Investigating the Effects of Donors and Alkyne Spacer on the Properties of Donor-Acceptor-Donor Xanthene-Based Dyes.
NIR dyes have become popular for many applications, including biosensing and imaging. For this reason, the molecular switch mechanism of the xanthene dyes makes them useful for in vivo detection and imaging of bioanalytes. Our group has been designing NIR xanthene-based dyes by the donor-acceptor-donor approach; however, the equilibrium between their opened and closed forms varies depending on the donors and spacer. We synthesized donor-acceptor-donor NIR xanthene-based dyes with an alkyne spacer via the Sonogashira coupling reaction to investigate the effects of the alkyne spacer and the donors on the maximum absorption wavelength and the molecular switching (ring opening) process of the dyes. We evaluated the strength and nature of the donors and the presence and absence of the alkyne spacer on the properties of the dyes. It was shown that the alkyne spacer extended the conjugation of the dyes, leading to absorption wavelengths of longer values compared with the dyes without the alkyne group. In addition, strong charge transfer donors shifted the absorption wavelength towards the NIR region, while donors with strong π-donation resulted in xanthene dyes with a smaller equilibrium constant. DFT/TDDFT calculations corroborated the experimental data in most of the cases. Dye 2 containing the N,N-dimethylaniline group gave contrary results and is being further investigated.


Cleanability of Metal Surface Finishes Found in Medical Devices and the Environment of Care.
The surface finish of reusable medical devices often is a consideration during design, with attention paid to utility, aesthetics, and cost. To study the cleanability of metal surfaces of varying roughness and finish, soil made of bovine blood and egg yolk was placed on nickel alloy surface of varying average roughness (Ra) values (nominal values of 2-500 μin) and finishes (lapped, ground, milled, profiled, and shape turned). A commercially available wipe consisting of quaternary ammonium compound and less than 20% alcohol was applied for a total of eight wipe cycles to remove the soil. The wipe was applied in both horizontal and vertical directions. Evaluation methods for cleanliness include visual inspection and adenosine triphosphate (ATP) measurement. Rougher surfaces above nominal Ra of 250 were found to have higher ATP readings when wiped in both horizontal and vertical directions. In addition, different surface finishes have different cleanabilities despite similar nominal Ra. To ensure optimal cleaning, surfaces should be cleaned in multiple directions. In the future, similar studies will be coupled with efficacy studies and surfaces made with other materials will be investigated.


Osteopontin is upregulated after mechanical brain injury and stimulates neurite growth from hippocampal neurons through β1 integrin and CD44.
Brain trauma induces a multitude of reactions at molecular, cellular, and tissue levels, some of which are beneficial to recovery, whereas others are detrimental. Osteopontin (OPN), a glycosylated phosphoprotein, can be found in both the soluble form and as an extracellular matrix constituent in several tissues in the vertebrate body, but its function after brain injury is largely unknown. In this study, the expression of OPN after an experimental traumatic brain injury in rats was examined and its effects on hippocampal neurons and cortical astrocytes were studied using cell-culture techniques. OPN had no influence astrocyte behavior in a scratch assay. However, hippocampal neurons grew well on an OPN substrate with growth comparable to that seen on laminin, but showed a higher degree of primary neurites. Finally, growth on OPN was mediated through β1 intregrins and CD44. These findings indicate that injury-induced OPN may support neurite sprouting, suggesting a role for this molecule in recovery from central nervous system trauma.


Folate and folate-binding protein content in dairy products.
Recent findings suggest a protective role for folates in the reduction of neural tube defects and possibly also coronary heart disease and cancer. Consequently, an increase in the daily intake of folates is warranted, which emphasizes the need for quantitative as well as qualitative measurements of dietary folates. Milk plays an important part in the food chain in many Western countries today. Several studies suggest that folate-binding proteins might have an impact on folate absorption and therefore their concentrations are also important. The mean concentration of the predominant form of folate, 5-methyltetrahydrofolate (5-CH3THF), was determined using HPLC in thirteen selected dairy products; skim milk powder, two pasteurized milks, UHT milk, two fermented milks, three whey products and four different cheeses. All results were corrected for recovery by spiking the samples with 5-CH3THF. Effects of storage of dairy products on 5-CH3THF concentrations were also investigated; generally small and insignificant fluctuations were found, except for hard cheese, in which 5-CH3THF decreased significantly. There was a significant seasonal variation in the folate concentration of pasteurized milk which peaked in the summer months. The concentrations of folate-binding protein in skim milk powder and pasteurized milk analysed using an enzyme-linked immunosorbent assay were similar. UHT milk and fermented milk, both of which are processed at temperatures > 90 degrees C, contained significantly lower concentrations of folate-binding protein.


Predicting Sumatriptan Responsiveness Based on Structural Connectivity in Patients Newly Diagnosed With Migraine.
We aimed to determine whether structural brain connectivity is significantly associated with the response to sumatriptan in patients with migraine. We retrospectively enrolled patients with newly diagnosed migraine who underwent brain diffusion-tensor imaging (DTI) at the time of diagnosis, with regular follow-up for at least 6 months after the initial diagnosis. Patients were classified into good- and poor-responder groups according to their response to sumatriptan. We analyzed the structural connectivity using DTI by applying graph theory using DSI Studio software. We enrolled 59 patients (35 good responders and 24 poor responders) and 30 healthy controls. Global structural connectivity differed significantly between patients with migraine and healthy controls, while local structural connectivity differed significantly between good and poor responders. The betweenness centrality was lower in good responders than in poor responders in the left lateral geniculate thalamic nucleus (26.078 vs. 41.371, p=0.039) and right medial mediodorsal magnocellular thalamic nucleus (60.856 vs. 90.378, p=0.021), whereas was higher in good responders in the left lateral pulvinar thalamic nucleus (98.365 vs. 50.347, p=0.003) and right medial pulvinar thalamic nucleus (216.047 vs. 156.651, p=0.036). We found that structural connectivity in patients with migraine differed from that in healthy controls. Moreover, the local structural connectivity varied with the response to sumatriptan, which suggests that structural connectivity is a useful factor for predicting how a patient will respond to sumatriptan.


Phasor analysis of NADH FLIM identifies pharmacological disruptions to mitochondrial metabolic processes in the rodent cerebral cortex.
Investigating cerebral metabolism in vivo at a microscopic level is essential for understanding brain function and its pathological alterations. The intricate signaling and metabolic dynamics between neurons, glia, and microvasculature requires much more detailed understanding to better comprehend the mechanisms governing brain function and its disease-related changes. We recently demonstrated that pharmacologically-induced alterations to different steps of cerebral metabolism can be distinguished utilizing 2-photon fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotide (NADH) fluorescence in vivo. Here, we evaluate the ability of the phasor analysis method to identify these pharmacological metabolic alterations and compare the method's performance with more conventional nonlinear curve-fitting analysis. Visualization of phasor data, both at the fundamental laser repetition frequency and its second harmonic, enables resolution of pharmacologically-induced alterations to mitochondrial metabolic processes from baseline cerebral metabolism. Compared to our previous classification models based on nonlinear curve-fitting, phasor-based models required fewer parameters and yielded comparable or improved classification accuracy. Fluorescence lifetime imaging of NADH and phasor analysis shows utility for detecting metabolic alterations and will lead to a deeper understanding of cerebral energetics and its pathological changes.


Systematic angle random walk estimation of the constant rate biased ring laser gyro.
An actual account of the angle random walk (ARW) coefficients of gyros in the constant rate biased rate ring laser gyro (RLG) inertial navigation system (INS) is very important in practical engineering applications. However, no reported experimental work has dealt with the issue of characterizing the ARW of the constant rate biased RLG in the INS. To avoid the need for high cost precise calibration tables and complex measuring set-ups, the objective of this study is to present a cost-effective experimental approach to characterize the ARW of the gyros in the constant rate biased RLG INS. In the system, turntable dynamics and other external noises would inevitably contaminate the measured RLG data, leading to the question of isolation of such disturbances. A practical observation model of the gyros in the constant rate biased RLG INS was discussed, and an experimental method based on the fast orthogonal search (FOS) for the practical observation model to separate ARW error from the RLG measured data was proposed. Validity of the FOS-based method was checked by estimating the ARW coefficients of the mechanically dithered RLG under stationary and turntable rotation conditions. By utilizing the FOS-based method, the average ARW coefficient of the constant rate biased RLG in the postulate system is estimated. The experimental results show that the FOS-based method can achieve high denoising ability. This method estimate the ARW coefficients of the constant rate biased RLG in the postulate system accurately. The FOS-based method does not need precise calibration table with high cost and complex measuring set-up, and Statistical results of the tests will provide us references in engineering application of the constant rate biased RLG INS.


The role of time delays, slow processes, and chaos in modulating the cell-cycle clock.
The regulation of the cell cycle clock is examined using a theoretical model for the embryonic cell cycle, where the clock is described as a single-limit cycle [1]. By taking the coefficient of the autocatalytic reaction as proportional to the deviation of the system from its equilibrium state, we show how such clocks can be adjusted to function on several time scales. This feedback control, causing a periodic change in the sign of the autocatalytic reaction, may be interpreted as a periodic change in the ratio of cdc25/wee1 activity. Its introduction results in the appearance of a double limit cycle, signifying the acquisition of the G1 phase and the G2 phase, during embryonic development. Following the loss of stability of the double cycle, through a period-doubling bifurcation, another limit set|a strange attractor|is born. The complicated geometry of this strange attractor can be viewed as an unlimited reservoir of periods in the phase space. We hypothesize that the existence of such a reservoir is advantageous in morphogenetic tissues, such as the bone marrow, as it enables time- and site-specific selection of the optimal cell-cycle period for any specific microenvironment. This can be obtained by the addition of a time delay in the autocatalytic reaction, reflecting, for example, the influence of external molecular signals on cell-cycle progression.


