Dynamic knee stability estimated by finite helical axis methods during functional performance approximately twenty years after anterior cruciate ligament injury.
Finite helical axis (FHA) measures of the knee joint during weight-bearing tasks may capture dynamic knee stability following Anterior Cruciate Ligament (ACL) injury. The aim was to investigate dynamic knee stability during two-leg squat (TLS) and one-leg side hop (SH) in a long-term follow-up of ACL injury, and to examine correlations with knee laxity (KT-1000), osteoarthritis (OA, Kellgren-Lawrence) and knee function (Lysholm score). Participants were injured 17-28 years ago and then treated with surgery (n=33, ACLR) or physiotherapy only (n=37, ACLPT) and healthy-knee controls (n=33) were tested. Movements were registered with an optical motion capture system. We computed three FHA inclination angles, its' Anterior-Posterior (A-P) position, and an index quantifying directional changes (DI), during stepwise knee flexion intervals of ∼15°. Injured knees were less stable compared to healthy controls' and to contralateral non-injured knees, regardless of treatment: the A-P intersection was more anterior (indicating a more anterior positioning of tibia relative to femur) positively correlating with high laxity/low knee function, and during SH, the FHA was more inclined relative to the flexion-extension axis, possibly due to reduced rotational stability. During the TLS, A-P intersection was more anterior in the non-injured knee than the injured, and DI was higher, probably related to higher load on the non-injured knee. ACLR had less anterior A-P intersection than ACLPT, suggesting that surgery enhanced stability, although rotational stability may remain reduced. More anterior A-P intersection and greater inclination between the FHA and the knee flexion-extension axis best revealed reduced dynamic stability ∼23 years post-injury.


Semiquantitation of mouse dendritic cell migration in vivo using cellular MRI.
Despite recent therapeutic advances, including the introduction of novel cytostatic drugs and therapeutic antibodies, many cancer patients will experience recurrent or metastatic disease. Current treatment options, particularly for those patients with metastatic breast, prostate, or skin cancers, are complex and have limited curative potential. Recent clinical trials, however, have shown that cell-based therapeutic vaccines may be used to generate broad-based, antitumor immune responses. Dendritic cells (DC) have proved to be the most efficacious cellular component for therapeutic vaccines, serving as both the adjuvant and antigen delivery vehicle. At present it is not possible to noninvasively determine the fate of DC-based vaccines after their administration to human subjects. In this study, we demonstrate that in vitro-generated mouse DC can be readily labeled with superparamagnetic iron oxide nanoparticles, Feridex, without altering cell morphology, or their phenotypic and functional maturation. Feridex-labeling enables the detection of DC in vivo after their migration to draining lymph nodes using a 1.5 T clinical magnetic resonance scanner. In addition, we report a semiquantitative approach for analysis of magnetic resonance images and show that the Feridex-induced signal void volume, and fractional signal loss, correlates with the delivery and migration of small numbers of in vitro-generated DC. These findings, together with ongoing preclinical studies, are key to gaining information critical for improving the efficacy of therapeutic vaccines for the treatment cancer, and potentially, chronic infectious diseases.


Perioperative takotsubo cardiomyopathy: Implications for anesthesiologist.
Takotsubo cardiomyopathy (TCM) is characterized by transient ventricular dysfunction in the absence of obstructive coronary artery disease that may be triggered by an acute medical illness or intense physical or emotional stress. TCM is often confused with acute myocardial infarction given the similar electrocardiographic changes, cardiac enzymes, hemodynamic perturbations, and myocardial wall motion abnormalities. In the perioperative setting, the clinical picture may be more confusing because of the effect of anesthesia as well as hemodynamic changes related to the surgery itself. However, awareness of various other diagnostic modalities may enable clinicians to distinguish between the two, more systematically and with greater certainty. Despite the large body of literature, there still seems to be an overall paucity in our understanding of the etiopathogenesis, clinical characteristics, natural history, and management of this syndrome, especially in the perioperative setting. This narrative review seeks to present and synthesize the most recent literature on TCM and to identify gaps in current knowledge which can become the basis for future research.


The Effects of Compression-Garment Pressure on Recovery After Strenuous Exercise.
Compression garments are frequently used to facilitate recovery from strenuous exercise. To identify the effects of 2 different grades of compression garment on recovery indices after strenuous exercise. Forty-five recreationally active participants (n = 26 male and n = 19 female) completed an eccentric-exercise protocol consisting of 100 drop jumps, after which they were matched for body mass and randomly but equally assigned to a high-compression pressure (HI) group, a low-compression pressure (LOW) group, or a sham ultrasound group (SHAM). Participants in the HI and LOW groups wore the garments for 72 h postexercise; participants in the SHAM group received a single treatment of 10-min sham ultrasound. Measures of perceived muscle soreness, maximal voluntary contraction (MVC), countermovement-jump height (CMJ), creatine kinase (CK), C-reactive protein (CRP), and myoglobin (Mb) were assessed before the exercise protocol and again at 1, 24, 48, and 72 h postexercise. Data were analyzed using a repeated-measures ANOVA. Recovery of MVC and CMJ was significantly improved with the HI compression garment (P < .05). A significant time-by-treatment interaction was also observed for jump height at 24 h postexercise (P < .05). No significant differences were observed for parameters of soreness and plasma CK, CRP, and Mb. The pressures exerted by a compression garment affect recovery after exercise-induced muscle damage, with higher pressure improving recovery of muscle function.


Randomized clinical trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer (AXIS).
Postoperative portal vein infusion (PVI) of 5-fluorouracil (5-FU) is a well tolerated and widely applicable treatment for colorectal cancer that might have an enormous public health impact, even if it produced survival benefits of just a few per cent. Very large trials are required to detect such differences, and the Adjuvant X-ray and 5-FU Infusion Study (AXIS) is the largest such trial yet reported. Consenting patients with presumed colorectal cancer were randomized to surgery with or without 7 days of PVI (1 g 5-FU plus 5000 units heparin in 1 litre 5 per cent dextrose infused over each 24-h period). In addition, patients with rectal cancer could be randomized to radiotherapy or no radiotherapy to be given either before or after surgery. Between November 1989 and December 1997, 3583 patients were randomized with respect to PVI. The survival hazard ratios (95 per cent confidence interval (c.i.)) in all patients randomized and in the curatively resected subgroup (71.2 per cent of patients) were 1.00 (0.92 to 1.11) and 0.94 (0.83 to 1.06) respectively. Tests for heterogeneity suggested a greater treatment benefit for patients with colonic cancer than for patients with rectal cancer with respect to disease-free survival (hazard ratio 0.79 versus 1.03; P = 0.07), and there was a non-significant trend with respect to overall survival (hazard ratio 0.87 versus 1.03; P = 0.17). No survival benefit was seen in the 761 patients randomized with respect to radiotherapy; although not statistically significant, the impact on local recurrence rates was similar to that reported in the literature. No overall benefit of PVI was established in AXIS when colonic and rectal cancers were considered together, but the evidence suggesting a differential treatment effect according to site of cancer in AXIS was strongly supported by a meta-analysis incorporating the previous trials. Combining the data gave hazard ratios of 0.82 and 1.00 for colonic and rectal tumours respectively (test for interaction, P = 0.024), equating to an absolute survival benefit for patients with colonic cancer of 5.8 (95 per cent c.i. 2.8 to 8.5) per cent, a level close to that seen for prolonged systemic therapy.


High Resolution Marine Magnetic Survey of Shallow Water Littoral Area.
The purpose of this paper is to present a system developed for detection andaccurate mapping of ferro-metallic objects buried below the seabed in shallow waters. Thesystem comprises a precise magnetic gradiometer and navigation subsystem, both installedon a non-magnetic catamaran towed by a low-magnetic interfering boat. In addition wepresent the results of a marine survey of a near-shore area in the vicinity of Atlit, a townsituated on the Mediterranean coast of Israel, about 15 km south of Haifa. The primarypurpose of the survey was to search for a Harvard airplane that crashed into the sea in 1960.A magnetic map of the survey area (3.5 km² on a 0.5 m grid) was created revealing theanomalies at sub-meter accuracy. For each investigated target location a correspondingferro-metallic item was dug out, one of which turned to be very similar to a part of thecrashed airplane. The accuracy of location was confirmed by matching the position of theactual dug artifacts with the magnetic map within a range of ± 1 m, in a water depth of 9 m.


Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice.
Compounds approved for therapeutic use and in vitro inhibitors of severe acute respiratory syndrome coronavirus (SARS-CoV) were evaluated for inhibition in the mouse SARS-CoV replication model. A hybrid interferon, interferon alpha (IFN-alpha) B/D, and a mismatched double-stranded (ds) RNA interferon (IFN) inducer, Ampligen (poly I:poly C124), were the only compounds that potently inhibited virus titres in the lungs of infected mice as assessed by CPE titration assays. When mice were dosed intraperitoneally (i.p.) with IFN-alpha B/D once daily for 3 days beginning 4 h after virus exposure, SARS-CoV replication in the lungs of infected mice was reduced by 1 log10 at 10,000 and 32,000 IU; at the highest dose of 100,000 IU, virus lung titres were below detectable limits. Ampligen used i.p. at 10 mg/kg 4 h prior to virus exposure also reduced virus lung titres to below detectable limits. Nelfinavir, beta-D-N4-hydroxycytidine, calpain inhibitor VI, 3-deazaneplanocin A and Alferon (human leukocyte IFN-alpha-n3) did not significantly reduce lung virus titres in mice. Anti-inflammatory agents, chloroquine, amodiaquin and pentoxifylline, were also inactive in vivo, suggesting that although they may be useful in ameliorating the hyperinflammatory response induced by the virus infection, they will not significantly reduce the replication of the virus, the inducer of inflammatory response. Thus, anti-inflammatory agents may only be useful in treating virus lung infections if used in combination with agents that inhibit virus replication. In summary, the data suggest that induction of IFN by mismatched dsRNA or actual treatment with exogenous IFN-alpha can inhibit SARS-CoV replication in the lungs of mice.


