Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation.
Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.


Prevention of TGF-β-induced early liver fibrosis by a maleic acid derivative anti-oxidant through suppression of ROS, inflammation and hepatic stellate cells activation.
Current anti-fibrotic effect of antioxidants in vivo is disappointing due probably to the fact that once liver fibrogenesis is established it is too advanced to be reversed by anti-oxidation mechanism. We consider antioxidant may only act on the early phase of fibrogenesis. Thus, we had previously established an early liver fibrosis animal model using an inducible expression vector (pPK9a), which contains TGF-β gene and was hydro-dynamically transferred into mice to induce a transient liver fibrosis. TGF-β1 has been well documented to up-regulate the expression of α2(1) collagen (Col 1A2) gene in the liver via the reactive oxygen species (ROS); the process triggers inflammation, leading to hepatic stellate cells (HSC) activation and liver fibrogenesis. Using our animal model and ROS, cyclooxygenase-2 (Cox-2) and Col 1A2 promoter assays as screening targets, we report here that a maleic acid derivative isolated from the Antrodia camphorata mycelium strongly decreases ROS production, promoter activity of Cox-2 and Col 1A2, intracellular calcium, expression of alpha-smooth muscle actin (α-SMA), Smad4-p-Smad2/3 co-localization in cell nucleus and the DNA binding activity of Sp1. Our results suggest that the maleic acid derivative prevents liver fibrosis at an early phase both in vitro and in vivo through the inhibition of ROS, inflammation and the activation of HSC.


Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate.
Cell growth requires fatty acids for membrane synthesis. Fatty acids are assembled from 2-carbon units in the form of acetyl-CoA (AcCoA). In nutrient and oxygen replete conditions, acetyl-CoA is predominantly derived from glucose. In hypoxia, however, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to acetyl-CoA increases. The significance of other acetyl-CoA sources, however, has not been rigorously evaluated. Here we investigate quantitatively, using (13)C-tracers and mass spectrometry, the sources of acetyl-CoA in hypoxia. In normoxic conditions, cultured cells produced more than 90% of acetyl-CoA from glucose and glutamine-derived carbon. In hypoxic cells, this contribution dropped, ranging across cell lines from 50% to 80%. Thus, under hypoxia, one or more additional substrates significantly contribute to acetyl-CoA production. (13)C-tracer experiments revealed that neither amino acids nor fatty acids are the primary source of this acetyl-CoA. Instead, the main additional source is acetate. A large contribution from acetate occurs despite it being present in the medium at a low concentration (50-500 μM). Acetate is an important source of acetyl-CoA in hypoxia. Inhibition of acetate metabolism may impair tumor growth.


Primary Renal Ewing Sarcoma in Children and Young Adults.
The Ewing sarcoma family of tumors (ESFT) are high-grade small round blue cell malignancies traditionally presenting in children and adolescents. The most common site of primary disease is bone, though extraskeletal primary sites are well-recognized. We present 6 cases of primary ESFT of the kidney and 1 case of the adrenal gland. Patients were 11 to 18 years of age at diagnosis. Metastases at diagnosis were present in most cases (n=6). All patients underwent surgery, and most received radiation (n=5). Five patients relapsed after initial remission. Comprehensive review of the primary renal ESFT literature was used to analyze various factors, including age, sex, disease metrics, metastases at diagnoses, and overall survival in a total of 362 cases. Notably, while the general ESFT population has reported rates of metastasis at diagnosis of 20% to 25%, this rate in the renal ESFT population was 53% with a rate of 59% in adolescent and young-adult patients (11 to 24 y). Nodal disease at diagnosis was present in 24% of renal ESFT cases compared with 3.2% in patients with primary skeletal ESFT. While this malignant process may share histologic and molecular features with its bone and soft tissue counterparts, primary renal ESFT presentations seem to be more aggressive and have worse outcomes.


Insights into brown adipose tissue evolution and function from non-model organisms.
Brown adipose tissue (BAT) enables adaptive thermoregulation through heat production that is catalyzed by mitochondrial uncoupling protein 1 (UCP1). BAT is frequently studied in rodent model organisms, and recently in adult humans to treat metabolic diseases. However, complementary studies of many non-model species, which have diversified to many more ecological niches, may significantly broaden our understanding of BAT regulation and its physiological roles. This Review highlights the research on non-model organisms, which was instrumental to the discovery of BAT function, and the unique evolutionary history of BAT/UCP1 in mammalian thermogenesis. The comparative biology of BAT provides a powerful integrative approach that could identify conserved and specialized functional changes in BAT and UCP1 by considering species diversity, ecology and evolution, and by fusing multiple scientific disciplines such as physiology and biochemistry. Thus, resolving the complete picture of BAT biology may fail if comparative studies of non-model organisms are neglected.


Characteristics of Colorectal Cancer in Khorramabad, Iran during 2013.
BACKGROUND Colorectal cancer is a common, deadly disease with different incidence rates in different parts of the world. The present study aims to investigate the clinical presentations, colonoscopic findings, and family history of colorectal cancer in the city of Khorramabad, Iran. METHODS This cross-sectional study, conducted in 2013, included 112 patients diagnosed with colorectal cancer by colonoscopy with pathological confirmation in addition to 112 individuals matched with patients for age and gender. Controls were chosen from the outpatients admitted to the Skin and Eye Clinics of ShohadaAshayer Hospital in Khorramabad who had no gastrointestinal diseases. A self-generated questionnaire was used to assess family history of smoking and gastrointestinal cancer history in immediate relatives of subjects from both groups. Fisher's exact test and odds ratios (OR) were used to analyze the data. RESULTS Based on the findings of this study, the most common clinical presentation in the patients was abdominal pain (67.9%). The sigmoid colon (40%) was the most common anatomical site of the tumor in men; the rectum (34.6%) and sigmoid colon (34.6%) were the most common sites in women, which was not statistically significant (p=0.21). There were 11 (19.6%) patients and 2 (3.6%) individuals in the control group who reported a history of colorectal cancer in their immediate relatives, which was statistically significant (p=0.008). CONCLUSION In this study, left-sided colon cancer was more common. Subjects with colon cancer had more positive FHx. This indicated that genetic factors, in addition to environmental factors, could increase the incidence of colorectal cancer in a community. A better identification of these factors would result in better control and management of this disease.


Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.
In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.


Detection of Sacroiliitis by Short-tau Inversion Recovery and T2-weighted Turbo Spin Echo Sequences: Results from the SIMACT Study.
To compare proton density-weighted short-tau inversion recovery (PD-STIR) and T2-weighted fat-suppressed turbo spin echo (T2-FS) sequences for detecting osteitis lesions of the sacroiliac joints (SIJ) in patients with chronic low back pain (CLBP). This prospective study included 110 patients with CLBP and suspected spondyloarthritis and 18 healthy controls. All 128 participants (age range: 19-57 yrs) underwent 3.0 Tesla magnetic resonance imaging (MRI) of the SIJ including PD-STIR and T2-FS. Two readers independently scored PD-STIR and T2-FS images for osteitis in separate sessions. Sum scores and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Images were further analyzed as to whether they fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criterion of a positive MRI (MRI+). Interreader agreement was calculated using intraclass correlation coefficients. Average osteitis sum scores were higher for T2-FS images (mean sum score of 4.10 in T2-FS vs 2.55 in PD-STIR, p = 0.017). Mean SNR was 16.54 for PD-STIR and 37.30 for T2-FS (p = 0.0289). Mean CNR was 4.14 for PD-STIR and 20.20 for T2-FS (p = 0.0212). For both readers, the ASAS MRI+ definition was more often fulfilled by T2-FS than by PD-STIR images, resulting in more patients being classified as having axial spondyloarthritis (axSpA): 68 patients using T2-FS versus 58 patients using PD-STIR. Interreader intraclass correlation coefficients were very good for both PD-STIR (0.91) and T2-FS (0.86). T2-FS sequences improve image quality and hence the detection of osteitis compared to the PD-STIR sequence. More patients were classified as axSpA based on a positive MRI by T2-FS.


Heterogeneous genetic structure in a Fagus crenata population in an old-growth beech forest revealed by microsatellite markers.
The within-population genetic structure of Fagus crenata in a 4-ha plot (200 x 200 m) of an old-growth beech forest was analysed using microsatellite markers. To assess the genetic structure, Moran's I spatial autocorrelation coefficient was calculated. Correlograms of Moran's I showed significant positive values less than 0.100 for short-distance classes, indicating weak genetic structure. The genetic structure within the population is created by limited seed dispersal, and is probably weakened by overlapping seed shadow, secondary seed dispersal, extensive pollen flow and the thinning process. Genetic structure was detected in a western subplot of 50 x 200 m with immature soils and almost no dwarf bamboos (Sasa spp.), where small and intermediate-sized individuals were distributed in aggregations with high density because of successful regeneration. By contrast, genetic structure was not found in an eastern subplot of the same size with mature soils and Sasa cover, where successful regeneration was prevented, and the density of the small and intermediate-sized individuals was low. Moreover, genetic structure of individuals in a small-size class (diameter at breast height < 12 cm) was more obvious than in a large-size class (diameter at breast height >/= 12 cm). The apparent genetic structure detected in the 4-ha plot was therefore probably the result of the structure in the western portion of the plot and in small and intermediate-sized individuals that successfully regenerated under the favourable environment. The heterogeneity in genetic structure presumably reflects variation in the density that should be affected by differences in regeneration dynamics associated with heterogeneity in environmental conditions.


