Quantitative evaluation of alpha- and beta-adrenoceptor modulation of [3H]choline release in guinea pig superior cervical ganglia.
[3H] Overflow evoked by 5 min supramaximal preganglionic stimulation at 1 pps has been studied in isolated guinea pig superior cervical ganglion preparations preincubated with [3H]choline. At 15 microM norepinephrine (NE) reduced both the [3H]choline overflow and endogenous acetylcholine release by 59.4 and 54.1% respectively; the dose-response curve for NE inhibitory action is described. Evidence is given that endogenous catecholamines effectively reduce ACh release from the ganglia. After blocking the inhibitory action of endogenous NE, a significant beta-adrenoceptor-mediated facilitatory effect on ACh release could be observed. Preincubation of the ganglia with different combinations of alpha 1 and alpha 2 agonists (phenylephrine, 10 microM and clonidine, 1 microM respectively) and antagonists (prazosin, 10 microM and yohimbine, 3 microM) showed that the adrenoceptors involved in alpha-mediated NE inhibition of ACh output are exclusively of the alpha 2-type.


A home-made animal model in comparison with a standard manikin for teaching percutaneous dilatational tracheostomy.
As airway management specialists, thoracic surgeons should be familiar with percutaneous dilatational tracheostomy. To optimize the learning curve, we propose a home-made pig model obtained from a slaughterhouse for training residents in the technical aspects of performing percutaneous dilatational tracheostomy. The satisfaction of the residents' training experience using this model was compared with that using a standard manikin model. Fifty residents participated in the present study. At the end of the session, each participant completed a questionnaire assessing the pig model and the manikin by assigning a score (ranging from 1 to 4) to five specific characteristics including (i) reality of skin turgor; (ii) landmark recognition; (iii) feasibility of the procedure; (iv) reality of the model and (v) preference of each model. The differences between models were statistically analysed. Forty-five participants completed the study. The pig model, compared with the manikin model, presented a higher value regarding the reality of skin turgor (1.7 ± 0.5 vs 0.4 ± 0.8; respectively, P < 0.0001); landmark recognition (3.8 ± 0.5 vs 2.0 ± 0.5; respectively; P < 0.0001) and reality of the model (3.0 ± 0.8 vs 1.3 ± 1.0; respectively; P < 0.0001). No difference was found regarding the feasibility of the procedure (3.7 ± 0.6 vs 3.5 ± 0.5; respectively, P = 0.1). The pig model was preferred to the manikin (3.2 ± 0.7 vs 1.6 ± 1.0; respectively, P < 0.0001). Our pig model allowed residents to develop the skills required for successful percutaneous dilatational tracheostomy. In particular, they developed confidence with certain manoeuvres such as needle and guide-wire placement, dilatation of the trachea and insertion of a cannula, before attempting the procedure on a live patient.


How Does Reduction Mammaplasty Surgical Technique Impact Clinical, Aesthetic, and Patient-Reported Outcomes?: A Comparison of the Superomedial and Inferior Pedicle Techniques.
A comprehensive comparison of surgical, aesthetic, and quality of life outcomes by reduction mammaplasty technique does not exist. We sought to ascertain the effect of technique on clinical, aesthetic, and patient-reported outcomes. Patients with symptomatic macromastia undergoing a superomedial or inferior pedicle reduction mammoplasty by a single surgeon were identified. BREAST-Q surveys were administered. Postoperative breast aesthetics were assessed in 50 matched-patients. Patient characteristics, complications, quality of life, and aesthetic scores were analyzed. Overall, 101 patients underwent reductions; 60.3% had a superomedial pedicle. Superomedial pedicle patients were more likely to have grade 3 ptosis (P < 0.01) and had significantly shorter procedure time (P < 0.01). Only the inferior pedicle technique resulted in wound dehiscence (P = 0.03) and reoperations from complications (P < 0.01). Those who underwent an inferior pedicle reduction were 4.3 times more likely to experience a postoperative complication (P = 0.03). No differences in quality of life existed between cohorts (P > 0.05). Superomedial pedicle patients received significantly better scarring scores (P = 0.03). The superomedial pedicle reduction mammoplasty technique provides clinical and aesthetic benefits compared with the inferior pedicle technique.


Anatomy and embryology of umbilicus in newborns: a review and clinical correlations.
Umbilicus is considered a mirror of the abdomen in newborns. Despite its importance, the umbilicus has been stated in literature and textbooks as discrete subjects with many body systems, such as the urinary, digestive, and cardiovascular ones. This article aimed to address the basic knowledge of the umbilicus in relation to clinical disorders under one integrated topic to aid physicians and surgeons in assessing newborns and infants. The umbilicus appears as early as the fourth week of fetal life when the folding of the embryonic plate occurs. The umbilicus appears initially as a primitive umbilical ring on the ventral aspect of the body. The primitive umbilicus contains the connecting stalk, umbilical vessels, vitelline duct and vessels, allantois, and loop of the intestine. Changes occur to form the definitive cord, which contains three umbilical vessels, namely, "one vein and two arteries," embedded in Wharton's jelly. After birth, the umbilical vessels inside the body obliterate and gradually form ligaments. Congenital disorders at the umbilicus include herniation, bleeding, and discharge of mucous, urine, or feces. Some of these disorders necessitate emergent surgical interference, whereas others may be managed conservatively. The umbilicus has many embryological remnants. Thus, the umbilicus is prone to various clinical disorders. Detecting these disorders as early as possible is essential to prevent or minimize possible complications.


The association of physical function with agitation and passivity in nursing home residents with dementia.
The purpose of this article is to examine the association of physical function with agitation and passivity in nursing home residents with dementia using direct observational measures. Data were analyzed using mixed model analysis of variance. This study was a secondary data analysis using baseline data yielded from a crossover experimental study. Univariate analyses showed that physical function, cognitive status, and education explained a significant amount of variance in agitation. When controlled for cognitive status and education, physical function lost significance and only explained 2.6% of the variance in agitation. It was found that physical function was not related to passivity. Environmental factors may be more salient antecedents for agitation and passivity in nursing home residents with moderate to severe cognitive impairment.


N-terminal acetylation and replicative age affect proteasome localization and cell fitness during aging.
Specific degradation of proteins is essential for virtually all cellular processes and is carried out predominantly by the proteasome. The proteasome is important for clearance of damaged cellular proteins. Damaged proteins accumulate over time and excess damaged proteins can aggregate and induce the death of old cells. In yeast, the localization of the proteasome changes dramatically during aging, possibly in response to altered proteasome activity requirements. We followed two key parameters of this process: the distribution of proteasomes in nuclear and cytosolic compartments, and the formation of cytoplasmic aggregate-like structures called proteasome storage granules (PSGs). Whereas replicative young cells efficiently relocalized proteasomes from the nucleus to the cytoplasm and formed PSGs, replicative old cells were less efficient in relocalizing the proteasome and had less PSGs. By using a microscopy-based genome-wide screen, we identified genetic factors involved in these processes. Both relocalization of the proteasome and PSG formation were affected by two of the three N-acetylation complexes. These N-acetylation complexes also had different effects on the longevity of cells, indicating that each N-acetylation complex has different roles in proteasome location and aging.


Extreme thrombocytosis--an unusual presentation of inflammatory bowel disease.
Thrombocytosis or a high platelet count (a count greater than 400 x 10(9)/L) is a common observation especially with the increased ordering of routine complete blood counts. When found, it may create a diagnostic challenge as transient elevations in platelet counts can occur for a number of reasons such as inflammation or infection, and these usually resolve spontaneously; but an elevated platelet count may be the only indication of an underlying serious disease to which no other clinical findings pertain. The report details a case of extreme thrombocytosis which masked an underlying diagnosis of inflammatory bowel disease.


Leiomyosarcoma of the uterus with sphenoid bone and orbital metastases.
A 55-year-old woman presented with a 1-week history of vision loss in the right eye associated with proptosis and diplopia. Past medical history was significant for high-grade leiomyosarcoma of the uterus status post total abdominal hysterectomy and bilateral salpingo-oophorectomy and postoperative pelvic radiation 18 months prior to presentation. Staging studies at the time of initial diagnosis of uterine leiomyosarcoma showed no evidence for metastatic disease. At presentation, CT and MRI showed a well-circumscribed 3.0 cm x 3.6 cm x 2.4 cm mass centered in the right greater sphenoid wing, extending into the middle cranial fossa and the superior and lateral orbital wall. Biopsy of the orbital mass revealed a poorly differentiated high-grade leiomyosarcoma, consistent with recurrent metastatic disease from the uterus. The patient subsequently underwent radiation treatment followed by a left orbital exenteration 6 months after the orbital biopsy. A left thoracostomy was performed 8 months after the orbital biopsy for a metastatic nodule in the left lower lobe of the lung. The clinicopathologic findings of this rare metastatic orbital lesion are presented.


Alpha interferon-induced antiretroviral activities: restriction of viral nucleic acid synthesis and progeny virion production in human immunodeficiency virus type 1-infected monocytes.
Alpha interferon (IFN-alpha) restricts multiple steps of the human immunodeficiency virus type 1 (HIV-1) life cycle. A well-described effect of IFN-alpha is in the modulation of viral nucleic acid synthesis. We demonstrate that IFN-alpha influences HIV-1 DNA synthesis principally by reducing the production of late products of reverse transcription. The magnitude of IFN-alpha-induced downregulation of HIV-1 DNA and/or progeny virion production was dependent on the IFN-alpha concentration, the duration of cytokine administration, the multiplicity of infection, the viral strain, and the cycles of viral infection. Interestingly, reductions in viral DNAs could not fully account for the observed IFN-alpha-induced abrogation of progeny virion production. These data, by our investigation of both single-cycle and spreading viral infections, support a predominant but not exclusive effect of IFN-alpha on viral DNA synthesis.


