Limb movement-induced hyperemia has a central hemodynamic component: evidence from a neural blockade study.
The purpose of this investigation was to partially remove feedback from type III/IV skeletal muscle afferents and determine how this feedback influences the central and peripheral hemodynamic responses to passive leg movement. Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure, leg vascular conductance (LVC), and leg blood flow (LBF) were measured during 2 min of passive knee extension in eight young men before and after intrathecal fentanyl injection. Passive movement increased HR by 14 beats/min from baseline to maximal response during control (CON) (65 ± 4 to 79 ± 5 beats/min, P < 0.05), whereas HR did not significantly increase with the fentanyl block (BLK). LBF and LVC increased in both conditions; however, these increases were attenuated and delayed during BLK [%change from baseline to maximum, LBF: CON 295 ± 109 vs. BLK 210 ± 86%, (P < 0.05); LVC: CON 322 ± 40% vs. BLK 231 ± 32%, (P < 0.04)]. In CON, HR, SV, CO, and LVC increased contributing to the hyperemic response. However, under BLK conditions, statistically insignificant increases in HR and SV combined to yield a small, but significant, increase in CO and an attenuated hyperemic response. Therefore, partially blocking skeletal muscle afferent feedback blunts the central hemodynamic response due to passive limb movement, which then results in an attenuated and delayed movement-induced hyperemia. In combination, these findings provide evidence that limb movement-induced hyperemia has a significant central hemodynamic component induced by peripheral nerve activation.


Projection in surrogate decisions about life-sustaining medical treatments.
To honor the wishes of an incapacitated patient, surrogate decision makers must predict the treatment decisions patients would make for themselves if able. Social psychological research, however, suggests that surrogates' own treatment preferences may influence their predictions of others' preferences. In 2 studies (1 involving 60 college student surrogates and a parent, the other involving 361 elderly outpatients and their chosen surrogate decision maker), surrogates predicted whether a close other would want life-sustaining treatment in hypothetical end-of-life scenarios and stated their own treatment preferences in the same scenarios. Surrogate predictions more closely resembled surrogates' own treatment wishes than they did the wishes of the individual they were trying to predict. Although the majority of prediction errors reflected inaccurate use of surrogates' own treatment preferences, projection was also found to result in accurate prediction more often than counterprojective predictions. The rationality and accuracy of projection in surrogate decision making is discussed.


High Mobility Organic Lasing Semiconductor with Crystallization-Enhanced Emission for Light-Emitting Transistors.
The development of high mobility organic laser semiconductors with strong emission is of great scientific and technical importance, but challenging. Herein, we present a high mobility organic laser semiconductor, 2,7-diphenyl-9H-fluorene (LD-1) showing unique crystallization-enhanced emission guided by elaborately modulating its crystal growth process. The obtained one-dimensional nanowires of LD-1 show outstanding integrated properties including: high absolute photoluminescence quantum yield (PLQY) approaching 80 %, high charge carrier mobility of 0.08 cm2 V-1 s-1 , Fabry-Perot lasing characters with a low threshold of 86 μJ cm-2 and a high-quality factor of ≈2400. Furthermore, electrically induced emission was obtained from an individual LD-1 crystal nanowire-based light-emitting transistor due to the recombination of holes and electrons simultaneously injected into the nanowire, which provides a good platform for the study of electrically pumped organic lasers and other related ultrasmall integrated electrical-driven photonic devices.


Hippophae rhamnoides polysaccharides dampen pseudorabies virus infection through downregulating adsorption, entry and oxidative stress.
Pseudorabies virus (PRV) is an alpha herpesvirus that causes pseudorabies. After 2011, new and more pathogenic PRV variants have caused huge economic losses to the pig industry. In addition, people have been reported to be infected with PRV. Therefore, developing new anti-PRV drugs is of great significance. In this study, we investigated the anti-PRV activity of Hippophae rhamnoides polysaccharides (HRP) in vitro. We found that HRP could significantly inhibit the infectivity of the PRV XJ5 strain in PK15 cells. Addition of HRP at different times of the virus life cycle mainly led to the inhibition of the adsorption and entry of virus into the cells. Our results revealed that HRP can reduce the malondialdehyde (MDA) content and reactive oxygen species (ROS) level in PRV-infected PK15 cells and increase the superoxide dismutase (SOD) activity. These results suggested that HRP can reduce PRV infection-induced oxidative stress. Therefore, HRP may act as an antiviral drug against newly emerging PRV variants.


Immobilisation hypercalcemia.
We studied 5 patients with immobilisation hypercalcemia. Plasma calcium was 3.28 +/- (SD) 0.26 mmol/l. Plasma parathyroid hormone (PTH) level was elevated in 3 patients and inappropriately detectable in 1. Nephrogenous cAMP, measured in 3 patients, was low-normal in 1 who had a normal PTH and zero in 2 who had elevated PTH. Quantitative bone histology was performed in 3 patients. 1 had evidence of increased resorption (osteoclast count 7.1/mm2 section area, normal 1.0 +/- 0.5) and had a high-normal bone formation rate. Another had a normal osteoclast count but no evidence of bone formation. The third had normal bone histology. We conclude that (a) the PTH appears to be biologically inactive and its elevation may be due, in some patients, to renal retention of carboxyterminal fragments; (b) the histologic pattern in bone is variable and not predictable from the duration of illness; (c) the mechanism by which immobilisation induces these changes is obscure, and (d) careful clinical assessment may be necessary to avoid misdiagnosing the condition as primary hyperparathyroidism.


[Status of sleep and influencing factors in employed floating population in China].
Objective: To understand the sleep status and related influencing factors among 18-59 years old employed floating population and to provide evidence for policy development. Methods: Data were gathered from the Chinese Floating Population Chronic Disease Surveillance (2012) program. Floating population were selected through multistage clustering sampling method and stratified by industries from China. Information on demographics, behavior-related risk factors, sleep duration and social pressure etc., were collected through face-to-face interview on questionnaires. After complex weighting of data, multivariable logistic regression method was used to explore the sleep status and related influencing factors among these employed floating people. Results: A total of 43 521 subjects were included in the study. The average sleep duration per day was 7.77 h, with females (7.87 h) higher than males (7.69 h). The prevalence of insufficient sleep was 12.3% (95%CI: 11.8%-12.7%), with 45-59 years old group (21.2%) higher than that of the 18-year olds (11.2%). Results from the multivariable logistic regression analysis showed that factors as gender, age, marital status, education, occupation, inflowing area, behavior-related risk factors, BMI, social pressure, self-rated health status and self-reported chronic diseases were the main factors that affecting the rates of sleep deficiency in this population. The prevalence rate of insufficient sleep was 1.18 times higher (95%CI: 1.07-1.31) in males than that in females, and 1.22 (95%CI: 1.11-1.33) times higher in smokers than that in the non-smokers, 1.31(95%CI: 1.16-1.49) times higher in excessive drinkers than that of the normal population, 1.46 (95%CI: 1.29-1.65) times and 1.33 (95%CI: 1.18-1.50) times in those with heavier workload and stress than those without. Conclusion: The prevalence of insufficient sleep among the employed floating population was affected by multiple factors that called for more attention by different departments of the government.


Effect of training on interlimb transfer of dexterity skills in healthy adults.
To examine transference of dexterity skills to the contralateral hand after ipsilateral hand training, retention of skills at 1 mo, and the influence of hand dominance, sex, and age on interlimb transfer of these skills. This is an interventional study involving 200 healthy adults in the age group of 20-30 yrs and >30 yrs, who were block randomized into experimental and control groups. Experimental group was further subdivided into dominant and nondominant hand training group and participants underwent 5 days unsupervised training on tasks aimed at improving precision and dexterity. Jebsen-Taylor hand function test was administered at baseline, postintervention, and 1-mo follow-up. Analysis was done by nonparametric tests of comparison. One hundred sixty-nine subjects completed the study. Transfer effect was noted from the dominant to the nondominant hand (P ≤ 0.001) and vice versa (P = 0.003) on the total test scores. This effect was retained at 1-mo follow-up. Dexterity skills are not consistently transferred to the contralateral hand after ipsilateral hand training. However, transference of gross motor skills of hand function does occur with retention effects up to 1 mo. Transfer of skills differs based on the hand trained and age of the individual.


Use of an accelerated immunization schedule for combined hepatitis A and B protection in the corporate traveler.
Increased international business travel to moderate or high endemic areas of hepatitis A and B may leave many business travelers at risk for infection if not vaccinated. Many international business travelers depart for hepatitis A and B endemic areas within 2 months of the decision to travel. Many of these travelers do not seek pretravel medical advice and are unaware of the risks and modes of acquiring hepatitis A and B. Monovalent vaccines and a combined hepatitis A and B vaccine are available and can be administered on an accelerated schedule. Because many areas endemic for hepatitis A are also endemic for hepatitis B, accelerated administration of the combined vaccine can offer protection for many international business travelers destined for areas endemic for both diseases and should be part of corporate travel immunization programs.


Contributions from the model systems programs to spinal cord injury research.
To review research developments across the Model Spinal Cord Injury Systems (MSCIS) program. Retrospective review of literature and web-based information. MSCIS program in general and its 16 currently funded centers. The MSCIS centers have been funded since 1970 by the US Department of Education to conduct research that contributes to the lives of persons with spinal cord injury (SCI). A review of this research suggests changes across time in terms of methods of investigation used to conduct research (eg, from demonstration studies to clinical trials) and selected study focuses, reflecting timely national priorities. Although initial studies were designed to describe medical factors and necessary treatment immediately after injury, most recent studies focus on broader social and environmental issues of living with SCI. In addition, a number of current investigations focus on new advances in medicine and technology geared toward recovery and increase in physical functioning. Research by the MSCIS has elevated the standards of care for SCI and inspired other researchers to develop larger and more sophisticated studies bridging the gap between basic and applied sciences and has inspired policy makers to continue to fund such needed research.


Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors.
Multiple myeloma in humans is frequently associated with mast cell infiltration and neovascularization, which correlate directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that primary murine mast cells express angiopoietin-1 (Ang-1) and low levels of VEGF-A but not Ang-2 and that 2 established murine plasmacytoma cell lines express high levels of VEGF-A but little or no Ang-1 or Ang-2. An in vivo angiogenesis assay using extracellular matrix components shows that mast cells and plasmacytoma cells, together, promote marked neovascularization composed of dilated vessels, which is prevented by neutralization of VEGF-A and Ang-1 but is only partially reduced by neutralization of either VEGF-A or Ang-1. Mast cells within extracellular matrix components express Ang-1, and recombinant Ang-1 together with plasmacytoma cells promotes extracellular matrix neovascularization similar to that induced by mast cells. A transplantation assay shows that primary mast cells accelerate tumor growth by established plasmacytoma cell lines and that neutralization of Ang-1 alone or with VEGF-A reduces significantly the growth of plasmacytomas containing mast cells. These results demonstrate that mast cell-derived Ang-1 promotes the growth of plasmacytomas by stimulating neovascularization and provide further evidence supporting a causal relationship between inflammation and tumor growth.


Bupropion-induced erythema multiforme.
The high rate of dermatologic adverse effects associated with bupropion use may extend to its sustained-release preparation, currently prescribed extensively for smoking cessation as well as for treatment of depressive conditions. We report what we believe to be the first case, in a 31-year-old woman, of erythema multiforme after administration of sustained-release bupropion (Wellbutrin SR) for treatment of depression. This report emphasizes that prescribers must aggressively follow up their patients who have rashes or urticaria, discontinuing the medication as soon as erythema multiforme is suspected and watching closely for the emergence of potentially life-threatening dermatologic conditions.


Brachial Artery "Low-Flow Mediated Constriction" Is Associated with Myocardial Perfusion Defect Severity and Mediated by an Altered Flow Pattern during Occlusion.
The relationship between low flow-mediated constriction (LFMC), a new proposed measure of endothelial function, with cardiovascular disease severity and its hypothesized stimulus, that is, low flow, has not been comprehensively evaluated. The study evaluated association between change in brachial artery diameter during constriction with severity of myocardial perfusion defect (PD) and alterations in different components of flow profile. Brachial artery responses to occlusion were assessed in 91 patients and 30 healthy subjects. Change in anterograde and retrograde blood flow velocities (delta anterograde blood flow velocity and retrograde blood flow velocity), anterograde shear rate and retrograde shear rate (delta ASR and RSR, respectively), and oscillatory shear index (delta) during forearm occlusion at 50 mm Hg above systolic pressure, from baseline was calculated. Myocardial perfusion was evaluated in patients using exercise single positron emission computed tomography and % myocardial PD was calculated from summed stress score. LFMC emerged as independent predictor of defect severity after correcting for age and gender (p = 0.014). Sixty-seven patients (73.6%) and 15 healthy subjects (50%) showed constriction during occlusion. In stepwise backward regression analysis, RSR contributed 35.5% and ASR contributed 20.1% of the total 63.9% variability in artery diameter during occlusion. The results suggest that LFMC is independently associated with myocardial perfusion severity and is "mediated" by an altered flow profile during occlusion.


Radius morphology variation in an adult South African cadaveric sample.
Sex estimation is a vital first step in developing a biological profile, and is usually metrically or morphoscopically assessed. Geometric morphometric analyses allow re-evaluation of both size and shape variation of skeletal elements, and more meaningful comparisons of sexual dimorphism of different ancestry groups. Additionally, it has shown that some postcranial bones may be more useful for ancestry estimation than previously thought. Geometric morphometric analysis was performed on the radii of 1049 South African individuals (417 females, 578 males) of the country's three largest ancestry groups to assess morphological variation according to sex and ancestry. Three-dimensional landmark datasets of radii were superimposed and scaled to a common centroid size using Generalized Procrustes Analysis. Mean centroid sizes of groups were compared using parametric statistics. Morphological variation was assessed using Discriminant Function Analysis, coupled with leave-one-out cross-validation to assess accuracies of sex and ancestry estimation. Covariation with size, age and year-of-birth were assessed through regression analysis. Male radii were larger and more robust than those of females, as generally observed following secondary sexual development. Black individuals had absolutely larger radii but more gracile morphologies, White individuals had both absolutely and proportionately larger radii, and Mixed individuals had the smallest radii but with similar robust morphologies as White individuals. Similar differences were also detected when variation was assessed according to sex and ancestry combined. Covariation was detected with size, age and year-of-birth. Differences between groups were sufficient to allow 70.9% classification accuracy of sex, 80.6% for ancestry, and 77.2% for sex and ancestry combined. These results show that postcranial bones like the radius show sufficient morphological variation to allow some accuracy in the estimation of sex, though variation between population groups tends to overshadow this variation, even when sex and ancestry are simultaneously considered. The greater ancestry variation allows for relatively good accuracies in estimation, even for highly heterogeneous South African groups that are subject to significant genetic and environmental influences.


[Changes in N-acetyl-beta-D-glucosaminidase in the urine of patients with pyelonephritis and glomerulonephritis].
The activity of N-acetyl-beta-D-glucosaminidase (NAGase) activity was determined in urine of patients with pyelonephritis and glomerulonephritis. Determination was done with the non-commercial "Boehringer-Mannheim" test reagents for research purposes only. The protein concentrations were measured in the same samples. The obtained results were compared with results obtained in the control group and the significant increase (p less than 0.001) in NAGase activity was found in both groups of patients. At the same time normal protein values were found in 33% of all cases. It can be concluded that NAGase is a more sensitive parameter for early detection of renal disease.


MicroPET and autoradiographic imaging of breast cancer alpha v-integrin expression using 18F- and 64Cu-labeled RGD peptide.
Cell adhesion molecules alphavbeta3 and alphavbeta5 play a pivotal role in tumor angiogenesis and metastasis. Antiangiogenic therapy by using small peptide antagonists of alphav-integrins slows tumor growth and prevents tumor spread. The ability to visualize and quantify integrin expression will enable selection of appropriate patients for clinical trials, following determination of treatment efficacy and development of new potent drugs. We have previously labeled cyclic RGD peptide c(RGDyK) with 125I and 18F and applied the radiotracers to both subcutaneous and orthotopic brain tumor models. Here we conjugated c(RGDyK) with 1,4,7,10-tetraaza-1,4,7,10-tetradodecane-N,N',N' ',N' "-tetraacetic acid (DOTA) and labeled the DOTA-RGD conjugate with 64Cu (t1/2) = 12.8 h, 19% beta+) in high radiochemical purity and specific activity. The tumor targeting ability and in vivo kinetics of 64Cu-DOTA-RGD was compared with [18F]FB-RGD and 125I-RGD in orthotopic MDA-MB-435 breast cancer model. All three radiotracers revealed fast blood clearance and high tumor-to-blood and tumor-to-muscle ratios. 125I-RGD had higher tumor uptake than the corresponding 18F and 64Cu analogues. [18F]FB-RGD indicated a fast tumor washout rate and an unfavorable hepatobiliary excretion pathway, resulting in significant activity accumulation in gallbladder and intestines. 64Cu-DOTA-RGD had prolonged tumor retention (1.44 +/- 0.09 %ID/g at 4 h postinjection) and persistent uptake in the liver. All three tracers revealed receptor specific tumor accumulation which were illustrated by effective blocking via coinjection with a blocking dose of c(RGDyK). Static microPET imaging and whole-body autoradiography showed strong contrast from the contralateral background. In conclusion, overall molecular charge and characteristics of radiolabels have profound effects on tumor accumulation and in vivo kinetics of radiolabeled RGD peptide. Further modification of the RGD peptide and optimization of the tracer for prolonged tumor uptake and improved in vivo kinetics are being explored.


Donor-Derived Leukemia in a Recipient of Double-Unit Cord Blood Transplantation for Acute Myeloid Leukemia: A Case Study and Literature Review.
We report a case of donor-derived leukemia (DDL) occurring 34 months after double-unit cord blood transplantation (CBT). Molecular analysis using short tandem repeat (STR) sequences proved the acute myeloid leukemia (AML) to be of dominant cord blood origin. Karyotype was normal and molecular analysis showed WT1 and EVI1 overexpression. Cytological and molecular remission were achieved with only induction and consolidation chemotherapy. Relapse occurred after 6 years of remission from one clone with only WT1 overexpression. Potential etiologies for donor cell leukemogenesis in the recipient are discussed, including occult leukemia in the donor or genetic predisposition to hematologic malignancies, impaired immune surveillance, induced or inherited stromal abnormalities, transformation of donor cells during engraftment via altered signals of the host tissues, and fusion of donor cells with residual leukemic cells leading to acquisition of oncogenes. Although cases of DDL occurring after umbilical CBT have already been reported, very few cases have been described arising after double-unit CBT. DDL cases following CBT previously described in the literature have been reviewed.


A pioneering study of dental fluorosis in the libyan population.
Fluorosis is a condition resulting from excessive ingestion of fluoride during early childhood leading to the formation of defective enamel. The increased fluoride content is thought to result in a metabolic alteration of ameloblasts, which results in defective matrix, and improper calcification of teeth. A total of 6244 patients between the ages of 6yrs to 60yrs, who presented to our outpatient clinic from October 2009 to December 2010 were included in the study. The study subjects were grouped according to their age into the following groups- 6-14 yrs, 15-25 yrs, 26-40 yrs, and 40-60yrs. Only permanent dentition was taken into consideration in this study. The overall prevalence of fluorosis in this study was 63.34% (3955 of 6244 patients). Men had a slightly higher prevalence of 64.27% compared to 62.28% among women. Prevention of fluorosis would require efforts at raising awareness among the people about the harmful effects of their dietary choices on their teeth. They also need to be educated about adequate and proper oral hygiene, such as brushing their teeth at least two times daily. How to cite this article: Sunil T K L, Shetty S, Annapoorna B M, Pujari S C, Reddy P S, Nandlal B. A Pioneering Study of Dental Fluorosis in the Libyan Population. J Int Oral Health 2013; 5(3):67-72.


