healthy HIV-Uninfected African Adults.
Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses. In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured. The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration. Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses. ClinicalTrials.gov NCT01264445.


Triplex-mediated analysis of cytosine methylation at CpA sites in DNA.
Modified triplex-forming oligonucleotides distinguish 5-methyl cytosine from unmethylated cytosine in DNA duplexes by differences in triplex melting temperatures. The discrimination is sequence-specific; dramatic differences in stabilisation are seen for CpA methylation, whereas CpG methylation is not detected. This direct detection of DNA methylation constitutes a new approach for epigenetic analysis.


Your resting brain CAREs about your risky behavior.
Research on the neural correlates of risk-related behaviors and personality traits has provided insight into mechanisms underlying both normal and pathological decision-making. Task-based neuroimaging studies implicate a distributed network of brain regions in risky decision-making. What remains to be understood are the interactions between these regions and their relation to individual differences in personality variables associated with real-world risk-taking. We employed resting state functional magnetic resonance imaging (R-fMRI) and resting state functional connectivity (RSFC) methods to investigate differences in the brain's intrinsic functional architecture associated with beliefs about the consequences of risky behavior. We obtained an individual measure of expected benefit from engaging in risky behavior, indicating a risk seeking or risk-averse personality, for each of 21 participants from whom we also collected a series of R-fMRI scans. The expected benefit scores were entered in statistical models assessing the RSFC of brain regions consistently implicated in both the evaluation of risk and reward, and cognitive control (i.e., orbitofrontal cortex, nucleus accumbens, lateral prefrontal cortex, dorsal anterior cingulate). We specifically focused on significant brain-behavior relationships that were stable across R-fMRI scans collected one year apart. Two stable expected benefit-RSFC relationships were observed: decreased expected benefit (increased risk-aversion) was associated with 1) stronger positive functional connectivity between right inferior frontal gyrus (IFG) and right insula, and 2) weaker negative functional connectivity between left nucleus accumbens and right parieto-occipital cortex. Task-based activation in the IFG and insula has been associated with risk-aversion, while activation in the nucleus accumbens and parietal cortex has been associated with both risk seeking and risk-averse tendencies. Our results suggest that individual differences in attitudes toward risk-taking are reflected in the brain's functional architecture and may have implications for engaging in real-world risky behaviors.


Low-level methylmercury exposure as a risk factor for neurologic abnormalities in adults.
Methylmercury is a neurotoxicant that bio-accumulates in the aquatic food chain and is present in all fish. Little is known about the effects of long-term low-dose exposure to methylmercury in adults. The aim of this study was to determine whether a dose-response relationship exists between long-term methylmercury exposure and neurological abnormalities in aboriginal Quebec Cree adults for whom fish is a dietary staple. We re-analysed data from a 1977 cross-sectional study conducted by Kofman and collaborators on a group of Quebec Cree individuals claiming ill health from local fish consumption. In the original 1977 study, 306 adult participants aged 18-82 years were assessed for methylmercury exposure. Tremor and other neurologic outcomes were assessed with a clinical examination. The investigators did not find clinical evidence of methylmercury intoxication based on an analysis of covariance. We used ordinal regression to obtain odds ratios for the relationship between total hair mercury levels and neurologic abnormalities. Hair mercury concentrations ranged from 0.5 to 46 ppm (parts per million). A 6 ppm increase in hair mercury was associated with increasing levels of tremor (OR, 2.22; 95% CI, 1.15-4.26) in adults under 40 years of age. There was no association with nine other outcomes considered, nor with tremor among older persons. Odds ratios were not influenced by gender, smoking, alcohol use, or co-morbidity. : Dose-dependent effects of methylmercury on tremor may occur below the commonly accepted 50 ppm threshold, particularly in young adults. These effects may be detectable by clinical examination. However, the results should be interpreted with caution given that alcohol use was probably under-reported and that multiple outcomes were studied.


Clay illuviation provides a long-term sink for C sequestration in subsoils.
Soil plays a key role in the global carbon (C) cycle. Most current assessments of SOC stocks and the guidelines given by Intergovernmental Panel on Climate Change (IPCC) focus on the top 30 cm of soil. Our research shows that, when considering only total quantities, most of the SOC stocks are found in this top layer. However, not all forms of SOC are equally valuable as long-term stable stores of carbon: the majority of SOC is available for mineralisation and can potentially be re-emitted to the atmosphere. SOC associated with micro-aggregates and silt plus clay fractions is more stable and therefore represents a long-term carbon store. Our research shows that most of this stable carbon is located at depths below 30 cm (42% of subsoil SOC is located in microaggregates and silt and clay, compared to 16% in the topsoil), specifically in soils that are subject to clay illuviation. This has implications for land management decisions in temperate grassland regions, defining the trade-offs between primary productivity and C emissions in clay-illuviated soils, as a result of drainage. Therefore, climate smart land management should consider the balance between SOC stabilisation in topsoils for productivity versus sequestration in subsoils for climate mitigation.


Convexity Shape Prior for Binary Segmentation.
Convexity is a known important cue in human vision. We propose shape convexity as a new high-order regularization constraint for binary image segmentation. In the context of discrete optimization, object convexity is represented as a sum of three-clique potentials penalizing any 1- 0- 1 configuration on all straight lines. We show that these non-submodular potentials can be efficiently optimized using an iterative trust region approach. At each iteration the energy is linearly approximated and globally optimized within a small trust region around the current solution. While the quadratic number of all three-cliques is prohibitively high, we design a dynamic programming technique for evaluating and approximating these cliques in linear time. We also derive a second order approximation model that is more accurate but computationally intensive. We discuss limitations of our local optimization and propose gradual non-submodularization scheme that alleviates some limitations. Our experiments demonstrate general usefulness of the proposed convexity shape prior on synthetic and real image segmentation examples. Unlike standard second-order length regularization, our convexity prior does not have shrinking bias, and is robust to changes in scale and parameter selection.


