Spontaneous locomotor activity in late-stage chicken embryos is modified by stretch of leg muscles.
Chicks initiate bilateral alternating steps several days before hatching and adaptively walk within hours of hatching, but emergence of precocious walking skills is not well understood. One of our aims was to determine whether interactions between environment and movement experience prior to hatching are instrumental in establishing precocious motor skills. However, physiological evidence of proprioceptor development in the chick has yet to be established; thus, one goal of this study was to determine when in embryogenesis proprioception circuits can code changes in muscle length. A second goal was to determine whether proprioception circuits can modulate leg muscle activity during repetitive limb movements for stepping (RLMs). We hypothesized that proprioception circuits code changes in muscle length and/or tension, and modulate locomotor circuits producing RLMs in anticipation of adaptive locomotion at hatching. To this end, leg muscle activity and kinematics were recorded in embryos during normal posture and after fitting one ankle with a restraint that supported the limb in an atypical posture. We tested the hypotheses by comparing leg muscle activity during spontaneous RLMs in control posture and ankle extension restraint. The results indicated that proprioceptors detect changes in muscle length and/or muscle tension 3 days before hatching. Ankle extension restraint produced autogenic excitation of the ankle flexor and reciprocal inhibition of the ankle extensor. Restraint also modified knee extensor activity during RLMs 1 day before hatching. We consider the strengths and limitations of these results and propose that proprioception contributes to precocious locomotor development during the final 3 days before hatching.


The data-and-signals cellular automaton and its application to growing structures.
In a traditional cellular automaton (CA) a cell is implemented by a rule table defining its state at the next time step, given its present state and those of its neighbors. The cell thus deals only with states. We present a novel CA where the cell handles data and signals. The cell is designed as a digital system comprising a processing unit and a control unit. This allows the realization of various growing structures, including self-replicating loops and biomorphs. We also describe the hardware implementation of these structures within our electronic wall for bio-inspired applications, the BioWall.


Novel pH-responsive dextrin nanogels for doxorubicin delivery to cancer cells with reduced cytotoxicity to cardiomyocytes and stem cells.
The aim of this study was to develop pH-responsive dextrin nanogels (DNGs) capable of triggered intracellular DOX release at the lower pH of cancer cells. DNGs were prepared by an emulsion cross-linking method using glyoxal as cross-linker to create an acid-labile bond. A higher molecular weight of dextrin with increasing mole ratio of dextrin to glyoxal decreased the average diameter of DNGs. DNGs showed slightly negative surface charge and pH-responsive behavior. The in vitro drug release was slow at pH 7.4 and increased with decreasing pH (pH 5>6.8). The cytotoxicity of DOX-loaded DNGs in mesenchymal stem cells and cardiomyocytes was lower than that of free DOX. Moreover, DOX-loaded DNGs were efficiently internalized by tumor cells with rapid release of DOX into the nucleus. Thus, DOX-loaded DNGs were successful for intracellular targeted anti-tumor drug delivery and reducing side-effects to non-tumor cells such as cardiomyocytes and stem cells.


[Acute toxicological studies of captopril in rats and mice].
The acute toxicity of captopril, a potential inhibitor of angiotensin converting enzyme, was studied in Sprague-Dawley rats and ICR mice. In the oral administration, a decrease of spontaneous motor activity, lacrimation, salivation and decline of body temperature was noted in the rats and mice. In the mice, tarry stool was also noted. The LD50 was estimated as: 4249 mg/kg in male mice, 5050 mg/kg in female mice, 4336 mg/kg in male rats and 4245 mg/kg in female rats, In the dead animals, a hemorrhagic erosion or ulcer was recognized in the glandular stomach. An intravenous captopril in mice, caused immediate death by dyspnea in some animals within 3 minutes, but delayed death was also occurred within 24 hours showing a decrease of spontaneous motor activity and decline of body temperature. The LD50 was estimated as 3154 mg/kg in male mice and 3225 mg/kg in female mice. A single intravenous administration of captopril in dose of 1600 mg/kg did not cause any death in the rats of both sexes. The mice of both sexes well tolerated a single subcutaneous administration of captopril in a dose of 2400 mg/kg. No death occurred in rats of both sexes received subcutaneously captopril in a dose of 1200 mg/kg. At an injection site, a necrotic ulcer was noted in the skin of rats and mice which received subcutaneously captopril in a dose of 1600 mg/kg or more and 1200 mg/kg, respectively.


Fluidization of wet granulates under shear.
Small amounts of a wetting liquid render sand a stiff and moldable material. The cohesive forces between the sand grains are caused by capillary bridges at the points of contact. Due to the finite strength of these bridges wet sand undergoes a transition from an arrested (i.e., solidified) to a fluidized state under an externally applied shear force. The transition between these two dynamic states is studied in a MD-type simulation of a two-dimensional assembly of bidisperse frictionless disks under the action of a cosine force profile. In addition to soft core repulsion the disks interact through a hysteretic and short ranged attractive force modeling the effect of the capillary bridges. In this model the transition between the fluidized and the arrested state is discontinuous and hysteretic. The parameter dependence of the critical force for solidification is modeled by combining theoretical arguments with a detailed numerical exploration of the transition. We address a range of densities from slightly below close packing until slightly above densities where the system approaches a shear-banded state. Differences and similarities of the transition in wet granulates to the jamming transition are also addressed.


Parenteral antibiotics reduce bifidobacteria colonization and diversity in neonates.
We investigated the impact of parenteral antibiotic treatment in the early neonatal period on the evolution of bifidobacteria in the newborn. Nine babies treated with intravenous ampicillin/gentamicin in the first week of life and nine controls (no antibiotic treatment) were studied. Denaturing gradient gel electrophoresis was used to investigate the composition of Bifidobacterium in stool samples taken at four and eight weeks. Bifidobacteria were detected in all control infants at both four and eight weeks, while only six of nine antibiotic-treated infants had detectable bifidobacteria at four weeks and eight of nine at eight weeks. Moreover, stool samples of controls showed greater diversity of Bifidobacterium spp. compared with antibiotic-treated infants. In conclusion, short-term parenteral antibiotic treatment of neonates causes a disturbance in the expected colonization pattern of bifidobacteria in the first months of life. Further studies are required to probiotic determine if supplementation is necessary in this patient group.


A comparison of two different methods for the serum opacity reaction of Streptococci group A. Occurrence of antibodies against opacity factor in human sera.
For detection of the opacity factor (OF) in streptococcus group A, two different methods, the slide technique and the blood agar technique, have been compared. The results agree closely. The reaction of OF positive strains on the blood agar medium seems, however, to be more difficult to interpret than the clear-cut opalescence in the slide reaction. Antibody to serum opacity factor was demonstrated in human sera using the solid agar method. Such antibodies were demonstrated in 26 out of a total of 46 ASO positive sera examined.


Application of population pharmacokinetic modeling in early clinical development of the anticancer agent E7820.
The aim of this study was to assess the population pharmacokinetics (PopPK) of the novel oral anti-cancer agent E7820. Both a non-linear mixed effects modeling analysis and a non-compartmental analysis (NCA) were performed and results were compared. Data were obtained from a phase I dose escalation study in patients with malignant solid tumors or lymphomas. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to the start of subsequent cycles. A one compartment model with linear elimination from the central compartment was shown to give adequate fit, while absorption was described using a turnover model. Final population parameter estimates of basic PK parameters obtained with the PopPK method were (RSE): clearance, 6.24 L/h (7.1%), volume of distribution, 66.0 L (8.5%), mean transit time to the absorption compartment, 0.638 h (6.5%). The intake of food prior to dose administration slowed absorption (2.8-fold, RSE 13%) and increased relative bioavailability of E7820 by 36% (RSE 14%), although the effect on C (max) and AUC was not significant. Comparison with the NCA approach showed approximately equal PK parameter estimates and food effect measures, although specific advantages of PopPK included efficiency in use of data and more appropriate assessment of variability.


L-Carnitine ameliorates glycerol-induced myoglobinuric acute renal failure in rats.
There is increasing evidence indicating that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced myoglobinuric acute renal failure (ARF). During times of war and natural disasters, myoglobinuric ARF can assume epidemic proportions. Thus, early and effective renoprotective treatments are of utmost importance. It has been shown that L-carnitine, used as a safe and effective nutritional supplement for more than three decades, is effective in preventing renal injury in many renal injury models involving oxidative stress. The present study was performed to investigate the effects of L-carnitine in an experimental model of myoglobinuric ARF. Four groups of rats were employed in this study: group 1 served as a control; group 2 was given glycerol (10 mL/kg, i.m.); group 3 was given glycerol plus L-carnitine (100 mg/kg, i.p.), starting at the same time as the glycerol injection; group 4 was given glycerol plus L-carnitine (100 mg/kg, i.p.), starting 48h before the glycerol injection. After glycerol injections, the i.p. injections of L-carnitine were repeated every 24h for four days. Ninety-six hours after glycerol injections, blood samples and kidney tissues were taken from the anesthetized rats. Urea and creatinine levels in plasma, N-acetyl-beta-D-glucosaminidase activity in urine, and malondialdehyde levels and catalase enzyme activity in kidney tissue were determined. Histopathological changes and iron accumulation in the kidney tissue were evaluated. In this study, glycerol administration led to marked renal oxidative stress, as well as severe functional and morphological renal deterioration. L-carnitine, possibly via its antioxidant properties, ameliorates glycerol-induced myoglobinuric kidney injury.