Spontaneously occluded left atrial appendage in a patient with atrial fibrillation and stroke: a case report.
The left atrial appendage (LAA) is the main source of thromboembolism in atrial fibrillation (AF). Transcatheter closure is non-inferior to warfarin therapy in preventing stroke. A patient with two consecutive strokes associated with AF was referred for transcatheter LAA occlusion (LAAO). Preprocedural cardiac CT and transoesophageal echocardiography demonstrated a spontaneously occluded LAA with a smooth left atrial surface, with stationary results at 6- and 12-month imaging follow-up. Warfarin was discontinued, and life-long aspirin instigated. Left atrial appendage occlusion has shown non-inferiority to warfarin for prevention of stroke, cardiovascular death, and all-cause mortality. No benefits from anticoagulation have been demonstrated in patients with embolic stroke of undetermined source. In the present case, we observed that the LAA was occluded and, therefore, treated with aspirin monotherapy assuming similar efficacy as transcatheter LAAO.


Omental actinomycosis imitating a foreign body infection.
Actinomycosis is a rare chronic disease caused by a group of anaerobic Gram-positive bacteria that colonize the mouth, colon, and urogenital tract. Infection involving the cervicofacial area is the most common clinical presentation, followed by that of the pelvic and thoracic areas. The preoperative diagnosis of abdominal actinomycosis is difficult because the condition can be easily confused with malignancy, tuberculosis, or other inflammatory diseases. We report a case of omental actinomycosis mimicking a foreign body. Actinomycosis is diagnosed based on the histopathologic demonstration of sulfur granules in a tissue or organ that was surgically removed. Following confirmative diagnosis by surgical intervention, the patient was treated with oral doxycycline 100 mg twice daily for 6 months. A follow-up abdominopelvic computed tomography after 16 months showed no evidence of inflammation. Moreover, the patient no longer had disease-associated symptoms and exhibited normal laboratory findings.


The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas.
Fifty-three patients with resected pancreatic adenocarcinoma were studied to determine if adjuvant chemo-radiation causes severe lymphopenia and if this is associated with adverse outcomes. Total lymphocyte counts (TLC) were normal in 91% before adjuvant chemo-radiation. Two months later, TLC fell by 63% (p < .0001) with 45% of patients having TLC < 500 cells/mm(3). Median survival in patients with low TLC was 14 versus 20 months (p = .048). Multivariate analysis revealed a significant association between treatment related lymphopenia and survival (HR 2.2, p = .014). Adjuvant chemo-radiation induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.


Human lung fibroblasts express interleukin-6 in response to signaling after mast cell contact.
Asthma is a chronic inflammatory disease of the airways. Mast cell-derived cytokines may mediate both airway inflammation and remodeling. It has also been shown that fibroblasts can be the source of proinflammatory cytokines. In the human airways, mast cell-fibroblast interactions may have pivotal effects on modulating inflammation. To study this further, we cocultured normal human lung fibroblasts (NHLF) with a human mast cell line (HMC-1) and assayed for production of interleukin (IL)-6, an important proinflammatory cytokine. When cultured together, NHLF/HMC-1 contact induced IL-6 secretion. Separation of HMC-1 and NHLF cells by a porous membrane inhibited this induction. HMC-1-derived cellular membranes caused an increase in IL-6 production in NHLF. Activation of p38 MAPK was also seen in cocultures by Western blot, whereas IL-6 production in cocultures was significantly inhibited by the p38 inhibitor SB203580. IL-6 production in cocultures was minimally inhibited by a chemical inhibitor of nuclear factor-kappaB (Bay11), indicating that nuclear factor-kappaB may have a minimal role in signaling IL-6 production in mast cell/fibroblasts cocultures. Blockade of inter-cellular adhesion molecule-1, tumor necrosis factor-RI, and surface IL-1beta with neutralizing antibodies failed to significantly decrease IL-6 production in our coculture, indicating that other receptor-ligand associations may be responsible for this activation. These novel studies reveal the importance of cell-cell interactions in the complex milieu of airway inflammation.


Validation of the 3-Minute All-Out Exercise Test for Shuttle Running Prescription.
Saari, A, Dicks, ND, Hartman, ME, and Pettitt, RW. Validation of the 3-minute all-out exercise test for shuttle running prescription. J Strength Cond Res 33(6): 1679-1685, 2019-A 3-minute all-out exercise test (3 MT) for running has been developed to determine critical speed (CS) and finite capacity for running speeds > CS (D') which allow for the prediction of time limits (TLIMs) associated with running different distances. Most team sports require shuttle running; however, the 3 MT was validated for uninterrupted, track running and not shuttle running. The purpose of this study was to examine the efficacy of shuttle running 3 MT to determine CS and D'. A total of 12 subjects were tested using a baseline 3 MT along with 3 separate distance time trials of all-out shuttle running to determine true CS and D'. The 3 MT (2.94 ± 0.39 m·s) and the true CS (3.00 ± 0.36 m·s) for shuttle running did not differ (p = 0.71) and had a coefficient of variation (CV) of 7.7%. Conversely, D' from the 3 MT exceeded true D' by 42 m (p = 0.04, CV = 36%). The TLIMs estimated for the 3 different distances were within ∼2-6% (p = 0.60). Based on these outcomes, the shuttle run 3 MT may offer a suitable method for prescribing shuttle running interval training.


Identification and differentiation of Taylorella equigenitalis and Taylorella asinigenitalis by lipopolysaccharide O-antigen serology using monoclonal antibodies.
Lipopolysaccharides (LPSs) from Taylorella equigenitalis, the causative agent of contagious equine metritis, and T. asinigenitalis were compared by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Lipopolysaccharide profiles of 11 T. equigenitalis strains were similar, but different from the profiles of 3 T. asinigenitalis strains, and the profiles of 2 T. asinigenitalis strains were similar to each other. The serological specificities of the LPSs from these 14 strains were examined by immunoblotting and enzyme-linked immunosorbent assay with monoclonal antibodies (MAbs) to the LPSs of the T. equigenitalis and T. asinigenitalis type strains and T. asinigenitalis strain 2329-98. A MAb to T. equigenitalis LPS O-polysaccharide (O-PS) (M2560) reacted with LPSs from all T. equigenitalis strains but did not react with LPSs from the 3 T. asinigenitalis strains or with 43 non-Taylorella bacteria. Three MAbs to the T. asinigenitalis type strain LPS O-PS or core epitopes (M2974, M2982, M3000) reacted with the homologous strain and T. asinigenitalis strain Bd 3751/05, but not with any of the other bacteria. Five MAbs to T. asinigenitalis 2329-98 LPS O-PS or core epitopes (M2904, M2907, M2910, M2923, M2929) reacted only with this strain. Proton nuclear magnetic resonance spectra of the O-PSs of the type strains of T. equigenitalis and T. asinigenitalis provided fingerprint identification and differentiation of these 2 organisms. The serological results were consistent with our previous finding that the O-antigen of the type strain of T. equigenitalis, being a linear polymer of disaccharide repeating [-->4)-alpha-L-GulpNAc3NAcA-(1-->4)-beta-D-ManpNAc3NAcA-(1-->] units, differs from that of the T. asinigenitalis O-antigen polymer that is composed of repeating [-->3)-beta-D-QuipNAc4NAc-(1-->3)-beta-D-GlcpNAmA-(1-->] units. Lipopolysaccharide O-PS could be a specific marker for identification and differentiation of T. equigenitalis and T. asinigenitalis, and provide the basis for the development of specific detection assays for T. equigenitalis.


Past or present? Relative contributions of developmental and adult conditions to adult immune function and coloration in mallard ducks (Anas platyrhynchos).
Developmental conditions affect adult physiological processes and phenotypic traits, including those associated with both survival and reproduction. Carotenoids are molecules that generate sexually attractive coloration, and these pigments are acquired throughout life and can affect antioxidant capacity and immunocompetence of young and old animals. However, few studies have tracked carotenoid status and condition during development and into adulthood to understand how ontogeny affects later-life health and coloration of both males and females. We reared male and female mallard ducks (Anas platyrhynchos) from hatch to adulthood, measured circulating carotenoid titers and body condition (i.e., size-adjusted body mass) throughout development, and assessed adult immune function and integumentary carotenoid-based beak and foot coloration. We found that adult immune function (wing web swelling response to phytohemagglutinin; PHA) in males was positively correlated with body condition during the growth period of development, rather than adult condition, and similarly that both male and female beak coloration was associated with developmental, rather than adult, body condition. We also found associations between coloration and health during adulthood; males with more carotenoid-rich beaks (a sexually attractive feature) tended to have a more robust adult PHA response and a greater antibody response to a novel antigen, while females with less carotenoid-rich beaks had greater antibody responsiveness at adulthood. In addition, male beak color changed over the course of the 24-h PHA test in proportion to the degree of PHA swelling. However, intensity of foot coloration (a trait of unknown sexual significance) was not associated with any condition, carotenoid, or immune metric for males or females. Taken together, our findings implicate key developmental components to the expression of both survival- and reproduction-related traits at adulthood, but that for a dynamic trait like beak color, there are also important adult conditions that can alter signal expression.


Measurement of limb circumferences with three-dimensional ultrasound for fetal weight estimation.
A large number of formulae have been published for fetal weight estimation. This study examines the possibility of using three-dimensional ultrasound to measure the limb circumference. This technology provides us with the opportunity to visualize two simultaneous, orthogonal planes, allowing the exact determination of the transverse plane at the mid-point of the limb. A total of 157 patients were scanned in the week prior to delivery. The following variables were measured in 154 fetuses: biparietal diameter, head circumference, transverse abdominal diameter, abdominal circumference, femur length, thigh circumference and arm circumference. The whole population was split into three subgroups according to the abdominal circumference centile (< 10th centile, 10-90th centile, and > 90th centile), because this single variable has the strongest correlation with neonatal weight (R = 0.901). With forward stepwise multiple regression analysis, four models were elaborated, one for the whole population and one for each subgroup. The small-for-dates fetuses need a targeted formula including only two variables, thigh circumference and femur length. Our data suggest that the thigh circumference measurement improves the estimation for growth-retarded fetuses and that the arm circumference improves the weight prediction for the others. The measurement of the two variables, made possible with three-dimensional ultrasound, has improved our results in fetal weight estimation.