Characterizing the soil microbiome and quantifying antibiotic resistance gene dynamics in agricultural soil following swine CAFO manure application.
As agriculture industrializes, concentrated animal feeding operations (CAFOs) are becoming more common. Feces from CAFOs is often used as fertilizer on fields. However, little is known about the effects manure has on the soil microbiome, which is an important aspect of soil health and fertility. In addition, due to the subtherapeutic levels of antibiotics necessary to keep the animals healthy, CAFO manure has elevated levels of antibiotic resistant bacteria. Using 16s rRNA high-throughput sequencing and qPCR, this study sought to determine the impact of swine CAFO manure application on both the soil microbiome and abundance of select antibiotic resistance genes (ARGs) and mobile element genes (erm(B), erm(C), sul1, str(B), intI1, IncW repA) in agricultural soil over the fall and spring seasons. We found the manure community to be distinct from the soil community, with a majority of bacteria belonging to Bacteroidetes and Firmicutes. The soil samples had more diverse communities dominated by Acidobacteria, Actinobacteria, Proteobacteria, Verrucomicrobia, and unclassified bacteria. We observed significant differences in the soil microbiome between all time points, except between the spring samples. However, by tracking manure associated taxa, we found the addition of the manure microbiome to be a minor driver of the shift. Of the measured genes, manure application only significantly increased the abundance of erm(B) and erm(C) which remained elevated in the spring. These results suggest bacteria in the manure do not survive well in soil and that ARG dynamics in soil following manure application vary by resistance gene.


Cost-effectiveness of routine childhood vaccination for hepatitis A in the United States.
Economic analysis is an important component in formulating national policy. We evaluated the economic impact of hepatitis A vaccination of all US children ages 12 to 23 months as compared with no vaccination and with current implementation of the preexisting (issued in 1999), regional policy. We developed a Markov model of hepatitis A that followed a single cohort from birth in 2005 through death or age 95 years. From the societal perspective, the model compared the outcomes that resulted from routine vaccination at age 1 year to 2 scenarios: no hepatitis A vaccination and hepatitis A vaccination at levels observed in 2003 under the preexisting policy. We evaluated the economic impact of vaccination nationwide, in areas where vaccination was already recommended, and in areas where no previous recommendation existed. Without childhood vaccination, the approximately 4 million children in the 2005 birth cohort would be expected over their lifetimes to have 199,000 hepatitis A virus infections, including 74,000 cases of acute hepatitis A and 82 deaths, resulting in 134 million dollars in hepatitis A-related medical costs and productivity losses. Compared with no vaccination, routine vaccination at age 1 year would prevent 172,000 infections, at a cost of 28,000 dollars per quality-adjusted life year saved. Compared with maintaining the levels of hepatitis A vaccination under the preexisting regional policy, routine vaccination at age 1 year would prevent an additional 112,000 infections, at a cost of 45,000 dollars per quality-adjusted life year saved. The cost-effectiveness of nationwide hepatitis A vaccination compared with no vaccination, and the incremental cost-effectiveness of this recommendation compared with preexisting recommendations, is similar to that of other accepted public health interventions. In October 2005, the Advisory Committee on Immunization Practices recommended extending hepatitis A immunization to all US children ages 12 to 23 months.


Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection.
Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor-driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12-induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.


Toward a taxonomy of attention shifting: individual differences in fMRI during multiple shift types.
Although task switching is often considered one of the fundamental abilities underlying executive functioning and general intelligence, there is little evidence that switching is a unitary construct and little evidence regarding the relationship between brain activity and switching performance. We examined individual differences in multiple types of attention shifting in order to determine whether behavioral performance and fMRI activity are correlated across different types of shifting. The participants (n = 39) switched between objects and attributes both when stimuli were perceptually available (external) and when stimuli were stored in memory (internal). We found that there were more switch-related activations in many regions associated with executive control--including the dorsolateral and medial prefrontal and parietal cortices--when behavioral switch costs were higher (poor performance). Conversely, activation in the ventromedial prefrontal cortex (VMPFC) and the rostral anterior cingulate was consistently correlated with good performance, suggesting a general role for these areas in efficient attention shifting. We discuss these findings in terms of a model of cognitive-emotional interaction in attention shifting, in which reward-related signals in the VMPFC guide efficient selection of tasks in the lateral prefrontal and parietal cortices.


Highly efficient 750 W tapered double-clad ytterbium fiber laser.
The results of theoretical and experimental studies of active tapered double-clad fibers, intending the optimization of its imperative parameters--tapering ratio, longitudinal profile, core/cladding diameters ratio, are presented. Using a refined taper geometry we have demonstrated power scaling of a ytterbium fiber laser pumped by low-brightness, cost-effective laser diodes up to 750 W, with 80% efficiency.


Cognitive dysfunction and medical morbidity in elderly outpatients with bipolar disorder.
The authors investigated the differences in cognitive function, medical burden, and sociodemographic characteristics between elderly community-dwelling bipolar patients and age-matched and education-matched normal individuals. Case-control study. Taipei Medical University Hospital, with 75 psychiatric beds, and Taipei City Psychiatric Center-a 612-bed psychiatric teaching hospital providing comprehensive psychiatric services. Eighty-two euthymic outpatients with bipolar I disorder aged older than 60 years received assessment for research purpose, 59 of whom were matched with one normal control for age and years of education. All subjects had measurements of cognitive function (Clock-drawing test and Mini-Mental State Examination [MMSE]). Medical morbidity and health condition were according to the medical records, results of free annual elderly health examination, and physical examination on research interviewing. Elderly bipolar patients were found to be more likely than the comparison group to have diabetes mellitus (27.1%), atopic diseases (20.3%), abnormal education-adjusted MMSE scores (32.2%), smoking habit (23.7%), and unfavorable social functioning (22%). Despite having noticeably higher heart rates, the bipolar patients' mean systolic blood pressure and prevalence of hypertension (44.1%) were significantly lower than those of the comparison group. Although community-dwelling elderly patients with bipolar disorder seem to be characterized by a greater likelihood of developing cognitive dysfunction and concurrent diabetes mellitus, there is no apparent increase in the morbidity of circulatory diseases, particularly less hypertension among those without previous dementia.


