Heparan Sulfate Proteoglycans as Attachment Factor for SARS-CoV-2.
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing an unprecedented global pandemic demanding the urgent development of therapeutic strategies. Microarray binding experiments, using an extensive heparan sulfate (HS) oligosaccharide library, showed that the receptor binding domain (RBD) of the spike of SARS-CoV-2 can bind HS in a length- and sequence-dependent manner. A hexasaccharide composed of IdoA2S-GlcNS6S repeating units was identified as the minimal binding epitope. Surface plasmon resonance showed the SARS-CoV-2 spike protein binds with a much higher affinity to heparin (K D = 55 nM) compared to the RBD (K D = 1 μM) alone. It was also found that heparin does not interfere in angiotensin-converting enzyme 2 (ACE2) binding or proteolytic processing of the spike. However, exogenous administered heparin or a highly sulfated HS oligosaccharide inhibited RBD binding to cells. Furthermore, an enzymatic removal of HS proteoglycan from physiological relevant tissue resulted in a loss of RBD binding. The data support a model in which HS functions as the point of initial attachment allowing the virus to travel through the glycocalyx by low-affinity high-avidity interactions to reach the cell membrane, where it can engage with ACE2 for cell entry. Microarray binding experiments showed that ACE2 and HS can simultaneously engage with the RBD, and it is likely no dissociation between HS and RBD is required for binding to ACE2. The results highlight the potential of using HS oligosaccharides as a starting material for therapeutic agent development.


The accessibility of health services to young deaf adolescents in Ghana.
Quality health care is a fundamental human right, which is enshrined in several international and domestic legislative instruments. In the Ghanaian context, there are reports that adults with disabilities encounter barriers in their attempts to access health care. However, scholarly attention is yet to explore the perspectives of young people and adolescents with disabilities. Therefore, this quantitative study was conducted from the perspective of critical disability studies, where young deaf adolescents (YDAs) were regarded as right bearers, and where they shared their perspectives on health accessibility decisions, barriers, and needs. Sixty-seven participants, made up of 44 male and 23 female students, took part in this quantitative study. Although many YDAs who took part in this study indicated that it was not difficult to access health facilities, they claim to have encountered communication barriers. Sign language interpreters in health facilities and introduction of sign language courses in health training institutions to improve communication between health professionals and deaf patients have been suggested as ways of addressing the barriers faced by YDAs in Ghana.


Mean Arterial Pressure to Central Venous Pressure Ratio: A Novel Marker for Right Ventricular Failure After Left Ventricular Assist Device Placement.
Early right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and often leads to increased morbidity and mortality. It is difficult to predict early RVF on the basis of clinical and hemodynamic parameters. We investigated the utility of mean arterial pressure (MAP) to central venous pressure (CVP) ratio in predicting early RVF. We analyzed a retrospective cohort of 212 consecutive patients who underwent hemodynamic assessment before destination-therapy LVAD implantation. Patients were followed for early RVF and mortality. Receiver operating characteristic (ROC) analysis was used to determine discriminative capacity of MAP/CVP and tested the diagnostic and prognostic value of median MAP/CVP threshold. The ROC analysis demonstrated that pre-LVAD MAP/CVP was associated with an area under the ROC curve of 0.65 (95% confidence interval 0.58-0.73; P < .001). MAP/CVP threshold <7.5 (simple nearest-to-median value) was associated with 70% sensitivity and 56% specificity for early RV failure. Patients with MAP/CVP <7.5 had a higher incidence of post-LVAD RVF than those with a ratio ≥7.5 (44% vs 23%, respectively; P = .001). Right ventricular assist device requirement was higher in the MAP/CVP <7.5 group (11% vs 2%; P = .01). All-cause mortality was higher in the MAP/CVP <7.5 group (annualized mortality 26% vs 16%; log-rank P = .017). MAP-CVP ratio provided incremental prognostic value for RVF and all-cause mortality beyond established Heartmate II and RVF risk scores. Our findings suggest that pre-LVAD MAP/CVP <7.5 is associated with early RVF and increased mortality risk. This novel parameter can be used in risk stratification of LVAD candidates. Prospective validation of our findings is needed.


Aortic and mitral insufficiency complicating fulminant systemic lupus erythematosus.
The cardiac complications of systemic lupus erythematosus (SLE) include a multitude of valvular, myocardial, and pericardial abnormalities resulting from acute and chronic inflammation involving the endocardium, myocardium, and/or pericardium. A case of acute, severe, aortic, and mitral insufficiency occurring as discrete complications of consecutive flares of SLE in the same patient is described with particular emphasis on the clinical and gross pathologic findings. The cardiac complications of SLE, both from a pathologic and clinical standpoint, are reviewed in the context of the uniqueness of this case.


Accreditation: a cultural control strategy.
The purpose of this paper is to describe and understand the effects of the accreditation process on organizational control and quality management practices in two Quebec primary-care health organizations. A multiple-case longitudinal study was conducted taking a mixed qualitative/quantitative approach. An analytical model was developed of the effects of the accreditation process on the type of organizational control exercised and the quality management practices implemented. The data were collected through group interviews, semi-directed interviews of key informers, non-participant observations, a review of the literature, and structured questionnaires distributed to all the employees working in both institutions. The accreditation process has fostered the implementation of consultation mechanisms in self-assessment teams. Improving assessments of client satisfaction was identified as a prime objective but, in terms of the values promoted in organizations, accreditation has little effect on the perceptions of employees not directly involved in the process. As long as not all staff members have integrated the basis for accreditation and its outcomes, the accreditation process appears to remain an external, bureaucratic control instrument. This study provides a theoretical model for understanding organizational changes brought about by accreditation of primary services. Through self-assessment of professional values and standards, accreditation may foster better quality management practices.


Stereo channels with different temporal frequency tunings.
To investigate the spatial and temporal frequency tunings for stereopsis, we measured the contrast sensitivity for depth discrimination with variable spatiotemporal frequencies and disparities using drifting sinusoidal gratings. The results showed that the contrast sensitivity changed with the stimulus disparity and the disparity tuning function varied with the spatial frequency. The disparity in the peak sensitivity decreased proportionally with the spatial frequency (size-disparity correlation). Although the temporal frequency exhibited a limited influence on the peak disparity, the temporal frequency tuning varied with the spatial frequency. The shape of the temporal frequency tuning function was lowpass for higher spatial frequencies, whereas it was bandpass for low spatial frequencies. These results suggest that more than one channel with different temporal as well as spatial frequency tunings contribute to stereopsis.


CONTRASTING PATTERNS OF HERITABLE GEOGRAPHIC VARIATION IN SHELL MORPHOLOGY AND GROWTH POTENTIAL IN THE MARINE GASTROPOD BEMBICIUM VITTATUM: EVIDENCE FROM FIELD EXPERIMENTS.
Similar phenotypes do not always imply similar genotypes. In species distributed over a broad latitudinal range, geographical variation in morphological and life-history traits may reflect very different relations between genotypic and environmental effects on these traits. Patterns of selection among latitudinally separated sites may minimize phenotypic differences in life-history traits but promote phenotypic differences in form. Thus, for example, latitudinal variation in temperature often leads to genetically based metabolic differences that minimize differences in growth rate among populations at different latitudes (countergradient variation). However, variation in habitat experienced by the same populations may promote genetically based differences in shell form (cogradient variation). Few attempts have been made to assess simultaneously such mosaic effects of natural selection on the genetic basis of variation in both morphological and life-history traits among geographically separated populations. I quantified the extent to which widely separated populations of the rocky shore marine gastropod Bembicium vittatum exhibited genetic differences in shell shape, shell pattern, and growth rate. Bembicium vittatum occurs naturally at only three widely separated locations on the Western Australian coast. Individuals were transplanted from all three locations to a latitudinally intermediate site, where they were released in different pairwise combinations and allowed to reproduce. F1 offspring from crosses between same- or different-source parents were identified using allozyme markers. When grown in a common environment, offspring from same-source parents exhibited similar differences in shell shape and pattern, but dramatic differences in growth rates, compared to native populations. Genetic variation therefore exists for all three traits. Growth rates in the common environment were positively correlated with latitude of the source population, confirming the existence of countergradient variation for growth associated with metabolic compensation. In addition, for both shell shape and growth rate, hybrids exhibited phenotypes roughly midway between the same-source parents, suggesting that genetic differences have a large additive component. In contrast, when one parent had pigmented spots, the offspring also had spots, suggesting a strong dominance component to the genetic basis of shell pattern. Genetic differences therefore yield different morphological phenotypes but similar life-history phenotypes, among latitudinally distant populations, and confirm a pattern of mosaic evolution in B. vittatum.


Uncontrolled growth resulting from dedifferentiation in a skin cell proliferation model.
By introducing a small backward dedifferentiation probability of postmitotic cells to progenitor cells in a recently proposed skin cell proliferation model, the homeostasis of the system can be disrupted resulting in uncontrolled growth. It is found that when the dedifferentiation probability exceeds a small critical value, the stable fixed point of the system vanishes leading to unlimited cell growth resembling scenarios in carcinogenesis. Explicit expression for the critical dedifferentiation probability and phase diagram are calculated analytically and the associated nonlinear dynamics is analyzed. In the presence of stochastic fluctuations, our model predicts that the escape rate from homeostatic growth to uncontrolled growth is greatly enhanced by a small but finite dedifferentiation probability. These results are verified by numerical solutions of the dynamical system and chemical Langevin equations.