Mesangial cell expression of proto-oncogene Ets-1 during progression of mesangioproliferative glomerulonephritis.
Ets-1 is a transactivator of matrix-associated genes and key factor in neoangiogenesis. The expression of Ets-1 mRNA and protein was analyzed in healthy rat kidney and in a model for mesangioproliferative disease without and with inhibition of platelet-derived growth factor-B (PDGF-B) activity. Immunohistochemistry was performed using a specific noncrossreacting anti-Ets-1 antibody and included a counterstain with alpha-smooth muscle actin (alpha-SMA). Nuclear proteins from isolated glomeruli were analyzed by Western blotting. Changes in Ets-1 mRNA levels were detected by in situ hybridization and Northern blotting. PDGF-B antagonism was performed in nephritic rats by specific aptamers. The distribution of Ets-1-positive cells in healthy rats was heterogenous with exclusively nuclear staining of glomerular, tubular, and vascular cells. Profound changes were detected in the anti-Thy 1.1 glomerulonephritis. Nuclear Ets-1 staining was intense in mesangial cells, whereas podocyte and endothelial cell staining was unchanged. The strongest signal was seen on days 2 to 7. By Western blotting of glomerular proteins a single 52 kD band was detected in healthy rats, which was increased 4.5-fold after disease induction. At the same time a 54 kD band appeared that most likely represents phosphorylated Ets-1. Ets-1 transcripts were detected in mesangial cells that include exon IV but lack exon VII. A concordant 6.4-fold up-regulation of mRNA was detected in glomeruli. Specific PDGF-B antagonism by aptamer treatment from days 3 to 7 after disease induction led to reduced Ets-1 expression on day 7, correlating with decreased mesangial cell numbers. A temporal increase of mesangial cell Ets-1 expression correlates with mesangial cell activation in mesangioproliferative glomerulonephritis. PDGF-B may partially contribute to the increased expression.


The effect of high-volume online haemodiafiltration on nutritional status and body composition: the ProtEin Stores prEservaTion (PESET) study.
Compared with conventional haemodialysis (HD), online haemodiafiltration (OL-HDF) achieves a more efficient removal of uraemic toxins and reduces inflammation, which could favourably affect nutritional status. We evaluate the effect of OL-HDF on body composition and nutritional status in prevalent high-flux HD (HF-HD) patients. In all, 33 adults with chronic kidney disease (CKD) Stage 5 undergoing maintenance HF-HD were assigned to post-dilution OL-HDF (n = 17) or to remain on HF-HD (n = 16, control group) for 12 months. The primary outcome was the change in lean tissue mass (LTM), intracellular water (ICW) and body cell mass (BCM) assessed by multifrequency bioimpedance spectroscopy (BIS) at baseline and 4, 8 and 12 months. The rate of change in these parameters was estimated with linear mixed-effects models. Compared with OL-HDF, patients assigned to HF-HD experienced a gradual reduction in LTM, ICW and BCM. These differences reached statistical significance at Month 12, with a relative difference of 7.31 kg [95% confidence interval (CI) 2.50-12.11; P = 0.003], 2.32 L (95% CI 0.63-4.01; P = 0.008) and 5.20 kg (95% CI 1.74-8.66; P = 0.004) for LTM, ICW and BCM, respectively. The normalized protein appearance increased in the OL-HDF group compared with the HF-HD group [0.26 g/kg/day (95% CI 0.05-0.47); P = 0.002], with a relative reduction in high-sensitive C-reactive protein [-13.31 mg/dL (95% CI -24.63 to -1.98); P = 0.02] at Month 12. OL-HDF for 1 year compared with HF-HD preserved muscle mass, increased protein intake and reduced the inflammatory state related to uraemia and dialysis, supporting the hypothesis that high convection volume can benefit nutritional status and prevent protein-energy wasting in HD patients.


Intraosseous epidermoid cyst of the finger phalanx: a case report.
Epidermoid cysts of the finger phalanx are rare pseudotumours. They are benign lesions with a satisfactory outcome after excision. We describe a case of an epidermoid cyst in the distal phalanx of the ring finger. It was treated successfully and the patient had excellent functional results and radiological healing at one-year follow-up.


Passive tracking exploiting local signal conservation: the white marker phenomenon.
This article presents a novel approach to passive tracking of paramagnetic markers during endovascular interventions, exploiting positive contrast of the markers to their background, so-called "white marker tracking." The positive contrast results from dephasing of the background signal with a slice gradient, while near the marker the signal is conserved because a dipole field induced by the marker compensates the dephasing gradient. Theoretical investigation shows that a local gradient induced by the local dipole field will nearly always cancel the dephasing gradient somewhere, regardless of marker composition, gradient strength, orientation, and acquisition parameters. The actual appearance of the white marker is determined by the marker strength, echo-time, slice thickness, and gradient strength, as shown both theoretically and experimentally. The novel concept is demonstrated by tracking experiments in a flow phantom and in pig models and is shown to allow reliable and robust depiction of paramagnetic markers with positive contrast and significant suppression of the background signal.


Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response.
Mammalian cells respond to various kinds of stress, including nutritional stress, via pathways that are initiated by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 complex (eIF2alpha). Because the models used to study eIF2alpha-kinase-mediated responses to amino acid deficiency have commonly used media or diets devoid of 1 or more essential amino acids, we asked whether eIF2alpha-kinase-mediated responses would be induced in animals fed a more typical diet that was not as imbalanced as one in which 1 essential amino acid is totally absent. To answer this question, we fed rats soy protein-based diets that were either adequate or limiting in sulfur-containing amino acids (SAA). Rats fed a SAA-deficient diet (3.4 g methionine equivalents/kg diet) grew more slowly than rats fed the control diet (5.86 g methionine equivalents/kg diet). Analysis of liver from rats fed these diets for 7 d showed that the SAA-deficient rats had higher levels of eIF2alpha phosphorylation and higher levels of activating transcription factor (ATF) 4, ATF3, asparagine synthetase, solute carrier 7A11, cysteinyl-tRNA synthetase, and cystathionine gamma-lyase. On the other hand, components of the integrated stress response (ISR) known to promote apoptosis or translational recovery were not induced. Taken together, our results indicate that rats fed the SAA-deficient diet had a prolonged activation of an eIF2alpha kinase that leads to upregulation of adaptive components of the ISR.


Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma.
In vitro studies suggest that resistance to chemotherapy-induced apoptosis might explain poor response to therapy in fatal cases. Actual execution of apoptosis depends on proper functioning of effector caspases, particularly caspase 3, and on the expression levels of apoptosis-regulating proteins, including Bcl-2 and the recently identified granzyme B- specific protease inhibitor 9 (PI9). Thus, high levels of caspase 3 activation should reflect proper functioning of the apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and a favorable prognosis. We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these numbers with clinical outcome. Activation of caspase 3 in more than 5% of the tumor cells was strongly correlated with a highly favorable outcome. High numbers of Bcl-2- and PI9-positive tumor cells were found to predict unfavorable prognosis. This prognostic effect was strongly related to anaplastic lymphoma kinase (ALK) status: ALK-positive ALCL had significantly higher levels of active caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was almost completely restricted to ALK-negative cases. In conclusion, high numbers of active caspase 3-positive tumor cells predict a highly favorable prognosis in systemic ALCL patients. Poor prognosis is strongly related to high numbers of Bcl-2- and PI9-positive neoplastic cells. These data support the notion that a favorable response to chemotherapy depends on an intact apoptosis cascade. Moreover, these data indicate that differences in prognosis between ALK-positive and ALK-negative ALCL might be explained by differences in expression of apoptosis-inhibiting proteins.


Walking Aid Use in Canada: Prevalence and Demographic Characteristics Among Community-Dwelling Users.
Mobility limitations represent the third most prevalent cause of disability, affecting more than 1.9 million community-dwelling Canadians. Walking aids are often prescribed to reduce the impacts of mobility impairments. There are limited data on walking aids since 2004. The objectives of this study were to investigate the prevalence of walking aid use in Canada and to explore demographic characteristics among users of walking aids. The design used was a secondary analysis of a cross-sectional national survey. Data were obtained from the 2012 Canadian Survey on Disability from community-dwelling individuals who were 15 years old or older, had a self-identified activity limitation, and indicated that they used at least 1 walking aid (cane/walking stick/crutches or walker). Prevalence estimates were calculated as weighted frequencies. Analytic variables included walking aid type, sex, age, province/territory of residence, and main cause of activity limitation. Approximately 1,125,000 community-dwelling individuals who were 15 years old or older used walking aids, representing 4.1% of the Canadian population. Of these individuals, 962,290 used canes/walking sticks/crutches, and 465,340 used a walker. Users of walking aids were predominantly female, with a mean age of 68 years. Self-reported results reflect only the perceptions of individuals living in Canadian communities. Analyses excluded individuals in residential or long-term care settings and individuals living on First Nations reserves. Since 2004, there has been a 2% increase in the prevalence of walking aid use by the Canadian population, which is likely related to the aging of the population. The high prevalence of walking aid use highlights the need for better use of existing resources to ensure that individuals are receiving the correct devices. Results of this study suggest a need to evaluate the impact of device use to better understand how resources should be allocated for prescription and maintenance of walking aids and training of users.