Movement Speed and Accuracy in Space and Time: The Complementarity of Error Distributions.
Movement speed-accuracy trade-off is a function of the space-time constraints of the task. We investigated the space-time account of Hancock and Newell (1985) and the hypothesis of complementarity between the four moments of the error distribution in space and time. Twelve participants performed 15 conditions in a line drawing task composed of different spatial (10, 20, and 30 cm) and temporal (250 to 2,500 ms) criteria. The results showed that all moments of distributions changed systematically between conditions but there were some departures from the Hancock and Newell predictions. In contrast, individual analysis revealed the complementarity of the spatial and temporal error including a trade-off between the four moments of error. These findings support a complementary space-time account of movement speed and accuracy.


The Influence of the Vanishing Twin on the Perinatal Outcome of Surviving Singleton in IVF Pregnancy.
The purpose of this study was to clarify the influence of the vanishing twin (VT) on the perinatal outcomes in the surviving singleton and further identify the susceptible window. Retrospective cohort study. A total of 636 survivors of a vanished co-twin and 11,148 singleton controls were enrolled. The exposed group was further divided into early VT (EVT, VT ≤13 weeks, N = 593) and late VT subgroups (LVT, VT >13 weeks, N = 43) according to the gestational age of the twin vanishing. All participants were conceived through in vitro fertilization (IVF). Perinatal outcomes including gestational age, birthweight, and the incidence of preterm birth (PTB), low birthweight (LBW), small for gestational age (SGA), neonatal intensive care unit (NICU) admission, umbilical cord abnormality, jaundice of the newborn, and oligohydramnios were compared among the groups. In our birth cohort, about 5.4% of all singleton deliveries originated from vanishing twin pregnancies. Compared with the singletons, both early and late VT pregnancy had a significantly lower birth weight (3337.57±532.24 g and 2916.05±526.07 g vs. 3446.15±526.07 g; p < 0.001 and p < 0.001), more frequent neonatal jaundice (47.0% and 60.5% vs. 40.6%; p = 0.002 and p = 0.008), and decreased incidence of umbilical cord abnormality (15.5% and 7.0% vs. 19.9%; p = 0.009 and p = 0.034). Newborns in the early VT group were more likely to manifest as SGA (5.4% vs. 3.6%, p = 0.002) and suffered oligohydramnios (5.4% vs. 3.4%; p = 0.008) than the primary singletons. In addition, the gestational age of late VT survivors was shorter than that of the controls (37.25 ± 3.25 vs. 39.04 ± 1.63, p = 0.001) and had a significantly higher risk of PTB (30.2% vs. 6.6%; p < 0.001) and NICU admission (27.9% vs. 9.4%, p < 0.001). All differences except for SGA maintain significance after adjusting for maternal age, BMI, and parity. Singletons with a vanished co-twin had worse perinatal outcomes compared with the original singletons, with LVT burden even much on the survival one. Therefore, close monitoring during the perinatal period was suggested in this type of neonates. Moreover, elective single embryo transfer should also be fully considered which could tackle the problem at its root.


Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation.
IL28B single nucleotide polymorphisms are strongly associated with spontaneous HCV clearance and treatment response in non-transplant populations. A DDX58 single nucleotide polymorphism is associated with the antiviral response of innate lymphocytes. We aimed at evaluating the associations of donor and recipient IL28B (rs12979860 and rs8099917) and DDX58 (rs10813831) genotypes with severity of HCV recurrence after liver transplantation. In a case-control study of 523 liver transplantation recipients with HCV, we matched severe with mild recurrent HCV based on 2-year clinical and histologic follow-up. A total of 440 liver transplantation recipients (severe, n=235; mild, n=205) with recipient DNA and 225 (severe, n=123; mild, n=102) with both recipient and donor DNA were analyzed. IL28B [rs12979860, non-CC (vs. CC) and rs8099917, non-TT (vs. TT)] in the recipient-only analysis had higher risk of severe recurrent HCV [OR 1.57 and 1.58, p<0.05]. However, for the 225 with donor and recipient DNA, IL28B rs12979860 CC (vs. non-CC) and rs8099917 TT (vs. non-TT) and DDX58 rs10813831 non-GG (vs. GG) were associated with more (not less) severe recurrent HCV. The greatest risk of severe recurrent HCV was for rs12979860 CC donors in non-CC recipients (OR 7.02, p <0.001, vs. non-CC donor/recipient) and for rs8099917 TT donors in non-TT recipients (OR 5.78, p=0.001, vs. non-TT donor/recipient). These associations persisted after controlling for donor age, donor race, and donor risk index. IL28B and DDX58 single nucleotide polymorphisms that are favorable when present in the non-transplant setting or in the recipient are unfavorable when present in a donor liver graft.


Damage control laparotomy in trauma: a pilot randomized controlled trial. The DCL trial.
Although widely used in treating severe abdominal trauma, damage control laparotomy (DCL) has not been assessed in any randomized controlled trial. We conducted a pilot trial among patients for whom our surgeons had equipoise and hypothesized that definitive laparotomy (DEF) would reduce major abdominal complications (MAC) or death within 30 days compared with DCL. Eligible patients undergoing emergency laparotomy were randomized during surgery to DCL or DEF from July 2016 to May 2019. The primary outcome was MAC or death within 30 days. Prespecified frequentist and Bayesian analyses were performed. Of 489 eligible patients, 39 patients were randomized (DCL 18, DEF 21) and included. Groups were similar in demographics and mechanism of injury. The DEF group had a higher Injury Severity Score (DEF median 34 (IQR 20, 43) vs DCL 29 (IQR 22, 41)) and received more prerandomization blood products (DEF median red blood cells 8 units (IQR 6, 11) vs DCL 6 units (IQR 2, 11)). In unadjusted analyses, the DEF group had more MAC or death within 30 days (1.71, 95% CI 0.81 to 3.63, p=0.159) due to more deaths within 30 days (DEF 33% vs DCL 0%, p=0.010). Adjustment for Injury Severity Score and prerandomization blood products reduced the risk ratio for MAC or death within 30 days to 1.54 (95% CI 0.71 to 3.32, p=0.274). The Bayesian probability that DEF increased MAC or death within 30 days was 85% in unadjusted analyses and 66% in adjusted analyses. The findings of our single center pilot trial were inconclusive. Outcomes were not worse with DCL and, in fact, may have been better. A randomized clinical trial of DCL is feasible and a larger, multicenter trial is needed to compare DCL and DEF for patients with severe abdominal trauma. Level II.


Cell motility and spreading promoted by CEACAM6 through cyclin D1/CDK4 in human pancreatic carcinoma.
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) belongs to the human carcino-embryonic antigen (CEA) family. Numerous lines of studies have indicated that altered expression of CEACAM6 may have a role in carcinogenesis and development. However, few studies have defined functional roles and mechanisms of action. In the present study, the relationship between clinical and pathological parameters was also analyzed. The relative CEACAM6 protein expression of pancreatic carcinoma was significantly higher than that in non-cancerous tissue. Different clinical stages and lymph node metastasis between groups were significantly different (P<0.05). We used siRNA and forced-expression in multiple cell lines to define the role of CEACAM6 in the regulation of proliferation of pancreatic carcinoma in vitro and in vivo. Knockdown of endogenous CEACAM6 decreased proliferation of BxPC-3 and SW1990 cells. These changes significantly reduced cyclin D1 and CDK4 protein levels. Conversely, overexpression of CEACAM6 in MIA PaCa-2 cells stimulated proliferation and increased cyclin D1 and CDK4 protein levels. Our results confirm that CEACAM6 promoted cell proliferation, and these changes were mediated by cyclin D1/CDK4. These observations contribute to our understanding of the important roles of CEACAM6 in pancreatic carcinoma development and progression and could be a promising molecular target for the development of new diagnostic and therapeutic strategies of pancreatic carcinoma.


Lipopolysaccharides of the Heddleston serotypes of Pasteurella multocida.
Lipopolysaccharides (LPS) were extracted from 13 of the 16 Heddleston serotypes of Pasteurella multocida by phenol-chloroform-petroleum ether (PCP). Serotypes 3, 9, and 13 were extracted only by phenol-water (PW). After extraction of LPS of serotype 9 by PW, an additional LPS was isolated by PCP. All LPS contained glucose, 2-keto-3-deoxyoctonate, and heptose. Two isomers of heptose, D-glycero-D-mannoheptose and L-glycero-D-mannoheptose, were found in serotypes 2 and 5. Antisera made against purified LPS of serotypes 2 and 5 reacted with both heat-stable antigens and LPS from serotypes 2 and 5 in the gel-diffusion precipitin test. Antisera against serotype 2 LPS protected turkeys against challenge with capsulated serotype 5, indicating that a structural relationship exists between LPS of strains that cause hemorrhagic septicemia and fowl cholera. Rhamnose was a component of serotype 9 LPS, and galactose was found in all LPS, except for serotype 11. The LPS of serotype 13 contained an isomer of heptose that has not been identified. The LPS had buoyant densities in CsCl of 1.40 +/- 0.0148 g/ml, and all hemagglutinated chicken and turkey, but not sheep or horse, RBC.


Evidence of a novel role for monovalent cations in pyruvate kinase catalysis.
In the pyruvate kinase (EC 126.96.36.199) reaction, the complete enzyme-products complex consists of enzyme, pyruvate, ATP, a divalent cation, and a monovalent cation, usually K+. The dissociation of this complex can be slow permitting reversible enolization of pyruvate in this complex during the course of the forward reaction. High concentrations of each component in the enzyme-products complex inhibits the forward reaction, but only elevated concentrations of the monovalent cation decrease the net rate of product dissociation relative to that of pyruvate enolization. This result indicates that the monovalent cation can be the first component released from the enzyme-products complex and that the presence of an inhibiting monovalent cation concentration leads to re-formation of the complete complex, which is necessary for pyruvate enolization. The evidence suggests that the monovalent cation can bind and release with each turnover of the enzyme. While the data do not permit the conclusion that first release of monovalent cation is the exclusive pathway for dissociation of the enzyme-products complex, no other component once released can reassociate rapidly enough to form a complete complex during the forward reaction. Inhibition by these components must be attributed to the formation of abortive complexes.