Endoplasmic reticulum stress and the unfolded protein response regulate genomic cystic fibrosis transmembrane conductance regulator expression.
The unfolded protein response (UPR) is a cellular recovery mechanism activated by endoplasmic reticulum (ER) stress. The UPR is coordinated with the ER-associated degradation (ERAD) to regulate the protein load at the ER. In the present study, we tested how membrane protein biogenesis is regulated through the UPR in epithelia, using the cystic fibrosis transmembrane conductance regulator (CFTR) as a model. Pharmacological methods such as proteasome inhibition and treatment with brefeldin A and tunicamycin were used to induce ER stress and activate the UPR as monitored by increased levels of spliced XBP1 and BiP mRNA. The results indicate that activation of the UPR is followed by a significant decrease in genomic CFTR mRNA levels without significant changes in the mRNA levels of another membrane protein, the transferrin receptor. We also tested whether overexpression of a wild-type CFTR transgene in epithelia expressing endogenous wild-type CFTR activated the UPR. Although CFTR maturation is inefficient in this setting, the UPR was not activated. However, pharmacological induction of ER stress in these cells also led to decreased endogenous CFTR mRNA levels without affecting recombinant CFTR message levels. These results demonstrate that under ER stress conditions, endogenous CFTR biogenesis is regulated by the UPR through alterations in mRNA levels and posttranslationally by ERAD, whereas recombinant CFTR expression is regulated only by ERAD.


Spatiotemporal Tracking of Brain-Tumor-Associated Myeloid Cells in Vivo through Optical Coherence Tomography with Plasmonic Labeling and Speckle Modulation.
By their nature, tumors pose a set of profound challenges to the immune system with respect to cellular recognition and response coordination. Recent research indicates that leukocyte subpopulations, especially tumor-associated macrophages (TAMs), can exert substantial influence on the efficacy of various cancer immunotherapy treatment strategies. To better study and understand the roles of TAMs in determining immunotherapeutic outcomes, significant technical challenges associated with dynamically monitoring single cells of interest in relevant live animal models of solid tumors must be overcome. However, imaging techniques with the requisite combination of spatiotemporal resolution, cell-specific contrast, and sufficient signal-to-noise at increasing depths in tissue are exceedingly limited. Here we describe a method to enable high-resolution, wide-field, longitudinal imaging of TAMs based on speckle-modulating optical coherence tomography (SM-OCT) and spectral scattering from an optimized contrast agent. The approach's improvements to OCT detection sensitivity and noise reduction enabled high-resolution OCT-based observation of individual cells of a specific host lineage in live animals. We found that large gold nanorods (LGNRs) that exhibit a narrow-band, enhanced scattering cross-section can selectively label TAMs and activate microglia in an in vivo orthotopic murine model of glioblastoma multiforme. We demonstrated near real-time tracking of the migration of cells within these myeloid subpopulations. The intrinsic spatiotemporal resolution, imaging depth, and contrast sensitivity reported herein may facilitate detailed studies of the fundamental behaviors of TAMs and other leukocytes at the single-cell level in vivo, including intratumoral distribution heterogeneity and roles in modulating cancer proliferation.


Comparison of tricuspid and mitral annular plane systolic excursion in determination of acute blood loss in healthy volunteers.
Ultrasound is used more and more in determining acute blood loss. This study is to compare tricuspid annular plane systolic excursion (TAPSE) and mitral annular plane systolic excursion (MAPSE) measurement to determine volume loss pre and post blood donation in healthy volunteers. The systolic, diastolic and mean arterial blood pressures and pulses of the donors were measured in the standing and supine position by the attending physician, then, inferior vena cava (IVC), TAPSE and MAPSE measurements were made pre and post blood donation. Statistically significant differences were found in systolic blood pressure and pulse rate values that obtained in the standing position, and in the systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse values that obtained in the supine position (p < 0.05). The difference between IVC expiration (IVCexp) pre and post blood donation was 4.76 ± 2.94 mm, and the difference in IVC inspiration (IVCins) was 2.73 ± 2.91 mm. In addition, the MAPSE and TAPSE differences were 2.16 ± 1.4 mm and 2.98 ± 2.13 mm, respectively. Statistically significant differences were found between IVCins-exp, TAPSE and MAPSE values. TAPSE and MAPSE can be helpful in the early diagnosis of acute blood loss.


Bone sialoprotein enhances migration of bone marrow stromal cells through matrices by bridging MMP-2 to alpha(v)beta3-integrin.
BMSCs migrate through matrix barriers and differentiate into osteoblasts. BSP enhances osteogenic cell migration through basement membrane and collagen matrices in vitro by localizing MMP-2 on the cell surface through alpha(v)beta(3)-integrin. The specific mechanisms by which bone marrow stromal cells (BMSCs) leave their primary sites, move through matrices encountered during homing to their site of final differentiation, and remove preexisting matrices in preparation for bone matrix production are not well understood. The enhanced migration of human osteoblast precursor cells through matrix barriers by bone sialoprotein (BSP) was studied by a modified Boyden-chamber assay. The bridging of normally soluble matrix metalloproteinase 2 (MMP-2) to the cell surface receptor, alpha(v)beta(3)-integrin, by BSP was analyzed by flow cytometry. BSP enhanced the in vitro passage of BMSCs and pre-osteoblasts through matrix barriers (Matrigel and denatured type I collagen) in a dose-dependent manner. An intact ArgGlyAsp (RGD) was required in the BSP for enhanced migration through the barriers but was not sufficient, as shown by the inactivity of two other SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family members, osteopontin and dentin matrix protein-1. The specificity of the BSP enhancement activity was apparently caused by this molecule's ability to bridge MMP-2 to the cell surfaces. Pre-osteoblasts and their BMSC precursors may use MMP-2/BSP/integrin complexes to disrupt matrix barriers during migration to their final destinations in vivo.


The bone shielding versus dual-zone concept in treating thin-walled fresh extraction sockets with immediate implant placement: Soft and hard tissue changes. A randomized clinical trial.
To evaluate the ridge alterations and esthetic outcome 1 year after immediate implant placement using the dual-zone (DZ) technique versus the bone shielding concept in patients with intact thin-walled sockets in the esthetic zone. This randomized clinical trial included 26 patients with nonrestorable maxillary teeth in the esthetic zone who were randomly assigned to two groups (n = 13 each) to receive immediate implants using either the bone shielding concept or DZ. Definitive restorations were delivered after 2 months. Pink esthetic scores (PESs), vertical soft tissue alterations, and bucco-palatal ridge dimensional changes were measured and assessed using intra-oral digital scans at baseline and 1 year post-procedure. Labial bone thickness was measured using cone beam computed tomography scans at baseline and after 1 year. The bone shielding group provided bucco-palatal ridge thickness stability after 1 year (9.43 mm) compared to baseline values (9.82 mm), while DZ showed a significant loss in the bucco-palatal ridge thickness after 1 year (7.83) compared to baseline values (9.49). No significant difference was reported in the baseline bucco-palatal ridge thickness between the two groups (p = 0.6). After 1 year, the bone shielding group demonstrated 0.38 mm ridge shrinkage which was statistically significant (p = 0.0002) compared to 1.67 mm ridge shrinkage in the DZ group. In addition, the average total PES in the bone shielding group was 12.04 versus 10.28 in the DZ group. No significant difference was reported in the mesial papilla length between the DZ and the bone shielding group after 1 year (p > 0.05). However, the midfacial gingival margin (p = 0.026) and distal papilla were significantly higher in the DZ group (p = 0.0025). There was no significant difference in the mean ± SD mm bone gain at the apical level between the two studied groups after 1 year (p = 0.06) showing 0.85 ± 0.23 and 0.64 ± 0.32 mm, respectively. However, the bone shielding concept showed a statistically significant more bone gain mm (p < 0.001) at the (0.56 ± 0.43) and crestal (0.03 ± 0.8) levels after 1 year compared to DZ which revealed 0.18 ± 0.5 and 0.38 ± 0.29 mm bone loss, respectively. The bone shielding concept might offer a reliable alternative for restoring thin-walled sockets by minimizing postextraction ridge dimensional alterations effect following immediate implant placement in the esthetic zone. Nevertheless, the study suffers from confounding bias since there are two systematic differences between the groups, the barrier membrane type, and the level of bone filling. "This clinical trial was not registered prior to participant recruitment and randomization." NCT05381467.


Setting Up a Mental Health Clinic in the Heart of Rural Africa.
The World Health Organization defines health as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (WHO 1948). In Africa, mental health issues often come last on the list of priorities for policy-makers & people's attitudes towards mental illness are strongly influenced by traditional beliefs in supernatural causes/remedies. The massive burden attributed to mental illness in these communities, poses a huge moral, cultural/economic challenge and requires a concerted and integrated approach involving policy makers, mental health Practitioners, the general public, service users and their families and other stake holders to reverse the trend. Improving community awareness of mental illness. Change the negative perception of mental illness by the community. Providing a screening/referral pathway for mental illnesses. Providing supervision of patient care. Promote community participation on issues regarding mental health with a view to challenge existing traditional attitudes and beliefs, reduce stigma and promote health seeking behaviour.


Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance.
The pathogenesis of esophagus carcinoma involves a cascade process consisting of multiple factors and accumulation of gene mutations. It is known that vascular endothelial growth factor (VEGF) mainly regulates de novo vascular formation while B-cell lymphoma-2 (BCL-2) gene exerts a tumor-suppressing effect. The prominent expression of VEGFA and BCL-2 genes, along with the most famous tumor-suppressor gene, TP53, raise the possibly of gene interaction. This study therefore investigated the effect and correlation of TP53, BCL-2, and VEGFA genes on cell proliferation and apoptosis of esophagus carcinoma. A total of 30 male rats were prepared by subcutaneous injection of methyl-benzyl-nitrosamine (MBNA) to induce esophagus cancer, along with 30 controlled rats which received saline instead. After 4, 10, 20, or 30 weeks, rats were sacrificed to observe the morphological changes of esophageal mucosa. Cell apoptosis was quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay. Immunohistochemical (IHC) staining was employed to examine the expression of TP53, BCL-2 and VEGFA genes. With the progression of cancer, pathological damages of esophageal tissue aggravated while the cancer cell apoptosis gradually decreased compared to controlled animals. Protein levels of p53, Bcl-2, and VEGF in the model group were significantly elevated at each time point. Positive correlations existed between p53 and Bcl-2 or VEGF. Abnormally elevated expression of TP53, BCL-2, and VEGFA genes may participate in the proliferation of esophagus cancer cells in a synergistic manner.