National Trends in Pediatric CT Scans in South Korea: A Nationwide Cohort Study.
This study evaluated the rates and annual trends of pediatric CT scans in South Korea using a nationwide population-based database. Data regarding pediatric CT scan usage between 2012 and 2017 were retrieved from the health insurance review and assessment service. Data on the age, sex, diagnosis, and the anatomical area of involved patients were also extracted. A total of 576376 CT examinations were performed among 58527528 children aged below 18 years (9.8 scans/1000 children), and the number of CT examinations per 1000 children was noted to have increased by 23.2% from 9.0 in 2012 to 11.0 in 2017. Specifically, the number of CT examinations increased by 32.9% for the 6-12 years of age group (7.4/1000 to 9.8/1000) and by 34.0% for the 13-18 years of age group (11.4/1000 to 15.3/1000). Moreover, majority of the CT scans were limited to the head (39.1%), followed by the extremities (32.5%) and the abdomen (13.7%). Notably, the number of extremity CT scans increased by 83.6% (2.3/1000 to 4.2/1000), and its proportion as compared to other scans increased from 25.3% to 37.7%. CT scans in the pediatric population increased continuously from 2012 to 2017 at an annual rate of 4.4%. Therefore, physicians should balance the benefits of CT with its potential harms from associated radiation exposure in pediatric patients.


Detection of human papillomavirus DNA in feline premalignant and invasive squamous cell carcinoma.
Squamous cell carcinoma (SCC) is the most common malignant cutaneous and oral neoplasm of cats. Papillomavirus (PV) DNA has been identified in a proportion of feline Bowenoid in situ carcinomas (BISCs), cutaneous SCCs and a single oral SCC, but its exact role in the pathogenesis remains unknown. In humans, it has been suggested that ultraviolet (UV) light and human PV (HPV) may act as cofactors in cutaneous SCC carcinogenesis. Little is known about the influence of UV light on PV prevalence in feline cutaneous lesions, including actinic keratosis (AK). Additionally, PV prevalence in noncutaneous feline lesions, including oral SCC, is largely not known. This study aimed to determine the presence of PV in 84 cats with premalignant and invasive SCC from cutaneous and noncutaneous sites using polymerase chain reaction and to investigate an association with UV light. Papillomaviral DNA was amplified from two of 12 cases of AK, seven of 22 BISCs, nine of 39 cutaneous SCCs and two of 35 non-cutaneous SCCs. Of the PV DNA sequenced, 50% was most similar to HPV of the genus Betapapillomavirus, while the other 50% was most similar to Felis domesticus PV type 2. Exposure to UV was not associated with an increase in PV for cutaneous SCC. The results of this study suggest that in the cat, HPV DNA may be detectible within a higher percentage of squamous lesions than previously demonstrated, UV exposure may not be a confounder for PV presence, and noncutaneous lesions may have a low prevalence of PV.


Distinct neural activations correlate with maximization of reward magnitude versus frequency.
Choice selection strategies and decision-making are typically investigated using multiple-choice gambling paradigms that require participants to maximize expected value of rewards. However, research shows that performance in such paradigms suffers from individual biases towards the frequency of gains such that users often choose smaller frequent gains over larger rarely occurring gains, also referred to as melioration. To understand the basis of this subjective tradeoff, we used a simple 2-choice reward task paradigm in 186 healthy human adult subjects sampled across the adult lifespan. Cortical source reconstruction of simultaneously recorded electroencephalography suggested distinct neural correlates for maximizing reward magnitude versus frequency. We found that activations in the parahippocampal and entorhinal areas, which are typically linked to memory function, specifically correlated with maximization of reward magnitude. In contrast, maximization of reward frequency was correlated with activations in the lateral orbitofrontal cortices and operculum, typical areas involved in reward processing. These findings reveal distinct neural processes serving reward frequency versus magnitude maximization that can have clinical translational utility to optimize decision-making.


New concepts in neonatal seizures.
The immature brain is more prone to seizures than the older brain as a result of an imbalance between excitatory and inhibitory input. The depolarizing, rather than hyperpolarizing effect of GABA(A) during the first week of life in the rodent, and the delay in postsynaptic GABA(B) inhibition coupled with the over-expression of glutamatergic synapses contribute to this increased propensity toward seizures. It is now clear that seizures can be injurious to the immature brain, although the pattern of seizure-induced injury is age-related. While the immature brain is resistant to acute seizure-induced cell loss, there are functional abnormalities following seizures with impairment of visual-spatial memory and reduced seizure threshold. Neonatal seizures are also associated with a number of activity-dependent changes in brain development including altered synaptogenesis and reduction in neurogenesis. These results argue that neonatal seizures should no longer be considered as benign events.


[The meaning of the genetic code: reconstruction of the stage of prebiologic evolution].
According to a certain order in sets of the two first codon bases, 20 common amino acids can be divided into 5 families each containing 4 amino acids; the corresponding order in the distribution of codon bases can be easily detected, if common amino acids are distributed for the numbers of hydrogen atoms per molecule (Sukhodolets, 1980). In the present paper, the order in the distribution of codon bases is explained on the basis of the hypothesis claiming the prebiological existence of crystalline associates composed of amino acids and bases as free molecules. In these heterogeneous crystalline associates amino acids were analogs to the base douplets and the arrangement of molecules followed a certain rule, namely: 40 protons per molecular complex forming a standard structural compartment. It is proposed that the crystalline associates existed as lyotropic liquid crystals with hydrocarbons as solvent. The genetical code allows to discover two different original crystallization types for bases and amino acids. Therefore, the life possibly originates from combining in the same structure different crystallization patterns, which resulted in formation of a finite crystalline associate.


Influence of inclination angles on intra- and inter-limb load-sharing during uphill walking.
Uphill walking is an inevitable part of daily living, placing more challenges on the locomotor system with greater risk of falls than level walking does. The current study aimed to investigate the effects of inclination angles on the inter-joint and inter-limb load-sharing during uphill walking in terms of total support moment and contributions of individual joint moments to the total support moment. Fifteen young adults walked up walkways with 0°, 5°, 10° and 15° of slope while kinematic and kinetic data were collected and analyzed. With increasing inclination angles, the first peak of the total support moment was increased with unaltered individual joint contributions, suggesting an unaltered inter-joint control pattern in the leading limb to meet the increased demands. The second peak of the total support moment remained unchanged with increasing inclination angles primarily through a compensatory redistribution of the hip and knee moments. During DLS, the leading limb shared the majority of the whole body support moments. The current results reveal basic intra- and inter-limb load-sharing patterns of uphill walking, which will be helpful for a better understanding of the control strategies adopted and for subsequent clinical applications.


COX-2 dependent regulation of mechanotransduction in human breast cancer cells.
The ability of living cells to exert physical forces upon their surrounding is a necessary prerequisite for diverse biological processes, such as local cellular migrations in wound healing to metastatic-invasion of cancer. How forces are coopted in metastasis has remained unclear, however, because the mechanical interplay between cancer cells and the various stromal components has not been experimentally accessible. Current dogma implicates inflammation in these mechanical processes. Using Fourier transform traction microscopy, we measured the force-generating capacity of human breast cancer cells occupying a spectrum of invasiveness as well as basal and inducible COX-2 expression (MCF-7<SUM-149<MDA-MB-231). Compared with non-invasive MCF-7 and moderately-invasive SUM-149, poorly-differentiated MDA-MB-231 cells showed increased cellular dispersion on collagen matrix that was accompanied by emergent distribution of contractile stresses at the interface between the adherent cell and its substrate, defined herein as the traction field. In metastatic MDA-MB-231 cells, the local tractions were precisely tuned to the surrounding matrix rigidity in a physiologic range with the concomitant expression of mechanosensitive integrin β1. These discrete responses at the single-cell resolution were correlated with PGE2 secretion and were ablated by shRNA-mediated knockdown of COX-2. Both COX-2-silenced and COX-2-expressing cells expressed EP2 and EP4 receptors, but not EP1 and EP3. Exogenous addition of PGE2 increased cell tractions and stiffened the underlying cytoskeletal network. To our knowledge this is the first report linking the expression of COX-2 with mechanotransduction of human breast cancer cells, and the regulation of COX-2-PGE2-EP signaling with physical properties of the tumor microenvironment. Drug treatments aimed at reducing this mechanical interplay may have therapeutic potential in the treatment of breast cancer.


KmerKeys: a web resource for searching indexed genome assemblies and variants.
K-mers are short DNA sequences that are used for genome sequence analysis. Applications that use k-mers include genome assembly and alignment. However, the wider bioinformatic use of these short sequences has challenges related to the massive scale of genomic sequence data. A single human genome assembly has billions of k-mers. As a result, the computational requirements for analyzing k-mer information is enormous, particularly when involving complete genome assemblies. To address these issues, we developed a new indexing data structure based on a hash table tuned for the lookup of short sequence keys. This web application, referred to as KmerKeys, provides performant, rapid query speeds for cloud computation on genome assemblies. We enable fuzzy as well as exact sequence searches of assemblies. To enable robust and speedy performance, the website implements cache-friendly hash tables, memory mapping and massive parallel processing. Our method employs a scalable and efficient data structure that can be used to jointly index and search a large collection of human genome assembly information. One can include variant databases and their associated metadata such as the gnomAD population variant catalogue. This feature enables the incorporation of future genomic information into sequencing analysis. KmerKeys is freely accessible at https://kmerkeys.dgi-stanford.org.