High-yield production and characterization of biologically active GST-tagged human topoisomerase IIα protein in insect cells for the development of a high-throughput assay.
DNA topoisomerase type II enzymes are well-validated targets of anti-bacterial and anti-cancer compounds. In order to facilitate discovery of these types of inhibitors human topoisomerase II in vitro assays can play an important role to support drug discovery processes. Typically, human topoisomerase IIα proteins have been purified from human cell lines or as untagged proteins from yeast cells. This study reports a method for the rapid over-expression and purification of active GST-tagged human topoisomerase IIα using the baculovirus mediated insect cell expression system. Expression of the GST fused protein was observed in the nuclear fraction of insect cells. High yields (40 mg/L i.e. 8 mg/10(9) cells) at >80% purity of this target was achieved by purification using a GST HiTrap column followed by size exclusion chromatography. Functional activity of GST-tagged human topoisomerase IIα was demonstrated by ATP-dependent relaxation of supercoiled DNA in an agarose gel based assay. An 8-fold DNA-dependent increase in ATPase activity of this target compared to its intrinsic activity was also demonstrated in a high-throughput ATPase fluorescence based assay. Human topoisomerase IIα inhibitors etoposide, quercetin and suramin were tested in the fluorescence assay. IC(50) values obtained were in good agreement with published data. These inhibitors also demonstrated ≥ 30-fold potency over the anti-bacterial topoisomerase II inhibitor ciprofloxacin in the assay. Collectively these data validated the enzyme and the high-throughput fluorescence assay as tools for inhibitor identification and selectivity studies.


Prevalence of diabetic retinopathy and maculopathy in Northland, New Zealand: 2011-2012.
To determine the prevalence of diabetic retinopathy and maculopathy in the Northland Diabetic Retinopathy Screening Programme. Retrospective analysis of the latest and most severe retinopathy and maculopathy grades from each patient in the programme. Data from 7098 screenings from 5647 diabetics were obtained, which represented approximately 77% of the total number of diagnosed diabetics in Northland. The two main ethnic groups in our study were New Zealand European (56.5%) and Maori (39.3%). Retinopathy was present in 19% of the Northland diabetic screening population: 13.6% had minimal non-proliferative diabetic retinopathy (NPDR), 5.4% had NPDR and 0.4% had Proliferative Diabetic Retinopathy (PDR). Ethnicity data for NPDR was 57% Maori, 38% European, and PDR 50% Maori, 45% European. Maculopathy was present in 11%. Maculopathy requiring treatment was present in 1.4% (Maori 48%, European 44%). The mean failure-to-attend rate was 31%. Rates of retinopathy and maculopathy detected by the Northland screening programme were comparable to rates reported in Waikato, lower than Wellington rates and lower than international averages. Maori were over-represented in patients with retinopathy and maculopathy, but underrepresented within the screening population. The success of this programme was undermined by the high failure-to-attend rate despite attempts to improve access.


Principal component similarity analysis of Raman spectra to study the effects of pH, heating, and kappa-carrageenan on whey protein structure.
Raman spectroscopy was used to elucidate structural changes of beta-lactoglobulin (BLG), whey protein isolate (WPI), and bovine serum albumin (BSA), at 15% concentration, as a function of pH (5.0, 7.0, and 9.0), heating (80 degrees C, 30 min), and presence of 0.24% kappa-carrageenan. Three data-processing techniques were used to assist in identifying significant changes in Raman spectral data. Analysis of variance showed that of 12 characteristics examined in the Raman spectra, only a few were significantly affected by pH, heating, kappa-carrageenan, and their interactions. These included amide I (1658 cm(-1)) for WPI and BLG, alpha-helix for BLG and BSA, beta-sheet for BSA, CH stretching (2880 cm(-1)) for BLG and BSA, and CH stretching (2930 cm(-1)) for BSA. Principal component analysis reduced dimensionality of the characteristics. Heating and its interaction with kappa-carrageenan were identified as the most influential in overall structure of the whey proteins, using principal component similarity analysis.


Nanoparticle-based CpG-oligonucleotide therapy for treating allergic asthma.
Allergic asthma is becoming increasingly prevalent in the developed world, and many common allergens are capable of inducing allergic asthma responses, particularly in atopic individuals. Unmethylated CpG-oligonucleotide (ODN) therapy can shift the immune response to mitigate these allergic responses. Therapeutic and prophylactic delivery of soluble CpG-ODN in preclinical studies has shown promise in treating existing asthma and preventing allergic responses upon subsequent allergen exposure, respectively. However, when CpG-ODN is coupled with nanoparticles or self assembled into nanostructures, improved efficacy of CpG-ODN treatment for several common allergens is observed in preclinical studies and clinical trials. Here we discuss the role of CpG-ODN in treating allergic asthma and how nanoparticle-based delivery can further enhance its therapeutic properties.


Inhibition of T cell proliferation specific for acetylcholine receptor epitopes related to myasthenia gravis with antibody to T cell receptor or with competitive synthetic polymers.
Long-term T cell lines and clones of C3H.SW origin specific to synthetic peptides representing immunogenic epitopes of the human aetylcholine receptor alpha-subunit were established. Using these lines and clones, it was possible to characterize the T cell recognition process of myasthenic epitopes. Testing a panel of N-and/or C-terminal truncated peptides it could be demonstrated that the deletion of the two C-terminal amino acids of peptides p195-212 and p259-271 resulted in a loss or reduction of the stimulatory capacity of the peptides towards the specific T cell lines. In contrast, no substantial effect on the stimulation of the line could be observed by shortening peptide p195-212 by up to five amino acids at the N-terminal end. The proliferation of T cell lines and clones specific to peptide p195-212 was inhibited by a mAb directed against the V beta 8 region of the T cell receptor. Furthermore, it was possible to block the peptide-specific proliferative responses of the lines and clones by the I-Ab restricted synthetic polypeptide (T, G)-A--L but not by the I-Ak restricted polypeptide antigen (H,G)-A--L. Similarly, p195-212 inhibited the proliferative response of the TCSW259-271 T cell line and p259-271 inhibited the specific proliferative response of the TCSW195-212 line. Moreover, the C-terminal shortened peptides inhibited significantly the in vitro stimulation of the T cell lines by the immunogenic peptides p195-212 and p259-271. The inhibition by the synthetic peptides or by (T,G)-A--L may be due to competitive blockade of the MHC binding site for the T cell line stimulating AChR peptides.


Bioequivalence of a new liquid formulation of benazepril compared with the reference tablet product.
To compare the bioequivalence and 'switchability' of two formulations of benazepril (tablet and liquid) after oral administration. Randomised cross-over design, followed by parallel comparison. Twelve mixed-breed dogs were administered either a tablet (Group A) or liquid formulation (Group B) of benazepril orally at 0.45 mg/kg daily for 4 days. With no washout period, the dogs then received the alternative treatment at the same dose for a further 4 days. Blood samples taken prior to treatment and serially after treatment were analysed for plasma concentrations of benazepril and benazeprilat and the activity and concentration of angiotensin-converting enzyme (ACE). The calculated percentage inhibition of ACE was defined as the primary outcome variable. No statistically significant differences were found between groups A and B for any variable evaluated. The mean (± SD) percentage of ACE inhibition was 85.5 ± 7.04% for the liquid formulation and 85.9 ± 6.66% for the tablet formulation. The mean of the ratios was 1.00 (80% confidence interval 0.96-1.04). No evaluated effect term (sequence, formulation or period) had any statistical effect on any outcome variable. This study supports a conclusion that, based on pharmacodynamic response, the liquid formulation of benazepril is bioequivalent to the reference tablet formulation. Further, the lack of a sequence effect supports the switchability of these two formulations.


Multi-Well Array Culture of Primary Human Hepatocyte Spheroids for Clearance Extrapolation of Slowly Metabolized Compounds.
Accurate prediction of human pharmacokinetics using in vitro tools is an important task during drug development. Albeit, currently used in vitro systems for clearance extrapolation such as microsomes and primary human hepatocytes in suspension culture show reproducible turnover, the utility of these systems is limited by a rapid decline of activity of drug metabolizing enzymes. In this study, a multi-well array culture of primary human hepatocyte spheroids was compared to suspension and single spheroid cultures from the same donor. Multi-well spheroids remained viable and functional over the incubation time of 3 days, showing physiological excretion of albumin and α-AGP. Their metabolic activity was similar compared to suspension and single spheroid cultures. This physiological activity, the high cell concentration, and the prolonged incubation time resulted in significant turnover of all tested low clearance compounds (n = 8). In stark contrast, only one or none of the compounds showed significant turnover when single spheroid or suspension cultures were used. Using multi-well spheroids and a regression offset approach (log(CLint) = 1.1 × + 0.85), clearance was predicted within 3-fold for 93% (13/14) of the tested compounds. Thus, multi-well spheroids represent a novel and valuable addition to the ADME in vitro tool kit for the determination of low clearance and overall clearance prediction. Graphical Abstract.


The distribution of oedema in the lower limb of patients with chronic critical limb ischaemia: a study with computed tomography.
A substantial number of patients with chronic critical limb ischaemia (CLI) have considerable oedema at the distal leg and foot of non deep venous thrombosis origin. The primary aim of the present study was to quantify the distribution of oedema in the different tissues of the leg and foot by applying computed tomography and planimetry. The interstitial fluid hydrostatic pressure (Pif) in the subcutaneous tissue was measured to evaluate the effect of oedema on local tissue pressure. Six men and 12 women with unilateral CLI and peripheral pitting oedema were included. Cross sectional areas (CSA) of subcutaneous tissue, muscle and bone were measured by computer tomography combined with planimetry to assess the distribution of oedema within the soft tissues. Pif was measured by "wick-in-needle" technique. The median total CSA of soft tissue, subcutaneous and muscle tissues at the foot level were respectively 17%, 34% and 9% greater in the limbs with CLI compared to the contralateral limb (p < 0.001). At ankle level these differences were 13%, 30% and 4%, respectively (p < 0.001). At the level of the calf these differences were not significant. Mean Pif in the limbs with CLI was 0.3 mmHg, significantly higher than in limbs without CLI (-1.8 mmHg), (p < 0.003). The study verified oedema of considerable magnitude at the ankle and foot. The great part of the oedema was located within the subcutaneous tissue, which was associated with a relatively moderate, but significant increase in Pif confirming the high compliance of the subcutaneous tissue. The combination of the excessive fluid and increased Pif in the interstitial tissue might aggravate the microcirculation. The aetiology of oedema formation is probably multifactorial.