Synapse-glia interactions at the vertebrate neuromuscular junction.
Glial cells are widely distributed throughout the nervous system, including at the chemical synapse. However, our knowledge of the role of glial cells at the synapse is rudimentary. Recent studies using a model synapse, the vertebrate neuromuscular junction (NMJ), have demonstrated that perisynaptic Schwann cells (PSCs), which are the glia juxtaposed to the nerve terminal at the NMJ, play active and essential roles in synaptic function, maintenance, and development. PSCs can respond to nerve activity by increasing intracellular calcium and are capable of modulating synaptic function in response to pharmacological manipulations. Studies using PSC ablation in vivo have shown that PSCs are essential for the long-term maintenance of synaptic structure and function at the adult NMJ. In vivo observations have also shown that PSCs guide presynaptic nerve terminal extension and dictate the pattern of innervation during synaptic regeneration and remodeling at adult NMJs. PSCs may also induce postsynaptic acetylcholine receptor aggregation. Furthermore, PSCs play an essential role in synaptic growth and maintenance during development of NMJs in vivo, and Schwann cell-derived factors can promote synaptogenesis and enhance synaptic transmission in tissue culture. These recent findings advance the emerging concept that glial cells help make bigger, stronger, and more stable synapses.


[A clinical analysis of hemophagocytic syndrome in autoimmune diseases].
To analyze the clinical features of patients with hemophagocytic syndrome (HPS) in autoimmune diseases (AID). We collected the data of 11 patients with AID complicated with HPS in Peking Union Medical College Hospital from 2004 to 2009. The underlying diseases, clinical features, laboratory findings and treatment outcomes were retrospectively analyzed. Of the 11 patients, 3 were male, 8 were female. Mean age was (30.7 ± 18.3) years. The underlying diseases included Still disease (n = 4), systemic lupus erythematosus(n = 3), and rheumatoid arthritis, primary Sjögren's syndrome, Wegener granulomatosis and Crohn disease in each one case. HPS was associated with the onset of AID (n = 4), active infection alone (n = 1) and both factors (n = 6). HPS was clinically characterized by high fever (100%), hepatosplenomegaly (72.7%), lymphadenopathy (63.3%) and central nervous system involvement (36.3%). 4 patients presented with disseminated intravascular coagulation (DIC) (36.3%). Laboratory data mainly manifested with cytopenia (100%), liver dysfunction (100%), hypofibrinogenemia (62.5%), hypertriglyceridemia (81.8%), serum ferritin > 500 µg/L (100%), low NK-cell activity (80%) and hemophagocytosis in bone marrow (100%). Based on treating underlying infections and use of corticosteroids and immunosuppressive agents in combination with intravenous immunoglobulins (IVIG) therapy, 5 patients recovered, 6 patients died. The mortality rate was 54.5%. DIC were associated with mortality (r = 0.69, P = 0.019). The episode of HPS always occurs simultaneously with multiple system involvement that was often difficult to distinguish from active AID. The present of DIC on HPS related with poor prognosis and high mortality. Corticosteroids and immunodepressant and IVIG may improve the prognosis of HPS, while anti-infection therapy is very important and necessary for the patients accompany with active infection.


Cell cycle model for growth rate and death rate in continuous suspension hybridoma cultures.
As a result of recent advances in flow cytometry, renewed interest is shown in modeling the kinetic behavior of cells in culture on the basis of cell cycle parameters. An important but often overlooked kinetic variable in hybridoma cultures is the cell death rate. Not only the overall cell growth but also the kinetics of nutrient metabolism and monoclonal antibody production have been shown to depend on the cell death rate in continuous suspension hybridoma cultures. The present study shows that the death rate in hybridoma cultures is proportional to the fraction of cells arrested in the G(1) phase of the cell cycle. The steady-state cell age distributions in the various phases of the division cycle have been calculated analytically. A simple mathematical model has been used to produce the profiles of the cycling and arrested cell fractions with respect to the dilution rate. The calculated steady-state growth rate, death rate, and viability profiles are shown to be in agreement with recently published experimental data from continuous suspension hybridoma cultures.


N-ethylmaleimide-sensitive fusion protein (NSF) is involved in central sensitization in the spinal cord through GluR2 subunit composition switch after inflammation.
Central sensitization, similar to long-term potentiation in the hippocampus, refers to the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord following tissue injury or nerve damage. In the course of inflammation, many proteins including glutamate receptors are assumed to be dynamically reorganized in the postsynaptic density (PSD) and involved in persistent pain. Mechanical hyperalgesia induced by intraplantar injection of complete Freund's adjuvant (CFA) was inhibited at 4 h, but not at 24 h, by indomethacin, an inhibitor of prostanoid synthesis. To elucidate the nature of the molecule(s) involved in the late phase of inflammatory pain, we analysed the PSD fraction prepared from the lumbar spinal cord of rats before and 24 h after CFA injection by conducting two-dimensional differential gel electrophoresis. N-ethylmaleimide-sensitive fusion protein (NSF) was identified as a downregulated protein in the PSD by MALDI-TOF MS and immunoblotting. Concomitant with the decrease in NSF, GluR2 and GluR3 were decreased and GluR1 was conversely increased in the PSD fraction 24 h after CFA injection. In vivo patch-clamp recordings of rats 24 h after CFA injection showed that excitatory postsynaptic currents of dorsal horn neurons evoked by pinch stimuli to inflamed skin were inwardly rectified and inhibited by 60% by philanthotoxin-433, a selective inhibitor of the Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These results suggest that peripheral inflammation gives rise to central sensitization in the spinal cord through subunit composition switch of AMPA receptors in the late phase.


Precueing imminent conflict does not override sequence-dependent interference adaptation.
Interference effects are largely reduced after cognitive conflicts in previous trials. This sequence-dependent interference adaptation is often seen as a consequence of strategic executive control. We sought to investigate whether sequential modulations are comparable with cue-induced strategic adjustments in spatial interference tasks. If so, reliable cues indicating the next compatibility condition should override effects caused by prior events. To this end, cues were introduced in a spatial stimulus-response compatibility task and a Simon task that either indicated the upcoming trial compatibility (rule cues) or the target position, which was not related to the S-R rule (position cues). The proportion of valid cues was either completely or predominantly valid. In both tasks cueing benefits for absolutely reliable rule cues were clearly present. Remarkably, sequential modulations were not influenced by effective rule cueing and vice versa. Even absolutely reliable information about prospective control demands did not cancel out sequence-dependent interference adaptation. In addition, the contingent negative variation-an event-related brain potential in the cue-target interval that is related to response preparation and readiness-showed additive effects of preceding compatibility and cue reliability. The present results indicate that processes underlying sequence-dependent interference adaptation differ from cue-induced strategic processes of cognitive control.


Kinetics of alpha-amylase synthesis from Bacillus amyloliquefaciens.
The microbial production of alpha-amylase from Bacillus amyloliquefaciens was investigated. The microorganism was grown using media containing glucose or maltose at 37 degrees C and under aerobic conditions in a 16-L fermentor. The alpha-amylase synthesis from maltose was not found to be inducible but was found to be subject to catabolite repression. The maltose uptake rate was observed to be the rate-limiting step compared to the conversion rate of maltose to glucose by intracellular alpha-glucosidase. The alpha-amylase activity achieved with maltose as a substrate was higher than that achieved with glucose. A slower growth rate and a higher cell density were obtained with maltose. The enzyme production pattern depended upon the nutrient composition of the medium.


[New approaches for recovery of erectile function in patients after radical prostatectomy].
Prostate cancer (PCa) is one of the most common maligmancies and causes of death among men. Radical prostatectomy (RP) is optimal and recommended treatment modality for localized prostate cancer. More than half of all men undergoing surgery experience problems with erectile function and existing treatments do not provide a positive effect. Thus, there is a need for new approaches to the restoration of erectile function in patients after RP. One of these is the use of cell technologies, namely the stromal-vascular fraction and autologous platelet-rich plasma. This review examines the results of preclinical and clinical studies investigating the efficacy and safety of these treatment options in erectile dysfunction.


Light and electron microscopical changes seen in acute tubular necrosis in renal allografts.
Seven renal biopsy specimens taken from three renal-allografted patients clinically suspected of having acute tubular necrosis were examined by light microscopy and five of these specimens were also examined by electron microscopy. The common findings in these three patients were as follows: The tubular lumina in all parts were dilated and the tubular epithelia were flat. Large vacuoles were occasionally observed within the tubular epithelial cell cytoplasm. These alterations were prominent in proximal convoluted tubules. Electron microscopically, the microvilli of the brush border of proximal convoluted tubules were loose and relatively short. The basal infoldings of proximal convoluted tubules were reduced or had disappeared. It could not be confirmed whether the large intracytoplasmic vacuoles apparent by light microscopic observation were intracytoplasmic or widened lateral intercellular spaces upon electron microscopy. In the most markedly damaged allograft of the three, a grayish hematoxylinophilic substance, which corresponded to autophagosomes with electron-dense round bodies upon electron microscopy, was often observed in the tubular epithelia. In addition, immature or regenerative tubular epithelia were observed. Most of these alterations were similar to those of acute ischemic change seen in non-renal transplantation.