Recurrent Clostridium difficile infection in intensive care unit patients.
The purpose of this study was to assess the 12-week cumulative incidence of recurrent Clostridium difficile infection (rCDI) and identify risk factors for rCDI in patients that acquired index C difficile infection (CDI) while in the intensive care unit (ICU). This retrospective single-center cohort study reviewed adult patients from 6 different ICUs who developed a CDI between February 2010 and September 2013. Out of 162 included ICU patients, 34 experienced rCDI. Risk of rCDI was higher in the ICU versus non-ICU group (21% vs 17%, P = .03). The incidence of rCDI was highest in the surgical intensive care unit (SICU) at 43.8%. A multivariable logistic regression model was constructed and identified 5 significant risk factors for rCDI: previous CDI (odds ratio [OR], 8.03; 95% confidence interval [CI], 1.90-34.02; P = .005), log10 ICU length of stay in days (OR, 3.67; 95% CI, 1.13-11.85; P = .03), acquisition of CDI in the medical intensive care unit (MICU) (OR, 5.35; 95% CI, 1.60-17.85; P = .006) or SICU (OR, 15.30; 95% CI, 4.09-57.23; P < .001), and chronic obstructive pulmonary disease (COPD) (OR, 3.55; 95% CI, 1.41-8.94; P = .007). ICU adults had a significantly higher 12-week incidence of rCDI than non-ICU patients. Risk factors for rCDI after acquisition of infection in an ICU include MICU and SICU patients, previous CDI, COPD, and length of stay.


Health risks posed to infants in rural China by exposure to short- and medium-chain chlorinated paraffins in breast milk.
Chlorinated paraffins (CPs) are complex mixtures of synthetic chemicals found widely in environmental matrices. Short-chain CPs (SCCPs) are candidate persistent organic pollutants under the Stockholm Convention. There should be great concern about human exposure to SCCPs. Data on CP concentrations in human breast milk is scarce. This is the first study in which background SCCP and medium-chain CP (MCCP) body burdens in the general rural population of China have been estimated and health risks posed to nursing infants by CPs in breast milk assessed. The concentrations of 48 SCCP and MCCP formula congeners were determined in 24 pooled human milk samples produced from 1412 individual samples from eight provinces in 2007 and 16 provinces in 2011. The samples were analyzed by comprehensive two-dimensional gas chromatography electron capture negative ionization high-resolution time-of-flight mass spectrometry. The median SCCP and MCCP concentrations were 303 and 35.7ngg-1 lipid weight, respectively, for the 2007 samples and 360 and 45.4ngg-1 lipid weight, respectively, for the 2011 samples. The C10 and C14 homologs were the dominant CP carbon-chain-length groups, contributing 51% and 82% of the total SCCP and MCCP concentrations, respectively. There are probably multiple CP sources to the general Chinese population and numerous exposure pathways. The median estimated daily SCCP and MCCP intakes for nursing infants were 1310 and 152ngkg-1d-1, respectively, in 2007 and 1520 and 212ngkg-1d-1, respectively, in 2011. SCCPs do not currently pose significant risks to infants in China. However, it is necessary to continuously monitor CP concentrations and health risks because CP concentrations in Chinese human breast milk are increasing.


Patent foramen ovale increases the risk of acute ischemic stroke in patients with acute pulmonary embolism leading to right ventricular dysfunction.
Patent foramen ovale (PFO) is an established risk factor for ischemic stroke. Since acute right ventricular dysfunction (RVD) observed in patients with PE can lead to right-to-left inter-atrial shunt via PFO, we hypothesized that PFO is a risk factor for ischemic stroke in PE with significant right ventricular dysfunction. 55 patients (31 F, 24M), median age 49 years (range 19-83 years) with confirmed PE underwent echocardiography for RVD and PFO assessment. High risk acute PE was diagnosed in 3 (5.5%) patients, while 16 (29%) hemodynamically stable with RVD patients formed a group with intermediate-risk PE. PFO was diagnosed in 19 patients (34.5%). Diffusion-weighted MRI of the brain for acute ischemic stroke (AIS) was performed in all patients 4.91 ± 4.1 days after admission. AIS was detected by MRI in 4 patients (7.3%). Only one stroke was clinically overt and resulted in hemiplegia. All 4 AIS occurred in the PFO positive group (4 of 19 patients), and none in subjects without PFO (21.0% vs 0%, p=0.02). Moreover, all AIS occurred in patients with RVD and PFO, and none in patients with PFO without RVD (50% vs 0%, p=0.038). Our data suggest that acute pulmonary embolism resulting in right ventricular dysfunction may lead to acute ischemic stroke in patients with patent foramen ovale. However, the clinical significance of such lesions remains to be determined.


Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.
Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.


Hyperparathyroidism and pregnancy. Report of a case and review of the literature.
A 28-year-old gravida III, with a history of two unsuccessful pregnancies, was admitted with hyperemesis gravidarum and was found to be suffering from hyperparathyroidism (HPT). She was treated surgically and was later delivered of a wellformed, premature girl. The literature is reviewed and the histories of 40 females (including the patient of this case report) with a minimum of 93 pregnancies while suffering from HPT shows, that HPT during pregnancy is a serious condition for the fetus as well as for the mother. There was an increased incidence of spontaneous abortion, perinatal death, premature birth and neonatal morbidity. The mothers suffered from increased episodes of renal calculi and hyperemesis gravidarum. The exacerbations nearly always occurred in the first and second trimesters or post partum.


An ultrastructural study of calcifying odontogenic cyst, especially calcified material.
The ultrastructural features of calcification in a case of calcifying odontogenic cyst (COC) were studied. Scanning electron microscopic examination of the inner parts of the cyst wall revealed many short microvilli, and X-ray microanalysis of the high-density masses in the intercellular parts showed prominent calcium peaks, which meant that these masses were calcified materials. On transmission electron microscopic observations, many calcifications exhibited a distinctive ring formation around the periphery of a central core that consisted of an amorphous structure. These calcifications were observed with necrotic remnants of nuclear material and many identifiable mitochondria, thin fibers, and epithelial cells. The cytoplasm of ghost cells consisted of numerous short electron-dense tonofilament bundles. Needle-like structures were shown in the tonofilament bundles. X-ray diffraction analysis showed that the needle-like crystals were hydroxyapatite. It is suggested that calcification in a COC may be related to degenerative mitochondria and tonofilament bundles of ghost cells.


Different Biomarkers of Response to Treatment with Selective Jak-1 Inhibitors in Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes progressive joint damage. The Janus kinase (JAK) inhibitors (JAK-I) represent a new therapeutic option for RA patients, blocking the intracellular JAK-STAT pathway. Today, no studies have been conducted to determine whether new biomarkers could better reflect disease activity in patients treated with JAK-I than traditional disease activity indicators. Thus, the aim of our study was to determine additional disease activity biomarkers in RA patients receiving selective JAK-1 inhibitors. we enrolled 57 patients with RA: 34 patients were treated with Upadacitinib (UPA) and 23 patients with Filgotinib (FIL). All patients were evaluated for clinimetry with DAS28 and Crohn's Disease Activity Index (CDAI), number of tender and swollen joints, Visual Analogic Scale (VAS), Physician Global Assessment (PhGA), and Health Assessment Questionnaire (HAQ), at baseline and at the 12th week of treatment. Lymphocyte subpopulations, complete blood count, erythrocyte sedimentation rate (ESR), C-Reactive Protein (CRP), anti-cyclic citrullinated peptide antibodies (APCA), rheumatoid factor (RF) IgM, interleukin 6 (IL-6), circulating calprotectin (cCLP), tumor necrosis factor α (TNFα), soluble urokinase Plasminogen Activator Receptor (suPAR), complement functional activity were measured at baseline and after the 12th week of treatment. in both groups of patients, we documented a significant reduction in the clinimetric parameters DAS28, CDAI, number of tender joints, number of swollen joints, VAS, PhGA, and HAQ. Moreover, significant differences were reported for laboratory parameters of ESR, CRP, IL-6, suPAR, cCLP, and PLT/L ratio in both groups. However, no difference was demonstrated between the two groups for changes in renal, hepatic, and lipid parameters. the suPAR and cCLP levels may lead towards a different therapeutic choice between UPA and FIL, with the expression of two different RA pathophenotypes directing FIL towards a lymphocyte-poor form and UPA towards a myeloid form of RA.


Cumulative lifetime stressor exposure assessed by the STRAIN predicts economic ambiguity aversion.
Uncertainty is inherent in most decisions humans make. Economists distinguish between two types of decision-making under non-certain conditions: those involving risk (i.e., known outcome probabilities) and those that involve ambiguity (i.e., unknown outcome probabilities). Prior research has identified individual differences that explain risk preferences, but little is known about factors associated with ambiguity aversion. Here, we hypothesized that cumulative exposure to major psychosocial stressors over the lifespan might be one factor that predicts individuals' ambiguity aversion. Across two studies (Study 1: n = 58, Mage = 25.7; Study 2: n = 188, Mage = 39.81), we used a comprehensive lifetime stressor exposure inventory (i.e., the Stress and Adversity Inventory for Adults, or STRAIN) and a standard economic approach to quantify risk and ambiguity preferences. Greater lifetime stressor exposure as measured by the STRAIN, particularly in early life, was associated with higher aversion to ambiguity but not risk preferences.


I and i antigens on normal and leukemic leukocytes.
Human leukocyte I and i antigens were quantitated using 125I labelled purified antibodies. Binding of these antibodies to leukocytes was dependent on reduced temperature. No significant difference in antigen content was observed between normal and leukemic myeloid leukocytes. B lymphocytes bound much greater amounts of both I and i antibodies than did T lymphocytes. Neoplastic lymphoid cells bound widely divergent amounts of both antibodies with chronic lymphocytic leukemia and lymphosarcoma cell leukemia cells binding much decreased amounts compared to normal lymphocytes. Cells from patients with hairy cell leukemia bound very large quantities of these antibodies in a cold dependent fashion. These elevated levels of binding were not due to nonspecific binding of IgM.