An ERP investigation of transposed-word effects in same-different matching.
Can several words be read in parallel, and if so, how is information about word order encoded under such circumstances? Here we focused on the bottom-up mechanisms involved in word-order encoding under the hypothesis of parallel word processing. We recorded EEG while participants performed a visual same-different matching task with sequences of five words (reference sequence followed by a target sequence each presented for 400 ms). The reference sequence could be grammatically correct or an ungrammatical scrambling of the same words (e.g., he wants these green apples/green wants these he apples). Target sequences for 'different' responses were created by either transposing two words in the reference (e.g., he these wants green apples/green these wants he apples), or by changing two words (e.g., he talks their green apples/green talks their he apples). Different responses were harder to make in the transposition condition, and this transposed-word effect started to emerge around 250 ms post-target onset. The transposed-word effect was first seen on an early onsetting N400 component, with reduced amplitudes (i.e., less negative ERPs) in the transposed condition relative to a two-word replacement condition. A later transposed-word effect was seen on a more temporally widespread positive-going component. Converging behavioral and EEG results showed no effects of reference grammaticality on 'different' responses nor an interaction with transposed-word effects. Our results point to the noisy, bottom-up association of word identities to spatiotopic locations as one means of encoding word order information, and one key source of transposed-word effects.


Life Cycle Assessment of Vehicle Lightweighting: Novel Mathematical Methods to Estimate Use-Phase Fuel Consumption.
Lightweighting is a key strategy to improve vehicle fuel economy. Assessing the life-cycle benefits of lightweighting requires a quantitative description of the use-phase fuel consumption reduction associated with mass reduction. We present novel methods of estimating mass-induced fuel consumption (MIF) and fuel reduction values (FRVs) from fuel economy and dynamometer test data in the U.S. Environmental Protection Agency (EPA) database. In the past, FRVs have been measured using experimental testing. We demonstrate that FRVs can be mathematically derived from coast down coefficients in the EPA vehicle test database avoiding additional testing. MIF and FRVs calculated for 83 different 2013 MY vehicles are in the ranges 0.22-0.43 and 0.15-0.26 L/(100 km 100 kg), respectively, and increase to 0.27-0.53 L/(100 km 100 kg) with powertrain resizing to retain equivalent vehicle performance. We show how use-phase fuel consumption can be estimated using MIF and FRVs in life cycle assessments (LCAs) of vehicle lightweighting from total vehicle and vehicle component perspectives with, and without, powertrain resizing. The mass-induced fuel consumption model is illustrated by estimating lifecycle greenhouse gas (GHG) emission benefits from lightweighting a grille opening reinforcement component using magnesium or carbon fiber composite for 83 different vehicle models.


The monoclonal antibody CJA3 down-regulates the susceptibility of human tumor cell lines to natural cell-mediated cytotoxicity.
While developing monoclonal antibodies (MoAb) to colorectal carcinoma (CRC) cells, we noted that one MoAb, termed CJA3, down-regulated natural cell-mediated cytotoxicity (NCMC) against CRC cell lines SW480 and SW620. The MoAb CJA3 was developed by immunizing a BALB/c mouse with fresh human colorectal adenocarcinoma cells. The antigen recognized by the MoAb CJA3 was expressed on several solid tumor cell lines and on one of the six lymphoreticular cell lines tested, but was not detected on normal peripheral blood lymphocytes (PBL). SDS-PAGE analysis of the antigen immunoprecipitated by the MoAb CJA3 from the CRC cell lines SW480 and SW620 and from the melanoma cell line MALME-3M revealed a component with a m.w. of 150,000. Preincubation of CRC cell lines SW480 and SW620 with the MoAb CJA3 for 16 hr reduced their susceptibility to NCMC by about 50%. Kinetic experiments showed that prolongation of the incubation of target cells with the MoAb CJA3 resulted in a time-dependent increase in the amount of MoAb bound. Maximum binding of the MoAb CJA3 was reached after 4 hr of incubation. The increase in antigen expression chronologically paralleled the decrease in NCMC target cell sensitivity, suggesting that the membrane alterations induced by the MoAb CJA3 were important for NCMC against these two cell lines.


Purification and Characterization of MxB.
MxB/Mx2 is an interferon-induced dynamin-like GTPase, which restricts a number of life-threatening viruses. Because of its N-terminal region, predicted to be intrinsically disordered, and its propensity to self-oligomerize, purification of the full-length protein has not been successful in conventional E. coli expression systems. In this chapter, we describe an expression and purification procedure to obtain pure full-length wild-type MxB from suspension-adapted mammalian cells. We further describe how to characterize its GTPase activity and oligomerization function.


Extraovarian peritoneal serous papillary carcinoma. A clinicopathologic study of 31 cases.
The rate and clinical features of patients admitted to King George V Hospital with extraovarian peritoneal serous papillary carcinoma during a 9-year period were reviewed. In this time, 31 of 236 (13%) patients with an initial diagnosis of invasive serous ovarian carcinoma fulfilled the surgicopathologic criteria for this entity. All patients had disseminated tumor equivalent to ovarian Stage III and IV disease (International Federation of Gynecology and Obstetrics [FIGO]) and with predominantly high-grade neoplasms. They were managed by surgical exploration, tumor debulking where possible, and postoperative chemotherapy. A comparison with a contemporaneous series of 139 patients with primary epithelial ovarian carcinoma matched for stage and grade of disease and managed similarly showed no difference in actuarial survival. The median survival times were 11.3 months for patients with extraovarian serous papillary carcinomas and 13.5 months for patients with equivalent primary ovarian neoplasms. The features of the disease and the treatment regimens used are discussed.


Sleep related bradyarrhythmic events and heart rate variability in apparently healthy individuals.
It is thought that abnormal cardiac impulses of the autonomic nervous system during sleep are responsible for sleep-related bradyarrhythmias. Despite a proposed common etiopathogenesis and having common name of "sleep-related bradyarrhythmias," precise importance of sinoatrial or atrioventricular (AV) node involvement remains elusive. This study aimed to determine whether there is a difference in sleeprelated bradyarrhythmias from the point of view of heart rate variability (HRV). Patients were evaluated using 24-hour Holter electrocardiogram monitor. After careful medical evaluation, apparently healthy individuals with sleep-related sinus pauses ≥2 seconds on at least 1 occasion or those in whom Mobitz type I AV block occurred were included. Frequency and time domain analyses were conducted for daytime, nighttime, and 24-hour period. Total of 37 patients with sinus pause(s), 40 patients with Mobitz type I AV block(s), and 40 healthy controls were included. On HRV analyses, all time and frequency domain parameters were better in sinus pause group for daytime, nighttime, and 24-hour average (p<0.05 for all). Results of heart rate-corrected HRV analyses still showed significantly better total power (TP) and very low frequency (VLF) in the sinus pause group compared with AV block group (TP: 7.1x10-3 vs. 5.4x10-3, p=0.011; VLF: 4.9x10-3 vs. 3.7x10-3, p=0.007). Despite proposed common autonomic mechanisms, sleep-related sinus pause cases demonstrated better HRV profile in comparison with Mobitz type I AV block.


Intraoperative assessment of stapes movement.
A method is described that allows, for the first time, intraoperative vibration modes assessment of the acoustically stimulated stapes by means of scanning laser Doppler interferometry (LDI). The study was designed to answer the following questions: 1) Is LDI practical for taking measurements during surgery? 2) Are the results comparable to the findings in temporal bone preparations? and 3) Do the vibration characteristics of the stapes change after the posterior incudal ligament is detached from the incus? Seven patients with profound bilateral hearing loss who were undergoing cochlear implantation were included in the study. The measurement system was easily applicable for intraoperative measurements and allowed contact-free analysis with very high accuracy. No major differences in the results from the live human subjects and temporal bone preparations were observed. The stapes movement was predominantly pistonlike at the lower frequencies and became complex at higher frequencies. Sacrificing the posterior incudal ligament had no statistically significant effect on stapes vibration.


Molecular Networks of Postia placenta Involved in Degradation of Lignocellulosic Biomass Revealed from Metadata Analysis of Open Access Gene Expression Data.
To understand the common gene expression patterns employed by P. placenta during lignocellulose degradation, we have retrieved genome wide transcriptome datasets from NCBI GEO database and analyzed using customized analysis pipeline. We have retrieved the top differentially expressed genes and compared the common significant genes among two different growth conditions. Genes encoding for cellulolytic (GH1, GH3, GH5, GH12, GH16, GH45) and hemicellulolytic (GH10, GH27, GH31, GH35, GH47, GH51, GH55, GH78, GH95) glycoside hydrolase classes were commonly up regulated among all the datasets. Fenton's reaction enzymes (iron homeostasis, reduction, hydrogen peroxide generation) were significantly expressed among all the datasets under lignocellulolytic conditions. Due to the evolutionary loss of genes coding for various lignocellulolytic enzymes (including several cellulases), P. placenta employs hemicellulolytic glycoside hydrolases and Fenton's reactions for the rapid depolymerization of plant cell wall components. Different classes of enzymes involved in aromatic compound degradation, stress responsive and detoxification mechanisms (cytochrome P450 monoxygenases) were found highly expressed in complex plant biomass substrates. We have reported the genome wide expression patterns of genes coding for information, storage and processing (KOG), tentative and predicted molecular networks involved in cellulose, hemicellulose degradation and list of significant protein-ID's commonly expressed among different lignocellulolytic growth conditions.