Serum estradiol level during withdrawal bleeding as a predictive factor for intermittent ovarian function in women with primary ovarian insufficiency.
The objective of this study was to assess the potential predictive factors for follicle growth, ovulation, and pregnancy rate in patients with primary ovarian insufficiency/premature ovarian failure (POI/POF). We enrolled 25 POI patients with desired fertility who were treated and monitored for a minimum of 7 months between the years of 2000-2009 into this retrospective study. The clinical, endocrinologic, chromosomal, and autoimmunologic parameters of these patients were collected. Furthermore, hormonal backgrounds on each of 620 treatment cycles were investigated. The main outcome measures were follicle growth, ovulation, and pregnancy rate. Four of 25 patients (16%) conceived while being monitored and undergoing treatment. Follicle growth, ovulation, and pregnancy rate were not significantly different as a function of parity, iatrogenic history (e.g., chemotherapy), age of disease onset, serum estradiol (E(2))/follicle stimulating hormone (FSH) level at the time of diagnosis, chromosomal abnormality, and positive autoantibody titer. The serum E2 levels on days 1-5 of withdrawal bleeding (Day 1-5 E(2)) were significantly higher in the cycles with successful follicle growth and ovulation than unsuccessful cycles (P<0.05). Receiver-operator characteristic curve analysis revealed the cut-off value of the Day 1-5 E(2) to be 15.5 pg/mL, and an area under the curve (AUC) value of 0.674 for follicle growth and 0.752 for ovulation. The results suggest that cycles with a Day 1-5 E(2)≥15.5 pg/mL have a higher rate of follicle growth and ovulation in patients with POI.


Murine anti-cytomegalovirus monoclonal antibodies with autoreactivity.
Certain murine monoclonal antibodies (mAb) raised against structural proteins of mouse cytomegalovirus (MCMV) display distinct patterns of multiple organ-autoreactivity in addition to their viral specificities. We analysed the autoreactivity of five such mAb by immunoperoxidase histochemistry, western immunoblot and enzyme-linked immunosorbent assay (ELISA). Four mAb recognized cellular autoantigens in the salivary gland, lung, heart, liver, kidney, ileum, striated muscle and brain, as detected by immunoperoxidase histochemistry. However, the mAb showed different specificities for nuclear, cytoplasmic and surface membrane antigens on various cell types in addition to common autoreactivities. Immunoblot analyses showed that some of the mAb recognized polypeptides of various molecular weights obtained from 100,000 g supernatants of normal BALB/c liver, brain, striated and cardiac muscle homogenates. Reactivity of the mAb with a 200,000 molecular weight (MW) polypeptide was similar to our previous finding of the reaction of late immune polyclonal sera with a 200,000 MW polypeptide, the heavy chain of myosin. The mAb reacted to the cardiac isoform of myosin as determined by ELISA and immunoblot. Reactivity of mAb with cardiac myosin, as detected by immunoblot, was removed by absorption with cardiac myosin and recovered in the eluate. However, cardiac myosin used in a competitive inhibition ELISA did not abrogate the reactivity of the mAb with MCMV antigens. These anti-MCMV mAb appear to be multispecific for both virus and self-antigens, including cardiac myosin, and possibly recognize these different antigens through partly similar or distinct antigen-binding sites.


Serotonergic perturbations in dystonia disorders-a systematic review.
Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions. Emerging data describe high prevalences of non-motor symptoms, including psychiatric co-morbidity, as part of the phenotype of dystonia. Basal ganglia serotonin and serotonin-dopamine interactions gain attention, as imbalances are known to be involved in extrapyramidal movement and psychiatric disorders. We systematically reviewed the literature for human and animal studies relating to serotonin and its role in dystonia. An association between dystonia and the serotonergic system was reported with decreased levels of 5-hydroxyindolacetic acid, the main metabolite of serotonin. A relation between dystonia and drugs affecting the serotonergic system was described in 89 cases in 49 papers. Psychiatric co-morbidity was frequently described, but likely underestimated as it was not systematically examined. Currently, there are no good (pharmaco)therapeutic options for most forms of dystonia or associated non-motor symptoms. Further research using selective serotonergic drugs in appropriate models of dystonia is required to establish the role of the serotonergic system in dystonia and to guide us to new therapeutic strategies.


A reevaluation of the inverse dynamic model for eye movements.
To construct an appropriate motor command from signals that provide a representation of desired action, the nervous system must take into account the dynamic characteristics of the motor plant to be controlled. In the oculomotor system, signals specifying desired eye velocity are thought to be transformed into motor commands by an inverse dynamic model of the eye plant that is shared for all types of eye movements and implemented by a weighted combination of eye velocity and position signals. Neurons in the prepositus hypoglossi and adjacent medial vestibular nuclei (PH-BT neurons) were traditionally thought to encode the "eye position" component of this inverse model. However, not only are PH-BT responses inconsistent with this theoretical role, but compensatory eye movement responses to translation do not show evidence for processing by a common inverse dynamic model. Prompted by these discrepancies between theoretical notions and experimental observations, we reevaluated these concepts using multiple-frequency rotational and translational head movements. Compatible with the notion of a common inverse model, we show that PH-BT responses are unique among all premotor cell types in bearing a consistent relationship to the motor output during eye movements driven by different sensory stimuli. However, because their responses are dynamically identical to those of motoneurons, PH-BT neurons do not simply represent an internal component of the inverse model, but rather its output. They encode and distribute an estimate of the motor command, a signal critical for accurate motor execution and learning.


Behavioural display systems across nine Anolis lizard species: sexual dimorphisms in structure and function.
Relationships between structure and function are a primary focus in biology, yet they are most often considered within individual species. Sexually dimorphic communication behaviours and the morphology of associated structures can vary widely, even among closely related species, and these traits provide an ideal opportunity to investigate the evolution of structure-function patterns. Using nine Anolis lizard species, we addressed a series of questions regarding sex differences in and the evolution of relationships between extension of the throat fan (dewlap) and morphology of the muscles and cartilage controlling it. The main results indicated that within species, males displayed the dewlap more often than females and consistently exhibited larger associated structures. These data are consistent with work in other vertebrates in which corresponding sex differences in reproductive morphology and behaviour have been documented. Across species, however, we found no evidence that the rate of dewlap extension evolved in association with dewlap morphology. Thus, we provide an example of traits that, when considered in a phylogenetic framework, exhibited limited associations between behaviour and morphology, perhaps as the result of constraints imposed by the ecological contexts in which different species occur.