In vitro antimicrobial activity of narasin against common clinical isolates associated with canine otitis externa.
Antimicrobial resistance and antimicrobial stewardship are of ever-increasing importance in veterinary medicine. Re-purposing of old drugs that are not used in human medicine is one approach that addresses the emergence of multidrug resistance in canine skin and ear infections, and can reduce the use of critically important human antibiotic classes. To determine the antimicrobial activity of narasin, a polyether ionophore conventionally used as a rumen modifier and anticoccidial agent in production animals, against common clinical isolates of canine otitis externa (OE). Clinical isolates (n = 110) from canine OE were tested, including 17 meticillin-susceptible Staphylococcus pseudintermedius (MSSP), 13 multidrug-resistant Staphylococcus pseudintermedius (MDRSP), and 20 each of β-haemolytic Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis and Malassezia pachydermatis. Bacterial and yeast isolates were subcultured, suspended in broth and inoculated into 96-well plates. Organisms were tested against concentrations of narasin ranging from 0.03 to 128 μg/mL. Minimal inhibitory concentrations (MICs) were determined after overnight incubation. Narasin MICs for staphylococcal and streptococcal isolates ranged from 0.06 to 0.25 μg/mL; MIC50 and MIC90 values for both organisms were 0.125 μg/mL. No MICs were achieved for Pseudomonas or Proteus isolates. There was a weak antifungal effect against M. pachydermatis isolates (MIC 32 to >128 μg/mL). Narasin was effective against Gram-positive bacteria and had antifungal activity at higher concentrations against M. pachydermatis. However, the lack of Gram-negative activity would prevent its use as a sole antimicrobial agent in cases of canine OE.


Metabolic fates of ammonia-N in ruminal epithelial and duodenal mucosal cells isolated from growing sheep.
The objective of this experiment was to determine the capability of ruminant gut tissues to detoxify ammonia-N using short-term incubations of isolated cells in vitro. Ruminal epithelial cells (REC) and duodenal mucosal cells (DMC) were isolated from growing Texel-Polypay ram lambs (n = 4) fed a pelleted forage:concentrate-based diet. Immediately after isolation, primary cells were incubated for 60 min with glucose (1mM), glutamate (1mM), [15N]ammonium chloride (5, 10, 20, or 40 mM), and 1 of 4 combinations of substrates (1 mM each) that could support urea synthesis [control, N-carbamoylglutamate (NCG); NCG + ornithine (ONCG); and ONCG + aspartate (AONCG)]. Treatments were arranged in a 4 x 4 factorial design. Incorporation of ammonia-15N into alanine, citrulline, arginine, and urea was determined by gas chromatography-mass spectrometry. For both cell types, ammonia-N transfer to alanine was lower when incubation medium contained NCG compared with control, whereas use of ammonia-N for net alanine synthesis increased quadratically with ammonia concentration regardless of substrate treatment. For REC, ammonia-N was not incorporated into citrulline, arginine, or urea, nor into arginine or urea by DMC. Ammonia-N use for net citrulline synthesis exhibited an inverse relationship with ammonia concentration, decreasing linearly as media ammonia concentration increased. Thus, ala-nine synthesis may be a significant metabolic pathway for ruminant gut tissues to detoxify ammonia-N when it is presented luminally at high concentrations as compared with detoxification by the ornithine-urea cycle. Furthermore, DMC do exhibit a metabolic capability to incorporate ammonia-N into citrulline, but low or absent activity of downstream enzymes of the ornithine-urea cycle appears to limit ammonia-N transfers to urea.


Infections in Hispanic immigrants.
Hispanic immigrants are an increasing portion of the United States (US) population. In addition to being at risk for diseases common in the US-born population, Hispanic immigrants also are at risk for infections that do not usually occur in the US-born population. Thus, such diseases as tuberculosis, neurocysticercosis, brucellosis, typhoid fever, malaria, amebiasis, viral exanthems, and hepatitis need to be considered in Hispanics who present with fever or focal lesions. When included in the differential diagnosis, most of these infections can be readily diagnosed and treated with currently available methods.


Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis.
Perilipin (Peri) A is a lipid droplet-associated phosphoprotein that acts dually as a suppressor of basal (constitutive) lipolysis and as an enhancer of cyclic AMP-dependent protein kinase (PKA)-stimulated lipolysis by both hormone-sensitive lipase (HSL) and non-HSL(s). To identify domains of Peri A that mediate these multiple actions, we introduced adenoviruses expressing truncated or mutated Peri A and HSL into NIH 3T3 fibroblasts lacking endogenous perilipins and HSL but overexpressing acyl-CoA synthetase 1 and fatty acid transporter 1. We identified two lipase-selective functional domains: 1) Peri A (amino acids 1-300), which inhibits basal lipolysis and promotes PKA-stimulated lipolysis by HSL, and 2) Peri A (amino acids 301-517), which inhibits basal lipolysis by non-HSL and promotes PKA-stimulated lipolysis by both HSL and non-HSL. PKA site mutagenesis revealed that PKA-stimulated lipolysis by HSL requires phosphorylation of one or more sites within Peri 1-300 (Ser81, Ser222, and Ser276). PKA-stimulated lipolysis by non-HSL additionally requires phosphorylation of one or more PKA sites within Peri 301-517 (Ser433, Ser492, and Ser517). Peri 301-517 promoted PKA-stimulated lipolysis by HSL yet did not block HSL-mediated basal lipolysis, indicating that an additional region(s) within Peri 301-517 promotes hormone-stimulated lipolysis by HSL. These results suggest a model of Peri A function in which 1) lipase-specific "barrier" domains block basal lipolysis by HSL and non-HSL, 2) differential PKA site phosphorylation allows PKA-stimulated lipolysis by HSL and non-HSL, respectively, and 3) additional domains within Peri A further facilitate PKA-stimulated lipolysis, again with lipase selectivity.


An Atom-Economical Method To Prepare Enantiopure Benzodiazepines with N-Carboxyanhydrides.
The development of a rapid, one-pot synthesis of diazepinones with simple reagents is described. N-Carboxyanhydrides (NCAs) are employed as amino acid building blocks that react with o-ketoanilines sequentially as electrophiles and nucleophiles to form diazepinones with water and carbon dioxide as byproducts. Notably, these reactions enable the coupling of stereodefined amino acid derived NCAs without racemization. This method is demonstrated by an improved synthesis of a key intermediate toward a bromodomain and extra-terminal (BET) bromodomain inihibitor.


Radical excision of invasive thymoma with intracardiac extension.
A patient with a low grade malignant thymoma who also had pleural, pericardial and cardiac invasion with intracardiac extension, presented with signs of superior vena cava obstruction, moderate hepatosplenomegaly and a mediastinal mass on a plain chest radiograph. Radical excision requiring cardiopulmonary bypass for the removal of the intracardiac extension into the right atrium was performed. Despite the patient's failure to receive radiotherapy treatment, he was alive one year after surgery. This case is reported because this mode of presentation of intracardiac extension of a thymoma is uncommon and because only this method of radical excision could ensure near-total removal of the mass and prevent early death from cardiovascular complications.


Evaluation of maize grain and polyunsaturated fatty acid (PUFA) as energy sources for breeding rams based on hormonal, sperm functional parameters and fertility.
The objective of the present study was to elucidate the effect of different sources of dietary energy (maize vs polyunsaturated fatty acid (PUFA) on semen functional parameters and fertility of adult rams. Eighteen adult rams were divided into two groups (maize and PUFA, n=9). The main energy source for the rams in the maize group was coarsely ground maize grain, whereas in the PUFA group it was sunflower oil (rich in 18:2 linoleic acid, an omega-6 acid). The ration was fed for a minimum period of 60 days and thereafter semen was collected for evaluation. The proportion of progressive forward motility was significantly (P<0.05) higher in the PUFA group compared with the maize group. Sperm lipid peroxidation as measured by malondialdehyde formation (µM per 1×10(9) spermatozoa) was significantly (P<0.05) higher in the PUFA group compared with the maize group. When the semen was diluted with Tris-egg yolk-citrate buffer and incubated for 24h at 4°C, the proportions of plasmalemma integrity, the sperm subpopulation positive for functional membrane and acrosomal integrities, and mitochondrial membrane potential were significantly (P<0.05) higher in PUFA-fed than in maize-fed animals. The different sources of energy did not influence the serum and seminal plasma IGF-I levels. The cleavage rate (percentage) did not differ significantly between PUFA- (45.4±4.91) and maize- (44.63±6.8) fed animals. In conclusion, PUFA feeding influenced sperm quality by altering or stabilising membrane integrity. The present study indicates that PUFA may improve semen quality but did not improve in vitro fertilisation.


The Drosophila phenotype gap - and how to close it.
Functional genomics (the elucidation of gene function in the context of a sequenced genome) depends critically on functional biology. Genetic model organisms have hitherto not attracted much physiological input, however. This skills mismatch, termed the phenotype gap, can be quantified by analysis of the annotations of sequenced genomes. This is illustrated in the context of Drosophila. In this case, it seems as if a shift from developmental biology to transport physiology and metabolism will be required to provide a more balanced skills base for post-genomics.


[Long-term survival in childhood acute lymphocitic leukemia (author's transl)].
Long-term results in the treatment of 116 patients of acute lymphocitic leukemia with ages between six months and seven years are reported. A first group A, formed by 76 patients, was treated with prednisone and vincristine as induction protocol and maintenance therapy with 6-mercaptopurine or methotrexate. No neuromeningeal prophylaxis was made, except some cases in which intratecal methotrexate was applied. 27 patients are alive, 21 of them (27,6%) remain in complete remission for more than three years. A second group B, formed by 40 patients, was treated more recently; with an induction protocol composed by prednisone, vincristine and L-asparaginase. All patients in this group received cranial irradiation and intratecal methotrexate. 31 patients are alive (77,5%), 13 of them (32,5%) remain in complete remission for more than two years. The evolution period in this group B is shorter, but some features are exposed which suggest the possibility of long-term better results.