Visualization of photothermal therapy by semiconducting polymer dots mediated photoacoustic detection in NIR II.
Visualization of photothermal therapy mediated by photothermal transduction agents (PTAs) is important to promote individual treatment of patients with low side effects. Photoacoustic detection has emerged as a promising noninvasive method for the visualization of PTAs distribution but still has limitations in temperature measurement, including poor measurement accuracy and low tissue penetration depth. In this study, we developed biocompatible semiconducting polymer dots (SPD) for in situ coupling of photothermal and photoacoustic detection in the near-infrared II window. SPD has dual photostability under pulsed laser and continuous-wave laser irradiation with a photothermal conversion efficiency of 42.77%. Meanwhile, a strong correlation between the photoacoustic signal and the actual temperature of SPD can be observed. The standard deviation of SPD-mediated photoacoustic thermometry can reach 0.13 °C when the penetration depth of gelatin phantom is 9.49 mm. Preliminary experimental results in vivo show that SPD-mediated photoacoustic signal has a high signal-to-noise ratio, as well as good performance in temperature response and tumor enrichment. Such a study not only offers a new nanomaterial for the visualization of photothermal therapy but will also promote the theranostic platform for clinical applications.


Hemodynamic determinants of thallium-201 lung uptake in patients during atrial pacing stress.
The present investigation was undertaken to define the hemodynamic determinants of lung uptake of thallium-201 (TI-201) in man during stress. Graded tachycardia was induced by atrial pacing with continuous hemodynamic monitoring in 21 patients (6 normal, 15 with coronary artery disease). At peak pacing, 80 MEq (2.2 mCi) of TI-201 was injected intravenously and imaging commenced within 5 minutes. Lung activity was expressed as a percentage of peak myocardial activity on the anterior image (Lung TI-201 Index). The influence of rest, peak and post pacing hemodynamic parameters including cardiac index, pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, pulmonary artery pressure, and heart rate on Lung TI-201 Index was examined using step-wise multiple regression. Change in cardiac index from rest to peak pacing was negatively correlated, while pulmonary capillary wedge pressure at peak pacing was positively correlated to Lung TI-201 Index (combined r value of 0.75). No other parameter had a significant correlation. In summary, lung uptake of TI-201 activity during atrial pacing stress appears to depend on: changes in cardiac output which may determine tissue contact time and thus influence extraction efficiency, and hydrostatic pressure in the pulmonary capillary bed.


Differential diagnosis of L26-positive, CD15-negative Hodgkin's disease and large B-cell lymphoma with a high content of reactive T-cells: a morphologic and immunohistochemical study.
B-cell non-Hodgkin's lymphomas with a marked preponderance of reactive T cells, so-called T-cell rich B-cell lymphomas (TCRBCLs), can be morphologically confused with Hodgkin's disease (HD). To establish helpful distinguishing features in paraffin sections, 10 cases of L26-positive, CD15-negative HD and 10 cases of TCRBCL were compared; 4 cases of HD had morphologic features of the nodular lymphocyte predominant (LP) type. Nine of 10 cases of HD contained fewer than 20 mitoses/20 high power fields (hpf) and only 1 had pericapsular involvement. In contrast, 9 of 10 TCRBCL had greater than 20 mitoses/20 hpf and 7 had perinodal infiltration. HDLP was easily distinguished from TCRBCL by the expanded dendritic meshworks outlining the L & H nodules and the high content of CD57-positive lymphocytes. The remaining 6 cases of non-LP L26-positive HD had a relatively distinctive immunostaining pattern, with absence of CD45 and discordant reactivity for L26 and Ki-B5 in Reed-Sternberg cells and variants. Only 3 cases of TCRBCL had a similar CD45 and L26/Ki-B5 immunostaining pattern, and these could be distinguished by demonstrable cytoplasmic light-chain restriction. These results show that evaluation of the mitotic count, pericapsular involvement, and immunohistochemical staining patterns for Ki-M4p, CD57, L26/Ki-B5, and CD45 can help to discriminate TCRBCL from L26-positive HD when only fixed material is available.


Oligodeoxynucleotide targeted to the alphav gene inhibits alphav integrin synthesis, impairs osteoclast function, and activates intracellular signals to apoptosis.
The alphav integrin subunit is highly expressed in osteoclasts where it dimerizes with beta1 and beta3 subunits to form receptors for vitronectin and bone sialoproteins. Inhibition of osteoclast adhesion and function has previously been achieved by alphavbeta3 antibodies or Arg-Gly-Asp-containing peptides which have the disadvantages of blocking a single receptor type, or of being rather nonspecific, respectively. Here we show that alphav integrin expression in rabbit osteoclasts can be inhibited by partially phosphorothioated antisense oligodeoxynucleotide (ODN) spanning the adenine-uracil-guanine (AUG) translational start site of the human/rabbit alphav gene, a procedure which offers the advantage of affecting all the alphav receptors with high efficiency. The alphav antisense ODN caused a dose-dependent, substrate-specific reduction of osteoclast adhesion and bone resorption. Control ODNs, such as sense, inverted, and mismatch, were without effect, providing evidence of specificity of the antisense reagent. It is likely as a consequence of loss of substrate interaction, the antisense ODN induced osteoclast retraction and apoptosis, increase of the cyclin/cyclin-dependent kinase complex inhibitor p21WAF1/CIP1, and inhibition of the cell survival gene, bcl-2. Although the expression of the cell death-promoting gene, bax, remained unchanged, a reduction of the bcl-2/bax ratio, known to underlie the intracellular signal to apoptosis, was observed. This finding led us to hypothesize that these changes could provide a link between reduction of alphav synthesis and osteoclast programmed death. In conclusion, this study provides novel insights into the use of alphav antisense ODN as an efficacious mechanism for blocking osteoclast function and underscores for the first time the involvement of integrins in bone cell apoptosis. In vivo studies may verify potential application of this ODN as alternative therapy for bone diseases.


Knowledge, attitudes and practice of dentists concerning the occupational risks of hepatitis B virus in Al Jouf Province, Saudi Arabia.
Hepatitis B virus (HBV) is a well-recognized occupational risk for all health care workers (HCWs) worldwide. In Saudi Arabia, very little is known about knowledge, attitudes, and practice of dentists toward occupational risk of HBV. Our study was conducted to assess the same parameters. During February 2012, a cross-sectional survey of 48 dentists with mean age 38 ± 11.2 years was carried out at the primary health care centers in Al Jouf Province of Saudi Arabia. The dentists were asked to fill a valid questionnaire containing their socio-demographic data, and well-designed questions about their knowledge base, attitudes and practice toward occupational risk of HBV. The data were processed and analyzed using the SPSS (version 17) (IBM SPSS Inc., Chicago, IL, USA) program and the level of significance were set at P < 0.05. Response rate of 85.4% yielded 41 questionnaires for analysis. Majority of the dentists surveyed 34 (82.9%) perceived that they are at high risk of contracting and spreading HBV, and 28 (68.3%) had a concern to get HBV. More than half 23 (56.1%) were willing to achieve continuity of care for HBsAg-positive patients. The vast majority 39 (95.1%) believed that HBV vaccine is safe, and 34 (82.9%) were vaccinated. Less than half 17 (41.5%) recognized that HBV is resistant to alcohol and some detergents. During surgical procedures, only 14 (34.1%) always use double gloves and 19 (46.3%) always use goggles. Almost all dentists surveyed were willing to subscribe in a regular training programs about HBV. More education focusing on occupational risk of HBV is recommended for dentists.


Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo.
Valproic acid (VPA) has long been the most widely used antiepileptic drug (AED) for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. However, long-term VPA treatment has several adverse effects on the male reproductive system notably on endocrine functions and/or spermatic parameters. In utero exposure of the fetus to VPA is well known to be associated with a higher risk of several congenital malformations including those of male reproductive organs. Subsequent generations of AEDs, such as carbamazepine (CARB) and lamotrigine (LAM), are considered safer and are currently recommended for women of child-bearing age with epilepsy. Because anomalies of the male genital tract mostly result from endocrine imbalance during fetal life, we hypothesized that AEDs could directly impair testis differentiation. We thus aimed at identifying and characterizing the effects of VPA, CARB, and LAM on the differentiation and function of the different testicular cell types, and at understanding the mechanisms underlying these effects. By using ex vivo culture of first-trimester human fetal testes, we show that VPA induces multiple endocrine disruptive effects, compared with the milder ones caused by CARB and LAM. AED also subtly altered the germ cell lineage in distinct manners. Transcriptomic analysis of VPA-induced alterations highlighted a very broad range of effects on the fetal testis. Overall, our results show that AEDs can behave as endocrine disruptors for the human fetal testis ex vivo. This is consistent with, and likely underlies, the VPA-induced male genital tract masculinization abnormalities observed in patients.


Dysphagia In Multiple Sclerosis Patients: Diagnostic And Evaluation Strategies.
Dysphagia after multiple sclerosis (MS) is a common disabling symptom which can lead to serious complications. Regular screening and assessment of dysphagia in patients with MS are important. Using valid and reliable instruments to measure dysphagia in MS patients is a crucial component in clinical practice and of research quality. There are various strategies to diagnose and assess the dysphagia in patients with MS. Screening strategies are for early diagnosis of the dysphagia. Clinical, non-instrumental strategies are used to verify the presence and to determine the severity and cause of dysphagia. Instrumental strategies are complementary to clinical examination to provide objective data on the various aspects of swallowing dysfunctions. This review revealed a few validated tools for dysphagia assessment in MS. The Dysphagia in Multiple Sclerosis Questionnaire (DYMUS) and the Mann Assessment of Swallowing Ability (MASA) are the only validated MS-specific dysphagia tools. Further development of valid and reliable MS-specific screening and assessment tools that can be administered rapidly and scored easily to detect dysphagia and evaluate clinical outcomes in adults with MS is imperative. Until then, validation and metric evaluation of the screening and assessment tools currently available are required.