Problems in diagnosing scabies, a global disease in human and animal populations.
Scabies is a worldwide disease and a major public health problem in many developing countries, related primarily to poverty and overcrowding. In remote Aboriginal communities in northern Australia, prevalences of up to 50% among children have been described, despite the availability of effective chemotherapy. Sarcoptic mange is also an important veterinary disease engendering significant morbidity and mortality in wild, domestic, and farmed animals. Scabies is caused by the ectoparasitic mite Sarcoptes scabiei burrowing into the host epidermis. Clinical symptoms include intensely itchy lesions that often are a precursor to secondary bacterial pyoderma, septicemia, and, in humans, poststreptococcal glomerulonephritis. Although diagnosed scabies cases can be successfully treated, the rash of the primary infestation takes 4 to 6 weeks to develop, and thus, transmission to others often occurs prior to therapy. In humans, the symptoms of scabies infestations can mimic other dermatological skin diseases, and traditional tests to diagnose scabies are less than 50% accurate. To aid early identification of disease and thus treatment, a simple, cheap, sensitive, and specific test for routine diagnosis of active scabies is essential. Recent developments leading to the expression and purification of S. scabiei recombinant antigens have identified a number of molecules with diagnostic potential, and current studies include the investigation and assessment of the accuracy of these recombinant proteins in identifying antibodies in individuals with active scabies and in differentiating those with past exposure. Early identification of disease will enable selective treatment of those affected, reduce transmission and the requirement for mass treatment, limit the potential for escalating mite resistance, and provide another means of controlling scabies in populations in areas of endemicity.


c-Src: bridging the gap between phosphorylation- and acidification-induced gap junction channel closure.
Gap junctions are a unique type of intercellular junction that mediate the direct exchange of small molecules between neighboring cells and play critical roles in the normal function of numerous organs. Mutations in the connexin proteins that make up gap junctions have been implicated in numerous human skin and neurosensory disorders. The ability of gap junctions to transmit molecules between cells is regulated by intracellular pH, the phosphorylation state of connexin, and the interaction of connexin with other cellular proteins. This Perspective focuses on the novel and complex events initiated by intracellular acidification resulting from tissue ischemia or hypoxia that lead to the interruption of intercellular communication between astrocytes. These events include alterations in connexin43 (Cx43) phosphorylation, disruption of beta-actin binding to Cx43, and the induced interaction of Cx43 with the c-Src tyrosine kinase, extracellular signal-regulated kinase 1 and 2, and mitogen-activated protein kinase phosphatase 1.


Emery-Dreifuss muscular dystrophy: linkage to markers in distal Xq28.
Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant. Family linkage studies have mapped X linked EMD to the distal long arm of the X chromosome but precise genetic localisation has been hampered by the rarity of this condition. We report three new families with X linked Emery-Dreifuss muscular dystrophy studied with DNA markers from Xq27-qter and three previously published families typed for additional markers. No recombination was observed with the red/green cone pigment locus, RGCP (lod score, Z = 2.46), the factor VIII coagulant gene locus, F8C (Z = 6.39), or with DXS115 (Z = 4.94). Two recombinants were observed which mapped EMD distal to DXS15 (DX13) and DXS52 (St14) respectively. Multipoint linkage analysis gave odds exceeding 200:1 for EMD being distal to these markers. A multipoint analysis incorporating published data gave the map cen-DXS304-9cM-DXS15-3cM-DXS52-2 cM-(RGCP,EMD)-3cM-F8C-2cM-DXS115 with odds of 120:1 in favour of a location for EMD between DXS52 and F8C as compared to the next best position distal to F8C.


Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.
To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.


Quantification of three-dimensional cell-mediated collagen remodeling using graph theory.
Cell cooperation is a critical event during tissue development. We present the first precise metrics to quantify the interaction between mesenchymal stem cells (MSCs) and extra cellular matrix (ECM). In particular, we describe cooperative collagen alignment process with respect to the spatio-temporal organization and function of mesenchymal stem cells in three dimensions. We defined two precise metrics: Collagen Alignment Index and Cell Dissatisfaction Level, for quantitatively tracking type I collagen and fibrillogenesis remodeling by mesenchymal stem cells over time. Computation of these metrics was based on graph theory and vector calculus. The cells and their three dimensional type I collagen microenvironment were modeled by three dimensional cell-graphs and collagen fiber organization was calculated from gradient vectors. With the enhancement of mesenchymal stem cell differentiation, acceleration through different phases was quantitatively demonstrated. The phases were clustered in a statistically significant manner based on collagen organization, with late phases of remodeling by untreated cells clustering strongly with early phases of remodeling by differentiating cells. The experiments were repeated three times to conclude that the metrics could successfully identify critical phases of collagen remodeling that were dependent upon cooperativity within the cell population. Definition of early metrics that are able to predict long-term functionality by linking engineered tissue structure to function is an important step toward optimizing biomaterials for the purposes of regenerative medicine.


[Diagnostic value of pediatric trauma score in blunt abdominal injuries].
It was reported that pediatric trauma score (PTS) is an important tool for the initial assessment of injury severity and could help in the triage of injured children as well. The aim of this study is to investigate the prognostic value of PTS in blunt abdominal traumas. Between 1997 and 2003, children with blunt abdominal trauma who treated in the Department of Pediatric Surgery, Trakya University Medical Faculty were evaluated with retrospective analysis. PTS was designated for each case. Individual morbidity and mortality were correlated with PTS. Data analysis were performed with Mann Whitney U test and ROC curve statistically. Seventy five patients were included in this study. The mean age of children was 7.5+/-4.2 years (10 months-15 years). Mechanisms of injury were as follows: automobile versus pedestrian 30, falls 18, motor vehicle crashes 14, bicycle accidents 7 and others 6. Forty two abdominal organ injuries were found.. PTS of the patients who had abdominal injuries were different statistically from others (p<0.05). On the ROC curve sensitivity and specificity were found as %74 and %12 respectively in those with PTS scores of 8. PTS was found to be of low sensitivity and specificity for blunt abdominal trauma patients.


Spending On Care After Surgery Driven By Choice Of Care Settings Instead Of Intensity Of Services.
The rising popularity of episode-based payment models for surgery underscores the need to better understand the drivers of variability in spending on postacute care. Examining postacute care spending for fee-for-service Medicare beneficiaries after three common surgical procedures in the period 2009-12, we found that it varied widely between hospitals in the lowest versus highest spending quintiles for postacute care, with differences of 129 percent for total hip replacement, 103 percent for coronary artery bypass grafting (CABG), and 82 percent for colectomy. Wide variation persisted after we adjusted for the intensity of postacute care. However, the variation diminished considerably after we adjusted instead for postacute care setting (home health care, outpatient rehabilitation, skilled nursing facility, or inpatient rehabilitation facility): It decreased to 16 percent for hip replacement, 4 percent for CABG, and 21 percent for colectomy. Health systems seeking to improve surgical episode efficiency should collaborate with patients to choose the highest-value postacute care setting.