[Cisplatin-induced apoptotic endonuclease EndoG inhibits telomerase activity and causes malignant transformation of human CD4+ T lymphocytes].
Alternative splicing of telomerase catalytic subunit hTERT pre-mRNA (human Telomerase Reverse Transcriptase) regulates telomerase activity. Increased expression of non-active splice variant hTERT results in inhibition of telomerase. Apoptotic endonuclease EndoG is known to participate in hTERT alternative splicing. Expression of EndoG can be induced in response to DNA damages. The aim of this study was to determine the ability of a DNA-damaging compound, cisplatin, to induce EndoG and its influence on alternative splicing of hTERT and telomerase activity in human CD4+ Т lymphocytes. Overexpression of EndoG in CD4+ T cells downregulated the expression of active full-length hTERT variant and upregulated its non-active spliced variant. Reduction of full-length hTERT caused downregulation of telomerase activity, shortening of telomeres length during cell divisions, converting cells to the replicative senescence state, activation of apoptosis and finally cell death. Few cells survived and underwent malignant transformation. Transformed cells have increased telomerase activity and proliferative potential compare to initial CD4+ T cells. These cells have phenotype of T lymphoblastic leukemic cells and are able to form tumors and cause death in experimental mice.


Potentials of Endothelial Colony-Forming Cells: Applications in Hemostasis and Thrombosis Disorders, from Unveiling Disease Pathophysiology to Cell Therapy.
Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells circulating in a limited number in peripheral blood. They can give rise to mature endothelial cells (ECs) and, with intrinsically high proliferative potency, contribute to forming new blood vessels and restoring the damaged endothelium in vivo. ECFCs can be isolated from peripheral blood or umbilical cord and cultured to generate large amounts of autologous ECs in vitro. Upon differentiation in culture, ECFCs are excellent surrogates for mature ECs showing the same phenotypic, genotypic, and functional features. In the last two decades, the ECFCs from various vascular disease patients have been widely used to study the diseases' pathophysiology ex vivo and develop cell-based therapeutic approaches, including vascular regenerative therapy, tissue engineering, and gene therapy. In the current review, we will provide an updated overview of past studies, which have used ECFCs to elucidate the molecular mechanisms underlying the pathogenesis of hemostatic disorders in basic research. Additionally, we summarize preceding studies demonstrating the utility of ECFCs as cellular tools for diagnostic or therapeutic clinical applications in thrombosis and hemostasis.


[Laboratory and clinical studies on cefotetan in respiratory tract infections].
Seventy five patients with respiratory infections, including 40 cases of acute pneumonia, 33 cases of secondary infection after chronic pulmonary diseases and 2 cases of pulmonary abscess, were treated with cefotetan (CTT, Yamatetan) by drip infusion in order to evaluate its clinical efficacy. The overall rate of effectiveness was 83.8%. CTT was examined comparatively with other beta-lactam antibiotics for antibacterial activity on clinically isolated strains of 3 major respiratory pathogens including Haemophilus influenzae, Branhamella catarrhalis and Streptococcus pneumoniae. Minimum inhibitory concentrations (MIC's) of CTT on H. influenzae were less than 3.13 micrograms/ml regardless of the production of beta-lactamase by these organisms. As to B. catarrhalis, CTT also exerted an antibacterial activity enough to control the proliferation of all the strains at a level of 1.56 micrograms/ml. Against S. pneumoniae, on the other hand, CTT exhibited the lowest activity of all the drugs tested but still showed MIC's of 3.13 micrograms/ml or less. Drip infusion of CTT at a dose of 2 g brought about an average maximum blood concentration of 342 +/- 25.7 micrograms/ml and an average half-life in blood of 2.48 +/- 0.41 hours Maximum sputum concentration of the drug, however, was variable among the cases tested, ranging from 0.40 to 1.80 micrograms/ml. Side effects of the drug were observed in 5 cases or 6.7%. Four of them had some allergic symptoms; i.e., pyrexia and eruption. One patient was especially diagnosed as possible drug-induced interstitial pneumonia during the treatment with the drug. The diagnosis was confirmed by transbronchial lung biopsy and lymphocyte blastogenesis by CTT in vitro. As to abnormal laboratory findings, blood transaminases were elevated during drug administration in 13 cases or 17.3%, but were reduced back to the normal level after the withdrawal of the drug.


[Pathogenic Mechanism and Diagnostic Testing for Drug Allergies].
Three stages of the pathogenic mechanism of drug allergies can be considered: antigen formation, immune reaction and inflammation/disorder reaction. Drugs are thought to form 4 types of antigens: drug only, polymers, drug-carrier conjugates, and metabolite-carrier complexes. Antigens are recognized by B cell receptors and T cell receptors. Helper T cells (Th) are differentiated into four subsets, namely, Th1, Th2, Th17 and regulatory T cells (Treg). Th1 produces interleukin (IL)-2 and interferon (IFN)-γ, and activates macrophages and cytotoxic T cells (Tc). Macrophages induce type IV allergies, and Tc lead to serious type IV allergies. On the other hand, Th2 produces IL-4, IL-5, and IL-6, etc., and activates B cells. B cells produce IgE antibodies, and the IgE antibody affects mast cells and induces type I allergies. Activated eosinophil leads to the chronic state of type I allergy. Diagnostic testing for allergenic drugs is necessary for patients with drug allergies. Because in vivo diagnostic tests for allergenic drugs are associated with a risk and burden to the patient, in vitro allergy tests are recommended to identify allergenic drugs. In allergy tests performed in vitro, cytological tests are more effective than serological tests, and the leukocyte migration test (LMT) presently has the highest efficacy. An LMT-chamber is better than LMT-agarose in terms of usability and sensitivity, and it can detect about 80% of allergenic drugs.


Harms of CT scanning prior to surgery for suspected appendicitis.
In this brief analysis we compare the risks and benefits of performing a CT scan to confirm appendicitis prior to surgery instead of operating based on the surgeon's clinical diagnosis. We conclude that the benefit of universal imaging is to avoid 12 unnecessary appendectomies but the cost of those 12 avoided surgeries is one cancer death due to the imaging.


HIV-1 adaptation to NK cell-mediated immune pressure.
The observation, by Alter et al., of the enrichment of NK cell "escape" variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response. According to this hypothesis, in order for NK cells to select for an escape variant, an individual must carry both the KIR and an HLA ligand that binds the variant peptide. In this study we estimate the proportion of the population that is capable of selecting for escape variants and use both epidemiological modelling and a model-free approach to investigate whether this proportion explains the observed variant enrichment. We found that the fraction of individuals within whom the variant would have a selective advantage was low and was unable to explain the high degree of enrichment observed. We conclude that whilst Alter et al's data is consistent with selection pressure, the mechanism that they postulate is unlikely. The importance of this work is two-fold. Firstly, it forces a re-evaluation of some of the clearest evidence that NK cells exert a protective effect in HIV-1 infection. Secondly, it implies that there is a significant aspect of immunology that is not understood: it is possible that KIRs bind much more widely than was previously appreciated; that a gene in linkage with the KIR genes is responsible for considerable peptide-dependent selection or that variant peptides are indirectly impacting KIR ligation.


β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy.
Nuclear activated β-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/β-catenin pathway mutations in APC/KRAS or β-catenin/KRAS genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic β-catenin signaling negatively regulates the expression of NHERF1 (Na+/H+ exchanger 3 regulating factor 1), a PDZ-adaptor protein that is usually lost or downregulated in early dysplastic adenomas to exacerbate nuclear β-catenin activity. Chromatin immunoprecipitation (ChIP) assays demonstrated that β-catenin represses NHERF1 via TCF4 directly, while the association between TCF1 and the Nherf1 promoter increased upon β-catenin knockdown. To note, the occurrence of a cytostatic survival response in settings of single β-catenin-depleted CRC cells was abrogated by combining NHERF1 inhibition via small hairpin RNA (shRNA) or RS5517, a novel PDZ1-domain ligand of NHERF1 that prevented its ectopic nuclear entry. Mechanistically, dual NHERF1/β-catenin targeting promoted an autophagy-to-apoptosis switch consistent with the activation of Caspase-3, the cleavage of PARP and reduced levels of phospho-ERK1/2, Beclin-1, and Rab7 autophagic proteins compared with β-catenin knockdown alone. Collectively, our data unveil novel β-catenin/TCF-dependent mechanisms of CRC carcinogenesis, also offering preclinical proof of concept for combining β-catenin and NHERF1 pharmacological inhibitors as a mechanism-based strategy to augment apoptotic death of CRC cells refractory to current Wnt/β-catenin-targeted therapeutics.


Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis.
The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect. In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor β-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients. Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation. These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC.


Assessing the validity of modulation transfer function evaluation techniques with application to small area and scanned digital detectors.
A novel prototype step and shoot x-ray system, the intelligent imaging system (I-Imas), has been developed in the UCL Radiation Physics laboratories. The system uses collimators to split the beam into two: the first, "scout" beam, strongly attenuated, identifies regions of interest in the image. This information is then fed back to the system so that the intensity of the second beam is modulated to optimize the dose distribution--i.e., "interesting" regions of the sample receive a higher dose, whereas other regions receive a lower one. Such systems may be capable of improved diagnostic capability at the same overall patient dose levels as typical when using large area digital plates. This acquisition mode means that large overall images are obtained by aligning many smaller images. This paper investigates the effects that this acquisition modality has on the overall spatial resolution of the system. We review different modulation transfer function (MTF) evaluation techniques and those shown to be optimal are used in the investigation of two considerations key to such a system: (i) whether there is a minimum size sensor whose MTF can accurately be determined using these techniques and (ii) whether the MTF of the large overall image differs significantly from those of the many constituent images. As the use of step and shoot systems is becoming more and more widespread, both are important considerations. We found that, for a fixed pixel pitch, the MTF is determined marginally less accurately the smaller the sensor area, with the perceived resolution varying by up to 0.1 lp/mm. It was also found that use of such a step and shoot technique does cause a very small overall degradation in resolution. The resolution of overall images was calculated to be 0.1 lp/mm lower than that of the individual images acquired.