Factors Influencing Graft Function following MPFL Reconstruction: A Dynamic Simulation Study.
Medial patellofemoral ligament (MPFL) reconstruction is currently the primary surgical procedure for treating recurrent lateral patellar instability. The understanding of graft function has largely been based on studies performed with normal knees. The current study was performed to characterize graft function following MPFL reconstruction, focusing on the influence of pathologic anatomy on graft tension, variations with knee flexion, and the influence on patellar tracking. Knee squatting was simulated with 15 multibody dynamic simulation models representing knees being treated for recurrent lateral patellar instability. Squatting was simulated in a preoperative condition and following MPFL reconstruction with a hamstrings tendon graft set to allow 0.5 quadrants of lateral patellar translation with the knee at 30 degrees of flexion. Linear regressions were performed to relate maximum tension in the graft to parameters of knee anatomy. Repeated measures comparisons evaluated variations in patellar tracking at 5-degree increments of knee flexion. Maximum graft tension was significantly correlated with a parameter characterizing lateral position of the tibial tuberosity (maximum lateral tibial tuberosity to posterior cruciate ligament attachment distance, r 2 = 0.73, p < 0.001). No significant correlations were identified for parameters related to trochlear dysplasia (lateral trochlear inclination) or patella alta (Caton-Deschamps index and patellotrochlear index). Graft tension peaked at low flexion angles and was minimal by 30 degrees of flexion. MPFL reconstruction decreased lateral patellar shift (bisect offset index) compared with preoperative tracking at all flexion angles from 0 to 50 degrees of flexion, except 45 degrees. At 0 degrees, the average bisect offset index decreased from 0.81 for the preoperative condition to 0.71. The results indicate that tension within an MPFL graft increases with the lateral position of the tibial tuberosity. The graft tension peaks at low flexion angles and decreases lateral patellar maltracking. The factors that influence graft function following MPFL reconstruction need to be understood to limit patellar maltracking without overloading the graft or over constraining the patella.


Prediction of Diagnostic Gene Biomarkers Associated with Immune Infiltration for Basal Cell Carcinoma.
Basal cell carcinoma (BCC) is a frequent tumor of the surface layer of skin or its accessories, and ranks first among the prevalence of skin cancer cases. However, its pathogenesis remains unclear. The purpose of this analysis was to scientifically evaluate the role of mRNAs in the occurrence and progression of BCC and further elucidate their underlying potential molecular mechanisms of action. Differentially expression genes (DEGs) between nineteen BCC cases and five controls which initiate from the GSE103439 and GSE7553 datasets were identified and the transcriptome sequencing information was obtained. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and Gene Ontology (GO) annotation were performed. Logistic regression (LASSO) and support vector machine (SVM) analyses were performed to identify candidate biomarkers obtained from protein-protein interaction (PPI) analysis. The tumor microenvironment comprising hub genes in BCC was investigated by immune infiltration analysis. The expression of two representative hub genes (KIF23 and NCAPG) was measured by qRT-PCR. Finally, the potential miRNAs and lncRNAs related to the hub genes were analyzed on relevant websites to obtain a ceRNA interaction network. Twenty-seven DEGs were identified. Fifteen hub genes were screened in the protein-protein interaction network. These showed marked enrichment in the cell cycle and p53 signaling pathway. FGF20, KIF23, and NCAPG were identified as the diagnostic markers of BCC. Immune cell infiltration analysis suggested their significant association with T cells CD4 memory activated, macrophages M1, and natural killer (NK) resting cells. Two miRNAs and twelve lncRNAs were used to construct the lncRNA-miRNA-mRNA ceRNA network. FGF20, KIF23, and NCAPG are potential diagnostic markers of BCC. Our findings may shed new light on the molecular mechanisms underlying BCC occurrence.


The effect of posture on the normal and pathological auditory startle reflex.
The effect of posture on the EMG pattern of the normal auditory startle reflex was investigated. The startle response to an unexpected auditory tone was studied in eleven normal subjects when standing, and in six normal subjects when sitting relaxed or tonically plantar flexing both feet. Reflex EMG activity was recorded in the tibialis anterior and soleus about twice as frequently when standing, than when sitting relaxed. In addition, the median latencies to onset of reflex EMG activity in the tibialis anterior and soleus were about 40 and 60 ms shorter during standing, than when sitting relaxed. No short latency EMG activity was recorded in the calf muscles during tonic plantar flexion of the feet, while sitting. The effect of posture on the EMG pattern of the pathological auditory startle reflex was studied in five patients with hyperekplexia. In three patients the latency to onset of reflex EMG activity in the tibialis anterior was shorter when standing, than when sitting relaxed. The EMG pattern of the reflex response to sound was studied in detail in two of these patients and consisted of up to three successive components. The expression of each EMG component depended on the postural set of the limbs. In particular, a distinct short latency component was found in posturally important muscles following auditory stimulation. This short latency component was not recorded when sitting relaxed. It is concluded that the EMG pattern of the physiological and pathological auditory startle response is not fixed, but may change with the postural stance of the body. This finding supports the theory that the normal startle reflex and the abnormal startle reflex in hyperekplexia have a common brainstem origin.


Antibiotic lock technique for prevention of cuffed tunnel catheter associated bacteremia.
Central venous cuffed tunnel catheters are commonly used for short term or long term hemodialysis access. However, catheter-associated bacteremia is a common complication. It has been suggested that the addition of antibiotics to the catheter during the interdialytic interval results in a decrease in bacterial colonization and thereby a decrease in catheter associated infections. To test this hypothesis, a prospective, randomized study was performed comparing a gentamicin citrate mixture to standard heparin as the catheter lock. The effect of covering the catheter hub in a sterile bag on the infection rate was additionally tested. From January 1999 to April 2000, all patients who underwent tunnel catheter placement or change (55 catheters) in the Nephrology Interventional Laboratory at Louisiana State University Health Sciences Center in Shreveport, were prospectively randomized as follows: group 1 (n=14): Antibiotic lock with tricitrasol (46.7%), gentamicin (40 mg/ml) and saline in a ratio of 1:5:5 and catheter hub covered with a sterile plastic bag after cleaning with a 10% povidone iodine solution; group 2 (n=22): Heparin lock and sterile plastic bag over catheter hub after cleaning with povidone iodine; and group 3 (n=19): Heparin lock alone. The primary end points of the study were catheter-associated bacteremia and thrombosis. Catheter loss due to access maturation, transplant or transfer were censored. There were a total of 4,805 at risk patient-days. The total number of catheter associated bacteremias were one in group 1, four in group 2 and four in group 3. The number of catheter associated bacteremias per 1000 patient-days in each group was 0.62, 3.05, and 2.11 respectively. The sixty day percent survival of catheters in each group was 74 +/- 12, 55 +/- 12 and 59 +/- 11 respectively. 1) Tricitrasol and gentamicin as an antibiotic lock reduced the incidence of catheter associated bacteremia; 2) Covering the catheter hub with a sterile bag did not provide an additional advantage; 3) The antibiotic lock improved overall survival of catheters.


Cloning and functional characterization of salamander rod and cone arrestins.
To clone, localize, and determine functional binding characteristics of rod and cone arrestins from the retina of the tiger salamander (Ambystoma tigrinum). Two arrestins from salamander retina were cloned on the basis of their homology to known arrestins from other species. The expression pattern of these arrestins (SalArr1 and SalArr2) in the retina was determined by immunocytochemistry and in situ hybridization. SalArr1 and SalArr2 were expressed and functionally characterized. Both immunocytochemistry and in situ hybridization show that SalArr1 and SalArr2 localized specifically to rod and cone photoreceptors, respectively. SalArr1 demonstrated a characteristic high selectivity for light-activated phosphorylated rhodopsin (P-Rh*) and significant species selectivity, binding preferentially to amphibian rhodopsin over bovine rhodopsin. Mutant constitutively active forms of SalArr1 demonstrated a 2- to 4-fold increase in P-Rh* binding (compared with wild-type protein) and an even more dramatic (up to 25-fold) increase in binding to unphosphorylated Rh* and dark P-Rh. Constitutively active SalArr1 mutants also showed a reduced specificity for amphibian rhodopsin. The ability of Escherichia coli-expressed SalArr1, SalArr2, and an SalArr1-3A (L369A,V370A,F371A) mutant to bind to frog Rh* and P-Rh* and to compete with tritiated SalArr1 for amphibian P-Rh* was compared. SalArr1 and its mutant form bound to amphibian P-Rh* with high affinity (Ki = 179 and 74 nM, respectively), whereas the affinity of SalArr2 for P-Rh* was substantially lower (Ki = 9.1 microM). SalArr1 and SalArr2 are salamander rod and cone arrestins, respectively. Crucial regulatory elements in SalArr1 are conserved and play functional roles similar to those of their counterparts in bovine rod arrestin. Rod and cone arrestins are relatively specific for their respective receptors.


Social network analysis of COVID-19 transmission in Karnataka, India.
We used social network analysis (SNA) to study the novel coronavirus (COVID-19) outbreak in Karnataka, India, and to assess the potential of SNA as a tool for outbreak monitoring and control. We analysed contact tracing data of 1147 COVID-19 positive cases (mean age 34.91 years, 61.99% aged 11-40, 742 males), anonymised and made public by the Karnataka government. Software tools, Cytoscape and Gephi, were used to create SNA graphics and determine network attributes of nodes (cases) and edges (directed links from source to target patients). Outdegree was 1-47 for 199 (17.35%) nodes, and betweenness, 0.5-87 for 89 (7.76%) nodes. Men had higher mean outdegree and women, higher mean betweenness. Delhi was the exogenous source of 17.44% cases. Bangalore city had the highest caseload in the state (229, 20%), but comparatively low cluster formation. Thirty-four (2.96%) 'super-spreaders' (outdegree ⩾ 5) caused 60% of the transmissions. Real-time social network visualisation can allow healthcare administrators to flag evolving hotspots and pinpoint key actors in transmission. Prioritising these areas and individuals for rigorous containment could help minimise resource outlay and potentially achieve a significant reduction in COVID-19 transmission.