A versatile bioink for three-dimensional printing of cellular scaffolds based on thermally and photo-triggered tandem gelation.
Layer-by-layer bioprinting is a logical choice for the fabrication of stratified tissues like articular cartilage. Printing of viable organ replacements, however, is dependent on bioinks with appropriate rheological and cytocompatible properties. In cartilage engineering, photocrosslinkable glycosaminoglycan-based hydrogels are chondrogenic, but alone have generally poor printing properties. By blending the thermoresponsive polymer poly(N-isopropylacrylamide) grafted hyaluronan (HA-pNIPAAM) with methacrylated hyaluronan (HAMA), high-resolution scaffolds with good viability were printed. HA-pNIPAAM provided fast gelation and immediate post-printing structural fidelity, while HAMA ensured long-term mechanical stability upon photocrosslinking. The bioink was evaluated for rheological properties, swelling behavior, printability and biocompatibility of encapsulated bovine chondrocytes. Elution of HA-pNIPAAM from the scaffold was necessary to obtain good viability. HA-pNIPAAM can therefore be used to support extrusion of a range of biopolymers which undergo tandem gelation, thereby facilitating the printing of cell-laden, stratified cartilage constructs with zonally varying composition and stiffness.


The nucleotide sequence of replication and maintenance functions encoded by plasmid pSC101.
The nucleotide sequence of 1100bp around the origin of replication of the pSC101 plasmid has been determined. This segment of DNA is capable of replication in the presence of a helper plasmid. The sequence data reveal similarities between pSC101 and several other replicons. The origin of replication contains three direct repeats of an 18bp sequence associated with a segment exceptionally rich in A-T base pairs. A promotor that probably directs transcription of a gene encoding an essential plasmid replication function is associated with a region of extensive potential secondary structure. The sequence presented here includes the sequence of the par region involved in partitioning of plasmids at cell division.


Chemoprophylaxis in gastrointestinal tumors.
Chemoprevention of gastrointestinal tumors uses natural or synthetic agents to arrest, retard or reverse the carcinogenesis process. The prospect of prevention is clearly appealing, especially for colorectal cancer (CRC), that represents the second most common cause of cancer-related death in the Western world. Aspirin is the best studied chemopreventive agent for CRC, with randomized trials demonstrating its efficacy in reducing recurrence of colorectal adenomas in higher risk patients. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Other nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors also reduce the incidence of colonic adenomas, but they are associated with gastrointestinal harms and important cardiovascular events, respectively. Furthermore, cumulative epidemiological and observational data suggest the potential role of hormones as a chemoprotective agent for CRC. The usefulness of folic acid, calcium, and vitamin D awaits further evaluation. Interestingly, combining different agents may maximize effectiveness while limiting drug toxicity. Although many agents have shown positive results in the field of chemoprevention, it cannot yet be accepted as standard medical practice for CRC. In the present review we discuss the most promising agents in CRC chemoprevention, together with their potential mechanisms of action in tumor inhibition.


C-terminal truncation of alpha-COP affects functioning of secretory organelles and calcium homeostasis in Hansenula polymorpha.
In eukaryotic cells, COPI vesicles retrieve resident proteins to the endoplasmic reticulum and mediate intra-Golgi transport. Here, we studied the Hansenula polymorpha homologue of the Saccharomyces cerevisiae RET1 gene, encoding alpha-COP, a subunit of the COPI protein complex. H. polymorpha ret1 mutants, which expressed truncated alpha-COP lacking more than 300 C-terminal amino acids, manifested an enhanced ability to secrete human urokinase-type plasminogen activator (uPA) and an inability to grow with a shortage of Ca2+ ions, whereas a lack of alpha-COP expression was lethal. The alpha-COP defect also caused alteration of intracellular transport of the glycosylphosphatidylinositol-anchored protein Gas1p, secretion of abnormal uPA forms, and reductions in the levels of Pmr1p, a Golgi Ca2+-ATPase. Overexpression of Pmr1p suppressed some ret1 mutant phenotypes, namely, Ca2+ dependence and enhanced uPA secretion. The role of COPI-dependent vesicular transport in cellular Ca2+ homeostasis is discussed.


Clinical effects of long-term metreleptin treatment in patients with lipodystrophy.
To evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy. Fifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health. At baseline, hemoglobin A1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides-479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities. Metreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy.


Continuing to Confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012-2013.
The Continuing to Confront COPD International Patient Survey aimed to estimate the prevalence and burden of COPD globally and to update findings from the Confronting COPD International Survey conducted in 1999-2000. Chronic obstructive pulmonary disease (COPD) patients in 12 countries worldwide were identified through systematic screening of population samples. Telephone and face-to-face interviews were conducted between November 2012 and May 2013 using a structured survey that incorporated validated patient-reported outcome instruments. Eligible patients were adults aged 40 years and older who were taking regular respiratory medications or suffered with chronic respiratory symptoms and reported either 1) a physician diagnosis of COPD/emphysema, 2) a physician diagnosis of chronic bronchitis, or 3) a symptom-based definition of chronic bronchitis. The burden of COPD was measured with the COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) Dyspnea Scale. Of 106,876 households with at least one person aged ≥40 years, 4,343 respondents fulfilled the case definition of COPD and completed the full survey. COPD prevalence ranged from 7% to 12%, with most countries falling within the range of 7%-9%. In all countries, prevalence increased with age, and in all countries except the US was greater among men (range 6%-14%) than among women (range 5%-11%). A significant disease burden was observed when considering COPD symptoms or health status, and showed wide variations across countries. Prevalence of moderate-to-severe dyspnea (mMRC scale ≥2) ranged from 27% to 61%, and mean CAT score ranged from 16.0 to 24.8, indicating medium-to-high impairment. This survey, representing 12 countries, showed similar rates of estimated COPD prevalence across countries that were higher than those reported a decade ago in the original Confronting COPD International Survey. A significant burden of COPD was demonstrated by symptoms and health care-resource use, similar to that reported in the original survey.


Relationship between eye dominance and pattern electroretinograms in normal human subjects.
The authors conducted a study in 100 non-smoker healthy normal human subjects to find a relationship between eye dominance and macular function as tested by using transient stimulus and electroretinography. Eye preference procedure was carried out using two reference points and pattern electroretinograms (PERGs) were recorded using black and white checks, each check subtending 23'. Trace averager was retriggered every 300 milliseconds (ms) with data collection time of 150 ms. The difference in PERG P50 amplitudes between right and left eyes was analyzed using Student's t test. There was no significant difference in PERG P50 amplitudes between the right and left eye dominant subjects as well as no significant differences between the right and left eyes in right eye dominants and left eye dominants, but in the left-eye dominant group the left eye PERG P50 amplitudes were significantly higher in females than males. Although pattern-reversal visual evoked potentials of healthy subjects provide electrophysiological evidence of lateralization in the nervous system, sensory eye dominance seems to have no correlation with macular function.


The Physical Work Environment and Sleep: A Latent Class Analysis.
To investigate the relationships between the physical work environment and sleep using a person-centered approach. A total of 542 Australian employees aged 18 to 60 years completed a survey assessing exposure to physical work environment stressors (eg, noise, poor air quality, and hazardous manual tasks), sleep timing and sleep quality, and relevant covariates. Latent class analysis (LCA) revealed three physical work environment classes: Infrequent exposure (51%); Occasional Exposure (31%); and Regular Exposure (18%). LCA also identified four sleep classes: Larks (24%); Typical sleep (43%); Insufficient sleep (20%); and Owls (13%). The Regular Exposure class was significantly associated with the Insufficient Sleep (odds ratio [OR] = 3.15, [1.29, 7.66]) and Owls (OR = 3.47 [1.24, 9.71]) classes. The person-centered approach provides important insights into how unique physical work environment experiences are linked with sleep.


[COVID-19 risk groups and their strategies for navigating information overload during the first year of the pandemic in Chile].
As a part of the EIS-COVID project on the access and use of information during the COVID-19 pandemic in Chile, the objective of this paper was to ascertain how people's informational environment was constructed during the first stage of the pandemic. It discusses the results of a qualitative study of people belonging to risk groups for COVID-19: people over 18 and under 65 with chronic diseases (hypertension and diabetes) and people 65 and over. Ninety semi-structured interviews were conducted in the Metropolitan and Valparaíso regions between September 2020 and January 2021. The results reveal the problematic nature of the information overload encountered by these groups and the strategies they used to navigate it: a) information avoidance; b) content corroboration and active search for reliable sources; and c) differentiated media use.


[Gynecologic pain syndrome as psychovegetative and reflex-mediated disorders and imbalances].
Chronic lower abdominal pain without organic findings represent a costly diagnostic and therapeutic problem. They are presumably caused by decentralized neurovegetative disturbances. Their treatment is a connection between somatotherapy and psychotherapy. The manifestations of these disorders are local sympathical hypertonia (with algodystrophical vasoconstrictions) or local parasympathical hypertonia and amphotonical disturbances with pathological vasodilatations, respectively, as well as accompanying disturbances of the local lymphatic system. Moreover, non-gynecological causes such as the musculus psoas syndrome are often not recognized. Diagnosis of the patient's neurovegetative status is an essential prerequisite of treatment. First, a relaxation by analgesia should take place, and then whole-body neurovegetative stimulations for centralization of the nervous control and, additionally, distant reflex and decongestive measures should be performed. For physiotherapeutical purposes, the inner genital is reached best via the vagina. In order to change the neural tonus of the Frankenhäuser ganglions the Vagimoran therapy is the optimal choice. The cutivisceral stimulations are applied via the segments S2-S4 and Th10-Th12 (suprapubical!). In future, chronotherapy in the framework of the imitation strategy and the consideration of therapeutical surroundings are essential elements of therapy.


Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells.
Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.


[Las cardiopatías congénitas en el 2018].
We present an update of the most relevant advances of three-dimensional echocardiography for the diagnosis of congenital heart diseases. The evolution of its treatment is analyzed, showing the results obtained in recent years. The functional and structural changes experienced in women with congenital heart disease during pregnancy are discussed, as well as the main health risks and the importance of teamwork in healthcare to treat these patients. Finally, we provide a review on the current situation in Mexico and outline some improvement recommendations.