Uptake of oleate from albumin solutions by rat liver. Failure to detect catalysis of the dissociation of oleate from albumin by an albumin receptor.
The hepatic removal of albumin-bound substances from plasma requires that they dissociate from albumin. Using indirect methods, we and others have proposed that dissociation may be catalyzed by interaction of albumin with the liver cell surface. This study looked for direct evidence of catalysis by comparing the rate of dissociation of oleate from albumin in vitro with the rate observed within the sinusoids of perfused rat liver. No evidence for catalysis was found. The rate of hepatic oleate removal from dilute albumin solutions did not exceed but instead closely paralleled the rate predicted from the in vitro dissociation rate constant (0.14s-1). These results suggest that under some conditions the liver can remove unbound material from the sinusoids faster than it can be replenished by dissociation from albumin, resulting in dissociation-limited removal. However, dissociation of oleate does not appear to be catalyzed by the liver.


Imputation approaches for estimating diagnostic accuracy for multiple tests from partially verified designs.
Interest often focuses on estimating sensitivity and specificity of a group of raters or a set of new diagnostic tests in situations in which gold standard evaluation is expensive or invasive. Various authors have proposed semilatent class modeling approaches for estimating diagnostic accuracy in this situation. This article presents imputation approaches for this problem. I show how imputation provides a simpler way of performing diagnostic accuracy and prevalence estimation than the use of semilatent modeling. Furthermore, the imputation approach is more robust to modeling assumptions and, in general, there is only a moderate efficiency loss relative to a correctly specified semilatent class model. I apply imputation to a study designed to estimate the diagnostic accuracy of digital radiography for gastric cancer. The feasibility and robustness of imputation is illustrated with analysis, asymptotic results, and simulations.


Glucose-6-phosphate dehydrogenase deficiency and lobar pneumonia. Fine structure of the liver.
Ultrastructural changes appeared in liver biopsy specimens from eight patients with glucose-6-phosphate dehydrogenase deficiency who developed jaundice during the course of lobar pneumonia. The observed changed indicate that the hyperbilirubinemia and jaundice that develop in patients with glucose-6-phosphate dehydrogenase deficiency with lobar pneumonia are caused partly by hemolysis and partly by intrahepatic cholestasis. The cholestasis may be caused by a genetic predisposition in enzyme-deficient individuals; the hemolysis may be induced by pulmonary infection in individuals with an enzyme deficiency.


Hemangiopericytoma of the uterus: a rare case of pelvic mass.
Hemangiopericytoma (HPC) is an uncommon perivascular tumor which may arise from anywhere in the body accounts for 1% of primary vascular tumors. Uterine hemangiopericytomas are usually low grade malignancies with better prognosis. The primary treatment is usually total hysterectomy and bilateral salpingo-oophorectomy. In this report, we aimed to evaluate the clinical characteristics of an 83 years of woman admitted to our clinic with pelvic mass who underwent laparotomy and underwent total hysterectomy and bilateral salpingo-ooforectomy. Postoperative pathology was hemangiopericytoma.


Health beliefs of school-age rural children in podoconiosis-affected families: A qualitative study in Southern Ethiopia.
Several studies have suggested investigation of health beliefs in children to be an important pre-condition for primary prevention of disease. However, little effort has been made to understand these in the context of podoconiosis. This study therefore aimed to explore the health beliefs of school-age rural children in podoconiosis-affected families. A cross sectional qualitative study was conducted in March 2016 in Wolaita Zone, Southern Ethiopia. Data were collected through in-depth individual interviews (IDIs) and focus group discussions (FGDs), with a total of one hundred seventeen 9 to15-year-old children recruited from podoconiosis affected families. The study revealed various misconceptions regarding risk factors for podoconiosis. Most children believed barefoot exposure to dew, worms, snake bite, frog urine, other forms of poison, and contact with affected people to be major causes of the disease. Their knowledge about the role of heredity and that of long term barefoot exposure to irritant mineral particles was also weak. Though most participants correctly appraised their susceptibility to podoconiosis in relation to regular use of footwear and foot hygiene, others based their risk perceptions on factors they think beyond their control. They described several barriers to preventive behaviour, including uncomfortable footwear, shortage and poor adaptability of footwear for farm activities and sports, and shortage of soap for washing. Children also perceived low self-efficacy to practice preventive behaviour in spite of the barriers. Health education interventions may enhance school-age children's health literacy and be translated to preventive action. Overcoming practical challenges such as shortage of footwear and other hygiene facilities requires other forms of interventions such as livelihood strengthening activities. Linking podoconiosis-affected families with local governmental or non-governmental organizations providing socio-economic support for households may assist school-age children in those families to sustainably engage in preventive behaviours.


[Cancer vaccine therapy using genetically modified induced pluripotent stem cell-derived dendritic cells expressing the TAA gene].
It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) poses a serious problem in DC-based immunotherapy. Therefore, we used induced pluripotent stem (iPS) cell-derived DCs (iPSDCs) instead. If the therapeutic efficacy of iPSDCs was equivalent to that of bone marrow-derived DCs( BMDCs), then the above-mentioned problems may be solved. In this study, we generated iPSDCs from iPS cells and compared their capacity to mature and migrate to the regional lymph nodes with that of BMDCs. We adenovirally transduced the hgp100 gene, which codes for a natural tumor antigen, into the DCs and immunized the mice with these genetically modified DCs. The cytotoxic activity of CD8( +) cytotoxic T lymphocytes( CTLs) was assayed using a 51Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results demonstrated that iPSDCs equaled BMDCs in terms of their maturation and migration capacity. Furthermore, hgp100-specific CTLs were generated in mice that were immunized with the genetically modified iPSDCs. These CTLs exhibited a high level of cytotoxicity against B16 cells, which is similar to that exhibited by CTLs generated in BMDCs immunized mice. Moreover, vaccination with genetically modified iPSDCs elicited a high level of therapeutic efficacy equaling that of vaccination with BMDCs. This study clarified experimentally that genetically modified iPSDCs are equivalent to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.


Effects of deoxynivalenol (DON) and its microbial biotransformation product deepoxy-deoxynivalenol (DOM-1) on a trout, pig, mouse, and human cell line.
Deoxynivalenol (DON), a trichothecene produced by various Fusarium species, is one of the most prevalent food- and feed-associated mycotoxins. The effects of DON and deepoxy-deoxynivalenol (DOM-1) were assessed in five different cell lines from different tissues and species starting from the first line of defense, the trout gill (RTgill-W1) and pig intestinal cells (IPEC-1 and IPEC-J2) over immune cells, as second line of defense (mouse macrophages RAW 264.7) to human liver cells (HepG2). Viability was assessed with a WST-1 assay, except for RTgill-W1, where a neutral red (NR) and sulforhodamine B (SRB) assay was performed. Additionally, more sensitive parameters, such as interleukin-, nitric oxide (NO)-, and albumin-release were determined. Viability was affected by DON at concentrations starting at 10 μmol/L (RTgill-W1), 0.9 μmol/L (IPEC-1), 3.5 μmol/L (IPEC-J2), and 0.9 μmol/L (HepG2), whereas DOM-1 did not have such an effect. Additionally, NO was decreased (0.84 μmol/L DON), whereas interleukin (IL)-6 was increased (0.42 μmol/L DON) in lipopolysaccharide (LPS)-stimulated DON-, but not DOM-1-treated RAW cells. Tumor necrosis factor (TNF)-α release, however, was not affected. Interestingly, albumin secretion of HepG2 cells was decreased by both DON and DOM-1 but at a much higher concentration for DOM-1 (228 versus 0.9 μmol/L for DON). 98.9% of DOM-1 was retrieved by liquid chromatography tandem mass spectrometry at the end of the experiment, proving its stability. In this study, IL-6 was the most sensitive parameter, followed by NO and albumin release and viability for HepG2 and IPEC-1.


[Viral hemorrhagic disease in a rabbit, a case report].
The clinical signs and pathological anatomical findings at post-mortem examination of two rabbits are characteristic of those of 'viral haemorrhagic disease'. Because of the very high mortality, the clinical signs, and the acute course, this viral disease, which has only recently been reported in Europe, could be mistaken for poisoning.


Shortened telomere in unremitted schizophrenia.
Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects. We measured telomere length as relative telomere/single-copy gene ratios in subjects with schizophrenia (n = 71) using quantitative real-time polymerase chain reaction. This was compared with relative telomere/single-copy gene ratios in age-matched controls without neuropsychiatric illness (n = 73). The relative telomere/single-copy gene ratios were significantly lower in subjects with unremitted schizophrenia when compared with control subjects (r = -0.281, P = 0.003), as well as the individuals with remitted schizophrenia. The lower relative telomere length in unremitted schizophrenia subjects may thus indicate shared biological pathways with other neurodegenerative disorders that are also characterized by increased cellular senescence.


Symmetry-adapted perturbation theory utilizing density functional description of monomers for high-spin open-shell complexes.
We present an implementation of symmetry-adapted perturbation theory (SAPT) to interactions of high-spin open-shell monomers forming high-spin dimers. The monomer spin-orbitals used in the expressions for the electrostatic and exchange contributions to the interaction energy are obtained from density functional theory using a spin-restricted formulation of the open-shell Kohn-Sham (ROKS) method. The dispersion and induction energies are expressed through the density-density response functions predicted by the time-dependent ROKS theory. The method was applied to several systems: NH...He, CN...Ne, H2O...HO2, and NH...NH. It provides accuracy comparable to that of the best previously available methods such as the open-shell coupled-cluster method with single, double, and noniterative triple excitations, RCCSD(T), with a significantly reduced computational cost.