Air-soil exchange of PCBs: levels and temporal variations at two sites in Turkey.
Seasonal distribution of polychlorinated biphenyls (PCBs) at the air-soil intersection was determined for two regions: one with urban characteristics where traffic is dense (BUTAL) and the other representing the coastal zone (Mudanya). Fifty-one air and soil samples were simultaneously collected. Total PCB (Σ82 PCB) levels in the soil samples collected during a 1-year period ranged between 105 and 7,060 pg/g dry matter (dm) (BUTAL) and 110 and 2,320 pg/g dm (Mudanya). Total PCB levels in the gaseous phase were measured to be between 100 and 910 pg/m(3) (BUTAL) and 75 and 1,025 pg/m(3) (Mudanya). Variations in the concentrations were observed depending on the season. Though the PCB concentrations measured in the atmospheres of both regions in the summer months were high, they were found to be lower in winter. However, while soil PCB levels were measured to be high at BUTAL during summer months, they were found to be high during winter months in Mudanya. The direction and amount of the PCB movement were determined by calculating the gaseous phase change fluxes at air-soil intersection. While a general PCB movement from soil to air was found for BUTAL, the PCB movement from air to soil was calculated for the Mudanya region in most of the sampling events. During the warmer seasons PCB movement towards the atmosphere was observed due to evaporation from the soil. With decreases in the temperature, both decreases in the number of PCB congeners occurring in the air and a change in the direction of some congeners were observed, possibly caused by deposition from the atmosphere to the soil. 3-CB and 4-CB congeners were found to be dominant in the atmosphere, and 4-, 5-, and 6-CBs were found to dominate in the surface soils.


New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS).
The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype-phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype-phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 ± 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869-878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 ± 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.


Endogenous glucose production and glucose effectiveness in type 2 diabetic subjects derived from stable-labeled minimal model approach.
Insulin sensitivity, glucose effectiveness, and endogenous glucose production (EGP) during stable-labeled, frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) were evaluated by a single-and two-compartment minimal model combined with nonparametric deconvolution in eleven nonobese Japanese type 2 diabetic patients. Four patients were treated with sulfonylureas, and the remaining seven with diet therapy alone. None had diabetic retinopathy and microalbuminuria. Their fasting glucose level was 117+/-7 mg/dl (mean +/- SE), and HbA1c was 6.6+/-0.3%. Age-, sex-, and BMI-matched subjects with normal glucose tolerance served as control subjects. Plasma insulin response to the stimuli and insulin sensitivity indexes (S(I), S(I)*, and S(I)2* were derived from a minimal model and single- and two-compartment-labeled minimal models) were impaired in the type 2 diabetic patients. The combined ability of glucose, per se, to increase its own uptake and suppress EGP (glucose effectiveness [SG]), which was derived from kinetic analysis of plasma glucose by a minimal model, was significantly lower in the type 2 diabetic patients (0.0132+/-0.0015 vs. 0.0203+/-0.0022; P<0.05). However, the ability of glucose, per se, to stimulate glucose uptake, assessed as S(G)* and S(G)2* from the kinetic analysis of labeled glucose by single- and two-compartment minimal model, was not impaired in those patients. EGP of the type 2 diabetic patients as a whole was suppressed to the level similar to that of the control subjects despite a higher plasma glucose level throughout FSIGT. When EGP in the diabetic subjects was analyzed, considering their recent glycemic control, the initial suppression was blunted in the patients with higher HbA1c levels. In conclusion, glucose mass action to stimulate glucose uptake remains near-normal in the lean Japanese type 2 diabetic patients of this study, whereas ability of glucose to suppress EGP is impaired in the patients with recent hyperglycemia. This blunted suppression of EGP might be one of the conspirators for decreased S(G) in subjects with type 2 diabetes.


Perceived Effectiveness of Flirtation Tactics: The Effects of sex, Mating Context and Individual Differences in US and Norwegian Samples.
Flirting involves various signals communicated between individuals. To attract potential mates, men and women exhibit flirtatious behavior to get the attention of, and potentially elicit sexual or romantic interest from, a desired partner. In this first large, preregistered study of judgement of the effectiveness of flirtation tactics based on Sexual Strategies Theory, we considered the effects of flirter's (actor) sex and mating contexts in addition to rater's (participant) sex across two cultures, Norway and the U.S. Culturally relevant covariates such as sociosexuality, extraversion, mate value, age, and religiosity were examined. Participants from Norway (N = 415, 56% women) and the US (N = 577, 69% women) responded to one of four different randomized questionnaires representing a factorial design considering either short-term versus long-term mating context and either female or male sex of actor. We found that sexual availability cues were judged more effective when employed by women in short-term mating contexts. Friendly contact, such as hugs or kissing on the cheek, was not. Cues to generosity and commitment were judged more effective when employed by men in long-term mating contexts. Humor was rated as more effective when used by men and in long-term contexts, and least effective when used by women in short term contexts. However, laughing or giggling at someone's jokes was an effective flirtation tactic for both sexes. Overall, predictions for culturally relevant covariates were not supported, but cultural differences were found in bodily displays, initial contact, and generosity. These findings dovetail neatly with findings from the self-promotion literature, and further support that flirtation is a universal mate signaling strategy.


The Medical Termination of Pregnancy Act: Need to keep pace with technology.
In the summer of 2017, the Supreme Court of India denied permission to abort a 26-week-old foetus, detected with Down syndrome at 22 weeks, to a family which already had a child with special needs, on the grounds that the 20-week mark specified in The Medical Termination of Pregnancy Act of 1971 had been crossed. An Act well formulated and ahead of its time at inception seems not to have kept pace with technology and to be in need of change. We argue that by denying the abortion the Court did not adhere to the core principle of ethics-respect for autonomy, beneficence, non-malfeasance, and justice-as the mother was not allowed to decide for herself and was forced to abide by the decision taken by the court.


Dietary folate intake during pregnancy and birth weight in Japan.
Inadequate folate status has been associated with many negative reproductive outcomes, such as neural tube defects (NTD), low birth weight and placental abruption. The objectives of this study were to evaluate the levels of dietary folate intake during pregnancy in Japanese women and the subsequent birth weight of their babies. A longitudinal prospective study was conducted with 197 women with a singleton pregnancy in 2005. Dietary folate was investigated 3 times: in the first trimester at 12 weeks, in the second trimester at 20 weeks and in third trimester at 32 weeks using a diet history questionnaire (DHQ). Non fasting blood samples were collected from the women for measurement of homocysteine, hemoglobin, ferritin, unbound iron-binding capacity (UIBC) and total iron-binding capacity (TIBC). Energy intake increased as pregnancy advanced, but not significantly. The daily intake of folate increased from 248.5 +/- 113.1 microg/d in the first trimester to 275.4 +/- 100.2 microg/d in the third trimester (P = 0.04). This was well below the recommended level of 440 microg/d and only 10% of mothers were above the levels. In the third trimester, plasma homocysteine concentration was significantly higher in the low folate group of less than 250 microg/d (P = 0.02), but not the first and second trimesters. Dietary folate intake and plasma homocysteine concentrations were not likely to be predictors of birth weight in our subjects. Our study shows that Japanese women's energy and folate intakes do not meet their energy needs during pregnancy and are at an extremely low recommended dietary allowance level throughout pregnancy.


In vitro and in vivo reversal of chloroquine resistance in Plasmodium falciparum with promethazine.
The effect of combining promethazine with chloroquine was examined against Plasmodium falciparum in vitro in the Aotus-P. falciparum model and in bioassays from volunteers given promethazine. The combination of chloroquine plus promethazine (1 x 10(-6) M) reversed chloroquine resistance in standard P. falciparum clones and patient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentrations (IC50s) for chloroquine against resistant parasites by 32-92%. Coadministration of promethazine with chloroquine also demonstrated a dose-dependent effect in Aotus monkeys infected with chloroquine-resistant P. falciparum. Monkeys were given a chloroquine dose (20 mg/kg of body weight for seven days), which normally has no effect on parasitemia, plus 10, 20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowest promethazine dose, but re-treatment with 20 mg/kg resulted in clearance of parasitemia. Initial treatment with chloroquine and 20 or 40 mg/kg of promethazine cleared parasitemia in some animals followed by recrudescence. Re-treatment at higher doses cured one monkey and resulted in initial clearance and delayed recrudescence 28 or 63 days after treatment in two monkeys. Recrudescent parasitemia in the two monkeys was low (10 parasites/microl of blood) and subsequently cleared without re-treatment. An in vitro bioassay model was developed to examine the effects of clinically achievable doses of promethazine on parasites susceptibilities in vitro. Plasma samples taken at hourly intervals from patients given a single oral dose of 25 mg of promethazine decreased the IC50 values for chloroquine by 20-58% with the most significant reductions occurring in plasma obtained from volunteers 3-4 hr after ingestion. Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no effect on chloroquine susceptibility, suggesting that study of the pharmacokinetic disposition and potential interaction is warranted to optimize the dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or prevention of chloroquine-associated pruritus or as an antiemetic suggest that the combination is safe and effective when used at standard dosages. The results from this study demonstrate that promethazine is a potent modulator of chloroquine resistance. Clinical evaluation of therapeutic regimens is required to validate clinical efficacy of this promising combination for treatment of uncomplicated chloroquine-resistant malaria.


Disposition kinetics of ketotifen from liposomal dry powder for inhalation in rat lung.
1. The aim of the present study was to understand the benefit of liposomal dry powder for inhalation (LDPI) of ketotifen fumarate (KF) over plain drug dry powder for inhalation as a pulmonary targetted drug-delivery system. 2. The KF liposomes, composed of egg phosphatidyl choline and cholesterol, were prepared by the lipid film hydration technique. The liposomal dispersion was freeze dried and formulated to a dry powder for inhalation. Values of 89.0-65.3% drug entrapment of freeze-dried liposomes were estimated in prepared batches. 3. Rehydrated KF liposomes formed by the hydration of LDPI or the plain KF solution was delivered to rat lungs by intratracheal instillation. Simultaneous monitoring of drug levels in the bronchoalveolar lavage and lung tissue enabled assessment of pulmonary drug disposition. 4. Cumulative drug levels in lung tissue after intratracheal administration revealed that with liposomes targetting factors were between 1.36 and 1.54. The maximal drug concentration in lung homogenate for LDPI was 42.0 micro g compared with 73.6 micro g for plain drug solution. 5. Similarly, the time to reach maximum drug concentration in the lung homogenate for liposomal dry powder was 9-12 h compared with 3 h for plain drug. 6. Hence, the use of LDPI of KF was found to provide desired drug levels in the lung for a long time and thereby increased pulmonary targetting 7. This is expected to enhance the therapeutic index of the drug and probably reduce the dose administered and the cost of therapy.