De novo production of the monoterpenoid geranic acid by metabolically engineered Pseudomonas putida.
Production of monoterpenoids as valuable chemicals using recombinant microbes is a growing field of interest. Unfortunately, antimicrobial activity of most monoterpenoids hampers a wide application of microorganisms for their production. Strains of Pseudomonas putida, a fast growing and metabolically versatile bacterium, often show an outstanding high tolerance towards organic solvents and other toxic compounds. Therefore, Pseudomonas putida constitutes an attractive alternative host in comparison to conventionally used microorganisms. Here, metabolic engineering of solvent tolerant Pseudomonas putida as a novel microbial cell factory for de novo production of monoterpenoids is reported for the first time, exemplified by geranic acid production from glycerol as carbon source. The monoterpenoic acid is an attractive compound for application in the flavor, fragrance, cosmetics and agro industries. A comparison between Escherichia coli, Saccharomyces cerevisiae and Pseudomonas putida concerning the ability to grow in the presence of geranic acid revealed that the pseudomonad bears a superior resilience compared to the conventionally used microbes. Moreover, Pseudomonas putida DSM 12264 wildtype strain efficiently oxidized externally added geraniol to geranic acid with no further degradation. Omitting external dosage of geraniol but functionally expressing geraniol synthase (GES) from Ocimum basilicum, a first proof-of-concept for de novo biosynthesis of 1.35 mg/L geranic acid in P. putida DSM 12264 was achieved. Doubling the amount of glycerol resulted in twice the amount of product. Co-expression of the six genes of the mevalonate pathway from Myxococcus xanthus to establish flux from acetyl-CoA to the universal terpenoid precursor isopentenylpyrophosphate yielded 36 mg/L geranic acid in shake flask experiments. In the bioreactor, the recombinant strain produced 193 mg/L of geranic acid under fed-batch conditions within 48 h. Metabolic engineering turned Pseudomonas putida DSM 12264, a versatile monoterpenoid oxidation biocatalyst, into an efficient microbial cell factory for de novo geranic acid production. Improvements by metabolic and process engineering are expected to further increase the product concentration. To the best of the authors' knowledge, this is the first example of a de novo production of a monoterpenoid with Pseudomonas putida and of a microbial monoterpenoic acid synthesis in general.


Nonadherence to breast and cervical cancer screening: what are the linkages to chronic disease risk?
Several preventive practices that reduce chronic disease risk have been associated with breast and cervical cancer screening, including maintenance of normal weight and avoidance of cigarette smoking. A history of certain chronic illnesses such as diabetes and cardiovascular disease has also been related to cancer screening. Nevertheless, studies that have attempted to identify women who are less likely to have had a recent breast or cervical cancer screening test have infrequently examined the associations of breast and cervical cancer screening with multiple health factors that influence chronic disease risk. To clarify relationships between cancer screening and health behaviors and other factors that influence chronic disease risk, we examined the self-reported breast and cervical cancer screening practices of women in the United States by using data from the 1999 Behavioral Risk Factor Surveillance System. The women were described according to their recent use of mammography and the Papanicolaou test, physician visits within the past year, health insurance coverage, and preventive practices that reduce chronic disease risk. Overall, 74.5% (95% CI, 73.9%-75.1%) of the women in this sample aged 40 years or older (n = 56,528) had received a mammogram within the past 2 years. The percentage of women who had been screened for breast cancer, however, varied widely by factors associated with reducing the risk of chronic disease (e.g., cholesterol check in the past 2 years, blood pressure check in the past 2 years, normal weight, avoidance of cigarette smoking) and having access to health care (e.g., health insurance coverage, recent physician visit). Similarly, 84.4% (95% CI, 83.9%-84.9%) of all women aged 18 years or older who had not undergone a hysterectomy (n = 69,113) had received a Papanicolaou test in the past 3 years, and factors associated with reduced chronic disease risk and health care access were related to having had a recent Papanicolaou test. The results of this study suggest that underscreened women who are at risk for breast and cervical cancer are likely to benefit from programs that identify and address coexisting prevention needs. The identification of coexisting prevention needs might assist in developing interventions that address multiple risks for chronic disease among women and might subsequently help improve the efficiency and effectiveness of prevention programs.


W.H.O. sponsored collaborative studies on nutritional anaemia in India. 1. The effects of supplemental oral iron administration to pregnant women.
A W.H.O. sponsored collaborative study of the effects of iron supplementation to pregnant women was carried out in Delhi (northern India) and Vellore (southern India). Supplementation was given under supervision from the 26th to the 36th or 38th week of pregnancy. A control group received only placebo; one group received vitamin B12 and folic acid alone; four groups received vitamin B12, folate and a daily iron supplement ranging from 30 to 240 mg of elemental iron as ferrous fumerate, and one further group received 120 mg of iron without B12 or folate. Groups receiving no iron showed a fall in mean stet concentration. Those receiving iron showed a rise in haemoglobin, the best results being in the groups receiving 120 and 240 mg of iron together with vitamin B12 and folate. Even in these groups however there was still a high prevalence of anaemia and iron deficiency at the end of the trial period. Iron alone did not produce as good results as iron plus vitamin B12 and folate. The supplementation had no detectable effect on the birth weight of the children, nor on the haemoglobin concentration of the infants at three months of age. The daily absorption of iron in the pregnant women, as judged from the increase in haemoglobin mass, was not as satisfactory as expected. Possible reasons for this are discussed. It is concluded that to provide these women with adequate iron a daily oral supplementation of 120 mg of elemental iron or more is needed. This can only be achieved by medicinal means. Before supplementation can be recommended on a public health scale, further information regarding the cost and expected benefits of such measures must be obtained.


xtalPiMS: a PiMS-based web application for the management and monitoring of crystallization trials.
A major advance in protein structure determination has been the advent of nanolitre-scale crystallization and (in a high-throughput environment) the development of robotic systems for storing and imaging crystallization trials. Most of these trials are carried out in 96-well (or higher density) plates and managing them is a significant information management challenge. We describe xtalPiMS, a web-based application for the management and monitoring of crystallization trials. xtalPiMS has a user-interface layer based on the standards of the Protein Information Management System (PiMS) and a database layer which links the crystallization trial images to the meta-data associated with a particular crystallization trial. The user interface has been optimized for the efficient monitoring of high-throughput environments with three different automated imagers and work to support a fourth imager is in progress, but it can even be of use without robotics. The database can either be a PiMS database or a legacy database for which a suitable mapping layer has been developed.