When pain really matters: A vicarious-pain brain marker tracks empathy for pain in the romantic partner.
In a previous study (Krishnan, 2016) we identified a whole-brain pattern, the Vicarious Pain Signature (VPS), which predicts vicarious pain when participants observe pictures of strangers in pain. Here, we test its generalization to observation of pain in a close significant other. Participants experienced painful heat (Self-Pain) and observed their romantic partner in pain (Partner-Pain). We measured whether (i) the VPS would respond selectively to Partner-Pain and (ii) the Neurologic Pain Signature (NPS), a measure validated to track somatic pain, would selectively respond to Self-Pain, despite the high interpersonal closeness between partners. The Partner-Pain condition activated the VPS (t = 4.71, p = 0.00005), but not the NPS (t = -1.03, p = 0.308). The Self-Pain condition activated the NPS (t = 13.70, p < .00005), but not the VPS (t = -1.03 p = 0.308). Relative VPS-NPS response differences strongly discriminated Partner-Pain vs. Self-Pain (cross-validated accuracy=97%, p < .000001). Greater interpersonal closeness between partners predicted greater VPS responses during Partner-Pain (r = 0.388, p = 0.050) and greater unpleasantness when observing the romantic partner in pain (r = 0.559, p = 0.003). The VPS generalizes across empathy paradigms and to an interactive social setting, and strongly activates when observing a close significant other in pain. VPS responses may be modulated by relevant interpersonal relationship factors. Self-Pain and Partner-Pain evoke non-overlapping large-scale neural representations.


Characteristics of past smokers.
We studied characteristics of past smokers according to the duration of cessation of smoking based on data from a population-based survey. Lifestyle, prevalences of various symptoms and diseases and other factors were compared among current smokers (8507 males and 2012 females), past smokers (4423 males and 684 females) and non-smokers (2431 males and 12,859 females) aged 40 years and over. Compared to current smokers, past smokers consumed more bread, milk, vegetables, fruit and black tea, and less rice, pickles, instant noodles, coffee and alcohol, had lower prevalences of cough, sputum and anorexia, participated more in cancer screening tests, weighed more, included more professional and administrative workers and had more non-smoking spouses. These characteristics resembled those of non-smokers. But past smokers had high prevalences of several cardiovascular and respiratory diseases compared to current smokers. Daily intake of coffee was inversely associated and daily intakes of fruit and milk were positively associated with the duration of abstinence from smoking after adjusting for other factors in both sexes. These results suggest that lifestyle of past smokers may contribute to risk reduction for several diseases.


In Situ Quantification of Lipids in Live Cells by Using Lipid-Binding Domain-Based Biosensors.
Lipid molecules contribute to a large extent to the regulation of cellular signaling, as cellular signals are generated primarily through the selective interaction of various cellular proteins with lipids in the plasma membrane. Hence the location, concentration, and duration of lipids on the cell membrane are critical for the selection of proteins and the initiation of signaling. To monitor the concentration and location of lipid molecules on the cell membrane, researchers have developed a variety of lipid biosensors that allow quantitative in situ visualization of lipid molecules in living cells based on lipid-binding domains with high specificity, sensitivity, and biocompatibility, providing a powerful tool for the study of cellular signaling mechanisms involving lipid molecules. In this review, we first introduced the emergence of lipid-binding domains and then focused on the practical considerations on how to implement the lipid sensor, including probe selection, modification, characterization, and imaging techniques. We then described experimental observables and the relevant physicochemical parameters in the context of single-molecule studies in cells. Finally, we presented our views on the future development of lipid sensors and methods for lipid quantification.


[Angiogenesis in intestinal villus].
The aim of this investigation was to study the mechanism of producing the villus micro circular channel pre and postnatal ontogenesis. As an object of the study we had taken the jejunum of a white rat. There was used the method of a scanning electron microscopy of corrosive preparations and serial half thin chips. It was shown that at the 16th day of embryogenesis, the villus hemocircular channel is presented as a blood vessel pincer. On the 20th-21st days on the corrosive preparations at the base of villus it's already produced like a leaf basket of micro vessels. On the 17th day from the birth still it is going increasing of blood vessels in the villus. Simultaneously begins increasing of the new villi of the intestine as well. On the top of blood vessel pincers the micro vessels twist sharply and create peculiar blood vessel plexus. We can suppose that in process of pre and postnatal ontogenesis, the main mechanism of formation of the intestine villus micro blood vessel divides the capillaries into two parallel tubes. Thus, during the villus maturation, intensive maturation processes of morphogenesis, angiogenesis and micro blood vessel constructions take place.


Oxygen Partial Pressure during Pulsed Laser Deposition: Deterministic Role on Thermodynamic Stability of Atomic Termination Sequence at SrRuO3/BaTiO3 Interface.
With recent trends on miniaturizing oxide-based devices, the need for atomic-scale control of surface/interface structures by pulsed laser deposition (PLD) has increased. In particular, realizing uniform atomic termination at the surface/interface is highly desirable. However, a lack of understanding on the surface formation mechanism in PLD has limited a deliberate control of surface/interface atomic stacking sequences. Here, taking the prototypical SrRuO3/BaTiO3/SrRuO3 (SRO/BTO/SRO) heterostructure as a model system, we investigated the formation of different interfacial termination sequences (BaO-RuO2 or TiO2-SrO) with oxygen partial pressure (PO2) during PLD. We found that a uniform SrO-TiO2 termination sequence at the SRO/BTO interface can be achieved by lowering the PO2 to 5 mTorr, regardless of the total background gas pressure (Ptotal), growth mode, or growth rate. Our results indicate that the thermodynamic stability of the BTO surface at the low-energy kinetics stage of PLD can play an important role in surface/interface termination formation. This work paves the way for realizing termination engineering in functional oxide heterostructures.


Importance of independent sit-to-stand ability in ambulatory patients with spinal cord injury.
Sit-to-stand (STS) is an important and basic activity for daily living. However, a few studies have reported information relating to STS ability in ambulatory patients with spinal cord injury (SCI). To investigate factors associated with the ability of independent sit-to-stand (iSTS) among ambulatory patients with SCI. Cross-sectional cohort study. Inpatient tertiary rehabilitation center and communities. Ambulatory patients with SCI. Sixty-nine independent ambulatory individuals with SCI who walked with or without a walking device were cross-sectionally interviewed and assessed for their demographics, SCI characteristics, iSTS ability (pass or fail), types of walking device used, balance ability, and lower limb support capability during STS. Forty-six subjects (67%) successfully performed iSTS ability (pass). The ability of iSTS was significantly associated with lower extremity muscle strength, lower limb support ability, balance control, and ability of walking with a single cane and without a walking device (P<0.01). The ability of iSTS is important for ambulatory patients with SCI as it related to ability of walking with minimal use of the upper extremities. Other significant associated factors provided important clue to promote ability of iSTS. The findings imply the use of iSTS ability as a simple and practical screening or monitoring tool for the ability of walking at least with a single cane. The improvement of lower extremity muscle strength, lower limb support ability, and balance control could improve iSTS ability of these individuals.


Separation of dilute aqueous butanol and acetone solutions by pervaporation through liquid membranes.
A simultaneous extraction-stripping process is proposed for separating volatile products from fermentation broths, it is based on pervaporation through a liquid membrane supported with a hydrophobic porous membrane. The liquid membrane prepared with oleyl alcohol was selected as the most suitable for separating volatile products resulting from acetone-butanol fermentation. The separation performance and stability of the oleyl alcohol liquid membrane were investigated by using dilute aqueous butanol and acetone solutions. The oleyl alcohol liquid membrane was found to be superior by far in both selectivity and permeability of butanol to the better known silicone rubber membrane in its high selectivity for alcohols. Using the oleyl alcohol liquid membrane, the dilute aqueous butanol solutions of around 4 g/L obtained in acetone-butanol fermentation could be concentrated up to 100 times. The stability of this liquid membrane was also quite good as long as the surface tension of the feed solution was less than the critical surface tension of the support membrane. No change in the separation performance was found after the continuous usage in a long period of 100 h.


Immunogenicity and protective efficacy of an EB66® cell culture-derived duck Tembusu virus vaccine.
The avian EB66® cell line, derived from duck embryonic stem cells, has been widely used for producing human and animal therapeutic proteins and vaccines. In current study we evaluated the potential use of EB66® cell line in a cell culture-derived duck Tembusu virus (DTMUV) vaccine development. After optimizing the growth conditions of DTMUV HB strain in EB66® cells, we successfully generated three batches of viruses with ELD50 titres of 105.9/0.1 ml, 105.3/0.1 ml and 105.5/0.1 ml, respectively, for using in the preparation of inactivated vaccines. The immunogenicity and protective efficacy of these EB66® cells-derived inactivated vaccines were examined in ducks. Results indicated that all three batches of vaccines induced haemagglutination-inhibition (HI) antibody response in immunized birds at 2 weeks after a single immunization. Immunized ducks and ducklings were protected against a virulent challenge at 4 weeks after a booster immunization. The duration of immunity was for 3-4 months after a booster immunization. These results demonstrated the feasibility of using EB66® cell line to grow up DTMUV for vaccine preparation. RESEARCH HIGHLIGHTS Duck Tembusu virus can be propagated in EB66® cells. EB66® cell-derived inactivated DTMUV vaccines are immunogenic and can provide protection against a virulent challenge. A long-lasting immunity is induced after a booster immunization.