A Crucial Role of the Frontal Operculum in Task-Set Dependent Visuomotor Performance Monitoring.
For adaptive goal-directed action, the brain needs to monitor action performance and detect errors. The corresponding information may be conveyed via different sensory modalities; for instance, visual and proprioceptive body position cues may inform about current manual action performance. Thereby, contextual factors such as the current task set may also determine the relative importance of each sensory modality for action guidance. Here, we analyzed human behavioral, functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) data from two virtual reality-based hand-target phase-matching studies to identify the neuronal correlates of performance monitoring and error processing under instructed visual or proprioceptive task sets. Our main result was a general, modality-independent response of the bilateral frontal operculum (FO) to poor phase-matching accuracy, as evident from increased BOLD signal and increased source-localized gamma power. Furthermore, functional connectivity of the bilateral FO to the right posterior parietal cortex (PPC) increased under a visual versus proprioceptive task set. These findings suggest that the bilateral FO generally monitors manual action performance; and, moreover, that when visual action feedback is used to guide action, the FO may signal an increased need for control to visuomotor regions in the right PPC following errors.


Phonetic complexity and stuttering in Turkish-speaking children who stutter.
The relationship between stuttering and phonetic complexity for words spoken by Turkish children who stutter was investigated. The research questions were: (1) Do Turkish-speaking children stutter more on unbound content words than on unbound function words? (2) Do Turkish-speaking children stutter more on words with higher phonetic complexity scores? Twenty-one monolingual children aged 6-11 years who had a clinical diagnosis of stuttering participated. Speech samples were transcribed and lexical categories determined. Phonetic complexity was assessed by an adaptation of Index of Phonetic Complexity (IPC) for Turkish. Results revealed that the mean rank of unbound content words differed significantly from the mean rank of unbound function words and that stuttering frequency for unbound content words was significantly higher than for unbound function words.


Effect of transmyocardial laser revascularization on chronic ischemic hearts in sheep.
We investigated the effect of transmyocardial laser revascularization (TMR) on myocardial function and regional blood flow in an animal model of ischemic heart disease. Chronic ischemia was induced in 11 sheep by the application of coronary stenosis on the left anterior descending (LAD) and circumflex coronary artery (LCX). Ten weeks later, in six of them, transmyocardial channels were created in the anterior free wall and in the posterior wall of the left ventricle. Five animals served as controls. The myocardial function was assessed by echocardiography taken at baseline and every 2 weeks after coronary stenosis and after TMR. Myocardial perfusion was measured by colored microspheres, injected at baseline, immediately after coronary stenosis, before and after TMR, and at 20 weeks after coronary stenosis. The hearts were retrieved at 20 weeks for light microscopic examination. The left ventricular end-diastolic and end-systolic cavity area was elevated 20 weeks after coronary stenosis in the control and TMR groups. There was no difference between groups (analysis of variance; ANOVA, non-significant). The wall thickening fraction (WTF) decreased progressively and significantly after coronary stenosis in both groups. The WTF was further acutely reduced by TMR, and recovered gradually to the pre-TMR level. No significant difference in WTF was observed between the TMR and control groups. The resting myocardial blood flow was significantly increased by TMR at 20 weeks (P=0.03). Light microscopic examination revealed channel patency in 49% of the laser scars at 10 weeks post-TMR. A dense capillary network was observed at the edges of the surrounding scar. In an experimental model of ischemic heart disease, TMR developed angiogenesis in the lased channels, but, however, failed to improve myocardial function.


β-Glucan Size Controls Dectin-1-Mediated Immune Responses in Human Dendritic Cells by Regulating IL-1β Production.
Dectin-1/CLEC7A is a pattern recognition receptor that recognizes β-1,3 glucans, and its stimulation initiates signaling events characterized by the production of inflammatory cytokines from human dendritic cells (DCs) required for antifungal immunity. β-glucans differ greatly in size, structure, and ability to activate effector immune responses from DC; as such, small particulate β-glucans are thought to be poor activators of innate immunity. We show that β-glucan particle size is a critical factor contributing to the secretion of cytokines from human DC; large β-glucan-stimulated DC generate significantly more IL-1β, IL-6, and IL-23 compared to those stimulated with the smaller β-glucans. In marked contrast, the secretion of TSLP and CCL22 were found to be insensitive to β-glucan particle size. Furthermore, we show that the capacity to induce phagocytosis, and the relative IL-1β production determined by β-glucan size, regulates the composition of the cytokine milieu generated from DC. This suggests that β-glucan particle size is critically important in orchestrating the nature of the immune response to fungi.


Levels of some trace elements in selected autopsy organs, and in hair and blood samples from adult subjects of the Italian population.
This study, which is part of a research program for the determination of trace element reference levels in various human tissues for the Italian population, presents the concentrations of Se, Hg, Cr, Cs, Sc, Rb, Zn, Fe, Co, and Sb in lung, liver, spleen, and kidney autopsy samples taken from 14 adult subjects of the Italian population who died from accidental causes. Concentrations of the same trace elements are given also for blood and hair samples taken from subjects of the general Italian population and of a population group living in a small coastal town that has an average annual fish consumption well above the national average. The analytical method used was Instrumental Neutron Activation Analysis. The levels and distribution of the trace elements in the various human organs examined are analyzed and discussed.


Cell morphology and focal adhesion location alters internal cell stress.
Extracellular mechanical cues have been shown to have a profound effect on osteogenic cell behaviour. However, it is not known precisely how these cues alter intracellular mechanics to initiate changes in cell behaviour. In this study, a combination of in vitro culture of MC3T3-E1 cells and finite-element modelling was used to investigate the effects of passive differences in substrate stiffness on intracellular mechanics. Cells on collagen-based substrates were classified based on the presence of cell processes and the dimensions of various cellular features were quantified. Focal adhesion (FA) density was quantified from immunohistochemical staining, while cell and substrate stiffnesses were measured using a live-cell atomic force microscope. Computational models of cell morphologies were developed using an applied contraction of the cell body to simulate active cell contraction. The results showed that FA density is directly related to cell morphology, while the effect of substrate stiffness on internal cell tension was modulated by both cell morphology and FA density, as investigated by varying the number of adhesion sites present in each morphological model. We propose that the cells desire to achieve a homeostatic stress state may play a role in osteogenic cell differentiation in response to extracellular mechanical cues.


In vitro antibiofilm activity of Murraya koenigii essential oil extracted using supercritical fluid CO₂ method against Pseudomonas aeruginosa PAO1.
The antibiofilm activity of Murraya koenigii essential oil (EO) against Pseudomonas aeruginosa PAO1 was investigated in this study. A decrease in the production of rhamnolipid, extracellular polymeric substance and swarming motility was observed by the EO treatment (0.3% v/v). The static microtitre plate assay revealed 80% reduction in biofilm formation by P. aeruginosa PAO1 on M. koenigii EO treatment. Fluorescence microscopy and scanning electron microscopy analyses confirmed the reduction of biofilm formation in P. aeruginosa PAO1 when treated with M. koenigii EO. Gas chromatography-mass spectrometry analysis of the EO revealed the presence of well-known antibiofilm agents such as spathulenol (5.85%), cinnamaldehyde (0.37%) and linalool (0.04%). Cinnamaldehyde has not been previously reported in M. koenigii EO. The potent antibiofilm properties of M. koenigii EO may be effectively exploited in food and pharmaceutical industries as well as in controlling Pseudomonas biofilms on indwelling medical devices.


Study of differences in the VEGFR2 inhibitory activities between semaxanib and SU5205 using 3D-QSAR, docking, and molecular dynamics simulations.
Semaxanib (SU5416) and 3-[4'-fluorobenzylidene]indolin-2-one (SU5205) are structurally similar drugs that are able to inhibit vascular endothelial growth factor receptor-2 (VEGFR2), but the former is 87 times more effective than the latter. Previously, SU5205 was used as a radiolabelled inhibitor (as surrogate for SU5416) and a radiotracer for positron emission tomography (PET) imaging, but the compound exhibited poor stability and only a moderate IC(50) toward VEGFR2. In the current work, the relationship between the structure and activity of these drugs as VEGFR2 inhibitors was studied using 3D-QSAR, docking and molecular dynamics (MD) simulations. First, comparative molecular field analysis (CoMFA) was performed using 48 2-indolinone derivatives and their VEGFR2 inhibitory activities. The best CoMFA model was carried out over a training set including 40 compounds, and it included steric and electrostatic fields. In addition, this model gave satisfactory cross-validation results and adequately predicted 8 compounds contained in the test set. The plots of the CoMFA fields could explain the structural differences between semaxanib and SU5205. Docking and molecular dynamics simulations showed that both molecules have the same orientation and dynamics inside the VEGFR2 active site. However, the hydrophobic pocket of VEGFR2 was more exposed to the solvent media when it was complexed with SU5205. An energetic analysis, including Embrace and MM-GBSA calculations, revealed that the potency of ligand binding is governed by van der Waals contacts.


Advances and challenges in synthetic biology for mosquito control.
Mosquito-borne illnesses represent a significant global health peril, resulting in approximately one million fatalities annually. West Nile, dengue, Zika, and malaria are continuously expanding their global reach, driven by factors that escalate mosquito populations and pathogen transmission. Innovative control measures are imperative to combat these catastrophic ailments. Conventional approaches, such as eliminating breeding sites and using insecticides, have been helpful, but they face challenges such as insecticide resistance and environmental harm. Given the mounting severity of mosquito-borne diseases, there is promise in exploring innovative approaches using synthetic biology to bolster mosquitoes' resistance to pathogens, or even eliminate the mosquito vectors, as a means of control. This review outlines current strategies, future goals, and the importance of gene editing for global health defenses against mosquito-borne diseases.