Effects of simulated oilfield produced water on early seedling growth after treatment in a pilot-scale constructed wetland system.
Seed germination and early seedling growth bioassays were used to evaluate phytotoxicity of simulated oilfield produced water (OPW) before and after treatment in a subsurface-flow, pilot-scale constructed wetland treatment system (CWTS). Responses to untreated and treated OPW were compared among seven plant species, including three monocotyledons: corn (Zea mays), millet (Panicum miliaceum), and sorghum (Sorghum bicolor); and four dicotyledons: lettuce (Lactuca sativa), okra (Abelmoschus esculents), watermelon (Citrullus lanatus), and soybean (Glycine max). Phytotoxicity was greater in untreated OPW than in treated OPW. Exposures to untreated and treated OPW enhanced growth in some plant species (sorghum, millet, okra, and corn) relative to a negative control and reduced growth in other plant species (lettuce, soybean, and watermelon). Early seedling growth parameters indicated that dicotyledons were more sensitive to test waters compared to monocotyledons, suggesting that morphological differences between plant species affected phytotoxicity. Results indicated the following sensitivity scale for plant species: lettuce>soybean>watermelon>corn>okra≈millet>sorghum. Phytotoxicity of the treated OPW to lettuce and soybean, although concentrations of COCs were less than irrigation guideline concentrations, suggests that chemical characterization and comparison to guideline concentrations alone may not be sufficient to evaluate water for use in growing crops.


Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.
Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3-P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.


Dynamic properties of unstable motion of swirling premixed flames generated by a change in gravitational orientation.
The dynamic behavior of swirling premixed flames generated by the effect of the gravitational orientation has been experimentally and numerically investigated. When the gravitational direction relative to the flame front is changed, i.e., in inverted gravity (-1G), an unstable flame is formed in a limited domain of equivalence ratio and swirl number. The time history of flame front fluctuation shows that high-energy chaotic motion is superimposed on a periodic oscillation generated by unstable vortex motion in the combustion products. This results in the dynamic motion of the unstable flame becoming deterministically chaotic. This is clearly demonstrated by sophisticated nonlinear time series analysis, which has not been widely applied to the investigation of combustion phenomena.


Effect of dietary ornithine on the brain protein synthesis rate in hypophysectomized aged rats.
The purpose of this study was to determine whether the regulation of brain protein synthesis is mediated through changes in the plasma concentration of growth hormone (GH) when dietary ornithine treatment is manipulated in the hypophysectomized or sham-operated aged rats. Experiments were done on four groups of hypophysectomized and sham-operated (24-wk-old) male rats given 0% or 0.7% ornithine-HCl added to a 20% casein diet. The concentrations of plasma GH and fractional rates of protein synthesis in the brains increased significantly with the 20% casein+0.7% ornithine compared with the 20% casein diet alone in the sham-operated rats. However ornithine supplementation to the basal diet did not affect the rates of protein synthesis in the hypophysectomized rats. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA•d)] significantly correlated with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was also related to the fractional rate of protein synthesis in these organs. The results suggest that the treatment with ornithine is likely to increase the concentration of GH and the rate of brain protein synthesis in the sham-operated rats only, not in the hypophysectomized rats, and that the ornithine-induced increase in the concentration of GH may be primarily responsible for changes in the brain protein synthesis. The RNA activity is at least partly related to the fractional rate of brain protein synthesis.


The value of SCORAD and beyond. Towards a standardized evaluation of severity?
The clinical scoring systems of atopic dermatitis were analysed and compared. Some biological parameters that can correlate with the clinical score were also reviewed. After the definition of the disease based on validated clinical criteria, the second necessity was the availability of reliable severity scores to allow clinicians to verify the course of the disease and the efficacy of treatments. After many proposals, the SCORAD (SCORing Atopic Dermatitis), that required more than three years of work, was the first one that was validated. SCORAD is freely available from an internet site and can be easily calculated using dedicated software. EASI (Eczema Area and Severity Index) score has also been validated but it has been modified twice. Simpler systems include SASSAD (Six Area, Six Sign Atopic Dermatitis) and TIS score (Three-Item Severity score). In parallel, biological parameters were investigated. Eosinophil cationic protein, circulating basophils, major basic protein, soluble E-selectin, antistaphylococcal enterotoxin B, immunoglobulin E titres and macrophage-derived chemokine, can correlate significantly with the clinical score. The clinicians will not benefit directly from laboratory techniques and will employ clinical scores.


Targeting chloride transport in autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited kidney disease. Transepithelial fluid secretion is one of the key factors of cystogenesis in ADPKD. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the secretion of chloride, essentially mediated by the CFTR channel and stimulated by increased intracellular levels of 3',5'-cyclic adenosine monophosphate. This review focuses on the pathophysiology of fluid secretion in ADPKD based on the pioneering studies of Jared Grantham and colleagues, and on the follow-up investigations from the molecular level to the potential applications in ADPKD patients. Altogether, the studies of fluid and chloride transport in ADPKD paved the way for innovative therapeutic targets to prevent cyst volume expansion and thus, kidney disease progression.


Efficacy of an unwaxed dental floss impregnated with 2% chlorhexidine on control of supragingival biofilm: A randomized, clinical trial.
In the present study, we evaluated the antiplaque and antigingivitis efficacy of a dental floss impregnated with 2% chlorhexidine digluconate. Thirty dental students were randomly divided into three groups (n=10): (a) negative control (NC) group, in which no interproximal cleaning was performed; (b) the positive control (PC) group, which used a standard unwaxed dental floss twice daily; and (c) and the test group, which used a unwaxed dental floss impregnated with 2% chlorhexidine twice daily. Six surfaces per tooth were evaluated by the Quigley-Hein plaque index (Turesky modification) at the last appointment (day 15), and testing for the presence of marginal bleeding was performed using the marginal bleeding index (MBI) at both the baseline and last appointments. At day 15, the test group had the lowest mean plaque index (1.04±0.67), showing a statistically-significant difference compared to the NC group (1.40±0.65, P<.001) and PC group (2.30±0.73, P<.001). The PC and test groups showed a mean reduction of 70.2% and 87.26%, respectively, with significant reduction compared to baseline (P<.05) for the MBI. No statistically-significant difference was found between the PC and test groups (P=.126). Unwaxed dental floss impregnated with 2% chlorhexidine showed additional reductions in supragingival interproximal biofilm compared with a conventional unwaxed dental floss, without additional improvement in marginal bleeding.


Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T cells specifically inhibit Ewing sarcoma growth in vitro and in vivo.
The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion.In order to provide off-the-shelf products in the future, we successfully generated HLA-A*02:01-restricted T cell receptor (TCR) transgenic T cells directed against CHM1319 by retroviral transduction.After short-term expansion a 100% purified CHM1319-TCR-transgenic T cell population expressed a CD62L+/CD45RO and CD62L+/CD45RA+ phenotype. These cells displayed specific in vitro IFNg and granzyme B release in co-culture with HLA-A*02:01+ ES cell lines expressing CHM1. When co-injected with ES cells in Rag2-/-É£c-/- mice, CHM1-specific TCR-transgenic T cells significantly inhibited the formation of lung and liver metastases in contrast to control mice. Lungs and livers of representative mice displayed CD8+ T cell infiltration in the presence (control group treated with unspecific T cells) and in the absence (study group) of metastatic disease, respectively. Furthermore, mice receiving unspecific T cells showed signs of graft-versus-host-disease in contrast to all mice, receiving CHM1319-TCR-transgenic T cells.CHM1319 specific TCR-transgenic T cells were successfully generated causing anti-ES responses in vitro and in vivo. In the future, CHM1319-TCR-transgenic T cells may control minimal residual disease rendering donor lymphocyte infusions more efficacious and less toxic.


Coexpressionfinder: a new algorithm for finding groups of coexpressed genes.
A new algorithm is developed which is intended to find groups of genes whose expression values change in a concordant manner in a series of experiments with DNA arrays. This algorithm is named as CoexpressionFinder. It can find more complete and internally coordinated groups of gene expression vectors than hierarchical clustering. Also, it finds more genes having coordinated expression. The algorithm's design allows parallel execution. The algorithm is implemented as a Java application which is freely available at: http://www.bioinformatics.ru/cf/index.jsp and http://bioinformatics.ru/cf/index.jsp.


In Vivo Elasticity Mapping of Posterior Ocular Layers Using Acoustic Radiation Force Optical Coherence Elastography.
We used acoustic radiation force optical coherence elastography (ARF-OCE) to map out the elasticity of retinal layers in healthy and diseased in vivo rabbit models for the first time. A healthy rabbit eye was proptosed and imaged using ARF-OCE, by measuring the tissue deformation after an acoustic force is applied. A diseased retinal inflammation model was used to observe the contrast before and after disease formation. Retinal histologic analysis was performed to identify layers of the retina corresponding with the optical images. The general trend of the retinal layer elasticity is increasing stiffness from the ganglion side to the photoreceptor side, with the stiffest layer being the sclera. In a healthy rabbit model, the mechanical properties varied from 3 to 16 kPa for the five layers that were identified via optical imaging and histology (3.09 ± 0.46, 3.82 ± 0.88, 4.53 ± 0.74, 6.59 ± 2.27, 16.11 ± 5.13 kPa). In the diseased model, we have induced optical damage in a live rabbit and observed a change in the stiffness trend in its retina. High sensitivity elasticity maps can be obtained using the ARF-OCE system to differentiate different retinal layers. Subtle changes in the mechanical properties during the onset of diseases, such as retinal degeneration, can be measured and aid in early clinical diagnosis. This study validates our imaging system for the characterization of retinal elasticity for the detection of retinal diseases in vivo.