Compensatory sweating after thoracoscopic sympathectomy: characteristics, prevalence and influence on patient satisfaction.
This prospective study aimed at investigating predictive factors for compensatory sweating after thoracoscopic sympathectomy. From 2000 to 2002, 80 patients (53 females and 27 males) underwent thoracoscopic sympathectomy to treat hyperhidrosis. Patient ages ranged from 12 to 56 years, and the mean post-operative follow-up period was 42.51 +/- 5.98 months. Patient satisfaction with the results was evaluated through the use of a rating scale. The procedure was performed bilaterally: at the T2 level for facial hyperhidrosis; at the T3-T4 level for axillary hyperhidrosis; and at the T3 level for palmar hyperhidrosis. Post-operatively, 68 patients (85.0%) presented compensatory sweating, which was classified as mild in 23 (33.8%), moderate in 23 (33.8%) and severe in 22 (32.4%). Considering the final surgical results, 70 patients (87.5%) were satisfied with the outcome of the operation, whereas 10 patients (12.5%) were dissatisfied. The level of patient satisfaction varied according to gender, age, body mass index (BMI) and extent of denervation. The compensatory sweating was more severe on the abdomen and back than on the legs. Although compensatory sweating, which is a common adverse effect of sympathectomy, occurred in the majority of cases, the level of patient satisfaction was high. The best candidates for thoracoscopic sympathectomy are young adult women with a BMI < 24.9 kg/m(2).


A new oleanene triterpene from Gladiolus segetum Ker-Gawl.
A new pentacyclic oleanene triterpene, 2beta, 3beta, 16alpha, 28-tetrahydroxy-olean-12-ene-23-oic acid (1), as well as the known pentacyclic triterpene medicagenic acid (2), have been isolated by different chromatographic techniques from the acid hydrolysate of the saponin fraction of Gladiolus segetum. The identification of these compounds was established by different methods of physical, chemical and spectral evidence.


The relationship of tinnitus, hyperacusis, and hearing loss.
The triad of tinnitus, hyperacusis, and hearing loss remains an often-underdiagnosed combination of symptoms that causes physical, mental, and emotional distress for millions of patients. To the best of our knowledge, no review has heretofore been published in the literature regarding the possible relationship among these three entities. We believe that these symptoms may have a common pathophysiology. Specifically, improper function of cochlear hair cells may result in a hearing loss secondary to the failure of these cells to propagate proper signals through the auditory centers. In response to an incongruous neural message, higher auditory cortical centers may adapt and remodel transmitted sound. This neuroplasticity may lead to an increased perception of volume in the auditory cortex (hyperacusis) and to the perception of phantom sounds (tinnitus). Awareness of the potential relationship among tinnitus, hyperacusis, and hearing loss may contribute to improved diagnosis, treatment, and follow-up for patients with these conditions.


Tuning the optical band gap of quantum dot assemblies by varying network density.
The effect of bulk network density on the extent of quantum confinement (probed by optical band gap) in CdSe quantum dot gels is evaluated. The CdSe gels were produced from controlled removal of surface thiolate ligands from CdSe quantum dots by adding 3% tetranitromethane. Two main techniques were employed to systematically vary the bulk density. First, different amounts of oxidizing agent were added to change the monolith density of the wet gel, followed by supercritical CO(2) drying to yield CdSe aerogels with different bulk densities. Experimental results suggest that a gradual and almost linear band gap decrease is observed when increasing the bulk density at the aerogel level. The fact that quantum confinement effects are largely preserved in aerogel constructs is consistent with SAXS data revealing the fractal nature of the network. Second, for a constant amount of oxidant, different drying techniques were used to yield CdSe gels with a larger density variation: aerogels (supercritical CO(2) dried), ambigels (hexane dried), and xerogels (acetone dried). A nonlinear trend for band gap decrease was found when comparing CdSe aerogels, ambigels, and xerogels, and the more dense ambi- and xerogels have broader absorption edges, suggestive of resonance transfer effects due to dipole-dipole interactions in non-homogeneous interacting systems. This is attributed to increased aggregation in the denser constructs (supported by TEM and SAXS data). Together, these data suggest that highly porous architectures, such as aerogels, are best suited for maintaining localized quantum confinement effects in 3D connected nanoparticle networks.


Comparison of dengue-1 virus envelope glycoprotein gene sequences from French Polynesia.
Dengue (DEN) is the leading arboviral infection of humans, with 100 million cases annually in the tropical areas of the world. The recent severe DEN-1 epidemic in French Polynesia in 2001, with an incidence rate of 16% and more than 45% of the cases with dengue hemorrhagic fever/dengue shock syndrome among 1,400 hospitalized children and eight fatalities, led us to study this new circulating strain. The entire envelope (E) gene of two French Polynesian DEN-1 virus isolates from the two epidemics of 1988-1989 (FP89) and 2001 (FP01) were sequenced and compared with 29 published DEN-1 virus E gene sequences. Phylogenetic relationships showed that the FP89 strain belonged to genotype V and the FP01 strain to genotype IV based on studies on the same region of DEN-1 virus genome (1,485 nucleotides). The recent dengue epidemic in French Polynesia in 2001 was probably due to the introduction of a new DEN-1 virus from Southeast Asia, since the minimum nucleotide divergence was 3.3% with A88, the Indonesian strain isolated in 1988 in Jakarta.


Restoration of human chorionic gonadotropin response in human myometrial smooth muscle cells by treatment with follicle-stimulating hormone (FSH): evidence for the presence of FSH receptors in human myometrium.
Human myometrial smooth muscle cells contain receptors for human chorionic gonadotropin (hCG)/luteinizing hormone (LH). Exogenous hCG and LH can cause a modest hyperplasia in myometrial smooth muscle cells in culture. This response is lost after about the third subculture of the cells. The present study investigated whether the loss of hCG response could be restored by co-culturing with human follicle stimulating hormone (FSH). The results showed that co-culturing with FSH can indeed restore a modest mitogenic response of hCG. However, FSH alone was not mitogenic. The FSH restoration of hCG response can be blocked by antibodies to FSH or hCG but not by non-specific rabbit IgG. The FSH treatment resulted in an increase of steady state levels of hCG/LH receptor mRNA and protein in myometrial smooth muscle cells. Since the FSH actions could be receptor mediated, we investigated the presence of FSH receptor mRNA transcripts and protein in freshly dispersed myometrial smooth muscle cells. Northern blotting demonstrated that myometrial smooth muscle cells, just as rat ovary, a classical target of FSH action, contain multiple FSH receptor mRNA transcripts. Western immunoblotting demonstrated that myometrial smooth muscle cells also contain a 60 kDA FSH receptor protein just as rat ovary and human granulosa cells used as positive control tissues. The immunocytochemistry also demonstrated that myometrial smooth muscle cells, as rat ovary and human granulosa cells, contain FSH receptor immunostaining. In summary, it is novel that FSH could restore the mitogenic response of hCG in human myometrial smooth muscle cells and these cells contain FSH receptors. These findings may have functional implications for direct regulation of human myometrium not only by hCG/LH but also by FSH.


The reaction behavior of [Cp2Mo2(CO)4(μ,η2:2-P2)] and [Cp''Ta(CO)2(η4-P4)] towards hydroxide and tert-butyl nucleophiles.
The reaction behavior of [Cp2Mo2(CO)4(μ,η2:2-P2)] (1) and [Cp''Ta(CO)2(η4-P4)] (2), respectively, towards the anions OH- and tBu- are reported. While the reaction of 1 with KOH gives the anionic complex [Cp2Mo2(CO)4(μ-PH2)]- (3) under a formal phosphorus atom abstraction, reaction with LitBu leads to the alkylation product [Cp2Mo2(CO)4(μ,η2:1-PPtBu)]- (4). The reactions of 2 with [IDipp-H][OH] ([IDipp-H]+ = 1,3-bis-(2,6-diisopropyl-phenyl)imidazolium) and LitBu yield [Cp''Ta(CO)2{η3-P4(O)H}]- (5) and [Cp''Ta(CO)2(η3-P4tBu)]- (6), respectively. Compounds 3, 4, 5 and 6 were comprehensively characterized by NMR spectroscopy and X-ray structure analysis.


The Interface between Cell Signaling Pathways and Pregnane X Receptor.
Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity.


Health Effect of Forest Bathing Trip on Elderly Patients with Chronic Obstructive Pulmonary Disease.
Forest bathing trip is a short, leisurely visit to forest. In this study we determined the health effects of forest bathing trip on elderly patients with chronic obstructive pulmonary disease (COPD). The patients were randomly divided into two groups. One group was sent to forest, and the other was sent to an urban area as control. Flow cytometry, ELISA, and profile of mood states (POMS) evaluation were performed. In the forest group, we found a significant decrease of perforin and granzyme B expressions, accompanied by decreased levels of pro-inflammatory cytokines and stress hormones. Meanwhile, the scores in the negative subscales of POMS decreased after forest bathing trip. These results indicate that forest bathing trip has health effect on elderly COPD patients by reducing inflammation and stress level.


Proton release from the histidine-tetrad in the M2 channel of the influenza A virus.
The activity of the M2 proton channel of the influenza A virus is controlled by pH. The tautomeric state and conformation of His37, a key residue in the M2 transmembrane four-helix bundle, controls the gating of the channel. Previously, we compared the energetics and dynamics of two alternative conformations of the doubly protonated state at neutral pH, namely, a 4-fold symmetric "histidine-box" and a 2-fold symmetric "dimer-of-dimers", and proposed a multiconfiguration model for this charge state. Here, we elaborate this model by further studying configurations of the His37 tetrad in the triply protonated state and its subsequent deprotonation via quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, starting with the aforementioned configurations, to gain information about proton release in a viral membrane environment. Interestingly, the two configurations converge under acidic pH conditions. Protons can be transferred from one charged His37 to a neighboring water cluster at the C-terminal side of the channel when the Trp41 gate is open transiently. With limited backbone expansion, the free energy barrier for proton release to the viral interior at low pH is ~6.5 kcal/mol in both models, which is much lower than at either neutral pH or for an isolated His37 cluster without a membrane environment. Our calculations also suggest that the M2 protein would seem to exclude the entrance of anions into the central channel through a special mechanism, due to the latter's potential inhibitory effect on proton conduction.


The feeding of patients in hospital: a review.
The feeding of patients in hospitals is a topical issue. This review considers the development of feeding practices in British hospitals and highlights disturbing aspects which may have a bearing on recovery. The issues highlighted may also exacerbate the problem of hospital-induced malnutrition. There is little evidence that the provision of food per se is a cause for concern. It is rather the many other factors which may contribute to the patients consuming an in adequate diet.