Structural biology of shared cytokine receptors.
Recent structural information for complexes of cytokine receptor ectodomains bound to their ligands has significantly expanded our understanding of the macromolecular topology and ligand recognition mechanisms used by our three principal shared cytokine signaling receptors-gp130, gamma(c), and beta(c). The gp130 family receptors intricately coordinate three structurally unique cytokine-binding sites on their four-helix bundle cytokine ligands to assemble multimeric signaling complexes. These organizing principles serve as topological blueprints for the entire gp130 family of cytokines. Novel structures of gamma(c) and beta(c) complexes show us new twists, such as the use of a nonstandard sushi-type alpha receptors for IL-2 and IL-15 in assembling quaternary gamma(c) signaling complexes and an antiparallel interlocked dimer in the GM-CSF signaling complex with beta(c). Unlike gp130, which appears to recognize vastly different cytokine surfaces in chemically unique fashions for each ligand, the gamma(c)-dependent cytokines appear to seek out some semblance of a knobs-in-holes shape recognition code in order to engage gamma(c) in related fashions. We discuss the structural similarities and differences between these three shared cytokine receptors, as well as the implications for transmembrane signaling.


Role of the nuclear envelope in calcium signalling.
The endoplasmic reticulum (ER) is the major Ca(2+) store inside the cell. Its organisation in specialised subdomains allows the local delivery of Ca(2+) to specific cell areas on stimulation. The nuclear envelope (NE), which is continuous with the ER, has a double role: it insulates the nucleoplasm from the cytoplasm and it stores Ca(2+) around the nucleus. Furthermore, all the constituents of the signalling cascade leading to Ca(2+) mobilisation are found in the NE; this allows the nuclear Ca(2+) to be regulated autonomously. On the other hand, cytosolic Ca(2+) transients can propagate within the nucleus via the nuclear pore complex. The variations in nuclear Ca(2+) concentration are important for controlling gene transcription and progression in the cell cycle. Recent data suggest that invaginations of the NE modify the morphology of the nucleus and may affect Ca(2+) dynamics in the nucleus and regulate transcriptional activity.


Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial).
Recent preclinical studies have discovered unique synergism between radiotherapy and immune checkpoint inhibitors, which has already brought significant survival benefit in lung cancer. In locally advanced rectal cancer (LARC), neoadjuvant radiotherapy plus immune checkpoint inhibitors have also achieved surprisingly high pathological complete response (pCR) rates even in proficient mismatch-repair patients. As existing researches are all phase 2, single-cohort trials, we aim to conduct a randomised, controlled trial to further clarify the efficacy and safety of this novel combination therapy. Eligible patients with LARC are randomised to three arms (two experiment arms, one control arm). Patients in all arms receive long-course radiotherapy plus concurrent capecitabine as neoadjuvant therapy, as well as radical surgery. Distinguishingly, patients in arm 1 also receive anti-PD-1 (Programmed Death 1) treatment starting at Day 8 of radiation (concurrent plan), and patients in arm 2 receive anti-PD-1 treatment starting 2 weeks after completion of radiation (sequential plan). Tislelizumab (anti-PD-1) is scheduled to be administered at 200 mg each time for three consecutive times, with 3-week intervals. Randomisation is stratified by different participating centres, with a block size of 6. The primary endpoint is pCR rate, and secondary endpoints include neoadjuvant-treatment-related adverse event rate, as well as disease-free and overall survival rates at 2, 3 and 5 years postoperation. Data will be analysed with an intention-to-treat approach. This protocol has been approved by the institutional ethical committee of Beijing Friendship Hospital (the primary centre) with an identifying serial number of 2022-P2-050-01. Before publication to peer-reviewed journals, data of this research will be stored in a specially developed clinical trial database. NCT05245474.


Effect of digitalis on estimated splanchnic blood flow.
Digitalis causes vasoconstriction of peripheral vasculature and has been shown to markedly decrease splanchnic blood flow in experimental animals in doses that are comparable to therapeutic doses in man. The effect of digitalis on splanchnic blood flow in heart failure in experimental animals and in man has been controversial. We found that i.v. ouabin reduced ESBF by 30% to 40% (p less than 0.001) in normal volunteer human subjects, that i.v. digoxin reduced ESBF by 15% to 25% (p less than 0.01) in normal subjects, and that oral digoxin had no discernible effect on ESBF in normal subjects. The difference between the effects of i.v. and oral administration appeared to be due to differences in peak blood levels, which were almost 10 times higher after i.v. administration. Glucagon prevented the effect of i.v. digoxin on ESBF in normal subjects. For patients in heart failure, the effect of i.v. digoxin on ESBF was variable: some patients had decreased ESBF but two had increased ESBF that seemed to be associated with a greater increase in cardiac output.


Repositioning Vitamin C as a Promising Option to Alleviate Complications associated with COVID-19.
Vitamin C, also known as L-ascorbic acid, is an essential vitamin with pleiotropic functions, ranging from antioxidant to anti-microbial functions. Evidence suggests that vitamin C acts against inflammation, oxidative stress, autophagy chaos, and immune dysfunction. The ability to activate and enhance the immune system makes this versatile vitamin a prospective therapeutic agent amid the current situation of coronavirus disease 2019 (COVID-19). Being highly effective against the influenza virus, causing the common cold, vitamin C may also function against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its associated complications. Severe infections need higher doses of the vitamin to compensate for the augmented inflammatory response and metabolic demand that commonly occur during COVID-19. Compelling evidence also suggests that a high dose of vitamin C (1.5 g/kg body weight) in inflammatory conditions can result in effective clinical outcomes and thus can be employed to combat COVID-19. However, further studies are crucial to delineate the mechanism underlying the action of vitamin C against COVID-19. The current review aims to reposition vitamin C as an alternative approach for alleviating COVID-19-associated complications.


[Mental foramens and dolphin hearing].
Detection thresholds of short broadband acoustic impulses with an energy maximum on frequencies 8, 16, 30 and 100 kHz was measured in the dolphin (Tursiops truncatus p.) with using techniques of behavioral responses in the indoor pool. At acoustic shielding of mental foramens, detection thresholds of these impulses worsen on 30, 34, 40 and 50 dB, respectively. The new original results obtained experimentally prove that mental foramens are the unique sound-conducting pathway for sounds of about 6-160 kHz frequency band (in consideration of stimulus broadbandness). In this connection the assumption that morphological structures of the lower jaw represent a specialized peripheral part of the dolphin hearing, which was based on studying of morphology and results of modelling, receives additional experimental confirmation. The mental foramens play part of external auditory canals and conduct all frequency range of the hearing of dolphin into fat body of the mandibular canal. Via fat body sounds transmit to a lateral side of an acoustical bone and into the middle and inner ear. From morphology similarity, it is possible to assume presence of the similar sound-conducting mechanism in Odontoceti.


Methyl deficiency causes reduction of the methyl-CpG-binding protein, MeCP2, in rat liver.
MeCP2 is a member of a family of proteins [methyl- (cytosine-guanine)CpG-binding proteins] that bind specifically to methylated DNA and induce chromatin remodeling and gene silencing. Dietary deficiency of folate, choline and methionine causes decreased tissue S-adenosylmethionine concentrations (methyl deficiency), global DNA hypomethylation, hepatic steatosis, cirrhosis and ultimately hepatic tumorigenesis in rodents. We investigated the effects of this diet on expression of MeCP2 during pre-neoplastic transformation of liver tissue. After 9 weeks, MeCP2 mRNA level was slightly higher in methyl-deficient rats compared with replete controls, while after 36 weeks, a difference in MeCP2 mRNA level was no longer observed. In contrast, MeCP2 protein level was reduced almost 2-fold in the deficient rats compared with replete controls at both 9 and 36 weeks. Conversely, a second methyl-CpG-binding protein, MBD2, showed increased levels of both message and protein at the two time points. Low MeCP2 protein in the deficient rats was associated with a low level of the co-repressor protein, Sin3a, at 36 weeks. Moreover, a known gene target of MeCP2, the tumor suppressor gene metallothionein-I, was over-expressed in the deficient rat livers at both 9 and 36 weeks, suggesting that reduction in MeCP2 may have functional consequences. Methyl deficiency also caused an increase in the ratio of long to short variants of MeCP2 transcripts. This finding suggests that reduced MeCP2 protein level is the result of a reduced rate of translation. Reduction of MeCP2 protein expression may influence the initiation and/or progression of hepatic cancer induced by methyl deficiency and may provide a useful marker of pre-neoplastic change.


Crop rotation and native microbiome inoculation restore soil capacity to suppress a root disease.
It is widely known that some soils have strong levels of disease suppression and prevent the establishment of pathogens in the rhizosphere of plants. However, what soils are better suppressing disease, and how management can help us to boost disease suppression remain unclear. Here, we used field, greenhouse and laboratory experiments to investigate the effect of management (monocropping and rotation) on the capacity of rhizosphere microbiomes in suppressing peanut root rot disease. Compared with crop rotations, monocropping resulted in microbial assemblies that were less effective in suppressing root rot diseases. Further, the depletion of key rhizosphere taxa in monocropping, which were at a disadvantage in the competition for limited exudates resources, reduced capacity to protect plants against pathogen invasion. However, the supplementation of depleted strains restored rhizosphere resistance to pathogen. Taken together, our findings highlight the role of native soil microbes in fighting disease and supporting plant health, and indicate the potential of using microbial inocula to regenerate the natural capacity of soil to fight disease.