Degradation of a pharmaceutical in HPLC grade methanol containing trace level formaldehyde.
An anomalous peak was observed in the HPLC/UV analysis of a developmental drug product. High resolution LC/MS revealed that the mass of this degradant was 12 Da greater than the drug substance, corresponding to a net gain of a single carbon atom. The degradant was reproduced by incubating the drug substance with formaldehyde, followed by isolation using normal phase chromatography and structure elucidation by NMR. It was determined to be an analytical artifact caused by the nucleophilic reaction of the drug substance with trace levels of formaldehyde in the methanol diluent. Typical formaldehyde levels in various grades of methanol were determined, leading to the adoption of spectrophotometric purity solvent to mitigate the recurrence of this artifact. This work demonstrates that even ppm levels of impurities in solvents can cause significant degradation of drug product and the HPLC grade solvents are not always suitable for HPLC analysis in drug product development.


Audiovisual Processing is Abnormal in Parkinson's Disease and Correlates with Freezing of Gait and Disease Duration.
Sensory and perceptual disturbances progress with disease duration in Parkinson's disease (PD) and probably contribute to motor deficits such as bradykinesia and gait disturbances, including freezing of gait (FOG). Simple reaction time tests are ideal to explore sensory processing, as they require little cognitive processing. Multisensory integration is the ability of the brain to integrate sensory information from multiple modalities into a single coherent percept, which is crucial for complex motor tasks such as gait. The aims of this study were to: 1. Assess differences in unisensory (auditory and visual) and multisensory processing speed in people with PD and age-matched healthy controls. 2. Compare relative differences in unisensory processing in people with PD with disease duration and freezing of gait status taking into account the motor delays, which are invariably present in PD. 3. Compare relative differences in multisensory (audiovisual) processing between the PD cohort and age-matched controls. 39 people with PD (23 with FOG) and 17 age-matched healthy controls performed a reaction time task in response to unisensory (auditory-alone, visual-alone) and multisensory (audiovisual) stimuli. The PD group were significantly slower than controls for all conditions compared with healthy controls but auditory reaction times were significantly faster than visual for the PD group only. These relative unisensory differences are correlated with disease duration and divide the PD group by FOG status, but these factors are co-dependent. Although multisensory facilitation occurs in PD, it is significantly less enhanced than in healthy controls. There are significant unisensory and multisensory processing abnormalities in PD. The relative differences in unisensory processing are specific to PD progression, providing a link between these sensory abnormalities and a motor feature of PD. Sensory disturbances have previously been postulated to be central to FOG but this is the first study to predict audiovisual processing abnormalities using FOG status. The multisensory processing abnormalities are independent of disease duration and FOG status and may be a potential biomarker for the disease.


Training in Readmission Reduction in an Indonesian Hospital.
The authors implemented a new discharge protocol to reduce readmission rates in a hospital in West Java, Indonesia. Forty nurses were trained in the use of the protocol. Results indicate that posttest group readmission rates were significantly lower after the implementation of protocol, from 6.11% to 4.21%. The protocol was effective in reducing readmissions for patients discharged from internal medicine, pulmonology, and women. Differences were also found by type of insurance or payment method, generally suggesting that the lower the socioeconomic status of the patients was, the more effective the discharge protocol was.


Disturbances of long-term memory in aphasic patients. A comparison of anterior and posterior lesions.
The performance of 20 aphasic patients on a verbal list-learning task was examined in relation to site of lesion, as documented by CT scan. Patients with lesions of the inferior frontal lobe and/or the basal ganglia were severely impaired in both acquisition and long-term retention of the list, while the performance of patients with posterior temporoparietal involvement was nearly normal. These results contrasted sharply with scores on short-term memory tests by the same patient groups which showed an opposite trend. The findings support a functional and neuroanatomical dissociation of short and long-term memory systems and suggest that neural connections of the inferior frontal lobe and the basal ganglia may be crucial for initiating the retrieval process.


The self-renewal of mouse embryonic stem cells is regulated by cell-substratum adhesion and cell spreading.
Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine, leukaemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, and this is accompanied by an increase in cell-substratum adhesion and cell spreading. The purpose of this study was to investigate the relationship between cell spreading and mESC differentiation. Using E14 and R1 mESC lines, we have restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biomaterial substrates, or by manipulating the cytoskeleton. We demonstrate that by restricting the degree of spreading by either method, mESCs can be maintained in an undifferentiated and pluripotent state. Under these conditions, self-renewal occurs without the need for LIF and is independent of nuclear translocation of tyrosine-phosphorylated STAT3 or β-catenin, which have previously been implicated in self-renewal. We also demonstrate that the effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as evidenced by the observations that inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA do not promote differentiation. These results show that mESC spreading and differentiation are regulated both by LIF and by cell-substratum adhesion, consistent with the hypothesis that cell spreading is the common intermediate step in the regulation of mESC differentiation by either LIF or cell-substratum adhesion.


The Clinical Practice of Assessing Cognitive Function in Adults Receiving Electroconvulsive Therapy: Whom Are We Missing?
Cognition can be affected by electroconvulsive therapy (ECT). Good clinical practice includes neuropsychological assessment, although this is seldom a part of routine clinical practice. It looks like a substantial part of patients fail to complete cognitive assessments. This constitutes a problem in the generalizability of published clinical research on cognitive side effects. Most studies of ECT-related cognitive adverse effects do not discuss this important issue of so-called cognitive test nonparticipants. Recent findings suggest that cognitive test nonparticipants are more severely ill, and probably more vulnerable to cognitive side effects. To examine the feasibility of a neuropsychological test battery in daily clinical practice, in an adult population referred for ECT. We reviewed the clinical records of 84 patients referred for ECT. Demographic and clinical characteristics of those patients who were able to complete our routine cognitive testing at baseline are compared with those who could not complete the assessment. From 84 ECT patients, 60 (71%) completed a pre-ECT cognitive assessment, whereas 24 (29%) did not. Patients with a unipolar depression, with psychotic symptoms, who started their treatment with a bitemporal electrode placement were more likely to be test noncompleters than test completers. Patients with a unipolar depression, with psychotic features, who are treated with a bitemporal electrode placement, have a higher likelihood of not completing a pre-ECT cognitive assessment. These patients probably represent a subgroup more vulnerable to cognitive side effects.


The Path-of-Probability Algorithm for Steering and Feedback Control of Flexible Needles.
In this paper we develop a new framework for path planning of flexible needles with bevel tips. Based on a stochastic model of needle steering, the probability density function for the needle tip pose is approximated as a Gaussian. The means and covariances are estimated using an error propagation algorithm which has second order accuracy. Then we adapt the path-of-probability (POP) algorithm to path planning of flexible needles with bevel tips. We demonstrate how our planning algorithm can be used for feedback control of flexible needles. We also derive a closed-form solution for the port placement problem for finding good insertion locations for flexible needles in the case when there are no obstacles. Furthermore, we propose a new method using reference splines with the POP algorithm to solve the path planning problem for flexible needles in more general cases that include obstacles.


Validation of a new scoring system: Rapid assessment faecal incontinence score.
To implement a quick and simple test - rapid assessment faecal incontinence score (RAFIS) and show its reliability and validity. From March 2008 through March 2010, we evaluated a total of 261 consecutive patients, including 53 patients with faecal incontinence. Demographic and comorbidity information was collected. In a single visit, patients were administered the RAFIS. The results obtained with the new score were compared with those of both Wexner score and faecal incontinence quality of life scale (FIQL) questionnaire. The patient without influence of the surgeon completed the test. The role of surgeon was explaining the meaning of each section and how he had to fill. Reliability of the RAFIS score was measured using intra-observer agreement and Cronbach's alpha (internal consistency) coefficient. Multivariate analysis of the main components within the different scores was performed in order to determine whether all the scores measured the same factor and to conclude whether the information could be encompassed in a single factor. A sample size of 50 patients with faecal incontinence was estimated to be enough to detect a correlation of 0.55 or better at 5% level of significance with 80% power. We analysed the results obtained by 53 consecutive patients with faecal incontinence (median age 61.55 ± 12.49 years) in the three scoring systems. A total of 208 healthy volunteers (median age 58.41 ± 18.41 years) without faecal incontinence were included in the study as negative controls. Pearson's correlation coefficient between "state" and "leaks" was excellent (r = 0.92, P < 0.005). Internal consistency in the comparison of "state" and "leaks" yielded also excellent correlation (Cronbach's α = 0.93). Results in each score were compared using regression analysis and a correlation value of r = 0.98 was obtained with Wexner score. As regards FIQL questionnaire, the values of "r" for the different subscales of the questionnaire were: "lifestyle" r = -0.87, "coping/behaviour" r = -0.91, "depression" r = -0.36 and "embarrassment" r = -0.90, (P < 0.01). A multivariate analysis showed that all the scoring systems measured the same factor. A single factor may explain 80.84% of the variability of FI, so all the scoring systems measure the same factor. Patient's continence improves when RAFIS and Jorge-Wexner scores show low values and when the values obtained in the FIQL questionnaire are high. RAFIS is a valid and reliable tool to assess Faecal Incontinence.


Mechanical and Electronic Video Stabilization Strategy of Mortars with Trajectory Correction Fuze Based on Infrared Image Sensor.
For a higher attack accuracy of projectiles, a novel mechanical and electronic video stabilization strategy is proposed for trajectory correction fuze. In this design, the complexity of sensors and actuators were reduced. To cope with complex combat environments, an infrared image sensor was used to provide video output. Following the introduction of the fuze's workflow, the limitation of sensors for mechanical video stabilization on fuze was proposed. Particularly, the parameters of the infrared image sensor that strapdown with fuze were calculated. Then, the transformation relation between the projectile's motion and the shaky video was investigated so that the electronic video stabilization method could be determined. Correspondingly, a novel method of dividing sub-blocks by adaptive global gray threshold was proposed for the image pre-processing. In addition, the gray projection algorithm was used to estimate the global motion vector by calculating the correlation between the curves of the adjacent frames. An example simulation and experiment were implemented to verify the effectiveness of this strategy. The results illustrated that the proposed algorithm significantly reduced the computational cost without affecting the accuracy of the motion estimation. This research provides theoretical and experimental basis for the intelligent application of sensor systems on fuze.