Association of low plasma cholesterol with mortality for cancer at various sites in men: 17-y follow-up of the prospective Basel study.
Low serum cholesterol has been associated with an increased risk of cancer mortality in various studies, which has led to uncertainty regarding the benefit of lower blood cholesterol. The aim of our study was to evaluate the association between low blood cholesterol (<5.16 mmol/L) and cancer at sites that have rarely been evaluated. We placed special emphasis on the potential confounding effect of antioxidant vitamins. Plasma concentrations of cholesterol and antioxidant vitamins were measured in 1971-1973 in 2974 men working in Basel, Switzerland. In 1990, the vital status of all participants was assessed. Two hundred ninety of the participants had died from cancer, 87 from lung, 30 from prostate, 28 from stomach, and 22 from colon cancer. Group means for plasma cholesterol concentrations did not differ significantly between survivors and those who died from cancer at any of the studied sites. With plasma cholesterol, vitamins C and E, retinol, carotene, smoking, and age accounted for in a Cox model, an increase in total cancer mortality in lung, prostate, and colon but not in stomach cancer mortality was observed in men >60 y of age with low plasma cholesterol. When data from the first 2 y of follow-up were excluded from the analysis, the relative risk estimates remained practically unchanged with regard to lung cancer but decreased for colon, prostate, and overall cancer. Increased cancer mortality risks associated with low plasma cholesterol were not explained by the confounding effect of antioxidant vitamins, but were attributed in part to the effect of preexisting cancer.


Treating self-injury: water mist spray versus facial screening or forced arm exercise.
In three experiments, the effect of water mist spray on self-injurious and collateral behaviors was compared with either facial screening or forced arm exercise. Water mist spray was as effective as facial screening in suppressing face-slapping in Experiment 1. However, it was not as effective as facial screening for self-injurious finger-licking in Experiment 2 or forced arm exercise for excessive ear-rubbing in Experiment 3. These results suggest that while water mist spray is effective, it may be less so than alternative procedures. In Experiments 2 and 3 there was a consistent decrease in the occurrence of untreated maladaptive behaviors. In addition, there was a moderate increase in appropriate social interaction in Experiment 2 and a substantial increase in Experiment 3.


Errors of temperature measurement with multiband infrared systems.
A model of the errors of temperature measurement with multiband systems was developed. Calculations of these errors for some measurement conditions and systems were carried out. It was shown that multiband systems are capable of producing accurate results of noncontact temperature measurement only in a limited number of applications and that to have small internal errors, they must be designed and built with much greater care than in the case of typical single-band systems.


IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection.
Influenza A virus (IAV) infection of the respiratory tract elicits a robust immune response, which is required for efficient virus clearance but at the same time can contribute to lung damage and enhanced morbidity. IL-21 is a member of the type I cytokine family and has many different immune-modulatory functions during acute and chronic virus infections, although its role in IAV infection has not been fully evaluated. In this report we evaluated the contributions of IL-21/IL-21 receptor (IL-21R) signaling to host defense in a mouse model of primary IAV infection using IL-21R knock out (KO) mice. We found that lack of IL-21R signaling had no significant impact on virus clearance, adaptive T cell responses, or myeloid cell accumulations in the respiratory tract. However, a subset of inflammatory cytokines were elevated in the bronchoalveolar lavage fluid of IL-21R KO mice, including IL-17. Although there was only a small increase in Th17 cells in the lungs of IL-21R KO mice, we observed a dramatic increase in gamma delta (γδ) T cells capable of producing IL-17 both after IAV infection and at steady state in the respiratory tract. Finally, we found that IL-21R signaling suppressed the accumulation of IL-17+ γδ T cells in the respiratory tract intrinsically. Thus, our study reveals a previously unrecognized role of IL-21R signaling in regulating IL-17 production by γδ T cells.


Detection of PAX3-FKHR and PAX7-FKHR fusion transcripts in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction using paraffin-embedded tissue.
Alveolar rhabdomyosarcoma (RMS) is associated with a characteristic chromosomal translocation t(2;13)(q35;q14). The genes involved in this translocation are paired box (PAX)3 on chromosome 2 and forkhead in RMS (FKHR) on chromosome 13. An occasional variant translocation t(1;13)(p36;q14) affecting PAX7 and FKHR on chromosomes 1 and 13, respectively, has also been described. Chromosomal translocations in RMS are detected using conventional cytogenetic analysis, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) on fresh or frozen tissue samples. We describe the results of RT-PCR analysis of PAX3-FKHR and PAX7-FKHR chimeric messages in formalin-fixed, paraffin-embedded tissue samples from 17 RMS cases. RNA was extracted from formalin-fixed, paraffin-embedded RMS tissue. Oligonucleotide primers corresponding to the regions of PAX3, PAX7 and FKHR were used for the detection of PAX3-FKHR and PAX7-FKHR chimeric messages. A seminested PCR of the PCR products was used to increase the sensitivity of detection. The amplified fragments were purified and directly sequenced to confirm the specificity of the methods. The PAX3-FKHR chimeric message was detected in all three cases of alveolar RMS but not in any of the 12 embryonal and two pleomorphic RMS cases. The PAX7-FKHR fusion transcript was detected in one case of embryonal RMS. The results indicate that the RT-PCR assay is a reliable method for the detection of the PAX3-FKHR fusion transcript of alveolar RMS in formalin-fixed, paraffin-embedded tissue. This simple method enables pathologists to identify chromosomal rearrangements in RMS as a diagnostic aid in cases where fresh or frozen tissue is not available.