Clinical Protocol to Promote Standardization of Basic Tinnitus Services by Audiologists.
Purpose Clinical services for tinnitus are needed by millions of people annually. These services have not been standardized, and patients are vulnerable to receiving services that may appear legitimate but are not based on research evidence. The purpose of this clinical focus article is to promote standardization of tinnitus services by proposing an efficient clinical protocol for audiologists. Method The suggested clinical protocol is based primarily on research conducted at the National Center for Rehabilitative Auditory Research for the past 2 decades, with the focus on 2 randomized controlled trials completed recently that showed efficacy of an audiologic protocol involving hearing aids and brief tinnitus counseling. The protocol is mostly consistent with clinical practice guidelines that have been published. Results The two National Center for Rehabilitative Auditory Research randomized controlled trials revealed significant reduction of tinnitus functional effects for both hearing aids and "combination instruments" (hearing aids with a built-in sound generator), although there were no significant differences between devices. Existing clinical practice guidelines for tinnitus are summarized with respect to their common recommendations for assessment and intervention. Conclusions A defined clinical protocol is suggested for audiologists, which includes a case history, appropriate referral, audiologic assessment, use of the Tinnitus and Hearing Survey ( Henry, Griest, et al., 2015 ), brief tinnitus counseling, hearing aids or combination instruments as warranted, follow-up assessment, and criteria for determining if further tinnitus-specific services are needed. Use of this protocol can help to promote standardization of tinnitus practice by audiologists.


Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation.
Both matrix metalloprotease (MMP) activity and cathepsin K (CK) activity have been implicated in cartilage turnover. We investigated the relative contribution of MMP activity and CK activity in cartilage degradation using ex vivo and in vivo models. Bovine articular cartilage explants were stimulated with oncostatin M (OSM) 10 ng/ml and tumor necrosis factor-alpha (TNF-alpha) 20 ng/ml in the presence or absence of the broad-spectrum MMP inhibitor GM6001 and the cysteine protease inhibitor, E64. Cartilage degradation was evaluated in the conditioned medium by glycosaminoglycans (GAG), hydroxyproline, and cross-linked C-telopeptide fragments of type II collagen (CTX-II), which were compared to immunohistochemical evaluations of proteoglycans and CTX-II. We assessed MMP expression by gelatine zymography and CK expression by immunohistochemistry. In vivo, CTX-II release was measured from CK-deficient mice. OSM and TNF-alpha combined induced significant (P<0.01) increase in cartilage degradation products measured by hydroxyproline and CTX-II compared to vehicle control. The cytokines potently induced MMP expression, assessed by zymography, and CK expression investigated by immunohistochemistry. Inhibition of MMP activity completely abrogated hydroxyproline and CTX-II release (P<0.01) and GAG release (P<0.05). In contrast, E64 resulted in increased CTX-II release by 100% (P<0.05) and inhibited GAG release by 30%. Up-regulation of CTX-II fragments was confirmed in vivo in CK null mice. Inhibition of MMP activity reduced both proteoglycan loss and type II collagen degradation. In contrast, inhibition of cysteine proteases resulted in an increase rather than a decrease in MMP derived fragments of collagen type II degradation, CTX-II, suggesting altered collagen metabolism.


Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.


Abnormal Ca2+ Signals in Reactive Astrocytes as a Common Cause of Brain Diseases.
In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca2+ signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca2+ signals. In an Alexander disease (AxD) model, hGFAP-R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca2+ signals. Because the abnormal astrocytic Ca2+ signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IP3RII), we reanalyzed these pathological events using IP3RII-deficient mice and found that all abnormal Ca2+ signals and pathologies were markedly reduced. These findings indicate that abnormal Ca2+ signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca2+ signals in reactive astrocytes may represent an underlying pathology common to multiple diseases.


Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality.
To determine the prognostic potential of a 24-gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP). Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time-dependent c-index analysis, Cox proportional hazards regression and Kaplan-Meier survival analysis. Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time-to-event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96-7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16-19.83; P < 0.001). The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.


An improved direct intermicroscopic (LM leads to SEM leads to TEM) correlative procedure for the examination of mammalian skeletal muscle.
The procedure for direct intermicroscopic (LM leads to SEM leads to TEM) correlation of muscle was modified. The major modification was the use of cryostat sections which showed far better ultrastructural preservation than did paraffin sections. The use of an osmium-thiocarbohydrazide ligand binding procedure (OTOTO) did not noticeably improve the scanning electron microscopic (SEM) image, but did result in a subsequent transmission electron microscopic (TEM) image which showed increased contrast of the intracellular membranous components. Besides improving the preservation at the TEM level of examination, the techniques used to locate the same structure or area previously examined under the complementary modes of microscopy (i.e. LM and SEM), were also refined.


The case for prioritizing implementation strategy fidelity measurement: benefits and challenges.
Implementation strategies are systematic approaches to improve the uptake and sustainability of evidence-based interventions. They frequently focus on changing provider behavior through the provision of interventions such as training, coaching, and audit-and-feedback. Implementation strategies often impact intermediate behavioral outcomes like provider guideline adherence, in turn improving patient outcomes. Fidelity of implementation strategy delivery is defined as the extent to which an implementation strategy is carried out as it was designed. Implementation strategy fidelity measurement is under-developed and under-reported, with the quality of reporting decreasing over time. Benefits of fidelity measurement include the exploration of the extent to which observed effects are moderated by fidelity, and critical information about Type-III research errors, or the likelihood that null findings result from implementation strategy fidelity failure. Reviews of implementation strategy efficacy often report wide variation across studies, commonly calling for increased implementation strategy fidelity measurement to help explain variations. Despite the methodological benefits of rigorous fidelity measurement, implementation researchers face multi-level challenges and complexities. Challenges include the measurement of a complex variable, multiple data collection modalities with varying precision and costs, and the need for fidelity measurement to change in-step with adaptations. In this position paper, we weigh these costs and benefits and ultimately contend that implementation strategy fidelity measurement and reporting should be improved in trials of implementation strategies. We offer pragmatic solutions for researchers to make immediate improvements like the use of mixed methods or innovative data collection and analysis techniques, the inclusion of implementation strategy fidelity assessment in reporting guidelines, and the staged development of fidelity tools across the evolution of an implementation strategy. We also call for additional research into the barriers and facilitators of implementation strategy fidelity measurement to further clarify the best path forward.


Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro.
In mammalian cells, DNA double-strand breaks are predominantly repaired by non-homologous end joining (NHEJ). During repair, the Ku70/80 heterodimer (Ku), XRCC4 in complex with DNA Ligase 4 (X4L4), and XLF form a flexible scaffold that holds the broken DNA ends together. Insights into the architectural organization of the NHEJ scaffold and its regulation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) have recently been obtained by single-particle cryo-electron microscopy analysis. However, several regions, especially the C-terminal regions (CTRs) of the XRCC4 and XLF scaffolding proteins, have largely remained unresolved in experimental structures, which hampers the understanding of their functions. Here, we used magnetic resonance techniques and biochemical assays to comprehensively characterize the interactions and dynamics of the XRCC4 and XLF CTRs at atomic resolution. We show that the CTRs of XRCC4 and XLF are intrinsically disordered and form a network of multivalent heterotypic and homotypic interactions that promotes robust cellular NHEJ activity. Importantly, we demonstrate that the multivalent interactions of these CTRs led to the formation of XLF and X4L4 condensates in vitro which can recruit relevant effectors and critically stimulate DNA end ligation. Our work highlights the role of disordered regions in the mechanism and dynamics of NHEJ and lays the groundwork for the investigation of NHEJ protein disorder and its associated condensates inside cells with implications in cancer biology, immunology and the development of genome editing strategies.


Identifying workers at risk for high health care expenditures: a short questionnaire.
The objective of this study was to create and measure the predictive accuracy of a brief questionnaire for screening new workers to identify those at increased risk for generating high health care insurance expenditures during the following year. Such an instrument could help health plans and providers intervene to mitigate the health risks of identified high-risk workers. We mailed a 53-item questionnaire to members of a "derivation cohort" (adult food processing workers, n = 15496) and obtained records of the eligible respondents' health insurance expenditures during the following year. Using multiple linear regression, we identified eight of the questions that predicted future expenditures most accurately, and created a formula to predict total expenditures from answers to these questions. To validate the formula's predictive accuracy, we used the eight-item questionnaire to survey two "validation cohorts" (transportation workers, n = 7445; and their dependents, n = 5562), inserted responses into the scoring formula, classified respondents into high-risk (top 10%) or low-risk (lower 90%) groupings, and then compared health insurance expenditures generated by the high- and low-risk groups during the following year. In the derivation cohort, age, sex, regular use of medications, frequent visits to physicians, and having arthritis, diabetes, cancer, or high cholesterol predicted future health care expenditures. In the worker and dependent validation cohorts, the respondents classified by the formula as high-risk generated insurance expenditures during the following year that were 2.4 and 1.8 times greater than those generated by the members of the low-risk groups (p < 0.001). An eight-item questionnaire and its scoring formula can identify high-risk groups of workers that will generate high health care expenditures during the following year. Healthcare organizations could use this questionnaire to help target new workers for care management and disease management interventions.