Laparoscopic versus open pancreatoduodenectomy: a meta-analysis of randomized controlled trials.
the evidence with regard to the benefit of laparoscopic surgery for pancreatoduodenectomy is conflicting. The aim of this meta-analysis was to compare the short-term outcomes in patients undergoing laparoscopic or open pancreatoduodenectomy via randomized controlled trial studies. PubMed, Embase and Cochrane Library databases were searched for studies addressing laparoscopic versus open pancreatoduodenectomy up to February 2019. Only randomized controlled trial studies were included. three randomized controlled trial studies were identified, which included a total of 224 patients. Statistically significant differences were found with regard to estimated blood loss in favor of laparoscopic pancreatoduodenectomy (WMD, -150.9 ml; 95% CI, -167.61 to -134.18; p < 0.001) but with longer operative time (WMD, 97.66 min; 95% CI, 21.28 to 174.05; p = 0.01). No significant differences were found for severe postoperative complications (defined as Clavien-Dindo grade ≥ III complications), complication-related mortality within 90 days, blood transfusion requirements, length of hospital stay, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, surgical site infection, readmission rate, reoperation rate, harvested lymph nodes and R0 resection rate. the perioperative safety of laparoscopic pancreatoduodenectomy, which may have an advantage of lower estimated blood loss, is comparable to that of open pancreatoduodenectomy. Currently, a small volume of cases may be an important reason that affects the evaluation between laparoscopic and open pancreatoduodenectomy. Further evaluation of laparoscopic pancreatoduodenectomy will require large randomized control trials.


C14orf132 gene is possibly related to extremely low birth weight.
Despite extensive research the genetic component of extremely low birth weight (ELBW) in newborns has remained obscure. The aim of the case study was to identify candidate gene(s) causing ELBW in newborns and hypotrophy in infants. A family of four was studied: mother, father and two ELBW-phenotype children. Studies were made of the medical conditions of the second child at birth and post-partum - peculiar phenotype, micro-anomalies, recurrent infections, suspicion of autoimmune hepatitis, multifactorial encephalopathy and suspected metabolic and chromosomal abnormalities. Whole genome single nucleotide polymorphism (SNP) genotyping array was used to investigate the genomic rearrangements in both affected children using peripheral blood DNA samples. Whole blood transcriptome was assessed by using RNA sequencing (RNA-seq) in all four family members. RNA-seq identified a single gene - C14orf132 (chromosome 14 open reading frame 132) differentially expressed, with the level of the transcript significantly lower in the blood samples of the children. Copy number variant (CNV) analysis did not reveal any pathogenic CNVs in the region of C14orf132 gene of both affected children. We demonstrated the importance of combining whole genome CNV and transcriptome analysis in identification of the candidate gene(s) in case studies. We propose the C14orf132 gene expression to be associated with the ELBW-phenotype. C14orf132 gene is a novel long non-coding RNA (lincRNA) with unknown function, which might be associated with the pre- and early postnatal developmental delay through the altered gene expression.


Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport.
Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia, that is insulin resistance and beta-cell dysfunction. Progressive beta-cell failure, in addition to side effects associated with many current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of glycaemic control in patients with type 2 diabetes mellitus (T2DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with T2DM. Most recently, specific inhibitors of the renal sodium-glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of the iR unique mechanism of action, which is independent of insulin secretion and insulin action, these agents are effective in lowering the plasma glucose concentration in all stages of the disease and can be combined with all other antidiabetic agents. In this review, we will summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agents.


Interpenetration as a mechanism for liquid-liquid phase transitions.
We study simple lattice systems to demonstrate the influence of interpenetrating bond networks on phase behavior. We promote interpenetration by using a Hamiltonian with a weakly repulsive interaction with nearest neighbors and an attractive interaction with second-nearest neighbors. In this way, bond networks will form between second-nearest neighbors, allowing for two (locally) distinct networks to form. We obtain the phase behavior from analytic solution in the mean-field approximation and exact solution on the Bethe lattice. We compare these results with exact numerical results for the phase behavior from grand canonical Monte Carlo simulations on square, cubic, and tetrahedral lattices. All results show that these simple systems exhibit rich phase diagrams with two fluid-fluid critical points and three thermodynamically distinct phases. We also consider including third-nearest-neighbor interactions, which give rise to a phase diagram with four critical points and five thermodynamically distinct phases. Thus the interpenetration mechanism provides a simple route to generate multiple liquid phases in single-component systems, such as hypothesized in water and observed in several model and experimental systems. Additionally, interpenetration of many such networks appears plausible in a recently considered material made from nanoparticles functionalized by single-strands of DNA.


Optimisation of dynamic nuclear polarisation of [1-(13)C] pyruvate by addition of gadolinium-based contrast agents.
Dynamic nuclear polarisation (DNP) of carbon-13 ((13)C) enriched endogenous compounds provides a novel means for magnetic resonance imaging and spectroscopy of biological processes. Adding small amounts of gadolinium-based contrast agents (GBCAs) to the (13)C-enriched substrate matrix increases the amount of hyperpolarisation that can be achieved, but also may decrease the longitudinal relaxation time (T(1)) of the (13)C nucleus in solution. This study examined the effects of five different GBCA at concentrations of 0.5, 1, 2, and 3 mM on [1-(13)C]-enriched pyruvic acid. It was found that contrast agents with an open chain structure (Gadobenate dimeglumine, Gadopentetate dimeglumine, Gadodiamide) caused the largest enhancement (up to 82%) in solid state polarisation relative to solutions without GBCA. In the liquid state, T(1) of pyruvate decreased by as much as 62% and polarisation was much lower (70%) relative to solutions without GBCA added. Conversely, for GBCA with macrocyclic structures (Gadoterate meglumine, Gadoteridol), the solid state polarisation enhancement was only slightly less than the open chain GBCA, but enhanced polarisation was retained much better in the liquid state with minimal decrease in T(1) (25% at the highest GBCA concentrations). Near maximum polarisation in the solid state was obtained at a GBCA concentration of 2 mM, with a higher concentration of 3 mM producing minimal improvement. These results indicate that the macrocyclic contrast agents provide the best combination of high solid state and liquid state polarisations with minimal loss of T(1) in experiments with hyperpolarised (13)C-enriched pyruvate. This suggests that macrocyclic contrast agents should be the GBCA of choice for maximising signal in experiments with hyperpolarised (13)C-enriched pyruvate, particularly for in vivo measurements where shortened substrate T(1) is especially problematic.


Pillow use: the behavior of cervical stiffness, headache and scapular/arm pain.
Pillows are intended to support the head and neck in a neutral position to minimize biomechanical stresses on cervical structures whilst sleeping. Biomechanical stresses are associated with waking cervical symptoms. This paper adds to the scant body of research investigating whether different pillow types produce different types and frequencies of waking symptoms in asymptomatic subjects. A random-allocation block-design blinded field trial was conducted in a large South Australian regional town. Subjects were side-sleepers using one pillow only, and not receiving treatment for cervicothoracic problems. Waking cervical stiffness, headache and scapular/arm pain were recorded daily. Five experimental pillows (polyester, foam regular, foam contour, feather, and latex) were each trialed for a week. Subjects' 'own' pillow was the control (a baseline week, and a washout week between each experimental pillow trial week). Subjects reported waking symptoms related to known factors (other than the pillow), and subjects could 'drop out' of any trial pillow week. Disturbed sleep unrelated to the pillow was common. Waking symptoms occurring at least once in the baseline week were reported by approximately 20% of the subjects on their 'own' pillow. The feather trial pillow performed least well, producing the highest frequency of waking symptoms, while the latex pillow performed best. The greatest number of 'drop outs' occurred on the feather pillow. The foam contour pillow performed no better than the foam regular pillow. 'Own' pillows did not guarantee symptom-free waking, and thus were a questionable control. The trial pillows had different waking symptom profiles. Latex pillows can be recommended over any other type for control of waking headache and scapular/arm pain.


Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome.
To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorectal adenoma-carcinoma sequence are involved in Peutz-Jeghers syndrome (PJS) related tumorigenesis. Thirty nine polyps and five carcinomas from 17 patients (from 13 families) with PJS were analysed for loss of heterozygosity (LOH) at 19p13.3 (STK11/LKB1 gene locus), 5q21 (APC gene locus), 18q21-22 (Smad4 and Smad2 gene locus), and 17p13 (p53 gene locus), and evaluated for immunohistochemical staining of p53. In addition, mutational analysis of K-ras codon 12, APC, and p53 and immunohistochemistry for Smad4 expression were performed on all carcinomas. LOH at 19p was seen in 15 of the 39 polyps and in all carcinomas (n = 5). Interestingly, six of the seven polyps from patients with cancer had LOH, compared with nine of the 31 polyps from the remaining patients (p = 0.01). In one polyp from a patient without a germline STK11/LKB1 mutation, no LOH at 19p or at three alternative PJS candidate loci (19q, 6p, and 6q) was found. No LOH at 5q was observed. However, mutational analysis revealed an APC mutation in four of the five carcinomas. LOH at 17p was not seen in polyps or carcinomas; immunohistochemistry showed expression of p53 in one carcinoma and focal expression in three polyps. At subsequent sequence analysis, no p53 mutation was found. One carcinoma had an activating K-ras codon 12 mutation and another carcinoma showed 18q LOH; however, no loss of Smad4 expression was seen. These results provide further evidence that STK11/LKB1 acts as a tumour suppressor gene, and may be involved in the early stages of PJS tumorigenesis. Further research is needed to see whether LOH in PJS polyps could be used as a biomarker to predict cancer. Differences in molecular genetic alterations noted between the adenoma-carcinoma sequence and PJS related tumours suggest the presence of a distinct pathway of carcinogenesis.