Two war-torn soldiers: combat-related trauma through an intersubjective lens.
The author, himself an Iraq war veteran, presents a contemporary psychodynamic understanding, known as intersubjective therapy, of combat-related Post-traumatic Stress Disorder (PTSD). At the onset of this case example, the patient was highly suicidal and his PTSD symptoms had not responded to a first-line treatment: manualized cognitive processing therapy. Robert Stolorow's intersubjective, psychodynamic approach to traumatic emotional experiences was then selected for treatment, and illustrates how combat in Afghanistan shattered this soldier's world and self experience. Therapeutic action arises from this intersubjective perspective by providing a relational home so that unendurable emotions can be borne, processed, and integrated to achieve a more constant and individualized sense of self. Being a two-person model of therapy, the author also describes how his work with this traumatized soldier affected him, ultimately contributing to his own sense of authentic existing. The author discusses the need for therapists to recognize and acknowledge to traumatized patients their shared finitude and the ubiquity of trauma. In the Postscript, the patient describes what he felt was therapeutic and contrasts this to his previous experiences with manualized cognitive processing therapy.


The Effect of Calcium and Halide Ions on the Gramicidin A Molecular State and Antimicrobial Activity.
Gramicidin A (gA) forms several convertible conformations in different environments. In this study, we investigated the effect of calcium halides on the molecular state and antimicrobial activity of gramicidin A. The molecular state of gramicidin A is highly affected by the concentration of calcium salt and the type of halide anion. Gramicidin A can exist in two states that can be characterized by circular dichroism (CD), mass, nuclear magnetic resonance (NMR) and fluorescence spectroscopy. In State 1, the main molecular state of gramicidin A is as a dimer, and the addition of calcium salt can convert a mixture of four species into a single species, which is possibly a left-handed parallel double helix. In State 2, the addition of calcium halides drives gramicidin A dissociation and denaturation from a structured dimer into a rapid equilibrium of structured/unstructured monomer. We found that the abilities of dissociation and denaturation were highly dependent on the type of halide anion. The dissociation ability of calcium halides may play a vital role in the antimicrobial activity, as the structured monomeric form had the highest antimicrobial activity. Herein, our study demonstrated that the molecular state was correlated with the antimicrobial activity.


Load Determination for the 3-Minute All-Out Exercise Test for Cycle Ergometry.
To investigate a new power-to-body-mass (BM) ratio 3-min all-out cycling test (3MT(%BM)) for determining critical power (CP) and finite work capacity above CP (W'). The gas-exchange threshold (GET), maximal oxygen uptake (VO2max), and power output evoking VO2max (W(peak)) and GET (W(GET)) for cycle ergometry were determined in 12 participants. CP and W' were determined using the original "linear factor" 3MT (3MT(rpm^2)) and compared with CP and W' derived from a procedure, the 3MT(%BM), using the subject's body mass and self-reported physical activity rating (PA-R), with values derived from linear regression of the work-time model and power-inverse-time model (1/time) data from 3 separate exhaustive square-wave bouts. The VO2max, VO(2GET), W(peak), and W(GET) values estimated from PA-R and a non-exercise-regression equation did not differ (P > .05) from actual measurements. Estimates of CP derived from the 3MT(%BM) (235 ± 56 W), 3MT(rpm^2) (234 ± 62 W), work-time (231 ± 57 W), and 1/time models (230 ± 57 W) did not differ (F = 0.46, P = .72). Similarly, estimates of W' between all methods did not differ (F = 3.58, P = .07). There were strong comparisons of the 3MT(%BM) to 1/time and work-time models with the average correlation, standard error of the measurement, and CV% for critical power being .96, 8.74 W, and 4.64%, respectively. The 3MT(%BM) is a valid, single-visit protocol for determining CP and W'.


Functional optical coherence tomography reveals localized layer-specific activations in cat primary visual cortex in vivo.
Surface neural activity has been widely visualized using optical intrinsic signal imaging (OISI) from various cortical sensory areas. OISI of the cortical surface with a CCD camera gives integrated information across a depth of a few hundred micrometers. We visualize depth-resolved activation patterns of cat primary visual cortex by functional optical coherence tomography (fOCT). A comparison of the depth-integrated results of fOCT maps with the optical intrinsic signal profiles shows fairly good agreement. Our results reveal layer-specific activation patterns and indicate that the activation was not homogeneous.


Tomato allergy: clinical features and usefulness of current routinely available diagnostic methods.
Tomato contains many allergens but their clinical relevance is poorly defined and the usefulness of available diagnostic methods is unknown. To assess the clinical usefulness of current diagnostic methods for tomato allergy. Ninety-six adults with plant food allergy were grouped based on their reactivity to PR-10, profilin, and lipid transfer protein (LTP). Tomato allergy was ascertained by history and a positive skin prick test (SPT) to fresh tomato. SPT with a commercial extract and immunoglobulin (Ig) E measurements were carried out. In total, 36%, 8%, 28%, 18%, 8%, and 1% of patients were sensitized to PR-10, profilin, both PR-10 and profilin, LTP alone, LTP plus PR-10 or profilin, and genuine tomato allergens, respectively. Tomato allergy was detected in 32 (33%) of the 96 patients and was significantly associated with profilin hypersensitivity (P < .001). The sensitivity of SPT was good in all subgroups, but specificity was poor in many cases. ImmunoCAP sensitivity was acceptable in profilin reactors, but very poor in PR-10 reactors. IgE levels were not associated with tomato allergy in any of the subgroups. Similarly, birch and peach-specific IgE levels were not associated with tomato allergy in PR-10/profilin or in LTP reactors, respectively. Both SPT and ImmunoCAP worked well in the only patients with true tomato allergy. Birch- and tomato-specific IgE levels were not associated in patients monosensitized to PR-10, but they were correlated in profilin groups (P < .005). Peach- and tomato-specific IgE levels were correlated (P < .001) in LTP-allergic patients. Tomato allergy occurs via sensitization towards different proteins. Component-resolved diagnosis helps to define clinical subgroups with different risk levels.


Crystal growth, transport, and the structural and magnetic properties of Ln(4)FeGa(12) with Ln = Y, Tb, Dy, Ho, and Er.
Ln(4)FeGa(12), where Ln is Y, Tb, Dy, Ho, and Er, prepared by flux growth, crystallize with the cubic Y(4)PdGa(12) structure with the Im3m space group and with a = 8.5650(4), 8.5610(4), 8.5350(3), 8.5080(3), and 8.4760(3) A, respectively. The crystal structure consists of an iron-gallium octahedra and face-sharing rare-earth cuboctahedra of the Au(3)Cu type. Er(4)Fe(0.67)Ga(12) is iron-deficient, leading to a distortion of the octahedral and cuboctahedral environments due to the splitting of the Ga2 site into Ga2 and Ga3 sites. Further, interstitial octahedral sites that are unoccupied in Ln(4)FeGa(12) (Ln = Y, Tb, Dy, and Ho) are partially occupied by Fe2. Y(4)FeGa(12) exhibits weak itinerant ferromagnetism below 36 K. In contrast, Tb(4)FeGa(12), Dy(4)FeGa(12), Ho(4)FeGa(12), and Er(4)Fe(0.67)Ga(12) order antiferromagnetically with maxima in the molar magnetic susceptibilities at 26, 18.5, 9, and 6 K. All of the compounds exhibit metallic electric resistivity, and their iron-57 Mossbauer spectra, obtained between 4.2 and 295 K, exhibit a single-line absorption with a 4.2 K isomer shift of ca. 0.50 mm/s, a shift that is characteristic of iron in an iron-gallium intermetallic compound. A small but significant broadening in the spectral absorption line width is observed for Y(4)FeGa(12) below 40 K and results from the small hyperfine field arising from its spin-polarized itinerant electrons.


Metal- and Photocatalyst-Free, Visible-Light-Initiated C3 α-Aminomethylation of Quinoxalin-2(1H)-ones via Electron Donor-Acceptor Complexes.
We report a metal- and photocatalyst-free C3 α-aminomethylation of quinoxalin-2(1H)-ones with N-alkyl-N-methylanilines. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between quinoxalin-2(1H)-ones and N-alkyl-N-methylanilines. The present method provides a mild and environmentally friendly protocol that exhibits good atom economy and excellent functional group tolerance to obtain a library of biologically significant C3 α-aminomethylated quinoxalin-2(1H)-ones in good yields.


Iron replacement therapy in the routine management of blood donors.
Iron depletion or deficiency in blood donors frequently results in deferrals for low hemoglobin (Hb), yet blood centers remain reluctant to dispense iron replacement therapy to donors. During a 39-month period, 1236 blood donors deferred for a Hb level of less than 12.5 g/dL and 400 nondeferred control donors underwent health history screening and laboratory testing (complete blood counts, iron studies). Iron depletion and deficiency were defined as a ferritin level of 9 to 19 and less than 9 µg/L in females and 18 to 29 and less than 18 µg/L in males. Deferred donors and iron-deficient control donors were given a 60-pack of 325-mg ferrous sulfate tablets and instructed to take one tablet daily. Another 60-pack was dispensed at all subsequent visits. In the low-Hb group, 30 and 23% of females and 8 and 53% of males had iron depletion or deficiency, respectively, compared with 29 and 10% of females and 18 and 21% of males in the control group. Iron-depleted or -deficient donors taking iron showed normalization of iron-related laboratory parameters, even as they continued to donate. Compliance with oral iron was 68%. Adverse gastrointestinal effects occurred in 21% of donors. The study identified 13 donors with serious medical conditions, including eight with gastrointestinal bleeding. No donors had malignancies or hemochromatosis. Iron depletion or deficiency was found in 53% of female and 61% of male low-Hb donors and in 39% of female and male control donors. Routine administration of iron replacement therapy is safe and effective and prevents the development of iron depletion and deficiency in blood donors.


Recent and prospective population growth in the U.S.S.R.: 1979-2025.
"This report presents the results and assumptions of a set of projections of the population of the USSR, 1979-2025. Trends in population size and age-sex composition as well as fertility, mortality, and emigration are discussed.... The projections show that the population of the USSR will grow throughout the period to 2025. The working age population will grow very slowly for at least the next 10 years, and will not recapture the rapid growth experienced in the 1970s. The pension-age population will double in size between 1980 and 2025."