Pollinator-mediated reproductive isolation among dioecious fig species (Ficus, Moraceae).
The extent of isolation among closely related sympatric plant species engaged in obligate pollination mutualisms depends on the fitness consequences of interspecies floral visitation. In figs (Ficus), interspecific gene flow may occur when pollinating wasps (Agaonidae) visit species other than their natal fig species. We studied reproductive isolation in a clade of six sympatric dioecious fig species in New Guinea. Microsatellite genotyping and Bayesian clustering analysis of the fig community indicated strong reproductive barriers among sympatric species. A total of 1-2% of fig populations consisted of hybrid individuals. A new experimental method of manipulating fig wasps investigated the reproductive consequences of conspecific and heterospecific pollinator visitation for both mutualists. Fig wasps introduced to Ficus hispidioides pollinated and oviposited in receptive figs. Seed development and seedling growth were largely comparable between conspecific and heterospecific crosses. Heterospecific pollinator fitness, however, was significantly less than that of conspecific pollinators. Heterospecific pollinators induced gall formation but offspring did not develop to maturity in the new host. Selection on pollinators maintaining host specificity appears to be an important mechanism of contemporary reproductive isolation among these taxa that could potentially influence their diversification.


Impact of direct-to-consumer genomic testing at long term follow-up.
There are few empirical data to inform the debate surrounding the use and regulation of direct-to-consumer (DTC) genome-wide disease risk tests. This study aimed to determine the long term psychological, behavioural, and clinical impacts of genomic risk testing for common disease. The Scripps Genomic Health Initiative is a prospective longitudinal cohort study of adults who purchased the Navigenics Health Compass, a commercially available genomic test. Web based assessments were administered at baseline, short (3 months), and long term (1 year) follow-up. 2240 participants completed either or both follow-ups and a subset of 1325 completed long term follow-up. There were no significant differences from baseline in anxiety (p=0.50), fat intake (p=0.34), or exercise (p=0.39) at long term follow-up, and 96.8% of the sample had no test related distress. Longitudinal linear mixed model analyses were consistent with results of cross-sectional analyses. Screening test completion was associated with sharing genomic test results with a physician (36.0% shared; p<0.001) and perceived utility of the test (61.5% high perceived utility; p=0.002), but was not associated with the genomic risk estimate values themselves. Over a third of DTC genomic test recipients shared their results with their own physician during an approximate 1 year follow-up period, and this sharing was associated with higher screening test completion. Genomic testing was not associated with long term psychological risks, and most participants reportedly perceived the test to be of high personal utility.


Regulation of diacylglycerol metabolism by vasoconstrictor hormones in intact small arteries.
The initiation of receptor-mediated small artery contraction is dependent on inositol 1,4,5-trisphosphate-stimulated release of stored calcium. The role of the other product of inositol lipid hydrolysis, 1,2-diacylglycerol, in maintaining contraction remains controversial. Therefore, we have determined the contractile response of rat subcutaneous small arteries (< 300 microns i.d.), when mounted as ring preparations in a myograph, to noradrenaline, angiotensin II, KCl-induced membrane depolarization, and a cell-permeable diglyceride, dioctanoylglycerol. In parallel experiments, the conversion of this diglyceride to dioctanoylphosphatidate was studied in 32P-labeled vessels. Dioctanoylglycerol produced a slow-onset sustained contraction that was dependent on extracellular calcium. This was accompanied by the generation of the lipid dioctanoylphosphatidate. Noradrenaline and KCl induced rapid-onset sustained contractions and increased the production of dioctanoylphosphatidate (75% and 91%, respectively). In addition, dioctanoylglycerol levels were reduced (41%) after noradrenaline stimulation, suggesting activation of diacylglycerol kinase. In contrast, the contractile response to angiotensin II was transient, and this agonist did not significantly affect the conversion of dioctanoylglycerol to phosphatidate. Noradrenaline markedly increased (fourfold) the formation of endogenous phosphatidate, whereas endogenous 1,2-diacylglycerol was increased (47%) with angiotensin II. These results demonstrate that phosphatidate formation is regulated by vasoconstrictor hormones during receptor-mediated contraction, independent of diglyceride mass. Modulation of the levels of lipid second messengers downstream from phospholipid hydrolysis may represent a mechanism by which agonists that act through the same signaling system produce different contractile responses.


Prognostic role of CD44 expression in osteosarcoma: evidence from six studies.
Numerous studies examining the relationship between CD44 expression and prognostic impact in patients with osteosarcoma have yielded inconclusive results. The aim of this meta-analysis was carried out to investigate the relationship between CD44 expression and the survival in patients with osteosarcoma. We therefore conducted a meta-analysis to provide a comprehensive evaluation of the prognostic role of CD44 expression on the overall survival rate and metastasis, which compared the positive and negative expression of CD44 in patients of the available studies. A detailed search was made in MEDLINE and EMBASE for relevant original articles published in English. Finally, a total of six studies with 329 osteosarcoma patients were involved to estimate the relationship between CD44 expression and metastasis of tumor and overall survival. Positive expressions of CD44 did not predict neoplasm metastasis (RR = 1.36, 95% CI: 1.00-1.84, P = 0.50), and the results indicated that higher expression of CD44 could not predict poorer survival in osteosarcoma with the pooled HR of 0.55 (95% CI: 0.27-1.13, P = 0.47). The findings from this present meta-analysis suggest that CD44 expression is not associated with overall survival rate and metastasis in osteosarcoma. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1373995521295618.


Brain characterization using normalized quantitative magnetic resonance imaging.
To present a method for generating reference maps of typical brain characteristics of groups of subjects using a novel combination of rapid quantitative Magnetic Resonance Imaging (qMRI) and brain normalization. The reference maps can be used to detect significant tissue differences in patients, both locally and globally. A rapid qMRI method was used to obtain the longitudinal relaxation rate (R1), the transverse relaxation rate (R2) and the proton density (PD). These three tissue properties were measured in the brains of 32 healthy subjects and in one patient diagnosed with Multiple Sclerosis (MS). The maps were normalized to a standard brain template using a linear affine registration. The differences of the mean value ofR1, R2 and PD of 31 healthy subjects in comparison to the oldest healthy subject and in comparison to an MS patient were calculated. Larger anatomical structures were characterized using a standard atlas. The vector sum of the normalized differences was used to show significant tissue differences. The coefficient of variation of the reference maps was high at the edges of the brain and the ventricles, moderate in the cortical grey matter and low in white matter and the deep grey matter structures. The elderly subject mainly showed significantly lower R1 and R2 and higher PD values along all sulci. The MS patient showed significantly lower R1 and R2 and higher PD values at the edges of the ventricular system as well as throughout the periventricular white matter, at the internal and external capsules and at each of the MS lesions. Brain normalization of rapid qMRI is a promising new method to generate reference maps of typical brain characteristics and to automatically detect deviating tissue properties in the brain.