Small expression tags enhance bacterial expression of the first three transmembrane segments of the apelin receptor.
G-protein coupled receptors (GPCRs) are inherently dynamic membrane protein modulators of various important cellular signaling cascades. The apelin receptor (AR or APJ) is a class A GPCR involved in numerous physiological processes, implicated in angiogenesis during tumour formation and as a CD4 co-receptor for entry of human immunodeficiency virus type 1 (HIV-1) to cells. Due to the lack of efficient methods to produce full-length GPCRs enriched with nuclear magnetic resonance (NMR) active (15)N, (13)C, and (or) (2)H isotopes, small GPCR fragments typically comprising 1-2 transmembrane segments are frequently studied using NMR spectroscopy. Here, we report successful overexpression of transmembrane segments 1-3 of AR (AR_TM1-3) in the C41(DE3) strain of Escherichia coli using an AT-rich gene tag previously reported to enhance cell-free expression yields. The resulting protein, with 6 additional N-terminal residues due to the expression tag, was purified using high-performance liquid chromatography (HPLC). Far UV circular dichroism spectropolarimetry demonstrates that AR_TM1-3 has the predicted ~40% α-helical character in membrane-mimetic environments. (1)H-(15)N HSQC NMR experiments imply amenability to high-resolution NMR structural characterization and stability in solution for weeks. Notably, this small expression tag approach may also be generally applicable to other membrane proteins that are difficult to express in E. coli.


15-Second conducted electrical weapon exposure does not cause core temperature elevation in non-environmentally stressed resting adults.
Conducted electrical weapons (CEW) are being incorporated into the use of force continuums of law enforcement agencies in increasing numbers. The use of these weapons has been controversial, especially as related to the sudden in-custody death (ICD) phenomenon. Hyperthermia has been reported in many ICDs attributed to excited delirium, illicit drug toxicity, or other causes. There is speculation that the electrical discharge from the CEWs may contribute to the hyperthermia, presumably from muscle tetany-induced thermogenesis. The objective of this study was to investigate the effect of a prolonged discharge of a CEW on core body temperature in human subjects. This was a prospective, observational study of non-environmentally stressed resting adult human volunteers. Volunteers were exposed to a 15-s continuous discharge from a TASER X26 CEW. A control group conducted usual activities of daily living (ADLs). Core body temperature was measured every 15s by a swallowed telemetric temperature measuring device. Descriptive statistics were applied. 31 subjects were enrolled. 17 subjects received the TASER X26 CEW exposure, and 10 subjects carried out usual ADLs as controls. The discharge from the TASER X26 CEW did not cause an elevation in core body temperature. The range in temperatures among all subjects was 33.1-38.3 degrees C, mean 36.7+0.6. The mean temperature 1 min after exposure was 37.4+0.4. There was no change in temperature from 1 min before the exposure to 1 min, 10 min, or 20 min after the exposure in the majority of patients. One patient had a 0.2 degree increase at 20 min, three patients had a 0.1 degree decrease in temperature at 10 min or 20 min. The mean temperature for subjects in the control group was 37.1, 95% CI=36.9-37.3, and the mean for subjects in the exposed group was 36.7, 95% CI=36.4-37.1. A 15-s discharge from a TASER X26 CEW does not increase the core body temperature of resting, non-environmentally stressed adult subjects. These results challenge the speculation that this weapon technology may be contributing to the hyperthermia in subjects who die from excited delirium, drug toxicity, or other causes while in custody.


Anaerobic co-digestion of microalgae Chlorella sp. and waste activated sludge.
The study investigated the growth characteristics of environmental algal strain, Chlorella, in the modified Zarrouk medium and its anaerobic co-digestion with waste activated sludge (WAS). Analysis of extracellular polymeric substances (EPS) in algal culture and WAS indicated that Chlorella secreted more EPS into the surrounding liquid than formed floc-associated EPS as in activated sludge. Mesophilic anaerobic digestion of algae alone required extended digestion period to produce methane, with biogas yield at 262 mL/gVSfed after 45 days of digestion. When algae was co-digested with varying amounts of WAS, 59-96% in mass, not only biogas yield of microalgae improved but the gas phase was reached more quickly. The dewaterability of co-digestion products were also better than two controls digesting WAS or algae only. These results suggest that anaerobic co-digestion of algae and sludge improves the digestibility of microalgae and could also bring synergistic effects on the dewaterability of digested products for existing anaerobic digesters.


Bis(μ-quinolin-8-olato)-κN,O:O;κO:N,O-bis-[chloridomethyl-phenyl-tin(IV)].
The Sn(IV) atom in the centrosymmetric dinculear title compound, [Sn(2)(CH(3))(2)(C(6)H(5))(2)(C(9)H(6)NO)(2)Cl(2)], shows a trans-C(2)SnNO(2)Cl distorted octa-hedral coordination [C-Sn-C = 157.83 (8)°]. The quinolin-8-olate anion chelates to the Sn atom; its O atom also binds to the inversion-related Sn atom, forming the dinuclear compound. In the crystal structure, weak inter-molecular C-H⋯Cl hydrogen bonding links the mol-ecules, forming supra-molecular chains running along [100].


Effects of chronic daily exposure to tobacco smoke on the high leukemic AKR strain of mice.
Daily exposure of the high leukemic AKR strain of mice to low levels of fresh tobacco smoke (TS) produces significantly different mortality profiles associated with both the sex of the animals and the age at which TS exposure commences. Females tend to be susceptible and die sooner than males, where a significant proportion of animals survives longer than age-matched controls. This prolongation of life appears to be due to a failure of the leukemic state to be mobilized in the TS-exposed males. Exposure of both the females and the males to the TS does not induce significant detectable immunological reactivity against the leukemic cells for several parameters tested, possibly due to a significant enhancement of suppressor activity in the serum of the chronically exposed animals over and above that which also occurs in age-matched control animals.


Redistribution of collateral blood flow from necrotic to surviving myocardium following coronary occlusion in the dog.
Early changes in collateral blood flow after acute coronary occlusion may be critical for survival of ischemic myocardium. We used 15-mum radioactive microspheres to study myocardial blood flow in thoracotomized dogs 10 minutes and 24 hours after occlusion of the left anterior descending coronary artery (LAD). The ischemic area was delineated by dye injected into the distal artery, and indentification of potentially ischemic samples was confirmed by a newly developed technique in which microspheres were excluded from the normally perfused LAD. Layers were separated into necrotic or normal as defined by gross inspection and confirmed by histological examination and creatine phosphokinase assay. Infarction always involved endocardial layers and extended toward the epicardium. Average myocardial blood flow in 48 necrotic samples from 16 dogs either remained low (less than 0.05 ml/min g-1) or declined, falling from 0.11 +/-0.02(SE) at 10 minutes to 0.05 +/-0.01 ml/min g-1 at 24 hours (P less than 0.001). In contrast, in the 32 normal-appearing samples which were ischemic at 10 minutes, flow increased from 0.24 +/-0.03 to 0.39 +/-0.04 ml/min g-1 (P less than 0.001). Flow in control myocardium was 1.43 +/-0.12 and 1.04 +/-0.07 ml/min g-1, respectively. Peripheral mean coronary arterial pressure increased from 26 +/- 3 to 35 +/- 3 mm Hg, largely because of enlargement of collateral vessels; collateral conductance calculated from retrograde flow in 14 dogs increased from 0.023 +/- 0.005 after occlusion to 0.051 +/- 0.009 ml/min mm Hg-1 24 hours later (P less than 0.001). Thus, coronary collateral blood flow is redistributed from necrotic endocardial layers to surviving epicardial ones. In combination with a developing collateral supply this process may be essential for sparing myocardium after coronary occlusion.


Enumeration of carboxyl groups carried on individual components of humic systems using deuteromethylation and Fourier transform mass spectrometry.
Here, we report a novel approach to enumeration of carboxylic groups carried by individual molecules of humic substances using selective chemical modification and isotopic labeling (deuteromethylation) and high-resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FTICR MS). Esterification was conducted with a use of thionyl chloride-deuteromethanol reagent under mild conditions to avoid transesterification. The deuteromethylated products were subjected to solid phase extraction using PPL Bond Elute cartridges prior to FTICR MS analysis. An amount of carboxyl groups in the individual molecular component was estimated from the length of identified deuteromethylation series. The method allowed for discerning between compounds with close elemental compositions possessing different protolytic properties. We found that different carboxylic moieties occupy distinct regions in molecular space of humic substances (HS) projected onto Van Krevelen diagram. These locations do not depend on the source of the humic material and can be assigned to carboxyl-rich alicyclic molecules (5 to 6 COOH), hydrolyzable tannins (3-4 COOH), lignins (1 to 2 COOH), condensed tannins and lignans (0 to 1 COOH), and carbohydrates (0 COOH). At the same time, the alignment pattern of these carboxylated species along the structural evolution lines in Van Krevelen diagrams was characteristic to the specific transformation processes undergone by the humic materials in the different environments. The obtained data enable mapping of molecular ensemble of HS with regards to their specific acidic compartments and might be used for directed fractionation of HS. Graphical abstract Selective isotopic labeling followed by FTICR MS enables discerning between humic molecules with close elemental compositions carrying different numbers of carboxylic groups.