Clinical significance of MYD88 non-L265P mutations in diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is a group of heterogeneous tumors with different molecular traits and clinical features. MYD88 is an oncogene that activates the nuclear factor κB pathway in DLBCL. MYD88 L265P mutation frequently occurs in DLBCL with poor prognosis, while the clinical significance of non-L265P mutations needs to be clarified. Next-generation sequencing was performed on a cohort of 356 patients with DLBCL to investigate the impact of MYD88 mutation. Ten MYD88 mutated variants were detected in 32% (114/356) of the cases. V217F, S219C, S222R, M232T, S243N, and T294P were identified as pathogenic variants. MYD88 non-L265P mutations occurred less than L265P mutation in DLBCL of the central nervous system and breast tissue. The coexistence of MYD88 non-L265P mutations with PIM1 mutation was also less than that of L265P mutation. The progression-free survival in patients with DLBCL with MYD88 non-L265P mutation was statistically better than in patients with MYD88 L265P mutation. The interpretation of variants of MYD88 mutation offers a precise guide for the management of DLBCL.


[H2O2-induced blood serum biochemiluminescence].
Significant differences in the intensities of H2O2-induced biochemiluminescence of venous and capillary blood sera were revealed, as was a direct relationship between this parameter and hemoglobin level in the samples; this permits a conclusion on the improper employment of H2O2-induced biochemiluminescence of blood serum in diagnostic studies.


Purification and properties of a manganese-containing superoxide dismutase from Acholeplasma laidlawii.
From the prokaryotic microorganism Acholeplasma laidlawii the major manganese-containing superoxide dismutase has been purified to homogeneity, as judged by polyacrylamide gel electrophoresis. The molecular mass of the enzyme was found to be 41 500 Da. It consists of two subunits of identical size and has an isoelectric point of 6.4. The enzyme contains 0.51 +/- 0.05 atoms of manganese per subunit. Its amino-acid composition and light absorption spectra are presented and compared with Mn- and Fe- containing superoxide dismutases from other prokaryotic organisms.


Hyperlactatemia reduces muscle glucose uptake and GLUT-4 mRNA while increasing (E1alpha)PDH gene expression in rat.
An increased basal plasma lactate concentration is present in many physiological and pathological conditions, including obesity and diabetes. We previously demonstrated that acute lactate infusion in rats produced a decrease in overall glucose uptake. The present study was carried out to further investigate the effect of lactate on glucose transport and utilization in skeletal muscle. In chronically catheterized rats, a 24-h sodium lactate or bicarbonate infusion was performed. To study glucose uptake in muscle, a bolus of 2-deoxy-[3H]glucose was injected in basal condition and during euglycemic-hyperinsulinemic clamp. Our results show that hyperlactatemia decreased glucose uptake in muscles (i.e., red quadriceps; P < 0.05). Moreover in red muscles, both GLUT-4 mRNA (-30% in red quadriceps and -60% in soleus; P < 0.025) and protein (-40% in red quadriceps; P < 0.05) were decreased, whereas the (E1alpha)pyruvate dehydrogenase (PDH) mRNA was increased (+40% in red quadriceps; P < 0.001) in lactate-infused animals. PDH protein was also increased (4-fold in red gastrocnemius and 2-fold in red quadriceps). These results indicate that chronic hyperlactatemia reduces glucose uptake by affecting the expression of genes involved in glucose metabolism in muscle, suggesting a role for lactate in the development of insulin resistance.


Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition.
The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-x(L) depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-x(L) inhibitors regardless of their p53 status.


Removal of Acid Black 1 and Basic Red 2 from aqueous solutions by electrocoagulation/Moringa oleifera seed adsorption coupling in a batch system.
The removal of Acid Black 1 (AB1) and Basic Red 2 (BR2) from aqueous solutions via an electrocoagulation (EC)/Moringa oleifera seeds (MOS) adsorption coupling process by using aluminum and stainless steel electrode in a batch reactor is described in this study. The influences of the operational parameters, i.e. current density, MOS dosage, and dye initial concentration, on degree of color removal were studied, and the unit energy demand, the unit electrode material demand, and the charge loading were calculated and discussed. The amounts of adsorbent and energy consumption were considered as main criteria of process evaluation, and ideal conditions were chosen. The addition of an appropriate MOS dosage (0.6 g/L for AB1 and 5 g/L for BR2) resulted in faster decolorization of dyes especially at lower current densities and was simultaneously accompanied by a significant reduction in contact time compared to the conventional simple EC process. The coupling process achieved degree of removals above 99.3% and 94% for AB1 and BR2, respectively. The EC/MOS coupling technique could be recommended to replace the conventional simple EC because of its high degree of removal, short contact time, and low energy consumption.


Linkage study of Best's vitelliform macular dystrophy (VMD2) in a large North American family.
Best's vitelliform macular dystrophy (VMD2) is an autosomal dominant retinal dystrophy for which the underlying biochemical cause is unknown. We used 11 genetic markers in the vicinity of the VMD2 gene in our study of a large North American family in which macular dystrophy characteristics overlap the broad definition of Best's disease. Significant evidence for linkage was found for markers D11S956 (Z = 5.88, theta = 0.04) and FCER1B (Z = 4.31, theta = 0.00). Recombination events localized the disease gene to the 5-cM interval D11S956-UGB, a genetic inclusion interval that substantially overlaps the VMD2 inclusion interval defined by recombinants at FCER1B and UGB observed by other research groups. The resulting exclusion of ROM1 from the genetic inclusion interval eliminates ROM1 defects as a possible cause of the disease in this family. Linkage studies of many families, including those that share most but not all features with classical Best's disease, will be needed to properly evaluate genetic heterogeneity and the range of phenotypic variation that can result from VMD2 defects.


A decade of nutraceutical patents: where are we now in 2018?
In the last 10 years, nutraceuticals have grown in interest to researchers, industry, and consumers and are now familiar in the collective imagination as a tool for preventing the onset of a disease. Often nutraceuticals are confused with biologically active phytochemicals/botanicals which can have health benefits. This is a misunderstanding however as the term nutraceutical refers to a product that must have a beneficial effect on health proven by clinical testing. Areas covered: A search has been performed on both recent patents and the literature regarding nutraceuticals focusing on the beneficial and proven health effects on pathological conditions to give an overview of the state-of-the-art developments in this area. Patents and literature data addressing specific pathological conditions are discussed. Expert opinion: Nutraceuticals represent a challenge for the future of drug-based pharmacotherapy, and, at the same time, are a powerful tool for the prevention of chronic disease. They are not proposed as an alternative to drugs, but instead, can be helpful to complement a pharmacological therapy and prevent the onset of chronic diseases in subjects who do not qualify for conventional pharmacological treatment.


Functional characterization of GH-like homolog in amphioxus reveals an ancient origin of GH/GH receptor system.
Amphioxus belongs to the subphylum cephalochordata, an extant representative of the most basal chordates. Despite many studies on the endocrine system of amphioxus, no evidence showed the presence of pituitary hormones. In this study, we clearly demonstrated the existence of a functional GH-like hormone in amphioxus, which is able to bind purified GH receptors, stimulate IGF-I expression, promote growth rate of fish, and rescue embryonic defects caused by a shortage of GH. We also showed the presence of a GH/prolactin-like-binding protein containing the entire hormone binding domain of GH/prolactin receptors in amphioxus, which is widely expressed among tissues, and interacts with the GH-like hormone. It is clear from these results that the GH/GH receptor-like system is present in amphioxus and, hence, in all classes of chordates. Notably, the GH-like hormone appears to be the only member of the vertebrate pituitary hormones family in amphioxus, suggesting that the hormone is the ancestral peptide that originated first in the molecular evolution of the pituitary hormones family in chordates. These data collectively suggest that a vertebrate-like neuroendocrine axis setting has already emerged in amphioxus, which lays a foundation for subsequent formation of hypothalamic-pituitary system in vertebrates.


Helicobacter pylori Induces Disturbances in Gastric Mucosal Akt Activation through Inducible Nitric Oxide Synthase-Dependent S-Nitrosylation: Effect of Ghrelin.
Gastric mucosal inflammatory response to H. pylori and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in apoptosis and the disturbances in NO signaling pathways. Here, we report that H. pylori LPS-induced enhancement in the mucosal inducible nitric oxide synthase (iNOS) was associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. Further, we demonstrate that the LPS effect on Akt inactivation, manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser(473), was susceptible to suppression by iNOS inhibition. Moreover, the countering effect of hormone, ghrelin, on the LPS-induced changes in Akt activity was reflected in the loss in Akt S-nitrosylation and the increase in its phosphorylation at Ser(473), as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection leads to Akt inactivation through S-nitrosylation that exerts the detrimental effect on the processes of cNOS activation through phosphorylation. We also report that ghrelin protection against H. pylori-induced disturbances is manifested in a marked increase in Akt activity and evoked by a decrease in the kinase S-nitrosylation and the increase in its phosphorylation at Ser(473).


Cloning and characterization of a retroviral plasmid, pCC1, for combination suicide gene therapy.
Introduction of the herpes simplex virus thymidine kinase (HSV-TK) gene into mammalian cells confers specific sensitivity to killing by the anti-herpes drug ganciclovir (GCV). This gene has therefore been used in a number of cancer gene therapy protocols as a therapeutic gene. However, the therapeutic efficacy of HSV-TK/GCV in cancer gene therapy experiments can be augmented by additional therapeutic genes. We have cloned a retroviral plasmid, pCC1, containing a fusion gene of HSV-TK and Sh-ble driven by an internal simian virus 40 early promoter. This gene encodes a fusion protein that confers GCV sensitivity and Zeocin resistance when introduced into mammalian cells. A multiple cloning site (MCS) allows the introduction of a second therapeutic gene under the transcriptional control of the Moloney murine leukemia virus 5' long terminal repeat. We have generated packaging cell lines electroporated with pCC1 or pCC1 rtIL-2 S (rat interleukin-2 gene cloned in the sense direction in the MCS), the supernatants of which transfer GCV sensitivity only, or both GCV sensitivity and rtIL-2 production, respectively to rat ovarian cancer cells. This plasmid may be useful for the study of combination suicide gene therapy strategies.