Changes and Clinical Value of Serum miR-24 and miR-223 Levels in Patients with Severe Pneumonia.
Severe pneumonia progresses rapidly, so early assessment of the severity and prognosis is crucial for reducing mortality rates. We explore the role of serum microRNA-24 (miR-24) and microRNA-223 (miR-223) in the prognosis of severe pneumonia. There were a total of 96 patients with general pneumonia, 94 patients with severe pneumonia, and 93 healthy people, who were enrolled in this study. The levels of serum miR-24 and miR-223 were detected by real-time fluorescent quantitative PCR in all groups. The serum miR-223 level in the severe group was higher than that in the common group and the control group, and the miR-24 level was lower than that in the common group and the control group (P<0.05). The serum miR-223 levels and APACHEII scores in the death group were higher than those in the survival group on the first, third, and seventh day after admission, while the miR-24 levels were lower than those in the survival group (P<0.05). The proportion of patients with mechanical ventilation in the death group was higher than that in the survival group (P<0.05). The level of serum miR-24 was negatively correlated with APACHEII score and mechanical ventilation in patients who died of severe pneumonia (P<0.05), and miR-223 was positively correlated with APACHEII score and mechanical ventilation (P<0.05). The AUC predicted by serum miR-24, miR-223, and APACHEII scores alone and jointly were 0.867, 0.839, 0.791, and 0.952, respectively. MiR-24 and miR-223 are protective and independent risk factors for mortality in severe pneumonia patients, respectively (P<0.05). MiR-24 was a protective factor affecting the death of patients with severe pneumonia, and miR-223 was an independent risk factor affecting the death of patients with severe pneumonia (P<0.05). The combination of serum miR-24 and miR-223 levels on the first day after admission and APACHEII score can effectively predict prognosis.


Impact of external resistance and maximal effort on force-velocity characteristics of the knee extensors during strengthening exercise: a randomized controlled experiment.
It remains controversial whether maximal effort attained by high external resistance is required to optimize muscle adaptation to strengthening exercise. Here, we compared different training protocols reaching maximal effort with either high-resistance (HImax, 80% of 1-repetition maximum [1RM]) or low-resistance (LOmax, ≤40% 1RM). Thirty-six young volunteers were randomly assigned to 9 weeks of leg extension training at either HImax (1 set of 10-12 repetitions at 80% 1RM), LO (1 set of 10-12 repetitions at 40% 1RM, no maximal effort), or LOmax (1 set of 10-12 repetitions at 40% 1RM, preceded [no rest] by 60 repetitions at 20-25% 1RM). Knee extension 1RM was measured preintervention and postintervention and before the 7th, 13th, and 19th training sessions. Preintervention and postintervention, knee extensor static (PTstat) and dynamic (PTdyn) peak torque, maximal work (MW), and speed of movement at 20% (S20), 40% (S40), and 60% (S60) of PTstat were recorded with a Biodex dynamometer. All the groups showed a significant increase in 1RM, with a greater improvement in HImax from the 13th session on (p < 0.05). The HImax was the only group that significantly increased PTstat (+7.4 ± 8.1%, p = 0.01). The LOmax showed a significantly greater increase in S20 (+6.0 ± 3.2%), PTdyn (+9.8 ± 5.6%), and MW (+15.1 ± 10.6%) than both HImax and LO (p = 0.044 for S20, p = 0.030 for PTdyn, p = 0.025 for MW) and was the only group that increased in S40 (+7.7 ± 9.7%, p = 0.032). In conclusion, significant differences between HImax and LOmax on force-velocity characteristics of the knee extensors were found, although maximal effort was achieved in both training regimens. Thus, LOmax may not be considered as a replacement for HImax but rather as an alternative with different training-specific adaptations.


Uptake, distribution, and oxidation of fatty acids by Leishmania mexicana amastigotes.
Fatty acid uptake, distribution, and beta-oxidation were investigated in Leishmania mexicana amastigotes. The uptake of radiolabeled palmitic, stearic, and oleic acids was similar, reaching 3-6 nmol/10(8) cells in 2 min and 8-12 nmol/10(8) cells in 60 min. The percent of radiolabeled fatty acid that was esterified in the form of triglycerides or phospholipids increased from less than 25% at 2 min to 65-86% at 60 min. The dehydrogenase(s) in an amastigote granule fraction were unusual in that the Vmax for long-chain substrates (0.95-1.6 delta Abs units/min-mg protein) approximated the Vmax for short-chain substrates (0.82-2.0 delta Abs units/min-mg protein), and the Km for long-chain substrates was high (approximately 250 microM), in contrast to data for a mammalian liver mitochondrial fraction. The high Vmax and Km for long-chain substrates suggest a biochemical mechanism for the postulated high utilization of fatty acids as an energy source for amastigotes. Although the primary anti-leishmanial agent, Sb in the form of Pentostam, inhibited oxidation of palmitic acid to CO2 by intact organisms, Sb did not significantly inhibit fatty acid uptake or esterification by organisms, or beta-oxidation by the granule fraction, and the mechanism of action of Sb remains unclear.


CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.
The irreversible loss of cardiomyocytes due to oxidative stress is the main cause of heart dysfunction following ischemia/reperfusion (I/R) injury and ageing-induced cardiomyopathy. Here, we report that CUEDC2, a CUE domain-containing protein, plays a critical role in oxidative stress-induced cardiac injury. Cuedc2(-/-) cardiomyocytes exhibited a greater resistance to oxidative stress-induced cell death. Loss of CUEDC2 enhanced the antioxidant capacity of cardiomyocytes, promoted reactive oxygen species (ROS) scavenging, and subsequently inhibited the redox-dependent activation of signaling pathways. Notably, CUEDC2 promoted E3 ubiquitin ligases tripartite motif-containing 33 (TRIM33)-mediated the antioxidant enzyme, glutathione peroxidase 1 (GPX1) ubiquitination, and proteasome-dependent degradation. Ablation of CUEDC2 upregulated the protein level of GPX1 in the heart significantly. Strikingly, in vivo, the infarct size of Cuedc2(-/-) heart was significantly decreased after I/R injury, and aged Cuedc2(-/-) mice preserved better heart function as the overall ROS levels in their hearts were significantly lower. Our results demonstrated a novel role of CUEDC2 in cardiomyocyte death regulation. Manipulating CUEDC2 level might be an attractive therapeutic strategy for promoting cardiomyocyte survival following oxidative stress-induced cardiac injury.


Oral immunization with attenuated Salmonella vaccine expressing Escherichia coli O157:H7 intimin gamma triggers both systemic and mucosal humoral immunity in mice.
Human infections with EHEC such as O157:H7 have been a great concern for worldwide food-industry surveillance. This pathogen is commonly associated with bloody diarrhea that can evolve to the life-threatening hemolytic uremic syndrome. Animals are the natural reservoir where this pathogen remains asymptomatically, in steps of ingestion and colonization of the bowel. The bacterium is shed in the feces, contaminating the surroundings, including water and food that are directed for human consumption. A major player in this colonization process is intimin, an outer membrane adhesion molecule encoded by the E. coli attachment and effacement (eae) gene that has been shown to be essential for intimate bacterial attachment to eukaryotic host cells. In an attempt to reduce the colonization of animal reservoirs with EHEC O157:H7, we designed a vaccine model to induce an immune response against intimin gamma. The model is based on its recombinant expression in attenuated Salmonella, used as a suitable vaccine vector because of its recognized ability to deliver recombinant antigens and to elicit all forms of immunity: mucosal, systemic, and humoral responses. To test this model, mice were orally immunized with a S. enterica serovar Typhimurium strain carrying the pYA3137eaeA vector, and challenged with E. coli O157:H7. Here we show that immunization induced the production of high levels of specific IgG and IgA antibodies and promoted reduction in the fecal shedding of EHEC after challenge. The live recombinant vaccine reported herein may contribute to the efforts of reducing animal intestinal mucosa colonization.


[The send-off].
It appears that Hesnard never confined his analysand to theoretical constraints that could have been alienating. His deep respect for the Other seems to have allowed each of them to find with him something in addition to the clarifications of personal analysis, a richness which allowed each of them to blossom according to their own interests.


Training-induced changes in muscle CSA, muscle strength, EMG, and rate of force development in elderly subjects after long-term unilateral disuse.
The ability to develop muscle force rapidly may be a very important factor to prevent a fall and to perform other tasks of daily life. However, information is still lacking on the range of training-induced neuromuscular adaptations in elderly humans recovering from a period of disuse. Therefore, the present study examined the effect of three types of training regimes after unilateral prolonged disuse and subsequent hip-replacement surgery on maximal muscle strength, rapid muscle force [rate of force development (RFD)], muscle activation, and muscle size. Thirty-six subjects (60-86 yr) were randomized to a 12-wk rehabilitation program consisting of either 1) strength training (3 times/wk for 12 wk), 2) electrical muscle stimulation (1 h/day for 12 wk), or 3) standard rehabilitation (1 h/day for 12 wk). The nonoperated side did not receive any intervention and thereby served as a within-subject control. Thirty subjects completed the trial. In the strength-training group, significant increases were observed in maximal isometric muscle strength (24%, P < 0.01), contractile RFD (26-45%, P < 0.05), and contractile impulse (27-32%, P < 0.05). No significant changes were seen in the two other training groups or in the nontrained legs of all three groups. Mean electromyogram signal amplitude of vastus lateralis was larger in the strength-training than in the standard-rehabilitation group at 5 and 12 wk (P < 0.05). In contrast to traditional physiotherapy and electrical stimulation, strength training increased muscle mass, maximal isometric strength, RFD, and muscle activation in elderly men and women recovering from long-term muscle disuse and subsequent hip surgery. The improvement in both muscle mass and neural function is likely to have important functional implications for elderly individuals.