Which is the most accurate formula to estimate fetal weight in women with severe preterm preeclampsia?
To identify the most accurate formula to estimate fetal weight (EFW) from ultrasound parameters in severe preterm preeclampsia. In a prospective study, serial ultrasound assessments were performed in 123 women with severe preterm preeclampsia. The EFW, calculated for 111 live born, normal, singleton fetuses within 7 days of delivery using 38 published formulae, was compared to the actual birth weight (ABW). Accuracy was assessed by correlations, mean (absolute and signed) (%) errors, % correct predictions within 5-20% of ABW and limits of agreement. Accuracy was highly variable. Most formulae systematically overestimated ABW. Five Hadlock formulae utilizing three or four variables and Woo 3 formula had the highest accuracy and did not differ significantly (mean absolute % errors 6.8-7.2%, SDs 5.3-5.8%, > 75% of estimations within 10% of ABW and 95% limits of agreement between -18/20% and +14/15%). They were not negatively affected by clinical variables but had some inconsistency in bias over the ABW range. All other formulae, including those targeted for small, preterm or growth restricted fetuses, were inferior and/or affected by multiple clinical variables. In this GA window, Hadlock formulae using three or four variables or Woo 3 formula can be recommended.


Competition between Loss of H2 versus H+H in the Fragmentation of the Fluorene Cation.
The fluorene cation is a frequently studied molecule in the context of fragmentation experiments. This is because of its potential role in interstellar chemistry, notably as a precursor of PAH cages. In this paper, we analyze H, H+ , H2 and H 2 + ${{\rm{H}}_2^ + }$ losses from the fluorene cation using the SMF (Statistical Molecular Fragmentation) model. We calculate the probabilities of all the 534 possible fragmentation channels as a function of the excitation energy, up to the loss of three hydrogens. Four different types of hydrogen atom pairings (from the same carbon, from the same ring, from different rings and across-the-bay) have been tested in order to determine which types contribute to the actual production of hydrogen molecules. The simulated breakdown curves are in very good agreement with different experimental results when same ring pairing is taken into account. It was possible to deduce from the model the locations of the emitted H, H+ , H2 and H 2 + ${{\rm{H}}_2^ + }$ species.


Survey among survivors of the 1995 Ebola epidemic in Kikwit, Democratic Republic of Congo: their feelings and experiences.
This study describes experiences of the survivors of the 1995 Ebola epidemic in Kikwit, Democratic Republic of Congo. Most of the survivors in our sample had cared for a sick family member before becoming ill themselves, and most had never heard of Ebola before they developed symptoms and therefore did not suspect that they were infected by the virus. Fear, denial and shame were their principal initial feelings. After release from hospital, survivors were abandoned by family or friends more often than they had expected. Belief in god was an important aid to all of them. Their most negative experiences were witnessing other people dying in the isolation ward of the Kikwit General Hospital, and the reluctance of hospital personnel to treat them. During Ebola outbreaks more attention should be given to the psychosocial implications of such an epidemic. Information campaigns should include antidiscrimination messages and more psychosocial support should be given to patients and their families.


Tumour necrosis factor-alpha- vs. growth factor deprivation-promoted cell death: different receptor requirements for mediating nerve growth factor-promoted rescue.
Physiological and pathological aging of the central nervous system (CNS) is characterized by functional neuronal impairments which may lead to perturbed cell homeostasis and eventually to neuronal death. Many toxic events may underlie age-related neurodegeneration. These include the effects of beta amyloid, Tau and mutated presenilin proteins, free radicals and oxidative stress, pro-inflammatory cytokines and lack of growth factor support, which can be individually or collectively involved. Taken individually, these toxicants can induce very diverse cell responses, thus requiring individually targeted corrective interventions upstream of common cell death (apoptotic) pathways. Recent preliminary evidence suggests that the pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha) and growth factor withdrawal can both activate a common apoptotic pathway in nerve growth factor (NGF)-responsive PC12 cells involving caspase 3, albeit through very distinct upstream pathways: the former through active signalling and the latter through passive or lack of survival signalling. Here, we show that NGF can rescue PC12 cells from both growth factor withdrawal- and TNFalpha-promoted cell death. However, NGF rescue from growth factor withdrawal requires NGF signalling through the high-affinity tyrosine kinase receptor (TrkA), while NGF rescue from TNFalpha-promoted cell death requires NGF signalling through the low-affinity p75NTR receptor. These results strengthen the idea that prevention of age- or pathology-associated neurodegeneration may require varied molecular approaches reflecting the diversity of the toxicants involved, possibly acting simultaneously.


The muscle twitch profile assessed with motor unit magnetic resonance imaging.
Localised signal voids in diffusion-weighted (DW) images of skeletal muscle have been postulated to occur as a result of muscle fibre contraction and relaxation. We investigated the contrast mechanism of these signal voids using a combination of modelling and experimental measurements by employing DW and phase contrast (PC) imaging sequences. The DW signal and PC signal were simulated for each time point of a theoretical muscle twitch. The model incorporated compaction (simulating actively contracting muscle fibres) and translation (simulating passively moving surrounding fibres). The model suggested that the DW signal depended on contraction time and compaction whereas the PC signal depended on contraction time, compaction and translation. In a retrospective study, we tested this model with subgroup analyses on 10 healthy participants. Electrical nerve stimulation was used to generate muscle twitches in lower leg muscles; the resulting force was measured using an MR-compatible force transducer. At current levels causing a visible muscle twitch (~13 mA), the width of the first signal drop in the DW signal (mean ± SD: 103 ± 20 ms) was comparable with the force contraction time (93 ± 34 ms; intraclass correlation coefficient [ICC] = 0.717, P = .010). At current levels activating single motor units (~9 mA), the contraction time determined from the DW signal was 75 ± 13 ms and comparable with the PC contraction time (81 ± 15 ms; ICC = 0.925, P = .001). The maximum positive velocity was 0.55 ± 0.26 cm/s and the displacement was 0.20 ± 0.10 mm. Voxel-wise analysis revealed localised DW changes occurring together with more widespread phase changes. In conclusion, local signal attenuations in DW images following muscle fibre activation are primarily caused by compaction. The PC sequence also detects translating muscle tissue being passively pulled. The magnitude of the changes in DW and PC images depends on the twitch's contractile properties and percentage contraction. DW imaging and PC imaging can therefore measure twitch profiles of skeletal muscle fibres.


Nitrogen metabolism of four raw meat diets in domestic cats.
Little nutritional information has been collected from domestic cats fed raw meat diets. The objective of the present study was to evaluate differences in N metabolism of domestic cats fed raw beef-based diet (66 % crude protein (CP) and 20 % fat), bison-based diet (49 % CP and 39 % fat), elk-based diet (79 % CP and 6 % fat) and horse-based diet (60 % CP and 26 % fat). A total of eight intact adult female cats were fed to maintain body weight in a cross-over design. Daily food intake, faecal and urinary outputs, and N metabolism were measured. Dietary N was highly digestible (96.8 (SEM 0.7)) for all treatments. Urinary N accounted for a majority of total N excretion, and differences in total N excretion reflect differences in urinary N. Differences in N intake and N absorption were due to differences in CP levels among diets. N retention was similar to values reported in the literature for domestic cats fed purified and traditional extruded diets. Despite differences in protein concentrations and N intake, all raw meats tested maintained N metabolism.


Approximating selective sweeps.
The fixation of advantageous mutations in a population has the effect of reducing variation in the DNA sequence near that mutation. Kaplan et al. (1989) used a three-phase simulation model to study the effect of selective sweeps on genealogies. However, most subsequent work has simplified their approach by assuming that the number of individuals with the advantageous allele follows the logistic differential equation. We show that the impact of a selective sweep can be accurately approximated by a random partition created by a stick-breaking process. Our simulation results show that ignoring the randomness when the number of individuals with the advantageous allele is small can lead to substantial errors.


T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya.
HIV-infected children are less capable of mounting and maintaining protective humoral responses to vaccination against measles compared to HIV-uninfected children. This poses a public health challenge in countries with high HIV burdens. Administration of anti-retroviral therapy (ART) and revaccinating children against measles is one approach to increase measles immunity in HIV-infected children, yet it is not effective in all cases. Immune anergy and activation during HIV infection are factors that could influence responses to measles revaccination. We utilized a flow cytometry-based approach to examine whether T cell anergy and activation were associated with the maintenance of measles-specific immunoglobulin (Ig)G antibodies generated in response to measles revaccination in a cohort of HIV-infected children on ART in Nairobi, Kenya. Children who sustained measles-specific IgG for at least 1 year after revaccination displayed significantly lower programmed cell death 1 (PD-1) surface expression on CD8(+) T cells on a per-cell basis and exhibited less activated CD4(+) T cells compared to those unable to maintain detectable measles-specific antibodies. Children in both groups were similar in age and sex, CD4(+) T cell frequency, duration of ART treatment and HIV viral load at enrolment. These data suggest that aberrant T cell anergy and activation are associated with the impaired ability to sustain an antibody response to measles revaccination in HIV-infected children on ART.