Dementia in patients undergoing long-term dialysis: aetiology, differential diagnoses, epidemiology and management.
Dementia in patients undergoing long-term dialysis has not been clearly defined; however, four different entities have been described. Uraemic encephalopathy is a complication of uraemia and responds well to dialysis. Dialysis encephalopathy syndrome, the result of acute intoxication of aluminium caused by the use of an aluminium-containing dialysate, was a common occurrence prior to 1980. However, using modern techniques of water purification, such acute intoxication can now be avoided. Dialysis-associated encephalopathy/dementia (DAE) is always associated with elevated serum aluminium levels. Pathognomonic morphological changes in the brain have been described, but the mechanism for the entry of aluminium into the CNS is incompletely understood. The mechanisms involved in the pathogenesis of the neurotoxicity associated with aluminium are numerous. Although only a very small fraction of ingested aluminium is absorbed, the continuous oral aluminium intake from aluminium-based phosphate binders, and also of dietary or environmental origin, is responsible for aluminium overload in dialysis patients. Age-related dementia, especially vascular dementia, occurs in patients undergoing long-term dialysis as frequently as it does in the general population. The differential diagnoses of dialysis-associated dementias should include investigation for metabolic encephalopathies, heavy metal or trace element intoxications, and distinct structural neurological lesions such as subdural haematoma, normal pressure hydrocephalus, stroke and, particularly, hypertensive encephalopathy and multi-infarct dementia. To prevent DAE, dietary training programmes should aim to achieve the lowest phosphate intake and pharmacological tools should be used to keep serum phosphate levels below 2 mmol/L. To prevent vascular dementia, lifestyle modification should be undertaken, including optimal physical activity and fat intake, nicotine abstinence, and targeting optimal blood glucose, cholesterol and triglyceride levels, and blood pressure, to those outlined in current recommendations.


Effect of dietary cholesterol, trans and saturated fatty acids on serum lipoproteins in non-human primates.
Nine cynomolgus monkeys were rotated randomly through four dietary treatments with each treatment lasting 6 weeks. A wash-out period of 4 weeks was maintained between each dietary rotation. The animals were fed diets containing 32% energy fat derived from palm olein (POL), lauric-myristic-rich oil blend (LM), American Heart Association (AHA) rich oil blend and hydrogenated soybean oil blend (trans). Diets were fed with (phase 1) or without (phase 2) the addition of dietary cholesterol (0.1%). In phase 1, when animals were fed without dietary cholesterol, plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) was significantly raised and high-density lipoprotein cholesterol (HDL-C) was significantly depressed by the trans diets relative to all other dietary treatments. The resulting LDL-C/HDL-C ratio was also significantly increased. The LM diet increased TC significantly relative to the AHA diet while LDL-C was significantly increased compared to both POL and AHA. Apolipoprotein (apo) B was not affected significantly by these dietary treatments. Apo A1 was significantly increased by POL relative to all other dietary treatments. The trans diet reduced apo A1 and the resulting apo B/A1 ratio was increased significantly by trans relative to all other dietary treatments. Addition of 0.1% dietary cholesterol to these diets almost doubled the plasma TC and LDL-C in all dietary treatments. However, HDL-C was only marginally higher with the addition of dietary cholesterol. The LM + C (cholesterol added) diet resulted in the highest TC and LDL-C that was significant compared to all other dietary treatments. Trans + C increased TC compared to POL + C and AHA + C diets while increases in the LDL-C did not attain significance. The addition of dietary cholesterol did not affect HDL-C between treatments whereas plasma triglycerides were significantly increased by the trans + C diet relative to all other treatments. Both the trans + C and LM + C diets increased apo B and decreased apo A1 relative to the POL + C and AHA + C diets. The resulting apo B/A1 ratio was similarly altered. These results affirm that the lauric + myristic acid combination, along with trans fatty acids, increased lipoprotein-associated coronary heart disease risk factors compared to either POL or AHA.


Elastic fiber components and protease inhibitors in pinguecula.
The nature of the abnormal elastotic materials seen in pingueculae and their insensitivity to elastase are poorly understood. The authors investigated their composition by immunoelectron microscopy using antibodies to elastic fiber components, serum and tissue components known to be associated with elastosis in other sites. The abnormal elastic fibers showed labeling for elastin, microfibrillar protein, and amyloid P where these components never co-localize normally, indicating the fibers are not simply immature but aberrant in organization. There was mild positivity for the serum protease inhibitor alpha-1 antitrypsin at the edges of the abnormal elastic tissue and marked positivity for lysozyme. The more superficial region of pingueculae had similar elastic constituents but no fiber formation and a paucity of elastic microfibrils. The subepithelial dense concretions showed strong staining for lysozyme, the first component to be identified in these aggregates. Amyloid P and lysozyme are characteristic components of dermal elastosis, postulated to have an inhibitory effect on elastolytic processes, indirectly affecting the control of elastogenesis. The greater prominence of nonfiber-forming aggregates in pingueculae may be related to their marked deficiency of elastic microfibrils compared with dermal elastoses. This difference speaks for more severe actinic cellular damage in the poorly protected conjunctival tissue.


A randomized, controlled cross-over trial of dermally-applied lavender (Lavandula angustifolia) oil as a treatment of agitated behaviour in dementia.
Lavender essential oil shows evidence of sedative properties in neurophysiological and animal studies but clinical trials of its effectiveness as a treatment of agitation in people with dementia have shown mixed results. Study methods have varied widely, however, making comparisons hazardous. To help remedy previous methodological shortcomings, we delivered high grade lavender oil in specified amounts to nursing home residents whose agitated behaviours were recorded objectively. 64 nursing home residents with frequent physically agitated behaviours were entered into a randomized, single-blind cross-over trial of dermally-applied, neurophysiologically active, high purity 30% lavender oil versus an inactive control oil. A blinded observer counted the presence or absence of target behaviours and rated participants' predominant affect during each minute for 30 minutes prior to exposure and for 60 minutes afterwards. Lavender oil did not prove superior to the control oil in reducing the frequency of physically agitated behaviours or in improving participants' affect. Studies of essential oils are constrained by their variable formulations and uncertain pharmacokinetics and so optimal dosing and delivery regimens remain speculative. Notwithstanding this, topically delivered, high strength, pure lavender oil had no discernible effect on affect and behaviour in a well-defined clinical sample. Australian and New Zealand Clinical Trials Registry (ACTRN 12609000569202).


Minimal oxidation and inflammogenicity of pristine graphene with residence in the lung.
Two-dimensional graphitic carbon, graphene, is a new form of nanomaterial with great potential in a wide variety of applications. It is therefore crucial to investigate the behaviour of graphene in biological systems to assess potential adverse effects that might follow from inhalation exposure. In this study we focussed on medium-term effects of graphene in lung tissue by investigating the pulmonary inflammation 6 weeks after pharyngeal aspiration of unoxidised multilayered graphene platelets (GPs) in mice and assessed their biopersistence in the lung tissue using Raman spectroscopy. Additionally, GP degradation in vitro was examined after horseradish peroxidase (HRP) treatment up to 1 week. Building on our previous report showing acute inflammation in mice lungs at 1 day, pristine GP showed minimal inflammation in mouse lungs after 6 weeks even though no degradation of GP in lung tissue was observed and large deposits of GP were evident in the lungs. Raman analysis of GP in tissue sections showed minimal oxidation, and in vitro examinations of enzymatic oxidation of GP via HRP and H2O2 showed only slight increases in ID/IG ratio and the appearance of the Raman D' band at 1620 cm(-1) (surrogates of graphene oxidation). Our results showing non-inflammogenicity at medium time points have important implications in the hazard identification of GPs following inhalation exposure and for their use in biomedical applications. Additionally, the biopersistence of pristine GP in vivo with no associated inflammation could open the way to applications in tissue engineering and drug delivery.


Associations between dietary intake and body fat independent of genetic and familial environmental background.
To determine whether habitual dietary intake was associated with body fat mass and body fat distribution, independently of possible confounding by the genetic and shared environmental background. We examined correlations between intrapair differences in specific dietary composition and intake of foods and macronutrients in relation to differences in anthropometric phenotypes in a population-based sample of monozygotic twins. Data originated from a cross-sectional study, conducted in 1997-2000, of healthy twin pairs with measured anthropometry and information from food frequency questionnaire supplemented by self-reported weight from 1994 to 2002 and self-reported waist circumference from 2002. For this study, 153 men and 158 women identical twin pairs were included. Intrapair differences in dietary factors and anthropometry were studied using correlation analyses. Only few statistically significant correlations between intrapair differences in dietary intake and anthropometry were found. Consistent positive associations were found between intake of sugar-sweetened soft drinks and body fat in men, but not in women. Intake of vegetable oil was inversely associated with waist change in men. Only the latter finding remained significant when accounting for multiple testing. Only few associations between individually modifiable dietary factors and body fat measures were found, and only among men. Intake of vegetable oil was inversely related to waist change and intake of sugar-sweetened soft drinks was directly related to body fat in men.