The in vitro efficacy of antimicrobial agents against the pathogenic free-living amoeba Balamuthia mandrillaris.
The free-living amoeba Balamuthia mandrillaris causes usually fatal encephalitis in humans and animals. Only limited studies have investigated the efficacy of antimicrobial agents against the organism. Assay methods were developed to assess antimicrobial efficacy against both the trophozoite and cyst stage of B. mandrillaris (ATCC 50209). Amphotericin B, ciclopirox olamine, miltefosine, natamycin, paromomycin, pentamidine isethionate, protriptyline, spiramycin, sulconazole and telithromycin had limited activity with amoebacidal levels of > 135-500 μM. However, diminazene aceturate (Berenil(®) ) was amoebacidal at 7.8 μM and 31.3-61.5 μM for trophozoites and cysts, respectively. Assays for antimicrobial testing may improve the prognosis for infection and aid in the development of primary selective culture isolation media.


[The effect of halothane or sevoflurane anesthesia on the extracellular concentration of dopamine and its metabolites examined by in vivo microdialysis techniques].
Volatile anesthetics induce changes in the extracellular concentration of dopamine (DA) metabolites in the rat striatum and their metabolism might be modified in different manners by different anesthetics. Although, we have studied DA metabolism during anesthesia using in vivo microdialysis techniques, time dimensional changes were not assessed concerning the difference between anesthetics. In the current investigation, the rats were anesthetized with halothane or sevoflurane, which has different blood solubility, and investigated the effect of anesthetics and time-related development on DA metabolism. The rats were implanted with a microdialysis probe in the striatum and perfusate was introduced to HPLC every 20 min. Anesthesia was induced with halothane or sevoflurane for 20 or 60 min, and methamphetamine 2 mg x kg(-1) was administered during or after inhalation. Both anesthetic agents increased the concentration of DA metabolites, and dose and time dependency was more obvious with sevoflurane than with halothane. The increase of metabolites was prolonged after halothane anesthesia (20 min), but the effect of methamphetamine administered immediately after anesthesia on DA release was not enhanced by halothane anesthesia. Sevoflurane, not halothane anesthesia, antagonized methamphetamine-induced decrease of metabolites. Not only the difference of blood solubility between halothane and sevoflurane and anesthetic effect of time dependency, but also another pharmacological property affects DA metabolism, including the change in the activity of dopamine transporter during inhalation of anesthetics.


Deconstructing the manifest dream.
A major part of the analyst's task is to discover the basis for the patient's misidentification of his present life situation with significant but threatening events of his earlier life, now repressed and inaccessible to conscious recall. Reconstructing the patient's history is a crucial step in this process of discovery, but the dynamic relation between the present and the past must be reconstructed as well. The structure of the manifest dream contains the key to this relation. The imagery of the dream is a composite of experimental materials drawn from important drive-related events of the present and the past. The complex formed by the manifest dream and the patient's associations provides the analyst with data about both of these distinct sets of drive-related experiences. As Freud's discussion of his M elusine dream illustrates, one associative thread can be traced to an experience that incorporates a conflicted current wish. Another thread will lead to an experience in which a repressed wish of childhood has been expressed. Where the two associative threads converge, in the composite imagery of the dream, the basis for the identification between the wishes of the present and the past will be exposed. An understanding of the structure of the manifest dream helps to clarify some of the important theoretical issues left unresolved in Freud's writings. These include: the function of the day residue and the mechanism through which it is formed, the relation of the screen memory to the associative process, and the differing roles of condensation and displacement in dream construction and free association. A simple procedure is described for enhancing the recovery of the significant childhood memories whose details have been incorporated into the composite imagery of the manifest dream.


Inferring bovine tuberculosis transmission between cattle and badgers via the environment and risk mapping.
Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is one of the most challenging and persistent health issues in many countries worldwide. In several countries, bTB control is complicated due to the presence of wildlife reservoirs of infection, i.e. European badger (Meles meles) in Ireland and the UK, which can transmit infection to cattle. However, a quantitative understanding of the role of cattle and badgers in bTB transmission is elusive, especially where there is spatial variation in relative density between badgers and cattle. Moreover, as these two species have infrequent direct contact, environmental transmission is likely to play a role, but the quantitative importance of the environment has not been assessed. Therefore, the objective of this study is to better understand bTB transmission between cattle and badgers via the environment in a spatially explicit context and to identify high-risk areas. We developed an environmental transmission model that incorporates both within-herd/territory transmission and between-species transmission, with the latter facilitated by badger territories overlapping with herd areas. Model parameters such as transmission rate parameters and the decay rate parameter of M. bovis were estimated by maximum likelihood estimation using infection data from badgers and cattle collected during a 4-year badger vaccination trial. Our estimation showed that the environment can play an important role in the transmission of bTB, with a half-life of M. bovis in the environment of around 177 days. Based on the estimated transmission rate parameters, we calculate the basic reproduction ratio (R) within a herd, which reveals how relative badger density dictates transmission. In addition, we simulated transmission in each small local area to generate a first between-herd R map that identifies high-risk areas.


Predictors of happiness during the COVID-19 pandemic in mothers of infants and/or preschoolers: a pre-COVID-19 comparative study in Japan.
Happiness may help to prevent negative physiological outcomes in response to life events; however, factors contributing to happiness during the COVID-19 pandemic have not been longitudinally investigated. This study explored the predictors of happiness in mothers of young children in Japan using comparable data that were obtained before and during the COVID-19 pandemic. We conducted the baseline survey in February 2020, and 4 months later, we also conducted the follow-up survey. Throughout all 47 prefectures in Japan, 4,700 (100 respondents/prefecture) mothers of infants and/or preschoolers (0-6 years) participated in the baseline online survey; 2,489 of these also participated in the follow-up survey. We performed hierarchical multiple regression analysis and our final model indicated that maternal happiness during COVID-19 pandemic was positively related to employment status (homemaker, β = 0.052, p = 0.014), levels of available social support (average, β = 0.052, p = 0.012, high, β = 0.055, p = 0.010) and happiness score before the pandemic (β = 0.467, p < 0.001), and satisfaction toward the measures against the COVID-19 at partners' workplace (average, β = 0.129, p < 0.001; high, β = 0.279, p < 0.001), preventive behavior against COVID-19 (average, β = 0.055, p = 0.002; high, β = 0.045, p = 0.015) and positive attitudes/thinking (β = 0.087, p < 0.001) during the pandemic. In contrast, poor mental health (K6 ≥5, β = -0.042, p = 0.011) before the pandemic and negative changes during the pandemic (≥3, β = -0.085, p < 0.001) were negatively related to maternal happiness during the pandemic. Our final model explained 44.9% of the variance in mothers' happiness during the COVID-19 pandemic. Satisfaction toward the measures against the COVID-19 at partners' workplace, preventive behavior, and positive attitudes/thinking were especially important for maternal happiness during the COVID-19 pandemic. Future study is needed to consider measures against infectious diseases in the workplace that are desirable for the well-being of parents with young children, taking into account the gender perspective.


[A Case of Renal Oncocytosis with Bilateral Multiple Renal Masses].
A 63-year-old man with microscopic hematuria underwent contrast-enhanced CT, which showed multiple bilateral renal masses. Percutaneous biopsy results indicated renal oncocytosis. The tumors remained unchanged for 3 years. Renal oncocytosis is a very rare tumor, but it is an established disease entity characterized by numerous oncocytic tumors and diffuse (sporadic) renal parenchymal epithelial oncocytic changes on an analysis histopathology. Although renal oncocytosis can be sporadic or part of Birt-Hogg-Dube syndrome (BHDS), our case did not associate with BHDS because of absence of lung cyst.


Does combined treatment with novel antidepressants and a dopamine D3 receptor agonist reproduce cocaine discrimination in rats?
It is established that dopamine (DA) neurotransmission plays a critical role in the behavioral (e.g. discriminative stimulus) effects of cocaine in rodents. Nonetheless, research has also demonstrated that reciprocal signaling between DA and monoamine neurotransmitters, i.e. serotonin (5-HT) and norepinephrine (NE) has important implication for understanding the actions of cocaine. The present study was focussed on the ability of novel antidepressant drugs (milnacipram, reboxetine and venlafaxine), which affect either NE or both 5-HT and NE reuptake mechanism, to alter (enhance or antagonize) the discriminative stimulus effects of cocaine. Moreover, we investigated if the combined treatment with those drugs and a DA D3 receptor agonist (pramipexole) could reproduce cocaine discrimination. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, ip) from saline (ip) in a two-choice, water-reinforced fixed-ratio 20 drug discrimination paradigm. Given alone, none of antidepressant drugs induced substitution for the cocaine-lever responses. Pramipexole (0.25 mg/kg) produced a partial substitution for cocaine (i.e. 43-52% cocaine-lever responding). In combination experiments, milnacipram (10 mg/kg) or reboxetine (10 mg/kg) given with submaximal doses of cocaine (1.25-5 mg/kg) did not affect the cocaine dose-response curve or its ED50 values. Venlafaxine (10 mg/kg) given in combination with submaximal doses of cocaine (0.6-5 mg/kg) produced significant enhancement of cocaine discrimination with a leftward shift in the cocaine dose-response curve and a decrease in its ED50 value. Pretreatment with either milnacipram (10 mg/kg) or reboxetine (10 mg/kg) failed to modulate the partial substitution evoked by pramipexole (0.25 mg/kg). On the other hand, venlafaxine (10 mg/kg) given in combination with a submaximal dose of pramipexole (0.25 mg/kg), which separately elicited 16 and 42% the cocaine-lever responses, produced significant enhancement of cocaine discrimination (up to 99% of the drug-lever responding). These results indicate that the discriminative stimulus effects of cocaine in rats can be enhanced by venlafaxine or mimicked by the combination with this antidepressant drug and the DA D3 receptor agonist. This finding, together with the recent data reporting the lack of rewarding properties of venlafaxine and the attenuation of morphine dependence and withdrwal signs in rats by the drug, may indicate a possible therapeutic use of this antidepressant in cocaine abuse.