Gallstone lithotripsy (GSL): results of the Technomed Sonolith 3000 multicenter trials.
Gallstone lithotripsy (GSL) with the Technomed Sonolith 3000 extracorporeal lithotripter was studied in a multisite, international cooperative trial involving the United States, France, and Italy. All participating sites worked under a common protocol to investigate the safety and efficacy of GSL for symptomatic gallstone patients. These collective results are from a mix of 25 academic and community hospital sites using fixed and transportable/mobile versions of the lithotripter. As of November 1, 1990, 661 patients have been treated in this two-arm randomized study (GSL Only vs GSL + Ursodiol [Actigall]). Patients were treated with up to 2,500 shocks per session and only two treatments were allowed. All machines had standardized pressure settings (850 bar nominal) and operator adjustment of output voltage was not allowed. We saw no statistically significantly different results in initial fragmentation between patients pre-loaded with ursodiol for 2 weeks and those treated by GSL alone. Gallbladder clearance rates did vary with the stone number, size, and burden as well as the adequacy of initial fragmentation. In the GSL + Ursodiol Arm of the trial, 46.2% of patients with solitary, 5-to 20-mm calculi are stone-free at 6 months.


Advances in NMR Spectroscopy of Weakly Aligned Biomolecular Systems.
The measurement and application of residual dipolar couplings (RDCs) in solution NMR studies of biological macromolecules has become well established over the past quarter of a century. Numerous methods for generating the requisite anisotropic orientational molecular distribution have been demonstrated, each with its specific strengths and weaknesses. In parallel, an enormous number of pulse schemes have been introduced to measure the many different types of RDCs, ranging from the most widely measured backbone amide 15N-1H RDCs, to 1H-1H RDCs and couplings between low-γ nuclei. Applications of RDCs range from structure validation and refinement to the determination of relative domain orientations, the measurement of backbone and domain motions, and de novo structure determination. Nevertheless, it appears that the power of the RDC methodology remains underutilized. This review aims to highlight the practical aspects of sample preparation and RDC measurement while describing some of the most straightforward applications that take advantage of the exceptionally precise information contained in such data. Some emphasis will be placed on more recent developments that enable the accurate measurement of RDCs in larger systems, which is key to the ongoing shift in focus of biological NMR spectroscopy from structure determination toward gaining improved understanding of how molecular flexibility drives protein function.


Endogenous calcitonin gene-related peptide modulates tachycardiac but not bradycardiac baroreflex in rats.
Effects of intracisternally administered human calcitonin gene-related peptide (8-37) [hCGRP-(8-37)], an antagonist, and hCGRP, an agonist of the CGRP receptor in the rat central nervous system, on baroreflex sensitivity (BRS) were studied in conscious male rats. Each rat sequentially received intracisternally injected 0.9% saline and then hCGRP-(8-37) at doses of 1, 2.5, and 5 nmol in a volume of 10 microliters at an interval of 15 min. Five minutes after each injection, sodium nitroprusside (SNP, 10 micrograms/kg) or phenylephrine hydrochloride (PE, 2 micrograms/kg) was intravenously administered to induce reflex tachycardia or bradycardia, respectively. Intracisternally administered hCGRP-(8-37) increased BRS of the reflex tachycardia induced by SNP in a dose-related manner but did not change the BRS after PE. Intracisternally injected hCGRP significantly decreased the BRS after SNP. The lowering effect of hCGRP on BRS after SNP was inhibited by hCGRP-(8-37) injected before hCGRP. These results suggest that endogenous CGRP in the lower brain stem is selectively involved in the tachycardiac but not the bradycardiac baroreflex and modulates the baroreflex in an inhibitory rather than facilitatory fashion.


[A case of surgical resection for liver metastasis of gastric cancer with portal vein tumor thrombus].
A 58-year-old man presented with anorexia and weight loss in April 2010. Endoscopic examination revealed a type 3 tumor extending from the gastric cardia to the antrum. Preoperative imaging showed liver metastasis (S8; 2 cm) and direct invasion of the cancer into the pancreas. We administered 4 courses of chemotherapy (DCS) for the unresectable tumor; the impact of the therapy was partial response (PR). We performed total gastrectomy, D2 dissection, splenectomy, distal pancreatectomy, and partial hepatectomy (S8) in April 2011. The patient was treated with 8 courses of adjuvant chemotherapy with S-1. In April 2012, abdominal computed tomography (CT) revealed a solitary recurrent lesion in the liver (S2). After 7 courses of chemotherapy(weekly paclitaxel), abdominal CT and magnetic resonance imaging (MRI) revealed a tumor thrombus in the portal vein extending from P2 to the umbilical portion (UP). We performed left hepatectomy and cholecystectomy due to the absence of new lesions. Histopathological findings revealed that the poorly differentiated adenocarcinoma had metastasized to the liver. Abdominal CT revealed the presence of multiple recurrent metastases in the liver, 4 months after the surgery. The patient died 27 months after the initial surgery and 7 months after the last operation.


C9C5 positive mature oligodendrocytes are a source of Sonic Hedgehog in the mouse brain.
In the mature rodent brain, Sonic Hedgehog (Shh) signaling regulates stem and progenitor cell maintenance, neuronal and glial circuitry and brain repair. However, the sources and distribution of Shh mediating these effects are still poorly characterized. Here, we report in the adult mouse brain, a broad expression pattern of Shh recognized by the specific monoclonal C9C5 antibody in a subset (11-12%) of CC1+ mature oligodendrocytes that do not express carbonic anhydrase II. These cells express also Olig2 and Sox10, two oligodendrocyte lineage-specific markers, but not PDGFRα, a marker of oligodendrocyte progenitors. In agreement with oligodendroglial cells being a source of Shh in the adult mouse brain, we identify Shh transcripts by single molecule fluorescent in situ hybridization in a subset of cells expressing Olig2 and Sox10 mRNAs. These findings also reveal that Shh expression is more extensive than originally reported. The Shh-C9C5-associated signal labels the oligodendroglial cell body and decorates by intense puncta the processes. C9C5+ cells are distributed in a grid-like manner. They constitute small units that could deliver locally Shh to its receptor Patched expressed in GFAP+ and S100β+ astrocytes, and in HuC/D+ neurons as shown in PtcLacZ/+ reporter mice. Postnatally, C9C5 immunoreactivity overlaps the myelination peak that occurs between P10 and P20 and is down regulated during ageing. Thus, our data suggest that C9C5+CC1+ oligodendroglial cells are a source of Shh in the mouse postnatal brain.


In vitro growth of murine T cells. VI. Accelerated skin graft rejection caused by adoptively transferred cells expanded in T cell growth factor.
The ability of adoptively transferred cytotoxic T cells expanded in T cell growth factor (TCGF) to induce accelerated graft rejection of B10.BR skin grafts from normal B6AF1 recipient mice was tested. In vitro sensitized cells expanded in regular TCGF were capable of accelerating graft rejection when adoptively transferred i.v. 1 day after grafting. Cells expanded in LF-TCGF (lectin-free) were more effective in accelerating graft rejection than cells expanded in lectin containing TCGF. Nonsensitized cells or cells sensitized to irrelevant B10.D2 antigenic determinants in vitro and subsequently expanded in LF-TCGF were unable to induce accelerated rejection of the B10.BR grafts. Expanded cytotoxic effector cells known to be immunologically active in vivo were also unable to accelerate graft rejection if irradiated with 2000 R before adoptive transfer. The ability of cells to lyse the appropriate targets in 4-hr 51Cr release assays correlated poorly with the effectiveness of these cells after in vivo injection. These studies are the first to demonstrate that cytotoxic cells expanded in TCGF are capable of mediating a cytotoxic function in vivo.


Stability analysis for neural dynamics with time-varying delays.
By using the usual additive neural-network model, a delay-independent stability criterion for neural dynamics with perturbations of time-varying delays is derived. We extend previously known results obtained by Gopalsamy and He to the time varying delay case, and present decay estimates of solutions of neural networks. The asymptotic stability is global in the state space of neuronal activations. From the techniques used in this paper, it is shown that our criterion ensures stability of neural dynamics even when the delay functions vary violently with time. Our approach provides an effective method for the stability analysis of neural dynamics with delays.


The Meaning of the Sperm Donor for Heterosexual Couples: Confirming the Position of the Father.
In the literature, relatively little attention has been paid to the meaning of donor involvement in the intimate couple dyad. The current study aimed to enrich our understanding of couples' meaning-making regarding the anonymous sperm donor and how they dealt with the donor involvement. Semi-structured interviews were conducted with nine couples, who had at least one child conceived through sperm donation. Our thematic analysis showed that the donor conception was seen as a different path to create a normal family. Once the family was formed, most couples avoided talking about the donor because it was perceived as disrupting men's growing confidence in their position as father. Participants tried to confirm the position of the father to protect the family relationships. Uncertainties about how they were perceived as parents showed the continuing dominance of genetic ties within our social discourse. Participants also dealt with reminders of the donor in their daily life. Overall, they tried to manage the space taken up by the donor and to protect the position of the father. We relate our findings to literature on topic avoidance and shared obliviousness in families. For counseling practice, it could be useful to explore couples' meaning-making about the donor as this seemed to serve family functioning.


Drug-related lupus.
All physicians should be alerted to the many drugs and other agents that are associated with drug-related lupus, as there is an increasing number of such drugs. A wide range of immune responses and antibodies are being reported with this syndrome. A new concern is the perceived ability of new biologic treatments to induce these autoimmune phenomena. More in-depth studies of various environmental factors are providing new insights into possible mechanisms. These include the immune responses to the drugs, their metabolites, and drug-altered conjugates; bioactivation mechanisms of drug protein conjugation; the role of macrophages in antigen recognition and processing; and lastly, the important role of the acetylation of various drugs and the relationship to immunogenetic factors. Continued study of this human experimental model of lupus will help to clarify the etiology and mechanisms of systemic lupus erythematosus itself.