Combined administration of aspirin and a specific thrombin inhibitor in man.
Heparin is of limited value as an antithrombotic drug in the presence of platelet activation and residual thrombus. Greater anticoagulant activity can be achieved in vivo with more specific thrombin inhibitors. Heparin may also increase the risk of bleeding by an effect on platelets that is independent of its thrombin inhibitory activity. The pharmacodynamic and pharmacokinetic effects of a novel thrombin inhibitor, argatroban, were examined alone and in combination with aspirin in normal male volunteers. Argatroban induced a dose-dependent prolongation of the thrombin time and the activated partial thromboplastin time (aPTT). aPTT had returned to its pretreatment value 1 hour after stopping the infusion of argatroban. Six male subjects received an infusion of 1 micrograms/kg/min argatroban after the administration of two doses of 162.5 mg aspirin or a matching placebo. At this dose, aspirin decreased serum thromboxane B2 by a mean of 99% and prolonged the bleeding time (230 +/- 52 versus 320 +/- 113 seconds, p less than 0.01). Argatroban given alone increased thrombin time by 454 +/- 18% and aPTT by 160 +/- 3%. Steady-state plasma concentrations were achieved at 1 hour and declined exponentially with an elimination half-life of 24 +/- 4 minutes. Neither the anticoagulant effects nor the plasma concentrations of argatroban were altered by aspirin. Furthermore, argatroban did not increase the bleeding time when given alone and did not further prolong the bleeding time when combined with aspirin. The combination of aspirin and argatroban may prove to be an effective therapeutic strategy in the prevention of coronary thrombosis.


Substituted diphenyl ethers as a novel chemotherapeutic platform against Burkholderia pseudomallei.
Identification of a novel class of anti-Burkholderia compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in Burkholderia is an underexploited target that presents an opportunity for development of a new class of inhibitors. A library of substituted diphenyl ethers was used to identify FabI1-specific inhibitors for assessment in Burkholderia pseudomallei ex vivo and murine efficacy models. Active FabI1 inhibitors were identified in a two-stage format consisting of percent inhibition screening and MIC determination by the broth microdilution method. Each compound was evaluated against the B. pseudomallei 1026b (efflux-proficient) and Bp400 (efflux-compromised) strains. In vitro screening identified candidate substituted diphenyl ethers that exhibited MICs of less than 1 μg/ml, and enzyme kinetic assays were used to assess potency and specificity against the FabI1 enzyme. These compounds demonstrated activity in a Burkholderia ex vivo efficacy model, and two demonstrated efficacy in an acute B. pseudomallei mouse infection model. This work establishes substituted diphenyl ethers as a suitable platform for development of novel anti-Burkholderia compounds that can be used for treatment of melioidosis.


Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5.
KIT is a cell surface tyrosine kinase receptor whose ligand stem cell factor (SCF) triggers homodimerization and activation of downstream effector pathways involved in cell survival, proliferation, homing, or differentiation. KIT-activating mutations are major oncogenic drivers in subsets of acute myeloid leukemia (AML), in mast cell leukemia, and in gastrointestinal stromal tumors (GIST). The overexpression of SCF and/or wild-type (WT) KIT is also observed in a number of cancers, including 50% of AML and small cell lung cancer. The use of tyrosine kinase inhibitors (TKI) in these pathologies is, however, hampered by initial or acquired resistance following treatment. Using antibody phage display, we obtained two antibodies (2D1 and 3G1) specific for the most membrane proximal extracellular immunoglobulin domain (D5) of KIT, which is implicated in KIT homodimerization. Produced as single chain variable antibody fragments fused to the Fc fragment of a human IgG1, bivalent 2D1-Fc and 3G1-Fc inhibited KIT-dependent growth of leukemic cell lines expressing WT KIT (UT7/Epo) or constitutively active KIT mutants, including the TKI imatinib-resistant KIT D816V mutant (HMC1.2 cell line). In all models, either expressing WT KIT or mutated KIT, 2D1 and 3G1-Fc induced KIT internalization and sustained surface downregulation. However, interestingly, KIT degradation was only observed in leukemic cell lines with oncogenic KIT, a property likely to limit the toxicity of these antibodies in patients. These fully human antibody formats may represent therapeutic tools to target KIT signaling in leukemia or GIST, and to bypass TKI resistance of certain KIT mutants.


Analysis of plasma lipid peroxidation and antioxidant enzymes status in patients of oral leukoplakia: A case control study.
Imbalances between the oxidant-antioxidant status have been implicated in the pathogenesis of several diseases, including oral cancer. Mostly, all oral cancer lesions are preceded by a stage of premalignancy. The present study aims to evaluate lipid peroxidation and antioxidant status in the venous blood of patients with different clinicopathologic stages of leukoplakia. A case control study was designed with the inclusion of 20 new cases of histopathologically proven leukoplakia of various clinical stages along with an equal number of positive and negative control individuals. The concentrations of thiobarbituric acid reactive substances and the activities of the antioxidant enzymes, namely superoxide dismutase, reduced glutathione, glutathione peroxidase, and catalase, were estimated in plasma using spectrophotometric methods. The data are expressed as mean ± SD. The statistical comparisons between and within the study groups were performed by one-way analysis of variance followed by post hoc analysis. Karl Pearson correlation was performed for the biochemical parameters within the group and between the groups. For statistically significant correlations, simple linear regression was performed. Significant enhanced lipid peroxidation (P < 0.001) with a decrease in antioxidants (P < 0.001) was observed in the venous blood of leukoplakia patients compared with positive as well as negative controls. Accordingly, significant (P < 0.001) pattern of progression in thiobarbituric acid reactive substances levels was observed at various clinical stages among patients of both control groups. Among enzymes, glutathione showed significant (P < 0.001) reduction along the stages on comparison with two control groups. Enhanced lipid peroxidation and compromised antioxidant defense in plasma indicate the development of oxidative stress. Among the antioxidant enzymes, reduced glutathione and glutathione Pperoxidase may play a decisive role in malignant transformation.


Biomechanical effects of augmented ankle power output during human walking.
The plantarflexor muscles are critical for forward propulsion and leg swing initiation during the push-off phase of walking, serving to modulate step length and walking speed. However, reduced ankle power output is common in aging and gait pathology, and is considered a root biomechanical cause of compensatory increases in hip power generation and increased metabolic energy cost. There is a critical need for mechanistic insight into the precise influence of ankle power output on patterns of mechanical power generation at the individual joint and limb levels during walking. We also posit that rehabilitative approaches to improve locomotor patterns should consider more direct means to elicit favorable changes in ankle power output. Thus, here we used real-time inverse dynamics in a visual biofeedback paradigm to test young adults' ability to modulate ankle power output during preferred speed treadmill walking, and the effects thereof on gait kinematics and kinetics. Subjects successfully modulated peak ankle power in response to biofeedback targets designed to elicit up to ±20% of normal walking values. Increasing ankle power output alleviated mechanical power demands at the hip and increased trailing limb positive work, propulsive ground reaction forces and step lengths. Decreasing ankle power had the opposite effects. We conclude that ankle power generation systematically influences the workload placed on more proximal leg muscles, trailing leg mechanical output and step length. Our findings also provide a promising benchmark for the application of biofeedback to restore ankle power in individuals with deficits thereof due to aging and gait pathology.


Transorbital craniectomy for treatment of frontal lobe and olfactory bulb neoplasms in two dogs.
An 8-year-old spayed female Shih Tzu crossbreed dog (dog 1) and a 13-year-old neutered male Miniature Fox Terrier (dog 2) were evaluated for removal of neoplasms involving both the frontal lobe and olfactory bulb. Physical examination revealed decreased menace response and behavioral changes in both dogs. For dog 1, neuroanatomic localization of the lesion was the left forebrain region; for dog 2, neuroanatomic localization of the lesion was the right forebrain region. Both dogs underwent CT, and dog 1 also underwent MRI. Results of diagnostic imaging were consistent with frontal lobe and olfactory bulb neoplasia in both cases. Dog 1 had lysis of the frontal bone adjacent to the neoplasm. Both dogs underwent a transorbital craniectomy to permit surgical tumor removal. Dog 1 was discharged from the hospital 48 hours after surgery, at which time its mentation and cranial nerve examination findings were considered normal. Dog 2 developed neurologic deterioration after surgery but was ultimately discharged from the hospital after 72 hours, at which time its mentation appeared normal. The transorbital approach to the cranium provided excellent access to facilitate removal of frontal lobe and olfactory bulb neoplasms in these 2 dogs.


Whole grain intake and its cross-sectional association with obesity, insulin resistance, inflammation, diabetes and subclinical CVD: The MESA Study.
We examined the relationship between whole grain intake and obesity, insulin resistance, inflammation, diabetes and subclinical CVD using baseline data from the Multi-Ethnic Study of Atherosclerosis. Whole grain intake was measured by a 127-item FFQ in 5496 men and women free of CHD and previously known diabetes. Mean whole grain intake was 0.5 (sd 0.5) servings per d; biochemical measures reflect fasting levels. After adjustment for demographic and health behaviour variables, mean differences for the highest quintile of whole grain intake minus the lowest quintile of intake were 0.6 kg/m2 for BMI, 0.36 mg/l for C-reactive protein, 0.82 micromol/l for homocysteine, 0.15 mU/l*mmol/l for homeostasis model assessment (HOMA), 0.48 mU/l for serum insulin, 2.0 mg/dl for glucose and 5.7 % for prevalence of newly diagnosed impaired fasting glucose (glucose >or= 100 mg/dl or diabetes medication). These differences represent 11-13 % of a standard deviation of BMI, HOMA, glucose and impaired fasting glucose, but 23 %, 52 % and 80 % of a standard deviation of homocysteine, C-reactive protein and insulin, respectively. An inverse association between whole grains and urine albumin excretion was suggested but retained statistical significance after adjustment only in Chinese and Hispanic participants. No associations were observed between whole grain intake and two subclinical disease measures: carotid intima-media thickness and coronary artery calcification. Concordant with previous research, whole grain intake was inversely associated with obesity, insulin resistance, inflammation and elevated fasting glucose or newly diagnosed diabetes. Counter to hypothesis, however, whole grain intake was unrelated to subclinical CVD.