Differential regulation of CD40-mediated TNF receptor-associated factor degradation in B lymphocytes.
Engagement of CD40 on murine B cells by its ligand CD154 induces the binding of TNFR-associated factors (TRAFs) 1, 2, 3, and 6, followed by the rapid degradation of TRAFs 2 and 3. TRAF degradation occurs in response to signaling by other TNFR superfamily members, and is likely to be a normal regulatory component of signaling by this receptor family. In this study, we found that receptor-induced TRAF degradation limits TRAF2-dependent CD40 signals to murine B cells. However, TRAFs 1 and 6 are not degraded in response to CD40 engagement, despite their association with CD40. To better understand the mechanisms underlying differential TRAF degradation, mixed protein domain TRAF chimeras were analyzed in murine B cells. Chimeras containing the TRAF2 zinc (Zn) domains induced effective degradation, if attached to a TRAF domain that binds to the PXQXT motif of CD40. However, the Zn domains of TRAF3 and TRAF6 could not induce degradation in response to CD40, regardless of the TRAF domains to which they were attached. Our data indicate that TRAF2 serves as the master regulator of TRAF degradation in response to CD40 signaling, and this function is dependent upon both the TRAF Zn domains and receptor binding position.


Promoting accountability: hospital charity care in California, Washington state, and Texas.
Debate as to whether private hospitals meet their charitable obligations is heated. This study examines how alternative state approaches for ensuring hospital accountability to the community affects charitable expenditures and potentially affects access to care for the uninsured. Descriptive and multivariate analyses were used to compare private California hospitals' charity care expenditures with those of hospitals in Texas and Washington state. The key finding from this study is that net of hospital characteristics, market characteristics and community need, Texas hospitals were estimated to provide over 3 times more charity care and Washington hospitals were estimated to provide 66% more charity care than California hospitals. This finding suggests that more prescriptive community benefit or charity care requirements may be necessary to ensure that private hospitals assume a larger role in the care of the uninsured.


[Monitoring of formation of diclofenac sodium salt hydrates and their influence on the drug dissolution from prepared tablets].
NIR spectroscopy together with multivariate data analysis were used to analyze the hydrates of diclofenac sodium prepared from the non-aqueous solvents tetrahydrofuran and methanol under standard laboratory conditions at 20 °C and relative humidity less than 60%. It was confirmed that the developed PLS regression model can monitor the process of formation of hydrates. It was also found that the hydrated form of diclofenac sodium arises during the preparation of the dosage form the using technology of impregnating the solid carrier by non-aqueous solvents, which resulted in reducing of the drug release rate from prepared tablets up to twice. NIR spectroscopy was confirmed as one of the effective PAT (Process Analytical Technology) methods.


Hybrid angioplasty for left pulmonary artery stenosis after total correction of tetralogy of Fallot: report of one case.
Pulmonary artery stenosis is common in tetralogy of Fallot. Surgical correction usually achieves good results. For those patients undergoing total correction with residual pulmonary artery stenosis, percutaneous transluminal angioplasty (PTA) plays an important role. However, this might not be possible for complex anatomies. We report a 19-month-old boy who underwent total correction of tetralogy of Fallot at 1 year of age. He developed main pulmonary artery (MPA) aneurysm and left pulmonary artery (LPA) stenosis 4 months after the operation. PTA was attempted, but the guidewire failed to thread into the LPA due to the dilated MPA and tiny LPA ostium. A hybrid approach consisting of left anterior small thoracotomy and balloon angioplasty via the introducer sheath in the MPA was proposed. Rapid access to the LPA and successful balloon angioplasty followed by stenting concluded the hybrid intervention. Such intervention is a good alternative to treat this complex anatomy.


[RigiScan monitoring assists tadalafil medication in the treatment of penile ED].
To investigate the application value of RigiScan monitoring in assisting tadalafil medication. This self-control study included 89 ED patients (IIEF-5 < 21) treated in our hospital from August 2019 to July 2020. The patients underwent audiovisual sexual stimulation (AVSS), nocturnal penile tumescence and rigidity (NPTR) test, scoring on the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-Item Scale (GAD-7), blood routine test, blood biochemical analysis, and hormone secretion examination, which confirmed 21 cases of psychogenic, 28 cases of organic and 40 cases of mixed ED. We treated the patients with tadalafil at 5 mg/d for 30 days, followed by examination of their erectile function by IIEF-5 scoring and AVSS and comparison of their erectile function with the baseline. For some of the patients that responded poorly to tadalafil at 5 mg/d, we increased the dose to 20 mg and detected the efficacy by AVSS at 1 h after medication. For those with organic or mixed ED irreponsive to tadalafil at 20 mg, we performed screening for corpora cavernosal venous leakage (CCVL) by intracavernosal injectionof alprostadil and penile color Doppler duplex ultrasonography or used dynamic infusion cavernosometry and cavernosography (DICC) to confirm the diagnosis of CCVL. The effectiveness rates of 5 mg/d tadalafil on mild, moderate and severe ED were 85.4%, 53.1% and 43.8%, respectively, significantly higher on mild than on moderate and severe ED (P = 0.002), and its effectiveness rates on psychogenic, organic and mixed ED were 90.5%, 60.7% and 57.5%, respectively, remarkably higher on psychogenic than on organic and mixed ED (P = 0.026). For those with organic or mixed ED irresponsive to 5 mg/d tadalafil, the increased dose of 20 mg achieved an effectiveness rate of 64.3%. (P = 0.033). The results of DICC did not encourage tadalafil medication for the cases of organic or mixed ED with CCVL irresponsive to both 5 mg and 20 mg tadalafil. RigiScan monitoring plays a guiding role in tadalafil medication of ED and helps distinguish organic from psychogenic ED. Tadalafil at 5 mg/d produces a better effect on mild than on moderate and severe ED, and so does it on psychogenic than on organic and mixed ED. The dose of medication can be increased to 20 mg for organic and mixed ED irresponsive to 5 mg tadalafil, but tadalafil is not recommended for organic and mixed ED with CCVL irresponsive to both 5 mg and 20 mg tadalafil.


Testicular cancer: the importance of effective health education.
Testicular cancer is the commonest malignancy in the UK among men aged 20-34 years. Although rare, it is one of the most curable cancers. There is a correlation between the incidence of testicular cancer and age, histology, social class and geographical region. As survival is dependent on early detection, men should be encouraged to practise testicular self-examination at least every 6 months. Nurses are in an ideal position to teach and encourage such practice. However, for optimal effect, health education programmes need to take into account complexities, such as cultural diversity, if patients are to heed vital and in some cases life-sustaining advice.


Work exchange between quantum systems: the spin-oscillator model.
With the development of quantum thermodynamics it has been shown that relaxation to thermal equilibrium and with it the concept of heat flux may emerge directly from quantum mechanics. This happens for a large class of quantum systems if embedded into another quantum environment. In this paper, we discuss the complementary question of the emergence of work flux from quantum mechanics. We introduce and discuss two different methods to assess the work source quality of a system, one based on the generalized factorization approximation, the other based on generalized definitions of work and heat. By means of those methods, we show that small quantum systems can, indeed, act as work reservoirs. We illustrate this behavior for a simple system consisting of a spin coupled to an oscillator and investigate the effects of two different interactions on the work source quality. One case will be shown to allow for a work source functionality of arbitrarily high quality.


An epidemic of psychogenic illness in an electronics plant.
We investigated an outbreak of illness in electronics plant workers. Questionnaire data revealed that 98 employees experienced symptoms, including light- headedness , headache, sleepiness, and numbness/tingling of the face or extremities. Attack rates by work station followed no apparent pattern. Extensive medical and environmental evaluation, including air sampling for numerous solvents and gases, provided no physical or chemical explanation for the epidemic. Compared with well employees, ill employees were more commonly female, complained more frequently of bothersome odors, and believed that greater danger existed of the illness recurring. Blood gas analyses of seven of 11 ill workers showed respiratory alkalosis, consistent with hyperventilation. The poorly defined nature of this illness, the absence of exposures to environmental contaminants in concentrations exceeding recommended limits, and the evidence of hyperventilation suggest that this outbreak was an incident of industrial psychogenic illness.


The dynamics of success and failure: how post-behaviour evaluations relate to subsequent exercise intentions and behaviour.
Exercise behaviour change involves multiple experiences with success and failure. The Model of Action Phases (MAP) offers a dynamic account of how success and failure influence both immediate evaluations and future decisions and actions. However, predictions from the MAP have not been formally tested. A longitudinal daily diary study was used to examine how post-behaviour evaluations of exercise success and failure influence subsequent exercise intentions and behaviour. Participants (N = 104) set exercise goals, and then kept a daily online exercise diary for four weeks. Participants self-reported exercise behaviour, affective response to exercise, self-evaluations after success or failure at following through on intentions to exercise, and intentions to exercise in the next week. Multilevel modelling revealed significant within- and between-participant relationships among post-behaviour evaluations, intentions and subsequent behaviour. Findings supported MAP-derived predictions about how success and failure at exercise are associated with feelings about exercise and the self, and inform subsequent exercise intentions and behaviour. Positive post-behaviour evaluations of success or failure may stabilise positive intentions and aid maintenance of exercise behaviour. Implications of these MAP-based findings for intervention design are discussed.


Ginkgo biloba extract EGB761 protects against aging-associated diastolic dysfunction in cardiomyocytes of D-galactose-induced aging rat.
The aim of the present study was to make use of the artificially induced aging model cardiomyocytes to further investigate potential anti-aging-associated cellular diastolic dysfunction effects of EGB761 and explore underlying molecular mechanisms. Cultured rat primary cardiomyocytes were treated with either D-galactose or D-galactose combined with EGB761 for 48 h. After treatment, the percentage of cells positive for SA-β-gal, AGEs production, cardiac sarcoplasmic reticulum calcium pump (SERCA) activity, the myocardial sarcoplasmic reticulum calcium uptake, and relative protein levels were measured. Our results demonstrated that in vitro stimulation with D-galactose induced AGEs production. The addition of EGB761 significantly decreased the number of cells positive for SA-β-gal. Furthermore, decreased diastolic [Ca(2+)](i), curtailment of the time from the maximum concentration of Ca(2+) to the baseline level and increased reuptake of Ca(2+) stores in the SR were also observed. In addition, the level of p-Ser16-PLN protein as well as SERCA was markedly increased. The study indicated that EGb761 alleviates formation of AGEs products on SERCA2a in order to mitigate myocardial stiffness on one hand; on other hand, improve SERCA2a function through increase the amount of Ser16 sites PLN phosphorylation, which two hands finally led to ameliorate diastolic dysfunction of aging cardiomyocytes.