Biological auctions with multiple rewards.
The competition for resources among cells, individuals or species is a fundamental characteristic of evolution. Biological all-pay auctions have been used to model situations where multiple individuals compete for a single resource. However, in many situations multiple resources with various values exist and single reward auctions are not applicable. We generalize the model to multiple rewards and study the evolution of strategies. In biological all-pay auctions the bid of an individual corresponds to its strategy and is equivalent to its payment in the auction. The decreasingly ordered rewards are distributed according to the decreasingly ordered bids of the participating individuals. The reproductive success of an individual is proportional to its fitness given by the sum of the rewards won minus its payments. Hence, successful bidding strategies spread in the population. We find that the results for the multiple reward case are very different from the single reward case. While the mixed strategy equilibrium in the single reward case with more than two players consists of mostly low-bidding individuals, we show that the equilibrium can convert to many high-bidding individuals and a few low-bidding individuals in the multiple reward case. Some reward values lead to a specialization among the individuals where one subpopulation competes for the rewards and the other subpopulation largely avoids costly competitions. Whether the mixed strategy equilibrium is an evolutionarily stable strategy (ESS) depends on the specific values of the rewards.


In vitro susceptibility of Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium avium against some quinolones.
The in vitro susceptibility of Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium avium to ciprofloxacin, norfloxacin and ofloxacin was studied by the agar dilution method. All strains of Mycobacterium fortuitum were inhibited by 2 mg/ml or less of these antimicrobial agents. Concentrations higher than achievable blood levels were necessary to inhibit Mycobacterium chelonae and Mycobacterium avium.


Unilateral microtia reconstruction: is the position symmetrical?
A method of analyzing the head position of the reconstructed unilateral microtic ear relative to the normal side was developed and applied in the assessment of 78 microtic ear reconstructions. Two groups of patients were assessed. Group I included 58 unilateral microtia patients, some with no clinical evidence of lateral facial dysplasia and others with mild to moderate lateral facial dysplasia, as judged by three experienced clinical observers. Group II included 20 unilateral microtia patients with severe lateral facial dysplasia involvement. Of special interest was evidence of lateral facial dysplasia in 88 percent of the patients reviewed. A reproducible technique was developed to assess the position of the reconstructed ear. Three slides showing the normal ear, reconstructed ear, and anteroposterior views of each patient were projected onto a centimeter grid to provide life-size (5-cm) proportions. The normal side served as the control. Length, angulation, and height were compared between normal and reconstructed ears by using a clear film rhomboid pattern designed by choosing specific reproducible landmarks. In group I, the reconstructed ear was of acceptable length and angulation in 91 and 95 percent of the patients, respectively, and of proper height in 88 percent. The corresponding values in group II were 90, 95, and 90 percent. Efforts should be made at the time of original surgery to ensure that the reconstructed ear is not only aesthetically pleasing but also positioned correctly. The technique used by us is one example of an attempt to evaluate the resultant ear position in microtia reconstruction.


Less than 80% of absorbed iron is promptly incorporated into erythrocytes of infants.
Erythrocyte incorporation of an administered iron isotope has been used as a surrogate for iron retention on the assumption (validated in normal and iron-deficient adults) that 80-100% of the retained isotope is promptly incorporated into circulating erythrocytes. This assumption has not been validated in infants or children. The purpose of our study was to determine concurrently in normal infants absorption and erythrocyte incorporation of the stable isotope, (58)Fe. In a preliminary study (Study 1), we demonstrated that fecal excretion of ingested isotope occurs predominantly during the first 4 d after administration but continues beyond 7 d after ingestion, that is, beyond the point at which isotope in feces can be explained either by excretion of isotope that failed to enter enterocytes or by exfoliation of isotope-enriched enterocytes. In Study 2, we administered (58)Fe to nine younger (age 20-69 d) and nine older (age 165-215 d) term infants and collected feces for 11 d. Geometric mean retention of (58)Fe by the younger infants was 31.2% of intake at 4 d and 26.9% at 11 d, and by the older infants, 35.0% at 4 d and 32.5% at 11 d. Erythrocyte incorporation of (58)Fe 14 d after ingestion was 5.2% of the dose by the younger infants and 12.5% by the older infants. Utilization of retained (11 d) isotope thus was 19.8% by the younger infants and 38.3% by the older infants. We conclude that far less than 80% of retained isotope is promptly incorporated into erythrocytes (utilized) by infants.


Future prospects for targeted alpha therapy.
The objectives in the application of targeted alpha therapy (TAT) for cancer therapy are reviewed. These relate to elimination of isolated cancer cells, cell clusters and tumors. Requirements for isolated cancer cells are good cellular targeting, high specific activity, and very short range. The regression of cell clusters in the peri-vascular space requires high capillary permeability and short range cross fire whereas for developed tumors, good bioavailabilty and anti- capillary activity are essential. Current sources of alpha radiation are reviewed and the prospects for commercial sources for clinical application are discussed. The Ac:Bi generator is the most practical alpha source, bringing therapy to Nuclear Medicine with the same practicality as the Mo:Tc generator has for imaging. The status quo of TAT is briefly reviewed with respect to dose normalization, real time microdosimetry and biological dosimetry for deterministic and stochastic effects and toxicity. The role of Monte Carlo calculations is emphasized. The strengths and weaknesses of TAT are examined and the way forward for clinical acceptance is discussed.


[Tuberculosis Annual Report 2011--(1) Summary of tuberculosis notification statistics and tuberculosis in foreign nationals].
The Tuberculosis Surveillance Center (TSC) at the Research Institute of Tuberculosis has published a series of annual reports on tuberculosis (TB) statistics in Japan since 2008. These reports are based on information on the nationwide computerized TB surveillance system database, which has been in operation since 1987. This is the first of a new series of reports for the "TB Annual Report 2011" that includes a summary of TB statistics and an overview of TB cases with foreign nationality in 2011. A total of 22,681 cases with all types of TB were notified in 2011 with a notification rate of 17.7 per 100,000 population. The TB notification rates decreased to less than 20 per 100,000 population in 2007 and continued to decline until 2011. A total of 8,654 sputum-smear positive pulmonary TB were notified in 2011, at a rate of 6.8 per 100,000 population. The number of latent TB infection (LTBI) cases requiring prophylactic treatment drastically increased from 4,930 cases in 2010 to 10,046 cases in 2011. Surveillance data on TB cases with foreign nationality in Japan have been collected since 1998. The number of TB cases with foreign nationality increased from 739 in 1998 to 931 in 2004 but has been stagnated since then, that indicated 921 in 2011. The TB cases with foreign nationality accounted for 2.1 % of all new TB cases in 1998, and this percentage increased to 4.1% in 2011. Of note, new TB cases with foreign nationality aged 20-29 years accounted for 30.0% of all new TB cases among the same age group in 2011. Among the TB cases with foreign nationality, more than half were from China (29.6%) and the Philippines (23.7%) taken together. In most cases, foreign nationals developed TB within 5 years of entry into Japan, including 80.0% of those aged 10-19 years and 80.8% of those aged 20-29 years. Of these TB cases with foreign nationality, 27% were noted in full-time employees, followed by unemployed persons (21%) and students (20%). With an increase in the number of immigrants into Japan, the proportion of TB cases with foreign nationality is expected to increase, particularly among young adults and those from countries with a high burden of TB.


A general discussion of remote sensing of the atmosphere.
The current remote sensing activities for atmospheric studies are discussed with particular emphasis on earth orbiting satellites and the direction of research trends.


Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior-posterior lineage restriction in the developing wing of Drosophila.
It is thought that the posterior expression of the 'selector' genes engrailed and invected control the subdivision of the growing wing imaginal disc of Drosophila into anterior and posterior lineage compartments. At present, the cellular mechanisms by which separate lineage compartments are maintained are not known. Most models have assumed that the presence or absence of selector gene expression autonomously drives the expression of compartment-specific adhesion or recognition molecules that inhibit intermixing between compartments. However, our present understanding of Hedgehog signalling from posterior to anterior cells raises some interesting alternative models based on a cell's response to signalling. We show here that anterior cells that lack smoothened, and thus the ability to receive the Hedgehog signal, no longer obey a lineage restriction in the normal position of the anterior-posterior boundary. Rather these clones extend into anatomically posterior territory, without any changes in engrailed/invected gene expression. We have also examined clones lacking both en and inv; these too show complex behaviors near the normal site of the compartment boundary, and do not always cross entirely into anatomically anterior territory. Our results suggest that compartmentalization is a complex process involving intercompartmental signalling; models based on changes in affinity or growth will be discussed.


In Vivo Computing for Smart Tumor Targeting in Taxicab-Geometry Vasculature.
This paper investigates the tumor microenvironment regulated by densely interconnected capillaries, resulting in the distribution of tumor-induced biological gradient field (BGF) in taxicab-geometry vasculature (TGV). We aim to improve the efficiency of tumor targeting with the knowledge of BGF in TGV, which is facilitated by a swarm of magnetic nanorobots. An external system observes and records the nanorobot swarm (NS) reaction to the BGF. Then the NS is controlled to move toward the potential tumor location by an external magnetic field. In this way, the BGF formed under the constraint of TGV is the objective function to be optimized, where the tumor center corresponds to the maximum value. The high-risk tissue area is the domain of the objective function, while the NS plays the role of a computing agent. Subsequently, we propose the coordinate gradient descent (CGD) targeting strategy for NS steering. This strategy estimates the BGF in the direction perpendicular to the propagation direction of NS to improve the efficiency of tumor detection. In addition, it considers the limited lifespan of NS in vivo, where a memory step-size mechanism (MSM) is utilized to reduce the targeting time. We use computational experiments to show that the CGD strategy yields higher tumor-targeting probabilities than the brute-force search and the original gradient-descent-inspired targeting strategy for the BGF subject to TGV.