Telework during the pandemic: Patterns, challenges, and opportunities for people with disabilities.
Telework has benefits for many people with disabilities. The pandemic may create new employment opportunities for people with disabilities by increasing employer acceptance of telework, but this crucially depends on the occupational structure. We compare people with and without disabilities in the expansion of telework as the pandemic began, and the evolution of telework during the pandemic. We use U.S. data from the American Community Survey from 2008 to 2020 and the Current Population Survey over May 2020 to April 2022 period. Prevalence and trends are analyzed using linear probability and multinomial logit regressions. While workers with disabilities were more likely than those without disabilities to telework before the pandemic, they were less likely to telework during the pandemic. The occupational distribution accounts for most of this difference. Tight labor markets, as measured by state unemployment rates, particularly favor people with disabilities obtaining telework jobs. While people with cognitive/mental health and mobility impairments were the most likely to telework during the pandemic, tight labor markets especially favored the expansion of telework for people with vision impairments and difficulty with daily activities inside the home. Many people with disabilities benefit from working at home, and the pandemic has increased employer acceptance of telework, but the current occupational distribution limits this potential. Tighter labor markets during the recovery offer hope that employers will increasingly hire people with disabilities in both telework and non-telework jobs.


Spectrum of the isotropic diffuse gamma-ray emission derived from first-year Fermi Large Area Telescope data.
We report on the first Fermi Large Area Telescope (LAT) measurements of the so-called "extragalactic" diffuse gamma-ray emission (EGB). This component of the diffuse gamma-ray emission is generally considered to have an isotropic or nearly isotropic distribution on the sky with diverse contributions discussed in the literature. The derivation of the EGB is based on detailed modeling of the bright foreground diffuse Galactic gamma-ray emission, the detected LAT sources, and the solar gamma-ray emission. We find the spectrum of the EGB is consistent with a power law with a differential spectral index gamma = 2.41 +/- 0.05 and intensity I(>100 MeV) = (1.03 +/- 0.17) x 10(-5) cm(-2) s(-1) sr(-1), where the error is systematics dominated. Our EGB spectrum is featureless, less intense, and softer than that derived from EGRET data.


PREDOSE: a semantic web platform for drug abuse epidemiology using social media.
The role of social media in biomedical knowledge mining, including clinical, medical and healthcare informatics, prescription drug abuse epidemiology and drug pharmacology, has become increasingly significant in recent years. Social media offers opportunities for people to share opinions and experiences freely in online communities, which may contribute information beyond the knowledge of domain professionals. This paper describes the development of a novel semantic web platform called PREDOSE (PREscription Drug abuse Online Surveillance and Epidemiology), which is designed to facilitate the epidemiologic study of prescription (and related) drug abuse practices using social media. PREDOSE uses web forum posts and domain knowledge, modeled in a manually created Drug Abuse Ontology (DAO--pronounced dow), to facilitate the extraction of semantic information from User Generated Content (UGC), through combination of lexical, pattern-based and semantics-based techniques. In a previous study, PREDOSE was used to obtain the datasets from which new knowledge in drug abuse research was derived. Here, we report on various platform enhancements, including an updated DAO, new components for relationship and triple extraction, and tools for content analysis, trend detection and emerging patterns exploration, which enhance the capabilities of the PREDOSE platform. Given these enhancements, PREDOSE is now more equipped to impact drug abuse research by alleviating traditional labor-intensive content analysis tasks. Using custom web crawlers that scrape UGC from publicly available web forums, PREDOSE first automates the collection of web-based social media content for subsequent semantic annotation. The annotation scheme is modeled in the DAO, and includes domain specific knowledge such as prescription (and related) drugs, methods of preparation, side effects, and routes of administration. The DAO is also used to help recognize three types of data, namely: (1) entities, (2) relationships and (3) triples. PREDOSE then uses a combination of lexical and semantic-based techniques to extract entities and relationships from the scraped content, and a top-down approach for triple extraction that uses patterns expressed in the DAO. In addition, PREDOSE uses publicly available lexicons to identify initial sentiment expressions in text, and then a probabilistic optimization algorithm (from related research) to extract the final sentiment expressions. Together, these techniques enable the capture of fine-grained semantic information, which facilitate search, trend analysis and overall content analysis using social media on prescription drug abuse. Moreover, extracted data are also made available to domain experts for the creation of training and test sets for use in evaluation and refinements in information extraction techniques. A recent evaluation of the information extraction techniques applied in the PREDOSE platform indicates 85% precision and 72% recall in entity identification, on a manually created gold standard dataset. In another study, PREDOSE achieved 36% precision in relationship identification and 33% precision in triple extraction, through manual evaluation by domain experts. Given the complexity of the relationship and triple extraction tasks and the abstruse nature of social media texts, we interpret these as favorable initial results. Extracted semantic information is currently in use in an online discovery support system, by prescription drug abuse researchers at the Center for Interventions, Treatment and Addictions Research (CITAR) at Wright State University. A comprehensive platform for entity, relationship, triple and sentiment extraction from such abstruse texts has never been developed for drug abuse research. PREDOSE has already demonstrated the importance of mining social media by providing data from which new findings in drug abuse research were uncovered. Given the recent platform enhancements, including the refined DAO, components for relationship and triple extraction, and tools for content, trend and emerging pattern analysis, it is expected that PREDOSE will play a significant role in advancing drug abuse epidemiology in future.


Comparative biochemistry of chondroitin sulphate-proteins of cartilage and notochord.
Fragments that consisted mainly of two polysaccharide chains joined by a short polypeptide bridge (doublets) were prepared from chondroitin sulphate-proteins of lamprey, sturgeon, elasmobranch and ox connective tissues after hydrolysis with trypsin and chymotrypsin. Consideration of molecular parameters, compositions and behaviour on gel electrophoresis and density-gradient fractionation leads to a proposed parent structure for chondroitin sulphate-proteins. A single polypeptide chain of about 2000 amino acid residues contains alternating short and long repeating sequences. A short sequence consists of less than 10 amino acid residues with one N-terminal and one C-terminal serine residue, each of which carries a polysaccharide chain linked glycosidically to its hydroxyl group. This structure constitutes the doublet subunit. Some variation is introduced when the doublet subunit carries only a single polysaccharide chain. The long sequence contains about 35 amino acid residues and is subject to cleavage by trypsin and chymotrypsin. The main polypeptide is probably homologous in the vertebrate sub-phylum with strong conservation of structure suggested for the short sequence. However, polymorphism of polypeptide structures cannot be excluded.


Wearable and flexible sensors for user-interactive health-monitoring devices.
Flexible electronic devices that are lightweight and wearable are critical for personal healthcare systems, which are not restricted by time and space. To monitor human bio-signals in a non-invasive manner, skin-conforming, highly sensitive, reliable, and sustainable healthcare monitoring devices are required. In this review, we introduce flexible and wearable sensors based on engineered functional nano/micro-materials with unique sensing capabilities for detection of physical and electrophysiological vital signs of humans. In addition, we investigate key factors for the development of user-interactive healthcare devices that are customizable, wearable, skin-conforming, and monolithic (design), and have long-term monitoring capability with sustainable power sources. Finally, we describe potential challenges of developing current wearable healthcare devices for applications in fitness, medical diagnosis, prosthetics, and robotics.


Shear viscosity in hard-sphere and adhesive colloidal suspensions with reverse non-equilibrium molecular dynamics.
We employ the reverse non-equilibrium molecular dynamics method (RNEMD) of Müller-Plathe [Phys. Rev. E, 1999, 59, 4894] to calculate the shear viscosity of colloidal suspensions within the stochastic rotation dynamics-molecular dynamics (SRD-MD) simulation method. We examine the influence of different coupling schemes in SRD-MD on the colloidal volume fraction ϕc dependent viscosity from the dilute limit up to ϕc = 0.3. Our results demonstrate that the RNEMD method is a robust and reliable method for calculating rheological properties of colloidal suspensions. To obtain quantitatively accurate results beyond the dilute regime, the hydrodynamic interactions between the effective fluid particles in the SRD and the MD colloidal particles must be carefully considered in the coupling scheme. We benchmark the method by comparing with the hard sphere suspension case, and then calculate relative viscosities for colloids with mutually attractive interactions. We show that the viscosity displays a sharp increase at the onset of aggregation of the colloidal particles with increasing volume fraction and attraction.


Positive Affect Is Associated With Reduced Fixation in a Realistic Medical Simulation.
This study extends previous research by exploring the association between mood states (i.e., positive and negative affect) and fixation in practicing anesthetists using a realistic medical simulation. The impact of practitioner emotional states on fixation is a neglected area of research. Emerging evidence is demonstrating the role of positive affect in facilitating problem solving and innovation, with demonstrated implications for practitioner fixation. Twelve practicing anesthetists (4 females; Mage= 39 years; SD = 6.71) were involved in a medical simulation. Prior to the simulation, practitioners rated the frequency they had experienced various positive and negative emotions in the previous three days. During the simulation, the patient deteriorated rapidly, and anesthetists were observed for their degree of fixation. After the simulation, practitioners indicated the frequency of these same emotions during the simulation. Nonparametric correlations were used to explore the independent relationships between positive and negative affect and the behavioral measures. Only positive affect impacted the likelihood of fixation. Anesthetists who reported more frequent recent positive affect in the three days prior to the simulation and during the simulation tended to be less fixated as judged by independent raters, identified a decline in patient oxygen saturation more quickly, and more rapidly implemented the necessary intervention (surgical cricothyroidotomy). These findings have some real-world implications for positive affect in patient safety. This research has broad implications for professions where fixation may impair practice. This research suggests that professional training should teach practitioners to identify their emotions and understand the role of these emotions in fixation.