Functional characterization of residues within the carnitine/acylcarnitine translocase RX2PANAAXF distinct motif.
The mitochondrial carnitine/acylcarnitine carrier (CAC) is characterized by the presence of a distinct motif, RXXPANAAXF, within its sixth transmembrane alpha-helix. In this study, we analysed the role of the amino acids of this motif in the structure-function relationships of the human CAC by using two complementary approaches. First, we performed functional analysis in the model fungus Aspergillus nidulans of selected mutations with structural and functional relevance. Second, similar mutant human CACs were biochemically characterized after their reconstitution into liposomes. Both analyses have provided relevant information on the importance and role of the CAC motif residues in the activity and metabolic function of CAC. Only the two adjacent alanines, Ala281 and Ala282 in the human CAC, have been found not to be crucial for transport activity and in vivo function. Results obtained from amino acid substitutions of residues Arg275, Asn280 and Phe284 of human CAC together with structural analysis using molecular modelling of the carrier suggest that R275, N280 and F284 are involved in substrate binding during acylcarnitine/carnitine translocation. Furthermore, functional analysis of mutations of residues Pro278 and Ala279 in A. nidulans, together with kinetic data in reconstituted liposomes, suggest a predominant structural role for these amino acids.


A multicenter feasibility randomized controlled trial to assess the impact of incremental versus conventional initiation of hemodialysis on residual kidney function.
Twice-weekly hemodialysis, as part of incremental initiation, has reported benefits including preservation of residual kidney function (RKF). To explore this, we initiated a randomized controlled feasibility trial examining 55 incident hemodialysis patients with urea clearance of 3 ml/min/1.73 m2 or more across four centers in the United Kingdom randomized to standard or incremental schedules for 12 months. Incremental hemodialysis involved twice-weekly sessions, upwardly adjusting hemodialysis dose as RKF was lost, maintaining total (Dialysis+Renal) Std Kt/V above 2. Standard hemodialysis was thrice weekly for 3.5-4 hours, minimum Dialysis Std Kt/V of 2. Primary outcomes were feasibility parameters and effect size of group differences in rate of loss of RKF at six months. Health care cost impact and patient-reported outcomes were explored. Around one-third of patients met eligibility criteria. Half agreed to randomization; 26 received standard hemodialysis and 29 incremental. At 12 months, 21 incremental patients remained in the study vs 12 in the standard arm with no group differences in the urea clearance slope. Ninety-two percent of incremental and 75% of standard arm patients had a urea clearance of 2 ml/min/1.73 m2 or more at six months. Serious adverse events were less frequent in incremental patients (Incidence Rate Ratio 0.47, confidence interval 0.27-0.81). Serum bicarbonate was significantly lower in incremental patients indicating supplementation may be required. There were three deaths in each arm. Blood pressure, extracellular fluid and patient-reported outcomes were similar. There was no signal of benefit of incremental hemodialysis in terms of protection of RKF or Quality of Life score. Median incremental hemodialysis costs were significantly lower compared to standard hemodialysis. Thus, incremental hemodialysis appears safe and cost-saving in incident patients with adequate RKF, justifying a definitive trial.


Measuring Inappropriate Sexual Behavior Among University Students: Using the Randomized Response Technique to Enhance Self-Reporting.
This article analyzes the efficacy of the randomized response technique (RRT) in achieving honest self-reporting about sexual behavior, compared with traditional survey techniques. A complex survey was conducted of 1,246 university students in Spain, who were asked sensitive quantitative questions about their sexual behavior, either via the RRT (n = 754) or by direct questioning (DQ) (n = 492). The RRT estimates of the number of times that the students were unable to restrain their inappropriate sexual behavior were significantly higher than the DQ estimates, among both male and female students. The results obtained suggest that the RRT method elicits higher values of self-stigmatizing reports of sexual experiences by increasing privacy in the data collection process. The RRT is shown to be a useful method for investigating sexual behavior.


A type VI secretion-related pathway in Bacteroidetes mediates interbacterial antagonism.
Bacteroidetes are a phylum of Gram-negative bacteria abundant in mammalian-associated polymicrobial communities, where they impact digestion, immunity, and resistance to infection. Despite the extensive competition at high cell density that occurs in these settings, cell contact-dependent mechanisms of interbacterial antagonism, such as the type VI secretion system (T6SS), have not been defined in this group of organisms. Herein we report the bioinformatic and functional characterization of a T6SS-like pathway in diverse Bacteroidetes. Using prominent human gut commensal and soil-associated species, we demonstrate that these systems localize dynamically within the cell, export antibacterial proteins, and target competitor bacteria. The Bacteroidetes system is a distinct pathway with marked differences in gene content and high evolutionary divergence from the canonical T6S pathway. Our findings offer a potential molecular explanation for the abundance of Bacteroidetes in polymicrobial environments, the observed stability of Bacteroidetes in healthy humans, and the barrier presented by the microbiota against pathogens.


Formulas providing adequate pantothenic acid, vitamin D, manganese, iron and vitamin A for infants fed with mother's milk (aged 6-11 months) according to the Japanese Dietary Reference Intakes prepared by the Ministry of Health, Labour and Welfare (2005 edition).
Weaning formulas served in hospitals and care facilities in Japan should conform to dietary reference intakes (DRIs). We examined whether the DRI for breastfed infants aged 6-11 months can be satisfied in dietary practice, with a particular focus on the fulfilment rates for vitamins, minerals, trace elements and electrolytes in weaning formulas containing energy and protein at levels either greater than or equal to the DRIs, as well as on the dietary profiles of weaning formulas to achieve the DRI for every nutrient. The results showed that no weaning formulas examined in this study fulfilled the DRI for pantothenic acid (5 mg), vitamin D (4 microg), manganese (1.2 mg) or iron (5.5 mg). Furthermore, their vitamin A content exceeded the DRI (350 microg RE). The discrepancy between the guidelines and actual dietary practice is probably because of the fact that the estimated reference values poorly reflect the actual dietary intake in the target population; for example, the pantothenic acid and manganese DRIs for breastfed infants aged 6-11 months were set based on the breast milk intake of younger infants (0-5 months) in combination with the breast milk contents. Our results suggest that dietary guidance for infants should include information to promote proper intakes of vitamins A and D, and iron by reducing the amount of vitamin A-rich foods and utilizing dietary vitamin D and iron supplements including government-approved specified health foods.


Near Optimal Linear Algebra in the Online and Sliding Window Models.
We initiate the study of numerical linear algebra in the sliding window model, where only the most recent W updates in a stream form the underlying data set. Although many existing algorithms in the sliding window model use or borrow elements from the smooth histogram framework (Braverman and Ostrovsky, FOCS 2007), we show that many interesting linear-algebraic problems, including spectral and vector induced matrix norms, generalized regression, and lowrank approximation, are not amenable to this approach in the row-arrival model. To overcome this challenge, we first introduce a unified row-sampling based framework that gives randomized algorithms for spectral approximation, low-rank approximation/projection-cost preservation, and ℓ 1-subspace embeddings in the sliding window model, which often use nearly optimal space and achieve nearly input sparsity runtime. Our algorithms are based on "reverse online" versions of offline sampling distributions such as (ridge) leverage scores, ℓ 1 sensitivities, and Lewis weights to quantify both the importance and the recency of a row; our structural results on these distributions may be of independent interest for future algorithmic design. Although our techniques initially address numerical linear algebra in the sliding window model, our row-sampling framework rather surprisingly implies connections to the well-studied online model; our structural results also give the first sample optimal (up to lower order terms) online algorithm for low-rank approximation/projection-cost preservation. Using this powerful primitive, we give online algorithms for column/row subset selection and principal component analysis that resolves the main open question of Bhaskara et al. (FOCS 2019). We also give the first online algorithm for ℓ 1-subspace embeddings. We further formalize the connection between the online model and the sliding window model by introducing an additional unified framework for deterministic algorithms using a merge and reduce paradigm and the concept of online coresets, which we define as a weighted subset of rows of the input matrix that can be used to compute a good approximation to some given function on all of its prefixes. Our sampling based algorithms in the row-arrival online model yield online coresets, giving deterministic algorithms for spectral approximation, low-rank approximation/projection-cost preservation, and ℓ 1-subspace embeddings in the sliding window model that use nearly optimal space.


[Is subtotal resection of the colon actual for ulcerative colitis in the century of ileal reservoirs?].
The authors describe results of surgical treatment of 112 patients operated for a severe resistant form of ulcerative colitis (UC). In 26 (23.2%) of observations the operations were performed for complications, in 65 (58%)--for hormone-resistent, and in 21 (18.8%)--for hormone-dependent forms of UC. In 80 (71.4%) cases subtotal resection of the colon with ileo- and sigmostomies was fulfilled, in 26 (23.2%) a single stage ablation of all large intestine was fulfilled with the formation of permanent ileostomy and in 5 (5.4%) of observations the first step was finished with the formation of a reconstructive-plastic reservoir anastomosis. The number of complications in the nearest postoperative period was in 12.8% of patients, lethality was 2.3%. The development of a strict strategy of treatment for severe forms of the disease including the present-day using conservative and surgical methods of treatment depending on the individual character of each patient with UC made it possible to minimize the number of postoperative complications and decrease lethality and also to restore anal defecation with good functional results in 30.1% of operated patients.


The response of pediatric ribs to quasi-static loading: mechanical properties and microstructure.
Traumatic injury is a major cause of death in the child population. Motor vehicle crashes account for a large portion of these deaths, and a considerable effort is put forth by the safety community to identify injury mechanisms and methods of injury prevention. However, construction of biofidelic anthropomorphic test devices and computational models for this purpose requires knowledge of bone properties that is difficult to obtain. The objective of this study is to characterize the relationship between mechanical properties and measures of skeletal development in the growing rib. Anterolateral segments of 44 ribs from 12 pediatric individuals (age range: 5 months to 9 years) were experimentally tested in three-point bending. Univariate mixed models were used to assess the predictive abilities of development-related variables (e.g., age, stature, histomorphometry, cross-sectional geometry) on mechanical variables (material and structural properties). Results show that stature, in addition to age, may be a reliable predictor of bone strength, and that histomorphometry has potential to explain bone properties and to further our understanding of fracture mechanisms. For example, percent secondary lamellar bone (%Sd.Ar) successfully predicts peak force (F P) and Young's modulus (E). Application of these findings is not restricted to injury biomechanics, but can also be referenced in forensic and anthropological contexts.