Prevalence of primary adult lactose malabsorption in Pakistan.
Lactose absorption capacity was examined in 414 apparently healthy, adult Pakistani subjects. In a subgroup of 44 subjects, the lactose tolerance test was performed using both blood glucose and breath hydrogen determination. The remaining 370 probands were examined using a field version of the breath hydrogen test. In the total sample of 414 probands, 248 lactose malabsorbers were identified (60%). This result differs considerably from previous reports of very low frequencies of lactose malabsorption in Pakistan and neighbouring areas.


Genome wide transcriptome analysis reveals ABA mediated response in Arabidopsis during gold (AuCl(-) 4) treatment.
The unique physico-chemical properties of gold nanoparticles (AuNPs) find manifold applications in diagnostics, medicine and catalysis. Chemical synthesis produces reactive AuNPs and generates hazardous by-products. Alternatively, plants can be utilized to produce AuNPs in an eco-friendly manner. To better control the biosynthesis of AuNPs, we need to first understand the detailed molecular response induced by AuCl(-) 4 In this study, we carried out global transcriptome analysis in root tissue of Arabidopsis grown for 12- h in presence of gold solution (HAuCl4) using the novel unbiased Affymetrix exon array. Transcriptomics analysis revealed differential regulation of a total of 704 genes and 4900 exons. Of these, 492 and 212 genes were up- and downregulated, respectively. The validation of the expressed key genes, such as glutathione-S-transferases, auxin responsive genes, cytochrome P450 82C2, methyl transferases, transducin (G protein beta subunit), ERF transcription factor, ABC, and MATE transporters, was carried out through quantitative RT-PCR. These key genes demonstrated specific induction under AuCl4(-) treatment relative to other heavy metals, suggesting a unique plant-gold interaction. GO enrichment analysis reveals the upregulation of processes like oxidative stress, glutathione binding, metal binding, transport, and plant hormonal responses. Changes predicted in biochemical pathways indicated major modulation in glutathione mediated detoxification, flavones and derivatives, and plant hormone biosynthesis. Motif search analysis identified a highly significant enriched motif, ACGT, which is an abscisic acid responsive core element (ABRE), suggesting the possibility of ABA- mediated signaling. Identification of abscisic acid response element (ABRE) points to the operation of a predominant signaling mechanism in response to AuCl(-) 4 exposure. Overall, this study presents a useful picture of plant-gold interaction with an identification of candidate genes involved in nanogold synthesis.


Metaxalone-induced Immune Hemolytic Anemia.
Drug-induced immune hemolytic anemia (DIIHA) is a relatively uncommon cause of anemia, and its diagnosis can be challenging. Although beta-lactam antimicrobial agents are often associated with DIIHA, any medication can potentially cause it. We describe a patient presenting with yellow skin discoloration and orange-colored urine after starting metaxalone for treatment of lumbosacral sprain. Laboratory studies were consistent with warm hemolytic anemia. Symptoms improved remarkably after discontinuation of metaxalone, coupled with initiation of glucocorticoids and rituximab.


Muscle relaxants in the treatment of myofascial face pain. A literature review.
Among the different pharmacological approaches that could be adopted in the treatment of myofascial pain of masticatory muscles, attention has to be paid to muscle relaxants drugs, since very few studies evaluated their efficacy, despite most authors suggest their use. The present paper is a critical review of the literature on the use of the most common drugs with muscle relaxant effects (benzodiazepines, tricyclic antidepressants) and of a muscle relaxant drug (tizanidine hydrochloride) in the treatment of such condition. From literature data it emerged that these drugs had phases of alternate enthusiasm, characterized by a not constant clinical use and a fair interest in research. Nevertheless, within all the limitations that have been discussed in this paper, the use of muscle relaxants in patients with myofascial pain of masticatory muscles seems to be justifiable, even though further research is needed to verify their usefulness in terms of risk-benefit ratio.


Nonsuicidal Self-Injury and Suicidal Risk Among Emerging Adults.
Although nonsuicidal self-injury (NSSI) has been differentiated from suicidal behavior on the basis of nonlethal intent in the Diagnostic and Statistical Manual of Mental Disorders, NSSI often is associated with increased suicidal risk. However, there is a paucity of large-scale longitudinal examinations on the associations among NSSI, suicidal ideation, and suicidal attempts, particularly among community-based samples. In the present study, we examined whether NSSI in first-year university was associated with increased risk for later suicidal ideation and attempts over time among students. Participants included 940 emerging adults (70.8% female, mean age = 19.05 years) from a mid-sized Canadian university who volunteered to participate in a longitudinal research project starting in first-year university (participants were surveyed annually over five waves). Binary logistic regression analyses revealed that the odds of experiencing suicidal ideation across times 2-5 were 2.04 times as high for emerging adults who engaged in NSSI at baseline (even after controlling for suicidal ideation and attempts at baseline) as for individuals who did not engage in NSSI. Furthermore, the odds of attempting suicide across times 2-5 were 3.46 times as high for emerging adults who engaged in NSSI at baseline (even after controlling for suicidal ideation and attempts at baseline) as for individuals who did not engage in NSSI. Findings suggest that the presence of NSSI in first-year university may be an important marker of later suicidal risk, reflecting increased risk for both suicidal ideation and attempts across the university years among emerging adults.


Smoking alters the evolutionary trajectory of non-small cell lung cancer.
Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin α erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes.


Mechanisms Associated to Nitroxyl (HNO)-Induced Relaxation in the Intestinal Smooth Muscle.
The pharmacological properties of nitroxyl (HNO) donors in the gastrointestinal tract are unknown. We investigated the properties of this molecule in the regulation of gastrointestinal contractility focusing on its possible interaction with other gaseous signaling molecules such as NO and H2S. Organ bath, Ca2+ imaging, and microelectrode recordings were performed on rat intestinal samples, using Angeli's salt as HNO donor. Angeli's salt caused a concentration-dependent relaxation of longitudinal or circular muscle strips of the ileum and the proximal colon. This relaxation was strongly inhibited by the Rho-kinase inhibitor Y-27632 (10 μM), by the reducing agent DTT or by the inhibitor of soluble guanylate cyclase (sGC) ODQ (10 μM) alone or in combination with the inhibitors of the endogenous synthesis of H2S β-cyano-L-alanine (5 mM) and amino-oxyacetate (5 mM). Preventing endogenous synthesis of NO by the NO synthase inhibitor L-NAME (200 μM) did not affect the relaxation induced by HNO. HNO induced an increase in cytosolic Ca2+ concentration in colonic myocytes. It also elicited myocyte membrane hyperpolarization that amounted to -10.6 ± 1.1 mV. ODQ (10 μM) and Apamin (1 μM), a selective inhibitor of small conductance Ca2+-activated K+ channels (SKca), strongly antagonized this effect. We conclude that HNO relaxes the gastrointestinal tract musculature by hyperpolarizing myocytes via activation of the sGC/cGMP pathway similarly to NO, not only inhibiting the RhoK and activating MLCP as do both NO and H2S but also increasing cytosolic Ca2+ for activation of SK C a contributing to hyperpolarization.


The importance of dose in isocarboxazid therapy.
Little information is available on the effectiveness and safety of particular doses of isocarboxazid. In a study using isocarboxazid doses of 30 and 50 mg/day in depressed inpatients, the higher dose was well tolerated and did not result in any greater toxicity than the 30 mg dose. Significantly greater elevation of plasma serotonin (Week 2) and platelet MAO inhibition were seen with 50 mg/day. In nonmelancholic depressions, 50 mg proved to be more effective than 30 mg in symptoms of depression and anxiety. However, this did not apply to the vegetative-physiologic symptoms of depression.


Pharmacologic therapy: novel approaches for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is increasing in the United States and throughout the world. There have been a number of advances in the treatment of this disease within the last several decades, and these improved therapies continue to become available, making the prospects for the future encouraging. Bronchodilation is the treatment of choice, and we point out in this article the potential availability of many new bronchodilators. There will be several options in the beta(2)-agonist and the anticholinergic categories for once-a-day preparations. There will also be a number of products combining these categories of bronchodilators and inhaled steroids, and the combination products will be available in once-a-day preparations. Also under development are several candidates for specific and effective antiinflammatory agents in COPD. It is likely that our ability to control the inflammation underlying COPD will be a reality in the future. Although many new cases of COPD are being diagnosed in former smokers, for patients who smoke, the most important treatment is smoking cessation. A number of new drugs are available, and more will be brought to market in the future. We have highlighted the details of this important area.