Evidence for effective suppression of recombination in the chromosome 17q21 segment spanning RNU2-BRCA1.
Characterization of associations between polymorphic sites located throughout the approximately 200-400-kb variable-length region spanning RNU2-BRCA1 reveals nearly complete linkage disequilibrium. This segment spans the RNU2 array, which includes 6-30 tandem copies of the U2 snRNA gene, and an adjacent region containing NBR1, the LBRCA1 pseudogene, NBR2, and BRCA1 in a tandemly duplicated structure. A series of biallelic polymorphisms define two common haplotypes that do not vary significantly, in structure or frequency, between populations of primarily European (n=275) or Asian (n=34) ancestry. Lower-frequency variants occurring at distantly located sites within this region also show very strong associations. The rarer haplotype classes appear to be distinguished by mutational alteration and are not recombination products of the two major classes. The two major haplotypes also exhibit significantly different allele-length distributions for local simple tandem-repeat markers. The conservation of extensive distinct chromosomal haplotypes during a long period of human population expansion and divergence indicates that selective forces or specific chromosomal mechanisms result in effective recombination suppression. The extreme degree of long-range linkage disequilibrium at this locus may be exceeded only by that reported for the human MHC locus, where allele-specific functional interactions are believed to be significant. These findings have implications for the estimation of the time of origin of BRCA1 mutations having a founder effect, the interpretation of the significance of rare allelic variants, and the study of the origins of modern populations.


Enzyme activities and protein concentrations in serum of patients with hepatosplenic schistosomiasis.
The hepatosplenic form of Schistosoma mansoni infection contributes considerably to morbidity and mortality in endemic areas. The present study investigated serum protein concentrations and serum enzyme activities of 58 Sudanese patients with hepatosplenic schistosomiasis. All of them had a history of infection with S. mansoni and one or several episodes of oesophageal bleeding due to portal hypertension. Diagnosis was based on clinical (n = 24), ultrasonographical (n = 18) and histological (n = 16) grounds. The control group consisted of 40 Sudanese healthy blood donors. Serum albumin was found to be significantly lower in patients with hepatosplenic schistosomiasis (median = 37 g/l) than in controls (median = 47 g/l). Serum enzyme analysis revealed only minimal alterations of cellular enzyme activities, but a marked decrease of cholinesterase activity. Serum albumin concentration correlated significantly with cholinesterase activity. We conclude that liver function in patients with schistosomiasis and portal hypertension is partially disturbed. Low serum albumin and low cholinesterase activity reflected an impaired protein synthesis of the liver. Destruction of parenchymal liver cells was mild or absent.


Circulating immunoblasts in polymyalgia rheumatica.
The percentage of immunoblasts circulating in the peripheral blood has been examined in a group of 29 patients with polymyalgia rheumatica (PMR). Less than 0.5% of immunoblasts were found in healthy young controls, but 18 of 29 unselected patients with PMR were positive when first tested, a similar proportion to that found in rheumatoid arthritis. Raised immunoblasts were found in only one of 12 elderly controls. The presence of circulating immunoblasts correlated with the activity of polymyalgia both as assessed by the erythrocyte sedimentation rate (ESR) and as assessed by an independent clinical observer. This was true in the group overall and in those patients where serial studies were made. Patients studied from the time of disease presentation showed a concurrent fall in ESR and in immunoblasts on starting steroid therapy. Detection of circulating immunoblasts can be a useful additional test in the assessment of disease activity in PMR, especially in cases with a low ESR. The presence of circulating immunoblasts supports the concept of an immunological aetiology for PMR. This is strengthened by the finding that raised immunoglobulins were more common in patients with circulating immunoblasts.


Decision-Making Analytics Using Plural Resilience Parameters for Adaptive Management of Complex Systems.
It is critical for complex systems to effectively recover, adapt, and reorganize after system disruptions. Common approaches for evaluating system resilience typically study single measures of performance at one time, such as with a single resilience curve. However, multiple measures of performance are needed for complex systems that involve many components, functions, and noncommensurate valuations of performance. Hence, this article presents a framework for: (1) modeling resilience for complex systems with competing measures of performance, and (2) modeling decision making for investing in these systems using multiple stakeholder perspectives and multicriteria decision analysis. This resilience framework, which is described and demonstrated in this article via a real-world case study, will be of interest to managers of complex systems, such as supply chains and large-scale infrastructure networks.


Estimation of body weight using anthropometric parameters in Sri Lankan hospitalized adult patients.
Body weight is an important clinical parameter for accurate dosing of drugs with a narrow therapeutic window, However, it is difficult to measure the body weight of a patient if they cannot stand on a scale. There are several anthropometrics-based equations to estimate the body weight, but most of these are derived from white Caucasian populations and are not validated for South Asians. This study aimed to validate existing anthropometrics-based weight estimation equations and develop a new equation for the same purpose for Sri Lankan adults. This prospective study was conducted at the National Hospital of Sri Lanka over a 6-month period, split into a development and a validation phase. During the development phase, estimated body weight of patients by doctors and nurses and patients themselves were noted and compared against their actual body weight. In addition, 13 anthropometric measurements were taken, which were used to validate 12 anthropometrics-based equations to estimate body weight described in literature previously. Two new gender specific regression models to estimate the body weight in the local population was also derived and validated. A total of 502 (males = 249) and 217 (males = 108) patients were recruited for the development and validation phases respectively. Both doctors and patients had comparable accuracy in predicting body weight (p>0.05). All anthropometric based equations were significantly correlated with actual body weight (correlation coefficients: 0.741-0.869), and the new equations derived from the local data performed similarly to the best performing equation identified from the literature during validation phase. However, even the best of these equations could not outperform patient/physician estimates. When the patient weight cannot be measured, an estimate by the patient or the doctor may be the best substitute.


STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells.
The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34(pos) cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34(pos) cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFbeta with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34(pos) cells.


Amniotic Fluid Angiogenic and Inflammatory Factor Profiling in Foetal Down Syndrome.
Angiogenic factors are proteins that can potentially be related to certain foetal chromosomal abnormalities. The goal of this study was to determine the concentrations of 60 angiogenic factors in the amniotic fluid of women carrying foetuses with Down syndrome (DS). After analysis of the karyotyping results, for the purpose of this study, we chose 12 women with foetal DS. For the control group, we selected 12 healthy patients with uncomplicated pregnancies (15-18 weeks of gestation) who delivered healthy newborns at term. To assess the concentrations of proteins in the amniotic fluid, we used a protein macroarray, which enabled the simultaneous determination of 60 angiogenic factors per sample. In the amniotic fluid of women with foetal DS compared to patients with healthy foetuses, we reported significant decreases in the concentrations of 14 angiogenic factors, including leptin, angiopoietin 1 (ANG-1), angiostatin, epidermal growth factor (EGF), interleukin 1-beta (IL-1b), interleukin 4 (IL-4), interleukin 12p40 (IL-12p40), monocyte chemotactic protein 2 (MCP-2), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP-9), platelet endothelial cell adhesion molecule 1 (PECAM-1), transforming growth factor alpha (TGF alpha), vascular endothelial growth factor 2 (VEGFR2), and vascular endothelial growth factor 3 (VEGFR3). Based on our findings, we hypothesise that angiogenic factors may play roles in the pathogenesis of DS. Defining the factors' potential as biochemical factors of DS requires further investigation in a larger group of patients.


[The value of hepatic arterial infusion chemotherapy for liver metastases--discussion from viewpoints of prevention of hepatic death and QOL].
The value of hepatic arterial infusion chemotherapy for liver metastases was discussed from the viewpoints of the prevention of hepatic death and the negative effect on QOL, based on the results of repeated hepatic arterial infusion chemotherapy for 128 patients with unresectable liver metastases employing implantable catheter and port system. In 70% of patients, hepatic death due to metastases was prevented by this therapy, and the negative effect on QOL by this therapy was limited. Thus, in spite of the limited effects on the prolongation of survival compared with systemic chemotherapy, there is a reasonable basis for the use of hepatic arterial infusion chemotherapy as a treatment for unresectable liver metastases.


Long-range ordered structures in diblock copolymer melts induced by combined external fields.
The structure of diblock copolymer melts under a single external electric or shear field, as well as under combined orthogonal external fields was investigated using a cell dynamic system. The phase structure was determined by coupling the effects of the external fields with the original structure of the bulk free of external fields. The single electric or shear field generated long-range cylinders in asymmetric A4mB6m diblock copolymers and distorted lamellae in symmetric A5mB5m diblock copolymers. Successive orthogonal shear followed by an electric external field generated long-range lamellae in symmetrical A5mB5m systems. However, the simultaneous orthogonal electric and shear fields could more easily form long-range lamellae than the sequential orthogonal fields. The dynamical processes in diblock copolymer melts under orthogonal fields have been also examined.


Comparing clinical effectiveness and drug toxicity with hydrochlorothiazide and chlorthalidone using two potency ratios in a managed care population.
This study compared the clinical effectiveness and drug toxicity of chlorthalidone and hydrochlorothiazide. Electronic health records and claims data were used to identify patients initially prescribed chlorthalidone or hydrochlorothiazide. A total of 214 patients prescribed chlorthalidone 25 mg were matched with 428 patients prescribed hydrochlorothiazide 25 mg (1:1 potency ratio) and 214 patients prescribed hydrochlorothiazide 50 mg (1:2 potency ratio). Mean systolic blood pressure/diastolic blood pressure values at least 30 days after initial prescription were lower with chlorthalidone (132.2/74 mm Hg) compared with hydrochlorothiazide 25 mg (137.0/77.5 mm Hg) and hydrochlorothiazide 50 mg (138.6/78.5 mm Hg) (P<.05 for all comparisons). Goal systolic blood pressure/diastolic blood pressure values were achieved in a higher percentage of patients prescribed chlorthalidone (45.0%/78.3%) than with either hydrochlorothiazide 25 mg (32.1%/63.9%) or hydrochlorothiazide 50 mg (32.8%/68.9%) (P<.05 for all comparisons). Mean serum potassium was 3.94 mEq/L with chlorthalidone 25 mg, 4.13 mEq/L with hydrochlorothiazide 25 mg (P<.01 vs chlorthalidone), and 3.96 mEq/L with hydrochlorothiazide 50 mg. These findings indicate that chlorthalidone 25 mg is associated with a better antihypertensive response than hydrochlorothiazide 25 mg or 50 mg, without clinically significant differences in serum potassium.