Systematic Tuning and Multifunctionalization of Covalent Organic Polymers for Enhanced Carbon Capture.
Porous covalent polymers are attracting increasing interest in the fields of gas adsorption, gas separation, and catalysis due to their fertile synthetic polymer chemistry, large internal surface areas, and ultrahigh hydrothermal stabilities. While precisely manipulating the porosities of porous organic materials for targeted applications remains challenging, we show how a large degree of diversity can be achieved in covalent organic polymers by incorporating multiple functionalities into a single framework, as is done for crystalline porous materials. Here, we synthesized 17 novel porous covalent organic polymers (COPs) with finely tuned porosities, a wide range of Brunauer-Emmett-Teller (BET) specific surface areas of 430-3624 m(2) g(-1), and a broad range of pore volumes of 0.24-3.50 cm(3) g(-1), all achieved by tailoring the length and geometry of building blocks. Furthermore, we are the first to successfully incorporate more than three distinct functional groups into one phase for porous organic materials, which has been previously demonstrated in crystalline metal-organic frameworks (MOFs). COPs decorated with multiple functional groups in one phase can lead to enhanced properties that are not simply linear combinations of the pure component properties. For instance, in the dibromobenzene-lined frameworks, the bi- and multifunctionalized COPs exhibit selectivities for carbon dioxide over nitrogen twice as large as any of the singly functionalized COPs. These multifunctionalized frameworks also exhibit a lower parasitic energy cost for carbon capture at typical flue gas conditions than any of the singly functionalized frameworks. Despite the significant improvement, these frameworks do not yet outperform the current state-of-art technology for carbon capture. Nonetheless, the tuning strategy presented here opens up avenues for the design of novel catalysts, the synthesis of functional sensors from these materials, and the improvement in the performance of existing covalent organic polymers by multifunctionalization.


Surgical site infection: the "Achilles Heel" of all types of abdominal wall hernia reconstruction.
Surgical site infection is the most common hospital-acquired infection in surgical patients. Recently, public health organizations have updated prevention guidelines. This review discusses surgical site infections as a complication of abdominal wall reconstruction. The authors reviewed guidelines on prevention of surgical site infections from the Center for Disease Control and Prevention, World Health Organization, and National Institute for Health and Care Excellence and put them into context with the relevant abdominal wall reconstruction literature. This was the subject of the Nyhus-Wantz lecture given at The International Hernia Congress on March 14, 2018 in Miami, FL and is summarized here. Routine use of preoperative antibiotics in prosthetic groin hernia repair is not supported by the available literature. High-quality data on antibiotic prophylaxis in ventral (both primary and incisional) hernia repair is lacking, but it is widely utilized and may reduce SSIs. Recommended preventative strategies discussed in this manuscript include: treatment of remote site infections, perioperative normothermia and normoglycemia, avoidance of hypoxemia, antiseptic preparation of surgical team hands and patient skin, treatment of obesity, smoking cessation, correction of malnutrition, and physical conditioning. Surgical site infections lead to significant morbidity and mortality, hernia recurrences, prolonged hospital stay, and increased hospital costs. This makes surgical site infections the "Achilles Heel" of abdominal wall reconstruction. Strict adherence to standardized guidelines and preoperative optimization of patients' risk profiles are crucial to decrease the incidence of surgical site infections.


From hippocampus to whole-brain: The role of integrative processing in episodic memory retrieval.
Multivariate functional connectivity analyses of neuroimaging data have revealed the importance of complex, distributed interactions between disparate yet interdependent brain regions. Recent work has shown that topological properties of functional brain networks are associated with individual and group differences in cognitive performance, including in episodic memory. After constructing functional whole-brain networks derived from an event-related fMRI study of memory retrieval, we examined differences in functional brain network architecture between forgotten and remembered words. This study yielded three main findings. First, graph theory analyses showed that successfully remembering compared to forgetting was associated with significant changes in the connectivity profile of the left hippocampus and a corresponding increase in efficient communication with the rest of the brain. Second, bivariate functional connectivity analyses indicated stronger interactions between the left hippocampus and a retrieval assembly for remembered versus forgotten items. This assembly included the left precuneus, left caudate, bilateral supramarginal gyrus, and the bilateral dorsolateral superior frontal gyrus. Integrative properties of the retrieval assembly were greater for remembered than forgotten items. Third, whole-brain modularity analyses revealed that successful memory retrieval was marginally significantly associated with a less segregated modular architecture in the network. The magnitude of the decreases in modularity between remembered and forgotten conditions was related to memory performance. These findings indicate that increases in integrative properties at the nodal, retrieval assembly, and whole-brain topological levels facilitate memory retrieval, while also underscoring the potential of multivariate brain connectivity approaches for providing valuable new insights into the neural bases of memory processes. Hum Brain Mapp 38:2242-2259, 2017. © 2017 Wiley Periodicals, Inc.


Antibody-free, targeted mass-spectrometric approach for quantification of proteins at low picogram per milliliter levels in human plasma/serum.
Sensitive detection of low-abundance proteins in complex biological samples has typically been achieved by immunoassays that use antibodies specific to target proteins; however, de novo development of antibodies is associated with high costs, long development lead times, and high failure rates. To address these challenges, we developed an antibody-free strategy that involves PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing) for sensitive selected reaction monitoring (SRM)-based targeted protein quantification. The strategy capitalizes on high-resolution reversed-phase liquid chromatographic separations for analyte enrichment, intelligent selection of target fractions via on-line SRM monitoring of internal standards, and fraction multiplexing before nano-liquid chromatography-SRM quantification. Application of this strategy to human plasma/serum demonstrated accurate and reproducible quantification of proteins at concentrations in the 50-100 pg/mL range, which represents a major advance in the sensitivity of targeted protein quantification without the need for specific-affinity reagents. Application to a set of clinical serum samples illustrated an excellent correlation between the results obtained from the PRISM-SRM assay and those from clinical immunoassay for the prostate-specific antigen level.