Outcomes of Corynebacterium Peritonitis: A Multicenter Registry Analysis.
Corynebacterium is a rare cause of peritonitis that is increasingly being recognized in peritoneal dialysis (PD) patients. The aims of this study were to compare Corynebacterium peritonitis outcomes with those of peritonitis caused by other organisms and to examine the effects of type and duration of antibiotic therapy on outcomes of Corynebacterium peritonitis. Using Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data, we included all PD patients who developed peritonitis in Australia between 2004 and 2014. The primary outcome was peritonitis cure by antibiotic therapy, defined as resolution of a peritonitis episode with antibiotics alone and without being complicated by recurrence, relapse, catheter removal, hemodialysis transfer, or death. Peritonitis outcomes were analyzed using multivariable logistic regression. A total of 11,122 episodes of peritonitis in 5,367 patients were included. Of these, 162 episodes (1.5%) were due to Corynebacterium. Compared with Corynebacterium peritonitis, the odds of cure were lower in peritonitis due to Staphylococcus aureus (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45 - 0.97), Pseudomonas (OR 0.22, 95% CI 0.14 - 0.33), other gram-negative organisms (OR 0.52, 95% CI 0.35 - 0.75), fungi (OR 0.02, 95% CI 0.01 - 0.03), polymicrobial organisms (OR 0.32, 95% CI 0.22 - 0.47), and other organisms (OR 0.66, 95% CI 0.44 - 0.99) but similar for culture-negative and other gram-positive peritonitis. Similar results were observed for hemodialysis transfer and death. The outcomes of Corynebacterium peritonitis were not associated with the type of initial antibiotic selected (vancomycin vs cefazolin) or the duration of antibiotic therapy (≤ 14 days vs > 14 days). Outcomes for Corynebacterium peritonitis are generally favorable compared with other forms of peritonitis. Cure rates did not appear to differ if peritonitis was treated initially with vancomycin or cefazolin or if treatment duration was prolonged beyond 14 days.


Knowledge and compliance with medications in South East Asian refugees.
We evaluated knowledge about prescribed medications and compliance with taking those medications in 96 South East Asian refugees of different ethnic backgrounds seen in a primary care clinic. Two hundred and thirty (88%) of 262 prescribed medications were currently being taken by the patients. Although 97% of the medications were either named or described correctly, the correct rationale for taking the medication was known for only 79% and the correct dosage regimen for only 63%. Thirty-two (33%) of the 96 patients were not taking one or more of their prescribed medications, 17 (18%) were taking one or more medications not prescribed, 5 (5%) were taking duplicate forms of the same medication, and 4 (4%) were taking a medication that had been discontinued by the clinic provider. Seventy-two (75%) patients were taking one or more medications at an incorrect dose. Only 12 (12%) patients were fully compliant with all prescribed medications. We conclude that knowledge about and compliance with medications is a major problem among South East Asian patients attending a primary care refugee clinic.


Management of leisure time by prospective nurses.
A focus on the importance of leisure in the development of student nurses has been neglected in the 1990s. This study considers 444 prospective nurses on conventional, diploma and degree courses in two areas of England. It examines their activities associated with socializing, their social support networks and their use of clubs, sports and hobbies before entering nursing. It is evident that students enter nurse training with a wide variety of leisure experiences. Changing recruitment patterns and the structure of nurse training has an effect on the leisure needs of prospective nurses which must be addressed.


Exploring short k-mer profiles in cells and mobile elements from Archaea highlights the major influence of both the ecological niche and evolutionary history.
K-mer-based methods have greatly advanced in recent years, largely driven by the realization of their biological significance and by the advent of next-generation sequencing. Their speed and their independence from the annotation process are major advantages. Their utility in the study of the mobilome has recently emerged and they seem a priori adapted to the patchy gene distribution and the lack of universal marker genes of viruses and plasmids. To provide a framework for the interpretation of results from k-mer based methods applied to archaea or their mobilome, we analyzed the 5-mer DNA profiles of close to 600 archaeal cells, viruses and plasmids. Archaea is one of the three domains of life. Archaea seem enriched in extremophiles and are associated with a high diversity of viral and plasmid families, many of which are specific to this domain. We explored the dataset structure by multivariate and statistical analyses, seeking to identify the underlying factors. For cells, the 5-mer profiles were inconsistent with the phylogeny of archaea. At a finer taxonomic level, the influence of the taxonomy and the environmental constraints on 5-mer profiles was very strong. These two factors were interdependent to a significant extent, and the respective weights of their contributions varied according to the clade. A convergent adaptation was observed for the class Halobacteria, for which a strong 5-mer signature was identified. For mobile elements, coevolution with the host had a clear influence on their 5-mer profile. This enabled us to identify one previously known and one new case of recent host transfer based on the atypical composition of the mobile elements involved. Beyond the effect of coevolution, extrachromosomal elements strikingly retain the specific imprint of their own viral or plasmid taxonomic family in their 5-mer profile. This specific imprint confirms that the evolution of extrachromosomal elements is driven by multiple parameters and is not restricted to host adaptation. In addition, we detected only recent host transfer events, suggesting the fast evolution of short k-mer profiles. This calls for caution when using k-mers for host prediction, metagenomic binning or phylogenetic reconstruction.


Diversities of behavioral traits and neuropsychological function in different substance addiction.
There are various temperaments and personality characters that modulate the development of substance addiction. The pharmacological properties of substances would alter the homeostasis of brain function and influence the neuropsychological performance through different neurotransmissions which then facilitate diverse emotional and behavioral responses. Our goal is to assess the interaction between personality characteristics, neuropsychological performances and Stroop interference in alcoholics, heroin and amphetamine dependent persons. Subjects with alcohol (N=95), heroin (N=82) and amphetamine (N=57) dependence were recruited. Diagnostic interview and questionnaires evaluating the psychiatric symptoms were done, followed by neuropsychological assessments of Stroop and Wisconsin card sorting tests (WCST). Differences between the study groups were analyzed by one-way ANOVA with Scheffe's test. The individuals with alcohol dependence had significantly higher scores of neurotic, dysphoric and impulsive traits (P<0.001) than heroin and amphetamine dependent groups. In Stroop tests, the alcohol dependent subjects also showed delayed response on incongruent naming interferences compared to both of heroin and amphetamine groups (P<0.001). Perseverative errors and responses of WCST were significantly higher in heroin than in alcoholic dependent persons (P<0.01). Individuals with different substance dependence have distinct behavioral traits for developing addicted behaviors and had variant deficits of neuropsychological function.


Personality assessment and test interpretation of Mexican Americans: a critique.
Reviews the personality test assessment of Mexican Americans. Although there is a paucity of available research there are some indications that Mexican Americans differ in response patterning on projective devices. On objective instruments, problems involving fluency in English obscure the findings. Several recommendations are offered for increasing the efficiency of these instruments for use with Mexican American clients.


Web-based nutrition: a useful resource for cancer patients?
An accessible and affordable way to deliver behavior change programs to a large proportion of the growing community of cancer patients and survivors is through web-based methods of nutritional counselling. The aim of this systematic review was to evaluate the effectiveness of web-based nutritional therapies targeting physical activity, diet, and/or weight control for cancer patients or survivors, primarily disseminated via modern technologies (mobile phone applications) or online. The authors conducted a structured search of the PubMed database. Studies that have focused on physical activity (PA) and dietary change and/or weight control in adolescent and adult cancer patients and survivors have reported outcomes conducted via a broad modality. Nine articles focused on web-based nutrition for patients with cancer and cancer survivors. They were conducted in the United States, Australia, Korea, China, and in the United Kingdom, and were published between 2018 and 2022 in a variety of scientific journals. The number of participants ranged from 20 to 159. Web-based nutrition counselling helps cancer patients and survivors improve their dietary intake, impacts their weight and quality of life, and promotes a healthy lifestyle. Future research should evaluate (1) the differences in cost and coverage between face-to-face and web-based nutrition, (2) long-term outcomes, (3) cost-effectiveness, and last but not least, (4) the effectiveness of web-based nutrition in adolescents and children who suffer from cancer or who survived cancer, as nutritional status and body composition have a marked impact on clinical outcomes during and after treatment. The strength of this review lies in the large number of randomized controlled trials, which offer a guarantee of effectiveness and objectivity compared to cross-sectional studies.


An efficient voting algorithm for finding additive biclusters with random background.
The biclustering problem has been extensively studied in many areas, including e-commerce, data mining, machine learning, pattern recognition, statistics, and, more recently, computational biology. Given an n x m matrix A (n >or= m), the main goal of biclustering is to identify a subset of rows (called objects) and a subset of columns (called properties) such that some objective function that specifies the quality of the found bicluster (formed by the subsets of rows and of columns of A) is optimized. The problem has been proved or conjectured to be NP-hard for various objective functions. In this article, we study a probabilistic model for the implanted additive bicluster problem, where each element in the n x m background matrix is a random integer from [0, L - 1] for some integer L, and a k x k implanted additive bicluster is obtained from an error-free additive bicluster by randomly changing each element to a number in [0, L - 1] with probability theta. We propose an O(n(2)m) time algorithm based on voting to solve the problem. We show that when k >or= Omega(square root of (n log n)), the voting algorithm can correctly find the implanted bicluster with probability at least 1 - (9/n(2)). We also implement our algorithm as a C++ program named VOTE. The implementation incorporates several ideas for estimating the size of an implanted bicluster, adjusting the threshold in voting, dealing with small biclusters, and dealing with overlapping implanted biclusters. Our experimental results on both simulated and real datasets show that VOTE can find biclusters with a high accuracy and speed.


Evaluation of surgical treatments for the major lesion of bilateral silicotuberculosis.
The present communication deals with the follow-up study of 24 patients with bilateral silicotuberculosis in whom only unilateral operation was carried out for major lesions. The operative procedure consisted of pulmonary resection, thoracoplasty or combined operation such as cavernostomy, intracavitary filling of a pedunculated muscle flap and thoracoplasty. The follow-up period ranged 1 year to 12 years and 5 months. The results of surgical treatment for unilateral major lesions and their effect on the contralateral minor lesions were clinically assessed by alterations in the chest x-ray findings and tubercle bacilli in sputum. In 16 of 24 patients (67%) alleviation was obtained, whereas no change occurred in 3 (13%) and aggravation in 5 (21%). The surgical treatment for unilateral major lesion brought about 41% of improvement in the contralateral minor lesions. Contralateral minor lesions remained unchanged in 46% of patients and aggravated in 14%. This shows a value of the surgical threatment for bilateral silicotuberculosis. It should be emphasized that surgical treatments more aggressive than have been heretofore practiced can be employed.