Risk/benefit evaluation of NSAIDs in postoperative pain therapy.
NSAIDs are effective analgesics with a clear role in the management of postoperative pain. Following major surgery they are part of a balanced approach to analgesia using a combination of different drugs and techniques. Additional clinical benefits include less drowsiness and lack of respiratory side effects. But as they moderately affect bleeding time, their use may not be appropriate following surgery when surgical control of bleeding cannot be guaranteed. These agents should also be administered with caution in elderly patients whom are at risk for renal dysfunction. NSAIDs have specific contraindications that preclude their use for postoperative pain therapy and which should be known by all anesthesiologists.


Cancer mortality in a Texas county with prior uranium mining and milling activities, 1950-2001.
Uranium was discovered in Karnes County, Texas, in 1954 and the first uranium mill began operating in 1961 near Falls City. Uranium milling and surface and in situ mining continued in Karnes County until the early 1990s. Remediation of uranium tailings ponds was completed in the 1990s. There were three mills and over 40 mines operating in Karnes County over these years and potential exposure to the population was from possible environmental releases into the air and ground water. From time to time concerns have been raised in Karnes County about potential increased cancer risk from these uranium mining and milling activities. To evaluate the possibility of increased cancer deaths associated with these uranium operations, a mortality survey was conducted. The numbers and rates of cancer deaths were determined for Karnes County and for comparison for four 'control' counties in the same region with similar age, race, urbanisation and socioeconomic distributions reported in the 1990 US Census. Comparisons were also made with US and Texas general population rates. Following similar methods to those used by the National Cancer Institute, standardised mortality ratios (SMRs) were computed as the ratio of observed numbers of cancers in the study and control counties compared to the expected number derived from general population rates for the United States. Relative risks (RRs) were computed as the ratios of the SMRs for the study and the control counties. Overall, 1223 cancer deaths occurred in the population residing in Karnes County from 1950 to 2001 compared with 1392 expected based on general population rates for the US. There were 3857 cancer deaths in the four control counties during the same 52 year period compared with 4389 expected. There was no difference between the total cancer mortality rates in Karnes County and those in the control counties (RR = 1.0; 95% confidence interval 0.9-1.1). There were no significant increases in Karnes County for any cancer when comparisons were made with either the US population, the State of Texas or the control counties. In particular, deaths due to cancers of the lung, bone, liver and kidney were not more frequent in Karnes County than in the control counties. These are the cancers of a priori interest given that uranium might be expected to concentrate more in these tissues than in others. Further, any radium intake would deposit primarily in the bone and radon progeny primarily in the lung. Deaths from all cancers combined also were not increased in Karnes County and the RRs of cancer mortality in Karnes County before and in the early years of operations (1950-64), shortly after the uranium activities began (1965-79) and in two later time periods (1980-89, 1990-2001) were similar, 1.0, 0.9, 1.1 and 1.0, respectively. No unusual patterns of cancer mortality could be seen in Karnes County over a period of 50 years, suggesting that the uranium mining and milling operations had not increased cancer rates among residents.


The mechanisms of action of lithium. II. Effects on adenylate cyclase activity and beta-adrenergic receptor binding in normal subjects.
As part of a study of the effects of lithium carbonate on neurochemical function in man, platelet and lymphocyte adenylate cyclase activity and lymphocyte beta-adrenergic receptor binding characteristics were determined before and after 2 weeks of lithium treatment in 10 normal volunteers. Lithium had differential effects on platelet and lymphocyte adenylate cyclase activity. In platelets, basal and stimulated (guanyl imidodiphosphate [Gpp[NH]p] or cesium fluoride) adenylate cyclase activity was significantly augmented by lithium treatment. By contrast, in lymphocytes, Gpp(NH)p- and cesium fluoride-stimulated adenylate cyclase activity was unaffected, while basal activity was decreased modestly after lithium. These results are consistent with preclinical studies that suggest that lithium's effects on adenylate cyclase activity are specific with respect to tissue and brain region and that lithium may interfere with guanine nucleotide binding (G) protein function. Lithium treatment significantly increased the ratio of low- to high-affinity dissociation constants for agonist displacement of antagonist binding to lymphocyte beta-adrenergic receptors (thought to reflect coupling between the beta-adrenergic receptor and stimulatory G protein). Lithium had significant effects on measures associated with signal transduction that might be contrasted to its more subtle effects on neuronal function (norepinephrine release) and neuroendocrine systems (responses to serotoninergic challenge) in these same subjects (reported in a companion article). Lithium's primary site of action may be on signal transduction mechanisms. These effects subsequently may be manifested in changes in neurotransmitter function that may be important to lithium's mood-stabilizing actions.


Water and DMSO membrane permeability characteristics of in-vivo- and in-vitro-derived and cultured murine oocytes and embryos.
Although embryo cryopreservation is routine for many mammalian species, it is important to know how the fundamental cryobiology of these cells changes with development. Progressive cleavage divisions result in a reduction in the blastomere surface area available for water and cryoprotectant mass transport. Therefore, the membrane permeability of murine oocytes, zygotes, 2-cell, 4-cell, and 8-cell embryos to water (Lp), and dimethylsulphoxide (PDMSO), and the reflection coefficient, sigma (sigma) were determined. Oocytes or zygotes were recovered, cumulus cells removed, then cultured until use. Oocytes and embryos were immobilized and perfused with treatment solutions at 24 degrees C. Osmotically induced cell volume changes over time were videotaped followed by image analysis. The Lp values in the presence of dimethylsulphoxide (DMSO) were 0.77, 0.81, 0.94, 0.86, and 1.10 microm/min/atm, and the PDMSO values were 1.85, 2.04, 2.41, 1.95, and 1.25x10(-3) cm/min for oocytes, zygotes, 2, 4, and 8-cell embryos respectively. The Lp values in the presence of DMSO were significantly (P < 0.05) higher than those in the absence of DMSO. Treating the whole embryo as a single osmotic entity leads to significantly (P < 0.05) elevated PDMSO estimates relative to those based upon measurements of individual blastomeres. These data indicate that both Lp and PDMSO estimates are lower when predicted on an individual blastomere basis. The data also show that neither Lp nor PDMSO differ among oocytes, zygotes, 2-cell and 4-cell embryos. However, the significantly higher Lp and lower PDMSO of the 8-cell stage support the hypothesis that fundamental cryobiological differences may require developmental stage-specific embryo cryopreservation protocols.


Experimental energy response verification of XR type T radiochromic film.
This short note investigates the energy response characteristics of a relatively new high sensitivity radiochromic film (XR type T) and compares it to other radiochromic and radiographic films and thermoluminescent dosimeters. Results show that the energy response of the new XR type T film is relatively large over the range of therapeutic energies from 50 kVp superficial x-ray treatment to 18 MV high energy radiotherapy treatment. When normalized to 1 at a standard 6 MV radiotherapy x-ray energy the XR type T film produced a normalized dose response of approximately 6 in the energy range of 30 keV to 70 keV thus representing an increase in sensitivity at lower energies similar to that observed for radiographic x-ray films. This is quite different from previous versions of Gafchromic film where the energy response of the film decreases at lower energies down to levels approximately 0.6-0.7 for the same effective energies. This type of film has been optimized for use in diagnostic energy ranges producing a relatively uniform dose response in the 30 keV to 70 keV range.


Solid-state 13C NMR detection of a perturbed 6-s-trans chromophore in bacteriorhodopsin.
Solid-state 13C magic angle sample spinning NMR spectroscopy has been used to study the ionone ring portion of the chromophore of bacteriorhodopsin. Spectra were obtained from fully hydrated samples regenerated with retinals 13C labeled at positions C-5, C-6, C-7, C-8, and C-18 and from lyophilized samples regenerated with retinals labeled at C-9 and C-13. C-15-labeled samples were studied in both lyophilized and hydrated forms. Three independent NMR parameters (the downfield element of the C-5 chemical shift tensor, the C-8 isotropic chemical shift, and the C-18 longitudinal relaxation time) indicate that the chromophore has a 6-s-trans conformation in the protein, in contrast to the 6-s-cis conformation that is energetically favored for retinoids in solution. We also observe an additional 27 ppm downfield shift in the middle element of the C-5 shift tensor, which provides support for the existence of a negatively charged protein residue near C-5. Evidence for a positive charge near C-7, possibly the counterion for the negative charge, is also discussed. On the basis of these results, we present a new model for the retinal binding site, which has important implications for the mechanism of the "opsin shift" observed in bacteriorhodopsin.


Laser-Synthesized Elemental Boron Nanoparticles for Efficient Boron Neutron Capture Therapy.
Boron neutron capture therapy (BNCT) is one of the most appealing radiotherapy modalities, whose localization can be further improved by the employment of boron-containing nanoformulations, but the fabrication of biologically friendly, water-dispersible nanoparticles (NPs) with high boron content and favorable physicochemical characteristics still presents a great challenge. Here, we explore the use of elemental boron (B) NPs (BNPs) fabricated using the methods of pulsed laser ablation in liquids as sensitizers of BNCT. Depending on the conditions of laser-ablative synthesis, the used NPs were amorphous (a-BNPs) or partially crystallized (pc-BNPs) with a mean size of 20 nm or 50 nm, respectively. Both types of BNPs were functionalized with polyethylene glycol polymer to improve colloidal stability and biocompatibility. The NPs did not initiate any toxicity effects up to concentrations of 500 µg/mL, based on the results of MTT and clonogenic assay tests. The cells with BNPs incubated at a 10B concentration of 40 µg/mL were then irradiated with a thermal neutron beam for 30 min. We found that the presence of BNPs led to a radical enhancement in cancer cell death, namely a drop in colony forming capacity of SW-620 cells down to 12.6% and 1.6% for a-BNPs and pc-BNPs, respectively, while the relevant colony-forming capacity for U87 cells dropped down to 17%. The effect of cell irradiation by neutron beam uniquely was negligible under these conditions. Finally, to estimate the dose and regimes of irradiation for future BNCT in vivo tests, we studied the biodistribution of boron under intratumoral administration of BNPs in immunodeficient SCID mice and recorded excellent retention of boron in tumors. The obtained data unambiguously evidenced the effect of a neutron therapy enhancement, which can be attributed to efficient BNP-mediated generation of α-particles.


PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API.
PANTHER (Protein Analysis Through Evolutionary Relationships, http://www.pantherdb.org) is a resource for the evolutionary and functional classification of protein-coding genes from all domains of life. The evolutionary classification is based on a library of over 15,000 phylogenetic trees, and the functional classifications include Gene Ontology terms and pathways. Here, we analyze the current coverage of genes from genomes in different taxonomic groups, so that users can better understand what to expect when analyzing a gene list using PANTHER tools. We also describe extensive improvements to PANTHER made in the past two years. The PANTHER Protein Class ontology has been completely refactored, and 6101 PANTHER families have been manually assigned to a Protein Class, providing a high level classification of protein families and their genes. Users can access the TreeGrafter tool to add their own protein sequences to the reference phylogenetic trees in PANTHER, to infer evolutionary context as well as fine-grained annotations. We have added human enhancer-gene links that associate non-coding regions with the annotated human genes in PANTHER. We have also expanded the available services for programmatic access to PANTHER tools and data via application programming interfaces (APIs). Other improvements include additional plant genomes and an updated PANTHER GO-slim.


Enormous, rapidly growing breast mass.
Signs and symptoms of a rapidly enlarging breast mass are not only important for all clinicians to recognize and assess, but also are not uncommon occurrences. We describe a similar but unique case that developed into an enormous, 36 cm exophytic mass. A 51-year-old woman with history of psychiatric conditions presented for signs and symptoms of sepsis. It was determined that the source was an enormous 36 cm mass originating from the breast/chest wall. After stabilizing the patient with antibiotics, she underwent successful resection. Surgical margins were positive, and histopathology demonstrated bland spindle cells with stromal overgrowth. Together with clinical and histopathological information, the patient was diagnosed with a phyllodes tumor. Differential diagnosis of rapidly growing breast masses is discussed, which are not uncommon occurrences in clinical medicine. One etiology, phyllodes tumors, can grow into large, exophytic masses as described. Oncologic treatment is discussed, usually consisting of surgery with postoperative radiotherapy for high-risk features.


Reaction times can reflect habits rather than computations.
Reaction times (RTs) are assumed to reflect the underlying computations required for making decisions and preparing actions. Recent work, however, has shown that movements can be initiated earlier than typically expressed without affecting performance; hence, the RT may be modulated by factors other than computation time. Consistent with that view, we demonstrated that RTs are influenced by prior experience: when a previously performed task required a specific RT to support task success, this biased the RTs in future tasks. This effect is similar to the use-dependent biases observed for other movement parameters such as speed or direction. Moreover, kinematic analyses revealed that these RT biases could occur without changing the underlying computations used to perform the action. Thus the RT is not solely determined by computational requirements but is an independent parameter that can be habitually set by prior experience.


Molecular mapping of Factor XIIIa-enriched dendrocytes in the skin (Review).
The human dermis contains a series of dendritic cells which express different phenotypes including Factor XIIIa immunoreactivity. This compound is related to a blood coagulation factor participating in angiogenesis, in the final stages of the clotting cascade and in wound healing. In normal skin, Factor XIIIa is expressed in specific dermal dendrocytes (DD) derived from the monocyte/macrophage lineage or from a mesenchymal origin. DD are located predominantly around the microvasculature in the adventitial dermis, at the dermo-epidermal junction, and around skin appendages, but normally not within the epidermis. Increased numbers of Factor XIIIa+ DD are present in a host of specific cutaneous inflammatory and fibrotic conditions. In tumor pathology, immunophenotypic differences are found between dermatofibromas and other fibrohistiocytic entities, most notably dermatofibrosarcoma protuberans. In addition, Factor XIIIa+ DD are likely to be involved in the progression and regression of some malignancies including cutaneous melanoma and basal cell carcinoma.


Developing a facility strategy.
Successful planning for capital investment relies upon the ability of the management team to establish a cogent and comprehensive direction for facility development. The selection of an appropriate strategy integrates multiple issues: mission, service needs of the community, the external environment, the organization's ethos, current physical resources, operational systems, and vision. This paper will identify and discuss key components and data integral to formulating a facility strategy that outlines the basic direction for developing a facility master plan. The process itself will be presented as a working methodology that can be applied to the organization's resources and vision to generate a coherent facility strategy.


Health-related quality of life in children with epilepsy: development and validation of self-report and parent proxy measures.
To answer a need to include and measure accurately the impact and burden of epilepsy as outcomes of interventions with affected children, we developed and validated self-report and parent-proxy respondent health-related quality of life (HRQL) instruments for preadolescent children with epilepsy. We combined qualitative and quantitative research methods. Items were extracted from focus group discussions involving children with epilepsy and their parents. We created scales formatted with alternative paired options of forced responses and used factor analysis to generate relevant subscales and reduce the number of items. We checked internal consistency, assessed test-retest reliability 10-14 days apart, and documented construct validity. A sample of 381 children with epilepsy, age 6-15 years, and their parents independently completed a 67-item questionnaire, from which we chose five items for each subscale. The measures share four subscales, but each measure has an additional distinct subscale. The children and parents could discern differences and report differentially between the various aspects of the HRQL. Internal consistency measured with Cronbach's alpha was acceptable for all subscales; construct validity has been demonstrated from the testing of several hypotheses. Test-retest reliability examined with the intraclass correlation coefficient was satisfactory for the parents and for children age 8 years and older. The correlations between the mothers' and children's responses was poor to moderate. The data demonstrate sound psychometric properties for both related measures, which are easy to administer for children with epilepsy who are 8 years and older and their parents. The subscales encompass HRQL dimensions judged most important by children with epilepsy for the self-report measure and by parents for the proxy response measure. The parent-proxy measure should be useful as a complement to the child self-report measure in evaluating the validity of parental assessment of the child's health status; in longitudinal outcome research; and in HRQL assessment of children who are unable to respond independently.


Mechanical properties of layered poly (ethylene glycol) gels.
Poly(ethylene glycol) (PEG) hydrogels have become a popular material for biomedical applications because of their versatility in use and design. As these gels are readily crosslinked under UV, microfabrication techniques have been investigated to manufacture complex three dimensional structures to better mimic the in vivo environment. This work investigated whether a layering technique to fabricate gels offered sufficient strength between the layers to perform similarly in mechanical testing to unlayered gels. Two mechanical tests were performed: tensile tests and peel tests. The tensile tests, which examined sample gels whose test sections were crosslinked for different durations, demonstrated no statistical differences in elastic modulus between sample and control gels. As expected, a statistical increase in the elastic modulus was found with increased PEG concentration. Comparison of the yield stress between samples and controls illustrated differences with total crosslinking duration, which may be due to the decreased molecular weight of the chains with decreased crosslinking time. In peel tests, no statistical differences of maximum peel force were found between samples and controls. However, an increase in the maximum peel force was found with increasing concentration of PEG. Overall, this study demonstrates that the layering process described for the PEG gels has minimal impact on the tested mechanical properties of the system. As mechanical properties are critical to the design of tissue engineered devices, these results demonstrate that this fabrication method may be appropriate for further study as a scaffold for complex cellular systems.


Combinations of two capsid regions controlling canine host range determine canine transferrin receptor binding by canine and feline parvoviruses.
Feline panleukopenia virus (FPV) and its host range variant, canine parvovirus (CPV), can bind the feline transferrin receptor (TfR), while only CPV binds to the canine TfR. Introducing two CPV-specific changes into FPV (at VP2 residues 93 and 323) endowed that virus with the canine TfR binding property and allowed canine cell infection, although neither change alone altered either property. In CPV the reciprocal changes of VP2 residue 93 or 323 to the FPV sequences individually resulted in modest reductions in infectivity for canine cells. Changing both residues in CPV to the FPV amino acids blocked the canine cell infection, but that virus was still able to bind the canine TfR at low levels. This shows that both CPV-specific changes control canine TfR binding but that binding is not always sufficient to mediate infection.


Clinical outcomes of transoral robotic surgery for supraglottic squamous cell carcinoma: experience of a french evaluation cooperative subgroup of gettec.
Transoral, minimally invasive, organ preservation surgeries are increasingly used to treat laryngopharyngeal carcinomas to avoid the toxicity associated with combined chemoradiotherapy regimens. This study investigated the efficiency, safety, and functional outcomes of using transoral robotic surgery (TORS) to perform supraglottic laryngectomy (SGL). This was a multicenter study using a case series with planned data collection from 2009 to 2012 for patients with supraglottic squamous cell carcinomas (SCC) who underwent SGL using TORS. Eighty-four (84) of 262 patients underwent TORS for supraglottic SCC. Within 24 hours of surgery, 24% of the patients started on an oral diet. The median use of a feeding tube was 8 days for 76% of other patients. Definitive percutaneous gastrostomy feeding was necessary for 9.5% of the patients. 24% of the patients did require a tracheostomy, and the median use was 8 days. One percent (1%) of the patients had a definitive tracheostomy. Aspiration pneumonia was observed in 23% of the patients during the postoperative course, and was responsible for the death of one patient. Postoperative bleeding occurred in 18% of the patients. Based on the pathology results, 51% of the patients received adjuvant radiation therapy. TORS for SGL in intermediate stage SCC is a safe procedure with good functional outcomes and fast recovery times. However, adverse events can occur. Consequently, this technique requires good patient selection criteria to reduce the risk of postoperative complications.