Infection and arthritis.
Reactive arthritis is caused by an infection, and components of the triggering agent can be demonstrated at the site of inflammation. This fact has opened new views in studies regarding other rheumatic diseases, such as rheumatoid arthritis and ankylosing spondylitis. The possible role of infectious agents in their etiology and pathogenesis is being re-evaluated.


Scenario-based dialogue system based on pause detection toward daily health monitoring.
We have conducted research on building a robot dialogue system to support the independent living of older adults. In order to provide appropriate support for them, it is necessary to obtain as much information, particularly related to their health condition, as possible. As the first step, we have examined a method to allow dialogue to continue for longer periods. A scenario-based dialogue system utilizing pause detection for turn-taking was built. The practicality of adjusting the system based on the dialogue rhythm of each individual was studied. The system was evaluated through user studies with a total of 20 users, 10 of whom were older adults. The system detected pauses in the user's speech using the sound level of their voice, and predicted the duration and number of pauses based on past dialogue data. Thus, the system initiated the robot's voice-call after the user's predicted speech. Multiple turns of dialogue between robot and older adults are found possible under the system, despite several overlaps of robot's and users' speech observed. The users responded to the robot, including the questions related to health conditions. The feasibility of a scenario-based dialogue system was suggested; however, improvements are required.


Compassion in psychotherapy: the perspective of therapists nominated as compassionate.
Fourteen therapists nominated by peers as compassionate defined compassion in psychotherapy as connecting with the client's suffering and promoting change through action. They indicated that compassion was broader and deeper than empathy, helps clients feel understood, and relieves symptoms. Although indicating that compassion was innate, therapists felt it could be further awakened. Factors facilitating compassion in therapy were therapists feeling clients' suffering, understanding client dynamics, identifying with and liking clients, client involvement, and a good therapy relationship. Hindering factors included clients being resistant, being aggressive, having serious pathology, or violating boundaries; therapists having interfering personal issues, feeling incompetent, or having negative reactions to or not liking clients; and a poor therapy relationship. A theory regarding compassion in psychotherapy is proposed.


Approach to Patients with Malignant Melanoma of Unknown Primary Origin.
Although malignant melanoma accounts for 3% of skin cancers, it is responsible for 75% of deaths associated with skin cancer. In our study, all melanoma cases diagnosed and treated at our clinic were retrospectively reviewed, and the cases of unknown primary origin among them were examined in detail in terms of diagnosis and treatment. The patients with malignant melanoma treated at the inpatient services of our clinic between January 1991 and April 2017 were retrospectively screened in the records. These patients were evaluated for age, sex, tumor type, Breslow depth, metastasis, and treatment. Among these patients, four cases of unknown primary origin were examined in detail. During January 1991 and April 2017, 173 patients received inpatient care for malignant melanoma at our clinic. As regards to the melanoma subtypes, nodular type in 45 patients, acral lentiginous type in 43 patients, superficial spreading type in 63 patients, lentigo maligna melanoma in 15 patients, subungual type in 7 patients, and either unidentified melanoma or other subtypes in 10 patients were identified. The ideal treatment of a patient with melanoma is multidisciplinary, with plastic surgery having a central role.


Paclitaxel and Mortality Following Peripheral Angioplasty: An Adjusted and Case Matched Multicentre Analysis.
Paclitaxel based drug coated balloons (DCBs) and drug eluting stents (DESs) may be associated with increased mortality in patients with peripheral arterial occlusive disease (PAOD), based on a recent meta-analysis. This study, however, had a number of limitations, which have been discussed at great length among the vascular community. The aim of this research was to assess the association between paclitaxel based endovascular treatment (PTX) in the femoropopliteal (F-P) segment and mortality, adjusting for relevant risk factors and including patients with chronic limb threatening ischaemia (CLTI). This was a retrospective cohort study of a prospectively maintained multicentre (three sites) database of patients with claudication or CLTI. Patients having F-P angioplasty between 1 January 2014 and 30 May 2019 with or without PTX were included. Survival was compared in Cox regression analyses adjusted for parameters of the Charlson comorbidity index. A separate nested case matched (based on each individual's Charlson index) analysis was performed to compare mortality rates between those who received PTX and those who did not. A total of 2 071 patients were analysed: 966 patients (46.6%) were treated with PTX (952 [46%] had CLTI and 1 119 [54%] severe claudication [Rutherford stage 3]). Over a 24 month median follow up, 456 (22.1%) patients died. Using multivariable Cox regression, PTX was not associated with mortality (HR 0.94, p = .46), even when assessed separately for those with intermittent claudication (HR 1.30, p = .15) or CLTI (HR 0.81, p = .060). In the case matched analysis (885 matched pairs of patients), PTX was not associated with mortality (HR 0.89, p = .17). Paclitaxel dose and use of a DCB or DES were not associated with mortality in any subanalysis. When relevant risk factors were taken into account, there were no associations between PTX and mid term mortality in patients with PAOD.


[The decision to abort: the process and feelings involved].
In Brazil, induced abortion is considered a crime in the majority of cases, the result being that there is little official data on the subject. Little is known about the conditions under which abortions are induced This research was designed to shed light on the characteristics of the women who had had an abortion and to study the reasons why and conditions under which it occurred. The sample consisted of all employees (7,359) and students (2,231) in a university program in S o Paulo who were mailed a self-administered survey. Accompanying the questionnaire was a letter and self-addressed stamped envelope. 27% of the employees and 42% of the students returned the questionnaires. Of these, 1,314 employees and 138 students had had at least one pregnancy. The results presented in this study show that 465 of the employees and students ar some point had thought of having an abortion. They were divided into two groups: those who had had an abortion and those who had nos. The objective was to analyze the association of some characteristics of the women with their decision to have/not have an abortion and how they felt when faced with this decision. The proportion of women who had had an abortion was significantly lower among married women than singles. A larger percentage of women who had talked with a friend and/or husband/partner/boyfriend had decided to have an abortion than those who had talked to a parent or had not talked to anyone. More women who said they were not prepared to raise/educate a child had had an abortion as compared to those giving other reasons. Almost half of the women undergoing an abortion said that they felt bad emotionally and physically afterwards. Among those who had not had an abortion, almost two-fifths reported that they felt good, were happy, relieved, and did not regret their decision. The conclusion drawn from the population studied was that emotional and social factors played a significant role in the decision-making process for women considering an abortion.


Beyond blood pressure control. Effect of antihypertensive therapy on quality of life.
Although the value of treating all degrees of hypertension has been clearly established, a substantial percentage of patients fail to comply with drug therapy and thus do not receive the long-term benefits of blood pressure reduction. Antihypertensive drugs can have a negative impact on the patient's overall quality of life, as judged by their physical state, emotional well-being, cognitive acuity, and sexual and social functioning. These effects can be quite troubling to patients with a seemingly symptomless disease. In order to examine more closely the effects of different antihypertensive agents on quality of life, a double-blind, multicenter trial was conducted in which male patients were assigned to treatment with either methyldopa, propranolol or captopril for six months. Hydrochlorothiazide was added to the primary drug in patients whose blood pressure was not adequately controlled after eight weeks. Quality of life was evaluated using a battery of validated psychological assessment scales and indexes. Captopril was favored over methyldopa and propranolol on a number of the quality of life measures, including general well-being, physical symptoms, and sexual dysfunction. Addition of a diuretic negatively affected quality of life in all three primary drug groups, but captopril was still favored over the other primary drugs even when the effect of the diuretic was considered. The study demonstrated that quality of life is relevant and assessable and can be influenced by the choice of drug therapy. Greater attention by physicians to quality of life issues can hopefully improve patient compliance and extend the benefits of long-term antihypertensive therapy to more patients.


A validation and reduced form of the Female Condom Attitudes Scale.
The Female Condom Attitudes Scale is an instrument comprising five correlated factors derived from 15 Likert-scale survey items that measure women's attitudes toward the female condom. This scale originated from the 30-item scale of Choi, Gregorich, Anderson, Grinstead, and Gómez (2001; manuscript under review). Exploratory factor analysis of this scale extracted eight correlated factors. Reliability coefficients and confirmatory factor analyses refined the instrument by reducing the number of factors to five and halving the number of items. The reduced form of the Female Condom Attitudes Scale demonstrated both construct and convergent validity by predicting self-reported female condom use behavior. It also correlated with self-efficacy to use male condoms, sexual comfort, and attitudes toward the male condom. The five factors remaining in the final survey instrument were Sexual Pleasure Enhancement, Inconvenience, Improved Prophylaxis, Sexual Pleasure Inhibition, and Insertion Reluctance. Implications of these findings for basic and applied intervention research are discussed.


Unraveling the stability of cyclobutadiene complexes using aromaticity markers.
Cyclobutadiene (CBD) is the paradigmatic antiaromatic molecule but is known to form highly stable aromatic complexes, e.g. CBD-Fe(CO)3. This intriguing reversal of aromaticity from antiaromatic to aromatic terrain during the complexation process cannot be appropriately handled with single-reference-based theoretical techniques. We explore this aromaticity reversal, for the first time, by a detailed aromaticity analysis using magnetically induced current densities (MICD) and nucleus independent chemical shifts (NICS) using genuine ab initio multi-reference wavefunction-based theory. We trace the dramatic change of aromaticity for a prototypical cyclobutadiene complex, CBD-CH+ (CH+Fe(CO)3), considering a 3D potential energy surface for two independent parameters, namely the approach of CH+ and the automerization cross-section of cyclobutadiene. The 3D potential energy surfaces indicate the presence of a conical intersection/avoided crossing between the ground and the first excited state. The plot of aromaticity indices and the corresponding numerical values show that the change of aromaticity indices is drastic around the conical intersection/avoided crossing and automerization of cyclobutadiene plays a crucial role in the formation of cyclobutadiene complexes. Computations on analogous CBD-Be and CBD-CO systems (Be/COFe(CO)3) emphasize the generality of the conclusions drawn from the CBD-CH+ system.