Immunohistochemical detection of naturally occurring porcine Sapelovirus infection in Indian pigs.
We investigated immunohistochemical detection of porcine Sapelovirus (PSV) in naturally infected pigs of different ages. Forty-nine fecal samples, intestinal contents and other tissue samples from dead pigs were screened in previous study using reverse transcription polymerase chain reaction (RT-PCR) for PSV infection. Eight animals were positive for PSV based on RT-PCR examination. Gross lesions were recorded mainly in the large and small intestines. Microscopic examination of intestines showed severe enteritis. Tissue sections of all organs from PSV positive animals were immunostained using hyperimmune serum raised in rats against PSV that had been grown in a BHK-21 cell line. Staining of PSV was found only in the large and small intestines.


Determination of non-protein-bound plasma 1,25-dihydroxyvitamin D by symmetric (rate) dialysis.
Most of the total circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) is bound to plasma proteins, mainly vitamin D-binding protein (DBP) and albumin. Only a small fraction in plasma exists in the free form. It is widely assumed that the non-protein-bound free hormone reflects the biologically active fraction. We describe a dialysis method for the determination of plasma free 1,25(OH)2D which is relatively easy to perform. In this symmetric or "rate" dialysis method, identical samples are placed at both sides of a membrane. At one side, tritiated 1,25(OH)2D is added and the rate of transfer of this tritiated 1,25(OH)2D through a dialysis membrane is directly related to the free fraction of plasma 1,25(OH)2D. This method is much less susceptible toward tracer impurities than indirect equilibrium dialysis and centrifugal ultrafiltration. Moreover, it requires much less tracer. The intraassay coefficient of variation for the determination of the free fraction is 1.0%; the interassay variation is 7.7%. Comparison of the free fraction of 23 samples assessed with both centrifugal ultrafiltration and symmetric dialysis showed much higher values using the former method. No significant correlation between the two methods was found. The free fraction of 1,25(OH)2D in normal subjects as assessed with symmetric dialysis ranges from 0.049 to 0.103%.


Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus.
Extracellular protein toxins contribute to the pathogenesis of a wide variety of Staphylococcus aureus infections. The present study investigated the effects that cell-wall active antibiotics and protein-synthesis inhibitors have on transcription and translation of genes for Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin 1, in both methicillin-sensitive and methicillin-resistant S. aureus. Subinhibitory concentrations of nafcillin induced and prolonged mRNA for Panton-Valentine leukocidin, alpha-toxin, and toxic-shock syndrome toxin 1 and increased toxin production. In contrast, clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes. These results suggest (1) that protein-synthesis inhibition is an important consideration in the selection of antimicrobial agents to treat serious infections caused by toxin-producing gram-positive pathogens and (2) that, by inducing and enhancing toxin production, inadvertent use of beta-lactam antibiotics to treat methicillin-resistant S. aureus infections may contribute to worse outcomes.


Comparison of swallowing function in Parkinson's disease and progressive supranuclear palsy.
Dysphagia is common in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Although it is believed to be more common in PSP, there are no controlled data and no comparison of swallowing function between these two disorders. Our aim was to assess dysphagia and swallow function in patients with PSP and PD. Seven patients with PSP were matched to seven patients with PD on the basis of disease duration. Self-rated dysphagia, movement disorder disability, modified barium swallow results, and abnormalities noted on manometry of the lower esophageal sphincter, esophageal body, upper esophageal sphincter, and pharynx were compared between the two groups. Neither severity nor duration of dysphagia differed between the two groups. Patients with PSP had a significantly greater degree of disability [median (range) Hoehn & Yahr score, 4 (3-5) vs. 2 (1-2); P < 0.002]. Manometric abnormalities were similar for the two groups. Oral-phase abnormalities on modified barium swallow were significantly more frequent in PSP (four patients with PSP vs. no patients with PD; p < 0.005). Pharyngeal abnormalities did not differ. Modified barium-swallow scores correlated well with self-reported dysphagia severity for patients with PSP (r = 0.93; p < 0.05) but not for those with PD (r = 0.42; p = NS). The frequency of abnormalities noted during the oral phase was significantly increased in PSP. It is hypothesized that the sensory information conveyed due to this may account for the better correlation between symptoms and swallowing abnormalities and the belief that swallowing problems are more common in PSP.


Immune checkpoint inhibitors as mediators for immunosuppression by cancer-associated fibroblasts: A comprehensive review.
The tumor microenvironment (TME) is a significant contributor to cancer progression containing complex connections between cellular and chemical components and provides a suitable substrate for tumor growth and development. Growing evidence shows targeting tumor cells while ignoring the surrounding TME is not effective enough to overcome the cancer disease. Fibroblasts are essential sentinels of the stroma that due to certain conditions in TME, such as oxidative stress and local hypoxia, become activated, and play the prominent role in the physical support of tumor cells and the enhancement of tumorigenesis. Activated fibroblasts in TME, defined as cancer-associated fibroblasts (CAFs), play a crucial role in regulating the biological behavior of tumors, such as tumor metastasis and drug resistance. CAFs are highly heterogeneous populations that have different origins and, in addition to their role in supporting stromal cells, have multiple immunosuppressive functions via a membrane and secretory patterns. The secretion of different cytokines/chemokines, interactions that mediate the recruitment of regulatory immune cells and the reprogramming of an immunosuppressive function in immature myeloid cells are just a few examples of how CAFs contribute to the immune escape of tumors through various direct and indirect mechanisms on specific immune cell populations. Moreover, CAFs directly abolish the role of cytotoxic lymphocytes. The activation and overexpression of inhibitory immune checkpoints (iICPs) or their ligands in TME compartments are one of the main regulatory mechanisms that inactivate tumor-infiltrating lymphocytes in cancer lesions. CAFs are also essential players in the induction or expression of iICPs and the suppression of immune response in TME. Based on available studies, CAF subsets could modulate immune cell function in TME through iICPs in two ways; direct expression of iICPs by activated CAFs and indirect induction by production soluble and then upregulation of iICPs in TME. With a focus on CAFs' direct and indirect roles in the induction of iICPs in TME as well as their use in immunotherapy and diagnostics, we present the evolving understanding of the immunosuppressive mechanism of CAFs in TME in this review. Understanding the complete picture of CAFs will help develop new strategies to improve precision cancer therapy.


Allergen-specific exposure associated with high immunoglobulin E and eye rubbing predisposes to progression of keratoconus.
We report two male children with persistent allergic eye disease (AED) and keratoconus (KC). Both presented with symptoms of vernal keratoconjunctivitis and decreased vision. In view of unrelenting AED, serum immunoglobulin E (IgE) quantification and identification of specific allergens were advised. Increased serum IgE levels were observed in both cases. Sunflower and sheep wool were identified as specific allergens for the first and second patient respectively by skin patch test. There was complete resolution of symptoms of AED in both patients following avoidance of causative allergens. However, the progression of KC in both eyes of the first patient and one eye of the second patient was observed. They were advised collagen cross-linking. Elevated serum IgE indicates the presence of systemic allergy. Avoiding implicated allergens help alleviate ocular symptoms. Using serum IgE and identifying specific allergen can guide in the treatment of AED and thus prevent progressive KC due to eye rubbing and resulting inflammation.


TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.
Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions ΔE218 and ΔE224, resulting in a significant hypercontractile phenotype with congenital muscle stiffness, rather than weakness, and respiratory failure in one patient. The effect of the Tpm3.12 deletions on the contractile properties in dissected patient myofibers was measured. We used quantitative in vitro motility assay to measure Ca(2+) sensitivity of thin filaments reconstituted with recombinant Tpm3.12 ΔE218 and ΔE224. Contractility studies on permeabilized myofibers demonstrated reduced maximal active tension from both patients with increased Ca(2+) sensitivity and altered cross-bridge cycling kinetics in ΔE224 fibers. In vitro motility studies showed a two-fold increase in Ca(2+) sensitivity of the fraction of filaments motile and the filament sliding velocity concentrations for both mutations. These data indicate that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca(2+) sensitivity of the troponin-tropomyosin complex, resulting in abnormally active interaction of the actin and myosin complex. Both mutations are located in the charged motifs of the actin-binding residues of tropomyosin 3, thus disrupting the electrostatic interactions that facilitate accurate tropomyosin binding with actin necessary to prevent the on-state. The mutations destabilize the off-state and result in excessively sensitized excitation-contraction coupling of the contractile apparatus. This work expands the phenotypic spectrum of TPM3-related disease and provides insights into the pathophysiological mechanisms of the actin-tropomyosin complex.


Valorization of spent oyster mushroom substrate and laccase recovery through successive solid state cultivation of Pleurotus, Ganoderma, and Lentinula strains.
Spent mushroom substrate (SMS) of Pleurotus ostreatus was supplemented with wheat bran and soybean flour in various proportions to obtain C/N ratios of 10, 20, and 30, and their effect was evaluated in successive cultivation of Pleurotus ostreatus, Pleurotus pulmonarius, Ganoderma adspersum, Ganoderma resinaceum, and Lentinula edodes strains with respect to mycelium growth rate, biomass concentration, recovery of the enzyme laccase and crude exopolysaccharides, and also with additional fruiting body production. All fungi showed the highest growth rate on unamended SMS (C/N 30), with G. resinaceum being the fastest colonizer (Kr = 9.84 mm day-1), while biomass concentration maximized at C/N 10. Moreover, supplementation affected positively laccase activity, with P. pulmonarius furnishing the highest value (44,363.22 U g-1) at C/N 20. On the contrary, L. edodes growth, fruiting, and laccase secretion were not favored by SMS supplementation. Fruiting body formation was promoted at C/N 30 for Ganoderma and at C/N 20 for Pleurotus species. Exopolysaccharide production of further studied Pleurotus strains was favored at a C/N 20 ratio, at the initial stage of SMS colonization. The obtained results support the potential effective utilization of supplemented SMS for laccase production from Ganoderma spp. and for new fruiting body production of Pleurotus spp.


Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.
Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69-77. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.