The Interrelationship of Common Clinical Movement Screens: Establishing Population-Specific Norms in a Large Cohort of Military Applicants.
Musculoskeletal injuries (MSK-Is) are a leading cause of missed duty time and morbidity in the military. Modifiable risk factors for MSK-Is, such as inadequate core stability, poor movement patterns, and dynamic balance deficits, have not been identified in military applicants on entering service. To establish normative functional movement data using a series of screens in military applicants entering basic training and explore relationships among several movement tests. Cross-sectional study. Military Entrance Processing Station. A total of 1714 (1434 male, 280 female) military applicants entering the US Army (n = 546), Navy (n = 414), Air Force (n = 229), or Marine Corps (n = 525). We conducted the Functional Movement Screen (FMS), Y-Balance Test (YBT), overhead squat (OHS), and Landing Error Scoring System (LESS). Movements were assessed using the scoring convention for each screen. The FMS, YBT, OHS, and LESS scores and associations among the movement screens as well as clinical meaningfulness. A total of 1037 of the 1714 enrolled applicants were screened on the day they left for basic training. Normative means for this population were established: FMS = 14.7 ± 1.8, YBT anterior-reach difference = 3.1 ± 3.0 cm, mean YBT composite differences = 8.0 ± 6.8 cm, mean YBT composite percentage = 90.9% ± 8.3%, OHS errors = 5.0 ± 2.8, and LESS score = 5.7 ± 2.1. Backward regression results revealed that the YBT composite percentage was related to the FMS and OHS scores in males and to the FMS and LESS results in females. However, clinically meaningful relationships between the tests varied for both males and females. Sex-normative values for the FMS, YBT, OHS, and LESS screens were established for US military applicants, and some of the assessments overlapped. Overall, males performed better on the OHS and LESS and achieved a greater YBT composite percentage than females. The regression results revealed movement screen performance relationships that varied by sex and clinical meaningfulness. In future studies, we will determine if performance on any of the screens is associated with MSK-Is in basic trainees.


Characterizing the BHK-21 C5 cell line and determining cellular sensitivity to rubella virus compared with the routine cell (RK13).
The World Health Organization has strict rules and recommendations on the selection and use of cell substrates in laboratories. Given the widespread use of safe and secure cell substrates in the production and quality control of viral vaccines and also the high demand for vaccines against viral diseases, obligating the selection of a suitable cell substrate for cultivation and production of biological products. Animal cell lines play a valuable role in the preparation and propagation of viral seeds; thus, the current study used the BHK-21 cell line among others for viral checking with the aim of replacing the BHK-21 C5 cell line with the RK13 cell line to investigate the cytopathic effects of the rubella virus. To this end, attempts were made to determine the characteristics of the BHK-21 C5 cell line including cell growth characteristics and sterility tests to validate its safety and security. Then, by culturing the cells in a 96-well microplate, titration of the rubella virus was subsequently performed by preparing serial dilutions of the virus from 10-1 to 10-5 and inoculated to cell lines in order to compare the sensitivity of BHK-21 C5 and RK13 cell lines to rubella virus. Data analysis according to the results of the tests by ahead default, p-value < 0/05 was equal to p-value = 0.01 based on SPSS analysis with the paired-sample t-test. In addition, the box-plot diagram indicated a significant difference between these cell lines. Based on the results, the BHK-21 C5 cell line seems to be more sensitive to the rubella virus than others. Therefore, it can be used for production and quality control of the vaccine and in research and diagnosis of rubella.


Renagel: a new and different phosphate binder.
Renagel is a novel, nonabsorbed, phosphate binding polymer free of aluminum and calcium. In hemodialysis patients, Renagel: lowers serum phosphorus levels; lowers intact parathyroid hormone levels; lowers calcium x phosphorous levels; lowers total serum and low density lipoprotein (LDL) cholesterol; and is safe and well tolerated (Bleyer et al., 1997; Chertow, Burke, Dillon, et al., 1998; Chertow, Burke, Goldberg, et al., 1997; Chertow, Burke, Lazarus, et al., 1997; Goldberg et al., 1998; Slatopolsky, Burke, Dillon, & The Renagel Study Group, 1999). Renagel treatment decreased total and low-density lipoprotein (LDL) cholesterol, but had no effect on high-density lipoprotein (HDL) cholesterol and triglycerides (Goldberg et al., 1998; Slatopolsky et al., 1999). This cholesterol-lowering effect of Renagel was most apparent in patients with LDL cholesterol of 100 mg/dl or greater at baseline; therefore, it may be beneficial for some patients. Longer-term studies in ESRD patients are required to determine the potential benefit of lipid lowering (Slatopolsky et al., 1999). The nephrology staff is responsible for delivering optimal patient care. This new drug allows for adequate control of phosphorous without incidence of hypercalcemia, or aluminum related problems.


Electrowetting-driven liquid lens for ultrasound: Enabling controllable focal length and flexible beam steering.
Focused ultrasound is an increasingly popular non-invasive treatment modality. Still, its fixed focal point requires an array ultrasound transducer or scanning system to cover different therapeutic scenarios. To address this limitation, we developed an electrically-controlled liquid lens that enables dynamic beam focusing and steering of the incident plane ultrasound beam. The lens was carefully optimized for low-energy attenuation and low-voltage driving. We evaluated the performance of the lens using a homemade 5.5-MHz planar transducer with a 7.5-mm aperture. Our results demonstrate that the planar ultrasound beam can be adjusted to a focused beam with a focal length from 27 mm to 32 mm within 1 s by increasing the electric input (0-60 V) to the lens. Additionally, the beam angle of the ultrasound is tunable from -5 to 5° by adjusting the charge distribution on the lens. Our design enables real-time, fast-response, on-demand changing of focal length and beam angle for a single-element planar transducer. Our study presents a promising technology for altering the ultrasound beam of a planar single-element transducer for different ultrasound applications. The development of this electrically-controlled liquid lens has the potential to enhance the efficacy of focused ultrasound treatment and improve patient outcomes.


Cytochrome P450 (CYP) expression in human myeloblastic and lymphoid cell lines.
To explore the physiological roles of cytochrome P450 (CYP) in peripheral blood cells, we examined which isoforms of CYP families were expressed in human myeloid leukemia cell lines (U937, HL-60 and K562) and lymphoid cell lines (BALL-1, MOLT-4 and Jurkat) by RT-PCR. We observed relatively high expression of CYP1A1, CYP1B1, CYP2A6, CYP2A7, CYP2D6, and CYP2E1 in all cell types, but CYP2A13 and CYP2C9 expression was not detected. Expressions of aryl hydrocarbon (Ah) receptor and Ah receptor nuclear translocator (ARNT), which mediate induction of the CYP1 family, were also detected in all cell types. Cell-type specific expression of CYP3A4 and CYP3A5 was observed in MOLT-4 and K562 cells. Weak, but significant, expression of CYP3A7 was detected in K562 cells. The profile of CYP expression in the culture cells reported here provides information that furthers our understanding of the physiological roles of CYP enzymes in human blood cells.


Characterizing structural association alterations within brain networks in normal aging using Gaussian Bayesian networks.
Recent multivariate neuroimaging studies have revealed aging-related alterations in brain structural networks. However, the sensory/motor networks such as the auditory, visual and motor networks, have obtained much less attention in normal aging research. In this study, we used Gaussian Bayesian networks (BN), an approach investigating possible inter-regional directed relationship, to characterize aging effects on structural associations between core brain regions within each of these structural sensory/motor networks using volumetric MRI data. We then further examined the discriminability of BN models for the young (N = 109; mean age =22.73 years, range 20-28) and old (N = 82; mean age =74.37 years, range 60-90) groups. The results of the BN modeling demonstrated that structural associations exist between two homotopic brain regions from the left and right hemispheres in each of the three networks. In particular, compared with the young group, the old group had significant connection reductions in each of the three networks and lesser connection numbers in the visual network. Moreover, it was found that the aging-related BN models could distinguish the young and old individuals with 90.05, 73.82, and 88.48% accuracy for the auditory, visual, and motor networks, respectively. Our findings suggest that BN models can be used to investigate the normal aging process with reliable statistical power. Moreover, these differences in structural inter-regional interactions may help elucidate the neuronal mechanism of anatomical changes in normal aging.


Crotamine, a small basic polypeptide myotoxin from rattlesnake venom with cell-penetrating properties.
Crotamine, a low molecular weight cationic polypeptide from the venom of the South American rattlesnake Crotalus durissus terrificus is a natural cell-penetrating peptide with functional versatility. The presence of nine lysine residues and three disulfide bonds renders crotamine highly compact, stable and positively charged. Topologically, crotamine adopts an ancient β-defensin fold that is found in diverse families of endogenous and venom polypeptides dedicated to host defense. Crotamine is unique among several classes of bioactive peptides because it possesses both cell penetrating and antimicrobial activities and selective biological action toward some cell types at a given cell cycle phase. Because it can rapidly and efficiently translocate into actively proliferating cells, crotamine is being investigated for labeling highly replicating cells and for use as a chemotherapeutic adjuvant. Peptides derived from crotamine, nucleolar targeting peptides (NrTPs), have been designed and are being studied. NrTPs retain some crotamine properties, such as efficient cellular uptake and preferential nuclear localization whereas they improve upon other properties. For example, NrTPs are smaller than crotamine, show higher preferential nucleolar localization, and better facilitate ZIP-code localization of therapeutic proteins.


Emergence of chikungunya in Moonlapamok and Khong Districts, Champassak Province,the Lao People's Democratic Republic, May to September 2012.
Chikungunya is a vector-borne disease transmitted to humans by Aedes mosquitoes, which are widespread in the Lao People's Democratic Republic. However, chikungunya virus (CHIKV) had not been detected in the country before outbreaks reported in July 2012. The first outbreaks were detected through health care worker event-based surveillance. The case definition for the outbreaks was defined as a person with acute onset of fever (≥ 38 °C) and severe arthralgia (joint pain) or arthritis from 1 May 2012 in Champassak Province. Rapid response teams conducted active case finding, performed an environmental assessment including an entomological survey and implemented control measures. Descriptive analysis was undertaken in Microsoft Excel. There were 197 cases (attack rate 3.4%) of suspected chikungunya reported from 10 villages in Moonlapamok and Khong Districts of Champassak Province. All age groups (age range: seven months-74 years) were affected with slightly more female (56%) than male cases. Thirty-one per cent (16 of 52) of serum samples tested positive for CHIKV by polymerase chain reaction. The environmental assessment found poor water storage practices and high entomological indices. These outbreaks show the effectiveness of health care worker event-based surveillance and the importance of sharing of information across borders for detecting emerging diseases. Public health education is an important measure to prevent epidemics of chikungunya. Information about chikungunya should be supplied to health care workers in the region so they are alert to the potential spread and are able to implement control measures for this disease.