Trend and disease burden of bacillary dysentery in China (1991-2000).
We aimed to determine the burden of bacillary dysentery in China, its cross-regional variations, trends in morbidity and mortality, the causative bacterial species and antimicrobial resistance patterns. We extracted and integrated governmental statistics and relevant medical literature published from 1991 to 2000. Data were also collected from one general hospital each for the six provinces and Jin-an district, Shanghai, representative of six geographical regions and a modern city. In 2000, 0.8-1.7 million episodes of bacillary dysentery occurred of which 0.5 to 0.7 million were treated at health-care facilities and 0.15-0.20 million patients were hospitalized. The highest morbidity and mortality rates were among the youngest and oldest age groups. Bacillary dysentery peaked during the summer months. The major causative species was Shigella flexneri (86%) and the predominant S. flexneri serotype was 2a (80%). About 74-80% of Shigella isolates remained susceptible to fluorinated quinolones. We conclude that while morbidity and mortality due to bacillary dysentery has decreased considerably in China in the past decade due to increasing access to affordable health care and antibiotics, a considerable burden exists among the youngest and oldest age groups and in regions with low economic development. We suggest that while a vaccine would be effective for short- and medium-term control of bacillary dysentery, improved water supply, sanitation, and hygiene are likely to be required for long-term control.


The carbon-nitrogen balance of the nodule and its regulation under elevated carbon dioxide concentration.
Legumes have developed a unique way to interact with bacteria: in addition to preventing infection from pathogenic bacteria like any other plant, legumes also developed a mutualistic symbiotic relationship with one gender of soil bacteria: rhizobium. This interaction leads to the development of a new root organ, the nodule, where the differentiated bacteria fix for the plant the atmospheric dinitrogen (atmN2). In exchange, the symbiont will benefit from a permanent source of carbon compounds, products of the photosynthesis. The substantial amounts of fixed carbon dioxide dedicated to the symbiont imposed to the plant a tight regulation of the nodulation process to balance carbon and nitrogen incomes and outcomes. Climate change including the increase of the concentration of the atmospheric carbon dioxide is going to modify the rates of plant photosynthesis, the balance between nitrogen and carbon, and, as a consequence, the regulatory mechanisms of the nodulation process. This review focuses on the regulatory mechanisms controlling carbon/nitrogen balances in the context of legume nodulation and discusses how the change in atmospheric carbon dioxide concentration could affect nodulation efficiency.


An in vivo murine model of continuous intramedullary infusion of polyethylene particles.
Wear debris affects both initial osseointegration and subsequent bone remodeling of total joint replacements (TJRs). To study the complex cascade associated with the continuous generation of particles, a robust animal model is essential. To date, an animal model that incorporates continuously delivered particles to an intramedullary orthopaedic implant has not been available. In this study, we successfully infused clinically relevant ultra high molecular weight polyethylene particles, previously isolated from joint simulator tests, to the intramedullary space of the mouse femur for 4 weeks using a subcutaneous osmotic pump. Reduction of bone volume following the 4-week infusion of UHMWPE was detected by microCT. UHMWPE particles also changed the level of Alkaline Phosphatase expression in the infused femurs. Continuous infusion of particles to the murine bone-implant interface simulated the clinical scenario of local polymer wear particle generation and delivery in humans and can be used to further study the biological processes associated with wear debris particles.


Light-emitting diode-compatible probes for indirect detection of anions in CE.
A range of compounds were evaluated as probes for the indirect detection of inorganic ions using CE and light-emitting diodes (LEDs) as the light source. Emphasis was placed on examining probes likely to absorb strongly in the UV-Vis region near 350-430 nm as compounds, which absorb at longer wavelengths tend to be bulkier and adsorb onto the capillary wall. These probes should act as a replacement for the very effective but carcinogenic probe chromate. Two probes were identified and evaluated: p-nitrophenol and 4-hydroxy-3,5-dinitrobenzoic acid. The former showed the most potential with low-mobility anions, while the later had a moderate electrophoretic mobility and was more suitable for a wider mobility range of analytes. However, neither could match the efficiencies and LOD of chromate for the separation of the fast inorganic ions such as chloride, nitrate and sulphate. Nevertheless, application of the 4-hydroxy-3,5-dinitrobenzoic acid system to the determination of oxalate in Bayer liquors showed excellent sensitivity and selectivity.


Plasma brain-derived neurotrophic factor as a peripheral marker for the action mechanism of antidepressants.
Numerous studies have demonstrated that depression is associated with a decreased expression of brain-derived neurotrophic factor (BDNF). BDNF shows antidepressant-like effects in animal models. Therefore, we tested the hypothesis that BDNF might be a peripheral marker for the mechanism of action of antidepressant agents in humans. Thirty-two patients meeting the DSM-IV criteria for major depressive disorder and 50 normal control subjects were recruited for this study. Plasma BDNF levels and Hamilton Depression Rating Scales were measured at baseline and 6 weeks after antidepressant administration. At baseline, the mean plasma BDNF level was lower in the depressive patients (698.1 +/- 537.7 pg/ml) than in the control subjects (830.7 +/- 624.8 pg/ml), although the difference was not statistically significant (p = 0.33). The plasma BDNF levels in depressive patients significantly increased from 698.1 +/- 537.7 to 1,028.9 +/- 744.5 after 6 weeks of antidepressant treatment (p = 0.01). Moreover, plasma BDNF levels were significantly increased after 6 weeks of treatment in the responder group, while there was no statistically significant change in the unresponsive group. These results suggest that the therapeutic response after antidepressant administration might be attributable to the increase in BDNF levels. BDNF may play a critical role in the action mechanism of antidepressant drugs. Further studies with a larger number of subjects are needed to verify these findings.


Transcranial direct-current stimulation reduced the excitability of diaphragmatic corticospinal pathways whatever the polarity used.
We investigated effects of transcranial direct-current stimulation (tDCS) on the diaphragmatic corticospinal pathways in healthy human. Anodal, cathodal, and sham tDCS were randomly applied upon the left diaphragmatic motor cortex in twelve healthy right-handed men. Corticospinal pathways excitability was assessed by means of transcranial magnetic stimulation (TMS) elicited motor-evoked-potential (MEP). For each tDCS condition, MEPs were recorded before (Pre) tDCS then after 10 min (Post1, at tDCS discontinuation in the anodal and cathodal sessions) and 20 min (Post2). As result, both anodal and cathodal tDCS significantly decreased MEP amplitude of the right hemidiaphragm at both Post1 and Post2, versus Pre. MEP amplitude was unchanged versus Pre during the sham condition. The effects of cathodal and anodal tDCS applied to the diaphragm motor cortex differ from those observed during tDCS of the limb motor cortex. These differences may be related to specific characteristics of the diaphragmatic corticospinal pathways as well as to the diaphragm's functional peculiarities compared with the limb muscles.


Benchmarking Deep Networks for Predicting Residue-Specific Quality of Individual Protein Models in CASP11.
Quality assessment of a protein model is to predict the absolute or relative quality of a protein model using computational methods before the native structure is available. Single-model methods only need one model as input and can predict the absolute residue-specific quality of an individual model. Here, we have developed four novel single-model methods (Wang_deep_1, Wang_deep_2, Wang_deep_3, and Wang_SVM) based on stacked denoising autoencoders (SdAs) and support vector machines (SVMs). We evaluated these four methods along with six other methods participating in CASP11 at the global and local levels using Pearson's correlation coefficients and ROC analysis. As for residue-specific quality assessment, our four methods achieved better performance than most of the six other CASP11 methods in distinguishing the reliably modeled residues from the unreliable measured by ROC analysis; and our SdA-based method Wang_deep_1 has achieved the highest accuracy, 0.77, compared to SVM-based methods and our ensemble of an SVM and SdAs. However, we found that Wang_deep_2 and Wang_deep_3, both based on an ensemble of multiple SdAs and an SVM, performed slightly better than Wang_deep_1 in terms of ROC analysis, indicating that integrating an SVM with deep networks works well in terms of certain measurements.


Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study.
Worry is considered a key feature of generalized anxiety disorder (GAD), whose neural correlates are poorly understood. It is not known whether the brain regions involved in pathological worry are similar to those involved in worry-like mental activity in normal subjects or whether brain areas associated with worry are the same for different triggers such as verbal stimuli or faces. This study was designed to clarify these issues. Eight subjects with GAD and 12 normal controls underwent functional magnetic resonance imaging (fMRI) mood induction paradigms based on spoken sentences or faces. Sentences were either neutral or designed to induce worry. Faces conveyed a sad or a neutral mood and subjects were instructed to empathize with those moods. We found that the anterior cingulate and dorsal medial prefrontal cortex [Brodmann area (BA) 32/23 and BA 10/11] were associated with worry triggered by sentences in both subjects with GAD and normal controls. However, GAD subjects showed a persistent activation of these areas even during resting state scans that followed the worrying phase, activation that correlated with scores on the Penn State Worry Questionnaire (PSWQ). This region was activated during the empathy experiment for sad faces. The results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying.


The Influence of Sport-Field Properties on Muscle-Recruitment Patterns and Metabolic Response.
To investigate different sport-field properties' influence on muscle-recruitment patterns and metabolic response during a series of running and agility drills. Eleven male athletes were fitted with a standard multipurpose training shoe. The test protocol consisting of 4 high-intensity trials with 60-s rests between trials performed on 2 fields with different properties. Time-dependent field properties were measured using the American Standards for Testing and Materials protocol (F-1936). A 30-m pretest and posttest sprint determined fatigue and player performance. Electromyography (EMG) recorded muscle activity for vastus medialis, biceps femoris, gastrocnemius medial head, and tibialis anterior, and metabolic activity analyzed maximal oxygen consumption, heart rate, respiratory exchange ratio, metabolic equivalent, and energy expenditure. A difference was calculated for muscle activity across trials (P = .01) for both surfaces. Muscle activity was <13% on the field with less energy return (P = .01). Metabolic components (maximal oxygen consumption, heart rate, respiratory exchange ratio, metabolic equivalent, and energy expenditure) were significantly different across trials (P = .01) but not significantly different between fields. The participants completed the agility course (5.2%) faster on the field with greater energy return, while caloric expenditure was similar between fields. The findings indicate that field mechanical properties influence muscle-activation patterns. The field demonstrating the greatest magnitude of energy return produces the lowest sprint and agility course times; however, performing on a field exhibiting unfamiliar mechanical properties could cause the athlete to produce atypical movement patterns that might contribute to overuse of the neuromuscular system.