[A Case of Primary Intracranial Epithelioid Hemangioendothelioma].
Epithelioid hemangioendotheliomas(EHEs)most commonly occur in the liver, lung, bone, and soft tissues, but rarely in the brain. Here, we describe a case of primary intracranial epithelioid hemangioendothelioma manifested by an epileptic attack. A 53-year-old woman with no previous convulsive history presented at our hospital after experiencing a seizure. Magnetic resonance imaging revealed a mass in her right frontal lobe, with edema, which was well enhanced with gadolinium. Systemic computed tomography, on the other hand, did not show any tumor involvement in other organs. The patient underwent surgery, and a complete resection of the intracranial tumor was successfully performed. The histological diagnosis was an EHE. There was no evidence of tumor recurrence either in the brain or other organs at 3 years and 7 months after surgery. Because of its rarity, the exact prognosis of patients with an intracranial EHE has not been clearly established. Moreover, tumor recurrence following complete resection has been reported and thus regular follow-up examinations are considered necessary.


Environmentally persistent free radical-containing particulate matter competitively inhibits metabolism by cytochrome P450 1A2.
Combustion processes generate different types of particulate matter (PM) that can have deleterious effects on the pulmonary and cardiovascular systems. Environmentally persistent free radicals (EPFRs) represent a type of particulate matter that is generated after combustion of environmental wastes in the presence of redox-active metals and aromatic hydrocarbons. Cytochromes P450 (P450/CYP) are membrane-bound enzymes that are essential for the phase I metabolism of most lipophilic xenobiotics. The EPFR formed by chemisorption of 2-monochlorophenol to silica containing 5% copper oxide (MCP230) has been shown to generally inhibit the activities of different forms of P450s without affecting those of cytochrome P450 reductase and heme oxygenase-1. The mechanism of inhibition of rat liver microsomal CYP2D2 and purified rabbit CYP2B4 by MCP230 has been shown previously to be noncompetitive with respect to substrate. In this study, MCP230 was shown to competitively inhibit metabolism of 7-benzyl-4-trifluoromethylcoumarin and 7-ethoxyresorufin by the purified, reconstituted rabbit CYP1A2. MCP230 is at least 5- and 50-fold more potent as an inhibitor of CYP1A2 than silica containing 5% copper oxide and silica, respectively. Thus, even though PM generally inhibit multiple forms of P450, PM interacts differently with the forms of P450 resulting in different mechanisms of inhibition. P450s function as oligomeric complexes within the membrane. We also determined the mechanism by which PM inhibited metabolism by the mixed CYP1A2-CYP2B4 complex and found that the mechanism was purely competitive suggesting that the CYP2B4 is dramatically inhibited when bound to CYP1A2.


Oncocytic pleomorphic adenoma of the parotid gland.
A rare case of salivary gland pleomorphic adenoma, in which the majority of cells were oncocytic, is reported. The patient, a 53-year-old man, presented with a parotid gland mass that was otherwise asymptomatic. Surgical treatment consisted of a superficial parotid lobectomy. The specimen was prepared in standard fashion and studied by light and electron microscopy. The microscopic features were characteristic of salivary gland pleomorphic adenomas, however, both epithelial and "mesenchymal" elements were oncocytic. Such changes may occur focally in pleomorphic adenomas, but we were unable to find documentation of a wholly oncocytic variant in a review of the medical literature. From our clinical data and previous reports of pleomorphic adenomas with focal oncocytosis, it is concluded that such changes likely do not alter prognosis in affected patients. The possible significance of this lesion in regard to the histogenesis of salivary gland pleomorphic adenomas is discussed.


Prevalence of EGFR Mutations and Clinico-Pathological Characteristics of Chilean Lung Cancer Patients
Background: Lung cancer (LC) is the second leading cause of cancer death in Chile, causing >3,000 deaths every year. Epidemiological LC data in Chile is scarce and scattered. Here, we aimed to quantify the prevalence of Epidermal Growth Factor Receptor (EGFR) gene mutations in a Chilean cancer center. These data may identify individuals that could benefit from targeted therapies such as Tyrosine Kinase Inhibitors (TKIs). Methods: A total of 1,405 Biopsies from 1,381 LC patients were retrospectively analyzed retrieving clinical data from EGFR mutants including age, gender, histological type, smoking habits and type of EGFR mutation. We also analyzed overall survival (OS) rates. Results: From all patients 21.7% had clinically relevant EGFR mutations, and a median age at diagnosis of 65 years. Most were female (64%), classified as adenocarcinomas (94.5%), and non-smokers/light smokers (93.1%). The most prevalent mutation was exon-19 deletions (50.6%) followed by Leucine-to Arginine 858; OS was 15 months. Clinical follow-up information was available for 83 patients. The use of TKIs in these patients significantly improved OS. Conclusion: The prevalence of EGFR mutations in the studied population was 21.7%, comparable to other countries in Latin America. The most frequent EGFR mutation was exon-19 deletion, OS in this group was 15 months, and TKIs significantly improved OS.


Dopamine-Dependent Plasticity Is Heterogeneously Expressed by Presynaptic Calcium Activity across Individual Boutons of the Drosophila Mushroom Body.
The Drosophila mushroom body (MB) is an important model system for studying the synaptic mechanisms of associative learning. In this system, coincidence of odor-evoked calcium influx and dopaminergic input in the presynaptic terminals of Kenyon cells (KCs), the principal neurons of the MB, triggers long-term depression (LTD), which plays a critical role in olfactory learning. However, it is controversial whether such synaptic plasticity is accompanied by a corresponding decrease in odor-evoked calcium activity in the KC presynaptic terminals. Here, we address this question by inducing LTD by pairing odor presentation with optogenetic activation of dopaminergic neurons (DANs). This allows us to rigorously compare the changes at the presynaptic and postsynaptic sites in the same conditions. By imaging presynaptic acetylcholine release in the condition where LTD is reliably observed in the postsynaptic calcium signals, we show that neurotransmitter release from KCs is depressed selectively in the MB compartments innervated by activated DANs, demonstrating the presynaptic nature of LTD. However, total odor-evoked calcium activity of the KC axon bundles does not show concurrent depression. We further conduct calcium imaging in individual presynaptic boutons and uncover the highly heterogeneous nature of calcium plasticity. Namely, only a subset of boutons, which are strongly activated by associated odors, undergo calcium activity depression, while weakly responding boutons show potentiation. Thus, our results suggest an unexpected nonlinear relationship between presynaptic calcium influx and the results of plasticity, challenging the simple view of cooperative actions of presynaptic calcium and dopaminergic input.


Feasibility of blind aortic catheter placement in the prehospital environment to guide resuscitation in cardiac arrest.
Aortic catheter-based resuscitation therapies are emerging with laboratory investigations showing benefit in models of trauma-related noncompressible torso hemorrhage and nontraumatic cardiac arrest. For these investigational aortic catheter-based therapies to reach their greatest potential clinical benefit, the ability to initiate them in the prehospital setting will be important. Feasibility of prehospital aortic catheterization without imaging capability supports this potential and is described in this report. A physician prehospital response system was created in cooperation with the local emergency medical services system to provide invasive hemodynamic monitoring during cardiac arrest. Physicians were dispatched to all known or suspected prehospital cardiac arrests covered by the emergency medical services system. Physicians responded with a specialized vascular catheterization pack and a monitor with invasive pressure monitoring capability. The physicians performed blind thoracic aortic and central venous catheterizations in cardiac arrest patients in the prehospital setting to measure coronary perfusion pressure, to optimize closed-chest cardiopulmonary resuscitation technique, and to administer intra-aortic epinephrine. During a 2-year period, 22 medical cardiac arrest patients underwent prehospital invasive hemodynamic monitoring to guide resuscitation. Most patients had both aortic and central venous catheters inserted. The combination of intra-aortic epinephrine and adjustments in closed-chest cardiopulmonary resuscitation technique resulted in improved coronary perfusion pressure. Return of spontaneous circulation with survival to hospital admission was achieved in 50% (11 of 22) of these patients. This report demonstrates the feasibility of successful blind aortic and central venous catheterizations in the prehospital environment and supports the potential feasibility of other emerging aortic catheter-based resuscitation therapies.


Low-Grade Central Osteosarcoma: Report of Two Unusual Morphologic Variants.
Low-grade central osteosarcoma (LGCO) is a rare subtype of osteosarcoma, constituting < 2% of all osteosarcomas. If not treated appropriately, the tumor can recur with higher-grade disease. We report two cases of low-grade central osteosarcoma with unusual morphologic features and belonging to different age groups. Both presented with pain and swelling in the lower end of femur. Radiologically, both the lesions revealed a large mass with irregular borders and soft tissue invasion. One patient underwent above-knee amputation and wide local excision of tumor was done in the other patient. Histologically, both the tumors showed spindle cell proliferation displaying mild atypia. In synopsis with radiology, diagnosis of low-grade central osteosarcoma was made in both cases. These cases highlight the varied morphological spectrum of low-grade central osteosarcoma and underscore the diagnostic difficulties faced. Recognition of the variants of low-grade central osteosarcoma is based on aggressive radiological appearance and on adequate tumor sampling for histologic examination.