A hard lens with extended wear possibilities.
The variety of parameters affecting extended wear lenses makes it obvious that the ability to use a lens under an eye closed in sleep is by no means solely contingent upon the oxygen transmission characteristics of the material. This study shows that a new silicone acrylate lens apparently permits sufficient tear-flow to maintain a viable cornea while the lens is worn overnight. In this preliminary report, over eighty percent of the previously successful hard lens patients fitted with lenses made of this material were able to maintain contact lens wear on an extended basis.


[Health assessment of the elderly--a practical approach?].
Health assessment of elderly people as a routine procedure has been proposed in official reports and in the literature. Some programmes have been evaluated, including home visits and periodical health assessment programmes, but evaluation produces conflicting results. Whether health assessment of elderly people represents true or false safety depends on the association between risk factors and end points like mortality, morbidity, functional ability and quality of life. Who should be offered a health assessment, what should be the elements, and what is the scientific documentation for such an approach? Health assessment is of little value without follow-up. Periodic large-scale home visits or screening programmes are not recommended. Health assessment of old people at risk should be carried out by the general practitioner. The community has an obligation to plan for adequate medical services to prevent elderly people at risk to deteriorate without medical follow-up.


Anomalous diffusion in a monolayer of lightweight spheres fluidized in air flow.
This paper presents statistical analyses of random motions in a single layer of fluidized lightweight spherical particles. Foam polystyrene spheres were driven by an upward airflow through the sieve mesh, and their two-dimensional motion was acquired using image analysis. In the bulk region, the particle velocity distributions changed from Gaussian to heavy-tailed distribution as the bulk packing fraction ϕ_{b} was increased. The mean square displacement of the particles exhibited transition to subdiffusion at much lower ϕ_{b} than observed in previous studies using similar setup but with heavier particles. A slight superdiffusion and significant growth of the correlation length in the two-body velocity correlation was observed at further large ϕ_{b}. The effect of the wall on the dynamics of the particles was also investigated, and the anisotropy of the granular temperature was found to be a useful index to discriminate between the wall region and the bulk. The turbulence statistics in the wake of a particle indicated a strong wall-normal asymmetry of aerodynamic forcing as the "thermal" agitation in the wall region.


Surgical Outcomes of Solid Pseudopapillary Neoplasm of the Pancreas: A Single Institution's Experience of 16 Cases.
Solid-pseudopapillary tumor (SPT) of the pancreas is a rare tumor, generally characterized by a well-encapsulated mass. The aim of the current study was to analyse the clinicopathological characteristics and treatment outcomes of patients with SPT. In this study, we report our clinical experience with 16 cases of SPTs. Sixteen patients who underwent surgery for pathologically confirmed SPT were included. Data of the patients were reviewed from the prospectively recorded database. Patients' demographics, laboratory values, clinical presentation, radiological imaging findings, surgical treatment, perioperative complications, pathological features, post-operative course, and long-term survival were collected and analyzed. Statistical analyses were performed using the computer program Statistical Package for Social Sciences (SPSS) 16.0 for Windows. The tumors ranged from 2 to 11 cm in diameter and were located in the head in ten patients (62.5%), the neck in two patients (12.5%), and the body or tail in four patients (25%). All patients were women whose ages ranged from 21 to 79 years (mean age was 41.62 ± 15.08). Patients had resection margins free of tumor resections and there were no preoperative or postoperative mortalities. There was no recurrence or metastasis after the surgical resection. All patients were alive at a mean follow-up of 49.06 ± 29.53 months (range 6 to 99). SPT is a rare pancreatic neoplasm with a low malignant potential, and is common in young women. If SPT is diagnosed before surgery, complete surgical resection, generally enucleation is the most effective therapy for SPT.


Neural basis subserving the detection of postural instability: an fMRI study.
Human upright posture is a product of a complex dynamic system that relies on integration of input from multimodal sensory sources. Extensive research has explored the role of visual, vestibular, and somatosensory systems in the control of upright posture. However, the role of higher cognitive function in a participant's assessment of postural stability has been less studied. In previous research, we showed specific neural activation patterns in EEG associated with recognition of unstable postures in young healthy participants. Similar EEG patterns have been recently observed in regulation of posture equilibrium in dynamic stances. This article evaluates participants' postural stability in dynamic stances and neural activation patterns underlying visual recognition of unstable postures using event-related functional MRI (fMRI). Our results show that the "stable" participants were successful in recognition of unstable postures of a computer-animated body model and experienced egocentric motion. Successful recognition of unstable postures in these participants induces activation of distinct areas of the brain including bilateral parietal cortex, anterior cingulate cortex, and bilateral cerebellum. In addition, significant activation is observed in basal ganglia (caudate nucleus and putamen) but only during perception of animated postures. Our findings suggest the existence of modality-specific distributed activation of brain areas responsible for detection of postural instability.


Bias-field controlled phasing and power combination of gyromagnetic nonlinear transmission lines.
Gyromagnetic Nonlinear Transmission Lines (NLTLs) generate microwaves through the damped gyromagnetic precession of the magnetic moments in ferrimagnetic material, and are thus utilized as compact, solid-state, frequency agile, high power microwave (HPM) sources. The output frequency of a NLTL can be adjusted by control of the externally applied bias field and incident voltage pulse without physical alteration to the structure of the device. This property provides a frequency tuning capability not seen in many conventional e-beam based HPM sources. The NLTLs developed and tested are mesoband sources capable of generating MW power levels in the L, S, and C bands of the microwave spectrum. For an individual NLTL the output power at a given frequency is determined by several factors including the intrinsic properties of the ferrimagnetic material and the transmission line structure. Hence, if higher power levels are to be achieved, it is necessary to combine the outputs of multiple NLTLs. This can be accomplished in free space using antennas or in a transmission line via a power combiner. Using a bias-field controlled delay, a transient, high voltage, coaxial, three port, power combiner was designed and tested. Experimental results are compared with the results of a transient COMSOL simulation to evaluate combiner performance.


Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations.
Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.


A versatile chemo-enzymatic route to enantiomerically pure beta-branched alpha-amino acids.
A series of diastereoisomers of beta-methyl-beta-phenylalanine analogues 1a-f have been prepared in enantiomerically pure form using a combination of chemo- and biocatalysis. Starting from l-threonine methyl ester 2, a range of beta,beta-disubstituted didehydroamino acids were obtained as their (Z)-isomers 6a-f. Asymmetric hydrogenation of these alkenes, using either the [Rh(R,R)-Et-DuPhos(COD)]BF4 or [Rh(S,S)-Et-DuPhos(COD)]BF4 catalyst, followed by hydrolysis yielded two of the four possible sets of diastereoisomers of the beta-branched amino acid. Subsequent stereoinversion, using a stereoselective amino acid oxidase in combination with a nonselective reducing agent, furnished the remaining two sets of diastereomers.


Preparation, characterization and optimization of glipizide controlled release nanoparticles.
The purpose of the present study was to develop glipizide controlled release nanoparticles using alginate and chitosan thorough ionotropic controlled gelation method. Glipizide is a frequently prescribed second generation sulfonylurea which lowers the blood glucose in type-two diabetics. Quick absorption of the drug from the gastrointestinal tract along with short half- life of elimination makes it a good candidate for controlled release formulations. Alginate-chitosan nanoparticles (ACNP) are convenient controlled delivery systems for glipizide, due to both the release limiting properties of the system, and the bioadhesive nature of the polymers. In the present study, glipizide loaded alginate-chitosan nanoparticles (GlACNP) were prepared, and the particle characteristics including particle size (PS), zeta potential (ZP), entrapment efficiency (EE%), loading percent (LP), and mean release time (MRT), as well as the morphology of the nanoparticles, the drug-excipient compatibility, and the release kinetics along with the drug diffusion mechanism were evaluated. The results suggested that ionotropic controlled gelation method offers the possibility of preparing the nanoparticles in mild conditions in an aqueous environment, and can lead to the preparation of particles with favorable size, controlled release characteristics, and high entrapment efficiency, serving as a convenient delivery system for glipizide. The particle and release characteristics can be efficiently optimized using the Box-Behnken design. Based on the findings of the present study, it is expected that this novel formulation be a superior therapeutic alternative to the currently available glipizide delivery systems.


Distinct regulation of CD40-mediated interleukin-6 and interleukin-12 productions via mitogen-activated protein kinase and nuclear factor kappaB-inducing kinase in mature dendritic cells.
The role of mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) pathways, especially NF-kappaB-inducing kinase (NIK)-mediated alternative pathway, in CD40-mediated interleukin (IL)-6 and IL-12 productions by immature or mature dendritic cells (DCs) was investigated. Murine myeloid DCs were matured by treatment with lipopolysaccharide. CD40 ligation induced modest or vigorous cytokine productions in immature or mature DCs, respectively. After CD40 ligation, p38 MAPK was significantly activated in either immature or mature DCs. SB203580, a p38 MAPK inhibitor, markedly decreased CD40-mediated IL-6 and IL-12 productions in immature DCs. In mature DCs, SB203580 significantly decreased CD40-mediated IL-6 but not IL-12 production. On the other hand, CD40 ligation induced vigorous activation of the NF-kappaB alternative pathway including p100 phosphorylation and subsequent nuclear translocations of p52, a processed form of p100, and RelB in mature but not immature DCs. The CD40-mediated phosphorylation of p100 was completely abolished in NIK-mutated mature DCs. The NIK mutation markedly reduced CD40-mediated IL-12 but not IL-6 production by mature DCs. Taken together, we concluded that IL-6 and IL-12 productions in response to CD40 ligation were controlled by p38 MAPK and NIK mediated alternative pathway, respectively, in mature DCs.